Characterization of Rheumatoid Arthritis Subtypes Using Symptom Profiles, Clinical Chemistry and Metabolomics Measurements

Objective

The aim is to characterize subgroups or phenotypes of rheumatoid arthritis (RA) patients using a systems biology approach. The discovery of subtypes of rheumatoid arthritis patients is an essential research area for the improvement of response to therapy and the development of personalized medicine strategies.

Methods

In this study, 39 RA patients are phenotyped using clinical chemistry measurements, urine and plasma metabolomics analysis and symptom profiles. In addition, a Chinese medicine expert classified each RA patient as a Cold or Heat type according to Chinese medicine theory. Multivariate data analysis techniques are employed to detect and validate biochemical and symptom relationships with the classification.

Results

The questionnaire items ‘Red joints’, ‘Swollen joints’, ‘Warm joints’ suggest differences in the level of inflammation between the groups although c-reactive protein (CRP) and rheumatoid factor (RHF) levels were equal. Multivariate analysis of the urine metabolomics data revealed that the levels of 11 acylcarnitines were lower in the Cold RA than in the Heat RA patients, suggesting differences in muscle breakdown. Additionally, higher dehydroepiandrosterone sulfate (DHEAS) levels in Heat patients compared to Cold patients were found suggesting that the Cold RA group has a more suppressed hypothalamic-pituitary-adrenal (HPA) axis function.

Conclusion

Significant and relevant biochemical differences are found between Cold and Heat RA patients. Differences in immune function, HPA axis involvement and muscle breakdown point towards opportunities to tailor disease management strategies to each of the subgroups RA patient.     

Coding, recording and incidence of different forms of coronary heart disease in primary care

Objectives

To evaluate the coding, recording and incidence of coronary heart disease (CHD) in primary care electronic medical records.

Methods

Data were drawn from the UK General Practice Research Database. Analyses evaluated the occurrence of 271 READ medical diagnostic codes, including categories for ‘Angina’, ‘Myocardial Infarction’, ‘Coronary Artery Bypass Grafting’ (CABG), ‘percutaneous transluminal coronary angioplasty’ (PCTA) and ‘Other Coronary Heart Disease’. Time-to-event analyses were implemented to evaluate occurrences of different groups of codes after the index date.

Results

Among 300,020 participants aged greater than 30 years there were 75,197 unique occurrences of coronary heart disease codes in 24,244 participants, with 12,495 codes for incident events and 62,702 for prevalent events. Among incident event codes, 3,607 (28.87%) were for angina, 3,262 (26.11%) were for MI, 514 (4.11%) for PCTA, 161 (1.29%) for CABG and 4,951 (39.62%) were for ‘Other CHD’. Among prevalent codes, 20,254 (32.30%) were for angina, 3,644 (5.81%) for MI, 34,542 (55.09%) for ‘Other CHD’ and 4,262 (6.80%) for CABG or PCTA. Among 3,685 participants initially diagnosed exclusively with ‘Other CHD’ codes, 17.1% were recorded with angina within 5 years, 5.6% with myocardial infarction, 6.3% with CABG and 8.6% with PCTA. From 2000 to 2010, the overall incidence of CHD declined, as did the incidence of angina, but the incidence of MI did not change. The frequency of CABG declined, while PCTA increased.

Conclusion

In primary care electronic records, a substantial proportion of coronary heart disease events are recorded with codes that do not distinguish between different clinical presentations of CHD. The results draw attention to the need to improve coding practice in primary care. The results also draw attention to the importance of code selection in research studies and the need for sensitivity analyses using different sets of codes.     

Source of previous treatment for re-treatment TB cases registered under the National TB control Programme, India, 2010

Background

In 2009, nearly half (289,756) of global re-treatment TB notifications are from India; no nationally-representative data on the source of previous treatment was available to inform strategies for improvement of initial TB treatment outcome.

Objectives

To assess the source of previous treatment for re-treatment TB patients registered under India''s Revised National TB control Programme (RNTCP).

Methodology

A nationally-representative cross sectional study was conducted in a sample of 36 randomly-selected districts. All consecutively registered retreatment TB patients during a defined 15-day period in these 36 districts were contacted and the information on the source of previous treatment sought.

Results

Data was collected from all 1712 retreatment TB patients registered in the identified districts during the study period. The data includes information on 595 ‘relapse’ cases, 105 ‘failure’ cases, 437 ‘treatment after default (TAD)’ cases and 575 ‘re-treatment others’ cases. The source of most recent previous anti-tuberculosis therapy for 754 [44% (95% CI, 38.2%–49.9%)] of the re-treatment TB patients was from providers outside the TB control programme. A higher proportion of patients registered as TAD (64%) and ‘retreatment others’ (59%) were likely to be treated outside the National Programme, when compared to the proportion among ‘relapse’ (22%) or ‘failure’ (6%). Extrapolated to national registration, of the 292,972 re-treatment registrations in 2010, 128,907 patients would have been most recently treated outside the national programme.

Conclusions

Nearly half of the re-treatment cases registered with the national programme were most recently treated outside the programme setting. Enhanced efforts towards extending treatment support and supervision to patients treated by private sector treatment providers are urgently required to improve the quality of treatment and reduce the numbers of patients with recurrent disease. In addition, reasons for the large number of recurrent TB cases from those already treated by the national programme require urgent detailed investigation.     

Of Asian forests and European fields: Eastern U.S. plant invasions in a global floristic context

Background

Biogeographic patterns of species invasions hold important clues to solving the recalcitrant ‘who’, ‘where’, and ‘why’ questions of invasion biology, but the few existing studies make no attempt to distinguish alien floras (all non-native occurrences) from invasive floras (rapidly spreading species of significant management concern), nor have invasion biologists asked whether particular habitats are consistently invaded by species from particular regions.

Methodology/Principal Findings

Here I describe the native floristic provenances of the 2629 alien plant taxa of the Eastern Deciduous Forest of the Eastern U.S. (EUS), and contrast these to the subset of 449 taxa that EUS management agencies have labeled ‘invasive’. Although EUS alien plants come from all global floristic regions, nearly half (45%) have native ranges that include central and northern Europe or the Mediterranean (39%). In contrast, EUS invasive species are most likely to come from East Asia (29%), a pattern that is magnified when the invasive pool is restricted to species that are native to a single floristic region (25% from East Asia, compared to only 11% from northern/central Europe and 2% from the Mediterranean). Moreover, East Asian invaders are mostly woody (56%, compared to just 23% of the total alien flora) and are significantly more likely to invade intact forests and riparian areas than European species, which dominate managed or disturbed ecosystems.

Conclusions/Significance

These patterns suggest that the often-invoked ‘imperialist dogma’ view of global invasions equating invasion events with the spread of European colonialism is at best a restricted framework for invasion in disturbed ecosystems. This view must be superseded by a biogeographic invasion theory that is explicitly habitat-specific and can explain why particular world biotas tend to dominate particular environments.     

Graduate entry medicine: selection criteria and student performance

Background

Graduate entry medicine raises new questions about the suitability of students with different backgrounds. We examine this, and the broader issue of effectiveness of selection and assessment procedures.

Methods

The data included background characteristics, academic record, interview score and performance in pre-clinical modular assessment for two years intake of graduate entry medical students. Exploratory factor analysis is a powerful method for reducing a large number of measures to a smaller group of underlying factors. It was used here to identify patterns within and between the selection and performance data.

Principal Findings

Basic background characteristics were of little importance in predicting exam success. However, easily interpreted components were detected within variables comprising the ‘selection’ and ‘assessment’ criteria. Three selection components were identified (‘Academic’, ‘GAMSAT’, ‘Interview’) and four assessment components (‘General Exam’, ‘Oncology’, ‘OSCE’, ‘Family Case Study’). There was a striking lack of relationships between most selection and performance factors. Only ‘General Exam’ and ‘Academic’ showed a correlation (Pearson''s r = 0.55, p<0.001).

Conclusions

This study raises questions about methods of student selection and their effectiveness in predicting performance and assessing suitability for a medical career. Admissions tests and most exams only confirmed previous academic achievement, while interview scores were not correlated with any consequent assessment.     

Extracting diagnoses and investigation results from unstructured text in electronic health records by semi-supervised machine learning

Background

Electronic health records are invaluable for medical research, but much of the information is recorded as unstructured free text which is time-consuming to review manually.

Aim

To develop an algorithm to identify relevant free texts automatically based on labelled examples.

Methods

We developed a novel machine learning algorithm, the ‘Semi-supervised Set Covering Machine’ (S3CM), and tested its ability to detect the presence of coronary angiogram results and ovarian cancer diagnoses in free text in the General Practice Research Database. For training the algorithm, we used texts classified as positive and negative according to their associated Read diagnostic codes, rather than by manual annotation. We evaluated the precision (positive predictive value) and recall (sensitivity) of S3CM in classifying unlabelled texts against the gold standard of manual review. We compared the performance of S3CM with the Transductive Vector Support Machine (TVSM), the original fully-supervised Set Covering Machine (SCM) and our ‘Freetext Matching Algorithm’ natural language processor.

Results

Only 60% of texts with Read codes for angiogram actually contained angiogram results. However, the S3CM algorithm achieved 87% recall with 64% precision on detecting coronary angiogram results, outperforming the fully-supervised SCM (recall 78%, precision 60%) and TSVM (recall 2%, precision 3%). For ovarian cancer diagnoses, S3CM had higher recall than the other algorithms tested (86%). The Freetext Matching Algorithm had better precision than S3CM (85% versus 74%) but lower recall (62%).

Conclusions

Our novel S3CM machine learning algorithm effectively detected free texts in primary care records associated with angiogram results and ovarian cancer diagnoses, after training on pre-classified test sets. It should be easy to adapt to other disease areas as it does not rely on linguistic rules, but needs further testing in other electronic health record datasets.     

Good clinical teachers likely to be specialist role models: results from a multicenter cross-sectional survey

Context

Medical educational reform includes enhancing role modelling of clinical teachers. This requires faculty being aware of their role model status and performance. We developed the System for Evaluation of Teaching Qualities (SETQ) to generate individualized feedback on previously defined teaching qualities and role model status for faculty in (non) academic hospitals.

Objectives

(i) To examine whether teaching qualities of faculty were associated with their being seen as a specialist role model by residents, and (ii) to investigate whether those associations differed across residency years and specialties.

Methods & Materials

Cross-sectional questionnaire survey amongst 549 Residents of 36 teaching programs in 15 hospitals in the Netherlands. The main outcome measure was faculty being seen as specialist role models by residents. Statistical analyses included (i) Pearson''s correlation coefficients and (ii) multivariable logistic generalized estimating equations to assess the (adjusted) associations between each of five teaching qualities and ‘being seen as a role model’.

Results

407 residents completed a total of 4123 evaluations of 662 faculty. All teaching qualities were positively correlated with ‘being seen as a role model’ with correlation coefficients ranging from 0.49 for ‘evaluation of residents’ to 0.64 for ‘learning climate’ (P<0.001). Faculty most likely to be seen as good role models were those rated highly on ‘feedback’ (odds ratio 2.91, 95% CI: 2.41–3.51), ‘a professional attitude towards residents’ (OR 2.70, 95% CI: 2.34–3.10) and ‘creating a positive learning climate’ (OR 2.45, 95% CI: 1.97–3.04). Results did not seem to vary much across residency years. The relative strength of associations between teaching qualities and being seen as a role model were more distinct when comparing specialties.

Conclusions

Good clinical educators are more likely to be seen as specialist role models for most residents.     

Repetitive Behaviours in Patients with Gilles de la Tourette Syndrome: Tics,Compulsions, or Both?

Background

Repetitive behaviours (RB) in patients with Gilles de la Tourette syndrome (GTS) are frequent. However, a controversy persists whether they are manifestations of obssessive-compulsive disorder (OCD) or correspond to complex tics.

Methods

166 consecutive patients with GTS aged 15–68 years were recruited and submitted to extensive neurological, psychiatric and psychological evaluations. RB were evaluated by the YBOCS symptom checklist and Mini International Neuropsychiatric Interview (M.I.N.I), and classified on the basis of a semi-directive psychiatric interview as compulsions or tics.

Results

RB were present in 64.4% of patients with GTS (107/166) and categorised into 3 major groups: a ‘tic-like’ group (24.3%–40/166) characterised by RB such as touching, counting, ‘just right’ and symmetry searching; an ‘OCD-like’ group (20.5%–34/166) with washing and checking rituals; and a ‘mixed’ group (13.2%–22/166) with both ‘tics-like’ and ‘OCD-like’ types of RB present in the same patient. In 6.3% of patients, RB could not be classified into any of these groups and were thus considered ‘undetermined’.

Conclusions

The results confirm the phenomenological heterogeneity of RB in GTS patients and allows to distinguish two types: tic-like behaviours which are very likely an integral part of GTS; and OCD-like behaviours, which can be considered as a comorbid condition of GTS and were correlated with higher score of complex tics, neuroleptic and SSRIs treatment frequency and less successful socio-professional adaptation. We suggest that a meticulous semiological analysis of RB in GTS patients will help to tailor treatment and allow to better classify patients for future pathophysiologic studies.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00169351","term_id":"NCT00169351"}}NCT00169351     

From Where Are Tuberculosis Patients Accessing Treatment in India? Results from a Cross-Sectional Community Based Survey of 30 Districts

Background

Tuberculosis (TB) notification in India by the Revised National TB Control Programme (RNTCP) provides information on TB patients registered for treatment from the programme. There is limited information about the proportion of patients treated for TB outside RNTCP and where these patients access their treatment.

Objectives

To estimate the proportion of patients accessing TB treatment outside the RNTCP and to identify their basic demographic characteristics.

Methods

A cross sectional community-based survey in 30 districts. Patients were identified through a door-to-door survey and interviewed using a semi-structured questionnaire.

Results

Of the estimated 75,000 households enumerated, 73,249 households (97.6%) were visited. Of the 371,174 household members, 761 TB patients were identified (∼205 cases per 100,000 populations). Data were collected from 609 (80%) TB patients of which 331 [54% (95% CI: 42–66%)] were determined to be taking treatment ‘under DOTS/RNTCP’. The remaining 278 [46% (95% CI: 34–57%)] were on treatment from ‘outside DOTS/RNTCP’ sources and hence were unlikely to be part of the TB notification system. Patients who were accessing treatment from ‘outside DOTS/RNTCP’ were more likely to be patients from rural areas [adjusted Odds Ratio (aOR) 2.5, 95% CI (1.2–5.3)] and whose TB was diagnosed in a non-government health facility (aOR 14.0, 95% CI 7.9–24.9).

Conclusions

This community-based survey found that nearly half of self-reported TB patients were missed by TB notification system in these districts. The study highlights the need for 1) Reviewing and revising the scope of the TB notification system, 2) Strengthening and monitoring health care delivery systems with periodic assessment of the reach and utilisation of the RNTCP services especially among rural communities, 3) Advocacy, communication and social mobilisation activities focused at rural communities with low household incomes and 4) Inclusive involvement of all health-care providers, especially providers of poor rural communities.     

The effect of interpersonal psychotherapy and other psychodynamic therapies versus 'treatment as usual' in patients with major depressive disorder

Background

Major depressive disorder afflicts an estimated 17% of individuals during their lifetimes at tremendous suffering and costs. Interpersonal psychotherapy and other psychodynamic therapies may be effective interventions for major depressive disorder, but the effects have only had limited assessment in systematic reviews.

Methods/Principal Findings

Cochrane systematic review methodology with meta-analysis and trial sequential analysis of randomized trials comparing the effect of psychodynamic therapies versus ‘treatment as usual’ for major depressive disorder. To be included the participants had to be older than 17 years with a primary diagnosis of major depressive disorder. Altogether, we included six trials randomizing a total of 648 participants. Five trials assessed ‘interpersonal psychotherapy’ and only one trial assessed ‘psychodynamic psychotherapy’. All six trials had high risk of bias. Meta-analysis on all six trials showed that the psychodynamic interventions significantly reduced depressive symptoms on the 17-item Hamilton Rating Scale for Depression (mean difference −3.12 (95% confidence interval −4.39 to −1.86;P<0.00001), no heterogeneity) compared with ‘treatment as usual’. Trial sequential analysis confirmed this result.

Discussion

We did not find convincing evidence supporting or refuting the effect of interpersonal psychotherapy or psychodynamic therapy compared with ‘treatment as usual’ for patients with major depressive disorder. The potential beneficial effect seems small and effects on major outcomes are unknown. Randomized trials with low risk of systematic errors and low risk of random errors are needed.     

Maternal malaria, birth size and blood pressure in Nigerian newborns: insights into the developmental origins of hypertension from the Ibadan growth cohort

Background

Hypertension is an increasing health issue in sub-Saharan Africa where malaria remains common in pregnancy. We established a birth cohort in Nigeria to evaluate the early impact of maternal malaria on newborn blood pressure (BP).

Methods

Anthropometric measurements, BP, blood films for malaria parasites and haematocrit were obtained in 436 mother-baby pairs. Women were grouped to distinguish between the timing of malaria parasitaemia as ‘No Malaria’, ‘Malaria during pregnancy only’ or ‘Malaria at delivery’, and parasite density as low (<1000 parasites/µl of blood) and high (≥1000/µl).

Results

Prevalence of maternal malaria parasitaemia was 48%, associated with younger maternal age (p<0.001), being primigravid (p = 0.022), lower haematocrit (p = 0.028). High parasite density through pregnancy had the largest effect on mean birth indices so that weight, length, head and mid-upper arm circumferences were smaller by 300 g, 1.1 cm, 0.7 cm and 0.4 cm respectively compared with ‘No malaria’ (all p≤0.005). In babies of mothers who had ‘malaria at delivery’, their SBPs adjusted for other confounders were lower respectively by 4.3 and 5.7 mmHg/kg compared with ‘malaria during pregnancy only’ or ‘none’. In contrast the mean newborn systolic (SBP) and diastolic BPs (DBP) adjusted for birth weight were higher by 1.7 and 1.4 mmHg/kg respectively in babies whose mothers had high compared with low parasitaemia.

Conclusions

As expected, prenatal malarial exposure had a significant impact on fetal growth rates. Malaria at delivery was associated with the lowest newborn BPs while malaria through pregnancy, which may attenuate growth of the vascular network, generated higher newborn BPs adjusted for size. These neonatal findings have potential implications for cardiovascular health in sub-Saharan Africa.     

Preventing nerve function impairment in leprosy: validation and updating of a prediction rule

Background

To validate and update a prediction rule for estimating the risk of leprosy-related nerve function impairment (NFI).

Methodology/Principal Findings

Prospective cohort using routinely collected data, in which we determined the discriminative ability of a previously published rule and an updated rule with a concordance statistic (c). Additional risk factors were analyzed with a Cox proportional hazards regression model. The population consisted of 1,037 leprosy patients newly diagnosed between 2002 and 2003 in the health care facilities of the Rural Health Program in Nilphamari and Rangpur districts in northwest Bangladesh. The primary outcome was the time until the start of treatment. An NFI event was defined as the decision to treat NFI with corticosteroids after diagnosis. NFI occurred in 115 patients (13%; 95% confidence interval 11%–16%). The original prediction rule had adequate discriminative ability (c = 0.79), but could be improved by substituting one predicting variable: ‘long-standing nerve function impairment at diagnosis’ by ‘anti-PGL-I antibodies’. The adjusted prediction rule was slightly better (c = 0.81) and identified more patients with NFI (80%) than the original prediction rule (72%).

Conclusions/Significance

NFI can well be predicted by using the risk variables ‘leprosy classification’ and ‘anti-PGL-I antibodies’. The use of these two variables that do not include NFI offer the possibility of predicting NFI, even before it occurs for the first time. Surveillance beyond the treatment period can be targeted to those most likely to benefit from preventing permanent disabilities.     

Screening strategies for tuberculosis prevalence surveys: the value of chest radiography and symptoms

Background

We conducted a tuberculosis (TB) prevalence survey and evaluated the screening methods used in our survey, to assess if screening in TB prevalence surveys could be simplified, and to assess the accuracy of screening algorithms that may be applicable for active case finding.

Methods

All participants with a positive screen on either a symptom questionnaire, chest radiography (CXR) and/or sputum smear microscopy submitted sputum for culture. HIV status was obtained from prevalent cases. We estimated the accuracy of modified screening strategies with bacteriologically confirmed TB as the gold standard, and compared these with other survey reports. We also assessed whether sequential rather than parallel application of symptom, CXR and HIV screening would substantially reduce the number of participants requiring CXR and/or sputum culture.

Results

Presence of any abnormality on CXR had 94% (95%CI 88–98) sensitivity (92% in HIV-infected and 100% in HIV-uninfected) and 73% (95%CI 68–77) specificity. Symptom screening combinations had significantly lower sensitivity than CXR except for ‘any TB symptom’ which had 90% (95%CI 84–95) sensitivity (96% in HIV-infected and 82% in HIV-uninfected) and 32% (95%CI 30–34) specificity. Smear microscopy did not yield additional suspects, thus the combined symptom/CXR screen applied in the survey had 100% (95%CI 97–100) sensitivity. Specificity was 65% (95%CI 61–68). Sequential application of first a symptom screen for ‘any symptom’, followed by CXR-evaluation and different suspect criteria depending on HIV status would result in the largest reduction of the need for CXR and sputum culture, approximately 36%, but would underestimate prevalence by 11%.

Conclusion

CXR screening alone had higher accuracy compared to symptom screening alone. Combined CXR and symptom screening had the highest sensitivity and remains important for suspect identification in TB prevalence surveys in settings where bacteriological sputum examination of all participants is not feasible.     

Diagnostic accuracy of a loop-mediated isothermal PCR assay for detection of Orientia tsutsugamushi during acute Scrub Typhus infection

Background

There is an urgent need to develop rapid and accurate point-of-care (POC) technologies for acute scrub typhus diagnosis in low-resource, primary health care settings to guide clinical therapy.

Methodology/Principal Findings

In this study we present the clinical evaluation of loop-mediated isothermal PCR assay (LAMP) in the context of a prospective fever study, including 161 patients from scrub typhus-endemic Chiang Rai, northern Thailand.A robust reference comparator set comprising following ‘scrub typhus infection criteria’ (STIC) was used: a) positive cell culture isolate and/or b) an admission IgM titer ≥1∶12,800 using the ‘gold standard’ indirect immunofluorescence assay (IFA) and/or c) a 4-fold rising IFA IgM titer and/or d) a positive result in at least two out of three PCR assays.Compared to the STIC criteria, all PCR assays (including LAMP) demonstrated high specificity ranging from 96–99%, with sensitivities varying from 40% to 56%, similar to the antibody based rapid test, which had a sensitivity of 47% and a specificity of 95%.

Conclusions/Significance

The diagnostic accuracy of the LAMP assay was similar to realtime and nested conventional PCR assays, but superior to the antibody-based rapid test in the early disease course. The combination of DNA- and antibody-based detection methods increased sensitivity with minimal reduction of specificity, and expanded the timeframe of adequate diagnostic coverage throughout the acute phase of scrub typhus.     

Sounds Scary? Lack of Habituation following the Presentation of Novel Sounds

Background

Animals typically show less habituation to biologically meaningful sounds than to novel signals. We might therefore expect that acoustic deterrents should be based on natural sounds.

Methodology

We investigated responses by western grey kangaroos (Macropus fulignosus) towards playback of natural sounds (alarm foot stomps and Australian raven (Corvus coronoides) calls) and artificial sounds (faux snake hiss and bull whip crack). We then increased rate of presentation to examine whether animals would habituate. Finally, we varied frequency of playback to investigate optimal rates of delivery.

Principal Findings

Nine behaviors clustered into five Principal Components. PC factors 1 and 2 (animals alert or looking, or hopping and moving out of area) accounted for 36% of variance. PC factor 3 (eating cessation, taking flight, movement out of area) accounted for 13% of variance. Factors 4 and 5 (relaxing, grooming and walking; 12 and 11% of variation, respectively) discontinued upon playback. The whip crack was most evocative; eating was reduced from 75% of time spent prior to playback to 6% following playback (post alarm stomp: 32%, raven call: 49%, hiss: 75%). Additionally, 24% of individuals took flight and moved out of area (50 m radius) in response to the whip crack (foot stomp: 0%, raven call: 8% and 4%, hiss: 6%). Increasing rate of presentation (12x/min ×2 min) caused 71% of animals to move out of the area.

Conclusions/Significance

The bull whip crack, an artificial sound, was as effective as the alarm stomp at eliciting aversive behaviors. Kangaroos did not fully habituate despite hearing the signal up to 20x/min. Highest rates of playback did not elicit the greatest responses, suggesting that ‘more is not always better’. Ultimately, by utilizing both artificial and biological sounds, predictability may be masked or offset, so that habituation is delayed and more effective deterrents may be produced.     

Is There Evidence for Aetiologically Distinct Subgroups of Idiopathic Congenital Talipes Equinovarus? A Case-Only Study and Pedigree Analysis

Background

Idiopathic congenital talipes equinovarus (CTEV) is a common developmental foot disorder, the aetiology of which remains largely unknown. Some aspects of the epidemiology suggest the possibility of aetiologically distinct subgroups. Previous studies consider CTEV as a homogenous entity which may conceal risk factors in particular subgroups. We investigate evidence for aetiologically distinct subgroups of CTEV.

Methods

Parents of 785 probands completed a postal questionnaire. Family pedigrees were compiled by telephone. Case-only analysis was used to investigate interactions between risk factors and sex of the proband, CTEV laterality and CTEV family history.

Results

The male∶female ratio was 2.3∶1, 58% of probands were affected bilaterally and 11% had a first-second degree family history. There were modest interactions between family history and twin births (multivariate case - only odds ratio [ORca] = 3.87, 95%CI 1.19–12.62) and family history and maternal use of folic acid supplements in early pregnancy (ORca = 0.62, 95%CI 0.38–1.01); and between sex of the proband and maternal alcohol consumption during pregnancy (female, positive history and alcohol consumed: ORca = 0.33, 95%CI 0.12–0.89). Previous reports of an interaction between maternal smoking and family history were not confirmed. Relatives of female probands were affected more often than relatives of male probands.

Conclusions

These results provide tentative evidence for aetiologically distinct CTEV subgroups. They support the ‘Carter effect’, suggesting CTEV develops though a multifactorial threshold model with females requiring a higher risk factor ‘load’, and suggest areas where future aetiological investigation might focus. Large multi-centre studies are needed to further advance understanding of this common condition.     

Relationships between xylem vessel characteristics, calculated axial hydraulic conductance and size-controlling capacity of peach rootstocks

Background and Aims

Previous studies indicate that the size-controlling capacity of peach rootstocks is associated with reductions of scion water potential during mid-day that are caused by the reduced hydraulic conductance of the rootstock. Thus, shoot growth appears to be reduced by decreases in stem water potential. The aim of this study was to investigate the mechanism of reduced hydraulic conductance in size-controlling peach rootstocks.

Methods

Anatomical measurements (diameter and frequency) of xylem vessels were determined in shoots, trunks and roots of three contrasting peach rootstocks grown as trees, each with different size-controlling characteristics: ‘Nemaguard’ (vigorous), ‘P30-135’ (intermediate vigour) and ‘K146-43’ (substantially dwarfing). Based on anatomical measurements, the theoretical axial xylem conductance of each tissue type and rootstock genotype was calculated via the Poiseuille–Hagen law.

Key Results

Larger vessel dimensions were found in the vigorous rootstock (‘Nemaguard’) than in the most dwarfing one (‘K146-43’) whereas vessels of ‘P30-135’ had intermediate dimensions. The density of vessels per xylem area in ‘Nemaguard’ was also less than in ‘P30-135’and ‘K146-43’. These characteristics resulted in different estimated hydraulic conductance among rootstocks: ‘Nemaguard’ had higher theoretical values followed by ‘P30-135’ and ‘K146-43’.

Conclusions

These data indicate that phenotypic differences in xylem anatomical characteristics of rootstock genotypes appear to influence hydraulic conductance capacity directly, and therefore may be the main determinant of dwarfing in these peach rootstocks.Key words: Prunus, rootstock, vessel diameter, hydraulic conductance, dwarfing, xylem anatomy, Poiseuille–Hagen     

Acute pain and a motivational pathway in adult rats: influence of early life pain experience

Background

The importance of neonatal experience upon behaviour in later life is increasingly recognised. The overlap between pain and reward pathways led us to hypothesise that neonatal pain experience influences reward-related pathways and behaviours in adulthood.

Methodology/Principal Findings

Rat pups received repeat plantar skin incisions (neonatal IN) or control procedures (neonatal anesthesia only, AN) at postnatal days (P)3, 10 and 17. When adult, rats with neonatal ‘pain history’ showed greater sensory sensitivity than control rats following acute plantar skin incision. Motivational behaviour in the two groups of rats was tested in a novelty-induced hypophagia (NIH) paradigm. The sensitivity of this paradigm to pain-induced changes in motivational behaviour was shown by significant increases in the time spent in the central zone of the arena (43.7±5.9% vs. 22.5±6.7%, p<0.05), close to centrally placed food treats, and decreased number of rears (9.5±1.4 vs. 19.2±2.3, p<0.001) in rats with acute plantar skin incision compared to naive, uninjured animals. Rats with a neonatal ‘pain history’ showed the same pain-induced behaviour in the novelty-induced hypophagia paradigm as controls. However, differences were observed in reward-related neural activity between the two groups. Two hours after behavioural testing, brains were harvested and neuronal activity mapped using c-Fos expression in lateral hypothalamic orexin neurons, part of a specific reward seeking pathway. Pain-induced activity in orexin neurons of control rats (18.4±2.8%) was the same as in uninjured naive animals (15.5±2.6%), but in those rats with a ‘pain history’, orexinergic activity was significantly increased (27.2±4.1%, p<0.01). Furthermore the extent of orexin neuron activation in individual rats with a ‘pain history’ was highly correlated with their motivational behaviour (r = −0.86, p = 0.01).

Conclusions/Significance

These results show that acute pain alters motivational behaviour and that neonatal pain experience causes long-term changes in brain motivational orexinergic pathways, known to modulate mesolimbic dopaminergic reward circuitry.     

Losing the ability in activities of daily living in the oldest old: a hierarchic disability scale from the Newcastle 85+ study

Objectives

To investigate the order in which 85 year olds develop difficulty in performing a wide range of daily activities covering basic personal care, household care and mobility.

Design

Cross-sectional analysis of baseline data from a cohort study.

Setting

Newcastle upon Tyne and North Tyneside, UK.

Participants

Individuals born in 1921, registered with participating general practices.

Measurements

Detailed health assessment including 17 activities of daily living related to basic personal care, household care and mobility. Questions were of the form ‘Can you …’ rather than ‘Do you…’ Principal Component Analysis (PCA) was used to confirm a single underlying dimension for the items and Mokken Scaling was used to determine a subsequent hierarchy. Validity of the hierarchical scale was assessed by its associations with known predictors of disability.

Results

839 people within the Newcastle 85+ study for whom complete information was available on self-reported Activities of Daily Living (ADL). PCA confirmed a single underlying dimension; Mokken scaling confirmed a hierarchic scale where ‘Cutting toenails’ was the first item with which participants had difficulty and ‘feeding’ the last. The ordering of loss differed between men and women. Difficulty with ‘shopping’ and ‘heavy housework’ were reported earlier by women whilst men reported ‘walking 400 yards’ earlier. Items formed clusters corresponding to strength, balance, lower and upper body involvement and domains specifically required for balance and upper/lower limb functional integrity.

Conclusion

This comprehensive investigation of ordering of ability in activities in 85 year olds will inform researchers and practitioners assessing older people for onset of disability and subsequent care needs.