Background: Pain in a common symptom in adult-onset idiopathic dystonia (AOID). An appropriate tool to understand this symptom is needed to improve AOID patients’ care. We developed a rating instrument for pain in AOID and validated it in cervical dystonia (CD). Methods: Development and validation of the Pain in Dystonia Scale (PIDS) in three phases: 1. International experts and participants generated and evaluated the preliminary items for content validity; 2. The PIDS was drafted and revised, followed by cognitive interviews to ensure suitability for self-administration; and 3. the clinimetric properties of the final PIDS were assessed in 85 participants. Results: PIDS evaluates pain severity (by body part), functional impact and external modulating factors. It showed high test-retest reliability the total score (0.9, p<0.001), intraclass correlation coefficients higher than 0.7 for all items and high internal consistency (Cronbach’s alpha 0.9). Convergent validity analysis revealed a strong correlation between the PIDS severity score and the TWSTRS pain subscale (0.8, p<0.001), the brief pain inventory short form (0.7, p<0.001) and impact of pain on daily functioning (0.7, p<0.001). Conclusions: The PIDS is the first specific questionnaire developed to evaluate pain in patients with AOID with high-level clinimetric properties in people with CD.

Precision Medicine is an emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment, and lifestyle. Autoimmune diseases are those in which the body’s natural defense system loses discriminating power between its own cells and foreign cells, causing the body to mistakenly attack healthy tissues. These conditions are very heterogeneous in their presentation and therefore difficult to diagnose and treat. Achieving precision medicine in autoimmune diseases has been challenging due to the complex etiologies of these conditions, involving an interplay between genetic, epigenetic, and environmental factors. However, recent technological and computational advances in molecular profiling have helped identify patient subtypes and molecular pathways which can be used to improve diagnostics and therapeutics. This review discusses the current understanding of the disease mechanisms, heterogeneity, and pathogenic autoantigens in autoimmune diseases gained from genomic and transcriptomic studies and highlights how these findings can be applied to better understand disease heterogeneity in the context of disease diagnostics and therapeutics.

OBJECTIVES/GOALS: Patients who have experienced conjunctive mild traumatic brain injuries (mTBIs) suffer from a number of comorbidities, including chronic pain. Despite extensive studies investigating the underlying mechanisms of mTBI-associated chronic pain, the role of inflammation after mTBI and its contribution to long-term pain are still poorly understood. METHODS/STUDY POPULATION: Given the shifting dynamics of inflammation, it is important to understand the spatial-longitudinal changes and their effects on TBI-related pain. Utilizing a recently developed transgenic caspase-1 luciferase reporter mouse, we characterized the bioluminescence signal evident in both in vivo and ex vivo tissues following repetitive closed head mTBIs. This allowed us to reveal the spatiotemporal dynamics of caspase-1 activation in individual animals over time. Furthermore, we utilize various proteomic and behavioral assays to evaluate the role of caspase-1 mediated inflammation in the development and progression of injury-associated chronic pain. Lastly, by blocking inflammasome caspase-1 activation with a specific inhibitor, we assess its clinical potential as the next therapeutic approach to pain. RESULTS/ANTICIPATED RESULTS: We established that there were significant increases in bioluminescent signals upon protease cleavage in the brain, thorax, abdomen, and paws in vivo, which lasted for at least one week after each injury. Enhanced inflammation was also observed in ex vivo brain slice preparations following injury events that lasted for at least 3 days. Concurrent with the in vivo detection of the bioluminescent signal were persistent decreases in mouse hind paw withdrawal thresholds that lasted for more than two months postinjury. Using MCC950, a potent small molecule inhibitor of NLRP3 inflammasome-caspase 1 activity, we observed reductions in both caspase-1 bioluminescent signals in vivo and caspase-1 p45 expression by immunoblotting and an increase in hind paw withdrawal thresholds. DISCUSSION/SIGNIFICANCE: Overall, these findings suggest that neuroinflammation in the brain following repeated mTBIs is coincidental with a chronic nociplastic pain state, and repeated mTBI-associated events can be ameliorated by a highly specific small molecule inhibitor of NLRP3 inflammasome activation.

The radio signal transmitted by the Mars Express (MEX) spacecraft was observed regularly between the years 2013–2020 at X-band (8.42 GHz) using the European Very Long Baseline Interferometry (EVN) network and University of Tasmania’s telescopes. We present a method to describe the solar wind parameters by quantifying the effects of plasma on our radio signal. In doing so, we identify all the uncompensated effects on the radio signal and see which coronal processes drive them. From a technical standpoint, quantifying the effect of the plasma on the radio signal helps phase referencing for precision spacecraft tracking. The phase fluctuation of the signal was determined for Mars’ orbit for solar elongation angles from 0 to 180 deg. The calculated phase residuals allow determination of the phase power spectrum. The total electron content of the solar plasma along the line of sight is calculated by removing effects from mechanical and ionospheric noises. The spectral index was determined as $-2.43 \pm 0.11$ which is in agreement with Kolmogorov’s turbulence. The theoretical models are consistent with observations at lower solar elongations however at higher solar elongation ( $>$ 160 deg) we see the observed values to be higher. This can be caused when the uplink and downlink signals are positively correlated as a result of passing through identical plasma sheets.

This study examined relationships between foodborne outbreak investigation characteristics, such as the epidemiological methods used, and the success of the investigation, as determined by whether the investigation identified an outbreak agent (i.e. pathogen), food item and contributing factor. This study used data from the Centers for Disease Control and Prevention's (CDC) National Outbreak Reporting System and National Environmental Assessment Reporting System to identify outbreak investigation characteristics associated with outbreak investigation success. We identified investigation characteristics that increase the probability of successful outbreak investigations: a rigorous epidemiology investigation method; a thorough environmental assessment, as measured by number of visits to complete the assessment; and the collection of clinical samples. This research highlights the importance of a comprehensive outbreak investigation, which includes epidemiology, environmental health and laboratory personnel working together to solve the outbreak.

We present a timeseries of 14CO2 for the period 1910–2021 recorded by annual plants collected in the southwestern United States, centered near Flagstaff, Arizona. This timeseries is dominated by five commonly occurring annual plant species in the region, which is considered broadly representative of the southern Colorado Plateau. Most samples (1910–2015) were previously archived herbarium specimens, with additional samples harvested from field experiments in 2015–2021. We used this novel timeseries to develop a smoothed local record with uncertainties for “bomb spike” 14C dating of recent terrestrial organic matter. Our results highlight the potential importance of local records, as we document a delayed arrival of the 1963–1964 bomb spike peak, lower values in the 1980s, and elevated values in the last decade in comparison to the most current Northern Hemisphere Zone 2 record. It is impossible to retroactively collect atmospheric samples, but archived annual plants serve as faithful scribes: samples from herbaria around the Earth may be an under-utilized resource to improve understanding of the modern carbon cycle.

Who managed large corporations during the first half century of their emergence? How did modernizing firms navigate periods of rapid technological change such as those that swept the U.S. economy in the late nineteenth and early twentieth centuries? What role did engineers play in the management of large corporations? This paper draws on an original database of tens of thousands of mining and metallurgical engineers who graduated from universities during this period, examining patterns in their employment records, job descriptions, and career trajectories, matching our data on individual engineers with a linked database of mining and metallurgical corporations. We trace two distinct phases in engineers’ managerial role that corresponded to periods of rapid technological change and technological quiescence in the industry. We argue that explaining the rise of the modern corporation and the historical dynamics of corporate management requires a better understanding of technical expertise in management.

A single solution to promote higher animal welfare across the whole EU is unlikely due to significant regional differences and because what is most appropriate for each region depends on many factors. Based on analyses of eight member and candidate EU countries, this paper provides a conceptual framework, an ‘animal welfare roadmap’, which can be used to assess the stage of maturity of a country in farm animal welfare policy development and identify appropriate policy instruments and indicators to monitor progress towards higher animal welfare. The ‘roadmap’ consists of five sequential stages: increasing compliance with legislation; raising awareness; product development; mainstreaming; and integration of animal welfare with other issues. For each stage, specific policy instruments are identified alongside the category of stakeholders most likely to be influential in the implementation of each instrument. The policy instruments used to achieve these stages are those used by government departments/agencies, private enterprises, academic bodies or non-governmental organisations who formulate standards for animal welfare. These are supported by indicators best suited to document their effectiveness. Although we have emphasised how different situations and contexts within the EU mean that there is no single optimal policy instrument for the EU as a whole, but rather appropriate policy instruments should be selected according to the stage of development of a country or sector, we do propose a harmonised choice of indicators to allow benchmarking of changes at the EU level with regard to progress towards animal welfare.

Increasing litter size has long been a goal of pig breeders and producers, and may have implications for pig (Sus scrofa domesticus) welfare. This paper reviews the scientific evidence on biological factors affecting sow and piglet welfare in relation to large litter size. It is concluded that, in a number of ways, large litter size is a risk factor for decreased animal welfare in pig production. Increased litter size is associated with increased piglet mortality, which is likely to be associated with significant negative animal welfare impacts. In surviving piglets, many of the causes of mortality can also occur in non-lethal forms that cause suffering. Intense teat competition may increase the likelihood that some piglets do not gain adequate access to milk, causing starvation in the short term and possibly long-term detriments to health. Also, increased litter size leads to more piglets with low birth weight which is associated with a variety of negative long-term effects. Finally, increased production pressure placed on sows bearing large litters may produce health and welfare concerns for the sow. However, possible biological approaches to mitigating health and welfare issues associated with large litters are being implemented. An important mitigation strategy is genetic selection encompassing traits that promote piglet survival, vitality and growth. Sow nutrition and the minimisation of stress during gestation could also contribute to improving outcomes in terms of piglet welfare. Awareness of the possible negative welfare consequences of large litter size in pigs should lead to further active measures being taken to mitigate the mentioned effects.

Increasing litter size has long been a goal of pig (Sus scrofa domesticus) breeders and producers in many countries. Whilst this has economic and environmental benefits for the pig industry, there are also implications for pig welfare. Certain management interventions are used when litter size routinely exceeds the ability of individual sows to successfully rear all the piglets (ie viable piglets outnumber functional teats). Such interventions include: tooth reduction; split suckling; cross-fostering; use of nurse sow systems and early weaning, including split weaning; and use of artificial rearing systems. These practices raise welfare questions for both the piglets and sow and are described and discussed in this review. In addition, possible management approaches which might mitigate health and welfare issues associated with large litters are identified. These include early intervention to provide increased care for vulnerable neonates and improvements to farrowing accommodation to mitigate negative effects, particularly for nurse sows. An important concept is that management at all stages of the reproductive cycle, not simply in the farrowing accommodation, can impact on piglet outcomes. For example, poor stockhandling at earlier stages of the reproductive cycle can create fearful animals with increased likelihood of showing poor maternal behaviour. Benefits of good sow and litter management, including positive human-animal relationships, are discussed. Such practices apply to all production situations, not just those involving large litters. However, given that interventions for large litters involve increased handling of piglets and increased interaction with sows, there are likely to be even greater benefits for management of hyper-prolific herds.

Sea-level science has seen many recent developments in observations and modelling of the different contributions and the total mean sea-level change. In this overview, we discuss (1) the evolution of the Intergovernmental Panel on Climate Change (IPCC) projections, (2) how the projections compare to observations and (3) the outlook for further improving projections. We start by discussing how the model projections of 21st century sea-level change have changed from the IPCC AR5 report (2013) to SROCC (2019) and AR6 (2021), highlighting similarities and differences in the methodologies and comparing the global mean and regional projections. This shows that there is good agreement in the median values, but also highlights some differences. In addition, we discuss how the different reports included high-end projections. We then show how the AR5 projections (from 2007 onwards) compare against the observations and find that they are highly consistent with each other. Finally, we discuss how to further improve sea-level projections using high-resolution ocean modelling and recent vertical land motion estimates.

Racially and ethnically minoritized populations have been historically excluded and underrepresented in research. This paper will describe best practices in multicultural and multilingual awareness-raising strategies used by the Recruitment Innovation Center to increase minoritized enrollment into clinical trials. The Passive Immunity Trial for Our Nation will be used as a primary example to highlight real-world application of these methods to raise awareness, engage community partners, and recruit diverse study participants.