Multiple Methodological Limitations Research Articles

Propylthiouracil-induced vasculitis with alveolar hemorrhage after 31 years of treatment: a case report

BackgroundPropylthiouracil is an antithyroid medication that is associated with ANCA positivity, often in the absence of clinically overt vasculitis. Propylthiouracil-induced ANCA-associated vasculitis (AAV) is characterized by multiple antigenicity and presents similarly to other forms of drug-induced vasculitis.Case presentationWe report a case of a 49-year-old woman who developed propylthiouracil-induced AAV after 31 years of intermittent therapy. The patient presented with progressive respiratory and generalized symptoms. She was diagnosed with propylthiouracil-induced AAV with alveolar hemorrhage based on detection of ANCA and anti-MPO antibodies, exclusion of primary vasculitis, and symptom resolution following propylthiouracil withdrawal. The patient was treated with intravenous methylprednisolone, followed by oral prednisolone. Her symptoms resolved, and her laboratory and radiological tests improved within one week.ConclusionsResearch linking the duration of propylthiouracil use to the development of vasculitis is restricted by multiple methodological limitations. Maintaining a high index of clinical suspicion is a more reliable approach to detecting propylthiouracil-induced AAV than regular laboratory monitoring, given that patients with Graves’ disease may show ANCA positivity in the absence of medication use. Therefore, clinicians should remain vigilant for the varied presentations of propylthiouracil-induced AAV. Moreover, further research is recommended to investigate the possible link between the duration of PTU use and the onset of clinically overt vasculitis.

Machine learning-based prediction models unleash the enhanced production of fucoxanthin in Isochrysis galbana.

The marine microalga Isochrysis galbana is prolific producer of fucoxanthin, which is a xanthophyll carotenoid with substantial global market value boasting extensive applications in the food, nutraceutical, pharmaceutical, and cosmetic industries. This study presented a novel integrated experimental approach coupled with machine learning (ML) models to predict the fucoxanthin content in I. galbana by altering the type and concentration of phytohormone supplementation, thus overcoming the multiple methodological limitations of conventional fucoxanthin quantification. A novel integrated experimental approach was developed, analyzing the effect of varying phytohormone types and concentrations on fucoxanthin production in I. galbana. Morphological analysis was conducted to assess changes in microalgal structure, while growth rate and fucoxanthin yield correlations were explored using statistical analysis and machine learning models. Several ML models were employed to predict fucoxanthin content, with and without hormone descriptors as variables. The findings revealed that the Random Forest (RF) model was highly significant with a high of 0.809 and of 0.776 when hormone descriptors were excluded, and the inclusion of hormone descriptors further improved prediction accuracy to of 0.839, making it a useful tool for predicting the fucoxanthin yield. The model that fitted the experimental data indicated methyl jasmonate (0.2 mg/L) as an effective phytohormone. The combined experimental and ML approach demonstrated rapid, reliable, and cost-efficient prediction of fucoxanthin yield. This study highlights the potential of machine learning models, particularly Random Forest, to optimize parameters influencing microalgal growth and fucoxanthin production. This approach offers a more efficient alternative to conventional methods, providing valuable insights into improving fucoxanthin production in microalgal cultivation. The findings suggest that leveraging diverse ML models can enhance the predictability and efficiency of fucoxanthin production, making it a promising tool for industrial applications.

A naturalistic effectiveness study of maintenance therapies for the bipolar disorders.

Treatment decision-making for individuals with bipolar disorder can be difficult. Recommendations from clinical practice guidelines can be affected by multiple methodological limitations, while pharmaco-epidemiological data suggest great variety in prescription practices across regions. Given these inconsistencies, this study aimed to provide an alternative perspective on the effectiveness of common bipolar disorder maintenance treatments through considering naturalistic data. A total of 246 individuals with bipolar disorder (84 bipolar I [BP-I], 162 bipolar II [BP-II]) were recruited through clinics and/or websites. All were euthymic and had trialled at least one mood stabiliser. They completed an online survey containing questions on demographics, clinical variables, symptomatology, and the effectiveness/side effect profiles of any mood stabilisers (MSTs) or atypical antipsychotics (AAPs) that they have taken. Lithium and lamotrigine were the most commonly prescribed MSTs and the most effective at mood stabilisation. Lithium and lamotrigine appeared marginally more effective for BP-I and BP-II respectively, however, only the latter difference was statistically significant. Furthermore, lamotrigine had the more favourable side effect profile. Amongst the AAPs, quetiapine and olanzapine were the most commonly prescribed, but they were negligibly superior to other AAPs. This study clearly established a preference for lamotrigine in the maintenance treatment of BP-II. While the literature consistently emphasises the primacy of lithium in bipolar disorder treatment, its side effect profile as observed in this study remains a concern. Future research considering moderators of treatment response and concomitant medications could help to identify further nuances to consider for treatment decision-making.

The importance of awareness in face processing: A critical review of interocular suppression studies

Human faces convey essential information for understanding others’ mental states and intentions. The importance of faces in social interaction has prompted suggestions that some relevant facial features such as configural information, emotional expression, and gaze direction may promote preferential access to awareness. This evidence has predominantly come from interocular suppression studies, with the most common method being the Breaking Continuous Flash Suppression (bCFS) procedure, which measures the time it takes different stimuli to overcome interocular suppression. However, the procedures employed in such studies suffer from multiple methodological limitations. For example, they are unable to disentangle detection from identification processes, their results may be confounded by participants’ response bias and decision criteria, they typically use small stimulus sets, and some of their results attributed to detecting high-level facial features (e.g., emotional expression) may be confounded by differences in low-level visual features (e.g., contrast, spatial frequency). In this article, we review the evidence from the bCFS procedure on whether relevant facial features promote access to awareness, discuss the main limitations of this very popular method, and propose strategies to address these issues.

Post-COVID-19 condition in children: a COS is urgently needed

A rapidly increasing number of studies worldwide is investigating the frequency, characteristics, and risk factors of post-COVID-19 condition (also commonly known as long COVID) in adults1 and in children and young people.2 Some studies are also aiming to evaluate underlying mechanisms and treatment interventions in these populations. However, multiple methodological limitations have been highlighted, including a lack of standardisation of terminology and definitions1,3 and the absence of an agreed set of research and clinical outcomes that should be routinely assessed.

Preparation for traumatic events prior to exposure for service personnel

Introduction: Military personnel, first responders and health professionals on the front line of service are at risk of being exposed to non-mutable traumatic events. However, their professional education and training do not typically include ways to minimise their distress caused by witnessing a future trauma. The purpose of this scoping systematic review is to analyse the impact of intervention studies on measures of psychobehavioural adjustment to exposure to a future traumatic event. Materials and methods: A systematic search was conducted using PubMed, CINAHL, PsycINFO and the Cochrane Library plus a hand search of five journals, including Military Medicine and Journal of Trauma. Results: A total of 100 articles from an initial pool of 15 306 were assessed for inclusion on criteria and 10 manuscripts meeting the inclusion criteria were evaluated. Interventions focused on combating stress, relaxation techniques, resilience training, psychological skills training, preventing psychological morbidity or post-traumatic stress disorder, and stress management skills. Conclusions: Only 50% of the interventions significantly changed any outcomes. Studies had multiple methodological limitations including a limited number of training hours, trial bias, statistically underpowered designs, short follow-up periods and using inconsistent methods and measures to assessed impact. The paucity of preparatory intervention studies shows there is an urgent need for future research.

The Effects of Topic Familiarity on Text Quality, Complexity, Accuracy, and Fluency: A Conceptual Replication

AbstractUnderstanding the effects of second language writers’ topic familiarity on their subsequent writing performance has been a subject of great interest to researchers in second language acquisition and TESOL. However, prior studies have tended to suffer from multiple methodological limitations (e.g., no interrater reliability, limited or no control over important variables), which may call into question their results. In this conceptual replication, we highlight some of these issues by revisiting an influential study by He and Shi (2012), which explored the effects of ESL students’ topic familiarity on their writing performance as assessed by measures of text quality and complexity, accuracy, and fluency (CAF). Apart from highlighting the differences in our studies’ designs (e.g., the CAF measures and statistical analyses used), we highlight the similarities and differences in our findings. Finally, we close with a call for increased replication research in this area.

Machine learning-enabled phenotyping for GWAS and TWAS of WUE traits in 869 field-grown sorghum accessions.

Sorghum (Sorghum bicolor) is a model C4 crop made experimentally tractable by extensive genomic and genetic resources. Biomass sorghum is studied as a feedstock for biofuel and forage. Mechanistic modeling suggests that reducing stomatal conductance (gs) could improve sorghum intrinsic water use efficiency (iWUE) and biomass production. Phenotyping to discover genotype-to-phenotype associations remains a bottleneck in understanding the mechanistic basis for natural variation in gs and iWUE. This study addressed multiple methodological limitations. Optical tomography and a machine learning tool were combined to measure stomatal density (SD). This was combined with rapid measurements of leaf photosynthetic gas exchange and specific leaf area (SLA). These traits were the subject of genome-wide association study and transcriptome-wide association study across 869 field-grown biomass sorghum accessions. The ratio of intracellular to ambient CO2 was genetically correlated with SD, SLA, gs, and biomass production. Plasticity in SD and SLA was interrelated with each other and with productivity across wet and dry growing seasons. Moderate-to-high heritability of traits studied across the large mapping population validated associations between DNA sequence variation or RNA transcript abundance and trait variation. A total of 394 unique genes underpinning variation in WUE-related traits are described with higher confidence because they were identified in multiple independent tests. This list was enriched in genes whose Arabidopsis (Arabidopsis thaliana) putative orthologs have functions related to stomatal or leaf development and leaf gas exchange, as well as genes with nonsynonymous/missense variants. These advances in methodology and knowledge will facilitate improving C4 crop WUE.

Epidemiological Studies on the Association between Chronic Exposure to Road Traffic Noise and Blood Pressure: A Systematic Review with Meta-Analyses

The aim of this study was to review epidemiological studies on the association between chronic exposures to road traffic noise and prevalence of arterial hypertension as well as blood pressure by using meta-analyses. A systematic literature search in the databases Medline® and Web of science™ as well as the database OpenGrey was conducted to identify suitable studies, namely epidemiological observational studies assessing objective exposures to road traffic noise at the subject's home place with analysis of their potential associations with arterial hypertension or blood pressure. Whenever possible, overall effects for the different relationships were estimated with meta-analyses. For statistical analyses R for windows was used. A total of 31 eligible studies were identified. Meta-analyses were conducted for potential association between road traffic noise and prevalence of arterial hypertension in adults and for association with systolic and diastolic blood pressure in adults and children. There was a significant (p<0.01) increase of risk for arterial hypertension in adults when exposed to chronic road traffic noise with an increment of 7% per 5 dB(A). Overall effects for systolic blood pressure were positive but weak for children as well as adults without any statistical significance. For diastolic blood pressure there appeared to be no relationship with chronic exposure to road traffic noise in either of the two groups. Considering the multiple methodological limitations of studies examined as well as the high level of heterogeneity in all random effects models, the estimated overall effects must be interpreted with caution. To examine potential associations between road traffic noise and arterial hypertension or measured blood pressure appropriately, more prospective cohort studies are necessary with precise assessments of noise exposure as well as clinical endpoints and with adjustments for relevant cofactors.

Efficacy of hearing conservation education programs for youth and young adults: a systematic review

BackgroundMany youth and young adults experience high noise exposure compounded by lack of access to hearing health education. Although the need for hearing health education programs is evident, the efficacy of these programs for youth is unclear. We evaluated the literature for efficacy of various hearing conservation programs aimed at youth and young adults, and analyzed their strengths and limitations.MethodsStudies reporting results of hearing conservation or hearing loss prevention programs with youth or young adults, using randomized controlled trials, quasi-experimental designs, experimental design, or qualitative research, and published in peer-reviewed journals in English between 2001 and 2018 were included. Studies were found through searches of selected literature databases (i.e., PubMed, Google Scholar, NIOSH Toxline, and Scopus). Identified publications were assessed for relevance, and data were extracted from the studies deemed relevant.ResultsA total of 10 studies were included. Very little evidence of efficacy of hearing conservation educational programs was found in these studies. Several methodological limitations including lack of rigorous study designs, inadequate power, and application of inappropriate statistical analysis were noted. Some use of technology in programs (e.g., smartphone apps, mobile phone text messages, and computers) was observed, but conclusions as to the effectiveness of these tools were limited by the small number of studies and small sample sizes.ConclusionsThe number of studies of educational hearing conservation programs for youth and young adults was low. The efficacy of the program was not reported in most studies, and it is difficult to draw public health conclusions from these studies due to their multiple methodological limitations. While use of technology in hearing conservation educational programs offers promise, its effectiveness has not been studied.

Estimating the Population Size of Female Sex Workers in Three South African Cities: Results and Recommendations From the 2013-2014 South Africa Health Monitoring Survey and Stakeholder Consensus.

BackgroundRobust population size estimates of female sex workers and other key populations in South Africa face multiple methodological limitations, including inconsistencies in surveillance and programmatic indicators. This has, consequently, challenged the appropriate allocation of resources and benchmark-setting necessary to an effective HIV response. A 2013-2014 integrated biological and behavioral surveillance (IBBS) survey from South Africa showed alarmingly high HIV prevalence among female sex workers in South Africa’s three largest cities of Johannesburg (71.8%), Cape Town (39.7%), and eThekwini (53.5%). The survey also included several multiplier-based population size estimation methods.ObjectiveThe objective of our study was to present the selected population size estimation methods used in an IBBS survey and the subsequent participatory process used to estimate the number of female sex workers in three South African cities.MethodsIn 2013-2014, we used respondent-driven sampling to recruit independent samples of female sex workers for IBBS surveys in Johannesburg, Cape Town, and eThekwini. We embedded multiple multiplier-based population size estimation methods into the survey, from which investigators calculated weighted estimates and ranges of population size estimates for each city’s female sex worker population. Following data analysis, investigators consulted civil society stakeholders to present survey results and size estimates and facilitated stakeholder vetting of individual estimates to arrive at consensus point estimates with upper and lower plausibility bounds.ResultsIn total, 764, 650, and 766 female sex workers participated in the survey in Johannesburg, Cape Town, and eThekwini, respectively. For size estimation, investigators calculated preliminary point estimates as the median of the multiple estimation methods embedded in the IBBS survey and presented these to a civil society-convened stakeholder group. Stakeholders vetted all estimates in light of other data points, including programmatic experience, ensuring inclusion only of plausible point estimates in median calculation. After vetting, stakeholders adopted three consensus point estimates with plausible ranges: Johannesburg 7697 (5000-10,895); Cape Town 6500 (4579-9000); eThekwini 9323 (4000-10,000).ConclusionsUsing several population size estimates methods embedded in an IBBS survey and a participatory stakeholder consensus process, the South Africa Health Monitoring Survey produced female sex worker size estimates representing approximately 0.48%, 0.49%, and 0.77% of the adult female population in Johannesburg, Cape Town, and eThekwini, respectively. In data-sparse environments, stakeholder engagement and consensus is critical to vetting of multiple empirically based size estimates procedures to ensure adoption and utilization of data-informed size estimates for coordinated national and subnational benchmarking. It also has the potential to increase coherence in national and key population-specific HIV responses and to decrease the likelihood of duplicative and wasteful resource allocation. We recommend building cooperative and productive academic-civil society partnerships around estimates and other strategic information dissemination and sharing to facilitate the incorporation of additional data as it becomes available, as these additional data points may minimize the impact of the known and unknown biases inherent in any single, investigator-calculated method.

Peri-operative chemotherapy for muscle-invasive bladder cancer: status-quo in 2017.

The role of perioperative chemotherapy associated with radical cystectomy (RC) for muscle-invasive bladder cancer has been analyzed in several landmark randomized controlled trials (RCTs) over the past decades. With regard to neoadjuvant chemotherapy (NAC), a meta-analysis of level 1 evidence and long-term results from the largest RCTs support its use, which is currently advocated as the standard of care by most of the clinical guidelines worldwide. However, with regard to the delivery of adjuvant chemotherapy (AC), evidence is more contentious. Specifically, several meta-analyses demonstrated a survival benefit associated with the use of cisplatin-based regimen but investigators identified multiple methodological limitations in most of included RCTs. Nonetheless, AC is currently considered for fit patients with adverse pathological features at RC. It is noteworthy that the delivery of such cytotoxic treatment after surgery may maintain significant anti-tumor activity even in those patients who previously received NAC. Finally, given its greater response rate, the methotrexate, vinblastine, adriamycin plus cisplatin combination remains preferentially considered in the neoadjuvant setting, while the gemcitabine plus cisplatin combination is more commonly delivered in the adjuvant setting because of its better toxicity profile. However, no prospective evidence comparing efficacy of both regimens for NAC or AC is currently available.

Thrombophilia and assisted reproduction technology-any detrimental impact or unnecessary overuse?

The aim of this study is to provide an overview of the studies investigating a possible association between thrombophilia and assisted reproductive technology (ART) outcome. This is a literature review. Congenital thrombophilias (CoT) are reported to be associated with pregnancy loss. However, the association between CoT and early pregnancy loss is weak and does not necessarily support causation. CoT are more likely to be associated with late fetal loss. Even though data pooled from case-control and cohort studies suggest an increased risk of ART failure in women with CoTs, there seems no association when the analysis is confined to better quality cohort studies. The evidence supporting anticoagulation to improve ART outcome in CoT carriers is weak. Likewise, studies on antiphospholipid antibodies (APAs) and ART outcome suffer from multiple methodological limitations and a detrimental impact of APA positivity is controversial. Empirical administration of heparin or low molecular weight heparin to women with recurrent ART failures is supported by weak evidence. Importantly, thrombophilias are likely to increase thrombotic complications after ovarian stimulation for ART. Current evidence does not support routinely testing for or treatment of thrombophilia in the setting of ART nor in couples with implantation failure. A careful personal and family history should be obtained and a risk assessment for thrombotic complications should be made in every woman undergoing ovarian stimulation. If positive, testing for thrombophilia is warranted.

Cognitive functioning in meningioma patients: a systematic review.

This systematic review evaluates relevant findings and methodologic aspects of studies on cognitive functioning in meningioma patients prior to and/or following surgery with or without adjuvant radiotherapy. PubMed and Web of Science electronic databases were searched until December 2015. From 1012 initially identified articles, 11 met the inclusion criteria for this review. Multiple methodological limitations were identified which include the lack of pre-treatment assessments, variations in the number and types of neuropsychological tests used, the normative data used to identify patients with cognitive deficits, and the variety of definitions for cognitive impairment. Study results suggest that most of meningioma patients are faced with cognitive deficits in several cognitive domains prior to surgery. Following surgery, most of these patients seem to improve in cognitive functioning. However, they still have impairments in a wide range of cognitive functions compared to healthy controls. Suggestions are given for future research. Adequate diagnosis and treatment of cognitive deficits may ultimately lead to improved outcome and quality of life in meningioma patients.

Environmental exposure to metals, neurodevelopment, and psychosis.

This article presents a new hypothesis about the possible relation between early life exposure to metals and psychosis. We review limitations of available research, and discuss novel approaches to overcome previous methodological barriers. Mechanistic studies suggest a possible association between excess lead, manganese, cadmium, arsenic, or copper, and zinc deficiency, and several biochemical disturbances related to psychosis, such as altered neurotransmitters levels, excitotoxicity, and inflammation. Furthermore, studies suggest that some metals (lead, manganese, cadmium excess, and zinc deficiency) are associated with schizophrenia or psychosis-related phenotype. However, previous studies had multiple methodological limitations. Importantly, metal exposure was often measured after disease development and seldom determined during critical developmental periods. Most studies fell short of depicting the exact timing of exposure and the change in exposure over time. Here, we propose several methods to overcome these methodological limitations. There is a plausible role of early life exposure to metals in the cause of psychosis. Owing to methodological limitations in exposure measurement, this has not been well characterized. Considering the wide exposure to metals and the high cost of psychosis to society, this hypothesis should be rigorously examined.

Risk assessment and predicting outcomes in patients with depressive symptoms: a review of potential role of peripheral blood based biomarkers.

Depression is one of the major global health challenges and a leading contributor of health related disability and costs. Depression is a heterogeneous disorder and current methods for assessing its severity in clinical practice rely on symptom count, however this approach is unreliable and inconsistent. The clinical evaluation of depressive symptoms is particularly challenging in primary care, where the majority of patients with depression are managed, due to the presence of co-morbidities. Current methods for risk assessment of depression do not accurately predict treatment response or clinical outcomes. Several biological pathways have been implicated in the pathophysiology of depression; however, accurate and predictive biomarkers remain elusive. We conducted a systematic review of the published evidence supporting the use of peripheral biomarkers to predict outcomes in depression, using Medline and Embase. Peripheral biomarkers in depression were found to be statistically significant predictors of mental health outcomes such as treatment response, poor outcome and symptom remission; and physical health outcomes such as increased incidence of cardiovascular events and deaths, and all-cause mortality. However, the available evidence has multiple methodological limitations which must be overcome to make any real clinical progress. Despite extensive research on the relationship of depression with peripheral biomarkers, its translational application in practice remains uncertain. In future, peripheral biomarkers identified with novel techniques and combining multiple biomarkers may have a potential role in depression risk assessment but further research is needed in this area.

Predicting return to play after hamstring injuries

BackgroundPrevious studies on the prognostic value of clinical and MRI parameters for the time to return to play (TTRTP) in acute hamstring injuries showed only limited to moderate evidence for...

Mindfulness-Enhanced Cognitive Behavior Therapy for Problem Gambling: A Controlled Pilot Study

In recent years, mindfulness meditation has shown to be a promising approach for alleviating disability and dysfunction associated with a wide range of medical and psychiatric conditions. To date, there have been no controlled clinical studies of mindfulness for problem gambling (beyond case studies) despite the well-established presence of irrational beliefs and cognitive distortions which would suggest that mindfulness interventions would be particularly suitable. In the present study, a group, five-session, mindfulness intervention was integrated into an empirically-effective cognitive-behavioral therapy for problem gamblers. Compared to a wait list control the mindfulness intervention significantly reduced the severity of gambling, gambling urges and psychiatric symptoms at end-of-treatment. At the 3-month follow-up combining the results of both groups the results were maintained. In addition, a significant decrease in the proportion of the sample meeting criteria for pathological gambling was found. Those individuals who reported some mindfulness practice post-treatment showed significantly better clinical outcomes than did those who did not report any mindfulness practice suggesting that mindfulness did play a role in the outcomes observed. Taking into consideration the multiple methodological limitations of this pilot study there is sufficient evidence to further investigate the potential efficacy of mindfulness interventions for problem gambling.

A Systematic Review to Identify Challenges of Demonstrating Efficacy of HIV Behavioral Interventions for Gay, Bisexual, and Other Men Who Have Sex with Men (MSM)

Gay, bisexual, and other men who have sex with men (MSM) are disproportionately affected by HIV but few MSM-specific evidence-based interventions (EBIs) have been identified for this vulnerable group. We conducted a systematic review to identify reasons for the small number of EBIs for MSM. We also compared study, intervention and sample characteristics of EBIs versus non-EBIs to better understand the challenges of demonstrating efficacy evidence. Thirty-three MSM-specific studies were evaluated: Nine (27 %) were considered EBIs while 24 (73 %) were non-EBIs. Non-EBIs had multiple methodological limitations; the most common was not finding a significant positive effect. Compared to EBIs, non-EBIs were less likely to use peer intervention deliverers, include sexual communication in their interventions, and intervene at the community level. Incorporating characteristics associated with EBIs may strengthen behavioral interventions for MSM. More EBIs are needed for substance-using MSM, MSM of color, MSM residing in the south and MSM in couples.

Duration of gestation, size at birth and later childhood behaviour

Although many previous studies have reported an association between preterm birth or small size at birth and later behaviour, multiple methodological limitations threaten the validity of causal inferences from reported associations. The authors have examined the association between gestational age and gestational age-specific size at birth (weight, length and head circumference) and behaviour in a large sample of children born healthy at term. The data were from the 6.5-year follow-up of 13,889 Belarusian children who participated in the Promotion of Breastfeeding Intervention Trial, a cluster-randomised trial of a breast-feeding promotion intervention. Child behaviour was measured using the parent and teacher versions of the Strengths and Difficulties Questionnaire (SDQ). Differences in SDQ scores by gestational age and by birthweight, birth length and birth head circumference standardised for gestational age and sex (z-scores) were analysed after controlling for potentially confounding maternal and family factors. There was no association between gestational age and child behaviour after adjusting for potential confounding factors. Lower birthweight-for-gestational age was associated with higher scores in problem behaviours including total difficulties, conduct problems, hyperactivity, emotional symptoms and peer problems. Similar but smaller differences were observed with birth length and birth head circumference, but those differences were attenuated with adjustment for birthweight. The patterns of association were consistent in both parent and teacher assessments. Among school-age children born at term within normal range of birthweight, fetal growth, but not gestational age, was associated with behavioural problem scores.