Breastfeeding, the use of docosahexaenoic acid-fortified formulas in infancy and neuropsychological function in childhood

OBJECTIVE: To investigate the relation between breastfeeding, use of docosahexaenoic acid (DHA)-fortified formula and neuropsychological function in children. DESIGN: Prospective cohort study. SETTING: Southampton, UK. SUBJECTS: 241 children aged 4 years followed up from birth. MAIN OUTCOME MEASURES: IQ measured by the Wechsler Pre-School and Primary Scale of Intelligence (3rd edn), visual attention, visuomotor precision, sentence repetition and verbal fluency measured by the NEPSY, and visual form-constancy measured by the Test of Visual-Perceptual Skills (Non-Motor). RESULTS: In unadjusted analyses, children for whom breast milk or DHA-fortified formula was the main method of feeding throughout the first 6 months of life had higher mean full-scale and verbal IQ scores at age 4 years than those fed mainly unfortified formula. After adjustment for potential confounding factors, particularly maternal IQ and educational attainment, the differences in IQ between children in the breast milk and unfortified formula groups were severely attenuated, but children who were fed DHA-fortified formula had full-scale and verbal IQ scores that were respectively 5.62 (0.98 to 10.2) and 7.02 (1.56 to 12.4) points higher than children fed unfortified formula. However, estimated total intake of DHA in milk up to age 6 months was not associated with subsequent IQ or with score on any other test. CONCLUSIONS: Differences in children's intelligence according to type of milk fed in infancy may be due more to confounding by maternal or family characteristics than to the amount of long-chain polyunsaturated fatty acids they receive in milk

Three Decades of Changing Nutrient Stoichiometry from Source to Sea on the Swedish West Coast

European ecosystems have been subject to extensive shifts in anthropogenic disturbance, primarily through atmospheric deposition, climate change, and land management. These changes have altered the macronutrient composition of aquatic systems, with widespread increases in organic carbon (C), and declines in nitrogen (N) and phosphorus (P). Less well known is how these disturbances have affected nutrient stoichiometry, which may be a more useful metric to evaluate the health of aquatic ecosystems than individual nutrient concentrations. The Swedish west coast has historically experienced moderate to high levels of atmospheric deposition of sulfate and N, and eutrophication. In addition, coastal waters have been darkening with damaging effects on marine flora and fauna. Here, we present three decades of macronutrient data from twenty lakes and watercourses along the Swedish west coast, extending from headwaters to river mouths, across a range of land covers, and with catchments ranging 0.037-40,000 km(2). We find a high degree of consistency between these diverse sites, with widespread increasing trends in organic C, and declines in inorganic N and total P. These trends in individual macronutrients translate into large stoichiometric changes, with a doubling in C:P, and increases in C:N and N:P by 50% and 30%, showing that freshwaters are moving further away from the Redfield Ratio, and becoming even more C rich, and depleted in N and P. Although recovery from atmospheric deposition is linked to some of these changes, land cover also appears to have an effect; lakes buffer against C increases, and decreases in inorganic N have been greatest under arable land cover. Our analysis also detects coherently declining P concentrations in small forest lakes; so called (and unexplained) "oligotrophication." Taken together, our findings show that freshwater macronutrient concentrations and stoichiometry have undergone substantial shifts during the last three decades, and these shifts can potentially explain some of the detrimental changes that adjacent coastal ecosystems are undergoing. Our findings are relevant for all European and North American waters that have experienced historically high levels of atmospheric deposition, and provide a starting point for understanding and mitigating against the trajectories of long-term change in aquatic systems

Study protocol for the management of impacted maxillary central incisors: a multicentre randomised clinical trial: the iMAC Trial

BACKGROUND Failure of eruption of the maxillary permanent incisor teeth usually presents in the mixed dentition between the ages of 7 and 9 years. Missing and unerupted maxillary incisors can be regarded as unattractive and have a potentially negative impact on facial and dental aesthetics. The presence of a supernumerary tooth (or odontoma) is commonly responsible for failed eruption or impaction of the permanent maxillary incisors. The primary objective of this trial is to investigate the success of eruption associated with maxillary incisor teeth that have failed to erupt because of a supernumerary tooth in the anterior maxilla. METHODS This protocol describes an interventional multicentre two-arm randomised clinical trial. Participants meeting the eligibility criteria will be randomised (unrestricted equal participant allocation [1:1]) to either space creation with an orthodontic appliance, removal of the supernumerary tooth and application of direct orthodontic traction or space creation with an orthodontic appliance, removal of the supernumerary tooth and monitoring. The primary outcome of this trial is to determine the prevalence of successfully erupted maxillary central permanent incisors at 6 months following removal of the supernumerary tooth. Secondary outcome measures include (1) the effect of initial tooth position (assessed radiographically) on time taken for the tooth to erupt, (2) time taken to align the unerupted tooth to the correct occlusal position, (3) gingival aesthetics and (4) changes in the self-reported Oral Health Related-Quality of Life (OHRQoL) (pre-and post-treatment). DISCUSSION There is a lack of high-quality robust prospective studies comparing the effectiveness of interventions to manage this condition. Furthermore, the UK national clinical guidelines have highlighted a lack of definitive treatment protocols for the management of children who present with an unerupted maxillary incisor due to the presence of a supernumerary tooth. The results of this trial will inform future treatment guidelines for the management of this condition in young children. TRIAL REGISTRATION ISRCTN Registry ISRCTN12709966 . Registered on 16 June 2022

Dislocation interactions during low-temperature plasticity of olivine and their impact on the evolution of lithospheric strength

The strength of the lithosphere is typically modelled based on constitutive equations for steady-state flow. However, strain hardening may cause significant evolution of strength in the colder load-bearing portion of the lithosphere. Recent rheological data from low-temperature deformation experiments on olivine suggest that strain hardening occurs due to the presence of temperature-independent back stresses generated by long-range elastic interactions among dislocations. These interpretations provided the basis for a flow law that incorporates hardening by the development of back stress. Here, we test this dislocation-interaction hypothesis by examining the microstructures of olivine samples deformed plastically at room temperature either in a deformation-DIA apparatus at differential stresses of ≤4.3GPa or in a nanoindenter at applied contact stresses of ≥10.2GPa. High-angular resolution electron backscatter diffraction maps reveal the presence of geometrically necessary dislocations with densities commonly above 1014m−2 and intragranular heterogeneities in residual stress on the order of 1 GPa in both sets of samples. Scanning transmission electron micrographs reveal straight dislocations aligned in slip bands and interacting with dislocations of other types that act as obstacles. The resulting accumulations of dislocations in their slip planes, and associated stress heterogeneities, are consistent with strain hardening resulting from long-range back-stresses acting among dislocations and thereby support the form of the flow law for low-temperature plasticity. Based on these observations, we predict that back stresses among dislocations will impart significant mechanical anisotropy to deformed lithosphere by enhancing or reducing the effective stress. Therefore, strain history, with associated microstructural and micromechanical evolution, is an important consideration for models of lithospheric strength. The microstructural observations also provide new criteria for identifying the operation of back-stress induced strain hardening in natural samples and therefore provide a means to test the applicability of the flow law for low-temperature plasticity.This research was supported by Natural Environment Research Council grants NE/M000966/1 to LNH, AJW, and DW and 1710DG008/JC4 to LNH and AJW; European Plate Observing System Transnational Access grant EPOS-TNA-MSL 2018-022 to LNH; Advanced Photon Source General User Proposal 55176 to LNH, DLG, and WBD; and National Science Foundation Awards EAR-1361319 to WBD, EAR-1625032 to JMW, and EAR-1806791 to KMK

The selective prolyl hydroxylase inhibitor IOX5 stabilizes HIF-1α and compromises development and progression of acute myeloid leukemia

Acute myeloid leukemia (AML) is a largely incurable disease, for which new treatments are urgently needed. While leukemogenesis occurs in the hypoxic bone marrow, the therapeutic tractability of the hypoxia-inducible factor (HIF) system remains undefined. Given that inactivation of HIF-1α/HIF-2α promotes AML, a possible clinical strategy is to target the HIF-prolyl hydroxylases (PHDs), which promote HIF-1α/HIF-2α degradation. Here, we reveal that genetic inactivation of Phd1/Phd2 hinders AML initiation and progression, without impacting normal hematopoiesis. We investigated clinically used PHD inhibitors and a new selective PHD inhibitor (IOX5), to stabilize HIF-α in AML cells. PHD inhibition compromises AML in a HIF-1α-dependent manner to disable pro-leukemogenic pathways, re-program metabolism and induce apoptosis, in part via upregulation of BNIP3. Notably, concurrent inhibition of BCL-2 by venetoclax potentiates the anti-leukemic effect of PHD inhibition. Thus, PHD inhibition, with consequent HIF-1α stabilization, is a promising nontoxic strategy for AML, including in combination with venetoclax

Developing a core outcome set for fistulising perianal Crohn's disease

OBJECTIVE: Lack of standardised outcomes hampers effective analysis and comparison of data when comparing treatments in fistulising perianal Crohn's disease (pCD). Development of a standardised set of outcomes would resolve these issues. This study provides the definitive core outcome set (COS) for fistulising pCD. DESIGN: Candidate outcomes were generated through a systematic review and patient interviews. Consensus was established via a three-round Delphi process using a 9-point Likert scale based on how important they felt it was in determining treatment success culminating in a final consensus meeting. Stakeholders were recruited nationally and grouped into three panels (surgeons and radiologists, gastroenterologists and IBD specialist nurses, and patients). Participants received feedback fromtheir panel(in the second round) andall participants(in the third round) to allow refinement of their scores. RESULTS: A total of 295 outcomes were identified from systematic reviews and interviews that were categorised into 92 domains. 187 stakeholders (response rate 78.5%) prioritised 49 outcomes through a three-round Delphi study.The final consensus meeting of 41 experts and patients generated agreement on an eight domain COS. The COS comprised three patient-reported outcome domains (quality of life, incontinence and a combined score of patient priorities) and five clinician-reported outcome domains (perianal disease activity, development of new perianal abscess/sepsis, new/recurrent fistula, unplanned surgery and faecal diversion). CONCLUSION: A fistulising pCD COS has been produced by all key stakeholders. Application of the COS will reduce heterogeneity in outcome reporting, thereby facilitating more meaningful comparisons between treatments, data synthesis and ultimately benefit patient care

Mega-analysis of association between obesity and cortical morphology in bipolar disorders:ENIGMA study in 2832 participants

Background: Obesity is highly prevalent and disabling, especially in individuals with severe mental illness including bipolar disorders (BD). The brain is a target organ for both obesity and BD. Yet, we do not understand how cortical brain alterations in BD and obesity interact. Methods: We obtained body mass index (BMI) and MRI-derived regional cortical thickness, surface area from 1231 BD and 1601 control individuals from 13 countries within the ENIGMA-BD Working Group. We jointly modeled the statistical effects of BD and BMI on brain structure using mixed effects and tested for interaction and mediation. We also investigated the impact of medications on the BMI-related associations. Results: BMI and BD additively impacted the structure of many of the same brain regions. Both BMI and BD were negatively associated with cortical thickness, but not surface area. In most regions the number of jointly used psychiatric medication classes remained associated with lower cortical thickness when controlling for BMI. In a single region, fusiform gyrus, about a third of the negative association between number of jointly used psychiatric medications and cortical thickness was mediated by association between the number of medications and higher BMI. Conclusions: We confirmed consistent associations between higher BMI and lower cortical thickness, but not surface area, across the cerebral mantle, in regions which were also associated with BD. Higher BMI in people with BD indicated more pronounced brain alterations. BMI is important for understanding the neuroanatomical changes in BD and the effects of psychiatric medications on the brain.</p

The effects of implementing a point-of-care electronic template to prompt routine anxiety and depression screening in patients consulting for osteoarthritis (the Primary Care Osteoarthritis Trial): A cluster randomised trial in primary care

Background This study aimed to evaluate whether prompting general practitioners (GPs) to routinely assess and manage anxiety and depression in patients consulting with osteoarthritis (OA) improves pain outcomes. Methods and findings We conducted a cluster randomised controlled trial involving 45 English general practices. In intervention practices, patients aged ≥45 y consulting with OA received point-of-care anxiety and depression screening by the GP, prompted by an automated electronic template comprising five questions (a two-item Patient Health Questionnaire–2 for depression, a two-item Generalized Anxiety Disorder–2 questionnaire for anxiety, and a question about current pain intensity [0–10 numerical rating scale]). The template signposted GPs to follow National Institute for Health and Care Excellence clinical guidelines for anxiety, depression, and OA and was supported by a brief training package. The template in control practices prompted GPs to ask the pain intensity question only. The primary outcome was patient-reported current pain intensity post-consultation and at 3-, 6-, and 12-mo follow-up. Secondary outcomes included pain-related disability, anxiety, depression, and general health. During the trial period, 7,279 patients aged ≥45 y consulted with a relevant OA-related code, and 4,240 patients were deemed potentially eligible by participating GPs. Templates were completed for 2,042 patients (1,339 [31.6%] in the control arm and 703 [23.1%] in the intervention arm). Of these 2,042 patients, 1,412 returned questionnaires (501 [71.3%] from 20 intervention practices, 911 [68.0%] from 24 control practices). Follow-up rates were similar in both arms, totalling 1,093 (77.4%) at 3 mo, 1,064 (75.4%) at 6 mo, and 1,017 (72.0%) at 12 mo. For the primary endpoint, multilevel modelling yielded significantly higher average pain intensity across follow-up to 12 mo in the intervention group than the control group (adjusted mean difference 0.31; 95% CI 0.04, 0.59). Secondary outcomes were consistent with the primary outcome measure in reflecting better outcomes as a whole for the control group than the intervention group. Anxiety and depression scores did not reduce following the intervention. The main limitations of this study are two potential sources of bias: an imbalance in cluster size (mean practice size 7,397 [intervention] versus 5,850 [control]) and a difference in the proportion of patients for whom the GP deactivated the template (33.6% [intervention] versus 27.8% [control]). Conclusions In this study, we observed no beneficial effect on pain outcomes of prompting GPs to routinely screen for and manage comorbid anxiety and depression in patients presenting with symptoms due to OA, with those in the intervention group reporting statistically significantly higher average pain scores over the four follow-up time points than those in the control group. Trial registration ISRCTN registry ISRCTN4072198

Principal component analysis as an efficient method for capturing multivariate brain signatures of complex disorders—ENIGMA study in people with bipolar disorders and obesity

Multivariate techniques better fit the anatomy of complex neuropsychiatric disorders which are characterized not by alterations in a single region, but rather by variations across distributed brain networks. Here, we used principal component analysis (PCA) to identify patterns of covariance across brain regions and relate them to clinical and demographic variables in a large generalizable dataset of individuals with bipolar disorders and controls. We then compared performance of PCA and clustering on identical sample to identify which methodology was better in capturing links between brain and clinical measures. Using data from the ENIGMA-BD working group, we investigated T1-weighted structural MRI data from 2436 participants with BD and healthy controls, and applied PCA to cortical thickness and surface area measures. We then studied the association of principal components with clinical and demographic variables using mixed regression models. We compared the PCA model with our prior clustering analyses of the same data and also tested it in a replication sample of 327 participants with BD or schizophrenia and healthy controls. The first principal component, which indexed a greater cortical thickness across all 68 cortical regions, was negatively associated with BD, BMI, antipsychotic medications, and age and was positively associated with Li treatment. PCA demonstrated superior goodness of fit to clustering when predicting diagnosis and BMI. Moreover, applying the PCA model to the replication sample yielded significant differences in cortical thickness between healthy controls and individuals with BD or schizophrenia. Cortical thickness in the same widespread regional network as determined by PCA was negatively associated with different clinical and demographic variables, including diagnosis, age, BMI, and treatment with antipsychotic medications or lithium. PCA outperformed clustering and provided an easy-to-use and interpret method to study multivariate associations between brain structure and system-level variables. Practitioner Points: In this study of 2770 Individuals, we confirmed that cortical thickness in widespread regional networks as determined by principal component analysis (PCA) was negatively associated with relevant clinical and demographic variables, including diagnosis, age, BMI, and treatment with antipsychotic medications or lithium. Significant associations of many different system-level variables with the same brain network suggest a lack of one-to-one mapping of individual clinical and demographic factors to specific patterns of brain changes. PCA outperformed clustering analysis in the same data set when predicting group or BMI, providing a superior method for studying multivariate associations between brain structure and system-level variables.</p