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1.  Planned Variation in Preanalytical Conditions to Evaluate Biospecimen Stability in the National Children’s Study (NCS) 
BACKGROUND
Preanalytical conditions encountered during collection, processing, and storage of biospecimens may influence laboratory results. The National Children’s Study (NCS) is a planned prospective cohort study of 100,000 families to examine the influence of a wide variety of exposures on child health. In developing biospecimen collection, processing, and storage procedures for the NCS, we identified several analytes of different biochemical categories for which it was unclear to what extent deviations from NCS procedures could influence measurement results.
METHODS
A pilot study was performed to examine effects of preanalytic sample handling conditions (delays in centrifugation, freezing delays, delays in separation from cells, additive delay, and tube type) on concentrations of eight different analytes. 2,825 measurements were made to assess 15 unique combinations of analyte and handling conditions in blood collected from 151 women of childbearing age (≥20 individuals per handling condition).
RESULTS
The majority of analytes were stable under the conditions evaluated. However, levels of plasma interleukin-6 and serum insulin were decreased in response to sample centrifugation delays of up to 5.5 hours post collection (P<0.0001). In addition, delays in freezing centrifuged plasma samples (comparing 24, 48 and 72 hours to immediate freezing) resulted in increased levels of adrenocorticotropic hormone (P=0.0014).
CONCLUSIONS
Determining stability of proposed analytes in response to preanalytical conditions and handling helps to ensure high-quality specimens for study now and in the future. The results inform development of procedures, plans for measurement of analytes, and interpretation of laboratory results.
doi:10.1515/cclm-2013-0454
PMCID: PMC4100775  PMID: 23924524
ACTH; Biospecimen stability; CDT; estradiol; free T4; IGF-1; IL-6; Insulin; vitamin C; Preanalytical variation
2.  Using BD Laboratory Consulting Services™ to understand the impact of the preanalytical phase on sample quality and safety, a multi country perspective 
Biochemia Medica  2013;23(2):224.
Background
The complexity of the preanalytical (PA) phase has precluded standardisation of PA processes, despite its impact on sample quality, laboratory efficiency, or patient & healthcare worker safety. The BD Laboratory Consulting Services™ Preanalytical Review audits PA procedures and practices in hospitals in different countries. Processes were assessed from storage of blood collection materials through specimen collection, transportation, processing of the samples and the resulting sample quality. By following the samples through the complete process, it was possible to link specific PA attributes to sample quality deficiencies.
Materials and methods:
A consistent method and data collection form were used for audits (N = 48) of all blood collection systems. Data were collected by observation of the PA phase. Sample quality was assessed for laboratory samples of the same type.
Results:
The PA phase was observed for 3597 blood collection tubes over 1350 collections. Sample quality was assessed for 8016 chemistry and 3532 coagulation tubes. For collections that resulted in hemolysed samples, 48% had prolonged use of tourniquet, 31% used catheters and for 38% the disinfectant was not allowed to dry. For serum samples with fibrin where the PA process had been observed, 26% had less than 30 minutes between collection and centrifugation and 81% had not been mixed. The following list gives the percentage of collections where a particular behaviour was observed, incorrect patient identification procedure, 56%; tubes labelled prior to collection 61%; coagulation tubes filled to less than 90% of tube volume 7%; gloves not worn 37%; incorrect activation of needle safety device 19%.
Conclusions:
The BD Preanalytical Review standardised audit methodology allows comparison of results between departments and institutions. The prospective nature of the reviews permits identification of issues based on more data than from rejected samples alone and therefore affords a more complete understanding for those involved in the PA phase.
doi:10.11613/BM.2013.028
PMCID: PMC3900067
3.  Types and frequency of preanalytical mistakes in the first Thai ISO 9002:1994 certified clinical laboratory, a 6 – month monitoring 
Background
Reliability cannot be achieved in a clinical laboratory through the control of accuracy in the analytical phase of the testing process alone. Indeed a "mistake" can be defined as any defect occuring during the testing process. In the analysis of clinical specimens, there are many possible preanalytical sources of error. Therefore, the application of quality system to laboratory testing requires total quality management throughout the laboratory process, including the preanalytical and postanalytical phases. ISO 9002:1994 is a model for quality assurance in production, installation, and servicing, which includes a number of clauses providing guidance for implementation in clinical laboratories. Our laboratory at King Chulalongkorn Memorial Hospital, the largest Thai Red Cross Society hospital, is the first clinical laboratory in Thailand with ISO 9002:1994 certified for the whole unit.
Method
In this study, we evaluated the frequency and types of preanalytical mistakes found in our laboratory, by monitoring specimens requested for laboratory analyses from both in-patient and out-patient divisions for 6 months.
Result
Among a total of 935,896 specimens for 941,902 analyses, 1,048 findings were confirmed as preanalytical mistakes; this was a relative frequency of 0.11 % (1,048/935,896). A total of 1,240 mistakes were identified during the study period. Comparing the preanalytical mistakes to other mistakes in the laboratory process monitored in the same setting and period, the distribution of mistakes was: preanalytical 84.52 % (1,048 mistakes), analytical 4.35 % (54 mistakes), and postanalytical 11.13 % (138 mistakes). Of 1,048 preanalytical mistakes, 998 (95.2%) originated in the care units. All preanalytical mistakes, except for 12 (1.15 %) relating to the laboratory barcode reading machine, were due to human error.
Conclusion
Most mistakes occurred before samples were analysed, either during sampling or preparation for analysis. This suggests that co-operation with clinicians and personnel outside the laboratory is still the key to improvement of laboratory quality.
doi:10.1186/1472-6890-1-5
PMCID: PMC59663  PMID: 11696253
4.  Rationales, design and recruitment for the Elfe longitudinal study 
BMC Pediatrics  2009;9:58.
Background
Many factors act simultaneously in childhood to influence health status, life chances and well being, including pre-birth influences, the environmental pollutants of early life, health status but also the social influences of family and school. A cohort study is needed to disentangle these influences and explore attribution.
Methods
Elfe will be a nationally representative cohort of 20 000 children followed from birth to adulthood using a multidisciplinary approach. The cohort will be based on the INSEE Permanent Demographic Panel (EDP) established using census data and civil records. The sample size has been defined in order to match the representativeness criteria and to obtain some prevalence estimation, but also to address the research area of low exposure/rare effects. The cohort will be based on repeated surveys by face to face or phone interview (at birth and each year) as well as medical interview (at 2 years) and examination (at 6 years). Furthermore, biological samples will be taken at birth to evaluate the foetal exposition to toxic substances, environmental sensors will be placed in the child's homes. Pilot studies have been initiated in 2007 (500 children) with an overall acceptance rate of 55% and are currently under progress, the 2-year survey being carried out in October this year.
Discussion
The longitudinal study will provide a unique source of data to analyse the development of children in their environment, to study the various factors interacting throughout the life course up to adulthood and to determine the impact of childhood experience on the individual's physical, psychological, social and professional development.
doi:10.1186/1471-2431-9-58
PMCID: PMC2754449  PMID: 19772571
5.  History of the preanalytical phase: a personal view 
Biochemia Medica  2014;24(1):25-30.
In the 70ies of the last century, ther term “preanalytical phase” was introduced in the literature. This term describes all actions and aspects of the “brain to brain circle” of the medical laboratory diagnostic procedure happening before the analytical phase. The author describes his personal experiences in the early seventies and the following history of increasing awareness of this phase as the main cause of “laboratory errors”. This includes the definitions of influence and interference factors as well as the first publications in book, internet, CD-Rom and recent App form over the past 40 years. In addition, a short summary of previous developments as prerequesits of laboratory diagnostic actions is described from the middle age matula for urine collection to the blood collection tubes, anticoagulants and centrifuges. The short review gives a personal view on the possible causes of missing awareness of preanalytical causes of error and future aspects of new techniques in regulation of requests to introduction of quality assurance programs for preanalytical factors.
doi:10.11613/BM.2014.005
PMCID: PMC3936980  PMID: 24627712
influence factors; interference factors; preanalytical factors; amylase in urine; haemolytic samples; anticoagulants; blood collection tubes; centrifugation
6.  Access To Essential Maternal Health Interventions and Human Rights Violations among Vulnerable Communities in Eastern Burma 
PLoS Medicine  2008;5(12):e242.
Background
Health indicators are poor and human rights violations are widespread in eastern Burma. Reproductive and maternal health indicators have not been measured in this setting but are necessary as part of an evaluation of a multi-ethnic pilot project exploring strategies to increase access to essential maternal health interventions. The goal of this study is to estimate coverage of maternal health services prior to this project and associations between exposure to human rights violations and access to such services.
Methods and Findings
Selected communities in the Shan, Mon, Karen, and Karenni regions of eastern Burma that were accessible to community-based organizations operating from Thailand were surveyed to estimate coverage of reproductive, maternal, and family planning services, and to assess exposure to household-level human rights violations within the pilot-project target population. Two-stage cluster sampling surveys among ever-married women of reproductive age (15–45 y) documented access to essential antenatal care interventions, skilled attendance at birth, postnatal care, and family planning services. Mid-upper arm circumference, hemoglobin by color scale, and Plasmodium falciparum parasitemia by rapid diagnostic dipstick were measured. Exposure to human rights violations in the prior 12 mo was recorded. Between September 2006 and January 2007, 2,914 surveys were conducted. Eighty-eight percent of women reported a home delivery for their last pregnancy (within previous 5 y). Skilled attendance at birth (5.1%), any (39.3%) or ≥ 4 (16.7%) antenatal visits, use of an insecticide-treated bed net (21.6%), and receipt of iron supplements (11.8%) were low. At the time of the survey, more than 60% of women had hemoglobin level estimates ≤ 11.0 g/dl and 7.2% were Pf positive. Unmet need for contraceptives exceeded 60%. Violations of rights were widely reported: 32.1% of Karenni households reported forced labor and 10% of Karen households had been forced to move. Among Karen households, odds of anemia were 1.51 (95% confidence interval [CI] 0.95–2.40) times higher among women reporting forced displacement, and 7.47 (95% CI 2.21–25.3) higher among those exposed to food security violations. The odds of receiving no antenatal care services were 5.94 (95% CI 2.23–15.8) times higher among those forcibly displaced.
Conclusions
Coverage of basic maternal health interventions is woefully inadequate in these selected populations and substantially lower than even the national estimates for Burma, among the lowest in the region. Considerable political, financial, and human resources are necessary to improve access to maternal health care in these communities.
Luke Mullany and colleagues examine access to essential maternal health interventions and human rights violations within vulnerable communities in eastern Burma.
Editors' Summary
Background.
After decades of military rule, Burma has one of the world's worst health-care systems and high levels of ill health. For example, maternal mortality (deaths among women from pregnancy-related causes) is around 360 per 100,000 live births in Burma, whereas in neighboring Thailand it is only 44 per 100,000 live births. Maternal health is even worse in the Shan, Karenni, Karen and Mon states in eastern Burma where ethnic conflicts and enforced village relocations have internally displaced more than half a million people. Here, maternal mortality is thought to be about 1000 per 100, 000 live births. In an effort to improve access to life-saving maternal health interventions in these states, Burmese community-based health organizations, the Johns Hopkins Center for Public Health and Human Rights and the Global Health Access Program in the USA, and the Mae Tao Clinic (a health-worker training center in Thailand) recently set up the Mobile Obstetric Maternal Health Workers (MOM) Project. In this pilot project, local health workers from 12 communities in eastern Burma received training in antenatal care, emergency obstetrics (the care of women during childbirth), blood transfusion, and family planning at the Mae Tao Clinic. Back in Burma, these maternal health workers trained additional local health workers and traditional birth attendants. All these individuals now provide maternal health care to their communities.
Why Was This Study Done?
The effectiveness of the MOM project can only be evaluated if accurate baseline information on women's access to maternal health-care services is available. This information is also needed to ensure the wise use of scarce health-care resources. However, very little is known about reproductive and maternal health in eastern Burma. In this study, the researchers analyze the information on women's access to reproductive and maternal health-care services that was collected during the initial field implementation stage of the MOM project. In addition, they analyze whether exposure to enforced village relocations and other human rights violations affect access to maternal health-care services.
What Did the Researchers Do and Find?
Trained survey workers asked nearly 3000 ever-married women of reproductive age in the selected communities about their access to antenatal and postnatal care, skilled birth attendants, and family planning. They measured each woman's mid-upper arm circumference (an indicator of nutritional status) and tested them for anemia (iron deficiency) and infection with malaria parasites (a common cause of anemia in tropical countries). Finally, they asked the women about any recent violations of their human rights such as forced labour or relocation. Nearly 90% of the women reported a home delivery for their last baby. A skilled attendant was present at only one in 20 births and only one in three women had any antenatal care. One third of the women received postnatal care and only a third said they had access to effective contraceptives. Few women had received iron supplements or had used insecticide-treated bednets to avoid malaria-carrying mosquitos. Consequently, more than half the women were anemic and 7.2% were infected with malaria parasites. Many women also showed signs of poor nutrition. Finally, human rights violations were widely reported by the women. In Karen, the region containing most of the study communities, forced relocation tripled the risk of women developing anemia and greatly decreased their chances of receiving any antenatal care.
What Do These Findings Mean?
These findings show that access to maternal health-care interventions is extremely limited and that poor nutrition, anemia, and malaria, all of which increase the risk of pregnancy complications, are widespread in the communities in the MOM project. Because these communities had some basic health services and access to training in Thailand before the project started, these results probably underestimate the lack of access to maternal health-care services in eastern Burma. Nevertheless, it is clear that considerable political, financial, and human resources will be needed to improve maternal health in this region. Finally, the findings also reveal a link between human rights violations and reduced access to maternal health-care services. Thus, the scale of human rights violations will need to be considered when evaluating programs designed to improve maternal health in Burma and in other places where there is ongoing conflict.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050242.
This research article is further discussed in a PLoS Medicine Perspective by Macaya Douoguih
The World Health Organization provides information on all aspects of health in Burma (in several languages)
The Mae Tao Clinic also provides general information about Burma and its health services
More information about the MOM project is available in a previous publication by the researchers
The Burma Campaign UK and Human Rights Watch both provide detailed information about human rights violations in Burma
The United Nations Population Fund provides information about safe motherhood and ongoing efforts to save mothers' lives around the world
doi:10.1371/journal.pmed.0050242
PMCID: PMC2605890  PMID: 19108601
7.  ELF5 Suppresses Estrogen Sensitivity and Underpins the Acquisition of Antiestrogen Resistance in Luminal Breast Cancer 
PLoS Biology  2012;10(12):e1001461.
The transcription factor ELF5 is responsible for gene expression patterning underlying molecular subtypes of breast cancer and may mediate acquired resistance to anti-estrogen therapy.
We have previously shown that during pregnancy the E-twenty-six (ETS) transcription factor ELF5 directs the differentiation of mammary progenitor cells toward the estrogen receptor (ER)-negative and milk producing cell lineage, raising the possibility that ELF5 may suppress the estrogen sensitivity of breast cancers. To test this we constructed inducible models of ELF5 expression in ER positive luminal breast cancer cells and interrogated them using transcript profiling and chromatin immunoprecipitation of DNA followed by DNA sequencing (ChIP-Seq). ELF5 suppressed ER and FOXA1 expression and broadly suppressed ER-driven patterns of gene expression including sets of genes distinguishing the luminal molecular subtype. Direct transcriptional targets of ELF5, which included FOXA1, EGFR, and MYC, accurately classified a large cohort of breast cancers into their intrinsic molecular subtypes, predicted ER status with high precision, and defined groups with differential prognosis. Knockdown of ELF5 in basal breast cancer cell lines suppressed basal patterns of gene expression and produced a shift in molecular subtype toward the claudin-low and normal-like groups. Luminal breast cancer cells that acquired resistance to the antiestrogen Tamoxifen showed greatly elevated levels of ELF5 and its transcriptional signature, and became dependent on ELF5 for proliferation, compared to the parental cells. Thus ELF5 provides a key transcriptional determinant of breast cancer molecular subtype by suppression of estrogen sensitivity in luminal breast cancer cells and promotion of basal characteristics in basal breast cancer cells, an action that may be utilised to acquire antiestrogen resistance.
Author Summary
The molecular subtypes of breast cancer are distinguished by their intrinsic patterns of gene expression and can be used to group patients with different prognoses and treatment options. Although molecular subtyping tests are currently under evaluation, some of them are already in use to better tailor therapy for patients; however, the molecular events that are responsible for these different patterns of gene expression in breast cancer are largely undefined. The elucidation of their mechanistic basis would improve our understanding of the disease process and enhance the chances of developing better predictive and prognostic markers, new therapies, and interventions to overcome resistance to existing therapies. Here, we show that the transcription factor ELF5 is responsible for much of the patterning of gene expression that distinguishes the breast cancer subtypes. Additionally, our data suggest that ELF5 may also be involved in the development of resistance to therapies designed to stop estrogen stimulation of breast cancer. These effects of ELF5 appear to represent a partial carryover into breast cancer of its normal role in the mammary gland, where it is responsible for the development of milk-producing structures during pregnancy.
doi:10.1371/journal.pbio.1001461
PMCID: PMC3531499  PMID: 23300383
8.  Influence of blood specimen collection method on various preanalytical sample quality indicators 
Preanalytical errors contribute to a large proportion of total laboratory errors. In order to achieve continuous laboratory improvement, it is important to focus on all phases of patient specimen testing i.e. preanalytical, analytical and post-analytical. With large variations in the way venous blood specimens are collected using diverse devices in the country, the effect of such practices on specimen quality is not known. The purpose of this study was to monitor fourteen specimen preanalytical quality indicators in order to compare the usage of evacuated blood collection devices with needle and syringe open collection using either disposable tubes or re-washed glass vials. The study involved 26638 patient specimens assessed over a period of 6 months. The results demonstrated that evacuated closed blood collection resulted in an approximate 100-fold reduction in the incidence of hemolysis in samples. Similarly, there was a 200-fold reduction in incidence of insufficient specimen quantity while using evacuated collection system. It was also found that incidence of specimen contamination, improper volume of sample collected, and specimen spillage was also lower when the evacuated collection system was used. Further, it was also observed that the facility with a laboratory information system demonstrated much lower specimen identification and related errors. The observed results clearly demonstrate that the usage of the evacuated blood collection system resulted in improvement of preanalytical specimen quality as compared to needle and syringe usage.
doi:10.1007/s12291-008-0032-4
PMCID: PMC3453073  PMID: 23105740
Preanalytical; Vacutainer; Hemolysis; Total quality; Needle and Syringe; Open collection
9.  The quality of maternity care services as experienced by women in the Netherlands 
Background
Maternity care is all care in relation to pregnancy, childbirth and the postpartum period. In the Netherlands maternity care is provided by midwives and general practitioners (GPs) in primary care and midwives and gynecologists in secondary care. To be able to interpret women's experience with the quality of maternity care, it is necessary to take into account their 'care path', that is: their route through the care system.
In the Netherlands a new tool is being developed to evaluate the quality of care from the perspective of clients. The tool is called: 'Consumer Quality Index' or CQI and is, within a standardized and systematic framework, tailored to specific health care issues.
Within the framework of developing a CQI Maternity Care, data were gathered about the care women in the Netherlands received during pregnancy, childbirth, and the postpartum period. In this paper the quality of maternity care in the Netherlands is presented, as experienced by women at different stages of their care path.
Methods
A sample of 1,248 pregnant clients of four insurance companies, with their due date in early April 2007, received a postal survey in the third trimester of pregnancy (response 793). Responders to the first questionnaire received a second questionnaire twelve weeks later, on average four weeks after delivery (response 632). Based on care provider and place of birth the 'care path' of the women is described. With factor analysis and reliability analysis five composite measures indicating the quality of treatment by the care provider at different stages of the care path have been constructed. Overall ratings relate to eight different aspects of care, varying from antenatal care by a midwife or GP to care related to neonatal screening.
Results
41.5 percent of respondents remained in primary care throughout pregnancy, labor, birth and the postpartum period, receiving care from a midwife or general practitioner, 31.3% of respondents gave birth at home. The majority of women (58.5%) experienced referral from one care provider to another, i.e. from primary to secondary care or reverse, at least once. All but two percent of women had one or more ultrasound scans during pregnancy. The composite measures for the quality of treatment in different settings and by different care providers showed that women, regardless of parity, were very positive about the quality of the maternity care they received. Quality-of-treatment scores were high: on average 3.75 on a scale ranging from 1 to 4. Overall ratings on a 0 – 10 scale for quality of care during the antenatal period and during labor, birth and the postpartum period were high as well, on average 8.36.
Conclusion
The care path of women in maternity care was seldom straight forward. The majority of pregnant women switched from primary to secondary care and back at least once, during pregnancy or during labor and birth or both.
The results of the quality measures indicate that the quality of care as experienced by women is high throughout the care system. But with regard to the care during labor and birth the quality of care scores are higher when women know their care provider, when they give birth at home, when they give birth in primary care and when they are assisted by their own midwife.
doi:10.1186/1471-2393-9-18
PMCID: PMC2689853  PMID: 19426525
10.  Prediction of Clinical Outcomes in Primary Biliary Cirrhosis by Serum Enhanced Liver Fibrosis (ELF) Assay 
Hepatology (Baltimore, Md.)  2008;48(5):1549-1557.
Background
Primary biliary cirrhosis (PBC) is sometimes diagnosed based upon a positive antimitochondrial antibody in the appropriate clinical setting without a liver biopsy. While a liver biopsy can assess the extent of liver fibrosis and provide prognostic information, serum fibrosis markers avoid biopsy complications, sampling error, and provide results as a continuous variable, which may be more precise than categorical histological stages. The current study was undertaken to evaluate serum fibrosis markers as predictors of clinical progression in a large cohort of PBC patients.
Methods
Serial liver biopsies and serum samples were collected every 2 years in 161 PBC subjects for a median of 7.3 years. Clinical progression was defined as development of one or more of the following events: varices, variceal bleed, ascites, encephalopathy, liver transplant, or liver-related death. Serum HA, TIMP-1, and PIIINP were measured and entered into the previously validated Enhanced Liver Fibrosis (ELF) algorithm. The ability of ELF, histological fibrosis, bilirubin, MELD, and Mayo Risk Score to differentiate between individuals who would experience a clinical event from those who would not was evaluated at different time points.
Results
Event-free survival was significantly lower in those with high baseline ELF. Each 1 point increase in ELF was associated with a 3 fold increase in future complications. The prognostic performance of all tests was similar when performed close to the time of the first event. However, at earlier times in the disease process (4 and 6 years prior to the first event), the prognostic performance of ELF was significantly better than MELD or Mayo R score.
Conclusion
The ELF algorithm is a highly accurate non-invasive measure of PBC disease severity which provides useful long-term prognostic information.
doi:10.1002/hep.22517
PMCID: PMC2597274  PMID: 18846542
Mayo Risk Score; MELD; Biopsy; Metalloproteinase; Hyaluronic acid
11.  Validation of a blood protein signature for non-small cell lung cancer 
Clinical Proteomics  2014;11(1):32.
Background
CT screening for lung cancer is effective in reducing mortality, but there are areas of concern, including a positive predictive value of 4% and development of interval cancers. A blood test that could manage these limitations would be useful, but development of such tests has been impaired by variations in blood collection that may lead to poor reproducibility across populations.
Results
Blood-based proteomic profiles were generated with SOMAscan technology, which measured 1033 proteins. First, preanalytic variability was evaluated with Sample Mapping Vectors (SMV), which are panels of proteins that detect confounders in protein levels related to sample collection. A subset of well collected serum samples not influenced by preanalytic variability was selected for discovery of lung cancer biomarkers. The impact of sample collection variation on these candidate markers was tested in the subset of samples with higher SMV scores so that the most robust markers could be used to create disease classifiers. The discovery sample set (n = 363) was from a multi-center study of 94 non-small cell lung cancer (NSCLC) cases and 269 long-term smokers and benign pulmonary nodule controls. The analysis resulted in a 7-marker panel with an AUC of 0.85 for all cases (68% adenocarcinoma, 32% squamous) and an AUC of 0.93 for squamous cell carcinoma in particular. This panel was validated by making blinded predictions in two independent cohorts (n = 138 in the first validation and n = 135 in the second). The model was recalibrated for a panel format prior to unblinding the second cohort. The AUCs overall were 0.81 and 0.77, and for squamous cell tumors alone were 0.89 and 0.87. The estimated negative predictive value for a 15% disease prevalence was 93% overall and 99% for squamous lung tumors. The proteins in the classifier function in destruction of the extracellular matrix, metabolic homeostasis and inflammation.
Conclusions
Selecting biomarkers resistant to sample processing variation led to robust lung cancer biomarkers that performed consistently in independent validations. They form a sensitive signature for detection of lung cancer, especially squamous cell histology. This non-invasive test could be used to improve the positive predictive value of CT screening, with the potential to avoid invasive evaluation of nonmalignant pulmonary nodules.
doi:10.1186/1559-0275-11-32
PMCID: PMC4123246  PMID: 25114662
Lung cancer; Biomarker; SOMAmer; Proteomic; Squamous cell carcinoma; Diagnosis; Preanalytic variability; Sample bias
12.  A consensus protocol for the standardization of cerebrospinal fluid collection and biobanking 
Neurology  2009;73(22):1914-1922.
There is a long history of research into body fluid biomarkers in neurodegenerative and neuroinflammatory diseases. However, only a few biomarkers in CSF are being used in clinical practice. One of the most critical factors in CSF biomarker research is the inadequate powering of studies because of the lack of sufficient samples that can be obtained in single-center studies. Therefore, collaboration between investigators is needed to establish large biobanks of well-defined samples. Standardized protocols for biobanking are a prerequisite to ensure that the statistical power gained by increasing the numbers of CSF samples is not compromised by preanalytical factors. Here, a consensus report on recommendations for CSF collection and biobanking is presented, formed by the BioMS-eu network for CSF biomarker research in multiple sclerosis. We focus on CSF collection procedures, preanalytical factors, and high-quality clinical and paraclinical information. The biobanking protocols are applicable for CSF biobanks for research targeting any neurologic disease.
GLOSSARY
= clinically isolated syndrome;
= Expanded Disability Status Scale;
= immunoglobulin G;
= matrix-assisted laser desorption/ionization time-of-flight;
= multiple sclerosis;
= Multiple Sclerosis Functional Composite;
= secondary progressive multiple sclerosis.
doi:10.1212/WNL.0b013e3181c47cc2
PMCID: PMC2839806  PMID: 19949037
13.  Clinical biochemistry laboratory rejection rates due to various types of preanalytical errors 
Biochemia Medica  2014;24(3):376-382.
Introduction:
Preanalytical errors, along the process from the beginning of test requests to the admissions of the specimens to the laboratory, cause the rejection of samples. The aim of this study was to better explain the reasons of rejected samples, regarding to their rates in certain test groups in our laboratory.
Materials and methods:
This preliminary study was designed on the rejected samples in one-year period, based on the rates and types of inappropriateness. Test requests and blood samples of clinical chemistry, immunoassay, hematology, glycated hemoglobin, coagulation and erythrocyte sedimentation rate test units were evaluated. Types of inappropriateness were evaluated as follows: improperly labelled samples, hemolysed, clotted specimen, insufficient volume of specimen and total request errors.
Results:
A total of 5,183,582 test requests from 1,035,743 blood collection tubes were considered. The total rejection rate was 0.65 %. The rejection rate of coagulation group was significantly higher (2.28%) than the other test groups (P < 0.001) including insufficient volume of specimen error rate as 1.38%. Rejection rates of hemolysis, clotted specimen and insufficient volume of sample error were found to be 8%, 24% and 34%, respectively. Total request errors, particularly, for unintelligible requests were 32% of the total for inpatients.
Conclusions:
The errors were especially attributable to unintelligible requests of inappropriate test requests, improperly labelled samples for inpatients and blood drawing errors especially due to insufficient volume of specimens in a coagulation test group. Further studies should be performed after corrective and preventive actions to detect a possible decrease in rejecting samples.
doi:10.11613/BM.2014.040
PMCID: PMC4210258  PMID: 25351356
preanalytical error; quality indicator; specimen rejection
14.  SETIL: Italian multicentric epidemiological case–control study on risk factors for childhood leukaemia, non hodgkin lymphoma and neuroblastoma: study population and prevalence of risk factors in Italy 
Background
Aetiology of childhood leukaemia and childhood neoplasm is poorly understood. Information on the prevalence of risk factors in the childhood population is limited. SETIL is a population based case–control study on childhood leukaemia, conducted with two companion studies on non-Hodgkin Lymphoma (NHL) and neuroblastoma. The study relies on questionnaire interviews and 50 Hz magnetic field (ELF-MF) indoor measurements. This paper discusses the SETIL study design and includes descriptive information.
Methods
The study was carried out in 14 Italian regions (78.3% of Italian population aged 0–10). It included leukaemia, NHL and neuroblastoma cases incident in 0–10 year olds in 1998–2001, registered by the Italian Association of Paediatric Haematology and Oncology (AIEOP) (accrual over 95% of estimated incidence). Two controls for each leukaemia case were randomly sampled from the Local Health Authorities rolls, matched by gender, birthdate and residence. The same controls were used in NHL and neuroblastoma studies. Parents were interviewed at home on: physical agents (ELF-MF and ionizing radiation), chemicals (smoking, solvents, traffic, insecticides), occupation, medical and personal history of children and parents, infectious diseases, immunizations and associated factors. Occupational exposure was collected using job specific modules. ELF-MF was measured in the main rooms (spot measurement) and close to child’s bed (48 hours measurement).
Results
The study included: 683 leukaemia cases (87% ALL, 13% AnLL), 97 NHL, 155 neuroblastomas, and 1044 controls.
ELF-MF long term measurements were obtained for 61.1% of controls and 81.6% of leukaemia cases; 8.8% of controls were exposed at over 0.1 microTesla (μT), 3.5% and 2.1% at respectively over 0.2 and 0.3 μT. 25% of controls’ fathers had smoked over 10 cigarettes/day during the year of conception, varying according to education and region. Maternal smoking was less common (71.4% did not smoke in pregnancy). Maternal passive smoking during pregnancy was reported by 31.2% of controls; the child’s passive smoking for 28.6%.
Occupational exposure to solvents was estimated in 18.3% of controls’ fathers and 7.7% of mothers. Contact with public was more frequent among mothers (36.1%) than fathers (23.4%).
Conclusions
SETIL represents a data source on exposure of Italian children to a broad array of potential carcinogenic factors.
Electronic supplementary material
The online version of this article (doi:10.1186/s13052-014-0103-5) contains supplementary material, which is available to authorized users.
doi:10.1186/s13052-014-0103-5
PMCID: PMC4310183  PMID: 25539823
Leukaemia; Non hogdkin lymphoma; Neuroblastoma; Epidemiology; Risk factors
15.  What are the main environmental exposures associated with elevated IgE in Cuban infants? A population-based study 
Objective
Immunoglobulin E (IgE) plays a key role in allergy disease pathogenesis, but little is known about the environmental factors associated with higher IgE levels in infants. The aim of this study was to determine the risk factors for elevated serum total IgE infants living in Havana.
Methods
Eight hundred and seventy-seven infants provided blood samples. Data on allergic disease symptoms and a wide range of exposures were collected.
Results
The median IgE was 35IU/ml (interquartile range 13–96). The risk of having an IgE level above the median was higher for children who had been breastfed for 4 months or more (adjusted odds ratio (OR) 1.28; 95% confidence interval (CI): 1.02–1.61) and for children who reported cockroaches in their home (OR 1.30; 95% CI: 1.03–1.63). The risk was lower for children whose mother was in paid employment (OR 0.73; 95% CI: 0.54–0.97 compared with those who did not), for children living in homes where gas and electricity were used for cooking (OR 0.45; 95% CI: 0.32–0.62 compared with electricity only) and for children with domestic pets at birth (OR 0.83; 95% CI: 0.70-1.00). There was no association between paracetamol use and serum IgE levels.
Conclusions
Associations between gas fuel use and maternal employment indicate that IgE levels in early life are lower in children who may be living in relative affluence. The discrepancy in the effect of early exposure to pets or cockroaches may reflect differences in these allergens, or be confounded by relative affluence. Further investigation of this cohort will determine how these effects translate into the expression of allergic disease in later life.
Objectif
Les immunoglobulines E (IgE) jouent un rôle clé dans la pathogenèse de la maladie allergique, mais on sait peu sur les facteurs environnementaux associés à des taux plus élevés d'IgE chez les nourrissons. Le but de cette étude était de déterminer les facteurs de risque pour un taux élevé d'IgE sériques totales chez les nourrissons vivant à La Havane.
Méthodes
Des échantillons de sang ont été collectés chez 877 nourrissons. Les données sur les symptômes de la maladie allergique et sur une large gamme d'expositions ont été recueillies.
Résultats
La médiane des IgE était de 35 UI/ml (gamme interquartile: 13 à 96). Le risque d'avoir un taux d'IgE au-dessus de la médiane était plus élevé pour les enfants qui avaient été allaités pendant au moins quatre mois (odds ratio ajusté (OR): 1,28; intervalle de confiance (IC) à 95%: 1,02 à 1,61) et pour les enfants pour qui des cafards ont été signalés dans la maison (OR: 1,30; IC 95%: 1,03 à 1,63). Le risque était plus faible pour les enfants dont la mère possédait un emploi rémunéré (OR: 0,73; IC 95%: 0,54 à 0,97 par rapport à ceux dont les mères n'avaient pas cet emploi, pour les enfants vivant dans des foyers où le gaz et l’électricité étaient utilisés pour la cuisson (OR: 0,45; IC 95%: 0,32 à 0,62 par rapport à l'utilisation de l’électricité seule) et pour les enfants ayant des animaux domestiques à la naissance (OR: 0,83; IC 95%: 0,70 à 1,00). Il n'y avait pas d'association entre les taux d'IgE sériques et l'utilisation de paracétamol.
Conclusions
Les associations avec la consommation du gaz carburant et l'emploi de la mère indiquent que les taux d'IgE en début de vie sont plus faibles chez les enfants vivant dans une relative richesse. La différence dans l'effet de l'exposition précoce aux animaux de compagnie ou à des cafards pourrait refléter des différences dans ces allergènes, ou être confondu par la richesse relative. Une investigation plus approfondie de cette cohorte permettra de déterminer comment ces effets se traduisent dans l'expression de la maladie allergique plus tard dans la vie.
Objetivo
La inmunoglobulina E (IgE) juega un papel clave en la patogénesis de la enfermedad alérgica, pero se conoce poco sobre los factores ambientales asociados con unos niveles altos de IgE en los niños. El objetivo de este estudio era determinar los factores de riesgo de unos niveles elevados de IgE en sueros de niños viviendo en La Habana.
Métodos
Se obtuvieron muestras de sangre de 877 niños. Se recolectaron datos sobre los síntomas de la alergia y un amplio rango de exposiciones.
Resultados
La mediana de IgE era de 35 IU/ml (rango intercuartil 13–96). El riesgo de tener unos niveles altos de IgE, por encima de la mediana, era mayor en niños que habían sido amamantados durante cuatro meses o más (odds ratio (OR) ajustado 1.28; intervalo de confianza (IC) 95%: 1.02–1.61) y en niños para los que se había reportado presencia de cucarachas en sus hogares (OR 1.30; 95% CI: 1.03–1.63). El riesgo era menor para niños cuya madre tenía un empleo pagado (OR 0.73; IC 95%: 0.54–0.97 comparado con aquellos que no la tenían), para niños viviendo en hogares en los que se utilizaba gas y electricidad para cocinar (OR 0.45; IC 95%: 0.32–0.62 comparado con electricidad solamente) y para niños con mascotas domésticas en el momento de nacer (OR 0.83; IC 95%: 0.70–1.00). No existía una asociación entre el uso del paracetamol y los niveles de IgE en suero.
Conclusiones
Las asociaciones con el uso de gas como combustible y el empleo de la madre indican que los niveles de IgE en una etapa temprana de la vida son menores en niños viviendo con un cierto nivel de opulencia. Las discrepancias en el efecto de una exposición temprana a mascotas o cucarachas podría reflejar las diferencias en estos alergenos, aunque la relativa opulencia podría jugar como factor de confusión. Nuevos estudios con esta cohorte podrían determinar cómo estos efectos se traducen en la expresión de la enfermedad alérgica más adelante en la vida.
doi:10.1111/tmi.12293
PMCID: PMC4309505  PMID: 24674274
IgE; infants; risk factor; Cuba; allergy
16.  An ignored risk factor in toxicology: The total imprecision of exposure assessment 
Quality assurance of exposure biomarkers usually focuses on laboratory performance only. Using data from a prospective birth cohort study in the Faroe Islands, we have assessed the total imprecision of exposure biomarkers. As biomarkers of prenatal methylmercury exposure, mercury concentrations were determined in cord blood, cord tissue, and maternal hair. We determined their mutual correlations and their associations with the child's neurobehavioral effect variables at age 7 years. The exposure biomarkers correlated well with one another, but the cord blood mercury concentration showed the best associations with neurobehavioral deficits. Because at least three exposure parameters were available, factor analysis and structural equation modeling could be applied to determine the total imprecision of each biomarker. For the cord-blood parameter, the total imprecision was 25-30%, and almost twice as much for maternal hair. The total imprecision of these biomarkers much exceeded the normal laboratory variability of less than 5%. Such imprecision can cause underestimation of dose-related toxicity, and data analysis should therefore include sensitivity analyses that take this factor into account. Ignoring preanalytical imprecision may cause serious bias.
doi:10.1351/PAC-CON-09-05-04
PMCID: PMC2856963  PMID: 20419070
Environmental exposure; imprecision; quality assurance; risk assessment; uncertainty
17.  Biospecimen Reporting for Improved Study Quality 
Human biospecimens are subject to a number of different collection, processing, and storage factors that can significantly alter their molecular composition and consistency. These biospecimen preanalytical factors, in turn, influence experimental outcomes and the ability to reproduce scientific results. Currently, the extent and type of information specific to the biospecimen preanalytical conditions reported in scientific publications and regulatory submissions varies widely. To improve the quality of research utilizing human tissues, it is critical that information regarding the handling of biospecimens be reported in a thorough, accurate, and standardized manner. The Biospecimen Reporting for Improved Study Quality recommendations outlined herein are intended to apply to any study in which human biospecimens are used. The purpose of reporting these details is to supply others, from researchers to regulators, with more consistent and standardized information to better evaluate, interpret, compare, and reproduce the experimental results. The Biospecimen Reporting for Improved Study Quality guidelines are proposed as an important and timely resource tool to strengthen communication and publications around biospecimen-related research and help reassure patient contributors and the advocacy community that the contributions are valued and respected.
doi:10.1089/bio.2010.0036
PMCID: PMC3142856  PMID: 21826252
18.  Biospecimen Reporting for Improved Study Quality (BRISQ) 
Journal of proteome research  2011;10(8):3429-3438.
Human biospecimens are subject to a number of different collection, processing, and storage factors that can significantly alter their molecular composition and consistency. These biospecimen preanalytical factors, in turn, influence experimental outcomes and the ability to reproduce scientific results. Currently, the extent and type of information specific to the biospecimen preanalytical conditions reported in scientific publications and regulatory submissions varies widely. To improve the quality of research utilizing human tissues it is critical that information regarding the handling of biospecimens be reported in a thorough, accurate, and standardized manner. The Biospecimen Reporting for Improved Study Quality (BRISQ) recommendations outlined herein are intended to apply to any study in which human biospecimens are used. The purpose of reporting these details is to supply others, from researchers to regulators, with more consistent and standardized information to better evaluate, interpret, compare, and reproduce the experimental results. The BRISQ guidelines are proposed as an important and timely resource tool to strengthen communication and publications around biospecimen-related research and help reassure patient contributors and the advocacy community that the contributions are valued and respected.
doi:10.1021/pr200021n
PMCID: PMC3169291  PMID: 21574648
19.  Outcomes of planned home birth with registered midwife versus planned hospital birth with midwife or physician 
Background
Studies of planned home births attended by registered midwives have been limited by incomplete data, nonrepresentative sampling, inadequate statistical power and the inability to exclude unplanned home births. We compared the outcomes of planned home births attended by midwives with those of planned hospital births attended by midwives or physicians.
Methods
We included all planned home births attended by registered midwives from Jan. 1, 2000, to Dec. 31, 2004, in British Columbia, Canada (n = 2889), and all planned hospital births meeting the eligibility requirements for home birth that were attended by the same cohort of midwives (n = 4752). We also included a matched sample of physician-attended planned hospital births (n = 5331). The primary outcome measure was perinatal mortality; secondary outcomes were obstetric interventions and adverse maternal and neonatal outcomes.
Results
The rate of perinatal death per 1000 births was 0.35 (95% confidence interval [CI] 0.00–1.03) in the group of planned home births; the rate in the group of planned hospital births was 0.57 (95% CI 0.00–1.43) among women attended by a midwife and 0.64 (95% CI 0.00–1.56) among those attended by a physician. Women in the planned home-birth group were significantly less likely than those who planned a midwife-attended hospital birth to have obstetric interventions (e.g., electronic fetal monitoring, relative risk [RR] 0.32, 95% CI 0.29–0.36; assisted vaginal delivery, RR 0.41, 95% 0.33–0.52) or adverse maternal outcomes (e.g., third- or fourth-degree perineal tear, RR 0.41, 95% CI 0.28–0.59; postpartum hemorrhage, RR 0.62, 95% CI 0.49–0.77). The findings were similar in the comparison with physician-assisted hospital births. Newborns in the home-birth group were less likely than those in the midwife-attended hospital-birth group to require resuscitation at birth (RR 0.23, 95% CI 0.14–0.37) or oxygen therapy beyond 24 hours (RR 0.37, 95% CI 0.24–0.59). The findings were similar in the comparison with newborns in the physician-assisted hospital births; in addition, newborns in the home-birth group were less likely to have meconium aspiration (RR 0.45, 95% CI 0.21–0.93) and more likely to be admitted to hospital or readmitted if born in hospital (RR 1.39, 95% CI 1.09–1.85).
Interpretation
Planned home birth attended by a registered midwife was associated with very low and comparable rates of perinatal death and reduced rates of obstetric interventions and other adverse perinatal outcomes compared with planned hospital birth attended by a midwife or physician.
doi:10.1503/cmaj.081869
PMCID: PMC2742137  PMID: 19720688
20.  Global Stability of Plasma Proteomes for Mass Spectrometry-Based Analyses* 
Molecular & Cellular Proteomics : MCP  2012;11(6):M111.014340.
Peptide-based mass spectrometry approaches, such as multiple reaction monitoring, provide a powerful means to measure candidate protein biomarkers in plasma. A potential confounding problem is the effect of preanalytical variables, which may affect the integrity of proteins and peptides. Although some blood proteins undergo rapid physiological proteolysis ex vivo, the stability of most plasma proteins to preanalytical variables remains largely unexplored. We applied liquid chromatography-tandem mass spectrometry shotgun proteomics and multiple reaction monitoring analyses to characterize the stability of proteins at the peptide level in plasma. We systematically evaluated the effects of delay in plasma preparation at different temperatures, multiple freeze-thaw cycles and erythocyte hemolysis on peptide and protein inventories in prospectively collected human plasma. Time course studies indicated few significant changes in peptide and protein identifications, semitryptic peptides and methionine-oxidized peptides in plasma from blood collected in EDTA plasma tubes and stored for up to a week at 4 °C or room temperature prior to plasma isolation. Similarly, few significant changes were observed in similar analyses of plasma subjected to up to 25 freeze-thaw cycles. Hemolyzed samples produced no significant differences beyond the presence of hemoglobin proteins. Finally, paired comparisons of plasma and serum samples prepared from the same patients also yielded few significant differences, except for the depletion of fibrinogen in serum. Blood proteins thus are broadly stable to preanalytical variables when analyzed at the peptide level. Collection protocols to generate plasma for multiple reaction monitoring-based analyses may have different requirements than for other analyses directed at intact proteins.
doi:10.1074/mcp.M111.014340
PMCID: PMC3433892  PMID: 22301387
21.  Intrapulmonary Pharmacokinetics and Pharmacodynamics of Posaconazole at Steady State in Healthy Subjects▿  
We evaluated the pharmacokinetics (PK) and pharmacodynamics (PD) of posaconazole (POS) in a prospective, open-label study. Twenty-five healthy adults received 14 doses of POS oral suspension (400 mg twice daily) with a high-fat meal over 8 days. Pulmonary epithelial lining fluid (ELF) and alveolar cell (AC) samples were obtained via bronchoalveolar lavage, and blood samples were collected during the 24 h after the last dose. POS concentrations were determined using liquid chromatography with tandem mass spectrometry parameters. The maximum concentrations (Cmax) (mean ± standard deviation) in plasma, ELF, and ACs were 2.08 ± 0.93, 1.86 ± 1.30, and 87.7 ± 65.0 μg/ml. The POS concentrations in plasma, ELF, and ACs did not decrease significantly, indicating slow elimination after multiple dosing. The mean concentrations of POS in plasma, ELF, and ACs were above the MIC90 (0.5 μg/ml) for Aspergillus spp. over the 12-h dosing interval and for 24 h following the last dose. Area under the curve from 0 to 12 h (AUC0-12) ratios for ELF/plasma and AC/plasma were 0.84 and 33. AUC0-24/MIC90 ratios in plasma, ELF, and AC were 87.6, 73.2, and 2,860. Nine (36%) of 25 subjects had treatment-related adverse events during the course of the study, which were all mild or moderate. We conclude that a dose of 400 mg twice daily resulted in sustained plasma, ELF, and AC concentrations above the MIC90 for Aspergillus spp. during the dosing interval. The intrapulmonary PK/PD of POS are favorable for treatment or prevention of aspergillosis, and oral POS was well tolerated in healthy adults.
doi:10.1128/AAC.00663-08
PMCID: PMC2630621  PMID: 19029316
22.  Preanalytical phase – a continuous challenge for laboratory professionals 
Biochemia Medica  2012;22(2):145-149.
Preanalytical phase is the most vulnerable part of the total testing process and is considered to be among the greatest challenges to the laboratory professionals. However, preanalytical activities, management of unsuitable specimens and reporting policies are not fully standardized, nor harmonized worldwide. Several standards related to blood sampling and sample transportation and handling are available, but compliance to those guidelines is low, especially outside the laboratory and if blood sampling is done without the direct supervision of the laboratory staff. Furthermore, for some most critical procedures within the preanalytical phase, internationally accepted guidelines and recommendations as well as related quality measures are unfortunately unavailable. There is large heterogeneity in the criteria for sample rejection, the diff erent strategies by which unacceptable samples are managed, processed and test results reported worldwide. Management of unacceptable specimens warrants therefore immediate harmonization. Alongside the challenging and long road of patient safety, preanalytical phase off ers room for improvement, and Editors at Biochemia Medica Journal definitely hope to continue providing a respective mean for reporting studies on diff erent preanalytical phase topics. With pleasure and delight we invite potential future authors to submit their articles examining the quality of various preanalytical activities to Biochemia Medica. We will keep nurturing this topic as our prominent feature and by this we hope to be able to deliver valid evidence for some future guidelines and recommendations.
PMCID: PMC4062337  PMID: 22838180
preanalytical phase; errors; quality indicators; phlebotomy; blood sampling
23.  Types and Frequency of Preanalytical Errors in Haematology Lab 
Aim: This study was conducted to evaluate the frequency of the preanalytical errors occurring in a haematology laboratory.
Material and Methods: A retrospective study was conducted by collecting and analyzing data in duration of one year in the haematology section of the laboratory. Data for all the preanalytical variables according to the predefined categories were scanned. Both IPD and OPD patients were segregated.
Result: A total of 135808 samples were received in haematology lab during this period, out of which in 1339 samples, preanalytical errors were found, which approximately constituted 1 % of all samples.
Conclusion: Highest number of samples were rejected due to misidentification, that is 0.35 % and least number were rejected due to dilution of the samples, that is 0.04 %.
doi:10.7860/JCDR/2013/6399.3587
PMCID: PMC3879881  PMID: 24392380
Pre–analytical errors; Haematology; Laboratory
24.  Fracture Prevalence and Relationship to Endocrinopathy in Iron Overloaded Patients with Sickle Cell Disease and Thalassemia 
Bone  2008;43(1):162-168.
Transfusional iron overload leads to gonadal failure and low bone mass in patients with thalassemia (Thal). However, gonadal failure is rarely reported in transfused patients with sickle cell disease (SCD) and the literature regarding fracture prevalence in SCD is limited. The objective of this study was to assess self-reported fracture prevalence and its relationship to endocrinopathy in transfused Thal or SCD subjects and compare to non-transfused subjects with SCD (NonTxSCD). Eligibility was based on age ≥12 years and liver iron concentration ≥ 10 mg/g dry wt or serum ferritin ≥ 2000 ng/mL (Thal or TxSCD) or for NonTxSCD, ferritin < 500 ng/mL. Data were collected by patient interview and chart review at 31 clinical centers in the U.S., Canada and the U.K. 152 subjects with Thal (52% Male; 25.6±0.7 yrs), 203 subjects with TxSCD (44% Male, 24.7 ±0.9 years: Mean ± SE), and 65 NonTxSCD (50% Male, 22.2 ±1.3 yrs) were enrolled. Overall, male subjects with Thal were more likely to have sustained a fracture in their lifetime (51%) compared to TxSCD (28%) or NonTxSCD (32%) (p=0.005). There was no difference in fracture prevalence among women (Thal: 26%, TxSCD 17%, NonTxSCD: 16%). Fracture was most frequently reported in the upper extremities (53.3% of all fractures) while spine and pelvic fractures were relatively common for such a young cohort: 10.6%. Though overall fracture prevalence was not distinctly different from published healthy cohorts, fewer fractures occurred during the adolescent years. In multivariate analysis, the significant predictors of fracture prevalence were Thal diagnosis (Odds Ratio: 2.3; 1.2–4.6; 95%CI), male gender (OR: 2.6; 1.5–4.5), hypothyroidism (OR: 3.3; 1.1–9.8) and age (OR: 1.1; 1.03–1.08). These data suggest that despite similar iron burden, transfused patients with Thal are at greater risk for fracture than subjects with SCD. Male subjects with Thal and hypothyroidism are at particular risk for fracture, in contrast, transfused subjects with SCD had no greater risk of fracture compared to non-transfused SCD. Though ethnic differences in fracture risk cannot be ignored, endocrinopathy is rare in TxSCD which may also provide some protection from fracture.
doi:10.1016/j.bone.2008.03.003
PMCID: PMC2500183  PMID: 18430624
Fracture; Endocrinopathy; Iron Overload; Thalassemia; Sickle Cell Disease
25.  Extremely low frequency electromagnetic fields activate the ERK cascade, increase hsp70 protein levels and promote regeneration in Planaria 
Purpose
To use regenerating Planaria Dugesia dorotocethala as a model to determine whether an intermittent modulated extremely low frequency electro-magnetic field (ELF-EMF) produces elevated levels of the heat shock protein hsp70 and stimulates intracellular pathways known to be involved in injury and repair. We focused on serum response element (SRE) binding through the extra-cellular signal-regulated kinase (ERK) cascade.
Materials and methods
Planaria were transected equidistant between the tip of the head and the tip of the tail. Individual head and tail portions from the same worm were exposed to a 60 Hertz 80 milliGauss ELF- EMF for one hour twice daily for 15 days post transection under carefully controlled exposure conditions. The regenerating heads and tails were photographed and the lengths measured at 3-day intervals. In other experiments, the timing of the appearance of pigmented eyes was monitored in the tail portion at 12 hour intervals following transection in both ELF-EMF exposed and sham control. In some experiments protein lysates were analyzed for hsp70 levels, doubly phosphorylated (pp)-ERK, Elk-1 kinase activity and serum response factor (SRF) -SRE binding.
Results
ELF-EMF exposure during the initial 3-days post surgery caused a significant increase in regeneration for both heads and tails, but especially tails. The first appearance of eyes occurred at day seven post-transection in tail portions exposed to ELF-EMF. In the sham control tail samples the initial appearance of eyes occurred 48 hours later. Concurrently, ELF-EMF-exposed heads and tails exhibited an elevation in the level of hsp70 protein, an activation of an ERK cascade, and an increase in SRF-SRE binding.
Conclusion
Exposures to a modulated sinusoidal ELF-EMF were delivered by a Helmholtz configuration at a frequency of 60Hz and 80mG twice a day for one hour. This is accompanied by an increase in hsp70 protein levels, activation of specific kinases and up-regulation of transcription factors that are generally associated with repair processes.
doi:10.1080/09553000903072488
PMCID: PMC2999986  PMID: 19639507
Extremely low frequency-electromagnetic fields; hsp70; serum response element; ERKMAPK; transcription factor; regeneration

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