The INCLUDE study: INtegrating and improving Care for patients with infLammatory rheUmatological DisordErs in the community; identifying multimorbidity: Protocol for a pilot randomized controlled trial.

Background: Patients with inflammatory rheumatic conditions such as rheumatoid arthritis, polymyalgia rheumatica and ankylosing spondylitis are at increased risk of common comorbidities such as cardiovascular disease, osteoporosis and anxiety and depression which lead to increased morbidity and mortality. These associated morbidities are often un-recognized and under-treated. While patients with other long-term conditions such as diabetes are invited for routine reviews in primary care, which may include identification and management of co-morbidities, at present this does not occur for patients with inflammatory conditions, and thus, opportunities to diagnose and optimally manage these comorbidities are missed. Objective: To evaluate the feasibility and acceptability of a nurse-led integrated care review (the INtegrating and improving Care for patients with infLammatory rheUmatological DisordErs in the community (INCLUDE) review) for people with inflammatory rheumatological conditions in primary care. Design: A pilot cluster randomized controlled trial will be undertaken to test the feasibility and acceptability of a nurse-led integrated primary care review for identification, assessment and initial management of common comorbidities including cardiovascular disease, osteoporosis and anxiety and depression. A process evaluation will be undertaken using a mixed methods approach including participant self-reported questionnaires, a medical record review, an INCLUDE EMIS template, intervention fidelity checking using audio-recordings of the INCLUDE review consultation and qualitative interviews with patient participants, study nurses and study general practitioners (GPs). Discussion: Success of the pilot study will be measured against the engagement, recruitment and study retention rates of both general practices and participants. Acceptability of the INCLUDE review to patients and practitioners and treatment fidelity will be explored using a parallel process evaluation. Trial Registration: ISRCTN12765345

Relationship of anxiety with joint pain and its management: A population survey

Objectives The aims of the present study was to examine the associations between the severity of pain and anxiety in a community population reporting joint pain, and to investigate the management of joint pain in the presence of comorbid anxiety. Methods A population survey was carried out of people aged ≥45 years, registered with eight general practices in Cheshire, Shropshire and Staffordshire, UK. Respondents were asked to report pain intensity in their hands, hips, knees and feet (on a numerical rating scale), anxiety symptoms (Generalized Anxiety Disorder seven‐item [GAD‐7] scale) and guideline‐recommended treatments used to manage pain. Clinical anxiety was defined by a GAD‐7 score of 10 or more. Results A total of 11,222 respondents with joint pain were included in the analysis, with 1,802 (16.1%) reporting clinical anxiety. Respondents reporting more severe pain were more likely to report clinical anxiety (severe versus mild pain, odds ratio [OR] 5.36, 95% confidence interval [CI] 4.56 to 6.31). The number of pain sites was also positively associated with clinical anxiety (four versus one site; OR 3.64, 95% CI 3.09 to 4.30). Those with clinical anxiety were less likely to undertake general fitness exercises (OR 0.60, 95% CI 0.52 to 0.70), but more likely to diet (OR 1.43, 95% CI 1.21 to 1.69), use walking aids (OR 1.53, 95% CI 1.32 to 1.77) and assistive devices (OR 1.24, 95% CI 1.04 to 1.49), and more likely to use opioids (OR 1.34, 95% CI 1.18 to1.52). Conclusions Anxiety is common among patients presenting to primary care with joint pain. Patients with anxiety are likely to manage their joint pain differently to those without. Case‐finding to identify and treat anxiety would be appropriate in this population, with caution about opioid prescribing and consideration of exercise as an intervention

Impacts of carbohydrate-restricted diets on micronutrient intakes and status: a systematic review

A systematic review of published evidence on micronutrient intake/status with carbohydrate‐restricted diets (CRD) was conducted in Web of Science, Medline, Embase, Scopus, CENTRAL, and ClinicalTrials.gov up to October 2018. We identified 10 studies: seven randomized controlled trials (RCTs) (“Atkins”‐style, n = 5; “Paleolithic” diets, n = 2), two Atkins‐style noncontrolled trials and one cross‐sectional study. Prescribed carbohydrate varied 4% to 34% of energy intake. Only one noncontrolled trial prescribed multivitamin supplements. Dietary intakes/status were reported over 2 to 104 weeks, with weight losses from 2 to 9 kg. No diagnoses of deficiency were reported. Intakes of thiamine, folate, magnesium, calcium, iron, and iodine all decreased significantly (−10% to −70% from baseline) with any CRD types. Atkins diet trials (n = 6; 4%‐34%E carbohydrate) showed inconsistent changes in vitamin A, E, and β‐carotene intakes, while a single “Paleolithic” diet trial (28%E carbohydrate) reported increases in these micronutrients. One other “Paleolithic” diet (30%E carbohydrate) reported a rise in moderate iodine deficiency from 15% to 73% after 6 months. In conclusion, few studies have assessed the impacts of CRD on micronutrients. Studies with different designs point towards reductions in several vitamins and minerals, with potential risk of micronutrient inadequacies. Trial reporting standards are expected to include analysis of micronutrient intake/status. Micronutrients in foods and/or supplements should be considered when designing, prescribing or following CRDs

Oxygen: A Fundamental Property Regulating Pelagic Ecosystem Structure in the Coastal Southeastern Tropical Pacific

Background: In the southeastern tropical Pacific anchovy (Engraulis ringens) and sardine (Sardinops sagax) abundance have recently fluctuated on multidecadal scales and food and temperature have been proposed as the key parameters explaining these changes. However, ecological and paleoecological studies, and the fact that anchovies and sardines are favored differently in other regions, raise questions about the role of temperature. Here we investigate the role of oxygen in structuring fish populations in the Peruvian upwelling ecosystem that has evolved over anoxic conditions and is one of the world's most productive ecosystems in terms of forage fish. This study is particularly relevant given that the distribution of oxygen in the ocean is changing with uncertain consequences. Methodology/Principal Findings: A comprehensive data set is used to show how oxygen concentration and oxycline depth affect the abundance and distribution of pelagic fish. We show that the effects of oxygen on anchovy and sardine are opposite. Anchovy flourishes under relatively low oxygen conditions while sardine avoid periods/areas with low oxygen concentration and restricted habitat. Oxygen consumption, trophic structure and habitat compression play a fundamental role in fish dynamics in this important ecosystem. Conclusions/Significance: For the ocean off Peru we suggest that a key process, the need to breathe, has been neglected previously. Inclusion of this missing piece allows the development of a comprehensive conceptual model of pelagic fish populations and change in an ocean ecosystem impacted by low oxygen. Should current trends in oxygen in the ocean continue similar effects may be evident in other coastal upwelling ecosystems

Revisiting the Effect of Acute P. falciparum Malaria on Epstein-Barr Virus: Host Balance in the Setting of Reduced Malaria Endemicity

Burkitt's lymphoma (BL), an EBV-associated tumour, occurs at high incidence in populations where malaria is holoendemic. Previous studies in one such population suggested that acute P.falciparum infection impairs EBV-specific T-cell surveillance, allowing expansion of EBV infected B-cells from which BL derives. We re-examined the situation in the same area, The Gambia, after a reduction in malaria endemicity. Cellular immune responses to EBV were measured in children with uncomplicated malaria before (day 0) and after treatment (day 28), comparing EBV genome loads in blood and EBV-specific CD8+ T-cell numbers (assayed by MHC Class I tetramers and IFNγ ELISPOTS) with those seen in age- and sex-matched healthy controls. No significant changes were seen in EBV genome loads, percentage of EBV-specific CD8+ T-cells and IFNγ producing T-cells in acute versus convalescent samples, nor any difference versus controls. Regression assays performed also no longer detected any impairment of EBV-specific T-cell surveillance. Acute uncomplicated malaria infection no longer alters EBV-specific immune responses in children in The Gambia. Given the recent decline in malaria incidence in that country, we hypothesise that gross disturbance of the EBV-host balance may be a specific effect of acute malaria only in children with a history of chronic/recurrent malaria challenge

Comparative Genomic Analyses of Copper Transporters and Cuproproteomes Reveal Evolutionary Dynamics of Copper Utilization and Its Link to Oxygen

Copper is an essential trace element in many organisms and is utilized in all domains of life. It is often used as a cofactor of redox proteins, but is also a toxic metal ion. Intracellular copper must be carefully handled to prevent the formation of reactive oxygen species which pose a threat to DNA, lipids, and proteins. In this work, we examined patterns of copper utilization in prokaryotes by analyzing the occurrence of copper transporters and copper-containing proteins. Many organisms, including those that lack copper-dependent proteins, had copper exporters, likely to protect against copper ions that inadvertently enter the cell. We found that copper use is widespread among prokaryotes, but also identified several phyla that lack cuproproteins. This is in contrast to the use of other trace elements, such as selenium, which shows more scattered and reduced usage, yet larger selenoproteomes. Copper transporters had different patterns of occurrence than cuproproteins, suggesting that the pathways of copper utilization and copper detoxification are independent of each other. We present evidence that organisms living in oxygen-rich environments utilize copper, whereas the majority of anaerobic organisms do not. In addition, among copper users, cuproproteomes of aerobic organisms were larger than those of anaerobic organisms. Prokaryotic cuproproteomes were small and dominated by a single protein, cytochrome c oxidase. The data are consistent with the idea that proteins evolved to utilize copper following the oxygenation of the Earth

Use of Mutagenesis, Genetic Mapping and Next Generation Transcriptomics to Investigate Insecticide Resistance Mechanisms

Insecticide resistance is a worldwide problem with major impact on agriculture and human health. Understanding the underlying molecular mechanisms is crucial for the management of the phenomenon; however, this information often comes late with respect to the implementation of efficient counter-measures, particularly in the case of metabolism-based resistance mechanisms. We employed a genome-wide insertional mutagenesis screen to Drosophila melanogaster, using a Minos-based construct, and retrieved a line (MiT[w−]3R2) resistant to the neonicotinoid insecticide Imidacloprid. Biochemical and bioassay data indicated that resistance was due to increased P450 detoxification. Deep sequencing transcriptomic analysis revealed substantial over- and under-representation of 357 transcripts in the resistant line, including statistically significant changes in mixed function oxidases, peptidases and cuticular proteins. Three P450 genes (Cyp4p2, Cyp6a2 and Cyp6g1) located on the 2R chromosome, are highly up-regulated in mutant flies compared to susceptible Drosophila. One of them (Cyp6g1) has been already described as a major factor for Imidacloprid resistance, which validated the approach. Elevated expression of the Cyp4p2 was not previously documented in Drosophila lines resistant to neonicotinoids. In silico analysis using the Drosophila reference genome failed to detect transcription binding factors or microRNAs associated with the over-expressed Cyp genes. The resistant line did not contain a Minos insertion in its chromosomes, suggesting a hit-and-run event, i.e. an insertion of the transposable element, followed by an excision which caused the mutation. Genetic mapping placed the resistance locus to the right arm of the second chromosome, within a ∼1 Mb region, where the highly up-regulated Cyp6g1 gene is located. The nature of the unknown mutation that causes resistance is discussed on the basis of these results