Chronic gastritis (CG), a poorly understood entity, is a very common disease of the digestive tract and is difficult to cure. Chronic non-atrophic gastritis (CNG) is the most common type of CG. Even if treated with current standard chemotherapy, some patients will not be freed from this confusing disease. Many studies have shown traditional Chinese medicine (TCM) is more effective compared to chemotherapy in the treatment of chronic gastritis and no serious side effects have been identified. However, the studies that have been carried out were not scientifically rigorous trials. Our aim is to design a high-quality trial for a new TCM drug, the Jian-Wei-Qu-Tong Pills (JWQTP), to investigate the efficacy and safety of this new drug in treating chronic non-atrophic gastritis patients with spleen and stomach qi deficiency with damp-heat stasis syndrome (SSQDDSS).Helicobacter pylori (HP).This is a phase II, multicenter, parallel-group, double-blind, randomized and placebo-controlled trial. A total of 240 participants will be assigned to a high-dose group, a low-dose group or a placebo control group with a 1:1:1 ratio at five sites. Then, one dose (six 1-g pills), with a variable ratio between real drug and dummy drug according to the intervention protocol, will be taken three times a day before each meal for 8 weeks. The primary outcome is the eradication rate of epigastric pain. The secondary outcome includes the changes of endoscopic examination, histopathological examination, traditional Chinese medicine symptom scores and patient-reported outcome instrument scores for chronic gastrointestinal diseases and the eradication rate of Many CNG patients suffer from frequent, recurrent bouts of dyspeptic symptoms. This is the first clinical trial to evaluate the safety and efficacy of JWQTP in treating CNG with SSQDDSS in a multicenter, parallel-group, double-blind, randomized and placebo-controlled manner. This trial may not only provide evidence for a phase III clinical trial, but also a vision of an alternative option for CNG treatment.ChiCTR-TRC-14004088, was assigned by the Chinese Clinical Trial Registry on 7 January 2014.The registration number,  Helicobacter pylori (HP) infection is the most common cause of chronic gastritis worldwide, with the remaining cases arising due to smoking, drinking, duodenal juice reflux, food allergies, heredity, drug-induced injuries, immunity, Crohn’s disease, other infectious pathogens or radiation [Chronic gastritis (CG), which is induced by various causes, is a very common disease of the digestive tract and is an inflammatory condition of the gastric mucosa . Among tadiation -4. Chronadiation . Chronicadiation . Symptomadiation ,6. Howevadiation -11.Traditional Chinese medicine, which has been established for over 5,000 years, has been widely used to treat diseases, including CNG. Based on its clinical manifestations, CNG can be categorized as Weiwantong (stomach ache), Piman  or Caoza (gastritis discomfort) in the field of Chinese medicine (CM); TCM divides CNG into five common single syndrome patterns: (1) spleen (Pi) and stomach (Wei) deficiency syndrome (including spleen and stomach qi deficiency syndrome and spleen and stomach deficiency-cold syndrome); (2) incoordination between liver (Gan) and stomach syndrome (including liver qi invading stomach syndrome and stagnant heat in liver and stomach syndrome); 3) stomach yin deficiency syndrome; (4) spleen and stomach dampness-heat syndrome; and (5) blood stasis in stomach collaterals syndrome  stomach . The TCMA new TCM drug, the Jian-Wei-Qu-Tong Pills (JWQTP), is currently being manufactured by Anbang Pharmaceutical Limited by Share Ltd, Hunan, China. The prescription for this pill is based on both TCM theory and the clinical experience and herbal studies of prominent TCM doctors on the treatment of CNG. Components of the pill include: Radix Pseudostellariae, Rhizoma Coptidis, Rhizoma Atractylodis Macrocephalae, Semen Coicis, Rhizoma Pinelliae Preparata, Radix Notoginseng, Pollen Typhae, Herba Taraxaci Mongolici, Rhizoma Corydalis Yanhusuo, Cortex Magnoliae Officinalis and Radix Glycyrrhizae preparata. All of these herbs have been approved by the China Food and Drug Administration (CFDA). This pill can strengthen the spleen, supplement qi, clear heat, remove dampness and promote blood circulation to remove blood stasis and relieve pain. Thus, it can be used for spleen and stomach qi deficiency with damp-heat stasis syndrome (SSQDDSS) in CNG patients. Preclinical pharmacologic experiments, which have not been published, show that JWQTP can neutralize gastric acid; reduce gastric acidity, pepsin activity, free mucus, gastrin, TNF-α and IL-2; elevate the level of IL-4; create balance between the Th1 and Th2 cells; and then reduce inflammation in rats’ gastric mucosa to protect against CG. Furthermore, this treatment was able to eradicate HP in the gastric mucosa of mice to some degree, provide an analgesic effect and play a regulatory role on gastric emptying. Additionally, there was no evidence to show an adverse or toxic effect in toxicological studies.The specific objectives of this trial included evaluating the efficacy and safety of JWQTP in treating CNG patients with SSQDDSS, including any dose-effect relationship, and providing evidence for a Phase III clinical program.This current study is a phase II, multicenter, parallel-group, double-blind, randomized and placebo-controlled trial. The study will be conducted in compliance with the Declaration of Helsinki, Good Clinical Practice (GCP) Guidelines  and the A total of 240 patients will be enrolled at the following five sites: (1) West China Hospital of Sichuan University, (2) the first Affiliated Hospital of Guiyang College of Traditional Chinese medicine, (3) the first Affiliated Hospital of Hunan University of Chinese Medicine, (4) the first Affiliated Hospital of Guangxi University of Chinese Medicine and (5) the Ruikang Hospital affiliated to Guangxi University of Chinese Medicine. In other words, 48 patients will be recruited at each hospital.For randomization, the participants will be assigned into a high-dose group, a low-dose group or a placebo control group, with a 1:1:1 ratio using a stratified randomization method, with stratification by center. The randomization sequence will be created at the West China Hospital of Sichuan using SAS 9.2 software to determine the appropriate segment. Two copies of the randomization list will be kept in safe places - one by the West China Hospital of Sichuan University drug clinical trial agency and one by the sponsor of this study - during the study period. Each patient will receive a unique randomized test number corresponding to the specified drug, according to the group allocation. An emergency envelope has been prepared for each test number and is to be opened for treatment allocation only due to medical emergency.Referring to consensus on chronic gastritis in China  , consensMost symptomatic patients with CNG have nonspecific dyspepsia, such as epigastric pain, distention, belching, acid regurgitation, nausea, vomiting and loss of appetite.There is no finding in most patients’ physical examinations, although some patients may feel slight epigastric pain or discomfort when pressed on the upper abdomen. Only a tiny minority of these patients are gaunt or anemic.Because there is no specific symptom, the diagnosis of CNG relies primarily on endoscopic and histopathological examinations, particularly the latter. The fundamental appearance of non-atrophic gastritis shows red plaques , coarse and uneven mucosa, hemorrhagic spots/plaques, edematous mucosa, and exudates at endoscopy. No atrophic changes, intestinal metaplasia, dysplasia or pseudopyloric gland metaplasia are found in the histopathological examination of the gastric mucosa. Table Guidelines For Clinical Research On Chinese New Herbal Medicines [In acknowledgement of the consensus on diagnosis and treatment of chronic superficial gastritis with TCM  , The Peoentation), the CM 1. Primary symptom: epigastric pain.2. Secondary symptoms: weakness and lassitude, dry mouth/bitter taste in mouth, loss of appetite, distention and fullness, loose stool or belching.3. Tongue presentations: pale tongue, dark red tongue with ecchymosis or petechiae or enlarged and teeth-printed tongue.4. Tongue coating: yellow or yellowish greasy coating.5. Pulse presentations: thread and weak pulse or stringy pulse.A diagnosis of SSQDDSS should include the primary symptom, the first two secondary symptoms and more than one of the remaining four secondary symptoms, simultaneously combined with tongue presentations and pulse presentations.Inclusion criteria are:1. Diagnosis of CNG according to Western medicine (moderate or severe level of chronic inflammation and/or active inflammation).2. Diagnosis of spleen and stomach qi deficiency with damp-heat stasis syndrome, according to TCM syndrome differentiation.3. Aged between 18 and 65 years.4. Voluntary provision of written informed consent prior to enrollment.Exclusion criteria are:1. History of gastric surgery.2. Combined gastric ulcer, duodenal ulcer, special types of gastritis or gastrointestinal hemorrhage.3. Histopathological examination showing atrophic changes, intestinal metaplasia, dysplasia or suspected malignant changes in the gastric mucosa.4. Serious comorbidities of heart, lung, liver, kidney or blood system  and/or aspartate aminotransferase (AST) greater than 1.5 times the upper limit of normal, creatinine (Cr) greater than the upper limit of normal and so on) or having a life-threatening illness .5. Positive fecal occult blood test.6. Having received TCM or Western medicines to treat CNG in the last 2 weeks.7. Psychiatric disorders or a history of alcohol or drug abuse.8. Female patients preparing for a baby, pregnant or lactating.9. Allergic to the trial pills.10. Currently participating or enrolled in another drug trial over the last three months.11. Unclear TCM diagnosis of syndrome differentiation or too complicated SDs in TCM.12. Having been judged inappropriate to participate in the trial by investigators.Rejection criteria include:1. Misdiagnosis.2. The trial drug is taken at doses <80% or >120% of the requirement, or is not taken as directed.3. Patients do not cooperate or cannot complete follow-up.Withdrawal criteria include:1. Intolerance to worsening conditions.2. Quitting voluntarily.3. Having manifestations of hemorrhage of the digestive tract, such as melena or hematemesis during the study.4. Experiencing anaphylaxis following the trial drug’s administration.5. Adverse medical events occurring during the study, such as severe liver function damage, malignant tumors in other system, and accidental pregnancy or other reasons, as judged by the investigators, that might make the patient unlikely to complete the study.The study may be suspended early or terminated in the event of the following:1. Serious adverse event (SAE) caused by the trial drugs.2. The effect of the test drug is poor or even completely ineffective.3. Discovery of a blunder in the protocol or of a significant deviation between the protocol and actual practice4. The decision to terminate the study being made by the pharmaceutical supervisory and administrative department or by the sponsors, for any reason.Subjects will be permitted to continue concomitant treatment for comorbidities, such as hypertension, chronic bronchitis, stroke or skin disease, which will not affect the trial’s final results. However, they are forbidden to take any CM or Western medicine related to CNG, such as prokinetics, cholinergic agents, H2-receptor antagonists, proton pump inhibitors, mucosal-protective agents or antibiotics for the eradication of HP. Aspirin, nonsteroidal anti-inflammatory drugs, sedative hypnotics, antidepressants and opioids should be used sparingly. Each concomitant treatment should be documented strictly in the CRF, and once a subject is found to be taking forbidden drugs, he/she will be withdrawn from this study.The JWQTP and the dummy JWQTP will be manufactured by Anbang pharmaceutical Limited by Share Ltd, Hunan, China, with the approval of the CFDA for clinical studies only . Of note, the dummy JWQTP is not exactly the same as the test pill in color and smell. To make a blind test possible, all of the drugs are concealed in unified, sealed and opaque packages with the same labels that contain the drug name, the approval number of the pill, functions, usage, dosage, storage conditions, expiration dates for use and the manufacturer’s name. The drugs are administered by an independent clinical assistant in each center, who takes responsibility for the drug’s distribution, storage and return. Any members who have access to the drug will not participate in case observations or efficacy evaluations. Each package contains one dose (six 1-g pills) with a variable ratio between the real drug and the dummy drug, according to the intervention protocol. Patients will be randomized to a high-dose group, low-dose group or placebo control group, in which they will take 6 g real drugs, 4 g real drugs + 2 g dummy drugs or 6 g dummy drugs, respectively. All drugs will be taken orally with water before each meal three times a day for 8 weeks. A follow-up visit will be scheduled every 2 weeks after treatment. Patients who have not made a full recovery from CNG after the clinical study will receive conventional treatment. Details of the procedures and content are shown in Figure The eradication of epigastric pain is considered the primary outcome to evaluate therapeutic effects. The visual analogue scale (VAS) score  for epigastric pain was measured at every visit, ranging from 0 to 10, where a score of 0 suggests no epigastric pain and a score of 10 indicates the most severe epigastric pain. The eradication of epigastric pain is defined as a score of VAS that stops rising after dropping to 0 during the study. The eradication rate of epigastric pain will be compared among the three groups, together with the change in VAS scores before and after treatment in each group.The change in red plaques, hemorrhagic spots/plaques, erosion and bile reflux at endoscopy and the grade of active chronic inflammation and chronic inflammation in the gastric mucosa, depending on the histopathological examination of biopsy specimens, will be compared between visits one and six, according to the consensus on CG in China.The eradication rate of HP after treatment will be used to evaluate the effects of JWQTP.Guidelines for Clinical Research on Chinese New Herbal Medicines . In the symptom score system, the score of the primary symptom will be based on the severity, duration and frequency of the symptoms. Secondary symptoms will be scored by grading. The final point will be determined by the sum of all symptom scores. The CM therapeutic effect Index (CMTEI), as calculated with the following formula, will be used to evaluate treatment efficacy in the CM field.To evaluate the therapeutic effect in the CM field, the TCM symptom score system Table  will be The classification of treatment efficacy is shown as follows: CMTEI ≥95% indicates clinical recovery; 95% > CMTEI ≥70% indicates remarkable recovery; 70% > CMTEI ≥30% indicates modest recovery; and CMTEI < 30% indicates inefficiency.http://www.proqolid.org/) [Although the symptoms of chronic gastritis are not specific, the relief of clinical symptoms remains a major therapeutic aim. The patient-reported outcome (PRO) instrument for chronic gastrointestinal diseases (id.org/) , a 6-dimWe will perform the following tests on all subjects to screen for the JWQTP administration during the study: physical examination , complete blood cell count, urinalysis, stool examination, fecal occult blood test, liver function , serum total bilirubin (STB), and γ-glutamyl transpeptidase (γ-GT)), renal function  and electrocardiogram (ECG) at the first, fourth and sixth visits. In addition, a urine pregnancy test will be carried out for female patients of childbearing age Figure .The completed CRFs will be submitted to the statistical department after the inspections of the clinical investigators and trial inspectors for data entry and management. All data will be entered twice electronically using the EpiData3.1 database by two independent data managers to ensure data accuracy. The investigators will resolve any problems encountered by the data managers’ concerning the data as soon as possible. Then, the data managers will make corrections to the data, according to the investigators’ instructions. A blind review will be performed among the data managers, predominant investigator and sponsor to compile a report about the quality of data management. The database will be locked by the statistician, predominant investigator and sponsor after the blind review and confirmation of database accuracy. Then, the final trial dataset will be disclosed by an independent assistant according to the randomization list, where the data will be grouped into groups A, B or C, and an independent statistician will make statistical analysis using SAS 9.2 in a semi-blinded manner with no suggestion of the exact treatment allocation. Finally, the predominant investigator will write a conclusive report of the statistical analysis in an unblinded manner. Because there will be unified training prior to the study, regular supervisor’s visits, data review by the clinical investigators, revisions by the data managers and a blind review for the data after the study, no further data management committee will be set up to ensure the data’s accuracy and validity. Only the clinical investigators and trial inspector will have access to the medical records of the subjects, and they will all sign a confidentiality agreement. Anonymous data will be used for the inspection of the pharmaceutical supervisory and administrative department. Subjects’ medical records will be stored in the data archive of the drug clinical trial agency after analysis.The safety of subjects is of paramount importance during the study period, and every adverse event should be documented on the adverse event form (AEF) in great detail. Adverse events (AEs) include any new diseases and exacerbations of CNG or comorbidities related or unrelated to the treatment. Any fatal, life-threatening, disabling or event severe enough to warrant hospital admission or prolonged hospital stays occurring after any dose of treatment pill and at any time during this study should be considered an SAE. All of these data should be recorded on an AEF with the corresponding treatment and reported to the China Food and Drug Administration (CFDA), provincial-level Food and Drug Administration, sponsor and Independent Ethics Committee within 24 hours. Then, the sponsor will inform the other four sites as soon as possible. The severity of an AE is classified into three degrees: mild, moderate and severe. For the mild degree, a small amount of indisposition arises, which the subject can bear without any intervention and without influencing the trial. For the moderate degree, a moderate amount of indisposition develops, and some intervention should be taken to get the trial going. For the severe degree, an enormous amount of indisposition dictates that the subject should quit the trial for his or her own safety. In the case of an SAE, the investigator can break the blind to discover the subject’s treatment allocation by reading the emergency letter corresponding to the group allocation. Any AE related to the test drug will be treated for free. On a separate note, any subject with an intervention for AE must undertake a follow-up visit within half a month for his or her health.Based on the preliminary results of clinical research, no less than an estimated 55% total efficiency will be obtained with JWQTP treatment and approximately 30% will be obtained with the intervention of a placebo. Using a superiority test, no fewer than 66 subjects should be enrolled based on α = 0.05, β = 0.15 and power = 0.85 in each treatment group. Allowing for a 20% drop-out, we therefore propose the recruitment of a total sample size of 240 patients, with average distributions among the three groups.A full analysis set (FAS) is the primary analysis population for efficacy with an intention-to-treat principle. We estimate the missing data using the last observation carried forward (LOCF) method so that the population for the final analysis corresponds with that at the beginning of this study. The per-protocol set (PPS), in which all subjects enable themselves to finish the study according to the protocol, represents a subcardinal analysis population for efficacy. Descriptive statistics will be presented as the means, standard deviations, medians, minimum values and maximum values for continuous variables and as frequencies and percentages for categorical variables.An analysis of variance (ANOVA) or chi-square test will be used to compare baselines among patients, including demographic data, vital signs, history of diseases, basic treatment and so on. For the comparison of variations from the baseline to endpoint, Student’s t-test will be performed on variables with normal distributions, and the Wilcoxon rank sum test will be performed on variables with non-normal distributions. The evaluation of therapeutic effects will primarily be performed between baseline and visit six, in compliance with PPS, or the time to withdraw from the study, in compliance with FAS. In addition, the changes from baseline to visits two, three, four or five will be evaluated. For continuous variables regarding therapeutic effect, an ANOVA will be used for multiple comparisons of variation from baseline among different groups, and Dunnett’s tests will be used for comparisons within a group. A covariance analysis, adjusted for the baseline covariate, will be used to evaluate the differences of the symptom scores, VAS scores and PRO instrument scores among the groups considering the center effect. The least square mean in each group and the 95% confidence intervals of mean differences among groups will be calculated. The Cochran-Mantel-Haenszel test, stratified by center effect, and the logistic regression model, adjusted for covariates, will be used on categorical variables in addition to the chi-square test, Wilcoxon rank sum test or Fisher’s exact test. The total drop-out rate in each group will be compared with the drop-out rate due to AEs for drop-out analyses using chi-square test or Fisher’s exact test. For safety analyses, we will perform the chi-square test or Fisher’s exact test to evaluate the incidence rate of AEs among the groups and describe AEs using descriptive statistics through listing.All statistical tests will be performed by an independent statistician using SAS 9.2, assuming a two-sided test and a 0.05 level of significance.To date, CNG remains unclear and has no specific remedy. The presence or absence and severity of dyspepsia have no obvious correlations with the histopathological findings and endoscopic grading of CG . The theThis trial is preparing for recruitment of participants at the time of manuscript submission.Helicobacter pylori; JWQTP: Jian-Wei-Qu-Tong Pills; LOCF: last observation carried forward; PPS: per-protocol set; PRO: patient-reported outcome; SAE: serious adverse events; SD: syndrome differentiation; STB: serum total bilirubin; SSQDDSS: spleen and stomach qi deficiency with damp-heat stasis syndrome; TCM: traditional Chinese medicine; VAS: visual analog scale; γ-GT: γ-glutamyl transpeptidase.AE: adverse event; AEF: adverse event form; AIDS: acquired immunodeficiency syndrome; ALP: alkaline phosphatase; ALT: alanine aminotransferase; ANOVA: analysis of variance; AST: aspartate aminotransferase; CFDA: The China Food and Drug Administration; CG: chronic gastritis; CM: Chinese medicine; CMTEI: Chinese medicine therapeutic effect index; CNG: chronic non-atrophic gastritis; Cr: creatinine; CRF: case report form; ECG: electrocardiogram; FAS: full analysis set; HP: The authors declare that they have no competing interests.XX Z, WW C and QX participated in the planning, design and development of this trial. The trial will be performed under the careful supervision of QX, who will oversee the trial during the study. XX Z and WW C drafted the initial manuscript with equal contribution and should be considered co-first authors. RJ L, NS and PX contributed to the conception and design of the protocol and revised the manuscript critically for important intellectual content. BS and XN Y participated in the design and coordination of the study, as well as recruiting participants. All authors have reviewed and approved the final manuscript.


N lines, and fuzzy/linted seed line, F lines). Results showed that seed protein was higher in the fuzzy genotype in all sets, but seed oil was higher in fuzzless genotype in all sets. The concentrations of seed Ca and C were higher in all fuzzless genotypes, but N, S, B, Fe, and Zn were higher in most of the fuzzy genotypes. Generally, minerals were higher in leaves of F lines, suggesting the translocation of minerals from leaves to seeds was limited. The research demonstrated that fiber development could be involved in cottonseed composition. This may be due to the involvement of fiber development in carbon and nitrogen metabolism, and the mobility of nutrients from leaves (source) to seed (sink). This information is beneficial to breeders to consider fuzzless cottonseed for potential protein and oil use and select for higher oil or higher protein content, and to physiologists to further understand the mobility of minerals to increase the quality of cottonseed nutrition for food and feed.Cotton is an important crop in the world and is a major source of oil for human consumption and cotton meal for livestock. Cottonseed nutrition  determines the quality of seeds. Therefore, maintaining optimum levels of cottonseed nutrition is critical. Physiological and genetic mechanisms controlling the levels of these constituents in cottonseed are still largely unknown. Our previous research conducted under greenhouse conditions showed that seed and leaf nutrition differed between fuzzless and fuzzy seed isolines. Therefore, the objective of this research was to investigate the seed fuzz phenotype (trait) effects on seed protein, oil, N, C, S, and minerals in five sets of near-isogenic mutant cotton lines for seed fuzz in a 2-year experiment under field condition to evaluate the stability of the effect of the trait on seed nutrition. The isolines (genotypes) in each set differ for the seed fuzz trait (fuzzless/linted seed line,  Gossypium hirsutum (about 95% of the cultivated cotton), G. barbadense, G. arboreum, and G. herbaceum together (the last three represent about 5%)  is the predominant species commercially cultivated in the United States and produces two types of fiber on cottonseed, lint and fuzz. Lint fiber is economically valuable, and it is longer and develops faster than the fuzz  or n2n2  ; oil (such as C and N); carbohydrates ; metabolite synthesis ; integrity of cell membrane and cell wall structure (Ca and B); cell membrane, lipid synthesis, energy transfer and phosphorylation reactions, carbohydrate metabolism, and nutrient active uptake processes (P); and osmoregulation, stomatal closure, carbohydrate movement, and nutrient mobility (K). The physiological and biochemical roles of these nutrients in plant growth and development were previously reported  under field conditions. Our hypothesis was that because several metabolic processes including carbon metabolism and polysaccharide cell wall synthesis are involved in fiber development  747 F vs. SG 747 N; MD51ne F vs. MD51ne N; STV 7Agl F vs. STV 7Agl N; DP 5690 F vs. DP 5690 N; DES 119 F vs. DES 119 N. Genotype SA 243  was the fuzzless parent with the dominant fuzzless seed allele, 1N1N . Cotton bolls were harvested from 10 adjacent plants at three (2012) and four (2013) intervals to prevent the loss of fuzzless cottonseed content due to rain and wind. The harvest intervals were on 28 August, 6 September, and 27 September in 2012, and on 5 September, 12 September, 17 September, and 27 September in 2013. A defoliant was used prior to the last harvest date each year. Cottonseed samples were processed at the USDA ARS Cotton Ginning Laboratory at Stoneville, MS, USA and saw-ginned on 20 November 2012 and 12 November 2013. Cottonseed were collected and acid-delinted for seed composition analyses. Soil samples were taken across the field by dividing the field into four main sections and taking 20–25 samples from each section at depth of 30.5 cm. Therefore, one composite sample (combined 20–25 samples) represented each section. Analysis of the four samples, representing the four sections, showed uniformity in main soil nutrients. Therefore, the soil nutrients shown in here are average of the four sections representing the entire field. For leaf sampling, the most recent fully expanded leaves were taken from each plot. Fourteen leaves were taken from the middle two rows . Leaves were oven-dried at 65°C and ground into fine particle with Laboratory Mill 3600 . Seed and leaf C, N, K, Ca, Mn, and Zn were analyzed at the University of Georgia's Soil, Plant, and Water Laboratory, Athens, GA. Seed protein, oil, B, Fe, P, and leaf B, Fe, and P were analyzed as described below.A field experiment was conducted in 2012 and 2013 at Stoneville, MS, USA. Field management and growth conditions were previously detailed in Stetina et al. . Briefly−1 dwt.Boron concentrations in the most recently fully expanded leaves at boll stage and mature seeds were determined according to Lohse  using th−1 dwt.Iron concentrations in the most recently fully expanded leaves at boll stage and mature seeds were measured according to Bandemer and Schaible  and LoepPhosphorus concentrations in leaves and mature seeds were determined according to Cavell  using th3 in a microwave digestion system. The concentrations of minerals in the samples were determined using inductively coupled plasma spectrometry (ICP)   spectrometry . Protein and oil in cottonseed were analyzed by near infrared reflectance according to Wilcox and Shibles  and BellThis experiment was a part of a large experiment that was designed in a split-plot. The main plot was line (genotype), and plots were arranged in a randomized complete block design with 4 replications. The subplot was ginning method  compared with that of the main effect of year or line, the data were combined across the 2 years.ANOVA showed that year and line were the major sources of variability for seed composition constituents Table . Based ols Table , year waF) had higher concentrations of seed protein, N and S than lines with fuzzless seeds (N) (with exception of STV 7Agl N), but N lines had higher oil and C than in seeds of F lines  and Mn  did not follow the general trend of other nutrients of higher nutrient accumulation in F lines. Instead N did not differ between N and F lines in STV 7Agl, and Mn was higher in the N line for DP 5690, but did not differ between N and F lines in SG 747 and STV 7Agl. Except for Mn in DES 119, MD 51ne, and STV 7Agl, and Ca, P, and N for DP 5690, N and S and all minerals in leaves were higher in N lines than in F lines (Table F vs. N)   cultivars , planted at late April and late May, and under irrigated and non-irrigated (dryland) field conditions in Stoneville, MS, from 2005 to 2008. They found irrigation increased the concentrations of seed oil, but decreased seed protein. However, under dryland conditions, protein was higher than oil at late April and late May planting. Their results showed opposite trend between protein and oil, agreeing with the current results.The higher protein and lower oil concentrations in cottonseed may suggest there is a potential commercial use for fuzzless seed as a source for food (oil) and feed . Our results are in agreement with previous reports , cottonseed contained limited concentrations of B (<20 mg B kg−1). Soil used in our experiment had adequate B concentration (ranged from 1.5 to 2.0 mg kg−1) to support the crop. The limited mobility of B in cotton may be one reason of why cotton sometimes responds to foliar B application. Dordas  to soil moisture resulted from rainfall or higher temperatures and their effects on nutrients uptake and transport. Therefore, we cannot exclude the effect of weather conditions on seed nutrients accumulation in F and N genotypes or on genotypes in the two sets of isolines. Further research is needed to determine the response of F and N genotypes to growing conditions such as drought and heat under field conditions.Nutrient uptake, translocation, redistribution, and accumulation are processes controlling the accumulation of minerals in seeds  in seeds of some of the F lines could be due to limited mobility of the nutrients from leaves to seed and lower nutrients demand by seeds of these N line, resulting in higher accumulation of nutrients in leaves. Some N lines did not follow this pattern, and this could be due to genotypic differences and fuzz trait. The real mechanism of how the fuzz development is involved in differential nutrients between N and F lines are still not understood  to seed (sink). This information is beneficial to breeders for selection for higher oil or higher protein content, and to physiologist to further understand the mechanisms of mineral movement within plants. Understanding the mechanisms of nutrient mobility from leaves to seed would help for selecting for cottonseed with higher nutritional quality for human consumption and animal feed.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Breast cancer is the second largest disease affecting women worldwide. It remains the most frequently reported and leading cause of death among women in both developed and developing countries. Tamoxifen and raloxifene are commonly used selective estrogen receptor modulators for treatment of breast cancer in women with high risk, although resistance occurs by tamoxifen after 5 years of therapy and both drugs cause uterine cancer and thromboembolic events. Aromatase inhibitors (AIs) are one of the optional modes used for breast cancer treatment. The combination of AIs along with tamoxifen can also be beneficial. Various therapeutic agents from different sources are being studied, which further need to be improved for potential outcome. For this, clinical trials based on large number of patients with optimal dose and lesser side effects have to be more in practice. Despite the clinical trials going on, there is need of better molecular models, which can identify high risk population, new agents with better benefit having less side effects, and improved biomarkers for treating breast cancer. Breast cancer is the second leading cause of death in the female population worldwide. Each year, 200,000 new cases of invasive breast cancer are diagnosed . Breast Genetics has an important role in breast cancer. In about <5% of cases, breast–ovarian cancer syndrome occurs by inheritance including women having BRCA1 and BRCA2 mutation. The 90% of total genetics account to these mutations with a breast cancer risk of 60–80% affected cases. BRCA1 mutations predispose women to breast and ovarian cancers. BRCA1 in breast cancer has higher aneuploidy number than tumors, which do not have mutations in BRCA1 , 8. The The growth and differentiation of a cell is controlled by a regulated cell cycle. If there is uncontrolled proliferation of cells, it leads to cancer. This results in abnormal functioning of tissues, organ system in an organism. The cell cycle has checkpoints, which check the entry of cell from one phase to another phase and whether the functions are completed in each phase or not. These checkpoints are controlled by genes, which help in stimulating or inhibiting the cell division. These are proto-oncogenes and tumor suppressor genes. The cell cycle-dependent kinases are regulated by cyclins present in a cell and are required for cell division. They are regulated by CDK inhibitors, such as INK4 proteins and p21 and p27 of Cip and Kip family. The deregulation of CDKs results in uncontrolled proliferation and genomic defects in DNA repair mechanisms and DNA damage checkpoints and chromosomal instability. Mitotic checkpoints and DNA damage alterations cause increase in function of CDK, which leads to initiation of tumor. The cell cycle regulatory signals are not controlled as in a normal process of cell cycle. This leads to deregulated cell cycle, mutations, and genetic abnormalities .Epidermal growth factor receptor is from ErbB class of tyrosine kinase cell surface-based receptor including HER2, neu, or ErbB2 . The epiH2AFX is the genes coding histone H2A protein. The H2A, H2B, H3, and H4 are histone proteins present in two copies and form a histone octamer. The DNA is wrapped around these histones and forms nucleosome. DNA damage response is activated upon DNA damage in cells. Double-strand breaks activate phosphorylation of histone variant H2AX, which repairs DNA by activating proteins at damaged chromatin and at checkpoints arresting cell cycle. γ-H2AX helps to develop cancer therapies , 16, 17.PARP1 is a protein which repairs single-strand breaks in the DNA. PARP1 is also involved in differentiation, proliferation, and tumor transformation . It decrTumor suppressor protein, p53 is encoded by the TP53 gene in humans, which functions to inhibit cell proliferation to regulate cell cycle. It is known as the guardian of the genome as it maintains the cellular stability by preventing genetic mutation. In normal cells, low level of p53 is maintained by continuous degradation via Mdm-2, which is an ubiquitin ligase. The p53 activation occurs when there is a cellular stresses, such as DNA damage , phosphoc is released, apoptosis occurs, and stimulation of caspases leads to cell death resulting in stimulation of c-Jun N-terminal kinases (JNKs). JNK phosphorylates and downregulates the Bcl-2 and Bcl-XL, anti-apoptotic proteins. This leads to damage to mitochondrial membrane (Reactive oxygen species (ROS) contain oxygen reacting molecules and regulate cell signaling and homeostasis . It is gmembrane . The molmembrane .The upcoming studies are in practice based on whole genome arrays collection from patients, such as next-generation sequencing (NGS). Ion torrent sequencing is used for cancer DNA sequencing, which is less expensive . DNA and−) occurring in stages 2–4. The chemotherapeutic drugs are given in combinations for about a period of 3–6 months. One combination is known as AC, which is combination of cyclophosphamide with doxorubicin (adriamycin) (Chemotherapy is used in ER-negative breast cancer (ERiamycin) . Anotheriamycin) . CMF is iamycin) .HER2 is a tyrosine kinase-based cell receptor of epidermal growth factor group, which is overexpressed in some of the breast cancer cells. In breast cancer, the disease recurs and has less prognosis in about 25–30% cases where HER2 gene and its protein is overexpressed . As an aHormones are naturally occurring substances in the body whose function is to work as chemical messengers. There are various approaches, which have been used to treat hormone responsive breast cancer.Ovaries are the primary source of estrogen in premenopausal women. By eliminating or suppressing ovarian function, estrogen levels are reduced. Ovarian function when inhibited is called as ovarian ablation. It is permanent in which ovaries are removed called as oophorectomy or by treating with surgery and radiation. Another method is suppression of ovaries with drugs, which is not a permanent treatment and is called as gonadotropin (GnRH) or luteinizing hormone releasing hormone (LH-RH) agonists. They inhibit the ovaries to produce estrogen and prevents stimulus from the pituitary gland. The U.S. Food and Drug Administration has approved drugs for ovarian ablation, which are goserelin and leuprolide .In breast cells, estrogen helps in cell growth. Estrogen is made in the ovaries and tissues by aromatase enzyme. Estrogen binds to ER on the surface of cell. ERs reside on the surface, in cytoplasm, and in nucleus. When estrogen molecules are not present, these receptors are inactive but once the estrogen molecule enters cell, the estrogen binds to its receptors causing change in conformation of receptor. ER complex binds at their DNA-binding sites called as estrogen response elements. As a neoadjuvant therapy, drugs are used to inhibit the function of an enzyme called aromatase. They are given in postmenopausal women. The drug is used in combination in order to suppress ovarian function, as ovaries produce more aromatase and cannot be blocked by inhibitors in premenopausal women . AnastroThere are various drugs which intervene with estrogen action to activate the growth of breast cancer cells. SERMs are agents modulating function of estrogen in tissues. ERs are activated or inhibited in different tissues. The function of SERMs varies in different tissues depending on chemical structure of selective estrogen receptor modulator (SERM) as an antagonist in breast tissue and agonist in other tissues, such as bone and uterus. Tamoxifen in breast functions as an antagonist and in uterus as agonist. It has been found that the amount of co-activator 1 (SRC-1 and NCOA1) is in excess amount in uterus as compared to breast. Raloxifene in both acts as an antagonist. It has been found that raloxifene potentially enlists co-repressor proteins and in uterus acts as an antagonist. The three main drugs that act SERMs are tamoxifen (Nolvadex), raloxifene (Evista), and toremifene (Fareston) . Other aAromatase inhibitors are used to inhibit endogenous formation of estrogen from androgens. These act by inhibiting the function of the aromatase enzyme complex, which catalyzes this conversion . The actNatural compounds have been used in treatment of breast cancer, for example, luteolin in herbs, such as thyme, parsley, and vegetables, such as celery and broccolis, are used in women who have taken hormone replacement therapy. Luteolin reduces vessels feeding cancer cells. In another study, chemical nutrients were tested in broccoli, grapes, apples, tofu, and turmeric root . The comThere are various other agents which are used in combination with tamoxifen in breast cancer. Some of the agents are mentioned in Table Antiestrogen and estrogen therapies are developed with better outcome by finding out markers which can differentiate between Phases I and II breast cancer to overcome resistivity of different sets of drug. Anticancerous drugs are given in high doses, assumed on the basis of population studies. The pharmacological approach which decides the nature and mode of action of chemotherapy is in need of standardization of dose and response to a drug with better efficiency and less toxicity. A set of new biomarkers for breast cancer are needed to improve risk factors. Clinical trials need to be done in population having high risk with large samples and longer follow-up. The side effects and dose is needed to evaluate for different set of population having diversity. The chemoprevention and other therapeutic agents can be improved by keeping in mind above factors by physicians, oncologists, and patients. There is a need of molecular models for identification of high risk factors to identify new agents with more benefit ratio and less toxicity as a drug development program. Various approaches, such as improved clinical trials, combinatorial approach of different drugs, gene expression studies, and pharmacokinetics, will benefit right patients with right kind of drugs.SA: draft and writing, design, concept, editing; NM: design, concept, editing and approved; HC: draft and writing; MR: editing; PNP: editing; MAK: editing; MM: writing; GAS: writing; JJ: editing; AA: writing; MSJ: design, concept, editing, and approved.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The aim of the present study was to evaluate the relationship between BMI and tooth decay in a population of Iranian children. In this cross-sectional descriptive/analytical study, 1482 children were selected from kindergartens and preschool centers in Kerman, Iran. The children underwent examination of deciduous teeth (using the dmft index) after determination of height and weight for calculation of BMI. The relationship between BMI (after adjustment for age) and dmft was determined using Poisson's regression model. The mean of dmft in children with normal BMI was 1.5-fold that in subjects with extra body weight. Age had a significant effect on dmft. In addition, dmft was higher in boys compared to girls. The results of the present study showed that caries rate in the deciduous teeth of 3–6-year-old children decreases with an increase in body weight. Obesity is the result of chronic inconsistency between the intake and expenditure of energy. Studies have shown that the majority of children are overweight due to the intake of low-density foods instead of fruits and vegetables and also due to high-fat and high-carbohydrate foods and a sedentary life style; in addition, some socioeconomic factors are involved. Obesity consists of an exceedingly complex group of diseases and probably should be characterized as a syndrome. The etiologies that contribute to obesity and can be modified by physicians include dietary and exercise patterns, endocrine and metabolic diseases, genetic factors, environmental factors, familial and ethnic factors, stress, drugs, and abnormal regulation of body weight or body fat –4. DurinTo our knowledge no studies have so far been carried out in this respect in Iranian preschool children and also since there are contradictions in the results of studies carried out elsewhere in the world, the present study was undertaken to evaluate the relationship between the deciduous tooth decay and BMI in a population of 3–6-year-old Iranian children.P = 0.05, confidence coefficient 99%). The inclusion criteria were 3 years of age and full eruption of deciduous teeth (20 teeth). Children with conditions affecting body weight or tooth decay, including diabetes, hyperthyroidism, hypothyroidism, malignancies, and renal diseases, and those who had permanent teeth other than the first molars in the oral cavity were excluded from the study.The present cross-sectional descriptive/analytical study was carried out by clinical examination and the questionnaires were completed by an examiner. The subjects consisted of 3–6-year-old children in 23 kindergartens and preschool centers in Kerman, south east of Iran, in 2009-2010. Data were collected through clinical oral examinations, anthropometric measures, and structured questionnaires in order to assess socioeconomic conditions (level of education and job). A total of 1482 children were examined and data associated with different socioeconomic parameters were determined in 763 of the subjects. The sample size was estimated according to prior studies  wall measuring tape. A Microlife digital weighting machine (Japan) was used to determine children's weight while they were wearing light cloths without any shoes. Body max index (BMI) was calculated using this formula:BMI percentile of <5 for age: weight under normal,BMI percentile of ≥5 or <85: normal,BMI percentile of ≥85 or <95: at risk for obesity, BMI percentile >95: obese.A special form was completed for each child, which included personal data, age, gender, height, weight, and phone number. In subjects in whom the socioeconomic status was evaluated, the educational status of parents, parents' occupations, and the number of family members were also recorded in the form. BMI percentile was determined using standard tables based on age and gender. BMI was classified as follows , 7, 15:BP ≤ 0.05. The rate ratios (RR) and 95% confidence intervals were reported in relation to Poisson's model corresponding to dmft index. Data were analyzed using SPSS 16.In the next stage, the teeth were examined for caries, restorations, and extractions based on dmft using a disposable dental mirror under 100 W light based on criteria proposed by the WHO. A postgraduate student of pediatric dentistry, who had been trained for one week in the Department of Pediatric Dentistry in the Faculty by a trained assistant before examination, carried out all the procedural steps and calculations. The examiner was tested until intraexamination error decreased. Based on the study protocol, the WHO definition was used to diagnose caries and in determining decayed teeth (dt) the following clinical forms were considered carious lesion: white spots, a discolored area or an area with a rough surface; teeth with temporary dressings; and teeth with any form of restorative material with signs of recurrent carries , 16. Fre d, m, and  f components of dmft separately based on the age groups. Poisson's regression model showed that after adjustment for age, BMI had a significant effect on children's dmft (P = 0.0001), with an inverse relationship between these two variables. On the whole, the mean of dmft for children with normal BMI was 1.5-fold higher than that in children who were overweight. In addition, age had a significant effect on dmft (P = 0.0001). In this context, with a one-year increase in age, the mean of dmft was 1.3-fold higher (P = 0.7), mothers' educational status (P = 0.26), and fathers' occupation (P = 0.5) on children's dmft. However, some other variables, including fathers' educational status and mothers' occupation, had a significant effect on children's dmft (P = 0.0001). In this context, the mean of dmft in boys was 1.19-fold that in girls  were in the 3-4 age range, 451 (30.4%) were in the 4-5 age range, and 774 (52.2%) were in the 5-6 age range .  Table d higher . Variousn's dmft . In addiin girls . The preThe incidence of tooth decay is on the increase among Iranian children and adolescents. Azizi et al. reported a prevalence of 20.8% for obesity in 3–9-year-old children in Iran based on BMI. In addition, the prevalence of dmft in 3–9-year-old Iranian children was reported to be 1.9–3.6 . The relThe results showed a significant effect of BMI on children's dmft, with an inverse relationship between these two variables, consistent with the results of different studies carried out , 18–20. The reasons for the discrepancies between the results of various studies might be evaluated from different aspects as follows.Subjects' Age. The results of the present study showed that age has a significant effect on dmft; in other words, the mean dmft of children increases 1.5 times with a one-year increase in age: the mean of dmft increases by 32% with one-year increase in age. The majority of these studies have been carried out on subjects over 6 years of age [s of age , 25, 26.The recent international growth reference, The WHO Child Growth Standards Reference, is used to evaluate nutritional status. This growth reference is recommended for young children from birth to 5 years and provides a scientifically reliable yardstick of children's growth achieved under desirable health and nutritional conditions and establishes the breastfed infant as the normative model against which all alternative feeding methods must be measured in terms of growth, health, and development; however it was not recommended for the present study due to children's age .Tooth Decay and Obesity. Tooth decay and obesity are both considered multifactorial entities with predisposing genetic and environmental conditions and it is not possible to designate them as separate diseased conditions. In addition to the diet, some of the confounding factors involved in tooth decay are oral microflora, age, use of fluoride, and socioeconomic status. The effects of all these factors have not been evaluated in any study to date. Children who are underweight are more susceptible to infectious diseases such as tooth decay due to compromised immune system. In addition, families with children who are prone to obesity take greater care of their children's diet and provide them with less sweets and desserts, resulting in a low-caries prevalence in these children. The results of a study in Turkey (2011) showed that BMI increases in underweight children after receiving dental services [services . Althougservices , 29, 30.The results of the present study in subjects whose socioeconomic conditions were available showed that variables such as father's educational status and mother's occupation had a significant effect on children's dmft. Mother's occupation significantly altered caries status and children of mothers with better occupations experienced less caries; comparable results have been observed in previous studies –33. FathMarshall et al. (2007) reported that low socioeconomic status results in an increase in the incidence of caries and obesity. In addition, the results of a study by Cinar and Murtomaa (2011) in Turkey showed that higher dmft rates in children are associated with the parents' low socioeconomic status , 28–35. The present study showed that caries rate in the deciduous teeth of 3–6-year-old children decreases with an increase in body weight. On the whole, the mean of dmft for children with normal BMI was 1.5-fold that of children who were overweight.Since tooth decay and obesity are multifactorial conditions and their relationship with individuals' nutritional habits has been established, the triad of sugar, tooth decay, and obesity should be evaluated in various studies. Therefore, despite an inverse relationship between tooth decay and BMI in the present study, prevention of tooth decay and obesity should be considered more than ever; in addition, the 3-day analysis of the diet in children should be considered in future studies. And also, no cause–effect relationship can be deduced from a cross-sectional design study such as this one. Longitudinal designs would increase the knowledge on the determinants of dental caries.


Diabetes in pregnancy carries an increased risk of adverse pregnancy outcomes for both the mother and foetus, but it also provides an excellent early opportunity for intervention in the life course for both mother and baby. In the context of the escalating epidemic of chronic diseases among Indigenous Australians, it is vital that this risk is reduced as early as possible in the life course of the individual. The aims of the PANDORA Study are to: (i) accurately assess rates of diabetes in pregnancy in the Northern Territory (NT) of Australia, where 38% of babies are born to Indigenous mothers; (ii) assess demographic, clinical, biochemical, anthropometric, socioeconomic and early life development factors that may contribute to key maternal and neonatal birth outcomes associated with diabetes in pregnancy; and (iii) monitor relevant post-partum clinical outcomes for both the mothers and their babies.Eligible participants are all NT women with diabetes in pregnancy aged 16 years and over. Information collected includes: standard antenatal clinical information, diagnosis and management of diabetes in pregnancy, socio-economic status, standard clinical birth information . Cord blood is collected at the time of delivery and detailed neonatal anthropometric measurements performed within 72 hours of birth. Information will also be collected regarding maternal post-partum glucose tolerance and cardio-metabolic risk factor status, breastfeeding and growth of the baby up to 2 years post-partum in the first instance.This study will accurately document rates and outcomes of diabetes in pregnancy in the NT of Australia, including the high-risk Indigenous Australian population. The results of this study should contribute to policy and clinical guidelines with the goal of reducing the future risk of obesity and diabetes in both mothers and their offspring. In order to address the escalating epidemic of chronic diseases among Indigenous Australians [The antecedents of non-communicable diseases are early in life, beginning tralians , we needDiabetes in pregnancy includes gestational diabetes mellitus (GDM) and pre-existing diabetes (type 1 and type 2) in pregnancy. Rates of both pre-existing diabetes in pregnancy and GDM are higher in Indigenous Australian women compared to the general Australian population despite a younger age of giving birth . ParticuLarge international studies have reported the adverse perinatal and obstetric outcomes associated with hyperglycaemia in pregnancy  and the 2[We have developed a partnership between researchers, health care providers and policy organisations in the Northern Territory (NT), Australia, to address the issue of DIP in the high-risk population of the NT. The partnership includes a detailed research component: Pregnancy And Neonatal Diabetes Outcomes in Remote Australia – The PANDORA Study. The NT covers a large geographical area (1.35 million square kilometres), but has a relatively small population , with a population density of 0.2 people/km2. From 202.The aims of The PANDORA Study are:1) To accurately assess the rates of diabetes in pregnancy in the Northern Territory, Australia.2) To report demographic, clinical, biochemical, anthropometric and socioeconomic factors that may contribute to key maternal and neonatal outcomes associated with DIP in the NT.3) To monitor relevant clinical outcomes for both the mothers and their babies, and provide reliable information around future health risk for the NT.This study will be the research arm of the larger NT DIP Partnership Program. The NT DIP Partnership aims to: (i) improve systems and service delivery for all women in the NT with DIP, in order to improve outcomes for mother and baby; (ii) reduce the gap between evidence and practice in relation to screening, management and post-partum follow-up of women with DIP and their baby; (iii) establish systems that enable close monitoring of relevant clinical outcomes for mothers and babies. These aims will be achieved by: (i) establishing an NT DIP clinical register; (ii) developing and evaluating an appropriate model of care for DIP; (iii) instituting early universal detection of DIP; (iv) enhancing capacity of health care professionals in identifying and managing DIP; and (v) delivering a detailed research component to accurately assess antenatal characteristics and neonatal outcomes of DIP. The research component is The PANDORA Study and is described here.Participants will be residents of the Northern Territory, Australia. Participation in the study is facilitated through the following hospitals, Royal Darwin Hospital, Katherine District Hospital, Gove District Hospital, Alice Springs Hospital, Tennant Creek Hospital; Aboriginal Medical Services, Danila Dilba Health Services, Bagot Community Health Centre, Wurli Wurlinjang, Sunrise Health Service Aboriginal Cooperation, Miwatj Health Aboriginal Corporation, Central Australian Aboriginal Congress, Anyinginyi Health Aboriginal Corporation, Pintubi Homelands, Ampilatawatja Health Care Centre, Nganampa Health Council, Amoonguna; and health facilities, Healthy Living NT and NT Department of Health remote. Consultation with other Aboriginal Medical Services in the NT regarding their participation in the study is ongoing.Potential participants will be all NT women (Indigenous and non-Indigenous) with any type of diabetes in pregnancy . Participants are aged 16 years and above, from urban, rural and remote regions of the NT. A NT DIP Clinical Register was established in 2011–2012 as part of the larger NT DIP Partnership Program. Women with DIP from the NT are referred to the register and information maintained for clinical use by both specialist and primary health care teams. The register data are collected primarily by the senior diabetes nurse educators at Royal Darwin Hospital and Alice Springs Hospital, with additional referrals received from diabetes nurse educators at other sites, including Healthy Living NT, Katherine District Hospital and Gove District Hospital. Once the woman is in contact with either the specialist team or the research team, they are invited to participate in the research study (PANDORA).Major funding is provided by the National Health and Medical Research Council of Australia (NHMRC Partnership Project Grant #1032116). Additional support (including pilot funding) was received from NHMRC Program Grant #631947.The study is approved by the joint Menzies School of Health Research – Northern Territory Department of Health Human Research Ethics Committee, including the Aboriginal sub-committee. The study is also approved by the Central Australian Human Research Ethics Committee.Six research staff are employed over the course of the study. Two post-graduate research students are participating in the study and are substantially involved in data collection. All research staff members have prior health qualifications and experience: all are registered nurses, of whom two are also diabetes educators, and four are midwives. The post-graduate research students are a specialist endocrinologist and a paediatric endocrinologist.The Partnership involves considerable in-kind contribution from all partners: NT Department of Health, AMSANT, Baker IDI and Healthy Living NT .Potential participants have face-to-face discussion with a study staff member, are provided with visually enhanced written information about the study and given an opportunity to ask questions. An interpreter is employed to explain study information when required. Those who indicate interest in participating are then asked to complete written consent. Consent is obtained using the NHMRC Guidelines for Ethical Conduct in Aboriginal and Torres Strait Islander Health Research. All participants are informed that their participation is voluntary, that they can refuse or withdraw from participating, they need give no reason or justification for their decision to withdraw, and that it would not affect their medical care. A parent or guardian is asked to sign the form in addition to the participant if the participant is under 18 years old. Participants are asked to give separate consent for various elements of the study, including cord blood collection, baby body measurements, questionnaire and collecting further information from their medical records. They are informed that their cord blood samples will be stored at Menzies School of Health Research for 25 years and asked whether their cord blood samples could be used for future studies related to diabetes and cardiovascular disease.The diagnosis of GDM is based on the Australian Diabetes in Pregnancy Society (ADIPS) guidelines, which changed during the course of The PANDORA Study. Prior to 2012, guidelines were that all pregnant women be screened routinely for GDM at 24–28 weeks gestation with a 50 g glucose challenge test (GCT). A positive cut-off value after 1 hr in GCT was 7.8 mmol/L plasma glucose for the 50 g load. Women with a positive GCT proceeded to have a fasting 75 g oral glucose tolerance test (OGTT) for which the diagnostic criteria was one or more of the following values: fasting glucose ≥ 5.5 mmol/L or 2-h plasma glucose ≥ 8.0 mmol/L . From 20Once written consent is attained for the research study, the relevant clinical information for participants is transferred from the clinical register to the research study database. The following information is collected:(i) Antenatal data collected by the clinical team:a. Assessment of antenatal health: weight (in first and late third trimester), height, blood pressure, gravidity and parity, oral glucose tolerance test, HbA1c (when done), haemoglobin, serum creatinine, urine albumin-creatinine ratio, type of diabetes in pregnancy , estimated date of delivery (ultrasound)b. Additional standard antenatal care data is collected by the clinical team, and collated peri-partum by the research team: management of DIP , other medications, antenatal incidence of maternal hypoglycaemia (mild/severe), hospitalisation before delivery, other comorbidities, obstetric antenatal complications , antenatal mode of care and specialist involvement, vitamin D status, physical activity, dietary habits and Edinburgh depression scale score .(ii) Further antenatal data collected by the research team:a. Assessment of socio-economic status and related personal details by questionnaire: age, contact details, hospital record number, maternal and paternal ethnicity, first language, language spoken at home, ethnicity of maternal and paternal grandparents for Aboriginal and Torres Strait Islander participants, income source, ever worked, employment status, education level, housing tenure, landlord type , self-reported pre-pregnancy weight, pre-conception medication and pre-conception care.b. Medical history and medications- self report and from medical records (where available) including assessment of cigarette smoking, use of pituri (chewing of wild tobacco plants), tobacco chewing, alcohol and other recreational drugs used during pregnancy, past medical history and supplements/medications during pregnancy, maternal and paternal family history of diabetes.c. Maternal obstetric information: hypertension, pre-eclampsia, eclampsia, ultrasound scan of morphology, number of ultrasound scans for growth assessment.d. Additional questionnaires to assess stress and depression were performed in a sub-study of participants: Patient Health Questionnaire 9 (PHQ9) and adapted PHQ9 (iii) Postnatal data collected by the research teama. Neonatal information: location, birth date and time, birth outcome, time to first breastfeed, APGAR Score, shoulder dystocia, neonatal obstetric trauma, severe adverse event , major and minor congenital malformation, admission and length of stay to special care nursery, neonatal hypoglycaemia, hyperbilirubinaemia, phototherapy, exchange transfusion, hypoxic ischaemic encephalopathy, neonatal hypocalcaemia, meconium aspiration, respiratory distress, gestational age at delivery. Congenital malformations defined as: structural abnormalities detected prior to birth by ultrasound or at or soon after birth by clinical examination, X-ray, or ultrasound and, in the event of neonatal or perinatal death, by autopsy; and classified as major if fatal, potentially life threatening, likely to lead to serious handicap, or likely to lead to major cosmetic defect.b. Maternal obstetric information: mode of delivery, labour complications , need and reason for induction of labour, indication for caesarean or operative vaginal delivery.c. At discharge: breastfeeding at discharge, type of contraception planned, medications.(iv) Neonatal anthropometric measurements performed by the research team: neonates have anthropometric measurements completed within 72 hours of birth. If measurements are unable to be performed within 72 hours of birth, they may be performed up to 120 hours of birth and recorded as such. Neonatal anthropometric measurements are conducted with a calibrated scale for weight , a measuring board for length , Holtain calipers  for skin fold measurements, a measuring tape for circumferences, and a metal anthropometer (Scientific Martin Pelvimeter) for limb length. All limb and skin fold measures are made on the left side, except when the left limb is unavailable for access (eg the neonate had intravenous therapy in the left arm). For all measurements, the mean of the two measurements was used, unless a third measurement was taken (if the two measures differed by more than the prescribed amount). When a third measurement was taken, if two of three measurements differed by less than the pre-specified amount, the mean of those two was used, otherwise the mean of all three was used .a. A bare weight is obtained on a calibrated scale, and recorded to the nearest 5 gram. This procedure is repeated and recorded twice. A third measurement is performed if the first two measurements are not within 10 grams of each other.b. Length is obtained on a standardized plastic length board and recorded in centimetres. The infant is positioned on its back so that the vertebrae touch the base of the length board. The crown of the head lies against the vertical end of the length board. Keeping the infant’s head in the proper position, the examiner uses the thumb of his/her left hand and firmly presses the infant’s chest into the base of the length board to ensure that the spine is straight. The examiner then uses his/her right hand to extend the legs straight. When the infant’s body is positioned properly, the examiner measures the length with the movable foot board attached to the length board. Lengths are obtained and recorded to the nearest 0.1 cm at least twice. If lengths differ by more than 0.5 cm, a third length is taken and recorded.c. Circumference of the head is measured with a measuring tape, including the occipital protuberance, measured while the baby is quiet.d. Skinfold thickness assessment is performed at 3 sites. Study staff were trained by a Clinical and Data Coordinating Centre Staff member of the Hyperglycaemia and Adverse Pregnancy Outcomes (HAPO) Study, using the HAPO video and methods ,23. The e. The following additional body composition measures are performed in a detailed body-composition sub-study of the larger PANDORA Study:– Skin fold thickness assessment is performed at 2 additional sites: thigh and abdomen . The thi– Circumferences of the chest (across the nipple line), abdomen at the liver and umbilicus, and mid-portion of the upper and lower extremities are measured with a measuring tape.– Lengths of the upper and lower limbs are determined with a metal anthropometer.(v) Cord blood collection:A specimen of cord blood is obtained from all neonates born to the study participants for analysis of glucose, C-peptide, lipids, C-reactive protein, interleukin-6, adiponectin and leptin. The specimen is obtained by free drainage (free flow) of cord blood or drawn by needle aspiration (puncture) from a clamped segment of an umbilical vein. The specimen is stored in a foam cooler for transport to the hospital laboratory.(vi) Maternal follow-up information collected by research team:Six week post partum oral glucose tolerance test results for women with gestational diabetes, rates and duration of breast feeding, assessment at 24 months of metabolic and cardiovascular risk , use and mode of contraception, cigarette smoking, weight, medications, subsequent pregnancy.(vii) Follow up of baby:Any fatal event, identification of congenital abnormalities beyond birth, significant medical diagnoses, hospitalisation, growth at 1, 2,4, 6–8 and 15–18 months in the first instance. Additional funding will be sought for follow-up of the baby and mother beyond that detailed above.Collected cord blood samples are centrifuged for 10 minutes at 3000 revolutions per minute within 1–2 hours of collection. The time between collection and centrifugation is noted for all cord blood samples. Following centrifugation, plasma is divided from the blood tube ensuring no cells are transferred to sample vials.Vials are transported on ice for storage in -70°C freezers. Analysis of glucose and lipids are performed at each centre as outlined in Table All NT women with DIP, estimated to be 250–300 women/year, are eligible for the study with the exception of those aged <16 years. We expect that approximately 60% of these women will consent to the research study. Consent of participants for PANDORA commenced in November 2011 and is expected to continue until 2015. The estimated number of participants is at least 700 women.At the time of data collection, data is collected on paper forms and then entered into a Microsoft Access database. Data from each site is stored securely at Menzies School of Health Research (Darwin) or Baker IDI (Alice Springs). All statistical analysis will be performed using the latest available release of Stata software . Rates of diabetes in pregnancy (in NT and for Indigenous babies in NT) will be calculated using the denominators of all NT births and all births in the NT with Indigenous mothers . Analysis will be performed for summary statistics of rates of diabetes in pregnancy ; antenatal characteristics of women with DIP ; clinical management of DIP . Bivariate and multivariate associations will be determined for demographic, clinical , biochemical (including cord blood) and socioeconomic variables with the following key neonatal and maternal outcome variables: birth weight, gestational age, large for gestational age, neonatal hyperinsulinaemia (cord blood C-peptide >90th centile), neonatal adiposity , pre-eclampsia, birth injury/complication, adverse labour events, delivery mode and breastfeeding rates . Analyses will be performed for the whole group and stratified by ethnic group. After determining bivariate associations between variables (using Spearman correlations for continuous variables and two-tailed t-tests for dichotomous variables), risk factors will be selected for entry into logistic regression models using the backward selection method, the outcome variables being the end-points outlined above.The aims of the NT Diabetes in Pregnancy Partnership are to improve clinical care and outcomes of DIP in the NT, and to improve future health outcomes for both the mother and her baby through an integrated, multi-faceted approach. This includes a detailed research component, outlined above: the PANDORA Study. This study should provide answers to three key questions: (i) rates of diabetes in pregnancy in the NT, including the high risk Indigenous Australian population of remote and urban NT; (ii) demographic, clinical, biochemical, anthropometric and socioeconomic factors that may contribute to key maternal and neonatal outcomes associated with diabetes in pregnancy; and (iii) relevant clinical outcomes for mothers with DIP and their babies. The results of this study should contribute to policy and clinical practice guidelines of management of DIP and follow-up of mother and baby.The study includes detailed neonatal anthropometric measurements performed using skinfold measurements, limb lengths and body circumferences in order to accurately assess neonatal body fat. This method has been well validated and is reproducible ,25 with The study is likely to also inform the design of future work to reduce risk of future obesity, diabetes and cardiovascular disease in both the mothers and babies. Although better glycaemic management of pregnant women has been shown to reduce the rate of maternal and neonatal adverse outcomes in the short term ; to dateIn conclusion, the NT Diabetes in Pregnancy Partnership and PANDORA Study will have significance for policy and planning in the NT, as well as in other urban, rural and remote regions of Australia. Efforts to reduce risk as early as possible in the life course are crucial in order to reduce the gap between Indigenous and non-Indigenous health outcomes in Australia.All authors declare that they have no competing interests.LMB drove the design of the study protocol for funding and ethics applications, coordinated data collection and data management, and drafted the manuscript. LMB and AB initiated the study concept, design and partnership. AB, CC, JO, HDM, EM, JS, PZ, KOD provided important intellectual input into the study design, funding application and revision of the manuscript. CW, MK and SS contributed to project management, data collection, data management and revision of the manuscript. IL, DL, GD, S Corpus, PvD contributed to data collection and revision of the manuscript. S Chitturi, SE, MS, MH, CI, KD, MD, RL, JB, SS contributed intellectual input to the study design and revision of the manuscript. All authors were involved in revising the manuscript for important intellectual content and read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2393/13/221/prepub


Permission was not sought for listing Jennifer Johnson in the Acknowledgments for this article, and as a result, her name should not have been listed. We issue this Correction to update the Acknowledgments section, which should read as below:“We would like to acknowledge the Yukon-Kuskokwim Health Corporation and the Norton Sound Health Corporation, and all the people who so generously gave of their time and knowledge in each community, from the clinic to the tribal council to the city office to the stores to the schools.”We also take this opportunity to provide clarification on some additional items:The manuscript was reviewed and approved by the Norton Sound Health Corporation (Norton Sound Research Ethics Review Board), the Alaska Native Tribal Health Consortium (ANTHC) Health Research Review Committee (HRRC) on behalf of the ANTHC Board of Directors, and the Yukon Kuskokwim Health Corporation Executive Board of Directors .It has come to the attention of the PLOS ONE Editors that a number of dietary instruments for Alaska Native populations have been published, but were not cited in the article, including:Johnson JS, Nobmann ED, Asay E, Lanier AP. Developing a validated Alaska Native food frequency questionnaire for western Alaska, 2002–2006. Int J Circumpolar Health. 2009 Apr; 68(2):99–108. [10.3402/ijch.v71i0.17345. [Johnson JS, Nobmann ED, Asay E. Factors related to fruit, vegetable and traditional food consumption which may affect health among Alaska Native People in Western Alaska. Int J Circumpolar Health. 2012 Mar 19;71:17345. doi:


Neck and back pain are common and often account for absenteeism at work. Factors at work as well as fear–avoidance beliefs may influence sick-leave in these patients. The aims of this study were to assess: (1) how sick-listed patients in specialised care perceive demand, control, support, effort, reward, and overcommitment at work compared to a general reference group of workers; (2) if women and men report demand, control, support, effort, reward, and overcommitment differently; and (3) the association between psychological and social factors at work and fear–avoidance beliefs about work.A cross-sectional multicentre study was carried out in 373 patients on sick leave due to neck and back pain. Psychosocial work factors were measured by demand, control, and support, , and effort, reward and overcommitment . Fear avoidance beliefs about work were measured by the Fear–Avoidance Belief Questionnaire Work subscale (FABQ-W).Although the patients differed significantly from a reference working group regarding several subscales of demand, control, support, effort, reward, and overcommitment, the magnitude of these differences were small. The study population also reported significantly higher scores for ‘demand for physical endurance’ than the reference population, and Cohen’s d = 0.55 here indicated a medium degree of difference. Female patients reported significantly higher on support, whereas male patients reported significantly higher demand for physical endurance, quantitative demand, effort, and overcommitment. Demand for physical endurance, job control, job support, high reward, and overcommitment were significantly associated with FABQ-W.Perceived psychological and social factors at work were strongly associated with fear–avoidance beliefs about work in sick-listed neck and back patients. The demand for physical endurance, control, support, high reward, as well as overcommittment at work outweighed pain and added to the burden of emotional distress and disability regarding fear–avoidance beliefs. Neck and back disorders are common causes of pain and frequently lead to activity limitations and work absence. The total sickness benefit costs in Norway amounted to 36 billion Norwegian kroner (5 billion euros) in 2009. About 40% of the sick leave days were due to musculoskeletal disorders, with back pain as the predominant cause .Although back pain is a benign condition in most subjects, 10% are not able to resume work after 3 months ,3. TheseThe demand–control model developed by Karasek and colleagues ,8 is a 3Among patients referred to specialised care with LBP, the impact of psychosocial factors has been extensively documented . In thesThe aims of this study were to assess: (1) how sick-listed patients in specialised care perceive demand, control, support, effort, reward, and overcommitment at work compared to a general reference group of workers; (2) if women and men report demand, control, support, effort, reward, and overcommitment differently; and (3) the association between psychological and social factors at work and fear–avoidance beliefs about work.This was a cross-sectional multicentre study of patients on sick leave due to neck and LBP. The study was conducted in accordance with the Helsinki Declaration. It was evaluated by the Regional Committees for Medical and Health Research Ethics in Southeast Norway (S09024b 2009/1000) and according to the Norwegian guidelines authorised by the Data Protection for Research at Oslo University Hospital (1207–091208).We recruited patients referred to the neck and back outpatient clinic at Oslo University Hospital and St. Olavs University Hospital, Trondheim, Norway. Inclusion criteria were age 18–60 years, employed, and duration of sick leave between 4 weeks and 12 months. Exclusion criteria were patients in need of surgical treatment, cauda equina syndrome, and symptomatic spinal deformities, osteoporosis with fractures, inflammatory rheumatic diseases, other serious somatic or mental diseases, pregnancy, legal labour dispute, and insufficient Norwegian language to fill in the questionnaires. Between August 2009 and August 2011 a total of 3961 patients were screened for eligibility. The main reasons for ineligibility were: not sick-listed (50%); unemployed (26%); a disorder suitable for surgical treatment (7%); and lack of Norwegian language skills (6%). A total of 719 patients were eligible, and 408 of these gave their consent. A total of 31 included patients were removed from the analyses due to missing or incomplete scores on the Questionnaire for Psychological and Social Factors at Work (QPS) and ERI questionnaire, and 4 due to lacking responses in FABQ-W  to 10 (worst possible pain). Validity as evaluated to other pain measurements and reliability (ICC>0.8), have been documented previously . In the Functioning was measured by the Norwegian version of the Oswestry Disability Index (ODI) and Neck Disability Index (NDI) in patients with LBP and neck pain, respectively. Previous studies have reported the validity and high reliability  of ODI ,28 and NWaddell’s Fear–Avoidance Belief Questionnaire (FABQ) Norwegian version consists of two subscales, FABQ-W about work and FABQ-PA about physical activity. High reliability (ICC>0.8) and construct validity (Pearson correlation coefficient >0.6) have been documented previously ,31. The A short version of HSCL-10 was used to screen for psychological distress (depression and anxiety) during the previous 14 days. The 10 items were scored according to how much nuisance or inconvenience each symptom had caused, from 1  to 4 (very much). The sum of the items divided by the number of items was calculated and reported. The reliability  and validity as evaluated by high correlation to mental health measurements, have been reported previously ,33.QPS Nordic  is a quePsychosocial work factors according to the ERI model were obtained by using the Norwegian version of the ERI questionnaire. The evidence of validity and reliability has been documented previously ,15. TablThe reference groups for QPS Nordic subscales were obtained from the population used when constructing and validating the questionnaire . It const tests were used to compare the study population with the reference population and to compare differences between men and women regarding the QPS and ERI subscales. To assess the size of the differences, we calculated Cohen’s d values [We compared the average subscales values of the study population with the QPS reference population comprising 2010 employees from the four Nordic countries, from production industries, private service companies, health sector, and public administration , and thed values . Cohen’sHierarchical multiple regression analyses were performed to explore to what extent psychological and social work factors were related to FABQ-W. Missing values were treated as follows: if >5 items were missing, no total ODI/NDI scores were calculated. One or two missing items in HSCL-10 were substituted by the subject’s mean value. If more items were missing, the total HSCL-10 score was substituted by the mean value of the patient group, which was done with six participants. QPS and ERI scale scores were calculated as mean scores of completed items for those completing at least two-thirds of the corresponding items. In eight subjects more than one-third of the items in a subscale were missing. In order not to lose the information from these patients on other subscales, the total subscale was substituted by the mean value of the patient group. Subsequently, the calculations were performed in two steps. First, we divided possible independent variables into three boxes: demographic, relevant clinical variables, and psychosocial work factors. In each box, a standard regression analysis was performed, with variables entered one at a time. Variables with p values < 0.2 were finally included in a multivariate analysis. Age, gender, and other significant demographic variables were controlled for in all boxes. In the demographic box, educational level was collapsed into two categories based on FABQ-W distribution: those with or without a college/university degree. In the same way, the distribution of FABQ-W between the four occupational categories let us merge the two blue-collar categories into one. In the clinical box, pain, DI, HSCL-10, number of painful body regions, and number of comorbid conditions were included. The HSCL-10 was categorised into quartiles to examine the FABQ-W distribution. This exploration showed a linear variability of FABQ-W, and consequently, we kept HSCL-10 as a continuous variable. In the box with psychological and social work factors, job demands, job control, job support, effort, reward, overcommitment, and the single QPS item ‘Does your work require physical endurance?’ were included. The last item accounted for the physical burden at the work site. The response to this item was dichotomised into yes (4 or 5) or no . Each variable was assessed with respect to normal distribution. Owing to a highly skewed distribution, ‘reward’ was categorised into quartiles. Otherwise, the remaining variables were regarded as normally distributed and hence were kept as continuous variables.2 value was reported for each step. In the final model, a statistical significance level of p < 0.05 was adopted. Statistical analyses were performed using PASW Statistics, version 18 .Second, all variables with p < 0.2 from previous multivariate analyses were included in the final multiple regression analysis. Low colinearity was found between the independent variables. The RThe analyses were performed with full data registration from 373 patients.Demographic characteristics of the patients are reported in Table Fifty-three per cent of the patients reported to have been on sick leave for >100 days at the time of inclusion, yet 95% believed that in 2 years they would have returned to work. The age and gender distributions among consenters were similar to those of the neck and back outpatient population.The included patients differed significantly from the reference group with perceived lower quantitative and learning demands, lower control of decision and work pacing, and lower support from co-workers (p = 0.006). However, the magnitude of the difference was small (Cohen’s d < 0.23). We found a significant difference for the single item ‘Does your work require physical endurance?’ (p < 0.001) and a medium effect size (Cohen’s d = 0.55), supporting a higher reported physical endurance requirement by the study population compared to the reference group. Also, the study population reported significant higher effort and overcommitment, and lower reward than the reference population (p < 0.001), but the effect sizes were small (Cohen’s d between -0.26 and +0.34) , and support from friends and family  compared with male patients. Male patients, however, reported a significantly higher demand for physical endurance than female patients . They also reported significantly higher quantitative demand (p = 0.045), higher effort (p = 0.02), and higher overcommitment (p = 0.02) than female patients.The results from the regression analyses in each box are presented in Tables Similar results were obtained when analysing men and women separately, except for DI which was a predictor for FABQ-W only for men .In this study, the psychological and social work factors were significantly and relatively strongly associated with fear–avoidance beliefs about work. These factors, in addition to disability and psychological distress, explained 39% of fear–avoidance beliefs in patients on sick leave due to neck or back pain.Description of psychological and social factors at work and possible association with neck or back pain, have mainly been studied in worker populations ,16,37-39The study population reported higher demand for physical endurance than the reference population. It is well known that physical work demands are associated with LBP prevalence in specific occupational populations ,11,41 anThe mean pain score of 5–6 in the study population was comparable to that in other studies on sick-listed workers with chronic LBP in secondary care ,43-45. CPsychological distress in our study population, reported by HSCL-10, was much higher than in the general population . HoweverTo the best of our knowledge, the impact of psychosocial work factors on fear–avoidance beliefs has not been evaluated previously. The factors underlying fear–avoidance beliefs are important to capture because these beliefs are a major predictor of work loss and disability ,31,49-52The present cohort was recruited from individuals in specialised care, and selected regarding language skills. The similar age and gender distributions among the consenters and non-consenters and the screening of all referred patients for eligibility precluded a representative patient cohort. However, these patients had a wide variety of occupations, which may have concealed potential differences from the reference population. The perceived burden of work may have been influenced by LBP. Furthermore, the lack of more objective assessment of exposure was a limitation, along with most studies conducted in this field .The reference populations had a greater proportion of women and greater proportions with higher educational level or white-collar workers than the study population. This may have contributed to the difference regarding perception of demands for physical endurance.The regression analyses were performed with women and men together, and this may have concealed different associations for men and women. Although performing a stratified analysis resulted in reduction of power, we clearly saw that disability was of significance for men only. None of the significant associations showed diverging directions for men compared with women in this analysis.The use of a cross-sectional study design limited the analyses to explore associations, and not to draw any inference of causality in the associations found. The results imply a focus on the social and psychological factors at work in treatment and rehabilitation. However, as the actual prognostic value of the demand, control, and support in work for return to work in this patient population could not be established due to the cross-sectional design, a prospective study would be preferable as a basis for advices of implementation.Our study population of sick-listed neck and back pain patients reported mostly significant differences in average perception of demand, control, support, effort, reward, and overcommitment at work than workers in general, however, the differences were small. Perceived lower job control, higher job support, higher demand for physical endurance, and higher overcommitment were strongly associated with higher fear–avoidance beliefs about work in sick-listed neck and back pain patients. However, perception of higher reward was associated with lower fear–avoidance beliefs about work. The work-related factors outweighed pain and added to the burden of emotional distress and disability regarding fear–avoidance beliefs. The present study emphasises the need to focus on the work-related factors in sick-listed patients in specialised care.DI: Disability index; ERI: Effort–reward imbalance questionnaire; FABQ: Fear–avoidance belief questionnaire; FABQ-W: Fear–avoidance belief questionnaire about work; HSCL-10: Hopkins symptom checklist 10; LBP: Low back pain; NDI: Neck disability index; ODI: Oswestry disability index; QPS: Nordic questionnaire for psychological and social factors at work.The authors declare that they have no competing interests.KM participated in the design and coordination of the study, data acquisition, statistical analysis and interpretation of data, and drafting the manuscript. CR participated in the conception, design, and coordination of the study, analysis and interpretation of data, and critical revision of the manuscript. GHM participated in the design and coordination of the study, data acquisition, and critical revision of the manuscript. AK participated in the design and conception of the study, analysis and interpretation of data, and critical revision of the manuscript. EBH participated in the design and conception of the study, interpretation of data, and critical revision of the manuscript. GL participated in the design of the study, interpretation of data, and critical revision of the manuscript. LS participated in the statistical analysis and interpretation of data, and critical revision of the manuscript. BL participated in the conception and design of the study, analysis and interpretation of data, and critical revision of the manuscript. All authors read and approved the manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2474/14/329/prepub