Choosing Optimal Microcarcinoma Patients for Active Surveillance Study (Compass): Effectiveness Evaluation of a Preoperative Clinical Framework

ObjectiveActive surveillance (AS) is a management alternative for patients with low-risk papillary thyroid microcarcinoma (PTMC). To decide the best candidates for AS, clinicians can use a framework to classify PTMC patients as ideal, appropriate, or inappropriate. This study aimed to explore the correlation between the framework categories and surgical pathology.MethodsThis multicenter retrospective study was conducted between 2014 and 2016. We included 1997 patients who underwent thyroid surgery for the first time due to suspected PTMC and were confirmed as PTMC by postoperative pathology. The consistency of modified preoperative risk stratification and the pathologic condition were evaluated using a consistency ratio and the Kappa coefficient. Stratified analysis was also performed to test consistency in different age groups.ResultsBased on the decision-making framework, 558 (27.9%) patients could receive AS while 810 (40.6%) patients did not require immediate surgery according to the actual postoperative pathology. The sensitivity, false-positive rate, specificity, false-negative rate, and consistency rate were 82.39%, 56.91%, 43.09%, 17.61%, and 66.45%, respectively. The Kappa value was 0.268. Stratified analysis showed that the sensitivity was 87.7% among patients aged 18 to 59 years. In the group aged ≥60 years, the specificity was up to 87.5%, but the sensitivity was low.ConclusionThe results of the modified risk-stratified clinical decision-making framework did not have a high consistency with the postoperative results. However, the framework showed a good effect in selecting patients for immediate surgery in the younger group and patients for AS in the older group.     

Prognostic Value of ICH Score and ICH-GS Score in Chinese Intracerebral Hemorrhage Patients: Analysis From the China National Stroke Registry (CNSR)

Purpose

No strongevidenceofefficacycurrently exists for different intracerebral hemorrhage (ICH) scoring system in predicting the prognosis of ICH in the Chinese population. This study aimed to test the accuracyof the ICH score and the ICH grading scale (ICH-GS) score in predicting the favorable prognosis in a large cohort of ICH patients in China.

Methods

This study was a multicenter, prospective cohort study. Patients diagnosed with ICH between September 2007 and August 2008 from the nationwide China National Stroke Registry (CNSR) databasewere screened andenrolled in this study. Demographics of the patients, treatments, mortalityas well as the clinic and radiologic findings of ICH were collected.AnICH score and anICH-GS score were evaluated for all the patients atadmission. Follow-ups were conducted by phone at 3, 6 and 12 months after ICH onset. The modified Rankin scale (mRS) score was used to evaluate favorable functional outcome and was obtained at hospital dischargeand duringthe 3-, 6- and 12-month follow-up visits.

Results

There were 410 (12.6%) in-hospitalmortalityout of a total of 3,255 ICH patients. Thevalues of the Area Under Curve (AUC)at discharge, 3-, 6- and 12-month follow-up for ICH score were 0.72, 0.76, 0.76 and 0.75, respectively; whilethe numbers for the ICH-GS score were 0.71, 0.77, 0.78 and 0.78, respectively. At 6-month and 12-month follow-up, the ICH-GS score presented a significant better value in predicting favorable prognosis than did the ICH score (P=0.0003 and <0.0001, respectively).

Conclusion

Both the ICH and ICH-GS scores were effective inaccurately predicting the favorable functional outcome of ICH in the Chinese population. For mid-term and long-term prediction, the ICH-GS score was superiorover the ICH score.     

Managing Conflicts of Interest in the UK National Institute for Health and Care Excellence (NICE) Clinical Guidelines Programme: Qualitative Study

Background

There is international concern that conflicts of interest (COI) may bias clinical guideline development and render it untrustworthy. Guideline COI policies exist with the aim of reducing this bias but it is not known how such policies are interpreted and used by guideline producing organisations. This study sought to determine how conflicts of interest (COIs) are disclosed and managed by a national clinical guideline developer (NICE: the UK National Institute for Health and Care Excellence).

Methods

Qualitative study using semi-structured telephone interviews with 14 key informants: 8 senior staff of NICE’s guideline development centres and 6 chairs of guideline development groups (GDGs). We conducted a thematic analysis.

Results

Participants regard the NICE COI policy as comprehensive leading to transparent and independent guidance. The application of the NICE COI policy is, however, not straightforward and clarity could be improved. Disclosure of COI relies on self reporting and guideline developers have to take “on trust” the information they receive, certain types of COI (non-financial) are difficult to categorise and manage and disclosed COI can impact on the ability to recruit clinical experts to GDGs. Participants considered it both disruptive and stressful to exclude members from GDG meetings when required by the COI policy. Nonetheless the impact of this disruption can be minimised with good group chairing skills.

Conclusions

We consider that the successful implementation of a COI policy in clinical guideline development requires clear policies and procedures, appropriate training of GDG chairs and an evaluation of how the policy is used in practice.     

Cost-Effectiveness of a Specialist Geriatric Medical Intervention for Frail Older People Discharged from Acute Medical Units: Economic Evaluation in a Two-Centre Randomised Controlled Trial (AMIGOS)

BackgroundPoor outcomes and high resource-use are observed for frail older people discharged from acute medical units. A specialist geriatric medical intervention, to facilitate Comprehensive Geriatric Assessment, was developed to reduce the incidence of adverse outcomes and associated high resource-use in this group in the post-discharge period.ObjectiveTo examine the costs and cost-effectiveness of a specialist geriatric medical intervention for frail older people in the 90 days following discharge from an acute medical unit, compared with standard care.MethodsEconomic evaluation was conducted alongside a two-centre randomised controlled trial (AMIGOS). 433 patients (aged 70 or over) at risk of future health problems, discharged from acute medical units within 72 hours of attending hospital, were recruited in two general hospitals in Nottingham and Leicester, UK. Participants were randomised to the intervention, comprising geriatrician assessment in acute units and further specialist management, or to control where patients received no additional intervention over and above standard care. Primary outcome was incremental cost per quality adjusted life year (QALY) gained.ResultsWe undertook cost-effectiveness analysis for 417 patients (intervention: 205). The difference in mean adjusted QALYs gained between groups at 3 months was -0.001 (95% confidence interval [CI]: -0.009, 0.007). Total adjusted secondary and social care costs, including direct costs of the intervention, at 3 months were £4412 (€5624, $6878) and £4110 (€5239, $6408) for the intervention and standard care groups, the incremental cost was £302 (95% CI: 193, 410) [€385, $471]. The intervention was dominated by standard care with probability of 62%, and with 0% probability of cost-effectiveness (at £20,000/QALY threshold).ConclusionsThe specialist geriatric medical intervention for frail older people discharged from acute medical unit was not cost-effective. Further research on designing effective and cost-effective specialist service for frail older people discharged from acute medical units is needed.

Trial Registration

ISRCTN registry ISRCTN21800480 http://www.isrctn.com/ISRCTN21800480     

The germination characteristics of Alexandrium minutum (Dinophyceae), a toxic dinoflagellate from the Fal estuary (UK)

The germination characteristics of Alexandrium minutum cysts from the Fal estuary were studied at different conditions of temperature (4–24 °C) and salinity (15–35‰) and in the dark and low light intensity (2 μmol^?2 s^?1). Sediment sub-samples were directly cultured and processed at the end of the experiment for counts of non-germinated cysts. A decrease in the number of cysts was interpreted as germination that was calculated by comparison of the number of cysts over time with that of initial counts. The 50% germination time (time at which 50% of the total initial number of cysts had germinated) was calculated for each condition. A. minutum did not germinate in the dark but it germinated under all other conditions studied. Highest germination occurred at salinities of 30 psu and 35 psu and temperatures from 8 °C to 24 °C (germination rate—expressed as the inverse of the 50% germination time: 1.1–1.2). Lowest germination occurred at 15 psu and 4 °C and 24 °C (germination rate: 3.9–3.8). However, little variation in germination rates occurred across the conditions studied. As these conditions represent those likely in the estuary it is probable that A. minutum cysts on the surface of the sediments represent a constant source of cells to the water column and sediment disturbance (revealing buried cysts) could rapidly inoculate the water column with vegetative cells. This data was used to develop a model for Alexandrium germination from coastal sediments.     

Time Trends in Ischemic Stroke among Type 2 Diabetic and Non-Diabetic Patients: Analysis of the Spanish National Hospital Discharge Data (2003-2012)

Background

Type 2 Diabetes (T2DM) is the most rapidly increasing risk factor for ischemic stroke. We aimed to compare trends in outcomes for ischemic stroke in people with or without diabetes in Spain between 2003 and 2012.

Methods

We selected all patients hospitalized for ischemic stroke using national hospital discharge data. We evaluated annual incident rates stratified by T2DM status. We analyzed trends in the use of diagnostic and therapeutic procedures, patient comorbidities, and in-hospital outcomes. We calculated in-hospital mortality (IHM), length of hospital stay (LOHS) and readmission rate in one month after discharge. Time trend on the incidence of hospitalization was estimated fitting Poisson regression models by sex and diabetes variables. In-hospital mortality was analyzed using logistic regression models separate for men and women. LOHS were compared with ANOVA or Kruskal-Wallis when necessary.

Results

We identified a total of 423,475 discharges of patients (221,418 men and 202,057 women) admitted with ischemic stroke as primary diagnosis. Patients with T2DM accounted for 30.9% of total. The estimated incidence rates of discharges increased significantly in all groups. The incidence of hospitalization due to stroke (with ICD9 codes for stroke as main diagnosis at discharge) was higher among those with than those without diabetes in all the years studied. T2DM was positively associated with ischemic stroke with an adjusted incidence rate ratio (IRR) of 2.27 (95% CI 2.24–2.29) for men and 2.15 (95%CI 2.13–2.17) for women. Over the 10 year period LOHS decreased significantly in men and women with and without diabetes. Readmission rate remained stable in diabetic and non diabetic men (around 5%) while slightly increased in women with and without diabetes. We observed a significant increase in the use of fibrinolysis from 2002–2013. IHM was positively associated with older age in all groups, with Charlson Comorbidity Index > 3 and atrial fibrillation as risk factors. The IHM did not change significantly over time among T2DM men and women ranging from 9.25% to 10.56% and from 13.21% to 14.86%, respectively; neither did among non-diabetic women. However, in men without T2DM IHM decreased significantly over time. Diabetes was associated to higher IHM only in women (OR 1.07; 95% CI, 1.05–1.11).

Conclusions

Our national data show that incidence rate of ischemic stroke hospitalization increased significantly during the period of study (2003–2012). People with T2DM have more than double the risk of ischemic stroke after adjusting for other risk factors. Women with T2DM had poorer outcomes- IHM and readmission rates- than diabetic men. Diabetes was an independent factor for IHM only in women.     

Quality control of CD4+ T-lymphocyte enumeration: results from the last 9 years of the United Kingdom National External Quality Assessment Scheme for Immune Monitoring (1993-2001)

The human immunodeficiency virus (HIV) global epidemic has necessitated the routine enumeration of T-lymphocyte subsets, which has created a need for external quality assurance (EQA). The United Kingdom National External Quality Assessment Scheme (UK NEQAS) for Immune Monitoring provides EQA for 296 laboratories in 40 countries. In 1993, UK NEQAS developed and incorporated into its program stabilized whole blood that enables the accurate monitoring of laboratory performance. Overall, the mean interlaboratory coefficient of variation (CV) for percentage CD4(+) T-lymphocyte subset enumeration has fallen from 15% to less than 5%, as a direct result of the increased use of CD45/ side scatter (SSC) gating. Laboratories using alternative gating strategies (i.e., CD45/CD14 or forward scatter [FSC]/SSC) were about 7.4 times more likely to fail an EQA exercise. Furthermore, the adoption of single-platform technology resulted in a reduction of the overall mean interlaboratory CV for absolute CD4(+) T lymphocytes from 56% (prior to the widespread use of single-platform technology) to 9.7%. Individual laboratory deficiencies were also identified using a performance monitoring system and, through re-education by collaboration with the coordinating center, satisfactorily resolved. In conclusion, during the last 9 years, the UK NEQAS for Immune Monitoring program has highlighted the significant technological advances made by laboratories worldwide that undertake lymphocyte subset enumeration.     

The Malaysian Medication Adherence Scale (MALMAS): Concurrent Validity Using a Clinical Measure among People with Type 2 Diabetes in Malaysia

Medication non-adherence is a prevalent problem worldwide but up to today, no gold standard is available to assess such behavior. This study was to evaluate the psychometric properties, particularly the concurrent validity of the English version of the Malaysian Medication Adherence Scale (MALMAS) among people with type 2 diabetes in Malaysia. Individuals with type 2 diabetes, aged 21 years and above, using at least one anti-diabetes agent and could communicate in English were recruited. The MALMAS was compared with the 8-item Morisky Medication Adherence Scale (MMAS-8) to assess its convergent validity while concurrent validity was evaluated based on the levels of glycated hemoglobin (HbA1C). Participants answered the MALMAS twice: at baseline and 4 weeks later. The study involved 136 participants. The MALMAS achieved acceptable internal consistency (Cronbach’s alpha=0.565) and stable reliability as the test-retest scores showed fair correlation (Spearman’s rho=0.412). The MALMAS has good correlation with the MMAS-8 (Spearman’s rho=0.715). Participants who were adherent to their anti-diabetes medications had significantly lower median HbA1C values than those who were non-adherence (7.90 versus 8.55%, p=0.032). The odds of participants who were adherent to their medications achieving good glycemic control was 3.36 times (95% confidence interval: 1.09-10.37) of those who were non-adherence. This confirms the concurrent validity of the MALMAS. The sensitivity of the MALMAS was 88.9% while its specificity was 29.6%. The findings of this study further substantiates the reliability and validity of the MALMAS, in particular its concurrent validity and sensitivity for assessing medication adherence of people with type 2 diabetes in Malaysia.     

Laboratory Diagnosis and Characterization of Fungal Disease in Patients with Cystic Fibrosis (CF): A Survey of Current UK Practice in a Cohort of Clinical Microbiology Laboratories

There is much uncertainty as to how fungal disease is diagnosed and characterized in patients with cystic fibrosis (CF). A 19-question anonymous electronic questionnaire was developed and distributed to ascertain current practice in clinical microbiology laboratories providing a fungal laboratory service to CF centres in the UK. Analyses of responses identified the following: (1) current UK laboratory practice, in general, follows the current guidelines, but the scope and diversity of what is currently being delivered by laboratories far exceeds what is detailed in the guidelines; (2) there is a lack of standardization of fungal tests amongst laboratories, outside of the current guidelines; (3) both the UK CF Trust Laboratory Standards for Processing Microbiological Samples from People with Cystic Fibrosis and the US Cumulative Techniques and Procedures in Clinical Microbiology (Cumitech) Guidelines 43 Cystic Fibrosis Microbiology need to be updated to reflect both new methodological innovations, as well as better knowledge of fungal disease pathophysiology in CF; (4) there is a need for clinical medicine to decide upon a stratification strategy for the provision of new fungal assays that will add value to the physician in the optimal management of CF patients; (5) there is also a need to rationale what assays should be performed at local laboratory level and those which are best served at National Mycology Reference Laboratory level; and (6) further research is required in developing laboratory assays, which will help ascertain the clinical importance of ‘old’ fungal pathogens, as well as ‘emerging’ fungal pathogens.     

Environmental and Human Health Risk Assessment of Benzo(a)pyrene Levels in Agricultural Soils from the National Capital Region,Delhi, India

ABSTRACT

Exposure to benzo(a)pyrene (B(a)P) for health risk was studied in soils from the Delhi region, India. The mean and median concentrations of benzo(a)pyrene were 0.031 and 0.029 (±0.002) mg/kg, respectively. The lifetime average daily dose (LADD) for adults and children was 1.7 × 10^?8 mg kg^?1 d^?1 and 7.5 × 10^?8 mg kg^?1 d^?1, respectively, with incremental life time cancer risk (ILCR) of 1.2 × 10^?7 and 5.5 × 10^?7, respectively. The Index of Additive Cancer Risk (IACR) was 0.084. Our screening-level risk assessment shows that the observed ILCR and IACR values are much lower than the guideline values of 10^?6 ? 10^?4 (ILCR) and <1 (IACR), respectively, and therefore the measured B(a)P levels in soil may not portend environmental and human health risks.     

Oxidant-induced formation of a neutral flavosemiquinone in the Na+-translocating NADH:Quinone oxidoreductase (Na+-NQR) from Vibrio cholerae

The Na(+)-translocating NADH:quinone oxidoreductase (Na(+)-NQR) from the human pathogen Vibrio cholerae is a respiratory flavo-FeS complex composed of the six subunits NqrA-F. The Na(+)-NQR was produced as His(6)-tagged protein by homologous expression in V. cholerae. The isolated complex contained near-stoichiometric amounts of non-covalently bound FAD (0.78 mol/mol Na(+)-NQR) and riboflavin (0.70 mol/mol Na(+)-NQR), catalyzed NADH-driven Na(+) transport (40 nmol Na(+)min(-1) mg(-1)), and was inhibited by 2-n-heptyl-4-hydroxyquinoline-N-oxide. EPR spectroscopy showed that Na(+)-NQR as isolated contained very low amounts of a neutral flavosemiquinone (10(-3) mol/mol Na(+)-NQR). Reduction with NADH resulted in the formation of an anionic flavosemiquinone (0.10 mol/mol Na(+)-NQR). Subsequent oxidation of the Na(+)-NQR with ubiquinone-1 or O(2) led to the formation of a neutral flavosemiquinone (0.24 mol/mol Na(+)-NQR). We propose that the Na(+)-NQR is fully oxidized in its resting state, and discuss putative schemes of NADH-triggered redox transitions.     

Association of Adiposity and Mental Health Functioning across the Lifespan: Findings from Understanding Society (The UK Household Longitudinal Study)

Background

Evidence on the adiposity-mental health associations is mixed, with studies finding positive, negative or no associations, and less is known about how these associations may vary by age.

Objective

To examine the association of adiposity -body mass index (BMI), waist circumference (WC) and percentage body fat (BF%)- with mental health functioning across the adult lifespan.

Methods

Data from 11,257 participants (aged 18+) of Understanding Society: the UK Household Longitudinal Study (waves 2 and 3, 5/2010-7/2013) were employed. Regressions of mental health functioning, assessed by the Mental Component Summary (MCS-12) and the General Health Questionnaire (GHQ-12), on adiposity measures (continuous or dichotomous indicators) were estimated adjusted for covariates. Polynomial age-adiposity interactions were estimated.

Results

Higher adiposity was associated with poorer mental health functioning. This emerged in the 30s, increased up to mid-40s (all central adiposity and obesity-BF% measures) or early 50s (all BMI measures) and then decreased with age. Underlying physical health generally accounted for these associations except for central adiposity, where associations remained statistically significant from the mid-30s to50s. Cardiovascular, followed by arthritis and endocrine, conditions played the greatest role in attenuating the associations under investigation.

Conclusions

We found strong age-specific patterns in the adiposity-mental health functioning association that varied across adiposity measures. Underlying physical health had the dominant role in attenuating these associations. Policy makers and health professionals should target increased adiposity, mainly central adiposity, as it is a risk factor for poor mental health functioning in those aged between mid-30s to 50 years.     

Clinical effectiveness and cost effectiveness of zanamivir (Relenza): translating the evidence into clinical practice, a National Institute for Clinical Excellence view.

The UK National Institute for Clinical Excellence (NICE) is charged with the duty of providing informed guidance on clinical practice (clinical effectiveness and cost effectiveness) to patients and health professionals. The Appraisal Committee through its process of review of evidence advises NICE on the clinical effectiveness and cost effectiveness of new and existing technologies and their appropriate use within the National Health Service in England and Wales. The appraisal process takes into account both published and unpublished evidence as well as input from professional and patient and carer groups when coming to its decisions. The appraisal of a new technology often has to bridge the gap between the evidence required for licensing purposes and that needed to provide pragmatic advice to practising clinicians. The appraisal of zanamivir (Relenza) is an excellent working example of this difficult and important process.     

The Ferredoxin:NAD+ Oxidoreductase (Rnf) from the Acetogen Acetobacterium woodii Requires Na+ and Is Reversibly Coupled to the Membrane Potential

The anaerobic acetogenic bacterium Acetobacterium woodii has a novel Na⁺-translocating electron transport chain that couples electron transfer from reduced ferredoxin to NAD⁺ with the generation of a primary electrochemical Na⁺ potential across its cytoplasmic membrane. In previous assays in which Ti³⁺ was used to reduce ferredoxin, Na⁺ transport was observed, but not a Na⁺ dependence of the electron transfer reaction. Here, we describe a new biological reduction system for ferredoxin in which ferredoxin is reduced with CO, catalyzed by the purified acetyl-CoA synthase/CO dehydrogenase from A. woodii. Using CO-reduced ferredoxin, NAD⁺ reduction was highly specific and strictly dependent on ferredoxin and occurred at a rate of 50 milliunits/mg of protein. Most important, this assay revealed for the first time a strict Na⁺ dependence of this electron transfer reaction. The K_m was 0.2 mm. Na⁺ could be partly substituted by Li⁺. Na⁺ dependence was observed at neutral and acidic pH values, indicating the exclusive use of Na⁺ as a coupling ion. Electron transport from reduced ferredoxin to NAD⁺ was coupled to electrogenic Na⁺ transport, indicating the generation of Δ$\tilde{\mu }$_Na⁺. Vice versa, endergonic ferredoxin reduction with NADH as reductant was possible, but only in the presence of Δ$\tilde{\mu }$_Na⁺, and was accompanied by Na⁺ efflux out of the vesicles. This is consistent with the hypothesis that Rnf also catalyzes ferredoxin reduction at the expense of an electrochemical Na⁺ gradient. The physiological significance of this finding is discussed.     

Exploring the Mechanisms of a Patient-Centred Assessment with a Solution Focused Approach (DIALOG+) in the Community Treatment of Patients with Psychosis: A Process Evaluation within a Cluster-Randomised Controlled Trial

Background

DIALOG+ is a new intervention to make routine community mental health meetings therapeutically effective. It involves a structured assessment of patient concerns and a solution-focused approach to address them. In a randomised controlled trial, DIALOG+ was associated with better subjective quality of life and other outcomes in patients with psychosis, but it was not clear how this was achieved. This study explored the possible mechanisms.

Methods

This was a mixed-methods process evaluation within a cluster-randomised controlled trial. Focus groups and interviews were conducted with patients and clinicians who experienced DIALOG+ and were analysed using thematic analysis. The content of DIALOG+ sessions was recorded and analysed according to (i) the type of actions agreed during sessions and (ii) the domains discussed. The subjective quality of life measure was analysed with mixed-effects models to explore whether the effect of DIALOG+ was limited to life domains that had been addressed in sessions or consistent across all domains.

Results

Four qualitative themes emerged regarding the mechanisms of DIALOG+: (1) a comprehensive structure; (2) self-reflection; (3) therapeutic self-expression; and (4) empowerment. Patients took responsibility for the majority of actions agreed during sessions (65%). The treatment effect on subjective quality of life was largest for living situation (accommodation and people that the patient lives with) and mental health. Two of these domains were among the three most commonly discussed in DIALOG+ sessions (accommodation, mental health, and physical health).

Conclusion

DIALOG+ initiates positive, domain-specific change in the areas that are addressed in sessions. It provides a comprehensive and solution-focused structure to routine meetings, encourages self-reflection and expression, and empowers patients. Future research should strengthen and monitor these factors.

Trial Registration

ISRCTN Registry ISRCTN34757603.     

The side chain of ubiquinone plays a critical role in Na+ translocation by the NADH-ubiquinone oxidoreductase (Na+-NQR) from Vibrio cholerae

The Na⁺-pumping NADH-ubiquinone (UQ) oxidoreductase (Na⁺-NQR) is an essential bacterial respiratory enzyme that generates a Na⁺ gradient across the cell membrane. However, the mechanism that couples the redox reactions to Na⁺ translocation remains unknown. To address this, we examined the relation between reduction of UQ and Na⁺ translocation using a series of synthetic UQs with Vibrio cholerae Na⁺-NQR reconstituted into liposomes. UQ₀ that has no side chain and UQ_CH3 and UQ_C2H5, which have methyl and ethyl side chains, respectively, were catalytically reduced by Na⁺-NQR, but their reduction generated no membrane potential, indicating that the overall electron transfer and Na⁺ translocation are not coupled. While these UQs were partly reduced by electron leak from the cofactor(s) located upstream of riboflavin, this complete loss of Na⁺ translocation cannot be explained by the electron leak. Lengthening the UQ side chain to n-propyl (C₃H₇) or longer significantly restored Na⁺ translocation. It has been considered that Na⁺ translocation is completed when riboflavin, a terminal redox cofactor residing within the membrane, is reduced. In this view, the role of UQ is simply to accept electrons from the reduced riboflavin to regenerate the stable neutral riboflavin radical and reset the catalytic cycle. However, the present study revealed that the final UQ reduction via reduced riboflavin makes an important contribution to Na⁺ translocation through a critical role of its side chain. Based on the results, we discuss the critical role of the UQ side chain in Na⁺ translocation.     

Evaluation of the Growth Assessment Protocol (GAP) for antenatal detection of small for gestational age: The DESiGN cluster randomised trial

BackgroundAntenatal detection and management of small for gestational age (SGA) is a strategy to reduce stillbirth. Large observational studies provide conflicting results on the effect of the Growth Assessment Protocol (GAP) in relation to detection of SGA and reduction of stillbirth; to the best of our knowledge, there are no reported randomised control trials. Our aim was to determine if GAP improves antenatal detection of SGA compared to standard care.Methods and findingsThis was a pragmatic, superiority, 2-arm, parallel group, open, cluster randomised control trial. Maternity units in England were eligible to participate in the study, except if they had already implemented GAP. All women who gave birth in participating clusters (maternity units) during the year prior to randomisation and during the trial (November 2016 to February 2019) were included. Multiple pregnancies, fetal abnormalities or births before 24⁺¹ weeks were excluded. Clusters were randomised to immediate implementation of GAP, an antenatal care package aimed at improving detection of SGA as a means to reduce the rate of stillbirth, or to standard care. Randomisation by random permutation was stratified by time of study inclusion and cluster size. Data were obtained from hospital electronic records for 12 months prerandomisation, the washout period (interval between randomisation and data collection of outcomes), and the outcome period (last 6 months of the study). The primary outcome was ultrasound detection of SGA (estimated fetal weight <10th centile using customised centiles (intervention) or Hadlock centiles (standard care)) confirmed at birth (birthweight <10th centile by both customised and population centiles). Secondary outcomes were maternal and neonatal outcomes, including induction of labour, gestational age at delivery, mode of birth, neonatal morbidity, and stillbirth/perinatal mortality. A 2-stage cluster–summary statistical approach calculated the absolute difference (intervention minus standard care arm) adjusted using the prerandomisation estimate, maternal age, ethnicity, parity, and randomisation strata. Intervention arm clusters that made no attempt to implement GAP were excluded in modified intention to treat (mITT) analysis; full ITT was also reported. Process evaluation assessed implementation fidelity, reach, dose, acceptability, and feasibility. Seven clusters were randomised to GAP and 6 to standard care. Following exclusions, there were 11,096 births exposed to the intervention (5 clusters) and 13,810 exposed to standard care (6 clusters) during the outcome period (mITT analysis). Age, height, and weight were broadly similar between arms, but there were fewer women: of white ethnicity (56.2% versus 62.7%), and in the least deprived quintile of the Index of Multiple Deprivation (7.5% versus 16.5%) in the intervention arm during the outcome period. Antenatal detection of SGA was 25.9% in the intervention and 27.7% in the standard care arm (adjusted difference 2.2%, 95% confidence interval (CI) −6.4% to 10.7%; p = 0.62). Findings were consistent in full ITT analysis. Fidelity and dose of GAP implementation were variable, while a high proportion (88.7%) of women were reached. Use of routinely collected data is both a strength (cost-efficient) and a limitation (occurrence of missing data); the modest number of clusters limits our ability to study small effect sizes.ConclusionsIn this study, we observed no effect of GAP on antenatal detection of SGA compared to standard care. Given variable implementation observed, future studies should incorporate standardised implementation outcomes such as those reported here to determine generalisability of our findings.Trial registrationThis trial is registered with the ISRCTN registry, ISRCTN67698474.

Matias C Vieira and colleagues evaluate the Growth Assessment Protocol (GAP) for antenatal detection of small for gestational age in the DESiGN cluster randomised trial.