Background: A key efficacy indicator in generalized myasthenia gravis (gMG) treatment is improvement in MG-ADL score. Minimal symptom expression (MSE, MG-ADL total score of 0 or 1) is explored as a novel proposed treatment target in gMG in the phase 3 study of intravenous efgartigimod, ADAPT, and its open-label extension, ADAPT+. Methods: Post hoc analyses of acetylcholine receptor antibody positive participants in ADAPT (n=129) and ADAPT+ (n=111) were performed. Results: In ADAPT, 44.6% receiving efgartigimod achieved MSE vs 10.9% of participants given placebo. Despite less frequent assessment during ADAPT+, 40.5% of participants achieved MSE. Eighty-one percent of participants treated with efgartigimod who achieved MSE in ADAPT also achieved MSE during ADAPT+; 23% who had not achieved MSE in ADAPT did in ADAPT+. Achieving MSE was associated with substantial improvements in QMG, MGC, MG-QoL15r, and EQ-5D-5L mean scores of 11.4, 16.0, 12.4, and 0.3 points, respectively, from baseline to best score (across all visits). These drastic improvements resulted in quality of life (QoL) comparable to that of healthy populations. MSE achievement also resulted in sustained improvements in these disease-specific and QoL measures. Conclusions: Participants who achieved MSE showed substantial and consistent improvements across multiple disease measures and experienced QoL comparable to that of healthy populations.

The prioritization of English language in clinical research is a barrier to translational science. We explored promising practices to advance the inclusion of people who speak languages other than English in research conducted within and supported by NIH Clinical Translational Science Award (CTSA) hubs. Key informant interviews were conducted with representatives (n = 24) from CTSA hubs (n = 17). Purposive sampling was used to identify CTSA hubs focused on language inclusion. Hubs electing to participate were interviewed via Zoom. Thematic analysis was performed to analyze interview transcripts. We report on strategies employed by hubs to advance linguistic inclusion and influence institutional change that were identified. Strategies ranged from translations, development of culturally relevant materials and consultations to policies and procedural changes and workforce initiatives. An existing framework was adapted to conceptualize hub strategies. Language justice is paramount to bringing more effective treatments to all people more quickly. Inclusion will require institutional transformation and CTSA hubs are well positioned to catalyze change.

Research articles in the clinical and translational science literature commonly use quantitative data to inform evaluation of interventions, learn about the etiology of disease, or develop methods for diagnostic testing or risk prediction of future events. The peer review process must evaluate the methodology used therein, including use of quantitative statistical methods. In this manuscript, we provide guidance for peer reviewers tasked with assessing quantitative methodology, intended to complement guidelines and recommendations that exist for manuscript authors. We describe components of clinical and translational science research manuscripts that require assessment including study design and hypothesis evaluation, sampling and data acquisition, interventions (for studies that include an intervention), measurement of data, statistical analysis methods, presentation of the study results, and interpretation of the study results. For each component, we describe what reviewers should look for and assess; how reviewers should provide helpful comments for fixable errors or omissions; and how reviewers should communicate uncorrectable and irreparable errors. We then discuss the critical concepts of transparency and acceptance/revision guidelines when communicating with responsible journal editors.

Converting measurements of ice-sheet surface elevation change to mass change requires measurements of accumulation and knowledge of the evolution of the density profile in the firn. Most firn-densification models are tuned using measured depth–density profiles, a method which is based on an assumption that the density profile in the firn is invariant through time. Here we present continuous measurements of firn-compaction rates in 12 boreholes near the South Pole over a 2 year period. To our knowledge, these are the first continuous measurements of firn compaction on the Antarctic plateau. We use the data to derive a new firn-densification algorithm framed as a constitutive relationship. We also compare our measurements to compaction rates predicted by several existing firn-densification models. Results indicate that an activation energy of 60 kJ mol−1, a value within the range used by current models, best predicts the seasonal cycle in compaction rates on the Antarctic plateau. Our results suggest models can predict firn-compaction rates with at best 7% uncertainty and cumulative firn compaction on a 2 year timescale with at best 8% uncertainty.

OBJECTIVES/GOALS: We aimed to determine if GLP-1 receptor agonists exert beneficial effects on surrogate measures of cardiovascular function independently of weight loss. Our objective was to compare the outcomes between GLP-1 receptor agonist treatment versus a similar drug without cardiovascular benefit versus weight loss through diet alone. METHODS/STUDY POPULATION: We enrolled 88 individuals with obesity (BMI ≥ 30kg/m2) and pre-diabetes and randomized them in a 2:1:1 ratio to 14 weeks of the GLP-1 receptor agonist liraglutide, the dipeptidyl peptidase-4 inhibitor sitagliptin, or hypocaloric diet. Sitagliptin blocks degradation of endogenous GLP-1 but does not cause weight loss or lower adverse cardiovascular outcomes. Treatment was double-blinded and placebo-controlled for drug, and unblinded for diet. Primary endpoints were flow-mediated dilation (FMD) to assess endothelial vasodilatory function, and plasminogen activator inhibitor-1 (PAI-1) to assess endothelial fibrinolytic function. We used a general linear model for each outcome and included gender as a covariate for FMD. Baseline characteristics were similar. Mean age was 50, with 32% men and 13% black. RESULTS/ANTICIPATED RESULTS: At 14 weeks, diet and liraglutide caused weight loss (diet -4.3 ± 3.2 kg, P<0.01; liraglutide -2.7 ± 3.2, P<0.01), while sitagliptin did not (-0.7 ± 2.0, P=0.17). Diet did not improve FMD at 14 weeks compared to baseline (+0.9%, 95% CI [-1.5, 3.3], P=0.46). FMD tended to increase after liraglutide and sitagliptin but was not significant (liraglutide +1.2 [-0.3, 2.8], P=0.12; sitagliptin +1.6 [-0.6, 3.8], P=0.15). Given that liraglutide and sitagliptin work through the same GLP-1 pathway, we combined the liraglutide and sitagliptin groups for overall effect on FMD, which was significantly improved from baseline (+1.4 [0.1, 2.8], P=0.04). Diet and liraglutide improved PAI-1 at 14 weeks (diet -4.4U/mL, [-8.5, -0.2], P=0.04; liraglutide -3.4 [-6.0, -0.7], P=0.01), while sitagliptin did not (-1.4 [-5.1, 2.3], P=0.46). DISCUSSION/SIGNIFICANCE: Activation of the GLP-1 pathway by liraglutide or sitagliptin improves FMD independent of weight loss, while PAI-1 improvement is weight-loss dependent and is only seen after liraglutide or diet. Our study suggests the cardiovascular benefit of liraglutide may be due to combined improvements in endothelial vasodilatory and fibrinolytic function.

The Southern dietary pattern, derived within the REasons for Geographic And Racial Differences in Stroke (REGARDS) cohort, is characterised by high consumption of added fats, fried food, organ meats, processed meats and sugar-sweetened beverages and is associated with increased risk of several chronic diseases. The aim of the present study was to identify characteristics of individuals with high adherence to this dietary pattern. We analysed data from REGARDS, a national cohort of 30 239 black and white adults ≥45 years of age living in the USA. Dietary data were collected using the Block 98 FFQ. Multivariable linear regression was used to calculate standardised beta coefficients across all covariates for the entire sample and stratified by race and region. We included 16 781 participants with complete dietary data. Among these, 34·6 % were black, 45·6 % male, 55·2 % resided in stroke belt region and the average age was 65 years. Black race was the factor with the largest magnitude of association with the Southern dietary pattern (Δ = 0·76 sd, P < 0·0001). Large differences in Southern dietary pattern adherence were observed between black participants and white participants in the stroke belt and non-belt (stroke belt Δ = 0·75 sd, non-belt Δ = 0·77 sd). There was a high consumption of the Southern dietary pattern in the US black population, regardless of other factors, underlying our previous findings showing the substantial contribution of this dietary pattern to racial disparities in incident hypertension and stroke.

Gravitational waves from coalescing neutron stars encode information about nuclear matter at extreme densities, inaccessible by laboratory experiments. The late inspiral is influenced by the presence of tides, which depend on the neutron star equation of state. Neutron star mergers are expected to often produce rapidly rotating remnant neutron stars that emit gravitational waves. These will provide clues to the extremely hot post-merger environment. This signature of nuclear matter in gravitational waves contains most information in the 2–4 kHz frequency band, which is outside of the most sensitive band of current detectors. We present the design concept and science case for a Neutron Star Extreme Matter Observatory (NEMO): a gravitational-wave interferometer optimised to study nuclear physics with merging neutron stars. The concept uses high-circulating laser power, quantum squeezing, and a detector topology specifically designed to achieve the high-frequency sensitivity necessary to probe nuclear matter using gravitational waves. Above 1 kHz, the proposed strain sensitivity is comparable to full third-generation detectors at a fraction of the cost. Such sensitivity changes expected event rates for detection of post-merger remnants from approximately one per few decades with two A+ detectors to a few per year and potentially allow for the first gravitational-wave observations of supernovae, isolated neutron stars, and other exotica.

The SPARC tokamak is a critical next step towards commercial fusion energy. SPARC is designed as a high-field ($B_0 = 12.2$ T), compact ($R_0 = 1.85$ m, $a = 0.57$ m), superconducting, D-T tokamak with the goal of producing fusion gain $Q>2$ from a magnetically confined fusion plasma for the first time. Currently under design, SPARC will continue the high-field path of the Alcator series of tokamaks, utilizing new magnets based on rare earth barium copper oxide high-temperature superconductors to achieve high performance in a compact device. The goal of $Q>2$ is achievable with conservative physics assumptions ($H_{98,y2} = 0.7$) and, with the nominal assumption of $H_{98,y2} = 1$, SPARC is projected to attain $Q \approx 11$ and $P_{\textrm {fusion}} \approx 140$ MW. SPARC will therefore constitute a unique platform for burning plasma physics research with high density ($\langle n_{e} \rangle \approx 3 \times 10^{20}\ \textrm {m}^{-3}$), high temperature ($\langle T_e \rangle \approx 7$ keV) and high power density ($P_{\textrm {fusion}}/V_{\textrm {plasma}} \approx 7\ \textrm {MW}\,\textrm {m}^{-3}$) relevant to fusion power plants. SPARC's place in the path to commercial fusion energy, its parameters and the current status of SPARC design work are presented. This work also describes the basis for global performance projections and summarizes some of the physics analysis that is presented in greater detail in the companion articles of this collection.

Salmonella enterica serovar Wangata (S. Wangata) is an important cause of endemic salmonellosis in Australia, with human infections occurring from undefined sources. This investigation sought to examine possible environmental and zoonotic sources for human infections with S. Wangata in north-eastern New South Wales (NSW), Australia. The investigation adopted a One Health approach and was comprised of three complimentary components: a case–control study examining human risk factors; environmental and animal sampling; and genomic analysis of human, animal and environmental isolates. Forty-eight human S. Wangata cases were interviewed during a 6-month period from November 2016 to April 2017, together with 55 Salmonella Typhimurium (S. Typhimurium) controls and 130 neighbourhood controls. Indirect contact with bats/flying foxes (S. Typhimurium controls (adjusted odds ratio (aOR) 2.63, 95% confidence interval (CI) 1.06–6.48)) (neighbourhood controls (aOR 8.33, 95% CI 2.58–26.83)), wild frogs (aOR 3.65, 95% CI 1.32–10.07) and wild birds (aOR 6.93, 95% CI 2.29–21.00) were statistically associated with illness in multivariable analyses. S. Wangata was detected in dog faeces, wildlife scats and a compost specimen collected from the outdoor environments of cases’ residences. In addition, S. Wangata was detected in the faeces of wild birds and sea turtles in the investigation area. Genomic analysis revealed that S. Wangata isolates were relatively clonal. Our findings suggest that S. Wangata is present in the environment and may have a reservoir in wildlife populations in north-eastern NSW. Further investigation is required to better understand the occurrence of Salmonella in wildlife groups and to identify possible transmission pathways for human infections.

Improving geolocation accuracy in text data has long been a goal of automated text processing. We depart from the conventional method and introduce a two-stage supervised machine-learning algorithm that evaluates each location mention to be either correct or incorrect. We extract contextual information from texts, i.e., N-gram patterns for location words, mention frequency, and the context of sentences containing location words. We then estimate model parameters using a training data set and use this model to predict whether a location word in the test data set accurately represents the location of an event. We demonstrate these steps by constructing customized geolocation event data at the subnational level using news articles collected from around the world. The results show that the proposed algorithm outperforms existing geocoders even in a case added post hoc to test the generality of the developed algorithm.

Morelli, Potosky, Arthur, and Tippins (2017) make a timely and appropriate call for authors to create conceptual models of technology in industrial-organizational (I-O) psychology. We agree with their call, but we believe that Morelli et al. overlooked the contributions of related fields that conduct research on technology in the workplace that are already consistent with their call. For this reason, we briefly detail other fields that commonly study the dynamics of technology and its influence on the workplace, followed by a discussion regarding the place of I-O psychology in the broader scheme of technology research. This discussion can aid future authors in conceptualizing appropriate contributions to the study of technology in I-O psychology as well as identifying whether these contributions benefit other fields. Perhaps more importantly, this discussion can help identify where I-O psychology fits in the broader scheme of technology research and which associated fields may be most readily available to aid in the creation of new models—two questions that currently seem unanswered.

Elemental, chemical, and structural analysis of polycrystalline materials at the micron scale is frequently carried out using microfocused synchrotron X-ray beams, sometimes on multiple instruments. The Maia pixelated energy-dispersive X-ray area detector enables the simultaneous collection of X-ray fluorescence (XRF) and diffraction because of the relatively large solid angle and number of pixels when compared with other systems. The large solid angle also permits extraction of surface topography because of changes in self-absorption. This work demonstrates the capability of the Maia detector for simultaneous measurement of XRF and diffraction for mapping the short- and long-range order across the grain structure in a Ni polycrystalline foil.

Dansgaard–Oeschger (D–O) cycles had far-reaching effects on Northern Hemisphere and tropical climate systems during the last glacial period, yet the climatic response to D–O cycles in western North America is controversial, especially prior to 55 ka. We document changes in precipitation along the western slope of the central Sierra Nevada during early Marine Oxygen Isotope Stages (MIS) 3 and 4 (55–67 ka) from a U-series dated speleothem record from McLean's Cave. The timing of our multi-proxy geochemical dataset is coeval with D–O interstadials (15–18) and stadials, including Heinrich Event 6. The McLean's Cave stalagmite indicates warmer and drier conditions during Greenland interstadials (GISs 15–18), signified by elevated δ 18O, δ 13C, reflectance, and trace element concentrations, and less radiogenic 87Sr/86Sr. Our record extends evidence of a strong linkage between high-latitude warming and reduced precipitation in western North America to early MIS 3 and MIS 4. This record shows that the linkage persists in diverse global climate states, and documents the nature of the climatic response in central California to Heinrich Event 6.