External Validation of a Nomogram That Predicts the Pathological Diagnosis of Thyroid Nodules in a Chinese Population

Introduction

Nomograms are statistical predictive models that can provide the probability of a clinical event. Nomograms have better performance for the estimation of individual risks because of their increased accuracy and objectivity relative to physicians’ personal experiences. Recently, a nomogram for predicting the likelihood that a thyroid nodule is malignant was introduced by Nixon. The aim of this study was to determine whether Nixon’s nomogram can be validated in a Chinese population.

Materials and Methods

All consecutive patients with thyroid nodules who underwent surgery between January and June 2012 in our hospital were enrolled to validate Nixon’s nomogram. Univariate and multivariate analyses were used to identify the risk factors for thyroid carcinoma. Discrimination and calibration were employed to evaluate the performance of Nixon’s model in our population.

Results

A total of 348 consecutive patients with 409 thyroid nodules were enrolled. Thyroid ultrasonographic characteristics, including shape, echo texture, calcification, margins, vascularity and number (solitary vs. multiple nodules), were associated with malignance in the multivariate analysis. The discrimination of all nodules group, the group with a low risk of malignancy (predictive proportion <50%) and the group with a high risk of malignancy (predictive proportion ≥50%) using Nixon’s nomogram was satisfactory, and the area under the receiver operating characteristic curve of the three groups were 0.87, 0.75 and 0.72, respectively. However, the calibration was significant (p = 0.55) only in the high-risk group.

Conclusion

Nixon’s nomogram is a valuable predictive model for the Chinese population and has been externally validated. It has good performance for patients with a high risk of malignancy and may be more suitable for use with these patients in China.     

孤立性肺结节患者血清CEA、NSE、Cyfra21-1水平与结节直径的关系及联合高分辨率CT的诊断价值研究

摘要 目的：研究孤立性肺结节（SPN）患者血清癌胚抗原（CEA）、神经特异性烯醇化酶（NSE）、细胞角蛋白19片段（Cyfra21-1）水平与结节直径的关系及联合高分辨率CT的诊断价值。方法：将医院从2017年3月～2020年3月期间收治的SPN患者154例纳入研究。根据术后病理检查结果分为恶性结节组104例和良性结节组50例。对所有患者均进行高分辨率CT胸部增强扫描,并比较不同结节患者的CT影像征象表现。此外,检测并比较不同结节患者的血清CEA、NSE、Cyfra21-1水平,分析血清CEA、NSE、Cyfra21-1与结节直径的关系。通过受试者工作特征（ROC）曲线分析血清CEA、NSE、Cyfra21-1水平联合高分辨率CT诊断SPN良恶性的效能。结果：肺恶性结节患者胸部CT影像征象表现为毛刺征、深分叶征、胸膜凹陷征、血管集数征、棘突征人数占比均高于良性结节,而钙化征人数占比低于良性结节（均P＜0.05）。肺恶性结节患者的血清CEA、NSE、Cyfra21-1水平均明显高于良性结节患者（均P＜0.05）。结节最大直径＞2.0 cm的SPN患者血清CEA明显高于结节最大直径1.0～2.0 cm患者,而结节最大直径1.0～2.0 cm患者血清CEA明显高于结节最大直径＜1.0c m患者（均P＜0.05）;且经Spearman相关性分析显示,血清CEA水平与SPN患者结节直径呈正相关,而血清NSE、Cyfra21-1水平与SPN患者结节直径无相关性。经ROC曲线分析可得,血清CEA、NSE、Cyfra21-1联合高分辨率CT诊断SPN良恶性的曲线下面积、灵敏度、特异度均明显高于上述各项血清学指标和高分辨率CT单独诊断。结论：SPN患者血清CEA水平与结节直径呈正相关,而血清NSE、Cyfra21-1水平与结节直径无明显相关,血清CEA、NSE、Cyfra21-1联合高分辨率CT诊断SPN良恶性的价值较高。     

Evaluation of Preoperative Hematologic Markers as Prognostic Factors and Establishment of Novel Risk Stratification in Resected pN0 Non-Small-Cell Lung Cancer

Background

The aims of this study were to investigate whether the preoperative hematologic markers, the neutrophil-lymphocyte ratio (NLR) or the platelet-lymphocyte ratio (PLR) were prognostic indicators and to develop a novel risk stratification model in pN0 non-small-cell lung cancer (NSCLC).

Methods

We performed a retrospective analysis of 400 consecutive pN0 NSCLC patients. Prognostic values were evaluated by Cox proportional hazard model analyses and patients were stratified according to relative risks for patients’ survival.

Results

During the follow-up, 117 patients had cancer recurrence, and 86 patients died. In univariate analysis, age, gender, smoke status and tumor size as well as WBC, NEU, LYM, PLR and NLR were significantly associated with patients’ prognosis. In multivariate analysis, age, tumor size and NLR were independent predictors for patients’ overall survival (P = 0.024, 0.001, and 0.002 respectively). PLR didn’t associated with patients’ survival in multivariate analysis. Patients were stratified into 3 risk groups and the differences among the groups were significant according to disease free survival and overall survival (P = 0.000 and 0.000 respectively).

Conclusions

We confirmed that NLR other than PLR was an independent prognostic factor. Combination of NLR, age and tumor size could stratify pN0 NSCLC patients into 3 risk groups and enabled us to develop a novel risk stratification model.     

Treatment Default amongst Patients with Tuberculosis in Urban Morocco: Predicting and Explaining Default and Post-Default Sputum Smear and Drug Susceptibility Results

Setting

Public tuberculosis (TB) clinics in urban Morocco.

Objective

Explore risk factors for TB treatment default and develop a prediction tool. Assess consequences of default, specifically risk for transmission or development of drug resistance.

Design

Case-control study comparing patients who defaulted from TB treatment and patients who completed it using quantitative methods and open-ended questions. Results were interpreted in light of health professionals’ perspectives from a parallel study. A predictive model and simple tool to identify patients at high risk of default were developed. Sputum from cases with pulmonary TB was collected for smear and drug susceptibility testing.

Results

91 cases and 186 controls enrolled. Independent risk factors for default included current smoking, retreatment, work interference with adherence, daily directly observed therapy, side effects, quick symptom resolution, and not knowing one’s treatment duration. Age >50 years, never smoking, and having friends who knew one’s diagnosis were protective. A simple scoring tool incorporating these factors was 82.4% sensitive and 87.6% specific for predicting default in this population. Clinicians and patients described additional contributors to default and suggested locally-relevant intervention targets. Among 89 cases with pulmonary TB, 71% had sputum that was smear positive for TB. Drug resistance was rare.

Conclusion

The causes of default from TB treatment were explored through synthesis of qualitative and quantitative data from patients and health professionals. A scoring tool with high sensitivity and specificity to predict default was developed. Prospective evaluation of this tool coupled with targeted interventions based on our findings is warranted. Of note, the risk of TB transmission from patients who default treatment to others is likely to be high. The commonly-feared risk of drug resistance, though, may be low; a larger study is required to confirm these findings.     

Validation of the IHE Cohort Model of Type 2 Diabetes and the Impact of Choice of Macrovascular Risk Equations

Background

Health-economic models of diabetes are complex since the disease is chronic, progressive and there are many diabetic complications. External validation of these models helps building trust and satisfies demands from decision makers. We evaluated the external validity of the IHE Cohort Model of Type 2 Diabetes; the impact of using alternative macrovascular risk equations; and compared the results to those from microsimulation models.

Methods

The external validity of the model was analysed from 12 clinical trials and observational studies by comparing 167 predicted microvascular, macrovascular and mortality outcomes to the observed study outcomes. Concordance was examined using visual inspection of scatterplots and regression-based analysis, where an intercept of 0 and a slope of 1 indicate perfect concordance. Additional subgroup analyses were conducted on ‘dependent’ vs. ‘independent’ endpoints and microvascular vs. macrovascular vs. mortality endpoints.

Results

Visual inspection indicates that the model predicts outcomes well. The UKPDS-OM1 equations showed almost perfect concordance with observed values (slope 0.996), whereas Swedish NDR (0.952) and UKPDS-OM2 (0.899) had a slight tendency to underestimate. The R ² values were uniformly high (>0.96). There were no major differences between ‘dependent’ and ‘independent’ outcomes, nor for microvascular and mortality outcomes. Macrovascular outcomes tended to be underestimated, most so for UKPDS-OM2 and least so for NDR risk equations.

Conclusions

External validation indicates that the IHE Cohort Model of Type 2 Diabetes has predictive accuracy in line with microsimulation models, indicating that the trade-off in accuracy using cohort simulation might not be that large. While the choice of risk equations was seen to matter, each were associated with generally reasonable results, indicating that the choice must reflect the specifics of the application. The largest variation was observed for macrovascular outcomes. There, NDR performed best for relatively recent and well-treated patients, while UKPDS-OM1 performed best for the older UKPDS cohort.     

Assessing Risk Factors for Migraine: Differences in Gender Transmission

Aim

Our aim was to assess which specific factors are contributing to an increased risk of migraine in a group of 131 Portuguese families.

Methods

We studied 319 first-degree relatives, using a multilevel approach to account for the dependency among members from the same family. We included in the model relative’s gender, the proband’s gender and age-at-onset, to evaluate if any of these variables were associated with relative’s affection status. We also included in the model proband’s migraine subtype. We further assessed female and male transmissions within the proband nuclear family.

Results

Relatives’ gender was found to be a risk factor for migraine (Odds Ratio = 2.86; 95% CI = 1.75–4.67), with females at a higher risk. When splitting probands according to their migraine subtype, we found that none of the variables studied contributed to relatives of MA-probands affection-status. Our results also show a significant difference between proband’s transmission and the gender of the parents and offspring.

Conclusions

With this study, we showed that gender is truly a risk factor for migraine and that a gender-biased transmission is also observed. This reinforce the importance of identifying genes associated with migraine that are modulated by genes located in the sex chromosomes and the study of mitochondrial DNA or X-chromosome and hormonal-related effects associated with migraine susceptibility.     

Cohen’s h for detection of disease association with rare genetic variants

Background

The power of the genome wide association studies starts to go down when the minor allele frequency (MAF) is below 0.05. Here, we proposed the use of Cohen’s h in detecting disease associated rare variants. The variance stabilizing effect based on the arcsine square root transformation of MAFs to generate Cohen’s h contributed to the statistical power for rare variants analysis. We re-analyzed published datasets, one microarray and one sequencing based, and used simulation to compare the performance of Cohen’s h with the risk difference (RD) and odds ratio (OR).

Results

The analysis showed that the type 1 error rate of Cohen’s h was as expected and Cohen’s h and RD were both less biased and had higher power than OR. The advantage of Cohen’s h was more obvious when MAF was less than 0.01.

Conclusions

Cohen’s h can increase the power to find genetic association of rare variants and diseases, especially when MAF is less than 0.01.

Electronic supplementary material

The online version of this article (doi:10.1186/1471-2164-15-875) contains supplementary material, which is available to authorized users.     

The Quality of Spouses’ Social Networks Contributes to Each Other’s Cardiovascular Risk

Objectives

Although the quality of one’s own social relationships has been related to cardiovascular morbidity and mortality, whether a partner’s social network quality can similarly influence one’s cardiovascular risk is unknown. In this study we tested whether the quality of a partner’s social networks influenced one’s own ambulatory blood pressure (ABP).

Methods

The quality of 94 couples’ social networks was determined using a comprehensive model of relationships that separates out social ties that are sources of positivity(supportive), negativity (aversive), and both positivity and negativity (ambivalent). We then utilized statistical models (actor-partner analyses) that allowed us to separate out the links between one’s own social network quality on ABP (actor influences), a partner’s social network quality on ABP (partner influences), and a couple’s network quality combined on ABP (actor X partner interactions).

Results

Independent of one’s own relationship quality, results showed that an individual’s ABP was lower if their spouse had more supportive ties, and higher if a spouse had more aversive and ambivalent ties. In addition, couples’ networks in combination were associated with higher ABP but only if both had a low number of supportive ties, or a high number of aversive or ambivalent ties.

Conclusions

These data suggest that the social ties of those we have close relationships with may influence our cardiovascular risk and opens new opportunities to capitalize on untapped social resources or to mitigate hidden sources of social strain.     

Positive Association of Coronary Calcium Detected by Computed Tomography Coronary Angiography with Periprocedural Myocardial Infarction

Background

Periprocedural myocardial infarction (PMI) may occur in approximately 5% to 30% of patients undergoing percutaneous coronary intervention. Whether the morphology of coronary plaque calcium affects the occurrence of PMI is unknown.

Materials and Methods

A total of 616 subjects with stable angina and normal baseline cardiac troponin I levels who had undergone computed tomography angiography (CTA) were referred to elective percutaneous coronary intervention. The morphology of coronary calcium was determined by CTA analysis. PMI was defined as an elevation in 24-h post-procedural cardiac troponin I levels of > 5 times the upper limit of normal with either symptoms of myocardial ischemia, new ischemic electrocardiographic changes, or documented complications during the procedure. Logistic regression was performed to identify the effect of the morphology of coronary calcium on the occurrence of PMI.

Results

According to the presence or morphology of coronary calcium as shown by CTA, 210 subjects were grouped in the heavy calcification group, 258 in the mild calcification group, 40 in the spotty calcification group and 108 in the control group. The dissection rate was significantly higher in the heavy calcification group than in the control group (7.1 % vs. 1.9%, p = 0.03). The occurrence of PMI in the heavy calcification group was significantly higher than that in the control group (OR 4.38, 95% CI 1.80–10.65, p = 0.001). After multivariate adjustment, the risk of PMI still remained significantly higher in the heavy calcification group than in the control group (OR 4.04, 95% CI 1.50–10.89, p = 0.003).

Conclusions

The morphology of coronary calcium determined by CTA may help to predict the subsequent occurrence of PMI. A large amount of coronary calcium may be predictive of PMI.     

Development of a Melanoma Risk Prediction Model Incorporating MC1R Genotype and Indoor Tanning Exposure: Impact of Mole Phenotype on Model Performance

Background

Identifying individuals at increased risk for melanoma could potentially improve public health through targeted surveillance and early detection. Studies have separately demonstrated significant associations between melanoma risk, melanocortin receptor (MC1R) polymorphisms, and indoor ultraviolet light (UV) exposure. Existing melanoma risk prediction models do not include these factors; therefore, we investigated their potential to improve the performance of a risk model.

Methods

Using 875 melanoma cases and 765 controls from the population-based Minnesota Skin Health Study we compared the predictive ability of a clinical melanoma risk model (Model A) to an enhanced model (Model F) using receiver operating characteristic (ROC) curves. Model A used self-reported conventional risk factors including mole phenotype categorized as “none”, “few”, “some” or “many” moles. Model F added MC1R genotype and measures of indoor and outdoor UV exposure to Model A. We also assessed the predictive ability of these models in subgroups stratified by mole phenotype (e.g. nevus-resistant (“none” and “few” moles) and nevus-prone (“some” and “many” moles)).

Results

Model A (the reference model) yielded an area under the ROC curve (AUC) of 0.72 (95% CI = 0.69, 0.74). Model F was improved with an AUC = 0.74 (95% CI = 0.71–0.76, p<0.01). We also observed substantial variations in the AUCs of Models A & F when examined in the nevus-prone and nevus-resistant subgroups.

Conclusions

These results demonstrate that adding genotypic information and environmental exposure data can increase the predictive ability of a clinical melanoma risk model, especially among nevus-prone individuals.     

ROC Generated Thresholds for Field-Assessed Aerobic Fitness Related to Body Size and Cardiometabolic Risk in Schoolchildren

Objectives

1. to investigate whether 20 m multi-stage shuttle run performance (20mSRT), an indirect measure of aerobic fitness, could discriminate between healthy and overweight status in 9–10.9 yr old schoolchildren using Receiver Operating Characteristic (ROC) analysis; 2. Investigate if cardiometabolic risk differed by aerobic fitness group by applying the ROC cut point to a second, cross-sectional cohort.

Design

Analysis of cross-sectional data.

Participants

16,619 9–10.9 year old participants from SportsLinx project and 300 11–13.9 year old participants from the Welsh Schools Health and Fitness Study.

Outcome Measures

SportsLinx; 20mSRT, body mass index (BMI), waist circumference, subscapular and superilliac skinfold thicknesses. Welsh Schools Health and Fitness Study; 20mSRT performance, waist circumference, and clustered cardiometabolic risk.

Analyses

Three ROC curve analyses were completed, each using 20mSRT performance with ROC curve 1 related to BMI, curve 2 was related to waist circumference and 3 was related to skinfolds (estimated % body fat). These were repeated for both girls and boys. The mean of the three aerobic fitness thresholds was retained for analysis. The thresholds were subsequently applied to clustered cardiometabolic risk data from the Welsh Schools study to assess whether risk differed by aerobic fitness group.

Results

The diagnostic accuracy of the ROC generated thresholds was higher than would be expected by chance (all models AUC >0.7). The mean thresholds were 33 and 25 shuttles for boys and girls respectively. Participants classified as ‘fit’ had significantly lower cardiometabolic risk scores in comparison to those classed as unfit (p<0.001).

Conclusion

The use of the ROC generated cut points by health professionals, teachers and coaches may provide the opportunity to apply population level ‘risk identification and stratification’ processes and plan for “at-risk” children to be referred onto intervention services.     

A clinical in-hospital prognostic score for acute exacerbations of COPD

Background

The use of a severity score to help orientation decisions could improve the efficiency of care for acute exacerbations of COPD (AECOPD). We previously developed a score (‘2008 score’, based on age, dyspnea grade at steady state and number of clinical signs of severity) predicting in-hospital mortality in patients with AECOPD visiting emergency departments (EDs). External validity of this score remained to be assessed.

Objectives

To test the predictive properties of the ‘2008 score’ in a population of patients hospitalized in medical respiratory wards for AECOPD, and determine whether a new score specifically derived from this population would differ from the previous score in terms of components or predictive performance.

Methods

Data from a cohort study in 1824 patients hospitalized in a medical ward for an AECOPD were analyzed. Patients were categorized using the 2008 score and its predictive characteristics for in-hospital mortality rates were assessed. A new score was developed using multivariate logistic regression modeling in a randomly selected derivation population sample followed by testing in the remaining population (validation sample). Robustness of results was assessed by case-by-case validation.

Results

The 2008 score was characterized by a c-statistic at 0.77, a sensitivity of 69% and a specificity of 76% for prediction of in-hospital mortality. The new score comprised the same variables plus major cardiac comorbidities and was characterized by a c-statistic of 0.78, a sensitivity of 77% and specificity of 66%.

Conclusions

A score using simple clinical variables has robust properties for predicting the risk of in-hospital death in patients hospitalized for AECOPD. Adding cardiac comorbidities to the original score increased its sensitivity while decreasing its specificity.

Electronic supplementary material

The online version of this article (doi:10.1186/s12931-014-0099-9) contains supplementary material, which is available to authorized users.     

The Association between Aortic Calcification and Fracture Risk in Postmenopausal Women in China: The Prospective Chongqing Osteoporosis Study

Purpose

Fractures are associated with cardiovascular diseases in the elderly. The purpose of the present study was to investigate the association between aortic calcification (AC) and the risk of vertebral fractures in postmenopausal Chinese women.

Methods

A prospective study with 5 years of follow-up in 1724 postmenopausal women (aged 50 years old and older) was conducted from July 2005 to June 2010. Dual energy X-ray absorptiometry was utilized to evaluate bone mineral density (BMD). Aortic calcification score (ACS) was determined by a semi-quantitative method and was further categorized into four groups. Cox proportional hazards models were established to assess the association between AC and the risk of vertebral fractures.

Results

For subjects with AC, the incidence of vertebral fractures was higher than that of those without AC (p<0.01). After adjustment for age and other potential confounders, it was found that severe AC (G4, ACS>6; G3, ACS = 3–6) was associated with vertebral fractures. Severe AC (G4) was associated with non-vertebral fractures. There were higher risk for the vertebral fractures in two groups and higher risk for non-vertebral fractures in one group.

Conclusions

The results of the current study indicate that severe AC is associated with a significantly increased risk of vertebral fractures and non-vertebral fractures in postmenopausal women in China.     

Rapid Clinical Assessment to Facilitate the Triage of Adults with Falciparum Malaria,a Retrospective Analysis

Background

Most adults dying from falciparum malaria will die within 48 hours of their hospitalisation. An essential component of early supportive care is the rapid identification of patients at greatest risk. In resource-poor settings, where most patients with falciparum malaria are managed, decisions regarding patient care must frequently be made using clinical evaluation alone.

Methods

We retrospectively analysed 4 studies of 1801 adults with severe falciparum malaria to determine whether the presence of simple clinical findings might assist patient triage.

Results

If present on admission, shock, oligo-anuria, hypo- or hyperglycaemia, an increased respiratory rate, a decreased Glasgow Coma Score and an absence of fever were independently predictive of death. The variables were used to construct a simple clinical algorithm. When applied to the 1801 patients, this algorithm’s positive predictive value for survival to 48 hours was 99.4 (95% confidence interval (CI) 97.8–99.9) and for survival to discharge 96.9% (95% CI 94.3–98.5). In the 712 patients receiving artesunate, the algorithm’s positive predictive value for survival to 48 hours was 100% (95% CI 97.3–100) and to discharge was 98.5% (95% CI 94.8–99.8).

Conclusions

Simple clinical findings are closely linked to the pathophysiology of severe falciparum malaria in adults. A basic algorithm employing these indices can facilitate the triage of patients in settings where intensive care services are limited. Patients classified as low-risk by this algorithm can be safely managed initially on a general ward whilst awaiting senior clinical review and laboratory data.     

The Effectiveness of the Cardiovascular Disease Prevention Programme ‘KardioPro’ Initiated by a German Sickness Fund: A Time-to-Event Analysis of Routine Data

Background

Cardiovascular disease is the leading cause of morbidity and mortality in the developed world. To reduce this burden of disease, a German sickness fund (‘Siemens-Betriebskrankenkasse’, SBK) initiated the prevention programme ‘KardioPro’ including primary (risk factor reduction) and secondary (screening) prevention and guideline-based treatment. The aim of this study was to assess the effectiveness of ‘KardioPro’ as it is implemented in the real world.

Methods

The study is based on sickness fund routine data. The control group was selected from non-participants via propensity score matching. Study analysis was based on time-to-event analysis via Cox proportional hazards regression with the endpoint ‘all-cause mortality, acute myocardial infarction (MI) and ischemic stroke (1)’, ‘all-cause mortality (2)’ and ‘non-fatal acute MI and ischemic stroke (3)’.

Results

A total of 26,202 insurants were included, 13,101 participants and 13,101 control subjects. ‘KardioPro’ enrolment was associated with risk reductions of 23.5% (95% confidence interval (CI) 13.0–32.7%) (1), 41.7% (95% CI 30.2–51.2%) (2) and 3.5% (hazard ratio 0.965, 95% CI 0.811–1.148) (3). This corresponds to an absolute risk reduction of 0.29% (1), 0.31% (2) and 0.03% (3) per year.

Conclusion

The prevention programme initiated by a German statutory sickness fund appears to be effective with regard to all-cause mortality. The non-significant reduction in non-fatal events might result from a shift from fatal to non-fatal events.     

A Model to Discriminate Malignant from Benign Thyroid Nodules Using Artificial Neural Network

Objective

This study aimed to construct a model for using in differentiating benign and malignant nodules with the artificial neural network and to increase the objective diagnostic accuracy of US.

Materials and methods

618 consecutive patients (528 women, 161 men) with 689 thyroid nodules (425 malignant and 264 benign nodules) were enrolled in the present study. The presence and absence of each sonographic feature was assessed for each nodule - shape, margin, echogenicity, internal composition, presence of calcifications, peripheral halo and vascularity on color Doppler. The variables meet the following criteria: important sonographic features and statistically significant difference were selected as the input layer to build the ANN for predicting the malignancy of nodules.

Results

Six sonographic features including shape (Taller than wide, p<0.001), margin (Not Well-circumscribed, p<0.001), echogenicity (Hypoechogenicity, p<0.001), internal composition (Solid, p<0.001), presence of calcifications (Microcalcification, p<0.001) and peripheral halo (Absent, p<0.001) were significantly associated with malignant nodules. A three-layer 6-8-1 feed-forward ANN model was built. In the training cohort, the accuracy of the ANN in predicting malignancy of thyroid nodules was 82.3% (AUROC = 0.818), the sensitivity and specificity was 84.5% and 79.1%, respectively. In the validation cohort, the accuracy, sensitivity and specificity was 83.1%, 83.8% and 81.8%, respectively. The AUROC was 0.828.

Conclusion

ANN constructed by sonographic features can discriminate benign and malignant thyroid nodules with high diagnostic accuracy.     

Clinical Prediction in Early Pregnancy of Infants Small for Gestational Age by Customised Birthweight Centiles: Findings from a Healthy Nulliparous Cohort

Objective

Small for gestational age (SGA) infants comprise up to 50% of all stillbirths and a minority are detected before birth. We aimed to develop and validate early pregnancy predictive models for SGA infants.

Methods

5628 participants from SCOPE, a prospective study of nulliparous pregnant women, were interviewed at 15±1 weeks’ gestation. Fetal anthropometry, uterine and umbilical Doppler studies were performed at 20±1 weeks’. The cohort was divided into training (n = 3735) and validation datasets (n = 1871). All-SGA (birthweight <10th customised centile), Normotensive-SGA (SGA with normotensive mother) and Hypertensive-SGA (SGA with mother who developed hypertension) were the primary outcomes. Multivariable analysis was performed using stepwise logistic regression firstly using clinical variables and then with clinical and ultrasound variables. Receiver operator curves were constructed and areas under the curve (AUC) calculated.

Results

633 infants (11.3%) in the whole cohort were SGA; 465 (8.3%) Normotensive-SGA and 165 (3.0%) Hypertensive-SGA. In the training dataset risk factors for All-SGA at 15±1 weeks’ included: family history of coronary heart disease, maternal birthweight <3000 g and 3000 g to 3499 g compared with ≥3500 g, >12 months to conceive, university student, cigarette smoking, proteinuria, daily vigorous exercise and diastolic blood pressure ≥80. Recreational walking ≥4 times weekly, rhesus negative blood group and increasing random glucose were protective. AUC for clinical risk factors was 0.63. Fetal abdominal or head circumference z scores <10^th centile and increasing uterine artery Doppler resistance at 20±1 weeks’ were associated with increased risk. Addition of these parameters increased the AUC to 0.69. Clinical predictors of Normotensive and Hypertensive-SGA were sub-groups of All-SGA predictors and were quite different. The combined clinical and ultrasound AUC for Normotensive and Hypertensive-SGA were 0.69 and 0.82 respectively.

Conclusion

Predictors for SGA of relevance to clinical practice were identified. The identity and predictive potential differed in normotensive women and those who developed hypertension.     

The N-terminal Helix Controls the Transition between the Soluble and Amyloid States of an FF Domain

Background

Protein aggregation is linked to the onset of an increasing number of human nonneuropathic (either localized or systemic) and neurodegenerative disorders. In particular, misfolding of native α-helical structures and their self-assembly into nonnative intermolecular β-sheets has been proposed to trigger amyloid fibril formation in Alzheimer’s and Parkinson’s diseases.

Methods

Here, we use a battery of biophysical techniques to elucidate the conformational conversion of native α-helices into amyloid fibrils using an all-α FF domain as a model system.

Results

We show that under mild denaturing conditions at low pH this FF domain self-assembles into amyloid fibrils. Theoretical and experimental dissection of the secondary structure elements in this domain indicates that the helix 1 at the N-terminus has both the highest α-helical and amyloid propensities, controlling the transition between soluble and aggregated states of the protein.

Conclusions

The data illustrates the overlap between the propensity to form native α-helices and amyloid structures in protein segments.

Significance

The results presented contribute to explain why proteins cannot avoid the presence of aggregation-prone regions and indeed use stable α-helices as a strategy to neutralize such potentially deleterious stretches.