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Abstract High-precision searches for an electric dipole moment of the neutron (nEDM) require stable and uniform magnetic field environments. We present the recent achievements of degaussing and equilibrating the magnetically shielded room (MSR) for the n2EDM experiment at the Paul Scherrer Institute. We present the final degaussing configuration that will be used for n2EDM after numerous studies. The optimized procedure results in a residual magnetic field that has been reduced by a factor of two. The ultra-low field is achieved with the full magnetic-field-coil system, and a large vacuum vessel installed, both in the MSR. In the inner volume of $$\sim 1.4~\hbox {m}^3$$ ∼ 1.4 m 3 , the field is now more uniform and below 300 pT. In addition, the procedure is faster and dissipates less heat into the magnetic environment, which in turn, reduces its thermal relaxation time from $$12~\text {h}$$ 12 h down to $$1.5~\text {h}$$ 1.5 h .

Abstract We present a novel Active Magnetic Shield (AMS), designed and implemented for the n2EDM experiment at the Paul Scherrer Institute. The experiment will perform a high-sensitivity search for the electric dipole moment of the neutron. Magnetic-field stability and control is of key importance for n2EDM. A large, cubic, 5 m side length, magnetically shielded room (MSR) provides a passive, quasi-static shielding-factor of about $$10^5$$ 10 5 for its inner sensitive volume. The AMS consists of a system of eight complex, feedback-controlled compensation coils constructed on an irregular grid spanned on a volume of less than 1000 m $$^3$$ 3 around the MSR. The AMS is designed to provide a stable and uniform magnetic-field environment around the MSR, while being reasonably compact. The system can compensate static and variable magnetic fields up to $$\pm \, 50 \, {\upmu }\hbox {T}$$ ± 50 μ T (homogeneous components) and $$\pm \, 5 \, {\upmu }\hbox {T/m}$$ ± 5 μ T/m (first-order gradients), suppressing them to a few $${\upmu }\hbox {T}$$ μ T in the sub-Hertz frequency range. The presented design concept and implementation of the AMS fulfills the requirements of the n2EDM experiment and can be useful for other applications, where magnetically silent environments are important and spatial constraints inhibit simpler geometrical solutions.

Positrons are key to the production of cold antihydrogen. Here the authors report the sympathetic cooling of positrons by interacting them with laser-cooled Be+ ions resulting in a three-fold reduction of the temperature of positrons for antihydrogen synthesis.

Objective Despite being aware of the positive health-related outcomes of physical activity, many people remain inactive. The aim of this study is to apply a combination of constructs from the health action process approach and self-determination theory, as well as habit and morningness/eveningness, to predict physical activity engagement.Methods A prospective design was used to collect data from 136 participants (16–64 years old), at two-time points, one week apart. The sample consisted of 99 women, 36 men and 1 individual who identified as non-binary. Participants preferred time-of-day was measured using the Morningness-Eveningness Stability Scale (MESSi), while physical activity engagement was measured using the International Physical Activity Questionnaire (short-version). Two hierarchical, multiple regressions were conducted, to predict motivation to engage and to directly predict physical activity engagement. Furthermore, a mediation analysis was conducted to determine the effect of planning on physical activity engagement.Results Results showed that younger individuals and those with greater self-efficacy were more motivated to engage while planning directly predicted physical activity engagement. However, morningness/eveningness did not significantly predict engagement. Additionally, planning was found to mediate the motivation-engagement relationship.Conclusion This study demonstrates how planning influences individuals’ physical activity engagement, as well as the role self-efficacy and age play in their motivation to engage. Even though morningness/eveningness was not an important predictor, behaviour change techniques related to action planning and the use of multi-component approaches to behaviour change, could be used in interventions focused on increasing individuals’ physical activity engagement.

Abstract Background Healthcare workers faced unique challenges during the early months of the COVID-19 pandemic which necessitated rapid adaptation. Clinical event debriefings (CEDs) are one tool that teams can use to reflect after events and identify opportunities for improving their performance and their processes. There are few reports of how teams have used CEDs in the COVID-19 pandemic. Our aim is to explore the issues discussed during COVID-19 CEDs and propose a framework model for qualitatively analyzing CEDs. Methods This was a descriptive, qualitative study of a hospital-wide CED program at a quaternary children’s hospital between March and July 2020. CEDs were in-person, team-led, voluntary, scripted sessions using the Debriefing in Suspected COVID-19 to Encourage Reflection and Team Learning (DISCOVER-TooL). Debriefing content was qualitatively analyzed using constant comparative coding with an integrated deductive and inductive approach. A novel conceptual framework was proposed for understanding how debriefing content can be employed at various levels in a health system for learning and improvement. Results Thirty-one debriefings were performed and analyzed. Debriefings had a median of 7 debriefing participants, lasted a median of 10 min, and were associated with multiple systems-based process improvements. Fourteen themes and 25 subthemes were identified and categorized into a novel Input-Mediator-Output-Input Debriefing (IMOID) model. The most common themes included communication, coordination, situational awareness, team member roles, and clinical standards. Conclusions Teams identified diverse issues in their debriefing discussions related to areas of high performance and opportunities for improvement in their care of COVID-19 patients. This model may help healthcare systems to understand how CED tools can be used to accelerate organizational learning to promote safety and improve outcomes in changing clinical environments.

Abstract This research examines how the human genome and SES jointly and interactively shape verbal ability among youth in the U.S. The youth are aged 12–18 when the study starts. The research draws on findings from the latest GWAS as well as a rich set of longitudinal SES measures at individual, family and neighborhood levels from Add Health (N = 7194). Both SES and genome measures predict verbal ability well separately and jointly. More interestingly, the inclusion of both sets of predictors in the same model corrects for about 20% upward bias in the effect of the education PGS, and implies that about 20–30% of the effects of parental SES are not environmental, but parentally genomic. The three incremental R 2 s that measure the relative contributions of the two PGSs, the genomic component in parental SES, and the environmental component in parental SES are estimated to be about 1.5%, 1.5%, and 7.8%, respectively. The total environmental R 2 and the total genomic R 2 are, thus, 7.8% and 3%, respectively. These findings confirm the importance of SES environment and also pose challenges to traditional social-science research. Not only does an individual’s genome have an important direct influence on verbal ability, parental genomes also influence verbal ability through parental SES. The decades-long blueprint of including SES in a model and interpreting their effects as those of SES needs to be amended accordingly. A straightforward solution is to routinely collect DNA data for large social-science studies granted that the primary purpose is to understand social and environmental influences.

A recent synthesis study found 54% of the high-latitude peatlands have been drying and 32% have been wetting over the past centuries, illustrating their complex ecohydrological dynamics and highly uncertain responses to a warming climate.

Abstract Introduction Health equity for all patients is an important characteristic of an effective healthcare system. Bias has the potential to create inequities. In this study, we examine emergency department (ED) throughput and care measures for sex‐based differences, including metrics such as door‐to‐room (DTR) and door‐to‐healthcare practitioner (DTP) times to look for potential signs of systemic bias. Methods We conducted an observational cohort study of all adult patients presenting to the ED between July 2015 and June 2017. We collected ED operational, throughput, clinical, and demographic data. Differences in the findings for male and female patients were assessed using Poisson regression and generalized estimating equations (GEEs). A priori, a clinically significant time difference was defined as 10 min. Results A total of 106,011 adult visits to the ED were investigated. Female patients had 8‐min longer median length‐of‐stay (LOS) than males (P < 0.01). Females had longer DTR (2‐min median difference, P < 0.01), and longer DTP (5‐min median difference, P < 0.01). Females had longer median door‐to‐over‐the‐counter analgesia time (84 vs. 80, P = 0.58), door‐to‐advanced analgesia (95 vs. 84, P < 0.01), door‐to‐PO (by mouth) ondansetron (70 vs. 62, P = 0.02), and door‐to‐intramuscular/intravenous antiemetic (76 vs. 69, P = 0.02) times compared with males. Conclusion Numerous statistically significant differences were identified in throughput and care measures—mostly these differences favored male patients. Few of these comparisons met our criteria for clinical significance.

Abstract Study objective The objective of this study is to evaluate the prognostic accuracy of existing rules (San Francisco Syncope Rule [SFSR], Canadian Syncope Risk Score [CSRS], and FAINT score) in older adults. Methods This is a cohort study of adults aged ≥60 years presenting to an academic emergency department (ED) with syncope or near syncope. We used original criteria for all rules except for the FAINT score, in which N‐terminal pro–brain natriuretic peptide was largely missing from the extracted data. Patients were deemed positive for each rule if classified as non‐low risk. The primary outcome was the presence of 30‐day serious outcome, as defined by syncope research guidelines. Sensitivity and negative likelihood ratio (NLR) were calculated with 95% confidence intervals (CIs). Results A total of 404 ED visits (mean age of patients, 75.5 years) were included. Of these, 44 (10.9%) had a 30‐day serious outcome, and 24 (5.9%) had incomplete 30‐day follow‐up. SFSR was positive for 280 of 380 visits with complete follow‐up. Its sensitivity and NLR for predicting 30‐day serious outcomes were 86.4% (95% CI, 72.0%–94.3%) and 0.53 (95% CI, 0.25–1.15), respectively. The CSRS was positive for 299 of 380 visits (sensitivity was 88.6% [95% CI, 76.4%–95.7%], and NLR was 0.50 [95% CI, 0.22–1.17]). The modified FAI(N)T score was positive for 318 of 380 visits (sensitivity was 90.9% [95% CI, 77.4%–97.0%], and NLR was 0.53 [95% CI, 0.20–1.38]). Conclusion Existing rules are suboptimal to predict 30‐day serious outcomes in older adults presenting with syncope or near syncope to the ED.

Ultrasound (US) is being increasingly used to diagnose Giant Cell Arteritis (GCA). The traditional diagnostic Gold Standard has been temporal artery biopsy (TAB), but this is expensive, invasive, has a false-negative rate as high as 60% and has little impact on clinical decision-making. A non-compressible halo with a thickened intima-media complex (IMC) is the sonographic hallmark of GCA. The superficial temporal arteries (STA) and axillary arteries (AA) are the most consistently inflamed arteries sonographically and imaging protocols for evaluating suspected GCA should include at least these two arterial territories. Studies evaluating temporal artery ultrasound (TAUS) have varied considerably in size and methodology with results showing wide discrepancies in sensitivity (9–100%), specificity (66–100%), positive predictive value (36–100%) and negative predictive value (33–100%). Bilateral halos increase sensitivity as does the incorporation of pre-test probability, while prior corticosteroid use decreases sensitivity. Quantifying sonographic vasculitis using Halo Counts and Halo Scores can predict disease extent/severity, risk of specific complications and likelihood of treatment response. Regression of the Halo sign has been observed from as little as 2 days to as late as 7 months after initiation of immunosuppressive treatment and occurs at different rates in STAs than AAs. US is more sensitive than TAB and has comparable sensitivity to MRI and PET/CT. It is time-efficient, cost-effective and allows for the implementation of fast-track GCA clinics which substantially mitigate the risk of irreversible blindness. Algorithms incorporating combinations of imaging modalities can achieve a 100% sensitivity and specificity for a diagnosis of GCA. US should be a standard first line investigation in routine clinical care of patients with suspected GCA with TAB reserved only for those having had a normal US in the context of a high pre-test probability.

Clinical ethics support services (CESS) are employed in healthcare to improve patient care and help team members develop skills to recognize and navigate ethically challenging situations (ECS). The objective of this study was to evaluate the impact of ethics rounds, one form of CESS, on veterinary team members. An anonymous, online mixed-methods survey incorporating a 15-item instrument designed to assess the outcomes of moral case deliberation originally developed for human healthcare workers (the Euro-MCD 2.0), was developed. The survey was administered to veterinary team members prior to and following participation in a 90-min virtual ethics rounds session. A total of 23 sessions of virtual ethics rounds were held. In total, 213 individuals participated, and 89 completed both surveys (response rate 41.8%). Most respondents were female (n = 70, 81%). Most were veterinarians (n = 51, 59%), followed by other veterinary team members (practice manager, animal attendant) (n = 18, 21%), veterinary nurses or animal health technicians (n = 10, 12%) and veterinary students (n = 8, 9%). Age ranged from 20 to 73 (median 41, IQR 32–52, n = 87). While there was no statistically significant difference between overall modified Euro-MCD 2.0 scores between T1 and T2, there were statistically significant changes in 7 out of 15 Euro-MCD 2.0 items in the domains of moral competence and moral teamwork. Reflexive thematic analysis of free-text responses identified themes including the types, impact and barriers to resolving ECS, the impacts of ethics rounds on veterinary team members and constraints preventing veterinary team members from speaking up in the face of ECS. While participants largely described the impact of ethics rounds as beneficial (for example, by facilitating clarification of thinking about ECS, allowing participants to see ECS from the perspective of others and providing a safe space for discussion), reflecting on ECS could be stressful for participants. Active participation in ethics rounds may be inhibited in the context of power imbalance, or in settings where bullying occurs. Overall, carefully facilitated ethics rounds has the potential to improve the ability of veterinary team members to identify and navigate ECS, and potentially mitigate moral distress.

Abstract Repeated exposure to mild TBI (mTBI) has been linked to an increased risk of Alzheimer’s disease (AD), chronic traumatic encephalopathy (CTE) and other neurodegenerative diseases. Some pathological features typically observed in AD have been found in postmortem brains of TBI and CTE, hence treatments tested for AD have a potential to be effective against r-mTBI outcomes. Neuroinflammation may present a possible answer due to its central role both in acute brain injury and in chronic degenerative-like disorders. Our previous studies have shown that drug nilvadipine, acting as an inhibitor of spleen tyrosine kinase (SYK), is effective at reducing inflammation, tau hyperphosphorylation and amyloid production in AD mouse models. To demonstrate the effect of nilvadipine in the absence of age-related variables, we introduced the same treatment to young r-mTBI mice. We further investigate therapeutic mechanisms of nilvadipine using its racemic properties. Both enantiomers, (+)-nilvadipine and (−)-nilvadipine, can lower SYK activity, whereas (+)-nilvadipine is also a potent L-type calcium channel blocker (CCB) and shown to be anti-hypertensive. All r-mTBI mice exhibited increased neuroinflammation and impaired cognitive performance and motor functions. Treatment with racemic nilvadipine mitigated the TBI-induced inflammatory response and significantly improved spatial memory, whereas (−)-enantiomer decreased microgliosis and improved spatial memory but failed to reduce the astroglial response to as much as the racemate. These results suggest the therapeutic potential of SYK inhibition that is enhanced when combined with the CCB effect, which indicate a therapeutic advantage of multi-action drugs for r-mTBI.

Abstract Background Patients with end-stage kidney disease, receiving haemodialysis rely increasingly on informal carers to help manage their debilitating chronic disease. Informal carers may experience a negative impact on their quality of life exacting a toll on their physical, social and emotional well-being. Informal carers of patients with end-stage kidney disease receiving haemodialysis have significant unmet needs which may include physical and psychological issues, financial disadvantage and social isolation. Poor experiences of informal carers may also impact the experience of the patients for whom they care. The needs of this group of informal caregivers have been largely neglected, with little emphasis placed on supportive interventions that might assist and support them in their caring role. The aim of this study is therefore to explore the experiences and unmet needs of informal carers of people with end-stage kidney disease receiving haemodialysis and develop a psychosocial intervention to support them in their caring role. Methods This qualitative study will include a systematic review, semi-structured interviews with 30 informal carers and focus groups with renal health care professionals. Perceptions of care provision, caregiving experiences as well as contextual factors impacting the design and delivery of a psychosocial intervention for informal carers of patients with end-stage kidney disease, will be explored and will inform the development of a supportive intervention. Discussion The needs of informal carers of patients with end-stage kidney disease have been neglected with little emphasis placed on supportive interventions that might assist and support this group in their care giving role. This is in contrast to other chronic disease groups such as stroke, cancer and dementia. In these conditions well developed supportive interventions have significantly improved outcomes in regard to informal caregivers’ preparedness, competence, positive emotions and psychological well-being in terms of informal care provision. Support interventions could potentially improve the quality of life of those informal carers who provide care to patients with end-stage kidney disease receiving haemodialysis.

Background: Wearable sensors allow researchers to remotely capture digital health data, including physical activity, which may identify digital biomarkers to differentiate healthy and clinical cohorts. To date, research has focused on high-level data (e.g., overall step counts) which may limit our insights to whether people move differently, rather than how they move differently. Objective: This study therefore aimed to use actigraphy data to thoroughly examine activity patterns during the first hours following waking in arthritis patients (n = 45) and healthy controls (n = 30). Methods: Participants wore an Actigraph GT9X Link for 28 days. Activity counts were analysed and compared over varying epochs, ranging from 15 min to 4 h, starting with waking in the morning. The sum, and a measure of rate of change of cumulative activity in the period immediately after waking (area under the curve [AUC]) for each time period, was calculated for each participant, each day, and individual and group means were calculated. Two-tailed independent t tests determined differences between the groups. Results: No differences were seen for summed activity counts across any time period studied. However, differences were noted in the AUC analysis for the discrete measures of relative activity. Specifically, within the first 15, 30, 45, and 60 min following waking, the AUC for activity counts was significantly higher in arthritis patients compared to controls, particularly at the 30 min period (t = –4.24, p = 0.0002). Thus, while both cohorts moved the same amount, the way in which they moved was different. Conclusion: This study is the first to show that a detailed analysis of actigraphy variables could identify activity pattern changes associated with arthritis, where the high-level daily summaries did not. Results suggest discrete variables derived from raw data may be useful to help identify clinical cohorts and should be explored further to determine if they may be effective clinical biomarkers.

Abstract Background The ventricular system plays a vital role in blood-cerebrospinal fluid (CSF) exchange and interstitial fluid-CSF drainage pathways. CSF is formed in the specialized secretory tissue called the choroid plexus, which consists of epithelial cells, fenestrated capillaries and the highly vascularized stroma. Very little is currently known about the role played by the ventricles and the choroid plexus tissue in aging and Alzheimer’s disease (AD). Methods In this study, we used our state-of-the-art proteomic platform, a liquid chromatography/mass spectrometry (LC-MS/MS) approach coupled with Tandem Mass Tag isobaric labeling to conduct a detailed unbiased proteomic analyses of autopsied tissue isolated from the walls of the inferior horn of the lateral ventricles in AD (77.2 ± 0.6 yrs), age-matched controls (77.0 ± 0.5 yrs), and nonagenarian cases (93.2 ± 1.1 yrs). Results Ingenuity pathway analyses identified phagosome maturation, impaired tight-junction signaling, and glucose/mannose metabolism as top significantly regulated pathways in controls vs nonagenarians. In matched-control vs AD cases we identified alterations in mitochondrial bioenergetics, oxidative stress, remodeling of epithelia adherens junction, macrophage recruitment and phagocytosis, and cytoskeletal dynamics. Nonagenarian vs AD cases demonstrated augmentation of oxidative stress, changes in gluconeogenesis-glycolysis pathways, and cellular effects of choroidal smooth muscle cell vasodilation. Amyloid plaque score uniquely correlated with remodeling of epithelial adherens junctions, Fc γ-receptor mediated phagocytosis, and alterations in RhoA signaling. Braak staging was uniquely correlated with altered iron homeostasis, superoxide radical degradation and phagosome maturation. Conclusions These changes provide novel insights to explain the compromise to the physiological properties and function of the ventricles/choroid plexus system in nonagenarian aging and AD pathogenesis. The pathways identified could provide new targets for therapeutic strategies to mitigate the divergent path towards AD.

Background/objectiveDespite multiple attempts, no surrogate biomarker of Parkinson disease (PD) has been definitively identified. Alternatively, identifying a non-invasive biomarker is crucial to understanding the natural history, severity, and progression of PD and to guide future therapeutic trials. Recent work highlighted alpha synuclein-containing extracellular vesicles and Poly (ADP-ribose) polymerase (PARP-1) activity as drivers of PD pathogenesis and putative PD biomarkers. This exploratory study evaluated the role of alpha-synuclein-positive extracellular vesicles and PARP-1 activity in the plasma of PD patients as non-invasive markers of the disease's severity and progression.MethodsWe collected plasma of 57 PD patients (discovery cohort 20, replication cohort 37) and compared it with 20 unaffected individuals, 20 individuals with clinically diagnosed Alzheimer's disease, and 20 individuals with dementia with Lewy bodies. We analyzed alpha-synuclein-positive extracellular vesicles from platelet-free plasma by nanoscale flow cytometry and blood concentrations of poly ADP-ribose using sandwich ELISA kits.ResultsMedian concentration of α-synuclein extracellular vesicles was significantly higher in PD patients compared to the other groups (Kruskal-Wallis, p < .0001). In the discovery cohort, patients with higher α-synuclein extracellular vesicles had a higher Unified Parkinson Disease Rating Scale score (UPDRS III median = 22 vs. 5, p = 0.045). Seven out of 20 patients (35%) showed detectable PAR levels, with positive patients showing significantly higher levels of α-synuclein extracellular vesicles. In the replication cohort, we did not observe a significant difference in the PAR-positive cases in relationship with UPDRS III.ConclusionsNon-invasive determination of α-synuclein-positive extracellular vesicles may provide a potential non-invasive marker of PD disease severity, and longitudinal studies are needed to evaluate the role of α-synuclein-positive extracellular vesicles as a marker of disease progression.

In recent years, there has been debate about the optimal conceptualisation of psychopathology. Structural models of psychopathology have been developed to counter issues, including comorbidity and poor diagnostic stability prevalent within the traditional nosological approach. Regardless of the conceptualisation of psychological dysfunction, deficits in neurocognitive abilities have been claimed to be an aetiological feature of psychopathology. Explorations of the association between neurocognition and psychopathology have typically taken a linear approach, overlooking the potential interactive dynamics of neurocognitive abilities. Previously, we proposed a multidimensional hypothesis, where within-person interactions between neurocognitive domains are fundamental to understanding the role of neurocognition within psychopathology. In this study, we used previously collected psychopathology data for 400 participants on psychopathological symptoms, substance use, and performance on eight neurocognitive tasks and compared the predictive accuracy of linear models to artificial neural network models. The artificial neural network models were significantly more accurate than the traditional linear models at predicting actual (a) lower-level and (b) high-level dimensional psychopathology. These results provide support for the multidimensional hypothesis: that the study of non-linear interactions and compensatory neurocognitive profiles are integral to understanding the functional associations between neurocognition and of psychopathology.

Abstract Background Triple Negative breast cancer (TNBC) is a poor outcome subgroup of breast cancer defined based on the absence of expression of ERα and PR and HER2 amplification. These hard to treat cancers lack targeted treatment options and are therefore treated with a standard of care (SoC) generic cocktail of DNA damaging chemotherapy, with a wide range of clinical responses. While a subset of TNBC patients respond very well to this treatment, others receive no clinical benefit and die from their disease within a short time period. We currently lack biomarkers to prospectively identify patients likely to relapse and we lack alternate treatment options. Methods NUP98 protein expression was investigated in patient samples using two independent tissue microarrays (TMAs), as well as a normal breast TMA. Correlation with pathological response to various chemotherapy regimens was investigated. Results We have shown that high NUP98 is significantly associated with poor outcome in TNBC patient samples both by gene expression and IHC-based protein analysis. While trends linking NUP98 expression with poorer outcomes were observed in breast cancer overall (and more specifically in the LuminalB Her2- subgroup), significant correlations were observed in TNBC. This appeared to be specific to anthracycline based regimens as the association between NUP98 and response was not observed in patients treated with taxane-based chemotherapy. Conclusions We have identified a novel biomarker, NUP98, that can predict response to anthracycline based chemotherapy in TNBC. The ability to prospectively identify patients who are less likely to respond to SoC chemotherapy is a vital step in improving the overall survival of these patients.

Natural hepatitis C virus (HCV) infection is restricted to humans, whereas other primates such as rhesus macaques are non-permissive for infection. To identify human and rhesus macaque genes that differ or share the ability to inhibit HCV replication, we conducted a medium-throughput screen of lentivirus-expressed host genes that disrupt replication of HCV subgenomic replicon RNA expressing secreted Gaussia luciferase. A combined total of >800 interferon-stimulated genes (ISGs) were screened. Our findings confirmed established anti-HCV ISGs, such as IRF1, PKR and DDX60. Novel species–specific inhibitors were also identified and independently validated. Using a cell-based system that recapitulates productive HCV infection, we identified that over-expression of the ‘Rho Guanine Nucleotide Exchange Factor 3’ gene (ARHGEF3) from both species inhibits full-length virus replication. Additionally, replication of two mosquito-borne flaviviruses, yellow fever virus (YFV) and Zika virus (ZIKV), were also reduced in cell lines over-expressing ARHGEF3 compared to controls. In conclusion, we ascribe novel antiviral activity to the cellular gene ARHGEF3 that inhibits replication of HCV and other important human viral pathogens belonging to the Flaviviridae, and which is conserved between humans and rhesus macaques.

Abstract Objective: To investigate consumers’ knowledge about commonly purchased over‐the‐counter (OTC) products containing ibuprofen. Methods: Customers buying two popular OTC ibuprofen‐containing products (Nurofen™ or Nurofen Plus™) were asked to complete a short survey assessing their knowledge about the products. Results: The survey was completed by 262 respondents, most of whom were older than 50 years of age; female; well‐educated; with adequate functional health literacy. The majority correctly identified ibuprofen as an active ingredient and knew the correct intervals between doses. However, almost a third couldn't correctly identify the maximum daily dose and were unaware of some contraindications. Furthermore, fewer than half recognised potential side effects. Those who hadn't completed high school were significantly less likely to seek medical advice (when required) and significantly less likely to know when it was safe to take these products. Conclusions: The gaps in consumer knowledge, especially about the maximum daily dose, contraindications and potential side effects may be placing consumers at risk of experiencing ibuprofen‐related adverse events. Implications for public health: Improving consumer knowledge to address these gaps in their understanding about the safe use of popular OTC ibuprofen‐containing products is an important public health concern.

Abstract Improvements in cardiovascular disease (CVD) rates among young adults in the past 2 decades have been offset by increasing racial/ethnic and gender disparities, persistence of unhealthy lifestyle habits, overweight and obesity, and other CVD risk factors. To enhance the promotion of cardiovascular health among young adults 18 to 39 years old, the medical and broader public health community must understand the biological, interpersonal, and behavioral features of this life stage. Therefore, the National Heart, Lung, and Blood Institute, with support from the Office of Behavioral and Social Science Research, convened a 2‐day workshop in Bethesda, Maryland, in September 2017 to identify research challenges and opportunities related to the cardiovascular health of young adults. The current generation of young adults live in an environment undergoing substantial economic, social, and technological transformations, differentiating them from prior research cohorts of young adults. Although the accumulation of clinical and behavioral risk factors for CVD begins early in life, and research suggests early risk is an important determinant of future events, few trials have studied prevention and treatment of CVD in participants

Introduction Fetal Alcohol Spectrum Disorder (FASD) is a neurodevelopmental disorder caused by prenatal alcohol exposure (PAE). FASD research is a rapidly growing field that crosses multiple disciplines. To ensure research is relevant and meaningful for people living with FASD, their families, and the broader public there is a need to engage community members in setting priorities for research. Objectives Our primary objective was to formally identify the views of people living with FASD, their par- ents/caregivers, service providers, and the general community on the research priorities for FASD and alcohol use in pregnancy in Australia. Our secondary objective was to provide an overview of current research in the highest priority areas identified. Methods The approach for this study involved two community surveys and a consensus workshop, followed by a rapid literature review. Survey responses (n = 146) were collected and grouped using qualitative thematic analysis. The themes identified were then ranked in a second survey (n = 45). The 22 highest ranked themes were considered in a workshop with 21 community members, and consensus on the top ten priority areas was sought. The priority areas were grouped into conceptually similar topics and rapid literature reviews were undertaken on each. Results A diverse range of priorities was identified within key areas of prevention, diagnosis, and therapy. On request from participants, separate priority lists were developed by Aboriginal and non-Aboriginal participants. Conclusions There is need for a national network of researchers to take forward the research commenced by the Centre of Research Excellence, FASD Research Australia, in addressing community priorities.

Abstract Background Anecdotally it is well known that eating disorder memoirs are popular with people with anorexia nervosa and recovery stories are readily available online. However, no research to date has empirically explored whether such stories are helpful for current sufferers. The aim of the current pilot study was to explore the efficacy of recovery narratives as a means of improving motivation and self-efficacy and to qualitatively explore patient perspectives of such stories. Method Fifty-seven women with anorexia nervosa and subclinical anorexia nervosa participated in this online study. Participants were randomised to either receive recovery stories or to a wait-list control group. After completing baseline measures, participants read five stories about recovery, and completed post-intervention measures two weeks later. Results The quantitative results indicated that reading stories of recovery had no effect on motivation and self-efficacy over a two-week period. In contrast, the qualitative results showed that the stories generated thoughts about the possibility of recovery and the majority indicated they would recommend them to others. Conclusions This study adds to a growing body of research exploring the integration of voices of lived experience into treatment approaches. Future research should focus on 1) identifying for whom and at which stage of illness recovery stories might be helpful; 2) the mechanism via which they might operate; and 3) the most helpful way of presenting such stories.

Introduction: The diseases have a high prevalence in India, accounting for one fourth of the Tuberculosis (TB) cases in the world. The situation becomes more complicated due to the rising of Human Immunodeficiency virus/AIDS pandemic, the emergence of Multidrug- Resistance (MDR) TB, Pre Extensively Drug Resistance (Pre-XDR) TB, and Extensively Drug Resistance (XDR) TB. Therefore, new anti-TB drugs are urgently needed to treat MDR-TB, Pre XDR-TB, and XDR-TB. Linezolid was the first oxazolidinone compound licensed for clinical use. Aim: To evaluate the sensitivity and resistance of linezolid in Pre XDR-TB and XDR-TB patients at a tertiary care hospital, Jamnagar, Gujarat, India. Materials and Methods: This was a prospective study conducted from May 2017 to January 2018. Total sample received were 590 MDR-TB suspected cases. All samples were proceeded for rapid detection of MDR of Mycobacterium tuberculosis by direct Drug Susceptibility Testing (DST) using Bactec MGIT 960 system. Results: Out of the total 590 samples, 468 were culture positive among this: 14 (3%) were linezolid resistance, 9 were Pre XDRTB with linezolid resistance, 03 were XDR-TB with linezolid resistance and 2 were only linezolid resistance. A total of 454 (97%) were linezolid sensitive, 143 were Pre XDR-TB with linezolid sensitive and 19 were XDR-TB with linezolid sensitive. A total of 14 (3%) were HIV infected of which 2 had Pre XDR-TB and 1 had XDR-TB. All 14 were linezolid sensitive. Conclusion: The present study showed that linezolid was found to be highly sensitive (97%) with low (3%) resistance in MDR-suspected patients. Linezolid is effective in treatment of MDR-TB, Pre XDR-TB and XDR-TB patient, but while receiving linezolid, patients should be closely monitored for signs or symptoms of bone marrow toxicity and peripheral and optic neuropathy.

Introduction: Child abuse is a common condition in the emergency centres of South Africa. It is critical for both prehospital emergency care practitioners and emergency centre-based emergency medicine registrars to be competent in screening, diagnosing, treating, and documenting child abuse. Our goal was to assess the knowledge of child abuse management in a sample of prehospital emergency care practitioners and emergency medicine registrars in Cape Town, South Africa. Methods: A mixed-methods approach of quantitative and qualitative data was used to survey a sample of 120 participants (30 emergency medicine registrars and 90 prehospital emergency care practitioners: 30 Basic Life Support, 30 Intermediate Life Support, and 30 Advanced Life Support). An expert panel created the survey to ensure content validity and survey questions were designed to assess the perceived and actual knowledge of participants. We hypothesised that there would be significantly higher levels of perceived and actual knowledge in emergency medicine registrars compared to emergency care practitioners. An open-ended question on how participants felt dealing with child abuse was qualitatively analysed using thematic analysis. Results: There were significant differences in the levels of perceived knowledge (58% of emergency medicine registrars agreed that they felt adequately trained overall, versus 39% of emergency care practitioners; −19% difference, 95% CI −26% to −12%) and actual knowledge (83% of emergency medicine registrars with correct answers, versus 62% of emergency care practitioners; −21% difference, 95% CI −26% to −16%) among participants. Themes that emerged from qualitative analysis included personal distress, retaliation, frustration, medical system frustration, and personal competence concerns. Discussion: Significant perceived and actual knowledge deficits of child abuse management exist among both emergency care practitioners and emergency medicine registrars in this setting. Future interventions should address the need for guidelines and increased training opportunities to ensure the health and safety of abused children. Keywords: Paediatrics, Child abuse, Assessment, South Africa

Background. Online health information (OHI) is widely available and consulted by many people in Western countries to gain health advice. The main goal of the present study is to provide a detailed account of the experiences among people from various demographic backgrounds living in high-income countries, who have used OHI. Design and methods. Thematic analysis of 165 qualitative semi-structured interviews conducted among OHI users residing in Australia, Israel, the Netherlands, Norway, and Switzerland was performed. Results. The lived experience of people using OHI seem not to differ across countries. The interviews show that searches for OHI are motivated from curiosity, sharing of experiences, or affirmation for actions already taken. Most people find it difficult to appraise the information, leading them to cross-check sources or discuss OHI with others. OHI seems to impact mostly some specific types of health behaviors, such as changes in diet or physical activity, while it only plays a complementary role for more serious health concerns. Participants often check OHI before seeing their GP, but are reluctant to discuss online content with health care personnel due to expected negative reception. Conclusions. This study adds to the body of knowledge on eHealth literacy by demonstrating how OHI affects overall health behavior, strengthens patients’ ability to understand, live with, and prepare themselves for diverse health challenges. The increasing digitalization of health communication and health care calls for further research on digital divides and patient-professional relations. Health care professionals should acknowledge OHI seeking and engage in discussions with patients to enable them to appreciate OHI, and to support shared decision making in health care. The professionals can utilize patient’s desire to learn as a resource for health prevention, promotion or treatment, and empowerment.

Understanding the behaviour of grazing animals at pasture is crucial in order to develop management strategies that will increase the potential productivity of grazing systems and simultaneously decrease the negative impact on the environment. The objective of this review was to summarize and analyse the scientific literature that has addressed the site use preference of grazing cattle using global positioning systems (GPS) collars in the past 21 years (2000–2020) to aid the development of more sustainable grazing livestock systems. The 84 studies identified were undertaken in several regions of the world, in diverse production systems, under different climate conditions and with varied methodologies and animal types. This work presents the information in categories according to the main findings reviewed, covering management, external and animal factors driving animal movement patterns. The results showed that some variables, such as stocking rate, water and shade location, weather conditions and pasture (terrain and vegetation) characteristics, have a significant impact on the behaviour of grazing cattle. Other types of bio-loggers can be deployed in grazing ruminants to gain insights into their metabolism and its relationship with the landscape they utilise. Changing management practices based on these findings could improve the use of grasslands towards more sustainable and productive livestock systems.

It is thought that direct personal experience of extreme weather events could result in greater public engagement and policy response to climate change. Based on this premise, we present a set of future climate scenarios for Ireland communicated in the context of recent, observed extremes. Specifically, we examine the changing likelihood of extreme seasonal conditions in the long-term observational record, and explore how frequently such extremes might occur in a changed Irish climate according to the latest model projections. Over the period (1900–2014) records suggest a greater than 50-fold increase in the likelihood of the warmest recorded summer (1995), whilst the likelihood of the wettest winter (1994/95) and driest summer (1995) has respectively doubled since 1850. The most severe end-of-century climate model projections suggest that summers as cool as 1995 may only occur once every ∼7 years, whilst winters as wet as 1994/95 and summers as dry as 1995 may increase by factors of ∼8 and ∼10 respectively. Contrary to previous research, we find no evidence for increased wintertime storminess as the Irish climate warms, but caution that this conclusion may be an artefact of the metric employed. It is hoped that framing future climate scenarios in the context of extremes from living memory will help communicate the scale of the challenge climate change presents, and in so doing bridge the gap between climate scientists and wider society.

There is increasing evidence that nonalcoholic steatohepatitis (NASH) is a risk factor for hepatocellular carcinoma (HCC) in the absence of cirrhosis, a phenomenon termed noncirrhotic HCC. Early diagnosis of HCC is critical to a favorable prognosis. We tested the hypothesis that hydroxyproline content of liver biopsy samples is diagnostic for HCC in murine models of NASH induced by diet or by diet and chemicals. The training set comprised mice fed a standard diet or a fast-food diet with or without administration of thioacetamide. At harvest, livers from the modified diet cohort exhibited NASH with a subset of NASH livers exhibiting HCC. Hydroxyproline content was measured in liver biopsy samples with tissue in the NASH+HCC cohort sampled from the remote, nontumor parenchyma. Plotting the receiver operating characteristics (ROC) with hydroxyproline as the continuous variable against the absence or presence of HCC yielded an area under ROC of 0.87, a threshold of >0.18 μg hydroxyproline/mg liver and sensitivity of 91% with a specificity of 83.3%. The use of liver hydroxyproline content as a diagnostic for HCC in a test set comprising healthy, NASH and NASH+HCC livers proved 87% accurate.

Forebrain precursor cells are dynamic during early brain development, yet the underlying molecular changes remain elusive. We observed major differences in transcriptional signatures of precursor cells from mouse forebrain at embryonic days E8.5 vs. E10.5 (before vs. after neural tube closure). Genes encoding protein biosynthetic machinery were strongly downregulated at E10.5. This was matched by decreases in ribosome biogenesis and protein synthesis, together with age-related changes in proteomic content of the adjacent fluids. Notably, c-MYC expression and mTOR pathway signaling were also decreased at E10.5, providing potential drivers for the effects on ribosome biogenesis and protein synthesis. Interference with c-MYC at E8.5 prematurely decreased ribosome biogenesis, while persistent c-MYC expression in cortical progenitors increased transcription of protein biosynthetic machinery and enhanced ribosome biogenesis, as well as enhanced progenitor proliferation leading to subsequent macrocephaly. These findings indicate large, coordinated changes in molecular machinery of forebrain precursors during early brain development.

Evidence-based medical practice is best achieved by developing research understanding in medical practitioners. To this end, medical councils worldwide increasingly recognise the importance of medical schools graduating students with well-developed research skills and research capacity. To meet this need, the principles of programmatic assessment were implemented in designing a research and critical analysis curriculum and assessment program that aimed to enhance the research and critical analysis skills of medical students. The program was developed by mapping assessment tasks to a research capabilities framework that was in turn scaffolded to different levels of Miler’s pyramid. The curriculum and assessments were integrated with the science, clinical, and professional aspects of the medical course. The progressive longitudinal development of research skills, with feedback and academic mentoring, culminated in the students’ capacity to undertake an independent research project. Designing an assessment program for learning encouraged students to develop their research capacity by involving them in their learning.

General practice electronic health record (EHR) data have significant potential for clinical research. This study demonstrates the feasibility of utilising longitudinal EHR data analysis to address clinically relevant outcomes and uses the relationship between lipid medication prescription and all-cause mortality in the elderly as an exemplar for the validity of this methodology. EHR data were analysed to describe the association of lipid medication use, non-use or cessation with all-cause mortality in patients aged ≥75 years. Survival analysis with Cox regression was used to calculate hazard ratios, which were adjusted for confounders. There was no significant difference in all-cause mortality among patients according to their use, non-use, or cessation of lipid medications. The outcomes of this study correlate well with the results of other research works. This single-practice study demonstrates the feasibility and potential of analysing EHR data to address important clinical issues such as the relationship between all-cause mortality and lipid medication prescription in the elderly.

In the original publication of this article [1], the first name of the 3rd author is wrong.

The purpose of the study was to explore the perceptions held by British racing industry stakeholders of factors influencing racehorse welfare. Ten focus groups were held across the UK with a total of 42 stakeholders from a range of roles within racehorse care including trainers, stable staff and veterinarians. Participants took part in three exercises. Firstly, to describe the scenarios of a ‘best life’ and the minimum welfare standards a horse in training could be living under. Secondly, to identify the main challenges for racehorse welfare and thirdly, to recall any innovative or uncommon practices to improve welfare they had witnessed. Using thematic analysis, eight themes emerged from the first exercise. Two strands, factors that contribute to maintaining health and the horse-human relationship ran through all eight themes. Across all themes horses living the ‘best life’ were perceived as being treated as individuals rather than being part of a ‘one size fits all’ life when kept under minimum welfare standards. Health was both perceived as the main challenge to welfare as well as one open to innovative practices such as improved veterinary treatments. Data obtained, informed by the knowledge and expertise of experienced stakeholders, combined with practical animal welfare science will be used to develop the first British racehorse welfare assessment protocol.

Gulf War Illness (GWI) is a chronic multisymptom illness with a central nervous system component such as memory deficits, neurological, and musculoskeletal problems. There are ample data that demonstrate that exposure to Gulf War (GW) agents, such as pyridostigmine bromide (PB) and pesticides such as permethrin (PER), were key contributors to the etiology of GWI post deployment to the Persian GW. In the current study, we examined the consequences of acute (10 days) exposure to PB and PER in C57BL6 mice. Learning and memory tests were performed at 18 days and at 5 months post-exposure. We investigated the relationship between the cognitive phenotype and neuropathological changes at short and long-term time points post-exposure. No cognitive deficits were observed at the short-term time point, and only minor neuropathological changes were detected. However, cognitive deficits emerged at the later time point and were associated with increased astrogliosis and reduction of synaptophysin staining in the hippocampi and cerebral cortices of exposed mice, 5 months post exposure. In summary, our findings in this mouse model of GW agent exposure are consistent with some GWI symptom manifestations, including delayed onset of symptoms and CNS disturbances observed in GWI veterans.

Despite growing concerns about the welfare of horses in Great Britain (GB) there has been little surveillance of the welfare status of the horse population. Consequently we have limited knowledge of the range of welfare problems experienced by horses in GB and the situations in which poor welfare occurs. Thirty-one in-depth interviews were conducted with a cross -section of equine stakeholders, in order to explore their perceptions of the welfare problems faced by horses in GB. Welfare problems relating to health, management and riding and training were identified, including horses being under or over weight, stabling 24 hours a day and the inappropriate use of training aids. The interviewees also discussed broader contexts in which they perceived that welfare was compromised. The most commonly discussed context was where horses are kept in unsuitable environments, for example environments with poor grazing. The racing industry and travellers horses were identified as areas of the industry where horse welfare was particularly vulnerable to compromise. Lack of knowledge and financial constraints were perceived to be the root cause of poor welfare by many interviewees. The findings give insight into the range of welfare problems that may be faced by horses in GB, the contexts in which these may occur and their possible causes. Many of the problems identified by the interviewees have undergone limited scientific investigation pointing to areas where further research is likely to be necessary for welfare improvement. The large number of issues identified suggests that some form of prioritisation may be necessary to target research and resources effectively.

Repetitive mild traumatic brain injury (r-mTBI) results in neuropathological and biochemical consequences in the human visual system. Using a recently developed mouse model of r-mTBI, with control mice receiving repetitive anesthesia alone (r-sham) we assessed the effects on the retina and optic nerve using histology, immunohistochemistry, proteomic and lipidomic analyses at 3 weeks post injury. Retina tissue was used to determine retinal ganglion cell (RGC) number, while optic nerve tissue was examined for cellularity, myelin content, protein and lipid changes. Increased cellularity and areas of demyelination were clearly detectable in optic nerves in r-mTBI, but not in r-sham. These changes were accompanied by a ~25% decrease in the total number of Brn3a-positive RGCs. Proteomic analysis of the optic nerves demonstrated various changes consistent with a negative effect of r-mTBI on major cellular processes like depolymerization of microtubules, disassembly of filaments and loss of neurons, manifested by decrease of several proteins, including neurofilaments (NEFH, NEFM, NEFL), tubulin (TUBB2A, TUBA4A), microtubule-associated proteins (MAP1A, MAP1B), collagen (COL6A1, COL6A3) and increased expression of other proteins, including heat shock proteins (HSP90B1, HSPB1), APOE and cathepsin D. Lipidomic analysis showed quantitative changes in a number of phospholipid species, including a significant increase in the total amount of lysophosphatidylcholine (LPC), including the molecular species 16:0, a known demyelinating agent. The overall amount of some ether phospholipids, like ether LPC, ether phosphatidylcholine and ether lysophosphatidylethanolamine were also increased, while the majority of individual molecular species of ester phospholipids, like phosphatidylcholine and phosphatidylethanolamine, were decreased. Results from the biochemical analysis correlate well with changes detected by histological and immunohistochemical methods and indicate the involvement of several important molecular pathways. This will allow future identification of therapeutic targets for improving the visual consequences of r-mTBI.

Objective: To explore healthcare professionals’ views about the benefits and challenges of using information technology (IT) resources for educating patients about their warfarin therapy.Methods: A cross-sectional survey of both community and hospital-based healthcare professionals (e.g., doctors, pharmacists and nurses) involved using a purpose-designed questionnaire. The questionnaires were distributed using a multi-modal approach to maximise response rates.Results: Of the total 300 questionnaires distributed, 109 completed surveys were received (43.3% response rate). Over half (53.2%) of the healthcare participants were aged between 40-59 years, the majority (59.5%) of whom were female. Fifty nine (54.1%) participants reported having had no access to warfarin-specific IT-based patient education resources, and a further 19 (38.0%) of the participants who had IT-access reported that they never used such resources. According to the healthcare participants, the main challenges associated with educating their patients about warfarin therapy included: patient-related factors, such as older age, language barriers, cognitive impairments and/or ethnic backgrounds or healthcare professional factors, such as time constraints. The healthcare professionals reported that there were several aspects about warfarin therapy which they found difficult to educate their patients about which is why they identified computers and interactive touch screen kiosks as preferred IT devices to deliver warfarin education resources in general practices, hospital-based clinics and community pharmacies. At the same time, the healthcare professionals also identified a number of facilitators (e.g., to reinforce warfarin education, to offer reliable and easily comprehensible information) and barriers (e.g., time and costs of using IT resources, difficulty in operating the resources) that could impact on the effective implementation of these devices in educating patients about their warfarin therapy.Conclusion: The findings of the study suggest that there is a need for improving healthcare professionals’ use of, and access to IT-based warfarin education resources for patients. The study findings also suggest addressing the concerns raised by the healthcare professionals when implementing such IT resources successfully to help educate patients about their warfarin therapy.

Stickel's key agreement scheme was successfully cryptanalysed by V. Shpilrain when GL(n, q) is used as a platform. Shpilrain suggested the algebra of all (not necessarily invertible) n × n matrices defined over some finite ring R would make a more secure platform. He also suggested a more general method of generating keys, involving polynomials of matrices over R. When R = 𝔽q, we show that these variants of Stickel's scheme are susceptible to a linear algebra attack. We discuss other natural candidates for R, and conclude that until a suitable ring is proposed, the variant schemes may be considered insecure.

While ‘public health medicine’ is a specialised field, most medical practitioners practice ‘public health’ to some extent, e.g., undertaking preventative screening tests or advising individuals about lifestyle interventions. While requirements to demonstrate capability in public health are common to medical education around the world, medical programs face a challenge to integrate public health education and promote health advocacy in an environment where the doctor: patient relationship is at the core of learning. Students who spend part of their medical education working within general practice or community settings have an opportunity to observe and identify issues of public health importance, and to see how they impact at both a personal and a population level. This paper aims to illustrate how a year-long research project can provide an opportunity for medical students to learn about public health issues and methods to investigate them. Analysis was undertaken of the research topics chosen by eight successive cohorts of medical students, representing 519 students, who successfully completed a research project. Over half of the student research projects (51.8%) directly related to Australian national health priority areas of dementia, obesity, arthritis and musculoskeletal conditions, asthma, diabetes, mental health, injury prevention and control, cardiovascular health and cancer control, and a further 28.5% of projects had a specific public health focus, within domains that include lifestyles and health, communicable disease, and healthy growth and development. Researching public health topics in the community setting represents a practical way to engage medical students in learning about public health, and can help to develop their potential to become ‘clinician researchers’, investigating and understanding issues relevant to their communities.

This paper describes a cryptanalysis of MST3, a public key cryptosystem based on nonabelian groups recently proposed by Lempken, Magliveras, van Trung and Wei.

Schmid metaphyseal chondrodysplasia (MCDS) involves dwarfism and growth plate cartilage hypertrophic zone expansion resulting from dominant mutations in the hypertrophic zone collagen, Col10a1. Mouse models phenocopying MCDS through the expression of an exogenous misfolding protein in the endoplasmic reticulum (ER) in hypertrophic chondrocytes have demonstrated the central importance of ER stress in the pathology of MCDS. The resultant unfolded protein response (UPR) in affected chondrocytes involved activation of canonical ER stress sensors, IRE1, ATF6, and PERK with the downstream effect of disrupted chondrocyte differentiation. Here, we investigated the role of the highly conserved IRE1/XBP1 pathway in the pathology of MCDS. Mice with a MCDS collagen X p.N617K knock-in mutation (ColXN617K) were crossed with mice in which Xbp1 was inactivated specifically in cartilage (Xbp1CartΔEx2), generating the compound mutant, C/X. The severity of dwarfism and hypertrophic zone expansion in C/X did not differ significantly from ColXN617K, revealing surprising redundancy for the IRE1/XBP1 UPR pathway in the pathology of MCDS. Transcriptomic analyses of hypertrophic zone cartilage identified differentially expressed gene cohorts in MCDS that are pathologically relevant (XBP1-independent) or pathologically redundant (XBP1-dependent). XBP1-independent gene expression changes included large-scale transcriptional attenuation of genes encoding secreted proteins and disrupted differentiation from proliferative to hypertrophic chondrocytes. Moreover, these changes were consistent with disruption of C/EBP-β, a master regulator of chondrocyte differentiation, by CHOP, a transcription factor downstream of PERK that inhibits C/EBP proteins, and down-regulation of C/EBP-β transcriptional co-factors, GADD45-β and RUNX2. Thus we propose that the pathology of MCDS is underpinned by XBP1 independent UPR-induced dysregulation of C/EBP-β-mediated chondrocyte differentiation. Our data suggest that modulation of C/EBP-β activity in MCDS chondrocytes may offer therapeutic opportunities.