Unraveling plant-microbe symbioses using single-cell and spatial transcriptomics.

Plant-microbe symbioses require intense interaction and genetic coordination to successfully establish in specific cell types of the host and symbiont. Traditional RNA-seq methodologies lack the cellular resolution to fully capture these complexities, but single-cell and spatial transcriptomics (ST) are now allowing scientists to probe symbiotic interactions at an unprecedented level of detail. Here, we discuss the advantages that novel spatial and single-cell transcriptomic technologies provide in studying plant-microbe endosymbioses and highlight key recent studies. Finally, we consider the remaining limitations of applying these approaches to symbiosis research, which are mainly related to the simultaneous capture of both plant and microbial transcripts within the same cells.

High Prevalence of Atrial Fibrillation Found in the Capital of Greenland When Using Continuous Electrocardiogram Monitoring: A Cross-Sectional Study.

Background: Atrial fibrillation (AF) increases the risk of conditions such as ischemic stroke, dementia, and heart failure, and early detection is crucial. In Greenland, ischemic strokes are common, and the prevalences of AF risk factors are increasing. Studies based on 30-second electrocardiograms (ECGs) and diagnosis codes so far have indicated either a low prevalence of AF or a prevalence comparable to that in other Western countries, such as Denmark. However, using short, single-point ECGs may underestimate the true prevalence, as especially paroxysmal AF can be missed. With this study, we aim to estimate the prevalence of AF using 3-5-day continuous Holter recordings among people in Nuuk, the capital of Greenland. Methods: In this cross-sectional study, we estimated the prevalence of AF among the population aged ≥ 50 years in Greenland's capital, Nuuk. We used an ePatch to record continuous ECGs for 3-5 days, and questionnaires to assess demographic data, comorbidities, medication, symptoms, and risk factors for AF. Results: Of 226 participants (62% women), 21 (33% women) had either self-reported AF, AF on the recording, or both, equivalent to a prevalence of 9.3% (confidence interval [CI] 5.8-13.9). The age-stratified prevalence was 7.2% (CI 2.7-15.1) among those aged 50-59 years; 8.8% (CI 4.1-16.1) among those aged 60-69 years; and 18.2% (CI 7.0-35.5) among those aged ≥ 70 years. Conclusions: This study provides a novel insight into AF prevalence in Nuuk, emphasizing the potential underestimation in previous studies. Continuous ECG monitoring revealed a higher prevalence, especially among the younger age groups, urging a reevaluation of diagnostic practices in this unique population.

Contexte: La fibrillation auriculaire augmente le risque d'accidents vasculaires cérébraux (AVC) ischémiques, de démence et d'insuffisance cardiaque. Il est donc essentiel de la dépister rapidement. Au Groenland, les AVC ischémiques sont fréquents, et la prévalence des facteurs de risque de fibrillation auriculaire est à la hausse. Les études reposant sur des électrocardiogrammes (ECG) de 30 secondes et des codes de diagnostic ont jusqu'à présent révélé une faible prévalence de la fibrillation auriculaire ou une prévalence comparable à celle d'autres pays occidentaux, comme le Danemark. Cependant, l'utilisation d'ECG courts à un moment fixe dans le temps peut sous-estimer la prévalence réelle, car la fibrillation auriculaire paroxystique, en particulier, peut passer inaperçue. Cette étude a pour but d'estimer la prévalence de la fibrillation auriculaire en utilisant des enregistrements Holter continus de trois à cinq jours chez des habitants de Nuuk, la capitale du Groenland. Méthodologie: Dans cette étude transversale, nous avons estimé la prévalence de la fibrillation auriculaire dans la population de ≥ 50 ans de Nuuk, la capitale du Groenland. Nous avons utilisé un timbre électronique pour enregistrer des ECG en continu pendant trois à cinq jours, ainsi que des questionnaires pour recueillir les données démographiques et consigner les maladies concomitantes, les médicaments, les symptômes et les facteurs de risque de fibrillation auriculaire. Résultats: Sur 226 participants (dont 62 % étaient des femmes), 21 (33 % de femmes) présentaient, soit une fibrillation auriculaire autodéclarée, soit une fibrillation auriculaire selon l'enregistrement, soit les deux, ce qui correspond à une prévalence de 9,3 % (intervalle de confiance [IC] : 5,8 à 13,9). La prévalence stratifiée en fonction de l'âge était de 7,2 % (IC : 2,7 à 15,1) chez les 50 à 59 ans, de 8,8 % (IC : 4,1 à 16,1) chez les 60 à 69 ans et de 18,2 % (IC : 7,0 à 35,5) chez les 70 ans et plus. Conclusions: Cette étude fournit de nouveaux renseignements sur la prévalence de la fibrillation auriculaire à Nuuk et souligne la prévalence potentiellement sous-estimée dans les études précédentes. La surveillance continue de l'ECG a révélé une prévalence plus élevée, en particulier dans les tranches d'âge plus jeunes, ce qui incite à réévaluer les pratiques de diagnostic utilisées dans cette population particulière.

Phenotyping revealed tolerance traits and genotypes for acidity and aluminum toxicity in European Vicia faba L.

Soil acidity is a global issue; soils with pH <4.5 are widespread in Europe. This acidity adversely affects nutrient availability to plants; pH levels <5.0 lead to aluminum (Al3+) toxicity, a significant problem that hinders root growth and nutrient uptake in faba bean (Vicia faba L.) and its symbiotic relationship with Rhizobium. However, little is known about the specific traits and tolerant genotypes among the European faba beans. This study aimed to identify response traits associated with tolerance to root zone acidity and Al3+ toxicity and potentially tolerant genotypes for future breeding efforts. Germplasm survey was conducted using 165 genotypes in a greenhouse aquaponics system. Data on the root and shoot systems were collected. Subsequently, 12 genotypes were selected for further phenotyping in peat medium, where data on physiological and morphological parameters were recorded along with biochemical responses in four selected genotypes. In the germplasm survey, about 30% of genotypes showed tolerance to acidity and approximately 10% exhibited tolerance to Al3+, while 7% showed tolerance to both. The phenotyping experiment indicated diverse morphological and physiological responses among treatments and genotypes. Acid and Al3+ increased proline concentration. Interaction between genotype and environment was observed for ascorbate peroxidase activity, malondialdehyde, and proline concentrations. Genomic markers associated with acidity and acid+Al3+-toxicity tolerances were identified using GWAS analysis. Four faba bean genotypes with varying levels of tolerance to acidity and Al3+ toxicity were identified.

Zinc mediates control of nitrogen fixation via transcription factor filamentation.

Plants adapt to fluctuating environmental conditions by adjusting their metabolism and gene expression to maintain fitness1. In legumes, nitrogen homeostasis is maintained by balancing nitrogen acquired from soil resources with nitrogen fixation by symbiotic bacteria in root nodules2-8. Here we show that zinc, an essential plant micronutrient, acts as an intracellular second messenger that connects environmental changes to transcription factor control of metabolic activity in root nodules. We identify a transcriptional regulator, FIXATION UNDER NITRATE (FUN), which acts as a sensor, with zinc controlling the transition between an inactive filamentous megastructure and an active transcriptional regulator. Lower zinc concentrations in the nodule, which we show occur in response to higher levels of soil nitrate, dissociates the filament and activates FUN. FUN then directly targets multiple pathways to initiate breakdown of the nodule. The zinc-dependent filamentation mechanism thus establishes a concentration readout to adapt nodule function to the environmental nitrogen conditions. In a wider perspective, these results have implications for understanding the roles of metal ions in integration of environmental signals with plant development and optimizing delivery of fixed nitrogen in legume crops.

Harnessing cold adaptation for postglacial colonisation: Galactinol synthase expression and raffinose accumulation in a polyploid and its progenitors.

Allotetraploid white clover (Trifolium repens) formed during the last glaciation through hybridisation of two European diploid progenitors from restricted niches: one coastal, the other alpine. Here, we examine which hybridisation-derived molecular events may have underpinned white clover's postglacial niche expansion. We compared the transcriptomic frost responses of white clovers (an inbred line and an alpine-adapted ecotype), extant descendants of its progenitor species and a resynthesised white clover neopolyploid to identify genes that were exclusively frost-induced in the alpine progenitor and its derived subgenomes. From these analyses we identified galactinol synthase, the rate-limiting enzyme in biosynthesis of the cryoprotectant raffinose, and found that the extant descendants of the alpine progenitor as well as the neopolyploid white clover rapidly accumulated significantly more galactinol and raffinose than the coastal progenitor under cold stress. The frost-induced galactinol synthase expression and rapid raffinose accumulation derived from the alpine progenitor likely provided an advantage during early postglacial colonisation for white clover compared to its coastal progenitor.

Agreement between routinely used immunoassays for thyroid function testing in non-pregnant and pregnant adults.

OBJECTIVE: Thyroid function tests are common biochemical analyses, and agreement between the routinely used immunoassays is important for diagnosis and monitoring of thyroid disease. Efforts are continuously made to align the biochemical assays, and we aimed to evaluate the agreement between immunoassays used in a clinical laboratory setting among non-pregnant and pregnant adults. DESIGN: Cross-sectional study. PARTICIPANTS: Serum samples were obtained from 192 blood donors (non-pregnant adults) and from 86 pregnant women in the North Denmark Region with no known thyroid disease. MEASUREMENTS: Each sample was used for measurement of thyroid-stimulating hormone (TSH) with the routinely used automatic immunoassays in the regional Departments of Clinical Biochemistry (Alinity, Abbott Laboratories, Cobas, Roche Diagnostics, and Atellica, Siemens Healthineers) and reported as the median with 95% confidence interval (95% CI). RESULTS: In nonpregnant adults, the level of TSH was higher with Cobas and Atellica than with Alinity as reflected by median (Alinity: 1.39 mIU/L (95% CI: 1.30-1.51 mIU/L); Cobas: 1.57 mIU/L (95% CI: 1.48-1.75 mIU/L); Atellica: 1.74 mIU/L (95% CI: 1.61-1.83 mIU/L)). Similarly, a trend was seen towards higher median TSH with Cobas than with Alinity among pregnant women (Alinity: 1.90 mIU/L (95% CI: 1.37-2.82 mIU/L); Cobas: 2.33 mIU/L (95% CI: 1.69-3.62 mIU/L)). CONCLUSION: Results of thyroid function tests obtained with different immunoassays were not interchangeable when evaluated among pregnant and non-pregnant adults. The distinct differences are relevant for clinical decision making and emphasize the necessity of clinical laboratory information when different assays are used for diagnosis and monitoring of patients with thyroid disease.

ROBot-assisted physical training of older patients during acUte hospitaliSaTion-study protocol for a randomised controlled trial (ROBUST).

BACKGROUND: During hospitalisation, older patients spend most of their time passive in bed, which increases the risk of functional decline and negative adverse outcomes. Our aim is to examine the impact of robot-assisted physical training on functional status in older geriatric patients during acute hospitalisation. METHODS: This is a single-centre investigator-blinded placebo-controlled randomised controlled trial including geriatric patients aged ≥ 65 years, able to ambulate before hospitalisation, and with expected length of stay ≥ 2 days. In addition to standard physiotherapy treatment, the intervention group receive active robot-assisted resistance training and the control group passive robot-assisted sham training. Exclusion criteria are as follows: ambulation without assistance at the time of inclusion, known severe dementia, delirium, patients who have received less than three training sessions at discharge, terminal illness, recent major surgery/lower extremity fracture, conditions contradicting the use of training robot, lower extremity metastases, deemed unsuitable for robot-assisted training by a healthcare professional, or weight > 165 kg. The primary outcome is functional status assessed by change in Barthel Index-100 and 30-s chair stand test between inclusion and day of discharge. Secondary outcomes include functional status at 1- and 3-month follow-up, quality of life, depression, concern about falling, falls, cognition, qualitative interviews, need of homecare, discharge destination, readmissions, healthcare costs, sarcopenia, muscle quantity (bioimpedance), and mortality. Clinical meaningful change of the Barthel Index is 5 points. A recent study in geriatric patients reported a 6.9-point change following exercise. With a significance level of 5%, 80% power, and a drop-out rate of 20%, 244 participants per group (n = 488) are needed to detect the same mean difference. With a significance level of 5%, 80% power, and a drop-out rate of 20%, 74 participants per group (n = 148) are needed to detect a minimum clinical change of 2.6 repetitions for 30-s chair stand test. Recruitment started in January 2023 and is expected to continue for 19 months including follow-up. DISCUSSION: If our study shows that in-hospital robot-assisted training prevents functional decline in older patients, this may have a major impact on the individual patient due to increased wellbeing and a higher level of independency. In addition, society will benefit due to potential decrease in the need of municipality-delivered homecare following discharge. TRIAL REGISTRATION: ClinicalTrials.gov NCT05782855. Registration date: March 24, 2023.

Stimulating thyrotropin receptor antibodies in early pregnancy.

OBJECTIVES: Thyrotropin-receptor antibodies (TRAb) are used to diagnose Graves' hyperthyroidism in pregnant women. Bioassays provide a measure of thyrotropin-receptor stimulatory antibodies (TSI) specifically. The objective was to measure TSI in pregnant women for establishment of a pregnancy-specific cut-off and comparison with immunoassay measurements of TRAb. METHODS: The retrospective Danish study was performed within the North Denmark Region Pregnancy Cohort (2011-2015) that includes stored biobank samples from early pregnancy (median week 10) with immunoassay measurements of thyroid function parameters and TRAb. TSI were measured in the same samples using the Turbo TSI bioassay (Quidel/Ortho-Clinical Diagnostics) with a recommended cut-off of 0.0241 IU/L in non-pregnant adults. A pregnancy-specific TSI cut-off (95-percentile) was established using Regression on Order Statistics. RESULTS: The established TSI cut-off was 0.0418 IU/L (95 % CI: 0.0417-0.0419). Among women with early pregnancy hyperthyroidism (n=438), 43 women (9.8 %) were TSI positive using the established cut-off, and these women had lower TSH (median 0.008 mIU/L) compared to women with TSI levels below 0.0241 (median TSH 0.040 mIU/L) or in the range from 0.0241 to 0.0418 (median TSH 0.033 mIU/L). Among the 438 women with early pregnancy hyperthyroidism, 22 women were positive for TSI and TRAb, 388 were negative for both, and 28 women were positive for either TSI or TRAb. CONCLUSIONS: This is the first study on TSI measurements in a large cohort of early pregnant women. A pregnancy-specific cut-off for TSI was established and agreement in the classification with immunoassay measurements of TRAb was seen in 94 % of cases.

Synergistic effects of plant genotype and soil microbiome on growth in Lotus japonicus.

The biological interactions between plants and their root microbiomes are essential for plant growth, and even though plant genotype (G), soil microbiome (M), and growth conditions (environment; E) are the core factors shaping root microbiome, their relationships remain unclear. In this study, we investigated the effects of G, M, and E and their interactions on the Lotus root microbiome and plant growth using an in vitro cross-inoculation approach, which reconstructed the interactions between nine Lotus accessions and four soil microbiomes under two different environmental conditions. Results suggested that a large proportion of the root microbiome composition is determined by M and E, while G-related (G, G × M, and G × E) effects were significant but small. In contrast, the interaction between G and M had a more pronounced effect on plant shoot growth than M alone. Our findings also indicated that most microbiome variations controlled by M have little effect on plant phenotypes, whereas G × M interactions have more significant effects. Plant genotype-dependent interactions with soil microbes warrant more attention to optimize crop yield and resilience.

Evidence for an RNAi-independent role of Arabidopsis DICER-LIKE2 in growth inhibition and basal antiviral resistance.

Flowering plant genomes encode four or five DICER-LIKE (DCL) enzymes that produce small interfering RNAs (siRNAs) and microRNAs, which function in RNA interference (RNAi). Different RNAi pathways in plants effect transposon silencing, antiviral defense, and endogenous gene regulation. DCL2 acts genetically redundantly with DCL4 to confer basal antiviral defense. However, DCL2 may also counteract DCL4 since knockout of DCL4 causes growth defects that are suppressed by DCL2 inactivation. Current models maintain that RNAi via DCL2-dependent siRNAs is the biochemical basis of both effects. Here, we report that DCL2-mediated antiviral resistance and growth defects cannot be explained by the silencing effects of DCL2-dependent siRNAs. Both functions are defective in genetic backgrounds that maintain high levels of DCL2-dependent siRNAs, either with specific point mutations in DCL2 or with reduced DCL2 dosage because of heterozygosity for dcl2 knockout alleles. Intriguingly, all DCL2 functions require its catalytic activity, and the penetrance of DCL2-dependent growth phenotypes in dcl4 mutants correlates with DCL2 protein levels but not with levels of major DCL2-dependent siRNAs. We discuss this requirement and correlation with catalytic activity but not with resulting siRNAs, in light of other findings that reveal a DCL2 function in innate immunity activation triggered by cytoplasmic double-stranded RNA.

A nationwide registry-based observational study of thyroid disease incidence in the Faroe Islands.

OBJECTIVE: The occurrence of thyroid disease varies among populations. While the iodine nutrition level of the Faroese seems to have been decreasing over the past decades, there is no systematic evaluation of the thyroid disease pattern in the Faroe Islands. Such knowledge of thyroid disease occurrence in the North Atlantic region may support healthcare planning and prevention. To investigate incidence rates, including subtypes of thyroid diseases, and demographic characteristics of thyroid disease patients in the Faroe Islands, to improve understanding of the patterns and trends of these disorders. DESIGN AND METHOD: A registry-based observational study was conducted over 10 years, encompassing all adult Faroese individuals. PATIENTS AND MEASUREMENTS: Health records from general practitioners and hospitals were used to identify incident cases of thyroid diseases. Validation was performed using multiple data sources. The incidence rates were standardised using population data from the middle of the study period 2006-2018. RESULTS: Among the 1152 individuals diagnosed with thyroid disease, the standardised incidence rates per 100,000 person-years were 55 for hyperthyroidism and 112 for hypothyroidism, and around four times higher in women than in men. Hashimoto's thyroiditis was the dominant cause of hypothyroidism, while Graves' disease was the leading cause of hyperthyroidism. The incidence of hypothyroidism increases with age. A decreasing trend was observed over time for both hypothyroidism and hyperthyroidism. CONCLUSION: Considering the decrease in iodine nutrition levels over the past decades, we were surprised by the high incidence of autoimmune thyroid disease. The findings highlight the need for continuous monitoring of thyroid disease occurrence in coastal areas of the North Atlantic Ocean.

Quality of care among patients diagnosed with atrial fibrillation in Greenland.

This cross-sectional study sought to assess the prevalence of atrial fibrillation (AF) diagnosis in Greenland among various age groups and examine the corresponding quality of care. We collected data from Greenland's electronic medical records and evaluated the quality of care using six internationally recommended indicators, which are: percentage of AF patients with an assessment of smoking status within the previous year, an assessment of body mass index within the previous year, assessment of blood pressure within the previous year, measurement of thyroid stimulating hormone (TSH), treatment with an anticoagulant and percentage of patients with a measurement of serum-creatinine. We found the prevalence of AF among patients aged 20 years or older in Greenland to be 1.75% (95% CI 1.62-1.88). We found an increasing prevalence of AF with age and a greater proportion of men than women until the age of 74 years. Our study suggests that the associated quality of care could be higher as the requirement of only one of the six quality indicators was met. A lack of registration may partly explain this, and initiatives to improve the quality of care are recommended.

Endometriosis, polycystic ovary syndrome, and the thyroid: a review.

Endometriosis and polycystic ovary syndrome (PCOS) are common gynecological disorders that constitute a significant burden of disease in women of fertile age. The disorders share a link to female reproduction and infertility; however, divergent effects on menstrual cycle, related hormones, and body composition have been proposed. Disorders of the thyroid gland including abnormal thyroid dysfunction (hyperthyroidism or hypothyroidism) and/or markers of thyroid autoimmunity similarly show a female predominance and onset in younger age groups. We reviewed the literature on the association between endometriosis, PCOS, and thyroid disease up until July 1, 2023, and identified 8 original studies on endometriosis and thyroid disease and 30 original studies on PCOS and thyroid disease. The studies were observational and heterogeneous regarding the design, sample size, and definitions of exposure and outcome; however, a tendency was seen toward an association between hyperthyroidism and endometriosis. Especially an association between endometriosis and slightly elevated levels of thyroid-stimulating hormone receptor antibodies has been found and corroborated in studies from different populations. On the other hand, the literature review turned a focus toward an association between hypothyroidism and PCOS, however, with uncertainties as to whether the association is caused by hypothyroidism per se and/or the thyroid autoantibodies (thyroid peroxidase and thyroglobulin antibodies). More evidence is needed to substantiate an association between endometriosis, PCOS, and thyroid disease, and to differentiate between the role of thyroid function and thyroid autoimmunity. Furthermore, studies are warranted to extend knowledge on the different disease characteristics and underlying mechanisms.

Identification and Analysis of Myogenic Progenitors In Vivo During Acute Skeletal Muscle Injury by High-Dimensional Single-Cell Mass Cytometry.

Skeletal muscle regeneration is a dynamic process driven by adult muscle stem cells and their progeny. Mostly quiescent at a steady state, adult muscle stem cells become activated upon muscle injury. Following activation, they proliferate, and most of their progeny differentiate to generate fusion-competent muscle cells while the remaining self-renews to replenish the stem cell pool. While the identity of muscle stem cells was defined more than a decade ago, based on the co-expression of cell surface markers, myogenic progenitors were identified only recently using high-dimensional single-cell approaches. Here, we present a single-cell mass cytometry (cytometry by time of flight [CyTOF]) method to analyze stem cells and progenitor cells in acute muscle injury to resolve the cellular and molecular dynamics that unfold during muscle regeneration. This approach is based on the simultaneous detection of novel cell surface markers and key myogenic transcription factors whose dynamic expression enables the identification of activated stem cells and progenitor cell populations that represent landmarks of myogenesis. Importantly, a sorting strategy based on detecting cell surface markers CD9 and CD104 is described, enabling prospective isolation of muscle stem and progenitor cells using fluorescence-activated cell sorting (FACS) for in-depth studies of their function. Muscle progenitor cells provide a critical missing link to study the control of muscle stem cell fate, identify novel therapeutic targets for muscle diseases, and develop cell therapy applications for regenerative medicine. The approach presented here can be applied to study muscle stem and progenitor cells in vivo in response to perturbations, such as pharmacological interventions targeting specific signaling pathways. It can also be used to investigate the dynamics of muscle stem and progenitor cells in animal models of muscle diseases, advancing our understanding of stem cell diseases and accelerating the development of therapies.

Single-cell analysis identifies genes facilitating rhizobium infection in Lotus japonicus.

Legume-rhizobium signaling during establishment of symbiotic nitrogen fixation restricts rhizobium colonization to specific cells. A limited number of root hair cells allow infection threads to form, and only a fraction of the epidermal infection threads progress to cortical layers to establish functional nodules. Here we use single-cell analysis to define the epidermal and cortical cell populations that respond to and facilitate rhizobium infection. We then identify high-confidence nodulation gene candidates based on their specific expression in these populations, pinpointing genes stably associated with infection across genotypes and time points. We show that one of these, which we name SYMRKL1, encodes a protein with an ectodomain predicted to be nearly identical to that of SYMRK and is required for normal infection thread formation. Our work disentangles cellular processes and transcriptional modules that were previously confounded due to lack of cellular resolution, providing a more detailed understanding of symbiotic interactions.

Psychotropic drugs for patients with glaucoma.

This review offers a summary of the current knowledge of pshychotropic drugs and glaucoma. If exposed to psychotropic drugs, some patients may develop angle-closure glaucoma. Although rarely contraindicated, exposed predisposed and diagnosed patients should be followed-up by an ophthalmologist. It is still unclear if serotonin reuptake inhibitors increase the risk of angle-closure glaucoma. Tricyclic antidepressants and benzodiazepines should be used with caution in predisposed patients. The same applies to antipsychotic drugs, where first-generation antipsychotic drugs might have a smaller impact on the intraocular pressure than second-generation antipsychotic drugs.

Monotreatment With Conventional Antirheumatic Drugs or Glucocorticoids in Rheumatoid Arthritis: A Network Meta-Analysis.

Importance: This is the first network meta-analysis to assess outcomes associated with multiple conventional synthetic disease-modifying antirheumatic drugs and glucocorticoid. Objective: To analyze clinical outcomes after treatment with conventional synthetic disease-modifying antirheumatic drugs and glucocorticoid among patients with rheumatoid arthritis. Data Sources: With no time restraint, English language articles were searched in MEDLINE, Embase, Cochrane Central, ClinicalTrials.gov, and reference lists of relevant meta-analyses until September 15, 2022. Study Selection: Four reviewers in pairs of 2 independently included controlled studies randomizing patients with rheumatoid arthritis to mono-conventional synthetic disease-modifying antirheumatic drugs, glucocorticoid, placebo, or nonactive treatment that recorded at least 1 outcome of tender joint count, swollen joint count, erythrocyte sedimentation rate, and C-reactive protein level. Of 1098 assessed articles, 130 articles (132 interventions) were included. Data Extraction and Synthesis: The review followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guideline, and data quality was assessed by the Cochrane risk of bias tool RoB 2. Data were extracted by a single author and checked independently by 2 authors. Data were analyzed using a random effect model, and data analysis was conducted from June 2021 to February 2023. Main Outcomes and Measures: A protocol with hypothesis and study plan was registered before data recording. The most complete of recorded outcomes (tender joint count) was used as primary outcome, with imputations based on other outcomes to obtain a full analysis of all studies. Absolute change adjusted for baseline disease activity was assessed. Results: A total of 29 interventions in 275 treatment groups among 132 randomized clinical trials (mean [range], 71.0% [27.0% to 100%] females in studies; mean [range] of ages in studies, 53 [36 to 70] years) were identified, which included 13 260 patients with rheumatoid arthritis. The mean (range) duration of RA was 79 (2 to 243) months, and the mean (range) disease activity score was 6.3 (4.0 to 8.8). Compared with placebo, oral methotrexate was associated with a reduced tender joint count by 5.18 joints (95% credible interval [CrI], 4.07 to 6.28 joints). Compared with methotrexate, glucocorticoid (-2.54 joints; 95% CrI, -5.16 to 0.08 joints) and remaining drugs except cyclophosphamide (6.08 joints; 95% CrI, 0.44 to 11.66 joints) were associated with similar or lower tender joint counts. Conclusions and Relevance: This study's results support the present role of methotrexate as the primary reference conventional synthetic disease-modifying antirheumatic drug.

Biological variation in thyroid function tests in older adults and clinical implications.

OBJECTIVE: Interpreting thyroid function tests can be challenging due to inherent variation, and the need for tests rises with age. While age-related changes in thyrotropin (TSH) levels are known, the biological variation in older adults remains unclear. DESIGN: We recruited nineteen 65-99-year-old (older adults) without thyroid disease for monthly blood sampling for 1 year. PATIENTS AND MEASUREMENTS: Serum was stored at -20C°, and TSH, total thyroxine (TT4) and total triiodothyronine (TT3) were analysed in random order in a single batch for each participant. Results were compared to test results from 15 euthyroid men aged 24-53 years (younger adults) collected previously using a similar methodology. RESULTS: Interindividual coefficients of variation in older/younger adults were 46.7%/44.0% for TSH, 12.7%/19.5% for TT4 and 14.6%/22.4% for TT3. Intraindividual coefficients of variation (CVI ) were 19.0%/25.4% for TSH, 5.5%/10.8% for TT4 and 6.9%/13.2% for TT3. The index of individuality was below 0.6 for all hormones in all age groups. The number of samples required to determine the homoeostatic set-point at 10% precision in older adults was 14-21 for TSH and 2 for TT4 and TT3. TT4 in older adults was the only parameter in any group with comparable CVI between individuals (p = .22). CONCLUSIONS: CVI for TT4 and TT3 was halved in older compared to younger adults with two tests of TT4 needed to describe the individual set-point. Similar CVI between older adults caused TT4 to provide a reliable estimate of thyroid function, and the added value of measuring thyroxine could improve clinical practice.

Is the Pattern Changing? Atrial Fibrillation and Screening with Holter Electrocardiograms among Ischemic Stroke Patients in Greenland from 2016 to 2021.

A standardized examination regime for ischemic stroke (IS) patients was implemented in Greenland in 2010. Prevalence of atrial fibrillation (AF) of 32% was found among discharged IS patients from 2011 to 2012, and our study aims to estimate the use of Holter ECGs for AF diagnostics and the current prevalence of AF among IS patients in Greenland. Patients discharged from Queen Ingrid's Hospital in Nuuk between 2016 and 2021 with an ICD-10 diagnosis of IS or stroke without specification were included. Data on Holter recordings, age, gender, medical treatment with rivaroxaban or warfarin, and ICD-10 and ICPC codes for AF were extracted for each patient. The overall incidence of IS from 2016 to 2021 was 133/100,000 and unchanged since 2012. Sixty-eight of the study's IS patients (14.5%) had AF, and 46% of IS patients with Holter data accessible had a recording according to international recommendations. Our results indicate that fewer IS patients in Greenland have AF than previously. However, the insufficient use of Holter as a diagnostic tool may explain part of the drop, as well as improved preventive treatment with rivaroxaban among AF patients in Greenland. Regardless, IS remains common, and a focus on diagnostics and preventable risk factors should be maintained.