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Abstract Immune-mediated inflammatory diseases (IMIDs) are typically characterised by relapsing and remitting flares of inflammation. However, the unpredictability of disease flares impedes their study. Addressing this critical knowledge gap, we use the experimental medicine approach of immunomodulatory drug withdrawal in rheumatoid arthritis (RA) remission to synchronise flare processes allowing detailed characterisation. Exploratory mass cytometry analyses reveal three circulating cellular subsets heralding the onset of arthritis flare – CD45RO+PD1hi CD4+ and CD8+ T cells, and CD27+CD86+CD21- B cells – further characterised by single-cell sequencing. Distinct lymphocyte subsets including cytotoxic and exhausted CD4+ memory T cells, memory CD8+CXCR5+ T cells, and IGHA1+ plasma cells are primed for activation in flare patients. Regulatory memory CD4+ T cells (Treg cells) increase at flare onset, but with dysfunctional regulatory marker expression compared to drug-free remission. Significant clonal expansion is observed in T cells, but not B cells, after drug cessation; this is widespread throughout memory CD8+ T cell subsets but limited to the granzyme-expressing cytotoxic subset within CD4+ memory T cells. Based on our observations, we suggest a model of immune dysregulation for understanding RA flare, with potential for further translational research towards novel avenues for its treatment and prevention.

Background: In late March 2020, a “Stay Home, Stay Healthy” order was issued in Washington State in response to the COVID-19 pandemic. On May 1, a 4-phase reopening plan began. We investigated whether adjunctive prevention strategies would allow less restrictive physical distancing to avoid second epidemic waves and secure safe school reopening. Methods: We developed a mathematical model, stratifying the population by age, infection status and treatment status to project SARS-CoV-2 transmission during and after the reopening period. The model was parameterized with demographic and contact data from King County, WA and calibrated to confirmed cases, deaths and epidemic peak timing. Adjunctive prevention interventions were simulated assuming different levels of pre-COVID physical interactions (pC_PI) restored. Results: The best model fit estimated ~35% pC_PI under the lockdown which prevented ~17,000 deaths by May 15. Gradually restoring 75% pC_PI for all age groups between May 15-July 15 would have resulted in ~350 daily deaths by early September 2020. Maintaining

The determination of the mechanical properties of a brazed joint is an important factor to reach the metallurgical level of a joint development. This paper evaluates the mechanical properties, and its correlation with the joint microstructure, of a W-CuCrZr joint brazed in a high vacuum furnace using 80Cu-20Ti flexible filler material in tape form. This joint is meant to be implemented in the divertor application in future fusion power plants. Main experimental parameters were a brazing temperature of 960 °C and a dwell time of 10 min. The microstructure of the joint was constituted by Cu solid solution and Cu4Ti phases. This last phase was distributed in the W-braze interface. Mechanical properties were evaluated by means of Vickers microhardness and mechanical tests by applying pure shear loads. The microhardness profile of the brazed joint indicated that W remained with the as-received hardness but CuCrZr base material was softened after the brazing procedure. Shear strength of 96 ± 15 MPa was obtained for the brazed joint and fracture propagated at the W-braze interface.

Herpes simplex virus-2 (HSV-2) is shed episodically, leading to occasional genital ulcers and efficient transmission. The biology explaining highly variable shedding patterns, in an infected person over time, is poorly understood. We sampled the genital tract for HSV DNA at several time intervals and concurrently at multiple sites, and derived a spatial mathematical model to characterize dynamics of HSV-2 reactivation. The model reproduced heterogeneity in shedding episode duration and viral production, and predicted rapid early viral expansion, rapid late decay, and wide spatial dispersion of HSV replication during episodes. In simulations, HSV-2 spread locally within single ulcers to thousands of epithelial cells in

HIV diversity may be a useful biomarker for discriminating between recent and non-recent HIV infection. The high resolution melting (HRM) diversity assay was developed to quantify HIV diversity in viral populations without sequencing. In this assay, HIV diversity is expressed as a single numeric HRM score that represents the width of a melting peak. HRM scores are highly associated with diversity measures obtained with next generation sequencing. In this report, a software package, the HRM Diversity Assay Analysis Tool (DivMelt), was developed to automate calculation of HRM scores from melting curve data.DivMelt uses computational algorithms to calculate HRM scores by identifying the start (T1) and end (T2) melting temperatures for a DNA sample and subtracting them (T2 - T1 = HRM score). DivMelt contains many user-supplied analysis parameters to allow analyses to be tailored to different contexts. DivMelt analysis options were optimized to discriminate between recent and non-recent HIV infection and to maximize HRM score reproducibility. HRM scores calculated using DivMelt were compared to HRM scores obtained using a manual method that is based on visual inspection of DNA melting curves.HRM scores generated with DivMelt agreed with manually generated HRM scores obtained from the same DNA melting data. Optimal parameters for discriminating between recent and non-recent HIV infection were identified. DivMelt provided greater discrimination between recent and non-recent HIV infection than the manual method.DivMelt provides a rapid, accurate method of determining HRM scores from melting curve data, facilitating use of the HRM diversity assay for large-scale studies.

Abstract Background High stakes examinations used to credential trainees for independent specialist practice should be evaluated periodically to ensure defensible decisions are made. This study aims to quantify the College of Intensive Care Medicine of Australia and New Zealand (CICM) Hot Case reliability coefficient and evaluate contributions to variance from candidates, cases and examiners. Methods This retrospective, de-identified analysis of CICM examination data used descriptive statistics and generalisability theory to evaluate the reliability of the Hot Case examination component. Decision studies were used to project generalisability coefficients for alternate examination designs. Results Examination results from 2019 to 2022 included 592 Hot Cases, totalling 1184 individual examiner scores. The mean examiner Hot Case score was 5.17 (standard deviation 1.65). The correlation between candidates’ two Hot Case scores was low (0.30). The overall reliability coefficient for the Hot Case component consisting of two cases observed by two separate pairs of examiners was 0.42. Sources of variance included candidate proficiency (25%), case difficulty and case specificity (63.4%), examiner stringency (3.5%) and other error (8.2%). To achieve a reliability coefficient of > 0.8 a candidate would need to perform 11 Hot Cases observed by two examiners. Conclusion The reliability coefficient for the Hot Case component of the CICM second part examination is below the generally accepted value for a high stakes examination. Modifications to case selection and introduction of a clear scoring rubric to mitigate the effects of variation in case difficulty may be helpful. Increasing the number of cases and overall assessment time appears to be the best way to increase the overall reliability. Further research is required to assess the combined reliability of the Hot Case and viva components.

Vaccination was a key intervention in controlling the COVID-19 pandemic globally. In early 2021, Norway faced significant regional variations in COVID-19 incidence and prevalence, with large differences in population density, necessitating efficient vaccine allocation to reduce infections and severe outcomes. This study explored alternative vaccination strategies to minimize health outcomes (infections, hospitalizations, ICU admissions, deaths) by varying regions prioritized, extra doses prioritized, and implementation start time. Using two models (individual-based and meta-population), we simulated COVID-19 transmission during the primary vaccination period in Norway, covering the first 7 months of 2021. We investigated alternative strategies to allocate more vaccine doses to regions with a higher force of infection. We also examined the robustness of our results and highlighted potential structural differences between the two models. Our findings suggest that early vaccine prioritization could reduce COVID-19 related health outcomes by 8% to 20% compared to a baseline strategy without geographic prioritization. For minimizing infections, hospitalizations, or ICU admissions, the best strategy was to initially allocate all available vaccine doses to fewer high-risk municipalities, comprising approximately one-fourth of the population. For minimizing deaths, a moderate level of geographic prioritization, with approximately one-third of the population receiving doubled doses, gave the best outcomes by balancing the trade-off between vaccinating younger people in high-risk areas and older people in low-risk areas. The actual strategy implemented in Norway was a two-step moderate level aimed at maintaining the balance and ensuring ethical considerations and public trust. However, it did not offer significant advantages over the baseline strategy without geographic prioritization. Earlier implementation of geographic prioritization could have more effectively addressed the main wave of infections, substantially reducing the national burden of the pandemic.

Abstract Background Childrens’ outdoor active play is an important part of their development. Play behaviour can be predicted by a variety of physical and social environmental features. Some of these features are difficult to measure with traditional data sources. Methods This study investigated the viability of a machine learning method using Google Street View images for measurement of these environmental features. Models to measure natural features, pedestrian traffic, vehicle traffic, bicycle traffic, traffic signals, and sidewalks were developed in one city and tested in another. Results The models performed well for features that are time invariant, but poorly for features that change over time, especially when tested outside of the context where they were initially trained. Conclusion This method provides a potential automated data source for the development of prediction models for a variety of physical and social environment features using publicly accessible street view images.

Carer-workers are individuals providing regular unpaid care to an adult dependent while simultaneously employed in the paid labour market, and the group represents a significant portion of the Canadian adult population. Despite the prevalence of unpaid care in Canada, very limited research has explored the spatio-temporal tensions that carer-workers experience. The objective of this study is to explore the space–time constraints experienced by carer-workers. One way of measuring both space and time constraints on an individual is the foundational time geography concept of the Space-Time Prism, and its two-dimensional counterpart, the Potential Path Area (PPA). We collected three to seven day-long trip diaries of 25 carer-workers in the Greater Toronto and Hamilton Area in 2017–18, including all trips made over the diary period and whether the trip involved care work. We developed a customized Python tool and used Open Street Maps to derive PPAs for 12 of the sample carer-workers, which were aggregated to form daily PPAs. Descriptive analyses of the PPAs are presented, and comparisons of PPA size, and therefore, daily accessibility, across carer-workers’ sociodemographic and economic indicators, days of the week, and level of caregiving intensity are examined. Through its ability to represent, quantitatively and visually, the accessibility differences across various population groups, and to fill a gap in our understanding of carer-workers, the PPA represents an important methodological avenue for continuing research into carer-workers in Canada and around the world.

Abstract Achieving food security is a critical challenge of the Anthropocene that may conflict with environmental and societal goals such as increased energy access. The “fuel versus food” debate coupled with climate mitigation efforts has given rise to next-generation biofuels. Findings of this systematic review indicate just over half of the studies (56% of 224 publications) reported a negative impact of bioenergy production on food security. However, no relationship was found between bioenergy feedstocks that are edible versus inedible and food security (P value = 0.15). A strong relationship was found between bioenergy and type of food security parameter (P value

Abstract Background Geographic masks are techniques used to protect individual privacy in published maps but are highly under-utilized in research. This leads to continual violations of individual privacy, as sensitive health records are put at risk in unmasked maps. New approaches to geographic masking are required that foster accessibility and ease of use, such that they become more widely adopted. This article describes a new geographic masking method, called street masking, that reduces the burden on users of finding supplemental population data by instead automatically retrieving OpenStreetMap data and using the road network as a basis for masking. We compare it to donut geomasking, both with and without population density taken into account, to evaluate its efficacy against geographic masks that require slightly less and slightly more supplemental data. Our analysis is performed on synthetic data in three different Canadian cities. Results Street masking performs similarly to population-based donut geomasking with regard to privacy protection, achieving comparable k-anonymity values at similar median displacement distances. As expected, distance-based donut geomasking performs worst at privacy protection. Street masking also performs very well regarding information loss, achieving far better cluster preservation and landcover agreement than population-based donut geomasking. Distance-based donut geomasking performs similarly to street masking, though at the cost of reduced privacy protection. Conclusion Street masking competes with, if not out-performs population-based donut geomasking and does so without requiring any supplemental data from users. Moreover, unlike most other geographic masks, it significantly minimizes the risk of false attribution and inherently takes many geographic barriers into account. It is easily accessible for Python users and provides the foundation for interfaces to be built for non-coding users, such that privacy can be better protected in sensitive geospatial research.

Abstract Background Oligohydramnios is a condition of abnormally low amniotic fluid volume that has been associated with poor pregnancy outcomes. To date, the prevalence of this condition and its outcomes has not been well described in low and low-middle income countries (LMIC) where ultrasound use to diagnose this condition in pregnancy is limited. As part of a prospective trial of ultrasound at antenatal care in LMICs, we sought to evaluate the incidence of and the adverse maternal, fetal and neonatal outcomes associated with oligohydramnios. Methods We included data in this report from all pregnant women in community settings in Guatemala, Pakistan, Zambia and the Democratic Republic of Congo (DRC) who received a third trimester ultrasound as part of the First Look Study, a randomized trial to assess the value of ultrasound at antenatal care. Using these data, we conducted a planned secondary analysis to compare pregnancy outcomes of women with to those without oligohydramnios. Oligohydramnios was defined as measurement of an Amniotic Fluid Index less than 5 cm in at least one ultrasound in the third trimester. The outcomes assessed included maternal morbidity and fetal and neonatal mortality, preterm birth and low-birthweight. We used pairwise site comparisons with Tukey-Kramer adjustment and multivariable logistic models using general estimating equations to account for the correlation of outcomes within cluster. Results Of 12,940 women enrolled in the clusters in Guatemala, Pakistan, Zambia and the DRC in the First Look Study who had a third trimester ultrasound examination, 87 women were diagnosed with oligohydramnios, equivalent to 0.7% of those studied. Prevalence of detected oligohydramnios varied among study sites; from the lowest of 0.2% in Zambia and the DRC to the highest of 1.5% in Pakistan. Women diagnosed with oligohydramnios had higher rates of hemorrhage, fetal malposition, and cesarean delivery than women without oligohydramnios. We also found unfavorable fetal and neonatal outcomes associated with oligohydramnios including stillbirths (OR 5.16, 95%CI 2.07, 12.85), neonatal deaths

Clinical studies with time to event endpoints typically report the median follow-up (i.e., censoring) time for the subjects in the trial, alongside the median time to event. The reason for this is to provide information about the opportunity for subjects in the study to experience the event of interest (Betensky, 2015 [1]). The median follow-up time is often calculated from the Kaplan–Meier estimate for time to censoring. In most clinical studies, the censoring time is a composite measure, defined as the minimum of time to drop-out from the study and time to administrative end of study. The time to drop-out component may or may not be observed; it is observed only if drop-out occurs before the event and the end of the study. However, the time to end of study is observed for each subject, as it is the time from entry to the study to the calendar date that is administratively set as the end of the study. It is known even for subjects who have the event prior to the end of the study. This decomposition of the censoring time into a time that is itself potentially censored and a time that is fully observed raises the interesting question of whether estimation of the censoring distribution could be improved through a decoupling of these times. We demonstrate in simulations that consideration of censoring in this way yields reduced variability under some circumstances and should be used in practice. We illustrate these concepts through application to a meningioma study.

Abstract Background In many low and low-middle income countries, the incidence of polyhydramnios is unknown, in part because ultrasound technology is not routinely used. Our objective was to report the incidence of polyhydramnios in five low and low-middle income countries, to determine maternal characteristics associated with polyhydramnios, and report pregnancy and neonatal outcomes. Methods We performed a secondary analysis of the First Look Study, a multi-national, cluster-randomized trial of ultrasound during prenatal care. We evaluated all women enrolled from Guatemala, Pakistan, Zambia, Kenya and the Democratic Republic of Congo (DRC) who received an examination by prenatal ultrasound. We used pairwise site comparisons with Tukey-Kramer adjustment and multivariable logistic models with general estimating equations to control for cluster-level effects. The diagnosis of polyhydramnios was confrimed by an U.S. based radiologist in a majority of cases (62%). Results We identified 305/18,640 (1.6%) cases of polyhydramnios. 229 (75%) cases were from the DRC, with an incidence of 10%. A higher percentage of women with polyhydramnios experienced obstructed labor (7% vs 4%) and fetal malposition (4% vs 2%). Neonatal death was more common when polyhydramnios was present (OR 2.43; CI 1.15, 5.13). Conclusions Polyhydramnios occured in these low and low-middle income countries at a rate similar to high-income contries except in the DRC where the incidence was 10%. Polyhydramnios was associated with obstructed labor, fetal malposition, and neonatal death. Trial registration NCT01990625, November 21, 2013.

Background/purpose: The combination of ipsilateral floating shoulder and flail chest is a unique injury pattern that has not been previously described in the literature. We termed the injury pattern floating flail chest (FFC). The purpose of this study was to evaluate the effect of operative treatment of the shoulder girdle component to overall hospital length of stay (LOS). Methods: Forty-one patients were enrolled between two level I trauma centers identifying with a combination ipsilateral floating shoulder and flail chest injury, 23 treated with operative stabilization and 18 treated non-operatively. This retrospective cohort study evaluated the overall LOS and intensive care unit (ICU) days. Results: The operative group had decreased overall LOS (10.1 vs. 19.8 days, p = 0.02) and decreased ICU days (3.4 vs. 10.3, p = 0.04). Conclusion: This study describes a unique injury pattern that combines the floating shoulder and flail chest, FFC. Our study suggests that operative treatment of the shoulder girdle may decrease both overall LOS and ICU days in patients with FFC.

The global spread of the Finnish baby box without empirical evidence to support initiatives raises concern that the concepts of the box are being introduced uncritically in a diverse number of countries, spaces and places without concern for local historical, social, cultural and material understanding. Such appropriation of a significant cultural and social tool for infant health and well-being risks the material object – the box and its contents – being used to develop western, normative parenting practices whilst maintaining power relations between children, parents, expert others and between the Global North and South. To explicate these concerns this article explores potential problems of the box that empirical research is yet to explore including the promotion of westernised parenting practices and child development theory. This gives rise to concerns about colonisation and the need for ethical research practices in a project in Zambia seeking to meet the aims of the UN sustainable development goal 3 – for good health and well-being for all. We draw on sociomaterial understanding in a design project to develop a culturally sensitive and particular concept of the baby box for use in Zambia. One possible local solution is a ‘chitenge’, a multi-purpose garment, rather than a box.

In early 2020, COVID-19 infected people throughout the world and brought world commerce to a standstill. Many believe that governments and global businesses were not as prepared as they should have been. While academics have occasionally predicted the economic problems that could result from pandemics, until 2020, there had been scant research that addresses supply chain management issues during pandemics. Eighty-four percent of all pandemic supply chain research was published in the first ten months of 2020. Since the world now finds itself operating supply chains in response to the pandemic, this literature needs to be summarized and articulated for understanding and future research. This literature review addresses that need by summarizing the research which has been generated since 1997, focusing primarily on the bulk of the research that has been published since the COVID-19 pandemic began. Research tools are used to summarize the literature citations, and the articles are coded according to some important variables to further delineate their details. This research also includes a bibliometric co-citation analysis, which clusters the pandemic supply chain literature by author, journal, and article. The findings are that pre-COVID-19 research on pandemic supply chains was primarily about influenza and the healthcare supply chain, whereas post-COVID-19 research provides more analysis of the food supply chain and uses a wider variety of research methods, including simulation, modeling, and empirical methods.

OBJECTIVES:The aim of the study was to evaluate CMR myocardial first-pass perfusion in the injured region as well as the non-infarcted area in ST-elevation myocardial infarction (STEMI) patients few days after successful primary percutaneous coronary intervention (PCI). MATERIALS AND METHODS:220 patients with first time STEMI successfully treated with PCI (with or without postconditioning) were recruited from the Postconditioning in STEMI study. Contrast enhanced CMR was performed at a 1.5 T scanner 2 (1-5) days after PCI. On myocardial first-pass perfusion imaging signal intensity (SI) was measured in the injured area and in the remote myocardium and maximum contrast enhancement index (MCE) was calculated. MCE = (peak SI after contrast-SI at baseline) / SI at baseline x 100. RESULTS:There were no significant differences in first-pass perfusion between patients treated with standard PCI and patients treated with additional postconditioning. The injured myocardium showed a significantly lower MCE compared to remote myocardium (94 ± 55 vs. 113 ± 49; p < 0.001). When patients were divided into four quartiles of MCE in the injured myocardium (MCE injured myocardium), patients with low MCE injured myocardium had: significantly lower ejection fraction (EF) than patients with high MCE injured myocardium, larger infarct size and area at risk, smaller myocardial salvage and more frequent occurrence of microvascular obstruction on late gadolinium enhancement. MCE in the remote myocardium revealed that patients with larger infarction also had significantly decreased MCE in the non-infarcted, remote area. CONCLUSION:CMR first-pass perfusion can be impaired in both injured and remote myocardium in STEMI patients treated with primary PCI. These findings indicate that CMR first-pass perfusion may be a feasible method to evaluate myocardial injury after STEMI in addition to conventional CMR parameters.

Blockchain technology, popularized by Bitcoin cryptocurrency, is characterized as an open-source, decentralized, distributed database for storing transaction information. Rather than relying on centralized intermediaries (e.g., banks) this technology allows two parties to transact directly using duplicate, linked ledgers called blockchains. This makes transactions considerably more transparent than those provided by centralized systems. As a result, transactions are executed without relying on explicit trust [of a third party], but on the distributed trust based on the consensus of the network (i.e., other blockchain users). Applying this technology to improve supply chain transparency has many possibilities. Every product has a long and storied history. However, much of this history is presently obscured. Often, when negative practices are exposed, they quickly escalate to scandalous, and financially crippling proportions. There are many recent examples, such as the exposure of child labor upstream in the manufacturing process and the unethical use of rainforest resources. Blockchain may bring supply chain transparency to a new level, but presently academic and managerial adoption of blockchain technologies is limited by our understanding. To address this issue, this research uses the Unified Theory of Acceptance and Use of Technology (UTAUT) and the concept of technology innovation adoption as a foundational framework for supply chain traceability. A conceptual model is developed and the research culminates with supply chain implications of blockchain that are inspired by theory and literature review.

Flexible metabolic phenotypes allow animals to adjust physiology to better fit ecological or environmental demands, thereby influencing fitness. Summit metabolic rate (Msum = maximal thermogenic capacity) is one such flexible trait. Skeletal muscle and heart masses and myocyte metabolic intensity are potential drivers of Msum flexibility in birds. We examined correlations of skeletal muscle and heart masses and pectoralis muscle citrate synthase (CS) activity (an indicator of cellular metabolic intensity) with Msum in house sparrows (Passer domesticus) and dark-eyed juncos (Junco hyemalis) to determine whether these traits are associated with Msum variation. Pectoralis mass was positively correlated with Msum for both species, but no significant correlation remained for either species after accounting for body mass (Mb) variation. Combined flight and leg muscle masses were also not significantly correlated with Msum for either species. In contrast, heart mass was significantly positively correlated with Msum for juncos and nearly so (P = 0.054) for sparrows. Mass-specific and total pectoralis CS activities were significantly positively correlated with Msum for sparrows, but not for juncos. Thus, myocyte metabolic intensity influences Msum variation in house sparrows, although the stronger correlation of total (r = 0.495) than mass-specific (r = 0.378) CS activity with Msum suggests that both pectoralis mass and metabolic intensity impact Msum. In contrast, neither skeletal muscle masses nor pectoralis metabolic intensity varied with Msum in juncos. However, heart mass was associated with Msum variation in both species. These data suggest that drivers of metabolic flexibility are not uniform among bird species.