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Introduction: High baseline neutrophil-to-lymphocyte ratio (NLR) in rheumatoid arthritis (RA) has been associated with positive responses to biologic tumor necrosis factor inhibition and negative responses to conventional synthetic disease-modifying antirheumatic drug (csDMARD) triple therapy. Datasets from three randomized clinical trials in patients with RA were used to test the hypothesis that baseline NLR is associated with improved clinical response to filgotinib in methotrexate (MTX)-naïve or MTX-experienced RA populations. Methods: Patients from FINCH 1 (inadequate response to MTX, MTX-IR; NCT02889796), FINCH 2 (inadequate response to biologic DMARDs; NCT02873936), and FINCH 3 (MTX-naïve; NCT02886728) were classified as baseline NLR-High or baseline NLR-Low based on a previously published cut point of 2.7. In total, 3365 patients were included across the three studies. Differences in clinical outcomes and patient-reported outcomes (PROs) were determined using linear-regression models. Results: Control-arm patients (placebo + MTX/placebo + csDMARD) classified as NLR-High exhibited worse continuous clinical and PRO responses at week 12 across clinical trials compared to NLR-Low patients. In contrast, NLR-High patients who received FIL 200 mg + MTX/csDMARD exhibited consistently better responses after 12 weeks compared to NLR-Low patients across clinical trials, clinical endpoints, and PROs. These trends were most prominent among the MTX-IR population. Conclusion: The 2.7 baseline NLR cut point could be used to enrich for patients most likely to benefit from the addition of filgotinib to background MTX/csDMARD. Use of baseline NLR as part of therapeutic decision-making would not require additional diagnostics and could contribute to improved outcomes for patients with RA. Trial Registration: Clinicaltrials.gov: NCT02889796; NCT02873936; NCT02886728. Plain Language Summary: Rheumatoid arthritis is a disease that results in swollen and painful joints. There is currently no method to determine which treatment will work best for an individual patient. However, there may be identifying markers found in the blood that could indicate how a patient will respond to treatment. One of these possible markers is a ratio of two types of white blood cells, neutrophils and lymphocytes, which are part of the body's immune system and help the body detect and fight infection and other diseases. This ratio is referred to as the neutrophil-to-lymphocyte ratio. The current study evaluated whether the neutrophil-to-lymphocyte ratio at the beginning of treatment was associated with rheumatoid arthritis treatment outcomes. Blood test results were used from 3365 patients receiving filgotinib (a medicine used to treat rheumatoid arthritis) or other therapies as part of the FINCH clinical trials. Patients were classified as having a high or low neutrophil-to-lymphocyte ratio at the start of treatment. Patients receiving filgotinib over 24 weeks who had a high neutrophil-to-lymphocyte ratio showed less disease activity than patients whose ratio was low. This study provides support for the use of the neutrophil-to-lymphocyte ratio as a way to help determine whether a patient would benefit from filgotinib as part of their rheumatoid arthritis treatment and may help improve rheumatoid arthritis treatment outcomes. [ABSTRACT FROM AUTHOR]

To evaluate tumour necrosis factor inhibitor (TNFi) drug-levels and presence of anti-drug antibodies (ADAb) in patients with inflammatory arthritis who taper TNFi compared to TNFi continuation. Patients with rheumatoid arthritis, psoriatic arthritis, or axial spondyloarthritis on stable TNFi dose and in low disease activity ≥ 12 months were randomised (2:1) to disease activity-guided tapering or control. Blood samples at baseline, 12- and 18-months were evaluated for TNFi drug-levels and ADAb. In total, 129 patients were randomised to tapering (n = 88) or control (n = 41). Between baseline and month 18, a significant shift in TNFi drug-levels were observed in the tapering group resulting in fewer patients with high drug-levels (change: − 14% [95% CI − 27 to − 1%]) and more with low drug-levels (change: 18% [95% CI 5–31%]). Disease activity was equivalent between groups at 18 months, mean difference: RA − 0.06 (95% CI − 0.44 to 0.33), PsA 0.03 (95% CI − 0.36 to 0.42), and axSpA 0.16 (− 0.17 to 0.49), equivalence margins ± 0.5 disease activity points. ADAb were detected in eight patients, all from the tapering group. TNFi drug-level category or ADAb were not predictive for achieving successful tapering at 18 months. TNFi drug-levels decreased during tapering which indicate adherence to the tapering algorithm. Despite the difference in TNFi drug-levels at 18 months, disease activity remained equivalent, and only few tapering patients had detectable ADAb. These data do not support using TNFi drug-level and/or ADAb to guide the tapering decision but future research with larger trials is needed. Trial registration: EudraCT: 2017-001970-41, December 21, 2017. [ABSTRACT FROM AUTHOR]

Introduction: This study compared the clinical effectiveness of switching from tumor necrosis factor inhibitor (TNFi) to upadacitinib (TNFi-UPA), another TNFi (TNFi-TNFi), or an advanced therapy with another mechanism of action (TNFi-other MOA) in patients with rheumatoid arthritis (RA). Methods: Data were drawn from the Adelphi RA Disease Specific Programme™, a cross-sectional survey administered to rheumatologists and their consulting patients in Germany, France, Italy, Spain, the UK, Japan, Canada, and the USA from May 2021 to January 2022. Patients who switched treatment from an initial TNFi were stratified by subsequent therapy of interest: TNFi-UPA, TNFi-TNFi, or TNFi-other MOA. Physician-reported clinical outcomes including disease activity (with formal DAS28 scoring available for 29% of patients) categorized as remission, low/moderate/high disease activity, as well as pain were recorded at initiation of current treatment and ≥ 6 months from treatment switch. Fatigue and treatment adherence were measured ≥ 6 months from treatment switch. Inverse-probability-weighted regression adjustment compared outcomes by subsequent class of therapy: TNFi-UPA versus TNFi-TNFi, or TNFi-UPA versus TNFi-other MOA. Results: Of 503 patients who switched from their first TNFi, 261 were in TNFi-UPA, 128 in TNFi-TNFi, and 114 in TNFi-other MOA groups. At the time of switch, most patients had moderate/high disease activity (TNFi-UPA: 73%; TNFi-TNFi: 52%; TNFi-other MOA: 60%). After adjustment for differences in characteristics at point of switch, patients in TNFi-UPA group (n = 261) were significantly more likely to achieve physician-reported remission (67.7% vs. 40.3%; p = 0.0015), no pain (55.7% vs. 25.4%; p = 0.0007), and complete adherence (60.0% vs. 34.2%; p = 0.0049) compared with patients in TNFi-TNFi group (n = 121). Similar findings were observed for TNFi-UPA versus TNFi-other MOA groups (n = 111). Conclusion: Patients who switched from TNFi to UPA had significantly better clinical outcomes of remission, no pain, and complete adherence than those who cycled TNFi or switched to another MOA. [ABSTRACT FROM AUTHOR]

Malaria is a vector-borne disease that exacts a grave toll in the Global South. The epidemiology of Plasmodium vivax, the most geographically expansive agent of human malaria, is characterised by the accrual of a reservoir of dormant parasites known as hypnozoites. Relapses, arising from hypnozoite activation events, comprise the majority of the blood-stage infection burden, with implications for the acquisition of immunity and the distribution of superinfection. Here, we construct a novel model for the transmission of P. vivax that concurrently accounts for the accrual of the hypnozoite reservoir, (blood-stage) superinfection and the acquisition of immunity. We begin by using an infinite-server queueing network model to characterise the within-host dynamics as a function of mosquito-to-human transmission intensity, extending our previous model to capture a discretised immunity level. To model transmission-blocking and antidisease immunity, we allow for geometric decay in the respective probabilities of successful human-to-mosquito transmission and symptomatic blood-stage infection as a function of this immunity level. Under a hybrid approximation—whereby probabilistic within-host distributions are cast as expected population-level proportions—we couple host and vector dynamics to recover a deterministic compartmental model in line with Ross-Macdonald theory. We then perform a steady-state analysis for this compartmental model, informed by the (analytic) distributions derived at the within-host level. To characterise transient dynamics, we derive a reduced system of integrodifferential equations, likewise informed by our within-host queueing network, allowing us to recover population-level distributions for various quantities of epidemiological interest. In capturing the interplay between hypnozoite accrual, superinfection and acquired immunity—and providing, to the best of our knowledge, the most complete population-level distributions for a range of epidemiological values—our model provides insights into important, but poorly understood, epidemiological features of P. vivax. [ABSTRACT FROM AUTHOR]

To counterbalance a potential overemphasis on the state as the key unit of analysis in research on Asia-Europe relations, we examine how their major cities are interconnected. Analytically, this is achieved by applying a network model to data on the office locations of 175 globalized producer service firms. We examine the strength and orientation (for 2022) and the evolution (for 2010–2022) of these connections. We find that both Asia and Europe have more well-connected cities than any other world region and are characterized by a wide variety of levels of connectedness among their cities. However, the Asian system is somewhat top-heavier and showed more comprehensive connectivity gains. Most cities tend to be oriented towards their own region, albeit that there are some notable exceptions such as Luxembourg and New Delhi having an important trans-regional focus to their intercity connections, while London, Paris, Tokyo, Singapore, and Hong Kong show a relatively balanced profile. We argue that the time is ripe for a nuanced and context-specific approach to understanding how cities can engage on the global stage in general and in Asia-Europe relations in particular. [ABSTRACT FROM AUTHOR]

A characteristic of malaria in all its forms is the potential for superinfection (that is, multiple concurrent blood-stage infections). An additional characteristic of Plasmodium vivax malaria is a reservoir of latent parasites (hypnozoites) within the host liver, which activate to cause (blood-stage) relapses. Here, we present a model of hypnozoite accrual and superinfection for P. vivax. To couple host and vector dynamics for a homogeneously-mixing population, we construct a density-dependent Markov population process with countably many types, for which disease extinction is shown to occur almost surely. We also establish a functional law of large numbers, taking the form of an infinite-dimensional system of ordinary differential equations that can also be recovered by coupling expected host and vector dynamics (i.e. a hybrid approximation) or through a standard compartment modelling approach. Recognising that the subset of these equations that model the infection status of the human hosts has precisely the same form as the Kolmogorov forward equations for a Markovian network of infinite server queues with an inhomogeneous batch arrival process, we use physical insight into the evolution of the latter process to write down a time-dependent multivariate generating function for the solution. We use this characterisation to collapse the infinite-compartment model into a single integrodifferential equation (IDE) governing the intensity of mosquito-to-human transmission. Through a steady state analysis, we recover a threshold phenomenon for this IDE in terms of a parameter R 0 expressible in terms of the primitives of the model, with the disease-free equilibrium shown to be uniformly asymptotically stable if R 0 < 1 and an endemic equilibrium solution emerging if R 0 > 1 . Our work provides a theoretical basis to explore the epidemiology of P. vivax, and introduces a strategy for constructing tractable population-level models of malarial superinfection that can be generalised to allow for greater biological realism in a number of directions. [ABSTRACT FROM AUTHOR]

An effective and just industrial transition is necessary both to mitigate climate change and protect jobs, and as a precursor to enable other sectors to decarbonise. Activity is at an early stage and examples of successful sector-wide interventions to decarbonise industry do not yet exist. Governments of industrialised countries are beginning to develop policy and provide funding to support deployment of carbon capture and low-carbon hydrogen infrastructures into high-emitting industrial clusters, but options for sites outside of clusters, denoted here as 'dispersed sites', are also required. This paper takes a mixed methods approach to provide the first analysis of the issues facing dispersed industrial sites on their route to decarbonisation and to suggest solutions to the challenges they face. Using the UK as a case study, it first characterises dispersed sites in terms of location, emissions released, sectors involved, and size of companies affected. It then shows how these features mean that simply expanding the geographical scope of the present UK decarbonisation strategy, which focuses on the provision of carbon capture and low-carbon hydrogen, would face a number of challenges and so will need to be broadened to include a wider range of abatement options and other considerations to meet the needs of dispersed sites. While the solutions for each place will be different, these are likely to include some combination of the expansion of shared infrastructure, the development of local zero-carbon hubs, research into a wider range of novel abatement technologies and facilitating local participation in energy planning. The paper concludes with a discussion of remaining knowledge gaps before outlining how its findings might apply to industrial decarbonisation strategies in other countries. [ABSTRACT FROM AUTHOR]

In this paper, we consider the occupancy distribution for an open network of infinite server queues with multivariate batch arrivals following a non-homogeneous Poisson process, and general service time distributions. We derive a probability generating function for the transient occupancy distribution of the network and prove that it is necessary and sufficient for ergodicity that the expected occupancy time for each batch be finite. Further, we recover recurrence relations for the transient probability mass function formulated in terms of a distribution obtained by compounding the batch size with a multinomial distribution. [ABSTRACT FROM AUTHOR]

Clinically symptomatic type 1 diabetes (stage 3 type 1 diabetes) is preceded by a pre-symptomatic phase, characterised by progressive loss of functional beta cell mass after the onset of islet autoimmunity, with (stage 2) or without (stage 1) measurable changes in glucose profile during an OGTT. Identifying metabolic tests that can longitudinally track changes in beta cell function is of pivotal importance to track disease progression and measure the effect of disease-modifying interventions. In this review we describe the metabolic changes that occur in the early pre-symptomatic stages of type 1 diabetes with respect to both insulin secretion and insulin sensitivity, as well as the measurable outcomes that can be derived from the available tests. We also discuss the use of metabolic modelling to identify insulin secretion and sensitivity, and the measurable changes during dynamic tests such as the OGTT. Finally, we review the role of risk indices and minimally invasive measures such as those derived from the use of continuous glucose monitoring. [ABSTRACT FROM AUTHOR]

A normative electrographic activity map could be a powerful resource to understand normal brain function and identify abnormal activity. Here, we present a normative brain map using scalp EEG in terms of relative band power. In this exploratory study we investigate its temporal stability, its similarity to other imaging modalities, and explore a potential clinical application. We constructed scalp EEG normative maps of brain dynamics from 17 healthy controls using source-localised resting-state scalp recordings. We then correlated these maps with those acquired from MEG and intracranial EEG to investigate their similarity. Lastly, we use the normative maps to lateralise abnormal regions in epilepsy. Spatial patterns of band powers were broadly consistent with previous literature and stable across recordings. Scalp EEG normative maps were most similar to other modalities in the alpha band, and relatively similar across most bands. Towards a clinical application in epilepsy, we found abnormal temporal regions ipsilateral to the epileptogenic hemisphere. Scalp EEG relative band power normative maps are spatially stable across time, in keeping with MEG and intracranial EEG results. Normative mapping is feasible and may be potentially clinically useful in epilepsy. Future studies with larger sample sizes and high-density EEG are now required for validation. [ABSTRACT FROM AUTHOR]

The human brain extracts meaning using an extensive neural system for semantic knowledge. Whether broadly distributed systems depend on or can compensate after losing a highly interconnected hub is controversial. We report intracranial recordings from two patients during a speech prediction task, obtained minutes before and after neurosurgical treatment requiring disconnection of the left anterior temporal lobe (ATL), a candidate semantic knowledge hub. Informed by modern diaschisis and predictive coding frameworks, we tested hypotheses ranging from solely neural network disruption to complete compensation by the indirectly affected language-related and speech-processing sites. Immediately after ATL disconnection, we observed neurophysiological alterations in the recorded frontal and auditory sites, providing direct evidence for the importance of the ATL as a semantic hub. We also obtained evidence for rapid, albeit incomplete, attempts at neural network compensation, with neural impact largely in the forms stipulated by the predictive coding framework, in specificity, and the modern diaschisis framework, more generally. The overall results validate these frameworks and reveal an immediate impact and capability of the human brain to adjust after losing a brain hub. The human brain is a distributed system composed of highly interconnected hubs. Here, patients undergoing a rare operation reveal the immediate impact and compensatory brain network changes that occur when a key hub is removed. [ABSTRACT FROM AUTHOR]

Introduction: Our aim was to evaluate protein biomarker changes related to the administration of filgotinib, a Janus kinase (JAK) 1 preferential inhibitor, in patients with moderately to severely active rheumatoid arthritis (RA) with inadequate response to methotrexate. Methods: Plasma and serum samples were collected from patients enrolled in FINCH 1 (NCT02889796), a Phase 3 trial. Patients with stable backgrounds of methotrexate were randomly assigned once-daily oral filgotinib 200 or 100 mg, subcutaneous adalimumab 40 mg every 2 weeks (W), or placebo. Up to 35 biomarkers were analyzed at baseline, W4, and W12 with enzyme-linked immunosorbent assays and chemiluminescence and electrochemiluminescence assays. Results: At baseline, four distinct biomarker clusters were identified. The strongest intragroup correlations were in bone-cartilage resorption/inflammation and JAK/signal transducer and activator of transcription (STAT) signaling activity. At baseline, significant positive correlations were identified for cytokines with patient-reported pain and with patient measures of fatigue. Filgotinib reduced levels of cytokines associated with inflammation and cell migration as early as W4 and through W12. Compared to adalimumab, filgotinib induced significant reductions in bone-related turnover biomarkers, N-telopeptide of type 1 collagen and C-telopeptide 1, as well as biomarkers associated with baseline disease activity. No baseline predictors of therapeutic response to filgotinib were identified. Conclusions: Filgotinib reduced peripheral protein biomarkers associated with JAK/STAT signaling, inflammatory signaling, immune cell migration, and bone resorption as soon as W4 in FINCH 1. Effects were dose-dependent and consistent with the clinical efficacy of filgotinib observed in FINCH 1. The changes in peripheral biomarkers associated with filgotinib treatment in methotrexate-experienced patients are consistent with changes observed in both methotrexate-naïve and biologic disease-modifying antirheumatic drug-experienced RA populations. These data demonstrate dose-dependent effects of preferential JAK1 inhibition by filgotinib on peripheral blood protein biomarkers in methotrexate-experienced patients with RA. Trial Registration: ClinicalTrials.gov, NCT02889796. [ABSTRACT FROM AUTHOR]

We study a symmetric diffusion process on ℝ d , d ≥ 2, in divergence form in a stationary and ergodic random environment. The coefficients are assumed to be degenerate and unbounded but satisfy a moment condition. We derive upper off-diagonal estimates on the heat kernel of this process for general speed measure. Lower off-diagonal estimates are also shown for a natural choice of speed measure, under an additional mixing assumption on the environment. Using these estimates, a scaling limit for the Green function is proven. [ABSTRACT FROM AUTHOR]

Introduction: Tofacitinib is an oral Janus kinase inhibitor for treatment of ankylosing spondylitis (AS). Using mediation modelling, we describe interrelationships between fatigue, pain, morning stiffness, C-reactive protein (CRP) and tofacitinib treatment in patients with AS. Methods: Data from phase 2 (NCT01786668)/phase 3 (NCT03502616) studies of patients receiving tofacitinib 5 mg twice daily (BID) or placebo were used. Initial models included treatment as the independent binary variable (tofacitinib 5 mg BID versus placebo); fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue [FACIT-F; model A] or Bath AS Disease Activity Index [BASDAI] Q1 [model B]) as the dependent variable; and pain (total back pain/nocturnal spinal pain [model A] or pain measured by BASDAI Q2/3 [model B]), morning stiffness (BASDAI Q5/6) and CRP as mediator variables. Results: Pooled data from 370/371 patients were included in models A/B. Initial models demonstrated that tofacitinib treatment affects fatigue mainly indirectly via pain and morning stiffness. As a result, initial models were respecified to exclude direct treatment effect and the indirect effect via CRP. For respecified model A, 44.0% of the indirect effect of tofacitinib treatment on fatigue was mediated via back pain/morning stiffness, 40.0% via morning stiffness alone and 16.0% via back pain alone (all P < 0.05). For respecified model B, 80.8% of the indirect effect of tofacitinib treatment on fatigue was mediated via pain/morning stiffness and 19.2% via pain alone (both P < 0.05). Conclusions: In tofacitinib-treated patients with AS, improvements in fatigue were collectively mediated through combined treatment effects on morning stiffness and pain. [ABSTRACT FROM AUTHOR]

To better understand functional morphological adaptations to high elevation (> 3000 m above sea level) life in both North American and African mountain-associated rodents, we used microCT scanning to acquire 3D images and a 3D morphometric approach to calculate endocranial volumes and skull lengths. This was done on 113 crania of low-elevation and high-elevation populations in species of North American cricetid mice (two Peromyscus species, n = 53), and African murid rodents of two tribes, Otomyini (five species, n = 49) and Praomyini (four species, n = 11). We tested two distinct hypotheses for how endocranial volume might vary in high-elevation populations: the expensive tissue hypothesis, which predicts that brain and endocranial volumes will be reduced to lessen the costs of growing and maintaining a large brain; and the brain-swelling hypothesis, which predicts that endocranial volumes will be increased either as a direct phenotypic effect or as an adaptation to accommodate brain swelling and thus minimize pathological symptoms of altitude sickness. After correcting for general allometric variation in cranial size, we found that in both North American Peromyscus mice and African laminate-toothed (Otomys) rats, highland rodents had smaller endocranial volumes than lower-elevation rodents, consistent with the expensive tissue hypothesis. In the former group, Peromyscus mice, crania were obtained not just from wild-caught mice from high and low elevations but also from those bred in common-garden laboratory conditions from parents caught from either high or low elevations. Our results in these mice showed that brain size responses to elevation might have a strong genetic basis, which counters an opposite but weaker environmental effect on brain volume. These results potentially suggest that selection may act to reduce brain volume across small mammals at high elevations but further experiments are needed to assess the generality of this conclusion and the nature of underlying mechanisms. [ABSTRACT FROM AUTHOR]

Introduction: We sought to identify and compare treatment response groups based on individual patient responses (rather than group mean response) over time on the Clinical Disease Activity Index (CDAI) for rheumatoid arthritis (RA), in patients treated with baricitinib 4-mg in 4 phase 3 studies. Methods: Trajectory subgroups were identified within each study using growth mixture modeling. Following grouping, baseline characteristics and disease measures were summarized and compared. Results: In each study, three response trajectories were identified. In the three studies of patients naïve to biological disease-modifying anti-rheumatic drugs (bDMARDs) patients had, on average, high disease activity, as measured by CDAI. In these studies, a group of rapid responders (65–71% of patients) had the lowest baseline CDAI scores and achieved mean CDAI ≤ 10 by week 16. Gradual responders (10–17%) had higher baseline CDAI, but generally achieved low disease activity (CDAI ≤ 10) by week 24. A group of partial responders (18–22%) had higher baseline CDAI and did not achieve mean CDAI ≤ 10. In bDMARD-experienced patients, the subgroups were rapid responders, who achieved mean CDAI ≤ 10 (42% of patients); partial responders, with mean CDAI decrease of ~ 15 points from baseline (42% of patients); and limited responders (15% of patients). Changes in modified total sharp score (mTSS; assessed only in biologic-naïve patients) were below the smallest detectable difference at 24/52 weeks for > 90% of patients in each group, excepting partial responders in RA-BEGIN (≥ 75% no detectable change). Conclusion: In patients receiving baricitinib 4-mg, lower baseline CDAI was generally associated with rapid response, while higher baseline CDAI scores were generally seen for patients who either reached treatment targets more gradually, or who had a partial or limited response. Maintenance of response was observed with continued baricitinib treatment in all response groups and generally included maintenance of mTSS. Plain Language Summary: Baricitinib is an oral agent widely approved for the treatment of moderately to severely active rheumatoid arthritis). Although baricitinib (and other agents) have demonstrated efficacy at the population level, treatment responses vary considerably between individual patients. This study assessed four baricitinib phase 3 clinical studies and categorized patient responses into response groups based on the Clinical Disease Activity Index (CDAI) using a growth mixture model. We then evaluated baseline characteristics and corresponding disease measures within the response groups. In patients with no prior treatment with biological disease-modifying anti-rheumatic drugs (bDMARDs), 65–71% of patients had rapid responses to treatment, while smaller groups had gradual (10–17%) or partial (18–22%) responses. In patients with prior bDMARD experience, rapid and partial responders each comprised 42% of patients while 15% had limited response. Gradual responders generally had higher baseline CDAI versus rapid responders, but achieved low disease activity (LDA) by 24, versus 12 weeks for rapid responders. Across response groups, patients who continued treatment generally maintained their response up to 52 weeks, and where joint erosion was assessed (in bDMARD-naïve patients), generally saw maintenance of joints during continued therapy. The identification of a gradual responder group, which demonstrated good response but required more time to achieve LDA, is relatively novel and should be considered when setting treatment expectations, particularly in patients with high baseline disease activity. In addition, in bDMARD-experienced patients, many patients did not achieve LDA but maintained a substantial partial response with continued therapy. [ABSTRACT FROM AUTHOR]

Introduction: The aim of this work is to compare real-world outcomes of patients with rheumatoid arthritis (RA) receiving adalimumab (ADA) bio-originator (non-switchers) to those who had switched from ADA bio-originator to an ADA biosimilar (switchers) on the basis of the hypothesis that these outcomes would differ. Methods: Data were drawn from the Adelphi RA Disease Specific Programme™, a point-in-time survey of physicians and their patients in Europe (France, Germany, Italy, Spain, UK) in 2020. Physicians completed a questionnaire for their next ten adult patients with RA, followed by four additional patients who had switched from ADA bio-originator to an ADA biosimilar (switchers). Physician- and patient-reported outcomes (PROs) for switchers and non-switchers were compared by propensity score matching. Results: Three hundred and three rheumatologists provided data for 160 non-switchers and 225 switchers, 140 patients provided data; 51 non-switchers, 89 switchers. According to physician-reported disease activity, non-switchers were more likely to improve on their current ADA treatment than switchers (68%, n = 108 vs. 26%, n = 59 p < 0.001) and less likely to worsen (1%, n = 2 vs. 9%, n = 20; p < 0.01). Physician-reported patient adherence was significantly lower amongst switchers versus non-switchers (0.66 vs. 0.78, respectively; p = 0.04). More non-switchers than switchers were reported by their physicians to be consistent in taking their RA medicine (p < 0.001). Compared with non-switchers, PRO measures indicated quality of life was worse (EQ-5D Visual Analogue Scale: 62.9 vs. 71.9; p < 0.001) and activity impairment was greater (Work Productivity Activity Index: 31.0 vs. 24.4; p = 0.02) for switchers, with trends for poorer health status and greater pain. Conclusions: Non-medical switching in RA treatment may lead to unforeseen outcomes that should be considered by health decision-makers. [ABSTRACT FROM AUTHOR]

Introduction: Baricitinib, a Janus kinase (JAK) 1/2 inhibitor, is an approved treatment for rheumatoid arthritis (RA), atopic dermatitis (AD), and alopecia areata (AA). Further characterisation of adverse events of special interest (AESI) for JAK inhibitors in at-risk populations will improve benefit–risk assessment for individual patients and diseases. Methods: Data were pooled from clinical trials and long-term extensions in moderate-to-severe active RA, moderate-to-severe AD, and severe AA. Incidence rates (IR) per 100 patient-years of major adverse cardiovascular event (MACE), malignancy, venous thromboembolism (VTE), serious infection, and mortality were calculated for patients with low risk (younger than 65 years with no specified risk factors), and patients at risk (≥ 1 of: aged 65 years or older, atherosclerotic cardiovascular disease, diabetes mellitus, hypertension, current smoking, HDL cholesterol < 40 mg/dL, BMI ≥ 30 kg/m2, poor mobility on EQ-5D, or history of malignancy). Results: Datasets included baricitinib exposure up to 9.3 years with 14,744 person-years of exposure (PYE) (RA), 3.9 years with 4628 PYE (AD), and 3.1 years with 1868 PYE (AA). In patients with low risk (RA: 31%, AD: 48%, AA: 49%), IRs for MACE (0.05, 0.04, 0), malignancies (0.20, 0.13, 0), VTE (0.09, 0.04, 0), serious infection (1.73, 1.18, 0.6), and mortality (0.04, 0, 0) in the RA, AD, and AA datasets, respectively, were low. In patients at risk (RA: 69%, AD: 52%, AA: 51%), IRs were for MACE (0.70, 0.25, 0.10), malignancies (1.23, 0.45, 0.31), VTE (0.66, 0.12, 0.10), serious infection (2.95, 2.30, 1.05), and mortality (0.78, 0.16, 0) for RA, AD, and AA datasets, respectively. Conclusion: Populations with low risk have low incidence of the examined JAK inhibitor-related AESI. In the dermatologic indications, incidence is also low for patients at risk. Considering individual disease burden, risk factors, and response to treatment is relevant to make informed decisions for individual patients treated with baricitinib. [ABSTRACT FROM AUTHOR]

Daily levothyroxine (LT4) is the standard of care for the treatment of hypothyroidism; however, a small number of patients experience residual symptoms of hypothyroidism. Guidelines indicate that a trial with LT4 and liothyronine (LT3) could be attempted once other conditions have been addressed or excluded. Even so, currently, treatment of hypothyroidism can still be suboptimal. [ABSTRACT FROM AUTHOR]

Baricitinib is an oral, selective inhibitor of Janus kinase (JAK)1/JAK2 that transiently and reversibly inhibits many proinflammatory cytokines. This mechanism is a key mediator in a number of chronic inflammatory diseases; accordingly, baricitinib has been studied and approved for the treatment of several rheumatological and dermatological disorders, as well as COVID-19. This narrative review summarises and discusses the safety profile of baricitinib across these diseases, with special focus on adverse events of special interest (AESI) for JAK inhibitors, using integrated safety data sets of clinical trial data, and puts findings into context with the underlying risk in the respective disease populations, using supporting literature. We show that rates of infection with baricitinib generally reflected the inherent risk of the disease populations being treated, with serious infections and herpes zoster being more frequent in rheumatic diseases than in dermatological disorders, and herpes simplex being reported particularly in atopic dermatitis. Similarly, rates of major adverse cardiovascular events (MACE), venous thromboembolism (VTE) and malignancies were generally within or below the ranges reported for the respective disease populations, thereby reflecting the underlying risk; these events were therefore more frequent in patients with rheumatic diseases than in those with dermatological disorders, the latter of whom generally had low absolute risk. AESI were usually more common in patients with risk factors specific for each event. When a population similar to that of ORAL Surveillance was considered, the incidence rate of MACE with baricitinib was numerically lower than that reported with tofacitinib and similar to that of tumour necrosis factor inhibitors. No safety concerns were observed in hospitalised patients with COVID-19 who received baricitinib for up to 14 days. Identifying the patterns and likelihoods of AEs that occur during treatment in large groups of patients with different diseases can help the physician and patient better contextualise the benefit-to-risk ratio for the individual patient. [ABSTRACT FROM AUTHOR]

Introduction: Pain is a multidimensional factor and core domain of psoriatic arthritis (PsA). This analysis aimed to quantify the role of potential inflammation-associated outcomes on pain reduction in patients with PsA receiving tofacitinib, using mediation modeling. Methods: Pooled data were from two phase 3 studies (OPAL Broaden and OPAL Beyond) of patients with active PsA treated with tofacitinib 5 mg twice daily or placebo. Mediation modeling was utilized to quantify the indirect effects (via Itch Severity Item [ISI], C-reactive protein [CRP] levels, swollen joint count [SJC], Psoriasis Area and Severity Index [PASI], and enthesitis [using Leeds Enthesitis Index]) and direct effects (representing all other factors) of tofacitinib treatment on pain improvement. Results: The initial model showed that tofacitinib treatment affects pain, primarily indirectly, via ISI, CRP, SJC, PASI, and enthesitis (overall 84.0%; P = 0.0009), with 16.0% (P = 0.5274) attributable to the direct effect. The model was respecified to exclude SJC and PASI. Analysis of the final model revealed that 29.5% (P = 0.0579) of tofacitinib treatment effect on pain was attributable to the direct effect, and 70.5% (P < 0.0001) was attributable to the indirect effect. ISI, CRP, and enthesitis mediated 37.4% (P = 0.0002), 15.3% (P = 0.0107), and 17.8% (P = 0.0157) of the tofacitinib treatment effect on pain, respectively. Conclusions: The majority of the effect of tofacitinib on pain was collectively mediated by itch, CRP, and enthesitis, with itch being the primary mediator of treatment effect. Trial Registration: NCT01877668, NCT01882439. Graphical PLS: [ABSTRACT FROM AUTHOR]

The nature of the area of mathematical competitions as a design science is considered, historical roots of mathematical problem-solving competitions are traced, the complementary aspects of mathematics as theory building and as problem solving are touched upon in relation to the practice of competitions. Two historical figures, Euler and Erdős, emerge, and the appropriateness of many of Euler's mathematical ventures are seen as role models for competition mathematics as first put into practice in mathematical competitions towards the end of the nineteenth century. Distinctions and definitions are made, a venture into identifying competition syllabi and the principal types of reasoning employed in solving competition problems is explored, and a description of the many different types of competitions is considered. Interaction between the field of mathematics itself and problem-solving competitions is briefly explored, as are the possibilities that open when competitions and their access to huge amounts of data, both national and international, are taken into account in research belonging to mathematics education. Finally, the range of topics addressed in this special issue of ZDM is covered, along with some possible conclusions relating to the components of the overview. [ABSTRACT FROM AUTHOR]

We consider the patient-to-bed assignment problem that arises in hospitals. Both emergency patients who require hospital admission and elective patients who have had surgery need to be found a bed in the most appropriate ward. The patient-to-bed assignment problem arises when a bed request is made, but a bed in the most appropriate ward is unavailable. In this case, the next-best decision out of a many alternatives has to be made, according to some suitable decision making algorithm. We construct a Markov chain to model this problem in which we consider the effect on the length of stay of a patient whose treatment and recovery consists of several stages, and can be affected by stays in or transfers to less suitable wards. We formulate a dynamic program recursion to optimise an objective function and calculate the optimal decision variables, and discuss simulation techniques that are useful when the size of the problem is too large. We illustrate the theory with some numerical examples. [ABSTRACT FROM AUTHOR]

This correction notice is for an article titled "Filgotinib Modulates Inflammation-Associated Peripheral Blood Protein Biomarkers in Adults with Active Rheumatoid Arthritis and Prior Inadequate Response to Methotrexate." The correction addresses two errors in the original article. The first error is in a sentence under the "Prior Presentation" section, where the word "prevented" should have been "presented." The second error is in Table 1, where the data in the column headings for FIL200 and ADA were incorrectly aligned, and an arrow in the fifth row for IL-17A was incorrect and should have been an up arrow. The corrected table is provided in the notice. The original article has been corrected. [Extracted from the article]

In mathematical biology, there is a great deal of interest in producing continuum models by scaling discrete agent-based models governed by local stochastic rules. We discuss a particular example of this approach: a model for the proliferation of neural crest cells that can help us understand the development of Hirschprung’s disease, a potentially-fatal condition in which the enteric nervous system of a new-born child does not extend all the way through the intestine and colon. Our starting point is a discrete-state, continuous-time Markov chain model proposed by Hywood et al. (2013a) for the location of the neural crest cells that make up the enteric nervous system. Hywood et al. (2013a) scaled their model to derive an approximate second order partial differential equation describing how the limiting expected number of neural crest cells evolve in space and time. In contrast, we exploit the relationship between the above-mentioned Markov chain model and the well-known Yule-Furry process to derive the exact form of the scaled version of the process. Furthermore, we provide expressions for other features of the domain agent occupancy process, such as the variance of the marginal occupancy at a particular site, the distribution of the number of agents that are yet to reach a given site and a stochastic description of the process itself. [ABSTRACT FROM AUTHOR]

Forests affected by fragmentation are at risk of losing their primate populations over the long term. The impact of fragmentation on primate populations has been studied in several places in Africa, Asia and South America; however, there has been no discernible pattern of how primates react to forest disturbance and fragmentation. In fragmented habitats, the local extinction probability of a species increases due to a decrease in patch area and an increase in genetic isolation. Here we used microsatellite markers and mitochondrial DNA sequences to investigate how habitat fragmentation impacts on the genetic diversity and structure of a samango monkey population inhabiting forest patches in the Soutpansberg mountain range of northern South Africa. We sampled four local populations across the length of the mountain range and an additional outlying population from the Great Escarpment to the south. Our results indicate that local populations along the mountain range were historically more connected and less distinct than at present. In more recent times, a lack of contemporary gene flow is leading to a more pronounced genetic structure, causing population subdivision across the mountain and likely isolating the Soutpansberg population from the escarpment population to the south. Based on our results, we suggest that natural and anthropogenic fragmentation are driving population genetic differentiation, and that the matrix surrounding forests and their suitability for samango monkey utilisation play a role at the local scale. The degree of genetic isolation found for samango monkey populations in our study raises concerns about the long-term viability of populations across the mountain range. [ABSTRACT FROM AUTHOR]

Bats have been proposed as reliable bioindicators for monitoring bioaccumulation of elements and chemicals in natural and transformed ecosystems. Non-invasive methods are becoming more popular as research moves away from destructive methodologies. We present the first concentrations of 23 elements in Mops condylurus and Tadarida aegyptiaca (Molossidae) fur and blood from an opencast diamond mine and reference area using inductively coupled plasma mass spectrometry (ICP-MS). Concentrations of B, K, Rb and Cd in the bats' fur were significantly higher in the mining footprint compared to the reference area (P < 0.05). Other elements such as Zn and Hg were significantly higher in the blood of bats from the mining footprint than the reference area (P < 0.05), whereas Mn was significantly higher in the blood of bats from the reference area than from the mining footprint (P < 0.05). Sixteen of the 22 elements above the limit of detection, with the exception of Ba, were significantly higher in the fur samples than in the blood due to elements being incorporated over time into the fur as it grows, whereas blood reveals short-term exposure to elements. Concentrations of most of the elements were reasonably low except Al, Fe and Zn. In general, the element concentrations particularly in the fur samples were comparable with other international studies reporting elemental fur concentrations from anthropogenically impacted and natural areas. Fur and blood have the potential to be viable indicators of environmental toxicity, but research is required on toxic thresholds and physiological and ecological unknowns around element concentrations in bat tissues and organs. [ABSTRACT FROM AUTHOR]

Since entering the clinic 25 years ago, biologic TNF inhibitors have transformed the outlook for people with rheumatoid arthritis and set the standard for all other targeted therapies. Despite changes to the therapeutic landscape, TNF inhibitors look set to remain an important treatment option for the foreseeable future. [ABSTRACT FROM AUTHOR]

Civic education is a moral development imperative of the Indonesian national curriculum and the United Nation's policy on education for sustainable development. It was within this context that we investigated the impact of ethical dilemma story pedagogy (EDSP) on student learning in a constructivist Indonesian STEM learning environment. EDSP uses specially-designed stories to engage students in ethical decision-making for resolving sustainable development dilemmas occurring in their daily lives. The research was conducted in six Indonesian middle schools with 462 students of chemistry, and it was designed to lead to understanding of how well students engaged in a constructivist values learning environment aimed at developing chemistry knowledge/skills and ethical values for living sustainably in the 21st century. Data were collected using the Constructivist Values Learning Environment Survey (CVLES), classroom observations, student interviews and students' reflective journals. Generally, students had positive perceptions of their constructivist values learning environment, engaged deeply in chemistry learning, reflected critically on their values and the social use of chemistry, and practised mutually-respectful communication and collaborative decision-making as strategies for solving sustainability dilemmas. We conclude that ethical dilemma story pedagogy can play an important role in integrating STEM education and civic education. [ABSTRACT FROM AUTHOR]

Objectives: Mindfulness-based cognitive therapy (MBCT) is a well-evidenced relapse-prevention intervention for depression with a growing evidence-base for use in other clinical populations. The UK initiatives have outlined plans for increasing access to MBCT in clinical settings, although evidence suggests that access remains limited. Given the increased popularity and access to MBCT, there may be deviations from the evidence-base and potential risks of harm. We aimed to understand what clinicians believe should be best clinical practice regarding access to, delivery of, and adaptations to MBCT. Methods: We employed a two-stage Delphi methodology. First, to develop statements around best practices, we consulted five mindfulness-based experts and reviewed the literature. Second, a total of 59 statements were taken forward into three survey rating rounds. Results: Twenty-nine clinicians completed round one, with 25 subsequently completing both rounds two and three. Forty-four statements reached consensus; 15 statements did not. Clinicians agreed with statements regarding sufficient preparation for accessing MBCT, adherence to the evidence-base and good practice guidelines, consideration of risks, sufficient access to training, support, and resources within services, and carefully considered adaptations. The consensus was not reached on statements which reflected a lack of evidence-base for specific clinical populations or the complex decision-making processes involved in delivering and making adaptations to MBCT. Conclusions: Our findings highlight the delicate balance of maintaining a client-centred and transparent approach whilst adhering to the evidence-base in clinical decisions around access to, delivery of, and adaptations in MBCT and have important wide-reaching implications. [ABSTRACT FROM AUTHOR]

This article describes contrasting ideas for a set of topics in epidemiological thinking. The premise underlying this contribution to the special edition is that researchers develop their epidemiological thinking over time through interactions with other researchers who have a variety of in-practice commitments, such as to kinds of cases and methods of analysis, and not simply to a philosophical framework for explanation. I encourage discussants from philosophy and epidemiology to draw purposefully from across a range of topics and contrasting positions, and thereby pursue critical thinking in the sense of understanding ideas and practices better when we examine them in relation to alternatives. After an initial topic concerning practices for developing epidemiological literacy, a number of conceptual steps follow—the characterization of the very phenomena we might be concerned with, the scope and challenges of the field of epidemiology, the formulation of categories—before linking associations, predictions, causes and interventions and examining the confounding of purported links. Building on that conceptual basis, the remaining topics consist of issues or angles of analysis related to the complexities of inequalities within and between populations, context, and changes over the life course. The organization of topics derives from a graduate course that I teach that aims for epidemiological literacy, not technical ability in statistical formulas and data analysis, and shares the underlying premise and critical thinking goals of this article. During the topic-by-topic description, some assertions about explanation and intervention emerge, notably, that epidemiological–philosophical discussion about causality often leaves unclear or unexamined whether a modifiable factor shown to have been associated with a difference in the data from past observations should be thought of as factor that, when modified, would generate that difference going forward. The article concludes with a "Limitations of this Study" section that teases out different kinds of description–prescription relationship that are implied in undertaking philosophy of epidemiology and identifies some other considerations that are implied but not emphasized by this article. [ABSTRACT FROM AUTHOR]

We investigate the behavior of equilibria in an M/M/1 feedback queue where price- and time-sensitive customers are homogeneous with respect to service valuation and cost per unit time of waiting. Upon arrival, customers can observe the number of customers in the system and then decide to join or to balk. Customers are served in order of arrival. After being served, each customer either successfully completes the service and departs the system with probability q, or the service fails and the customer immediately joins the end of the queue to wait to be served again until she successfully completes it. We analyze this decision problem as a noncooperative game among the customers. We show that there exists a unique symmetric Nash equilibrium threshold strategy. We then prove that the symmetric Nash equilibrium threshold strategy is evolutionarily stable. Moreover, if we relax the strategy restrictions by allowing customers to renege, in the new Nash equilibrium, customers have a greater incentive to join. However, this does not necessarily increase the equilibrium expected payoff, and for some parameter values, it decreases it. [ABSTRACT FROM AUTHOR]

We present a broad literature survey of parameter and state estimation for queueing systems. Our approach is based on various inference activities, queueing models, observations schemes, and statistical methods. We categorize these into branches of research that we call estimation paradigms. These include: the classical sampling approach, inverse problems, inference for non-interacting systems, inference with discrete sampling, inference with queueing fundamentals, queue inference engine problems, Bayesian approaches, online prediction, implicit models, and control, design, and uncertainty quantification. For each of these estimation paradigms, we outline the principles and ideas, while surveying key references. We also present various simple numerical experiments. In addition to some key references mentioned here, a periodically updated comprehensive list of references dealing with parameter and state estimation of queues will be kept in an accompanying annotated bibliography. [ABSTRACT FROM AUTHOR]

Introduction: The outcome for pituitary endocrine function following endoscopic transsphenoidal surgery remains unclear. This study aims to evaluate endocrine outcomes following endoscopic surgery in order to provide a benchmark to assist in the counselling of patients perioperatively. Methods: A prospectively held pituitary database was retrospectively analysed for all adult pituitary adenoma patients undergoing endoscopic surgery from May 2011 to May 2017. All operations were performed by a single neurosurgeon at a regional centre for pituitary surgery. Functioning and non-functioning adenomas were included. Hormonal status was assessed at most recent follow-up. Results: One hundred forty-five patients (69 M, 76 F) were included in the study with a median age of 52 years. Median follow-up was 52 months. Eighty-eight patients (61%) were not taking any hormone replacement medications, whilst 57 patients (39%) required hormone replacement therapy (HRT) preoperatively. Preoperatively, 29 patients (20%) had hypothalamo-pituitary-adrenal (HPA) axis dysfunction, 39 patients (27%) had thyroid axis dysfunction, 11 males (16%) and 7 females (9%) had gonadal axis dysfunction, and one patient had preoperative diabetes insipidus. Postoperatively, 26 patients (18%) had a new deficiency in pituitary function, whilst 6 patients (11%) were able to cease HRT. Nineteen patients (13%) had new HPA axis deterioration, 12 (8%) had new thyroid axis dysfunction, 8 males (11%) and 4 females (5%) had gonadal axis deterioration, and 6 patients (4%) had new diabetes insipidus (DI). Conclusions: The ability to restore pituitary function following endoscopic surgery remains limited, whilst new deficits still occur. It is essential that patients are counselled accordingly as hormonal replacement therapy can have a significant impact on quality of life. Larger longer-term collaborative studies of endocrine outcome in endoscopic pituitary surgery are needed. [ABSTRACT FROM AUTHOR]

There are, say, I N i stations with passengers arriving at stations HT ht in Poisson processes with rate HT ht . Assume that the bus moves with constant speed HT ht between stations and takes a time with mean HT ht for some HT ht both to load and unload I X i passengers. This contrasts both with static spatial optimisation problems, (see [[7], Chapter 2] for some examples) and polling systems [[8]], where customers arrive in real time but the server does not take into account information about customer location when it moves between stations. [Extracted from the article]

Predicting either positive or negative response to specific therapies in rheumatoid arthritis (RA) is certainly welcome and the molecular signature response classifier (MSRC) appears most promising and useful. Considering Immuno-autonomics in Stratifying Successful Treatment of Rheumatoid Arthritis with Tumor Necrosis Factor Inhibition: Comment on Cohen et al. Keywords: Rheumatoid arthritis; Tumor necrosis factor inhibition; Immuno-autonomics; Heart rate variability EN Rheumatoid arthritis Tumor necrosis factor inhibition Immuno-autonomics Heart rate variability 305 307 3 02/06/22 20220201 NES 220201 This comment refers to the article available online at https://doi.org/10.1007/s40744-021-00330-y. [Extracted from the article]

We study a continuous-time random walk on Z d in an environment of random conductances taking values in (0 , ∞) . For a static environment, we extend the quenched local limit theorem to the case of a general speed measure, given suitable ergodicity and moment conditions on the conductances and on the speed measure. Under stronger moment conditions, an annealed local limit theorem is also derived. Furthermore, an annealed local limit theorem is exhibited in the case of time-dependent conductances, under analogous moment and ergodicity assumptions. This dynamic local limit theorem is then applied to prove a scaling limit result for the space-time covariances in the Ginzburg–Landau ∇ ϕ model. We also show that the associated Gibbs distribution scales to a Gaussian free field. These results apply to convex potentials for which the second derivative may be unbounded. [ABSTRACT FROM AUTHOR]

Malaria is a mosquito-borne disease that, despite intensive control and mitigation initiatives, continues to pose an enormous public health burden. Plasmodium vivax is one of the principal causes of malaria in humans. Antibodies, which play a fundamental role in the host response to P. vivax, are acquired through exposure to the parasite. Here, we introduce a stochastic, within-host model of antibody responses to P. vivax for an individual in a general transmission setting. We begin by developing an epidemiological framework accounting for P. vivax infections resulting from new mosquito bites (primary infections), as well as the activation of dormant-liver stages known as hypnozoites (relapses). By constructing an infinite server queue, we obtain analytic results for the distribution of relapses in a general transmission setting. We then consider a simple model of antibody kinetics, whereby antibodies are boosted with each infection, but are subject to decay over time. By embedding this model for antibody kinetics in the epidemiological framework using a generalised shot noise process, we derive analytic expressions governing the distribution of antibody levels for a single individual in a general transmission setting. Our work provides a means to explore exposure-dependent antibody dynamics for P. vivax, with the potential to address key questions in the context of serological surveillance and acquired immunity. [ABSTRACT FROM AUTHOR]

We review developments in the field of boundary-layer flow over complex topography, focussing on the period from 1970 to the present day. The review follows two parallel strands: the impact of hills on flow in the atmospheric boundary layer and gravity-driven flows on hill slopes initiated by heating or cooling of the surface. For each strand we consider the understanding that has resulted from analytic theory before moving to more realistic numerical computation, initially using turbulence closure models and, more recently, eddy-resolving schemes. Next we review the field experiments and the physical models that have contributed to present understanding in both strands. For the period 1970–2000 with hindsight we can link major advances in theory and modelling to the key papers that announced them, but for the last two decades we have cast the net wider to ensure that we have not missed steps that eventually will be seen as critical. Two important new themes are given prominence in the 2000–2020 period. The first is flow over hills covered with tall plant canopies. The presence of a canopy changes the flow in important ways both when the flow is nearly neutral and also when it is stably stratified, forming a link between our two main strands. The second is the use of eddy-resolving models as vehicles to bring together hill flows and gravity-driven flows in a unified description of complex terrain meteorology. [ABSTRACT FROM AUTHOR]

Ranchers and pastoralists worldwide manage and depend upon resources from rangelands (which support indigenous vegetation with the potential for grazing) across Earth's terrestrial surface. In the Great Plains of North America rangeland ecology has increasingly recognized the importance of managing rangeland vegetation heterogeneity to address conservation and production goals. This paradigm, however, has limited application for ranchers as they manage extensive beef production operations under high levels of social-ecological complexity and uncertainty. We draw on the ethics of care theoretical framework to explore how ranchers choose management actions. We used modified grounded theory analysis of repeated interviews with ranchers to (1) compare rancher decision-making under relatively certain and uncertain conditions and (2) describe a typology of practices used to prioritize and choose management actions that maintain effective stewardship of these often multi-generational ranches. We contrast traditional decision-making frameworks with those described by interviewees when high levels of environmental and market uncertainty or ecological complexity led ranchers toward use of care-based, flexible and relational frameworks for decision-making. Ranchers facing complexity and uncertainty often sought "middle-ground" strategies to balance multiple, conflicting responsibilities in rangeland social-ecological systems. For example, ranchers' care-based decision-making leads to conservative stocking approaches to "manage for the middle," e.g. to limit risk under uncertain weather and forage availability conditions. Efforts to promote heterogeneity-based rangeland management for biodiversity conservation through the restoration of patch burn grazing and prairie dog conservation will require increased valuation of ranchers' care work. [ABSTRACT FROM AUTHOR]

Thyroid stimulating hormone (TSH) is critical for normal development and metabolism. To better understand the genetic contribution to TSH levels, we conduct a GWAS meta-analysis at 22.4 million genetic markers in up to 119,715 individuals and identify 74 genome-wide significant loci for TSH, of which 28 are previously unreported. Functional experiments show that the thyroglobulin protein-altering variants P118L and G67S impact thyroglobulin secretion. Phenome-wide association analysis in the UK Biobank demonstrates the pleiotropic effects of TSH-associated variants and a polygenic score for higher TSH levels is associated with a reduced risk of thyroid cancer in the UK Biobank and three other independent studies. Two-sample Mendelian randomization using TSH index variants as instrumental variables suggests a protective effect of higher TSH levels (indicating lower thyroid function) on risk of thyroid cancer and goiter. Our findings highlight the pleiotropic effects of TSH-associated variants on thyroid function and growth of malignant and benign thyroid tumors. Thyroid stimulating hormone (TSH) is critical for normal development and metabolism. Here, the authors conduct a GWAS and suggest protective effect of higher TSH on risk of thyroid cancer and goitre. [ABSTRACT FROM AUTHOR]

We profiled gene expression signatures to distinguish rheumatoid arthritis (RA) from non-inflammatory arthralgia (NIA), self-limiting arthritis (SLA), and undifferentiated arthritis (UA) as compared to healthy controls as novel potential biomarkers for therapeutic responsiveness. Global gene expression profiles of PBMCs from 43 drug-naïve patients presenting with joint symptoms were evaluated and differentially expressed genes identified by comparative analysis with 24 healthy volunteers. Patients were assessed at presentation with follow up at 6 and 12 months. Gene ontology and network pathway analysis were performed using DAVID Bioinformatics Resources v6.7. Gene expression profiles were also determined after disease-modifying anti-rheumatic drug (DMARD) treatment in the inflammatory arthritis groups (i.e. RA and UA) and confirmed by qRT-PCR. Receiver operating characteristic (ROC) curves analysis and Area Under the Curve (AUC) estimation were performed to assess the diagnostic value of candidate gene expression signatures. A type I interferon (IFN) gene signature distinguished DMARD-naïve patients who will subsequently develop persistent inflammatory arthritis (i.e. RA and UA) from those with NIA. In patients with RA, the IFN signature is characterised by up-regulation of SIGLEC1 (p = 0.00597) and MS4A4A (p = 0.00000904). We also identified, EPHB2 (p = 0.000542) and PDZK1IP1 (p = 0.0206) with RA-specific gene expression profiles and elevated expression of the ST6GALNAC1 (p = 0.0023) gene in UA. ROC and AUC risk score analysis suggested that MSA4A (AUC: 0.894, 0.644, 0.720), PDZK1IP1 (AUC: 0.785, 0.806, 0.977), and EPHB2 (AUC: 0.794, 0.723, 0.620) at 0, 6, and 12 months follow-up can accurately discriminate patients with RA from healthy controls and may have practical value for RA diagnosis. In patients with early inflammatory arthritis, ST6GALNAC1 is a potential biomarker for UA as compared with healthy controls whereas EPHB2, MS4A4A, and particularly PDZK1IP1 may discriminate RA patients. SIGLEC1 may also be a useful marker of disease activity in UA. [ABSTRACT FROM AUTHOR]

Although protected areas (PAs) are declared to provide sanctuaries for biodiversity, they are increasingly threatened by the synergistic effects of anthropic factors, invasive alien species and climate change. Consequently, interventions are required to minimize the impacts of these threats on PAs' integrity. To inform these interventions in the South African context and under the current climate change scenario, we tested for geographic patterns of alien woody species across the network of 1,453 PAs using three alien invasion indices – alien species abundance, invaded area ratio and alien species richness. Our analysis shows that, under current climate change scenario, none of the PAs would be effective in shielding against alien plants and PAs that are geographically close tend to share similar invasion patterns. In addition, PAs that are hotspots of alien species are also geographically clustered but these findings are biome-dependent. Our outlier analysis reveals not only an island of disproportionately rich PAs in alien species, but also identifies some alien-poor PAs. We suggest that PAs that are hotspots of alien species as well as outliers of disproportionately rich PAs in alien species should be priority in monitoring and invasion control programmes in the context of the ongoing climate change. [ABSTRACT FROM AUTHOR]

Introduction: The Janus kinase (JAK) inhibitor therapeutic class has shown significant clinical benefit in the treatment of rheumatoid arthritis (RA). We sought to gain insight into the mode of action and immunological effects of filgotinib, a JAK1 selective inhibitor, in active RA by analyzing secreted and cell-based biomarkers key to RA pathophysiology in two phase 2b trials of filgotinib in active RA. Methods: Immune cell subsets and 34 serum biomarkers were analyzed longitudinally over 12 weeks using blood samples collected from patients with active RA receiving filgotinib (100 or 200 mg once daily) or placebo (PBO) in the two phase 2b trials (DARWIN 1, on a background of methotrexate, and DARWIN 2, as monotherapy). Results: Consistently across both studies, filgotinib treatment decreased multiple immune response biomarkers that have key roles in RA for immune response, and decreased markers that promote matrix degradation, angiogenesis, leukocyte adhesion, and recruitment. Filgotinib did not significantly modulate T and natural killer (NK) lymphoid subsets, but slightly increased B cell numbers after 12 weeks. Multiple correlations were observed for changes in biomarkers with disease activity score 28-CRP. MIP1β showed modest predictivity at baseline for ACR50 response at 12 weeks in the 100 mg filgotinib dose across both studies (AUROC, 0.65 and 0.67, p < 0.05). Conclusions: Filgotinib regulates biomarkers from multiple pathways, indicative of direct and indirect network effects on the immune system and the stromal response. These effects were not associated with reductions of major circulating lymphoid populations. Trial Registration: ClinicalTrials.gov, NCT01888874, NCT01894516. [ABSTRACT FROM AUTHOR]

Graves orbitopathy, also known as thyroid eye disease or thyroid-associated orbitopathy, is visually disabling, cosmetically disfiguring and has a substantial negative impact on a patient's quality of life. There is increasing awareness of the need for early diagnosis and rapid specialist input from endocrinologists and ophthalmologists. Glucocorticoids are the mainstay of treatment; however, recurrence occurs frequently once these are withdrawn. Furthermore, in >60% of cases, normal orbital anatomy is not restored, and skilled rehabilitative surgery is required. Clinical trials have shown that considerable benefit can be derived from the addition of antiproliferative agents (such as mycophenolate or azathioprine) in preventing deterioration after steroid cessation. In addition, targeted biologic therapies have shown promise, including teprotumumab, which reduces proptosis, rituximab (anti-CD20), which reduces inflammation, and tocilizumab, which potentially benefits both of these parameters. Other strategies such as orbital radiotherapy have had their widespread role in combination therapy called into question. The pathophysiology of Graves orbitopathy has also been revised with identification of new potential therapeutic targets. In this Review we provide an up-to-date overview of the field, outline the optimal management of Graves orbitopathy and summarize the research developments in this area to highlight future research questions and direct future clinical trials. [ABSTRACT FROM AUTHOR]

Malaria is an infectious disease with an immense global health burden. Plasmodium vivax is the most geographically widespread species of malaria. Relapsing infections, caused by the activation of liver-stage parasites known as hypnozoites, are a critical feature of the epidemiology of Plasmodium vivax. Hypnozoites remain dormant in the liver for weeks or months after inoculation, but cause relapsing infections upon activation. Here, we introduce a dynamic probability model of the activation-clearance process governing both potential relapses and the size of the hypnozoite reservoir. We begin by modelling activation-clearance dynamics for a single hypnozoite using a continuous-time Markov chain. We then extend our analysis to consider activation-clearance dynamics for a single mosquito bite, which can simultaneously establish multiple hypnozoites, under the assumption of independent hypnozoite behaviour. We derive analytic expressions for the time to first relapse and the time to hypnozoite clearance for mosquito bites establishing variable numbers of hypnozoites, both of which are quantities of epidemiological significance. Our results extend those in the literature, which were limited due to an assumption of collective dormancy. Our within-host model can be embedded readily in multiscale models and epidemiological frameworks, with analytic solutions increasing the tractability of statistical inference and analysis. Our work therefore provides a foundation for further work on immune development and epidemiological-scale analysis, both of which are important for achieving the goal of malaria elimination. [ABSTRACT FROM AUTHOR]