Publications by authors named "David Hughes"

781 Publications

Associations between Maternal Psychosocial Stress, DNA Methylation, and Newborn Birth Weight Identified by Investigating Methylation at Individual, Regional, and Genome Levels.

Hum Biol 2019 Apr;91(2):117-131

Department of Anthropology, University of Florida, Gainesville, Florida, USA.

Stress is known to affect health throughout life and into future generations, but the underlying molecular mechanisms are unknown. We tested the hypothesis that maternal psychosocial stress influences DNA methylation (DNAm), which in turn impacts newborn health outcomes. Specifically, we analyzed DNAm at individual, regional, and genome-wide levels to test for associations with maternal stress and newborn birth weight. Maternal venous blood and newborn cord blood ( = 24 and 22, respectively) were assayed for methylation at ∼450,000 CpG sites. Methylation was analyzed by examining CpG sites individually in an epigenome-wide association study (EWAS), as regional groups using variably methylated region (VMR) analysis in maternal blood only, and through the epigenome-wide measures using genome-wide mean methylation (GMM), Horvath's epigenetic clock, and mitotic age. These methylation measures were tested for association with three measures of maternal stress (maternal war trauma, chronic stress, and experience of sexual violence) and one health outcome (newborn birth weight). We observed that maternal experiences of war trauma, chronic stress, and sexual assault were each associated with decreased newborn birth weight ( < 1.95 × 10 in all cases). Testing individual CpG sites using EWAS, we observed no associations between DNAm and any measure of maternal stress or newborn birth weight in either maternal or cord blood, after Bonferroni multiple testing correction. However, the top-ranked CpG site in maternal blood that associated with maternal chronic stress and sexual violence before multiple testing correction is located near the gene. Testing at a regional level, we found increased methylation of a VMR in maternal blood near that was associated with chronic stress and sexual violence after Bonferroni multiple testing correction ( = 1.95 × 10 and 8.3 × 10, respectively). At the epigenomic level, cord blood GMM was associated with significantly higher levels of war trauma ( = 0.025) and was suggestively associated with sexual violence ( = 0.053). The other two epigenome-wide measures were not associated with maternal stress or newborn birth weight in either tissue type. Despite our small sample size, we identified associations even after conservative multiple testing correction. Specifically, we found associations between DNAm and the three measures of maternal stress across both tissues; specifically, a VMR in maternal blood and GMM in cord blood were both associated with different measures of maternal stress. The association of cord blood GMM, but not maternal blood GMM, with maternal stress may suggest different responses to stress in mother and newborn. It is noteworthy that we found associations only when CpG sites were analyzed in aggregate, either as VMRs or as a broad summary measure of GMM.
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http://dx.doi.org/10.13110/humanbiology.91.2.04DOI Listing
April 2019

The Role of Gut Barrier Dysfunction and Microbiome Dysbiosis in Colorectal Cancer Development.

Front Oncol 2021 15;11:626349. Epub 2021 Apr 15.

Cancer Biology and Therapeutics Laboratory, Conway Institute, School of Biomedical and Biomolecular Sciences, University College Dublin, Dublin, Ireland.

Accumulating evidence indicates that breakdown of the+ protective mucosal barrier of the gut plays a role in colorectal cancer (CRC) development. Inflammation and oxidative stress in the colonic epithelium are thought to be involved in colorectal carcinogenesis and the breakdown of the integrity of the colonic barrier may increase the exposure of colonocytes to toxins from the colonic milieu, enhancing inflammatory processes and release of Reactive Oxygen Species (ROS). The aetiological importance of the gut microbiome and its composition - influenced by consumption of processed meats, red meats and alcoholic drinks, smoking, physical inactivity, obesity - in CRC development is also increasingly being recognized. The gut microbiome has diverse roles, such as in nutrient metabolism and immune modulation. However, microbial encroachment towards the colonic epithelium may promote inflammation and oxidative stress and even translocation of species across the colonic lumen. Recent research suggests that factors that modify the above mechanisms, e.g., obesity and Western diet, also alter gut microbiota, degrade the integrity of the gut protective barrier, and expose colonocytes to toxins. However, it remains unclear how obesity, lifestyle and metabolic factors contribute to gut-barrier integrity, leading to metabolic disturbance, colonocyte damage, and potentially to CRC development. This review will discuss the interactive roles of gut-barrier dysfunction, microbiome dysbiosis, and exposure to endogenous toxins as another mechanism in CRC development, and how biomarkers of colonic mucosal barrier function may provide avenues for disease, prevention and detection.
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http://dx.doi.org/10.3389/fonc.2021.626349DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8082020PMC
April 2021

Variation of microRNA expression in the human placenta driven by population identity and sex of the newborn.

BMC Genomics 2021 Apr 20;22(1):286. Epub 2021 Apr 20.

Skolkovo Institute of Science and Technology, 121205, Moscow, Russia.

Background: Analysis of lymphocyte cell lines revealed substantial differences in the expression of mRNA and microRNA (miRNA) among human populations. The extent of such population-associated differences in actual human tissues remains largely unexplored. The placenta is one of the few solid human tissues that can be collected in substantial numbers in a controlled manner, enabling quantitative analysis of transient biomolecules such as RNA transcripts. Here, we analyzed microRNA (miRNA) expression in human placental samples derived from 36 individuals representing four genetically distinct human populations: African Americans, European Americans, South Asians, and East Asians. All samples were collected at the same hospital following a unified protocol, thus minimizing potential biases that might influence the results.

Results: Sequence analysis of the miRNA fraction yielded 938 annotated and 70 novel miRNA transcripts expressed in the placenta. Of them, 82 (9%) of annotated and 11 (16%) of novel miRNAs displayed quantitative expression differences among populations, generally reflecting reported genetic and mRNA-expression-based distances. Several co-expressed miRNA clusters stood out from the rest of the population-associated differences in terms of miRNA evolutionary age, tissue-specificity, and disease-association characteristics. Among three non-environmental influenced demographic parameters, the second largest contributor to miRNA expression variation after population was the sex of the newborn, with 32 miRNAs (3% of detected) exhibiting significant expression differences depending on whether the newborn was male or female. Male-associated miRNAs were evolutionarily younger and correlated inversely with the expression of target mRNA involved in neuron-related functions. In contrast, both male and female-associated miRNAs appeared to mediate different types of hormonal responses. Demographic factors further affected reported imprinted expression of 66 placental miRNAs: the imprinting strength correlated with the mother's weight, but not height.

Conclusions: Our results showed that among 12 assessed demographic variables, population affiliation and fetal sex had a substantial influence on miRNA expression variation among human placental samples. The effect of newborn-sex-associated miRNA differences further led to expression inhibition of the target genes clustering in specific functional pathways. By contrast, population-driven miRNA differences might mainly represent neutral changes with minimal functional impacts.
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http://dx.doi.org/10.1186/s12864-021-07542-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059241PMC
April 2021

Association of Pre-diagnostic Antibody Responses to Escherichia coli and Bacteroides fragilis Toxin Proteins with Colorectal Cancer in a European Cohort.

Gut Microbes 2021 Jan-Dec;13(1):1-14

Department of Medical Biosciences, Pathology, Umeå University, Ireland.

Experimental evidence has implicated genotoxic () and enterotoxigenic (ETBF) in the development of colorectal cancer (CRC). However, evidence from epidemiological studies is sparse. We therefore assessed the association of serological markers of and ETBF exposure with odds of developing CRC in the European Prospective Investigation into Nutrition and Cancer (EPIC) study.Serum samples of incident CRC cases and matched controls (n = 442 pairs) were analyzed for immunoglobulin (Ig) A and G antibody responses to seven proteins and two isoforms of the ETBF toxin via multiplex serology. Multivariable-adjusted conditional logistic regression analyses were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association of sero-positivity to and ETBF with CRC.The IgA-positivity of any of the tested antigens was associated with higher odds of developing CRC (OR: 1.42; 95% CI: 1.05-1.91). Dual-positivity for both IgA and IgG to and ETBF was associated with >1.7-fold higher odds of developing CRC, with a significant association only for IgG (OR: 1.75; 95% CI: 1.04, 2.94). This association was more pronounced when restricted to the proximal colon cancers (OR: 2.62; 95% CI: 1.09, 6.29) compared to those of the distal colon (OR: 1.24; 95% CI: 0.51, 3.00) (= 0.095). Sero-positivity to and ETBF was associated with CRC development, suggesting that co-infection of these bacterial species may contribute to colorectal carcinogenesis. These findings warrant further exploration in larger prospective studies and within different population groups.
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http://dx.doi.org/10.1080/19490976.2021.1903825DOI Listing
April 2021

Body fat composition and risk of rheumatoid arthritis: Mendelian randomisation study.

Arthritis Rheumatol 2021 Apr 12. Epub 2021 Apr 12.

Department of Health Data Science, University of Liverpool, Liverpool.

Observational studies showed obesity (defined using BMI) to be associated with rheumatoid arthritis (RA) risk, but its causal role remains unclear. Dramatic weight loss following bariatric surgery did not reduce RA risk [1]. Obesity is also paradoxically associated with reduced mortality among RA patients [2]. These inconsistencies may be due to challenges from confounding, reverse causation (chronic inflammation can induce changes to body composition), or limitations of BMI, which cannot distinguish fat from fat-free (lean) mass.
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http://dx.doi.org/10.1002/art.41766DOI Listing
April 2021

Stability in solution and chemoprotection by octadecavanadates(IV/V) in E. coli cultures.

J Inorg Biochem 2021 Jun 26;219:111438. Epub 2021 Mar 26.

Departamento de Química, Universidade Federal do Paraná, Curitiba, PR, Brazil. Electronic address:

Two mixed-valence octadecavanadates, (NH)(MeN)[VVOI]·MeNI·5HO (VI) and [{K(OH)VVO(PO)·4HO}] (VP), were synthesized and characterized by single-crystal X-ray diffraction analysis and FTIR, Raman, V NMR, EPR and UV/Vis/NIR spectroscopies. The chemoprotective activity of VI and VP towards the alkylating agent diethyl sulfate was assessed in E. coli cultures. The complex VI was nontoxic in concentrations up to 5.0 mmol L, while VP presented moderate toxicity in the concentration range 0.10 - 10 mmol L. Conversely, a ca. 35% enhancement in culture growth as compared to cells treated only with diethyl sulfate was observed upon addition of VI (0.10 to 2.5 mmol L), while the combination of diethyl sulfate with VP increased the cytotoxicity presented by diethyl sulfate alone. V NMR and EPR speciation studies showed that VI is stable in solution, while VP suffers partial breakage to give low nuclearity oxidometalates of vanadium(V) and (IV). According to the results, the chemoprotective effect depends strongly on the direct reactivity of the polyoxidovanadates (POV) towards the alkylating agent. The reaction of diethyl sulfate with VI apparently produces a new, rearranged POV instead of poorly-reactive breakage products, while VP shows the formation and subsequent consumption of low-nuclearity species. The correlation of this chemistry with that of other mixed-valence polyoxidovanadates, [HVVOPO] (V) and [VVOCl] (V), suggests a relationship between stability in solution and chemoprotective performance.
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http://dx.doi.org/10.1016/j.jinorgbio.2021.111438DOI Listing
June 2021

Insect Behavioral Change and the Potential Contributions of Neuroinflammation-A Call for Future Research.

Genes (Basel) 2021 Mar 24;12(4). Epub 2021 Mar 24.

Department of Entomology, College of Agricultural Sciences, Pennsylvania State University, University Park, State College, PA 16802, USA.

Many organisms are able to elicit behavioral change in other organisms. Examples include different microbes (e.g., viruses and fungi), parasites (e.g., hairworms and trematodes), and parasitoid wasps. In most cases, the mechanisms underlying host behavioral change remain relatively unclear. There is a growing body of literature linking alterations in immune signaling with neuron health, communication, and function; however, there is a paucity of data detailing the effects of altered neuroimmune signaling on insect neuron function and how glial cells may contribute toward neuron dysregulation. It is important to consider the potential impacts of altered neuroimmune communication on host behavior and reflect on its potential role as an important tool in the "neuro-engineer" toolkit. In this review, we examine what is known about the relationships between the insect immune and nervous systems. We highlight organisms that are able to influence insect behavior and discuss possible mechanisms of behavioral manipulation, including potentially dysregulated neuroimmune communication. We close by identifying opportunities for integrating research in insect innate immunity, glial cell physiology, and neurobiology in the investigation of behavioral manipulation.
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http://dx.doi.org/10.3390/genes12040465DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064348PMC
March 2021

Dietary intake of vitamin A, lung function, and incident asthma in childhood.

Eur Respir J 2021 Apr 1. Epub 2021 Apr 1.

Institute of Population Health Sciences, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.

Longitudinal epidemiological data are scarce on the relation between dietary intake of vitamin A and respiratory outcomes in childhood. We investigated whether a higher intake of preformed vitamin A or provitamin β-carotene in mid-childhood is associated with higher lung function and with asthma risk in adolescence.In the Avon Longitudinal Study of Parents and Children, dietary intakes of preformed vitamin A and β-carotene equivalents were estimated by food frequency questionnaire at 7 years of age. Post- bronchodilator forced expiratory volume in 1 s (FEV), forced vital capacity (FVC), and forced expiratory flow at 25-75% of FVC (FEF) were measured at 15.5 years and transformed to z scores. Incident asthma was defined by new cases of doctor-diagnosed asthma at age 11 or 14 years.In multivariable adjusted models, a higher intake of preformed vitamin A was associated with higher lung function and a lower risk of incident asthma: comparing top bottom quartiles of intake, regression coefficients (95% confidence intervals) for FEV and FEF were, respectively, 0.21 (0.05-0.38; P-trend 0.008) and 0.18 (0.03-0.32; P-trend 0.02); odds ratios (95% confidence intervals) for FEV/FVC ratio below the lower limit of normal and incident asthma were, respectively, 0.49 (0.27-0.90, P-trend 0.04) and 0.68 (0.47, 0.99; P-trend 0.07). In contrast, there was no evidence for association with β-carotene. We also found some evidence for modification of the associations between preformed vitamin A intake and lung function by and gene polymorphisms.A higher intake of preformed vitamin A, but not β-carotene, in mid-childhood is associated with higher subsequent lung function and lower risk of fixed airflow limitation and incident asthma.
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http://dx.doi.org/10.1183/13993003.04407-2020DOI Listing
April 2021

Plasma concentrations of advanced glycation end-products and colorectal cancer risk in the EPIC study.

Carcinogenesis 2021 Mar 29. Epub 2021 Mar 29.

Office of the Director, International Agency for Research on Cancer (IARC), Lyon, France.

Advanced glycation end-products (AGEs) are a heterogeneous group of compounds formed by the non-enzymatic reaction between amino-acids and reducing sugars, or dicarbonyls as intermediate compounds. Experimental studies suggest that AGEs may promote colorectal cancer, but prospective epidemiologic studies are inconclusive. We conducted a case-control study nested within a large European cohort. Plasma concentrations of three protein-bound AGEs: N ε-(carboxy-methyl)lysine (CML), N ε-(carboxy-ethyl)lysine (CEL) and N δ-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1) were measured by ultra-performance liquid chromatography tandem mass-spectrometry in baseline samples collected from 1,378 incident primary colorectal cancer cases and 1,378 matched controls. Multivariable-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were computed using conditional logistic regression for colorectal cancer risk associated with CML, CEL, MG-H1, total AGEs, and [CEL+MG-H1: CML] and [CEL:MG-H1] ratios. Inverse colorectal cancer risk associations were observed for CML (OR comparing highest to lowest quintile, ORQ5vs.Q1=0.40, 95%CI:0.27-0.59), MG-H1 (ORQ5vs.Q1=0.73, 95%CI:0.53 - 1.00) and total AGEs (OR Q5vs.Q1=0.52, 95%CI:0.37 - 0.73) whereas no association was observed for CEL. A higher [CEL+MG-H1: CML] ratio was associated with colorectal cancer risk (ORQ5vs.Q1=1.91, 95%CI:1.31-2.79). The associations observed did not differ by sex, or by tumour anatomical subsite. Although individual AGEs concentrations appear to be inversely associated with colorectal cancer risk, a higher ratio of methylglyoxal-derived AGEs versus those derived from glyoxal (calculated by [CEL+MG-H1: CML] ratio) showed a strong positive risk association. Further insight on the metabolism of AGEs and their dicarbonyls precursors, and their roles in colorectal cancer development is needed.
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http://dx.doi.org/10.1093/carcin/bgab026DOI Listing
March 2021

Spinoparabrachial projection neurons form distinct classes in the mouse dorsal horn.

Pain 2019 01 22. Epub 2019 Jan 22.

School of Biomedical Sciences and Pharmacy, Faculty of Health, University of Newcastle, Callaghan, New South Wales, Australia.

Projection neurons in the spinal dorsal horn relay sensory information to higher brain centres. The activation of these populations is shaped by afferent input from the periphery, descending input from the brain, and input from local interneuron circuits. Much of our recent understanding of dorsal horn circuitry comes from studies in transgenic mice; however, information on projection neurons is still based largely on studies in monkey, cat, and rat. We used viral labelling to identify and record from mouse parabrachial nucleus (PBN) projecting neurons located in the dorsal horn of spinal cord slices. Overall, mouse lamina I spinoparabrachial projection neurons (SPBNs) exhibit many electrophysiological and morphological features that overlap with rat. Unbiased cluster analysis distinguished 4 distinct subpopulations of lamina I SPBNs, based on their electrophysiological properties that may underlie different sensory signalling features in each group. We also provide novel information on SPBNs in the deeper lamina (III-V), which have not been previously studied by patch clamp analysis. These neurons exhibited higher action potential discharge frequencies and received weaker excitatory synaptic input than lamina I SPBNs, suggesting this deeper population produces different sensory codes destined for the PBN. Mouse SPBNs from both regions (laminae I and III-V) were often seen to give off local axon collaterals, and we provide neuroanatomical evidence they contribute to excitatory input to dorsal horn circuits. These data provide novel information to implicate excitatory input from parabrachial projection neuron in dorsal horn circuit activity during processing of nociceptive information, as well as defining deep dorsal horn projection neurons that provide an alternative route by which sensory information can reach the PBN.
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http://dx.doi.org/10.1097/j.pain.0000000000002194DOI Listing
January 2019

The effect of random-effects misspecification on classification accuracy.

Int J Biostat 2021 Mar 26. Epub 2021 Mar 26.

Health Data Science, University of Liverpool Faculty of Health and Life Sciences, Liverpool, UK.

Mixed models are a useful way of analysing longitudinal data. Random effects terms allow modelling of patient specific deviations from the overall trend over time. Correlation between repeated measurements are captured by specifying a joint distribution for all random effects in a model. Typically, this joint distribution is assumed to be a multivariate normal distribution. For Gaussian outcomes misspecification of the random effects distribution usually has little impact. However, when the outcome is discrete (e.g. counts or binary outcomes) generalised linear mixed models (GLMMs) are used to analyse longitudinal trends. Opinion is divided about how robust GLMMs are to misspecification of the random effects. Previous work explored the impact of random effects misspecification on the bias of model parameters in single outcome GLMMs. Accepting that these model parameters may be biased, we investigate whether this affects our ability to classify patients into clinical groups using a longitudinal discriminant analysis. We also consider multiple outcomes, which can significantly increase the dimensions of the random effects distribution when modelled simultaneously. We show that when there is severe departure from normality, more flexible mixture distributions can give better classification accuracy. However, in many cases, wrongly assuming a single multivariate normal distribution has little impact on classification accuracy.
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http://dx.doi.org/10.1515/ijb-2019-0159DOI Listing
March 2021

Genetically predicted circulating concentrations of micronutrients and risk of colorectal cancer among individuals of European descent: a Mendelian randomization study.

Am J Clin Nutr 2021 Mar 19. Epub 2021 Mar 19.

Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Background: The literature on associations of circulating concentrations of minerals and vitamins with risk of colorectal cancer is limited and inconsistent. Evidence from randomized controlled trials (RCTs) to support the efficacy of dietary modification or nutrient supplementation for colorectal cancer prevention is also limited.

Objectives: To complement observational and RCT findings, we investigated associations of genetically predicted concentrations of 11 micronutrients (β-carotene, calcium, copper, folate, iron, magnesium, phosphorus, selenium, vitamin B-6, vitamin B-12, and zinc) with colorectal cancer risk using Mendelian randomization (MR).

Methods: Two-sample MR was conducted using 58,221 individuals with colorectal cancer and 67,694 controls from the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry. Inverse variance-weighted MR analyses were performed with sensitivity analyses to assess the impact of potential violations of MR assumptions.

Results: Nominally significant associations were noted for genetically predicted iron concentration and higher risk of colon cancer [ORs per SD (ORSD): 1.08; 95% CI: 1.00, 1.17; P value = 0.05] and similarly for proximal colon cancer, and for vitamin B-12 concentration and higher risk of colorectal cancer (ORSD: 1.12; 95% CI: 1.03, 1.21; P value = 0.01) and similarly for colon cancer. A nominally significant association was also noted for genetically predicted selenium concentration and lower risk of colon cancer (ORSD: 0.98; 95% CI: 0.96, 1.00; P value = 0.05) and similarly for distal colon cancer. These associations were robust to sensitivity analyses. Nominally significant inverse associations were observed for zinc and risk of colorectal and distal colon cancers, but sensitivity analyses could not be performed. None of these findings survived correction for multiple testing. Genetically predicted concentrations of β-carotene, calcium, copper, folate, magnesium, phosphorus, and vitamin B-6 were not associated with disease risk.

Conclusions: These results suggest possible causal associations of circulating iron and vitamin B-12 (positively) and selenium (inversely) with risk of colon cancer.
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http://dx.doi.org/10.1093/ajcn/nqab003DOI Listing
March 2021

Safety, Tolerability, and Efficacy of Selinexor in a Patient With Relapsed Light Chain (AL) Amyloidosis.

Clin Lymphoma Myeloma Leuk 2021 May 6;21(5):e460-e463. Epub 2021 Jan 6.

Amyloidosis Center, Boston University School of Medicine, Boston, MA.

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http://dx.doi.org/10.1016/j.clml.2021.01.001DOI Listing
May 2021

Depression and anxiety symptoms at TNF inhibitor initiation are associated with impaired treatment response in axial spondyloarthritis.

Rheumatology (Oxford) 2021 Mar 13. Epub 2021 Mar 13.

Department of Rheumatology, Liverpool University Hospitals, Liverpool, UK.

Objectives: Depression and anxiety are associated with more severe disease in cross-sectional studies of axial spondyloarthritis (axSpA). We examined the association between baseline symptoms of depression or anxiety and response to TNF inhibitors (TNFi) in axSpA.

Methods: Biologic naïve participants from a national axSpA register completed the Hospital Anxiety and Depression Scale (HADS) before initiating TNFi. Symptoms of anxiety and depression were each categorised as moderate-severe (≥11), mild (8-10), and 'none' (≤7), and compared against: change in disease indices (BASDAI and ASDAS) over time and time to treatment discontinuation using marginal structural models. Inverse-probability weights balanced baseline age, gender, BMI, deprivation, education, and baseline values of respective indices.

Results: Of the 742 participants (67% male, mean age 45 years), 156 (23%) had moderate-severe and 26% mild depression; 256 (39%) had moderate-severe and 23% mild anxiety. Baseline disease activity was higher in higher HADS symptom categories for both depression and anxiety. Participants with moderate-severe depression had significantly poorer response compared with those with 'none' throughout follow-up. At 6 months, the difference was ∼2.2 BASDAI and 0.8 ASDAS units after balancing their baseline values. Equivalent comparisons for anxiety were 1.7 BASDAI and 0.7 ASDAS units. Treatment discontinuation was HR1.59 higher (95%CI 1.12, 2.26) in participants with moderate-severe anxiety compared with 'none'.

Conclusions: Symptoms of depression and anxiety at TNFi initiation are associated with significantly poorer treatment outcomes. Targeted interventions to optimise mental health have potential to substantially improve treatment response and persistence.
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http://dx.doi.org/10.1093/rheumatology/keab242DOI Listing
March 2021

The ketogenic diet preserves skeletal muscle with aging in mice.

Aging Cell 2021 04 6;20(4):e13322. Epub 2021 Mar 6.

Department of Neurobiology, Physiology and Behavior, University of California, Davis, CA, USA.

The causes of the decline in skeletal muscle mass and function with age, known as sarcopenia, are poorly understood. Nutrition (calorie restriction) interventions impact many cellular processes and increase lifespan and preserve muscle mass and function with age. As we previously observed an increase in life span and muscle function in aging mice on a ketogenic diet (KD), we aimed to investigate the effect of a KD on the maintenance of skeletal muscle mass with age and the potential molecular mechanisms of this action. Twelve-month-old mice were assigned to an isocaloric control or KD until 16 or 26 months of age, at which time skeletal muscle was collected for evaluating mass, morphology, and biochemical properties. Skeletal muscle mass was significantly greater at 26 months in the gastrocnemius of mice on the KD. This result in KD mice was associated with a shift in fiber type from type IIb to IIa fibers and a range of molecular parameters including increased markers of NMJ remodeling, mitochondrial biogenesis, oxidative metabolism, and antioxidant capacity, while decreasing endoplasmic reticulum (ER) stress, protein synthesis, and proteasome activity. Overall, this study shows the effectiveness of a long-term KD in mitigating sarcopenia. The diet preferentially preserved oxidative muscle fibers and improved mitochondrial and antioxidant capacity. These adaptations may result in a healthier cellular environment, decreasing oxidative and ER stress resulting in less protein turnover. These shifts allow mice to better maintain muscle mass and function with age.
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http://dx.doi.org/10.1111/acel.13322DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8045940PMC
April 2021

A Review of Novel Agents and Clinical Considerations in Patients With ATTR Cardiac Amyloidosis.

J Cardiovasc Pharmacol 2021 May;77(5):544-548

Department of Pharmacy, Boston Medical Center, Boston, MA.

Abstract: Transthyretin (ATTR) amyloidosis is a multisystem disease caused by organ deposition of amyloid fibrils derived from the misfolded transthyretin (TTR) protein. The purpose of this article is to provide an overview of current treatment regimens and summarize important considerations for each agent. A literature search was performed with the PubMed database for articles published through October 2020. Search criteria included therapies available on the market and investigational therapies used for ATTR amyloidosis treatment. Both prospective clinical trials and retrospective studies have been included in this review. Available therapies discussed in this review article are tafamidis, diflunisal, patisiran, and inotersen. Tafamidis is FDA approved for treatment of wild-type ATTR (ATTRwt) and hereditary ATTR (ATTRv) cardiomyopathy, and patisiran and inotersen are FDA approved for ATTRv polyneuropathy. Diflunisal does not have an FDA-labeled indication for amyloidosis but has been studied in ATTRv polyneuropathy and ATTRwt cardiomyopathy. Investigational therapies include a TTR stabilizer, AG10; 2 antifibril agents, PRX004 and doxycycline/tauroursodeoxycholic acid; and 2 gene silencers, vutrisiran and AKCEA-TTR-LRx; and clinical trials are ongoing. ATTR amyloidosis treatment selection is based on subtype and presence of cardiac or neurological manifestations. Additional considerations such as side effects, monitoring, and administration are outlined in this review.
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http://dx.doi.org/10.1097/FJC.0000000000001004DOI Listing
May 2021

Crop type exerts greater influence upon rhizosphere phosphohydrolase gene abundance and phylogenetic diversity than phosphorus fertilization.

FEMS Microbiol Ecol 2021 03;97(4)

Universidade Federal de São João del-Rei, Bioengineering, R. Padre João Pimentel, 80 - Dom Bosco, São João del-Rei, Minas Gerais, 36301-158, Brazil.

Rock phosphate is an alternative form of phosphorus (P) fertilizer; however, there is no information regarding the influence of P fertilizer sources in Brazilian Cerrado soils upon microbial genes coding for phosphohydrolase enzymes in crop rhizospheres. Here, we analyze a field experiment comparing maize and sorghum grown under different P fertilization (rock phosphate and triple superphosphate) upon crop performance, phosphatase activity and rhizosphere microbiomes at three levels of diversity: small subunit rRNA marker genes of bacteria, archaea and fungi; a suite of alkaline and acid phosphatase and phytase genes; and ecotypes of individual genes. We found no significant difference in crop performance between the fertilizer sources, but the accumulation of fertilizer P into pools of organic soil P differed. Phosphatase activity was the only biological parameter influenced by P fertilization. Differences in rhizosphere microbiomes were observed at all levels of biodiversity due to crop type, but not fertilization. Inspection of phosphohydrolase gene ecotypes responsible for differences between the crops suggests a role for lateral genetic transfer in establishing ecotype distributions. Moreover, they were not reflected in microbial community composition, suggesting that they confer competitive advantage to individual cells rather than species in the sorghum rhizosphere.
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http://dx.doi.org/10.1093/femsec/fiab033DOI Listing
March 2021

Student Perceptions of educational handovers.

Clin Teach 2021 Jan 19. Epub 2021 Jan 19.

Department of Learning Health Sciences, University of Michigan Medical School, Ann Arbor, Michigan, USA.

Background: Educational handovers can provide competency information about graduating medical students to residency program directors post-residency placement. Little is known about students' comfort with this novel communication.

Objective: To examine graduated medical students' perceptions of educational handovers.

Methods: The authors created and distributed an anonymous survey to 166 medical students at a single institution following graduation in the spring of 2018. Within this cohort, 40 students had an educational handover sent to their future program director. The survey explored comfort level with handovers (1=very uncomfortable; 5=very comfortable) and ideal content (e.g., student strengths, areas for improvement, goals, grades received after residency application). Respondents self-reported their performance in medical school and whether a handover was sent. Correlation analyses examined relationships between performance and other variables. T-tests examined differences between students who did and did not have a handover letter sent.

Results: The survey response rate was 40.4% (67/166) - 47.8% of students felt comfortable with handovers, 19.4% were neutral, and 32.8% were uncomfortable. There was no correlation between self-reported medical school performance and comfort level. Respondents felt most strongly that strengths should be included, followed by goals. Those who had a handover letter sent expressed significantly higher comfort level (3.8 ± 1.0 vs. 2.6 ±1.3, p=0.003) with this communication.

Conclusion: Medical students reported varying levels of comfort with educational handovers; however, those who had handovers sent had more positive perceptions. In order to improve the education continuum, it is essential to engage students in the development of this handover communication.
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http://dx.doi.org/10.1111/tct.13327DOI Listing
January 2021

Large-scale association analyses identify host factors influencing human gut microbiome composition.

Nat Genet 2021 02 18;53(2):156-165. Epub 2021 Jan 18.

Department of Twin Research & Genetic Epidemiology, King's College London, London, UK.

To study the effect of host genetics on gut microbiome composition, the MiBioGen consortium curated and analyzed genome-wide genotypes and 16S fecal microbiome data from 18,340 individuals (24 cohorts). Microbial composition showed high variability across cohorts: only 9 of 410 genera were detected in more than 95% of samples. A genome-wide association study of host genetic variation regarding microbial taxa identified 31 loci affecting the microbiome at a genome-wide significant (P < 5 × 10) threshold. One locus, the lactase (LCT) gene locus, reached study-wide significance (genome-wide association study signal: P = 1.28 × 10), and it showed an age-dependent association with Bifidobacterium abundance. Other associations were suggestive (1.95 × 10 < P < 5 × 10) but enriched for taxa showing high heritability and for genes expressed in the intestine and brain. A phenome-wide association study and Mendelian randomization identified enrichment of microbiome trait loci in the metabolic, nutrition and environment domains and suggested the microbiome might have causal effects in ulcerative colitis and rheumatoid arthritis.
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http://dx.doi.org/10.1038/s41588-020-00763-1DOI Listing
February 2021

Diagnostic delay in axial spondyloarthritis: a systematic review and meta-analysis.

Rheumatology (Oxford) 2021 Apr;60(4):1620-1628

Department of Biostatistics, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.

Background: Delay to diagnosis in axial SpA (axSpA) is longer than in many other rheumatic diseases. Prolonged delay is associate with poorer outcomes, including functional impairment and quality of life. Our aims were to describe global variation in delay to diagnosis, factors associated with delay, and delay compared with PsA.

Methods: We searched MEDLINE, PubMed, Embase and Web of Science using a predefined protocol. Diagnostic delay was defined as years between the age at symptom onset and at diagnosis. We pooled the mean delay using random effects inverse variance meta-analysis. We examined variations in pooled estimates using prespecified subgroup analyses and sources of heterogeneity using meta-regression.

Results: A total of 64 studies reported the mean diagnostic delay in axSpA patients. The pooled mean delay was 6.7 years (95% CI 6.2, 7.2) with high levels of heterogeneity. Delay to diagnosis did not improve over time when stratifying results by year of publication. Studies from high-income countries (defined by the World Bank) reported longer delays than those from middle-income countries. Factors consistently reported to be associated with longer delays were lower education levels, younger age at symptom onset and absence of extra-articular manifestations (EAMs). The pooled estimate for diagnostic delay from 8 PsA studies was significantly shorter, at 2.6 years (95% CI 1.6, 3.6).

Conclusion: For axSpA patients, delay to diagnosis remains unacceptably prolonged in many parts of the world. Patient factors (e.g. education) and disease presentation (onset age and EAMs) should inform campaigns to improve delay.
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http://dx.doi.org/10.1093/rheumatology/keaa807DOI Listing
April 2021

Complementary Syntheses Giving Access to a Full Suite of Differentially Substituted Phthalocyanine-Porphyrin Hybrids.

Angew Chem Int Ed Engl 2021 03 1;60(14):7632-7636. Epub 2021 Mar 1.

School of Chemistry, University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ, UK.

Phthalocyanines and porphyrins are often the scaffolds of choice for use in widespread applications. Synthetic advances allow bespoke derivatives to be made, tailoring their properties. The selective synthesis of unsymmetrical systems, particularly phthalocyanines, has remained a significant unmet challenge. Porphyrin-phthalocyanine hybrids offer the potential to combine the favorable features of both parent structures, but again synthetic strategies are poorly developed. Here we demonstrate strategies that give straightforward, controlled access to differentially substituted meso-aryl-tetrabenzotriazaporphyrins by reaction between an aryl-aminoisoindolene (A) initiator and a complementary phthalonitrile (B). The choice of precursors and reaction conditions allows selective preparation of 1:3 Ar-ABBB and, uniquely, 2:2 Ar-ABBA functionalized hybrids.
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http://dx.doi.org/10.1002/anie.202016596DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048519PMC
March 2021

Comorbidities in psoriatic arthritis: a systematic review and meta-analysis.

Rheumatol Int 2021 Feb 9;41(2):275-284. Epub 2021 Jan 9.

Musculoskeletal Biology, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, L69 3GA, UK.

The aims of this systematic review and meta-analysis were to: (1) describe the prevalence of commonly reported comorbidities in psoriatic arthritis (PsA), (2) compare the incidence and/or prevalence of comorbidities between PsA and control populations; and (3) examine the impact of comorbidities on PsA outcomes. We systematically searched Medline, PubMed, Scopus, and Web of Science using a predefined protocol in accordance with PRISMA guidelines. Studies reporting only one comorbidity, or a few closely related diseases within one organ system, were excluded. Where possible, meta-analysis was performed using random-effects models. We included 39 studies amounting to over 152 thousand PsA patients. We performed meta-analysis for the prevalence of 21 commonly reported comorbidities. The most prevalent comorbidities were hypertension (pooled prevalence 34%), metabolic syndrome (29%), obesity (27%), hyperlipidaemia (24%) and any cardiovascular diseases (19%). Eleven studies consistently showed higher prevalence of comorbidities in PsA than controls. Five studies showed that comorbid patients had more severe disease, poorer quality of life, and increased discontinuation of treatment. Comorbidities, particularly cardiometabolic disorders, were highly prevalent in PsA and more common than in healthy controls. Comorbidities were associated with adverse disease features, but more research is needed on their impact on longitudinal outcomes such as treatment response, work productivity and mortality.
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http://dx.doi.org/10.1007/s00296-020-04775-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835184PMC
February 2021

Projection Neuron Axon Collaterals in the Dorsal Horn: Placing a New Player in Spinal Cord Pain Processing.

Front Physiol 2020 21;11:560802. Epub 2020 Dec 21.

School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan, NSW, Australia.

The pain experience depends on the relay of nociceptive signals from the spinal cord dorsal horn to higher brain centers. This function is ultimately achieved by the output of a small population of highly specialized neurons called projection neurons (PNs). Like output neurons in other central nervous system (CNS) regions, PNs are invested with a substantial axon collateral system that ramifies extensively within local circuits. These axon collaterals are widely distributed within and between spinal cord segments. Anatomical data on PN axon collaterals have existed since the time of Cajal, however, their function in spinal pain signaling remains unclear and is absent from current models of spinal pain processing. Despite these omissions, some insight on the potential role of PN axon collaterals can be drawn from axon collateral systems of principal or output neurons in other CNS regions, such as the hippocampus, amygdala, olfactory cortex, and ventral horn of the spinal cord. The connectivity and actions of axon collaterals in these systems have been well-defined and used to confirm crucial roles in memory, fear, olfaction, and movement control, respectively. We review this information here and propose a framework for characterizing PN axon collateral function in the dorsal horn. We highlight that experimental approaches traditionally used to delineate axon collateral function in other CNS regions are not easily applied to PNs because of their scarcity relative to spinal interneurons (INs), and the lack of cellular organization in the dorsal horn. Finally, we emphasize how the rapid development of techniques such as viral expression of optogenetic or chemogenetic probes can overcome these challenges and allow characterization of PN axon collateral function. Obtaining detailed information of this type is a necessary first step for incorporation of PN collateral system function into models of spinal sensory processing.
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http://dx.doi.org/10.3389/fphys.2020.560802DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7779806PMC
December 2020

Seven-Coordinate Tb Complexes with 90% Quantum Yields: High-Performance Examples of Combined Singlet- and Triplet-to-Tb Energy-Transfer Pathways.

Inorg Chem 2021 Jan 4;60(2):892-907. Epub 2021 Jan 4.

Department of Chemistry, Federal University of Paraná, 81530-900 - Curitiba-PR, Brazil.

Seven-coordinate, pentagonal-bipyramidal (PBP) complexes [Ln(bbpen)Cl] and [Ln(bbppn)Cl], in which Ln = Tb (products and ), Eu ( and ), and Gd ( and ), with bbpen = ,'-bis(2-oxidobenzyl)-,'-bis(pyridin-2-ylmethyl)ethylenediamine and bbppn = ,'-bis(2-oxidobenzyl)-,'-bis(pyridin-2-ylmethyl)-1,2-propanediamine, were synthesized and characterized by single-crystal X-ray diffraction analysis, alternating-current magnetic susceptibility measurements, and photoluminescence (steady-state and time-resolved) spectroscopy. Under a static magnetic field of 0.1 T, the Tb complexes and revealed single-ion-magnet behavior. Also, upon excitation at 320 nm at 300 K, and presented very high absolute emission quantum yields (0.90 ± 0.09 and 0.92 ± 0.09, respectively), while the corresponding Eu complexes and showed no photoluminescence. Detailed theoretical calculations on the intramolecular energy-transfer rates for the Tb products indicated that both singlet and triplet ligand excited states contribute efficiently to the overall emission performance. The expressive quantum yields, , measured for and in the solid state and a dichloromethane solution depend on the excitation wavelength, being higher at 320 nm. Such a dependence was rationalized by computing the intersystem crossing rates () and singlet fluorescence lifetimes (τ) related to the population dynamics of the S and T levels. Thin films of product showed high air stability and photostability upon continuous UV illumination, which allowed their use as downshifting layers in a green light-emitting device (LED). The prototypes presented a luminous efficacy comparable with those found in commercial LED coatings, without requiring encapsulation or dispersion of in host matrixes. The results indicate that the PBP environment determined by the ethylenediamine (en)-based ligands investigated in this work favors the outstanding optical properties in Tb complexes. This work presents a comprehensive structural, chemical, and spectroscopic characterization of two Tb complexes of mixed-donor, en-based ligands, focusing on their outstanding optical properties. They constitute good molecular examples in which both triplet and singlet excited states provide energy to the Tb ion and lead to high values of .
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http://dx.doi.org/10.1021/acs.inorgchem.0c03020DOI Listing
January 2021

Accuracy of a Smartphone-Based Object Detection Model, PlantVillage Nuru, in Identifying the Foliar Symptoms of the Viral Diseases of Cassava-CMD and CBSD.

Front Plant Sci 2020 18;11:590889. Epub 2020 Dec 18.

Virus and Vector Ecology Group, International Institute of Tropical Agriculture (IITA), Dar es Salaam, Tanzania.

Nuru is a deep learning object detection model for diagnosing plant diseases and pests developed as a public good by PlantVillage (Penn State University), FAO, IITA, CIMMYT, and others. It provides a simple, inexpensive and robust means of conducting in-field diagnosis without requiring an internet connection. Diagnostic tools that do not require the internet are critical for rural settings, especially in Africa where internet penetration is very low. An investigation was conducted in East Africa to evaluate the effectiveness of Nuru as a diagnostic tool by comparing the ability of Nuru, cassava experts (researchers trained on cassava pests and diseases), agricultural extension officers and farmers to correctly identify symptoms of cassava mosaic disease (CMD), cassava brown streak disease (CBSD) and the damage caused by cassava green mites (CGM). The diagnosis capability of Nuru and that of the assessed individuals was determined by inspecting cassava plants and by using the cassava symptom recognition assessment tool (CaSRAT) to score images of cassava leaves, based on the symptoms present. Nuru could diagnose symptoms of cassava diseases at a higher accuracy (65% in 2020) than the agricultural extension agents (40-58%) and farmers (18-31%). Nuru's accuracy in diagnosing cassava disease and pest symptoms, in the field, was enhanced significantly by increasing the number of leaves assessed to six leaves per plant (74-88%). Two weeks of Nuru practical use provided a slight increase in the diagnostic skill of extension workers, suggesting that a longer duration of field experience with Nuru might result in significant improvements. Overall, these findings suggest that Nuru can be an effective tool for in-field diagnosis of cassava diseases and has the potential to be a quick and cost-effective means of disseminating knowledge from researchers to agricultural extension agents and farmers, particularly on the identification of disease symptoms and their management practices.
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http://dx.doi.org/10.3389/fpls.2020.590889DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7775399PMC
December 2020

Characterizing the reproducibility in using a liver microphysiological system for assaying drug toxicity, metabolism, and accumulation.

Clin Transl Sci 2020 Dec 31. Epub 2020 Dec 31.

Center for Drug Evaluation and Research, Office of Translational Sciences, Office of Clinical Pharmacology, Division of Applied Regulatory Science, US Food and Drug Administration, Silver Spring, Maryland, USA.

Liver microphysiological systems (MPSs) are promising models for predicting hepatic drug effects. Yet, after a decade since their introduction, MPSs are not routinely used in drug development due to lack of criteria for ensuring reproducibility of results. We characterized the feasibility of a liver MPS to yield reproducible outcomes of experiments assaying drug toxicity, metabolism, and intracellular accumulation. The ability of the liver MPS to reproduce hepatotoxic effects was assessed using trovafloxacin, which increased lactate dehydrogenase (LDH) release and reduced cytochrome P450 3A4 (CYP3A4) activity. These observations were made in two test sites and with different batches of Kupffer cells. Upon culturing equivalent hepatocytes in the MPS, spheroids, and sandwich cultures, differences between culture formats were detected in CYP3A4 activity and albumin production. Cells in all culture formats exhibited different sensitivities to hepatotoxicant exposure. Hepatocytes in the MPS were more functionally stable than those of other culture platforms, as CYP3A4 activity and albumin secretion remained prominent for greater than 18 days in culture, whereas functional decline occurred earlier in spheroids (12 days) and sandwich cultures (7 days). The MPS was also demonstrated to be suitable for metabolism studies, where CYP3A4 activity, troglitazone metabolites, diclofenac clearance, and intracellular accumulation of chloroquine were quantified. To ensure reproducibility between studies with the MPS, the combined use of LDH and CYP3A4 assays were implemented as quality control metrics. Overall results indicated that the liver MPS can be used reproducibly in general drug evaluation applications. Study outcomes led to general considerations and recommendations for using liver MPSs.
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http://dx.doi.org/10.1111/cts.12969DOI Listing
December 2020

Divergence of photosynthetic strategies amongst marine diatoms.

PLoS One 2020 28;15(12):e0244252. Epub 2020 Dec 28.

Climate Change Cluster, University of Technology Sydney, Ultimo, New South Wales, Australia.

Marine phytoplankton, and in particular diatoms, are responsible for almost half of all primary production on Earth. Diatom species thrive from polar to tropical waters and across light environments that are highly complex to relatively benign, and so have evolved highly divergent strategies for regulating light capture and utilization. It is increasingly well established that diatoms have achieved such successful ecosystem dominance by regulating excitation energy available for generating photosynthetic energy via highly flexible light harvesting strategies. However, how different light harvesting strategies and downstream pathways for oxygen production and consumption interact to balance excitation pressure remains unknown. We therefore examined the responses of three diatom taxa adapted to inherently different light climates (estuarine Thalassioisira weissflogii, coastal Thalassiosira pseudonana and oceanic Thalassiosira oceanica) during transient shifts from a moderate to high growth irradiance (85 to 1200 μmol photons m-2 s-1). Transient high light exposure caused T. weissflogii to rapidly downregulate PSII with substantial nonphotochemical quenching, protecting PSII from inactivation or damage, and obviating the need for induction of O2 consuming (light-dependent respiration, LDR) pathways. In contrast, T. oceanica retained high excitation pressure on PSII, but with little change in RCII photochemical turnover, thereby requiring moderate repair activity and greater reliance on LDR. T. pseudonana exhibited an intermediate response compared to the other two diatom species, exhibiting some downregulation and inactivation of PSII, but high repair of PSII and induction of reversible PSII nonphotochemical quenching, with some LDR. Together, these data demonstrate a range of strategies for balancing light harvesting and utilization across diatom species, which reflect their adaptation to sustain photosynthesis under environments with inherently different light regimes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0244252PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7769462PMC
March 2021

Comorbidity and response to TNF inhibitors in axial spondyloarthritis: longitudinal analysis of the BSRBR-AS.

Rheumatology (Oxford) 2020 Dec 28. Epub 2020 Dec 28.

Department of Rheumatology, Liverpool University Hospitals, Liverpool, L9 7AL.

Objective: Comorbidities influence disease assessment in axial spondyloarthritis (axSpA), but their association with response to TNF inhibitors (TNFi) is unclear. We examined associations between comorbidity history at TNFi initiation and: 1) change in disease indices over time; 2) binary response definitions; 3) time-to-treatment-discontinuation.

Methods: We studied participants starting their first TNFi from a national axSpA register. Comorbidity categories were created from 14 physician-diagnosed conditions and compared against: change in disease indices over time using linear mixed effects models; BASDAI50/2 (50% or 2-unit reduction) and BASDAI<4 at 6 months using logistic models; and time-to-treatment-discontinuation using Cox models. Models were adjusted for age, gender, BMI, deprivation and education.

Results: 994 were eligible for analysis (68% male, mean age 45 years); 21% had one comorbidity and 11% had ≥2. Baseline disease severity was higher in those with comorbidities across all indices, but absolute improvement over time was comparable for BASDAI and spinal pain. Participants with ≥2 comorbidities had smaller absolute improvement in BASFI and quality of life. This group also had numerically reduced odds of achieving BASDAI50/2 (OR 0.81; 95%CI 0.45, 1.45) and BASDAI<4 (OR 0.57; 95%CI 0.32, 1.04). Treatment discontinuation was increased in those with 2 comorbidities (HR 1.32; 95%CI 0.88, 2.00) and ≥3 comorbidities (HR 2.18; 95%CI 1.20, 3.93) compared to none.

Conclusions: Participants with multiple comorbidities had poorer treatment outcomes, particularly increased treatment discontinuation and poorer improvements in function and quality of life. These results inform clinicians and educate patients about response to the first TNFi given comorbidity burden.
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http://dx.doi.org/10.1093/rheumatology/keaa900DOI Listing
December 2020