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Introduction and Hypothesis: Previous work has suggested that refractory detrusor overactivity (DO) was commonly associated with urinary tract infection (UTI), which can lead to inflammatory changes in the bladder. This study aimed to investigate the concentrations of urinary cytokines in a large sample of women with refractory detrusor overactivity (DO) and age matched controls., Methods: The urinary concentration of 27 cytokines in 140 women (95 with refractory DO and 45 age matched controls (women without urge incontinence)) was determined using the Human Cytokine 27-plex Assay. Cytokine concentrations were correlated with a "UTI score", the presence or absence of bacteriuria or pyuria on the day of sample collection and a previous history of UTI., Results: Pro-inflammatory cytokines were increased in refractory DO women compared to the controls. In women with refractory DO, the UTI score significantly correlated with urinary cytokine concentrations in 15 of the 22 cytokines detected. A previous history of UTI did not affect urinary cytokine concentrations in refractory DO women with no current UTI. Increasing pyuria was associated with increasing concentrations of urinary cytokines., Conclusion: Careful comparison of cytokine concentrations in women with refractory DO versus age matched controls has shown that changes in pro-inflammatory cytokines are related to the UTI disease burden, suggesting that an underlying inflammatory response, together with UTI, may be an aetiological contributor to the development of refractory DO., Competing Interests: Declarations Ethical Approval All participants provided written informed consent and the protocol was approved by the Ethics review committee (HREC18/G/219 South East Sydney Local Health District). Conflict of Interest The authors declare no conflict of interest., (© 2024. The International Urogynecological Association.)

Decisions in forensic science are often binary. A firearms expert must decide whether a bullet was fired from a particular gun or not. A face comparison expert must decide whether a photograph matches a suspect or not. A fingerprint examiner must decide whether a crime scene fingerprint belongs to a suspect or not. Researchers who study these decisions have therefore quantified expert performance using measurement models derived largely from signal detection theory. Here we demonstrate that the design and measurement choices researchers make can have a dramatic effect on the conclusions drawn about the performance of forensic examiners. We introduce several performance models - proportion correct, diagnosticity ratio, and parametric and non-parametric signal detection measures - and apply them to forensic decisions. We use data from expert and novice fingerprint comparison decisions along with a resampling method to demonstrate how experimental results can change as a function of the task, case materials, and measurement model chosen. We also graphically show how response bias, prevalence, inconclusive responses, floor and ceiling effects, case sampling, and number of trials might affect one's interpretation of expert performance in forensics. Finally, we discuss several considerations for experimental and diagnostic accuracy studies: (1) include an equal number of same-source and different-source trials; (2) record inconclusive responses separately from forced choices; (3) include a control comparison group; (4) counterbalance or randomly sample trials for each participant; and (5) present as many trials to participants as is practical., (© 2024. The Author(s).)

Objective: To describe the trends in remission rates among RA patients in the OPAL dataset, spanning from 2009 to 2022, and provide insights into the effectiveness of evolving RA management approaches in real-world clinical settings., Methods: Patients with a physician diagnosis of RA and at least 3 visits between 1 January 2009 and December 2022 were identified in the OPAL dataset, an aggregated collection of data extracted from the electronic medical records of patients managed by 117 Australian rheumatologists. Demographics, disease history, prescribed medications and proportions of patients in Disease Activity Score 28-joint count C-reactive protein (DAS28CRP)) categories (remission, low disease activity (LDA), moderate disease activity (MDA) and high disease activity (HDA)) were described., Results: A large population (n = 48,388) of eligible patients with RA were identified in the OPAL dataset. A consistent and substantial improvement in DAS28CRP remission rates were found in (i) all patients, (ii) patients managed on conventional synthetic disease-modifying antirheumatic drugs (csDMARD) and (iii) patients treated with biological or targeted synthetic (b/ts)DMARD therapy, increasing from approximately 50% in 2009 to over 70% by 2022. The increase in DAS28CRP remission was accompanied by reduced proportions of patients in MDA and HDA states., Conclusion: This study highlights a consistent improvement in disease activity and rising remission rates among Australian RA patients within the OPAL dataset, offering the potential for enhanced patient outcomes and reduced disease burden., (© 2024. The Author(s).)

Objectives: To describe treatment patterns and persistence of tofacitinib, interleukin 17 inhibitors (IL-17Ai) and tumour necrosis factor inhibitors (TNFi), in patients with psoriatic arthritis (PsA)., Methods: Data from adult patients with PsA and who had received at least one prescription of tofacitinib, IL-17Ai or TNFi between May 2019 and September 2021 were sourced from the Australian OPAL dataset. Persistence, analysed via Kaplan-Meier methods, and propensity score matching between tofacitinib and bDMARD (IL-17Ai and TNFi) groups were conducted., Results: Of 16,692 patients with PsA, 1486 (n = 406 tofacitinib, n = 416 IL-17Ai and n = 664 TNFi) were included. More females were in the tofacitinib group (75.4%) than in the IL-17Ai (61.1%) and TNFi (64.8%) groups. Overall, 19.2% of tofacitinib patients were first line, compared with 41.8% of IL-17Ai and 62.8% of TNFi patients. In the overall population, the median persistence was 16.5 months (95% CI 13.8 to 19.5 months), 17.7 months (95% CI 15.8 to 19.6 months) and 17.2 months (95% CI 14.9 to 20.5 months) in the tofacitinib, IL-17Ai and TNFi groups, respectively. Persistence was similar in the tofacitinib/IL-17Ai matched population; however, in the tofacitinib/TNFi matched population, persistence was longer in the tofacitinib group (18.7 months, 95% CI 15.6 to 21.4 months) compared with the TNFi group (12.2 months, 95% CI 19.9 to 14.9 months)., Conclusions: In this Australian real-world dataset, tofacitinib was more frequently used in later lines and among a slightly higher proportion of female patients than IL-17Ai or TNFi. Overall, treatment persistence was similar for tofacitinib, IL-17Ai and TNFi, but tofacitinib exhibited longer persistence than TNFi in a matched population. Key Points • This is the first, large real-world study from Australia investigating the demographics, treatment patterns and comparative treatment persistence of patients with psoriatic arthritis (PsA) treated with tofacitinib and biologic disease-modifying drugs (bDMARDs). • The study suggests that tofacitinib is an effective intervention in PsA with at least comparable persistence to bDMARDs: tumour necrosis factor inhibitors (TNFi) and interleukin-17 A inhibitors (IL-17Ai)., (© 2024. The Author(s).)

Witnessing degradation and loss to one's home environment can cause the negative emotional experience of solastalgia. We review the psychometric properties of the 9-item Solastalgia subscale from the Environmental Distress Scale (Higginbotham et al. (EcoHealth 3:245-254, 2006)). Using data collected from three large, independent, adult samples (N = 4229), who were surveyed soon after the 2019/20 Australian bushfires, factor analyses confirmed the scale's unidimensionality, while analyses derived from Item Response Theory highlighted the poor psychometric performance and redundant content of specific items. Consequently, we recommend a short-form scale consisting of five items. This Brief Solastalgia Scale (BSS) yielded excellent model fit and internal consistency in both the initial and cross-validation samples. The BSS and its parent version provide very similar patterns of associations with demographic, health, life satisfaction, climate emotion, and nature connectedness variables. Finally, multi-group confirmatory factor analysis demonstrated comparable construct architecture (i.e. configural, metric, and scalar invariance) across validation samples, gender categories, and age. As individuals and communities increasingly confront and cope with climate change and its consequences, understanding related emotional impacts is crucial. The BSS promises to aid researchers, decision makers, and practitioners to understand and support those affected by negative environmental change., (© 2024. The Author(s).)

This paper presents a new test of object-matching ability: the Novel Object-Matching Test (NOM Test). Object-matching (or visual comparison) is a complex cognitive and perceptual visual comparison task undertaken by forensic scientists - yet no openly available, standardised and psychometrically validated test of object-matching ability exists. This is in contrast to other visual comparison domains like face-matching where many tests are widely available. In this paper, we present the development and psychometric validation of the first openly available object-matching test where people view two complex artificial visual patterns side-by-side and decide if they are from the same source or different sources. We provide normative data and psychometric properties for two long-form and two short-form versions of the test, and two additional versions designed to identify high and low-performers. We also provide evidence of discriminant validity and convergent validity that demonstrates the NOM Test correlates strongly with other object-matching tasks like fingerprint-matching - but not other tasks requiring cognitive-perceptual skill (e.g., visual intelligence). The NOM Test is free for research use with acknowledgment and is available at https://osf.io/pv6ye/ ., (© 2023. The Author(s).)

Objectives: This systematic review aimed to compare the weight change in people with or without binge eating who underwent various weight loss treatments., Methods: We searched for studies in PubMed, American Psychological Association, and Embase from inception to January 2022. The studies selected included assessment of binge eating and body weight before and after weight loss treatment in people of any age. The meta-analyses were conducted using Comprehensive Meta-Analysis (CMA). We used Egger's regression test, the funnel plot, and the Trim and Fill test to assess the risk of publication bias., Results: Thirty-four studies were included in the systematic review, with a total of 10.184 participants. The included studies were divided into three categories according to types of weight loss treatments, namely, (1) bariatric surgery; (2) pharmacotherapy isolated or combined with behavioral interventions; and (3) behavioral and/or nutritional interventions. The meta-analyses showed no significant difference in weight loss between people with or without binge eating engaged in weight loss treatments, with an overall effect size of - 0.117 (95% CI - 0.405 to 0.171; P = 0.426)., Conclusions: Our findings showed no difference in weight loss in people with or without pre-treatment binge eating who received various weight loss treatments. Weight loss treatments should not be withheld on the basis that they will not be effective in people with pre-treatment binge eating, albeit their safety and longer term impacts are unclear., Level of Evidence: Level I, at least one properly designed randomized controlled trials; systematic reviews and meta-analyses; experimental studies., (© 2023. The Author(s).)

Atherosclerotic plaques are fatty growths in artery walls that cause heart attacks and strokes. Plaque formation is driven by macrophages that are recruited to the artery wall. These cells consume and remove blood-derived lipids, such as modified low-density lipoprotein. Ineffective lipid removal, due to macrophage death and other factors, leads to the accumulation of lipid-loaded macrophages and formation of a necrotic lipid core. Experimental observations suggest that macrophage functionality varies with the extent of lipid loading. However, little is known about the influence of macrophage lipid loads on plaque fate. Extending work by Ford et al. (J Theor Biol 479:48-63, 2019) and Chambers et al. (A lipid-structured model of atherosclerosis with macrophage proliferation, 2022), we develop a plaque model where macrophages are structured by their ingested lipid load and behave in a lipid-dependent manner. The model considers several macrophage behaviours, including recruitment to and emigration from the artery wall; proliferation and apotosis; ingestion of plaque lipids; and secondary necrosis of apoptotic cells. We consider apoptosis, emigration and proliferation to be lipid-dependent and we model these effects using experimentally informed functions of the internalised lipid load. Our results demonstrate that lipid-dependent macrophage behaviour can substantially alter plaque fate by changing both the total quantity of lipid in the plaque and the distribution of lipid between the live cells, dead cells and necrotic core. The consequences of macrophage lipid-dependence are often unpredictable because lipid-dependent effects introduce subtle, nonlinear interactions between the modelled cell behaviours. These observations highlight the importance of mathematical modelling in unravelling the complexities of macrophage lipid accumulation during atherosclerotic plaque formation., (© 2023. The Author(s).)

Magnetic resonance electrical properties tomography (MREPT) is an emerging imaging modality to noninvasively measure tissue conductivity and permittivity. Implementation of MREPT in the clinic requires repeatable measurements at a short scan time and an appropriate protocol. The aim of this study was to investigate the repeatability of conductivity measurements using phase-based MREPT and the effects of compressed SENSE (CS), and RF shimming on the precision of conductivity measurements. Conductivity measurements using turbo spin echo (TSE) and three-dimensional balanced fast field echo (bFFE) with CS factors were repeatable. Conductivity measurement using bFFE phase showed smaller mean and variance that those measured by TSE. The conductivity measurements using bFFE showed minimal deviation with CS factors up to 8, with deviation increasing at CS factors > 8. Subcortical structures produced less consistent measurements than cortical parcellations at higher CS factors. RF shimming using full slice coverage 2D dual refocusing echo acquisition mode (DREAM) and full coverage 3D dual TR approaches further improved measurement precision. BFFE is a more optimal sequence than TSE for phase-based MREPT in brain. Depending on the area of the brain being measured, the scan can be safely accelerated with compressed SENSE without sacrifice of precision, offering the potential to employ MREPT in clinical research and applications. RF shimming with better field mapping further improves precision of the conductivity measures., (© 2023. The Author(s).)

The purpose of this study is to assess the impact of nuclear energy and renewable energy on CO 2 emissions in major top 10 nuclear-generating countries based on the Stochastic Impacts by Regression on Population, Affluence, and Technology (STIRPAT) model from 1993 to 2018. For comparison, the impact of renewable energy on emissions is also examined. For robust checking, four models would be used. The cross-sectional dependence (CD) test reveals the existence of CD in the panel data. Stationary tests indicate the selected variables have no unit root in 1st difference, and cointegration tests confirm the time series data in four multivariable models are long-run cointegrating relationship in each model. Fully modified ordinary least squares (FMOLS) and augmented mean group (AMG) are employed to estimate the long-run coefficients of independent variables, which reveals the positive impacts of variables on emissions. One percent increase in population, economic growth, carbon intensity, and nuclear or renewable energy consumption can lead to 0.984 ~ 1.060%, 1.001 ~ 1.012%, 1.000 ~ 1.011%, 0.009 ~ 0.011%, or 0.003 ~ 0.005% increase in emissions, respectively. Dumitrescu-Hurlin (DH) panel Granger causality test reveals that the causalities between the variables are mixed. Finally, some implications are proposed, such as limiting population quantity and improving the population quality, implementing a green economy, and developing safe nuclear and renewable energy., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Aim: To evaluate the accuracy of melphalan test dose pharmacokinetic (PK) predictions of the subsequent high dose (HDM) area under the concentration-versus-time curve (AUC) and to identify sources of prediction error (PE)., Methods: A prospective multicentre PK study was conducted in 40 myeloma patients of median age 60 (range:35-71) years using a 20 mg/m 2 test dose administered 1-3 days prior to HDM (predominantly 180 mg/m 2 ). PK data were collected post the test and high doses to compare predicted versus actual AUCs determined using the trapezoidal rule. Test and high dose infusion concentration, volume and duration and the time from preparation to infusion were compared using the paired Wilcoxin rank sign test. The impact of Melphalan administration parameters on PE was evaluated using the Mann-Whitney test. The predictive capacity of a previously published population PK (PopPK) model was also examined., Results: Predicted HDM AUC was within 15% of the observed values in only 63% of patients when analysed using the trapezoidal rule and 70% of patients using PopPK. Test dose infusion concentration, volume, duration and time from preparation to infusion were significantly lower than for HDM (p < 0.005). Test dose administration within 15 min of reconstitution (n = 5) was associated with significantly lower PE than administration times of 16-60 min (n = 22), p < 0.05. Test and HDM infusion concentrations were lower in patients with large PE (> ± 15%), but the differences were not significant (p = 0.078, 0.228, respectively)., Conclusion: Test dose PK has the potential to predict subsequent HDM exposure to achieve a target AUC once melphalan administration parameters are optimised to account for stability issues in the formulation., (© 2022. Crown.)

Despite decades of atlas production and use within multiple healthcare systems, and consistent reporting of geographical differences in the utilisation of services, significant levels of clinical variation persist. Drawing on over forty years of combined experience using atlases of clinical variation, we reflect on why that might be the case and explore the role of atlases have played in efforts to reduce inappropriate overuse, underuse and misuse of healthcare services. We contend that atlases are useful but, on their own, are not enough to drive change in clinical practice and improvement in patient outcomes. Building on four conceptual models we have published since 2017, we argue that atlases, with their focus on measuring healthcare utilisation by residents in different geographies, generally fail to provide sufficient information and statistical analyses to truly assess the nature of the variation and support action for change. They seldom use structures such as hospitals or teams as the unit of analysis to understand variation; they rarely feature the key elements of healthcare performance which underlie variation; they are mostly silent about how to assess whether the variation measured is warranted or truly unwarranted; nor do they identify evidence-based levers for change. This means that a stark choice confronts producers of atlases - to either continue with the current model and more explicitly rely on other players to undertake work to complete the 'data to action' cycle that is necessary to secure improvement; or to refine their offering - including more sophisticated performance measurement approaches, nuanced guides for interpretation of any differences found, support for the selection and application of levers for change that align with local context, and provision of evidence-based options for implementation., (© 2022. The Author(s).)

Epidemiological studies report high levels of anxiety and depression amongst adolescents. These psychiatric conditions and complex interplays of biological, social and environmental factors are important risk factors for suicidal behaviours and suicide, which show a peak in late adolescence and early adulthood. Although deaths by suicide have fallen globally in recent years, suicide deaths are increasing in some countries, such as the US. Suicide prevention is a challenging global public health problem. Currently, there aren't any validated clinical biomarkers for suicidal diagnosis, and traditional methods exhibit limitations. Artificial intelligence (AI) is budding in many fields, including in the diagnosis of medical conditions. This review paper summarizes recent studies (past 8 years) that employed AI tools for the automated detection of depression and/or anxiety disorder and discusses the limitations and effects of some modalities. The studies assert that AI tools produce promising results and could overcome the limitations of traditional diagnostic methods. Although using AI tools for suicidal ideation exhibits limitations, these are outweighed by the advantages. Thus, this review article also proposes extracting a fusion of features such as facial images, speech signals, and visual and clinical history features from deep models for the automated detection of depression and/or anxiety disorder in individuals, for future work. This may pave the way for the identification of individuals with suicidal thoughts., Competing Interests: Conflict of interestThe authors have declared that no competing interests exist., (© The Author(s), under exclusive licence to Springer Nature B.V. 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

The triumphant success of mRNA vaccines is a testimony to the important role drug delivery technologies have played in protecting billions of people against SARS-CoV-2 (or the Corona Virus Disease 2019; COVID-19). Several lipid nanoparticle (LNP) mRNA vaccines were developed and have been instrumental in preventing the disease by boosting the immune system against the pathogen, SARS-CoV-2. These vaccines have been built on decades of scientific research in drug delivery of mRNA, vaccines, and other biologicals. In this manuscript, several leading and emerging scientists in the field of drug delivery share their perspective on the role of drug delivery technologies in developing safe and efficacious vaccines, in a roundtable discussion. The authors also discussed their viewpoint on the current challenges, and the key research questions that should drive this important area of research., (© 2022. Controlled Release Society.)

Patient reported outcome measures (PROMs) capture impact of disease and treatment on quality of life, and have an emerging role in clinical trial outcome measurement. This study included a systematic review and quality appraisal of PROMs developed or validated for use in adults with uveitis or scleritis. We searched MEDLINE, EMBASE, PsycINFO, CINAHL and grey literature sources, to 5 November 2021. We used established quality criteria to grade each PROM instrument in multiple domains from A (high quality) to C (low quality), and assessed content development, validity, reliability and responsiveness. For instruments developed using classic test theory-based psychometric approaches, we assessed acceptability, item targeting and internal consistency. For instruments developed using Item Response Theory (IRT) (e.g. Rasch analysis), we assessed response categories, dimensionality, measurement precision, item fit statistics, differential item functioning and targeting. We identified and appraised four instruments applicable to certain uveitis types, but none for scleritis. Specifically, the National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ), a 3-part PROM for Birdshot retinochoroiditis (Birdshot Disease & Medication Symptoms Questionnaire [BD&MSQ], the quality of life (QoL) impact of Birdshot Chorioretinopathy [QoL BCR], and the QoL impact of BCR medication [QoL Meds], the Kings Sarcoidosis Questionnaire (KSQ), and a PROM for cytomegalovirus retinitis. These instruments had limited coverage for these heterogeneous conditions, with a focus on very rare subtypes. Psychometric appraisal revealed considerable variability between instruments, limited content development, and only one developed using Item Response Theory. In conclusion, there are few validated PROMs for patients with uveitis and none for scleritis, and existing instruments have suboptimal psychometric performance. We articulate why we do not recommend their inclusion as clinical trial outcome measures for drug licensing purposes, and highlight an unmet need for PROMs applicable to uveitis and scleritis., (© 2022. The Author(s).)

GFAP-IL6 transgenic mice are characterised by astroglial and microglial activation predominantly in the cerebellum, hallmarks of many neuroinflammatory conditions. However, information available regarding the proteome profile associated with IL-6 overexpression in the mouse brain is limited. This study investigated the cerebellum proteome using a top-down proteomics approach using 2-dimensional gel electrophoresis followed by liquid chromatography-coupled tandem mass spectrometry and correlated these data with motor deficits using the elevated beam walking and accelerod tests. In a detailed proteomic analysis, a total of 67 differentially expressed proteoforms including 47 cytosolic and 20 membrane-bound proteoforms were identified. Bioinformatics and literature mining analyses revealed that these proteins were associated with three distinct classes: metabolic and neurodegenerative processes as well as protein aggregation. The GFAP-IL6 mice exhibited impaired motor skills in the elevated beam walking test measured by their average scores of 'number of footslips' and 'time to traverse' values. Correlation of the proteoforms' expression levels with the motor test scores showed a significant positive correlation to peroxiredoxin-6 and negative correlation to alpha-internexin and mitochondrial cristae subunit Mic19. These findings suggest that the observed changes in the proteoform levels caused by IL-6 overexpression might contribute to the motor function deficits., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

This detailed 11-year longitudinal analysis calculated the public health cost of managing refractures in people aged ≥ 50 years in Australia's most populous state. It provides current and projected statewide health system costs associated with managing osteoporosis and provides a foundation to evaluate a novel statewide model of fracture prevention., Purpose: The purpose of this longitudinal analysis was to calculate current and projected refracture rates and associated public hospital utilisation and costs in New South Wales (NSW), Australia. These results will be used to inform scaled implementation and evaluation of a statewide Osteoporotic Refracture Prevention (ORP) model of care., Methods: Linked administrative data (inpatient admissions, outpatient attendances, Emergency Department presentations, deaths, cost) were used to calculate annual refracture rates and refracture-related service utilisation between 2007 and 2018 and healthcare costs between 2008 and 2019. Projections for the next decade were made using 'business-as-usual' modelling., Results: Between 2007 and 2018, 388,743 people aged ≥ 50 years experienced an index fracture and 81,601 had a refracture. Refracture was more common in older people (rising from a cumulative refracture rate at 5 years of 14% in those aged 50-64 years, to 44% in those aged > 90 years), women with a major index fracture (5-year cumulative refracture rate of 26% in females, compared to 19% for males) or minimal trauma index fracture and those with an osteoporosis diagnosis (5-year cumulative refracture rate of 36% and 22%, respectively in those with and without an osteoporosis diagnosis). Refractures increased from 8774 in 2008 to 14,323 in 2018. The annual cost of refracture to NSW Health increased from AU$130 million in 2009 to AU$194 million in 2019. It is projected that, over the next decade, if nothing changes, 292,537 refracture-related hospital admissions and Emergency Department presentations and 570,000 outpatient attendances will occur, at an estimated total cost to NSW Health of AU$2.4 billion., Conclusion: This analysis provides a detailed picture of refractures and associated projected service utilisation and costs over the next decade in Australia's most populous state. Understanding the burden of refracture provides a foundation for evaluation of a novel statewide ORP model of care to prevent refractures in people aged ≥ 50 years., (© 2022. Crown.)

Introduction: Sleep disturbance and fatigue are commonly reported in ankylosing spondylitis (AS) but specific prevalence and the relationship to disease control are unknown., Method: This retrospective non-interventional observational study of data from the OPAL dataset included patients with AS (ICD code M45, M45.0 or M08.1), aged 18 to 95 years and had completed ≥ 1 sleep questionnaire between 1 January 2019 and 30 September 2020. The prevalence of insomnia and obstructive sleep apnoea were assessed using the Insomnia Severity Index (ISI) and Multivariate Apnoea Prediction Index (MAPI), respectively. Propensity score (PS) matching based on sex, age and symptom duration increased comparability between patients administered tumour necrosis factor inhibitors (TNFi) and interleukin 17A inhibitors (IL-17Ai)., Results: Four hundred ninety-five patients were included. The mean ISI total score in the overall population was 8.6 ± 6.2. Self-reported moderate or severe clinical insomnia was present in 16% and 3.2% of patients, respectively. The mean MAPI score was 0.4 ± 0.3, self-reported apnoea was identified in 31.5% of patients and the mean FACIT-Fatigue score was 36.1 ± 10.7. In the PS matched population, the only treatment-related difference was the mean MAPI score (IL-17Ai 0.4 ± 0.3 and TNFi 0.3 ± 0.2, p = 0.046). Those with poor disease control (BASDAI ≥ 4) were more likely (odds ratio [OR] 7.29, 95% CI 2.37 to 22.46, p = 0.001) to have a greater severity of insomnia symptoms than those with good disease control., Conclusion: In this real-world AS cohort, poor disease control was associated with sleep disturbance. Little difference in sleep disturbance was observed between biologic TNFi and IL-17Ai treatment. Key Points • Sleep disturbance and fatigue are common in patients with ankylosing spondylitis. • In our real-world cohort, self-reported apnoea was reported in one-third of patients; and one in five patients reported moderate to severe insomnia. • Those with poor disease control were more likely to experience greater sleep disturbance than those with good disease control., (© 2021. The Author(s).)

In this review, we present our current understanding of peripartum cardiomyopathy (PPCM) based on reports of the incidence, diagnosis and current treatment options. We summarise opinions on whether PPCM is triggered by vascular and/or hormonal causes and examine the influence of comorbidities such as preeclampsia. Two articles published in 2021 strongly support the hypothesis that PPCM may be a familial disease. Using large cohorts of PPCM patients, they summarised the available genomic DNA sequence data that are expressed in human cardiomyocytes. While PPCM is considered a disease predominately affecting the left ventricle, there are data to suggest that some cases also involve right ventricular failure. Finally, we conclude that there is sufficient evidence to warrant an RNAseq investigation and that this would be most informative if performed at the cardiomyocytes level rather than analysing genomic DNA from the peripheral circulation. Given the rarity of PPCM, the combined resources of international human heart tissue biobanks have assembled 30 ventricular tissue samples from PPCM patients, and we are actively seeking to enlarge this patient base by collaborating with human heart tissue banks and research laboratories who would like to join this endeavour., Competing Interests: Competing interestsThe authors declare no competing interests., (© The Author(s) 2022.)

Objective: This study aimed to describe the real-world effectiveness and treatment persistence among patients with rheumatoid arthritis treated with monotherapy and combination therapy tofacitinib and biologic disease-modifying antirheumatic drugs (bDMARDs)., Methods: This was a post hoc analysis of a retrospective, non-interventional study that extracted data for patients treated with tofacitinib or bDMARDs from the Australian OPAL dataset between March 2015 and September 2018. Monotherapy tofacitinib and bDMARDs and combination therapy tofactinib and bDMARDs were propensity score matched and treatment effectiveness and persistence of the groups were evaluated., Results: In the bDMARD and tofacitinib monotherapy and combination therapy matched populations there were 1300 bDMARD initiators (n = 564 monotherapy) and 650 tofacitinib initiators (n = 282 monotherapy). In the bDMARD and tofacitinib monotherapy matched groups, 62.9% and 66.7% were in DAS-28 CRP disease remission after 18 months of treatment, respectively. In the combination therapy bDMARD and tofacitinib groups, 50% and 58.9% were in DAS-28 CRP disease remission after 18 months, respectively. The median treatment persistence was similar between the monotherapy bDMARD and tofacitinib treatment groups (36.7 months (95% CI 27.4 to "not reached') and 34.2 months (95%CI 30.3 to "not reached") respectively) as well as the combination therapy bDMARD and tofacitinib groups (32.2 months (95% CI 25.7 to 34.4) and 32.7 months (95%CI 28.7 to "not reached", respectively)., Conclusions: Patients receiving combination therapy with tofacitinib or bDMARDs had higher disease activity scores at index than patients receiving monotherapy. Monotherapy with tofacitinib or bDMARDs, and combination therapy with tofacitinib or bDMARDs demonstrated similar treatment effectiveness and persistence, respectively. Key Points • This study provides real-world evidence regarding effectiveness, treatment persistence, and treatment patterns, among patients with rheumatoid arthritis (RA) treated with monotherapy or combination therapy tofacitinib. • The study suggests that monotherapy and combination therapy tofacitinib is an effective intervention in RA with persistence and effectiveness comparable to bDMARDs., (© 2021. The Author(s).)

Coronary chronic total occlusions (CTO) are common in patients undergoing coronary angiography, yet the optimal management strategy remains uncertain, with conflicting results from randomized trials. Appropriate patient selection and careful periprocedural planning are imperative for successful patient management. We review the role of adjunctive imaging modalities including myocardial perfusion imaging (MPI), cardiac magnetic resonance imaging (CMR), echocardiography and computed tomography coronary angiography (CTCA) in myocardial ischemic quantification, myocardial viability assessment, as well as procedural planning for CTO revascularization. An appreciation of the value, indications and limitations of these modalities prior to planned intervention are essential for optimal management., (© 2020. American Society of Nuclear Cardiology.)

The evolution of territoriality reflects the balance between the benefit and cost of monopolising a resource. While the benefit of territoriality is generally intuitive (improved access to resources), our understanding of its cost is less clear. This paper combines: 1. a review of hypotheses and meta-analytic benchmarking of costs across diverse taxa; and 2. a new empirical test of hypotheses using a longitudinal study of free-living male territorial lizards. The cost of territoriality was best described as a culmination of multiple factors, but especially costs resulting from the time required to maintain a territory (identified by the meta-analysis) or those exacerbated by a territory that is large in size (identified by the empirical test). The meta-analysis showed that physiological costs such as energetic expenditure or stress were largely negligible in impact on territory holders. Species that used territories to monopolise access to mates appeared to incur the greatest costs, whereas those defending food resources experienced the least. The single largest gap in our current understanding revealed by the literature review is the potential cost associated with increased predation. There is also a clear need for multiple costs to be evaluated concurrently in a single species. The empirical component of this study showcases a powerful analytical framework for evaluating a range of hypotheses using correlational data obtained in the field. More broadly, this paper highlights key factors that should be considered in any investigation that attempts to account for the evolutionary origin or ecological variation in territorial behaviour within and between species., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Is the presence of cytoplasmic strings (CS) in human blastocysts associated with the probability of clinical pregnancy with fetal heart (CPFH) after transfer., Methods: This case-control study involved 300 single blastocyst transfers. 150 of these resulted in a CPFH (cases) while 150 did not (controls). All embryos were cultured in Embryoscope+ and AI software (IVY) was used to select the blastocyst with the highest score from the cohort for transfer. An embryologist, blind to the transfer outcome, recorded the CS number, location, and duration of their activity., Results: There was a significant difference in the number of blastocysts that contained CS, with 97.3% of women's blastocysts resulting in +CPFH containing the CS compared to 88.7% of blastocysts in women who did not have a pregnancy (p = 0.007, OR; 4.67, CI 95% 1.5-14.2). CS appeared 2.4 h earlier in embryo development in the +CPFH group compared to their negative counterparts (p = 0.007). There was a significant difference in the average number of CS/blastocyst with a higher number being present in those that achieved a clinical pregnancy (mean: 6.2, SD 2.9) compared to those that did not (mean: 4.6, SD 3.0) (p ≤ 0.0001). There was a significant increase in the number of vesicles seen traveling along the CS with more seen in the blastocysts resulting in a +CPFH (mean: 4.3 SD 2.1) compared to those in the -CPFH group (mean: 3.1, SD 2.1)., Conclusion: This study has shown that the presence of cytoplasmic strings in human blastocysts is associated with the probability of clinical pregnancy with fetal heart., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

A mechanistic understanding of fire-driven seedling recruitment is essential for effective conservation management of fire-prone vegetation, such as South African fynbos, especially with rare and threatened taxa. The genus Leucadendron (Proteaceae) is an ideal candidate for comparative germination studies, comprising 85 species with a mixture of contrasting life-history traits (killed by fire vs able to resprout; serotinous vs geosporous) and seed morphologies (nutlets vs winged achenes). Individual and combined effects of heat and smoke on seed germination of 40 species were quantified in the laboratory, and Bayesian inference applied to distinguish biologically meaningful treatment effects from non-zero, but biologically trivial, effects. Three germination syndromes were identified based on whether germination was dependent on, enhanced by, or independent of direct fire cues (heat and smoke). Seed storage location was the most reliable predictor of germination syndromes, with soil-stored seeds c. 80% more likely to respond to direct fire cues (primarily smoke) than canopy-stored seeds. Notable exceptions were L. linifolium, with an absolute requirement for smoke to germinate (the third serotinous species so reported), and two other serotinous species with smoke-enhanced germination. Nutlet-bearing species, whether serotinous or geosporous, were c. 70% more likely to respond to fire cues than winged seeds, but there was no evidence for an effect of phylogeny or persistence strategy on germination. This comprehensive account of seed germination characteristics and identification of germination syndromes and their predictors, supports propagation, conservation and restoration initiatives in this iconic fynbos genus and other fire-prone shrubs with canopy or soil-stored seeds.

Recent advances in Markov chain Monte Carlo (MCMC) extend the scope of Bayesian inference to models for which the likelihood function is intractable. Although these developments allow us to estimate model parameters, other basic problems such as estimating the marginal likelihood, a fundamental tool in Bayesian model selection, remain challenging. This is an important scientific limitation because testing psychological hypotheses with hierarchical models has proven difficult with current model selection methods. We propose an efficient method for estimating the marginal likelihood for models where the likelihood is intractable, but can be estimated unbiasedly. It is based on first running a sampling method such as MCMC to obtain samples for the model parameters, and then using these samples to construct the proposal density in an importance sampling (IS) framework with an unbiased estimate of the likelihood. Our method has several attractive properties: it generates an unbiased estimate of the marginal likelihood, it is robust to the quality and target of the sampling method used to form the IS proposals, and it is computationally cheap to estimate the variance of the marginal likelihood estimator. We also obtain the convergence properties of the method and provide guidelines on maximizing computational efficiency. The method is illustrated in two challenging cases involving hierarchical models: identifying the form of individual differences in an applied choice scenario, and evaluating the best parameterization of a cognitive model in a speeded decision making context. Freely available code to implement the methods is provided. Extensions to posterior moment estimation and parallelization are also discussed.

The COVID-19 pandemic and the policy measures to control its spread-lockdowns, physical distancing, and social isolation-have coincided with the deterioration of people's mental well-being. We use data from the UK Household Longitudinal Study (UKHLS) to document how this phenomenon is related to the situation of working parents who now have to manage competing time demands across the two life domains of work and home. We show that the deterioration of mental health is worse for working parents, and that it is strongly related to increased financial insecurity and time spent on childcare and home schooling. This burden is not shared equally between men and women, and between richer and poorer households. These inequalities ought to be taken into account when crafting policy responses., Competing Interests: Conflict of interestThe authors declare that they have no conflict of interest., (© The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature 2021.)

Purpose: Bacillus Calmette-Guerin (BCG) is a live attenuated vaccine with the potential of causing severe iatrogenic complications in patients with primary immunodeficiency diseases (PID) before and after hematopoietic stem cell transplantation (HSCT). We aim to investigate risk factors of post-HSCT BCG-related complications in PID patients., Methods: A retrospective analysis of pediatric PID patients who had received the BCG vaccine and underwent HSCT at Hadassah-Hebrew University Medical Center, between 2007 and 2019., Results: We found 15/36 (41.67%) patients who developed post-HSCT BCG-related complications. The most significant risk factor for developing BCG-related complications was T cell deficiency (47.6% of the non-complicated vs 83.3% of the BCGitis and 100% of the BCGosis groups had T cell lymphopenia, p = 0.013). None of the chronic granulomatous patients developed BCG-related manifestation post-transplant. Among T cell-deficient patients, lower NK (127 vs 698 cells/μl, p = 0.04) cell counts and NK-SCID were risk factors for ongoing post-HSCT BCGosis, as was pretransplant disseminated BCGosis (33.3% of patients with BCGosis vs none of the non-BCGosis patients, p = 0.04). Immune reconstitution inflammatory syndrome (IRIS) was observed in 3/5 patients with Omenn syndrome. Prophylactic antimycobacterial treatment was not proven effective., Conclusion: BCG vaccination can cause significant morbidity and mortality in the post-transplant T cell-deficient patient, especially in the presence of pre-transplant disease. Taking a detailed medical history prior to administering, the BCG vaccine is crucial for prevention of this complication.

Introduction: The aim of this study was to describe the real-world evidence for effectiveness, treatment persistence, and treatment patterns among patients in the community with rheumatoid arthritis treated with the JAK inhibitor tofacitinib., Methods: This was a retrospective, non-interventional cohort study that extracted data for new users of tofacitinib or biologic disease-modifying antirheumatic drugs (bDMARDs) from the Australian Optimizing Patient outcomes in Australian RheumatoLogy (OPAL) dataset between March 2015 and September 2018. Patients were propensity score matched at a 1:2 tofacitinib to bDMARD ratio based on age, sex, and selected baseline treatment combinations. Treatment effectiveness was evaluated using disease status measures. Treatment persistence was calculated and the percentage of patients receiving monotherapy or combination therapy at treatment initiation was evaluated., Results: Data from 2810 patients were extracted and 1950 patients were included in the matched population (1300 bDMARD initiators and 650 tofacitinib initiators). Patients were predominantly aged 55 to 74 years (57.8%) and female (81.2%). After 18 months of treatment, 52.4% and 57.8% of patients had achieved disease activity score (DAS) remission in the bDMARD and tofacitinib groups, respectively. The median treatment persistence for tofacitinib was similar to that for bDMARDs: 34.2 months (95% CI 32.2 to not reached) and 33.8 months (95% CI 28.8 to 40.4), respectively. In the overall population, more patients were prescribed tofacitinib as monotherapy (43.4%) compared with bDMARD monotherapy (33.4%)., Conclusions: Tofacitinib demonstrated treatment effectiveness and persistence similar to bDMARDs. Overall, there was a trend for more use of tofacitinib as monotherapy than bDMARDs. Key Points • This study provides real-world evidence regarding effectiveness, treatment persistence, and treatment patterns, among patients with rheumatoid arthritis (RA) in the community being treated with tofacitinib. • The study suggests that tofacitinib is an effective and enduring intervention in RA with tofacitinib persistence and effectiveness comparable to bDMARDs.

Our knowledge in the field of cardiac muscle and associated cardiomyopathies has been evolving incrementally over the past 60 years and all was possible due to the parallel progress in techniques and methods allowing to take a fresh glimpse at an old problem. Here, we describe an exciting tool used to examine the various states of the human cardiac myosin at the single molecule level. By imaging single Alexa 647 -ATP binding to permeabilised cardiomyocytes using total internal reflection fluorescence (TIRF) microscopy, we are able to acquire large populations of events in a short timeframe (~ 5000 sites in ~ 10 min) and measure each binding event with high spatio-temporal resolution. The applied algorithm decomposes the point pattern of single molecule binding events into individually distinct binding sites that enables us to recover kinetic parameters, such as bound or free time per site. This single molecule binding approach is a useful tool used to examine muscle contractility. Of particular importance is its application to probing the dynamic lifetimes and proportion of myosins in the super-relaxed state in human cardiomyopathies.

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Background: Double Burden of Malnutrition (DBM)-the coexistence of undernutrition along with overnutrition-is a significant public health issue in the Asia-Pacific region. The scope of the DBM in this region is largely unknown. This review aims to determine the prevalence of under- and overnutrition as major DBM components and to investigate whether there has been a shift from under- to overnutrition in the Asia-Pacific region., Methods: Online databases including PubMed and Web of Science were searched for original studies on DBM prevalence in the Asia-Pacific region; particularly, those published from January 2008 to December 2018 were screened for eligibility. We collected data on indicators of under- and overnutrition on the population level and adapted the ratio of prevalence of overweight/obesity versus prevalence of underweight as the main outcome indicator. Pooled prevalence estimates of DBM and the ratio of overnutrition versus undernutrition were generated using R (3.4.0)., Results: In total, 33 studies were included in this review. Pooled analysis demonstrated that DBM was generally presented among countries/areas in the Asia-Pacific region except in high-income countries (HICs). Overall, the prevalence of undernutrition was 8.8% (95% CI 7.3-10.6%) while overnutrition among the same population reached 23.0% (95% CI 20.3-26.0%). Countries in the Oceania region or HICs reported low level of undernutrition (less than 3%). All subgroup analysis (geolocation, income level, sex, age) reported pooled prevalence of overweight/obesity as more than 18%. Overall, the whole region and all subgroups were more likely to experience a higher prevalence of overnutrition than undernutrition, except that low- and lower-middle-income countries (L-MICs) had similar prevalence for over- and undernutrition., Conclusion: DBM in the Asia-Pacific region is alarmingly high and is titled toward overnutrition. As a result, future interventions/policy targeting to maintain a healthy weight for the population should not just focus on prevention and treatment toward one direction., Competing Interests: The authors declare no conflicts of interest., (© 2019 Atlantis Press International B.V.)

Mechanosensitive (MS) ion channels are integral membrane proteins which play a crucial role in fast signaling during mechanosensory transduction processes in living cells. They are ubiquitous and old in the evolutionary sense, given their presence in cells from all three kingdoms of life found on Earth, including bacterial, archaeal, and eukaryotic organisms. As molecular transducers of mechanical force, MS channels are activated by mechanical stimuli exerted on cellular membranes, upon which they rapidly and efficiently convert these stimuli into electrical, osmotic, and/or chemical intracellular signals. Most of what we know about the gating mechanisms of MS channels comes from the work carried out on bacterial channels. However, recent progress resulting from identification and structural information of eukaryotic K2P-type TREK and TRAAK as well as Piezo1 and Piezo2 MS channels has greatly contributed to our understanding of the common biophysical principles underlying the gating mechanism and evolutionary origins of these fascinating membrane proteins. Using Piezo1 channels as an example, we briefly describe in this review what we have learned about their biophysics, physiological functions, and potential roles in "mechanopathologies."

Environmental exposure to phthalates may contribute to an increased risk of asthma in children and adults. We aimed to assess the direction and strength of the association between urinary phthalates metabolites and current asthma in children and adults that participated in the National Health and Nutrition Examination Survey (NHANES) 2007-2012. Data on ten urinary phthalate metabolites, self-reported questionnaires, spirometry measures, and covariates were obtained from 7765 participants (28.1% were children aged 6-17 years) taking part in the NHANES 2007-2012. Asthma was assessed using self-reported questionnaires for children and adults, and via spirometry measures for adults alone. We used crude and adjusted logistic regression models to estimate the odds ratios (ORs) and 95% confidence interval (CI) per one log 10 unit change in the concentration of phthalate metabolites. We further modeled the effect modification by sex. Out of 10 metabolites, only mono-benzyl phthalate (MBzP) was positively associated with the prevalence of self-reported asthma in children, after adjusting for a range of potential confounders (odds ratio 1.54; 95% confidence interval 1.05-2.27). No significant relationship was observed for adults. The association of mono-ethyl phthalate (MEP) was modified by sex, with significantly increased odds of asthma among males [boys (2.00; 1.14-3.51); adult males (1.32; 1.04-1.69)]. While no other phthalates showed a positive relationship with current asthma in males, mono-(carboxynonyl) phthalate (MCNP) and mono-(3-carboxylpropyl) phthalate (MCPP) were inversely associated with spirometrically defined asthma in adult females. A sex-specific relationship in adults was evident when spirometry, but not self-reported measures were used to define asthma. We found no clear association between exposure to phthalates and current asthma, except for a significant relationship between MBzP metabolites and self-reported asthma in children. As a result, exposure to phthalates and asthma development and/or exacerbations remains controversial, suggesting a need for a well-designed longitudinal study.

Aims: To (i) describe tacrolimus (TAC) pre-dose concentrations (C 0 ), (ii) calculate apparent oral TAC clearance (CL/F HCT ) adjusted for measured haematocrit (HCTi) and standardised to a HCT of 45%, across three observation time points and (iii) explore if low TAC C 0 or high mean CL/F HCT are associated with an increased risk of rejection episodes early after lung transplantation., Methods: TAC whole blood concentration-time profiles and transbronchial biopsies were performed prospectively at weeks 3, 6 and 12 after lung transplantation. The TAC pre-dose concentration (C 0 ) was measured, and CL/F HCT was determined using non-compartmental analysis. The associations between TAC C 0 and CL/F HCT and rejection status were explored using repeated measures logistic regression., Results: Eighteen patients provided 377 TAC whole blood concentrations. Considerable variability around the median (IQR) CL/F HCT 6.8 (4.2-15.9) L h -1 , and the median C 0 12.7 (9.9-16.6) μg L -1 was noted. Despite adjustment for haematocrit, a significant decrease was observed in CL/F HCT in all patients over time: CL/F HCT 14 (5.4-23) at week 3, CL/F HCT 7.7 (4.5-12) at week 6 and CL/F HCT 3.9 (2.4-11) L h -1 at week 12 (p < 0.01). Seven (38.9%) patients experienced a single grade 2 rejection, whilst 11 (61.1%) patients experienced no rejection. Higher TAC C 0 were associated with a reduced risk of rejection OR 0.68 (95% CI 0.51-0.91, p = 0.02), and greater mean CL/F HCT was associated with an increased risk of rejection OR 1.34 (95% CI 1.01-1.81 p = 0.04)., Conclusion: Monitoring TAC C 0 , HCT and CL/F HCT in patients after lung transplantation may assist clinicians in detecting patients at risk of acute rejection and may guide future research into TAC and HCT monitoring after lung transplantation.

The human microbiome is intimately associated with human health, with a role in obesity, metabolic diseases such as type 2 diabetes, and divergent diseases such as cardiovascular and neurodegenerative diseases. The microbiome can be changed by diet, probiotics, and faecal transplants, which has flow-on effects to health outcomes. Photobiomodulation has a therapeutic effect on inflammation and neurological disorders (amongst others) and has been reported to influence metabolic disorders and obesity. The aim of this study was to examine the possibility that PBM could influence the microbiome of mice. Mice had their abdomen irradiated with red (660 nm) or infrared (808 nm) low-level laser, either as single or multiple doses, over a 2-week period. Genomic DNA extracted from faecal pellets was pyrosequenced for the 16S rRNA gene. There was a significant (p < 0.05) difference in microbial diversity between PBM- and sham-treated mice. One genus of bacterium (Allobaculum) significantly increased (p < 0.001) after infrared (but not red light) PBM by day 14. Despite being a preliminary trial with small experimental numbers, we have demonstrated for the first time that PBM can alter microbiome diversity in healthy mice and increase numbers of Allobaculum, a bacterium associated with a healthy microbiome. This change is most probably a result of PBMt affecting the host, which in turn influenced the microbiome. If this is confirmed in humans, the possibility exists for PBMt to be used as an adjunct therapy in treatment of obesity and other lifestyle-related disorders, as well as cardiovascular and neurodegenerative diseases. The clinical implications of altering the microbiome using PBM warrants further investigation.

Machine learning (ML) is a form of artificial intelligence which is placed to transform the twenty-first century. Rapid, recent progress in its underlying architecture and algorithms and growth in the size of datasets have led to increasing computer competence across a range of fields. These include driving a vehicle, language translation, chatbots and beyond human performance at complex board games such as Go. Here, we review the fundamentals and algorithms behind machine learning and highlight specific approaches to learning and optimisation. We then summarise the applications of ML to medicine. In particular, we showcase recent diagnostic performances, and caveats, in the fields of dermatology, radiology, pathology and general microscopy.

Social learning is thought to be advantageous as it allows an animal to gather information quickly without engaging in costly trial-and-error learning. However, animals should be selective about when and whom they learn from. Familiarity is predicted to positively influence an animal's reliance on social learning; yet, few studies have empirically tested this theory. We used a lizard (Liopholis whitii) that forms long-term monogamous pair bonds to examine the effects of partner familiarity on social learning in two novel foraging tasks, an association and a reversal task. We allowed female lizards to observe trained conspecifics that were either familiar (social mate) or unfamiliar execute these tasks and compared these two groups with control females that did not receive social information. Lizards preferentially relied on trial-and-error learning in the association task. In the reversal task, lizards that were demonstrated by familiar partners learnt in fewer trials compared to control lizards and made more correct choices. Our results provide some evidence for context-dependent learning with lizards differentiating between when they utilize social learning, and, to a limited degree, whom they learnt from. Understanding the role of the social context in which learning occurs provides important insights into the benefits of social learning and sociality more generally.

The aim was to describe the real-world treatment persistence of subcutaneous TNF inhibitors (TNFi) for patients with inflammatory rheumatic disease newly initiating treatment with biologic disease-modifying antirheumatic drugs (bDMARD). This was a retrospective cohort study that extracted data for new users of TNFi between 1 August 2010 and 31 August 2016 from the Australian Optimising Patient outcome in Australian RheumatoLogy (OPAL) registry. Patients were 1:1 propensity-score matched with golimumab based on their age, sex, year of index, C-reactive protein level, baseline treatment combination and disease. Treatment persistence was calculated. Data from 3749 patients were extracted (adalimumab n = 1518; certolizumab n = 298; etanercept n = 1068; golimumab n = 865). The mean (SD) ages of patients were 51.7 (14.2) years for adalimumab, 53.7 (14.0) years for certolizumab, 52.8 (14.3) years for etanercept and 52.3 (14.6) years for golimumab, with disease durations 7.7 (10.5), 8.8 (9.2), 8.1 (10.4) and 7.3 (9.7) years, respectively. Two thirds of the patients were women. There was no significant difference in treatment persistence by treatment in the overall population (adalimumab 33.6 [95% CI 28.6-40.7], certolizumab 24.8 [95% CI 21.3-42.1], etanercept 27.6 [95% CI 23.4-36.5], golimumab 30.3 [95% CI 23.26-36.5]; months, p = 0.545), or in the propensity score-matched population. No safety signals were detected. In this real-world biologic-naïve Australian inflammatory rheumatic disease cohort treated with subcutaneous TNF inhibitors during the period 2010-2016, there was no difference in treatment persistence between agents.

This clinical trial assessed the efficacy and toxicity of panitumumab combined with oxaliplatin and capecitabine as first-line treatment in KRAS exon 2 wild-type metastatic colorectal cancer (mCRC) patients. Patients with exon 2 KRAS wild-type mCRC received panitumumab 9 mg/Kg, oxaliplatin 130 mg/m 2 , and capecitabine 2000 mg/m 2 repeated every 3 weeks. The primary endpoint was objective response rate (ORR, minimum 42 responses). We retrospectively assessed mutations in genes implicated in CRC with massively parallel sequencing; ERBB2 and EGFR amplification with fluorescence in situ hybridization, and tumor-infiltrating lymphocyte density. Among 78 patients enrolled, 45 (57.7%) completed 6 cycles. Most common grade 3-4 toxicities were skin rash (19.2%), diarrhea (18%), and neuropathy (6.4%). Among 5 (6.4%) potentially treatment-related deaths, 2 (2.6%) were characterized toxic. Objective response occurred in 43 (55.1%) of the patients (complete 6.4% and partial response 48.7%; stable 17.9% and progressive disease 7.7%), while 3.8% were non-evaluable and 15% discontinued their treatment early. Additional mutations in KRAS/NRAS/BRAF were found in 11/62 assessable (18%) tumors. After 51 months median follow-up, median progression-free (PFS) was 8.1 and overall survival 20.2 months, independently of KRAS/NRAS/BRAF or PI3K-pathway mutation status. Patients with TP53 mutations (n = 34; 55%), as well as those with left colon primary tumors (n = 66; 85%), had significantly better PFS, also confirmed in multivariate analysis. Although the clinical trial met its primary endpoint, according to the current standards, the efficacy and tolerability of the drug combination are considered insufficient. Extended genotyping yielded interesting results regarding the significance of TP53 mutations.ClinicalTrials.gov identifier: NCT01215539, Registration date: Sep 29, 2010.

There is mounting evidence that social learning is not just restricted to group-living animals, but also occurs in species with a wide range of social systems. However, we still have a poor understanding of the factors driving individual differences in social information use. We investigated the effects of relative dominance on social information use in the eastern water skink (Eulamprus quoyii), a species with age-dependent social learning. We used staged contests to establish dominant-subordinate relationships in pairs of lizards and tested whether observers use social information to more quickly solve both an association and reversal learning task in situations where the demonstrator was either dominant or subordinate. Surprisingly, we found no evidence of social information use, irrespective of relative dominance between observer and demonstrator. However, dominant lizards learnt at a faster rate than subordinate lizards in the associative learning task, although there were no significant differences in the reversal task. In light of previous work in this species, we suggest that age may be a more important driver of social information use because demonstrators and observers in our study were closely size-matched and were likely to be of similar age.

Early developmental environment can have profound effects on individual physiology, behaviour, and learning. In birds and mammals, social isolation during development is known to negatively affect learning ability; yet in other taxa, like reptiles, the effect of social isolation during development on learning ability is unknown. We investigated how social environment affects learning ability in the family-living tree skink (Egernia striolata). We hypothesized that early social environment shapes cognitive development in skinks and predicted that skinks raised in social isolation would have reduced learning ability compared to skinks raised socially. Offspring were separated at birth into two rearing treatments: (1) raised alone or (2) in a pair. After 1 year, we quantified spatial learning ability of skinks in these rearing treatments (N = 14 solitary, 14 social). We found no effect of rearing treatment on learning ability. The number of skinks to successfully learn the task, the number of trials taken to learn the task, the latency to perform the task, and the number of errors in each trial did not differ between isolated and socially reared skinks. Our results were unexpected, yet the facultative nature of this species' social system may result in a reduced effect of social isolation on behaviour when compared to species with obligate sociality. Overall, our findings do not provide evidence that social environment affects development of spatial learning ability in this family-living lizard.