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The Bras d'Or terrane of central Cape Breton Island, Nova Scotia, Canada, contains a well-preserved record of the Ediacaran to early Cambrian evolution of Ganderia, a Gondwana-derived terrane in the northern Appalachian orogen. A complex assemblage of low- to high-grade metasedimentary rocks has varied detrital zircon signatures from laser ablation inductively coupled plasma mass spectrometry U-Pb zircon dating, but combining three or more samples yielded representative age spectra that support correlation of the low- and high-grade metasedimentary rocks throughout the Bras d'Or terrane and the corresponding Ganderian Brookville terrane of southern New Brunswick. In quartzite samples from the McMillan Flowage Formation in the northwestern Bras d'Or terrane, the youngest detrital zircons have ages >900 Ma, in contrast to previously studied psammitic and semipelitic samples from correlative units in the eastern Bras d'Or terrane in which youngest detrital ages are 620–600 Ma. Both quartzite and semipelitic samples from the McMillan Flowage Formation contain Neoproterozoic dates from zircon rims, which reflect metamorphic overgrowths during peak metamorphism at ca. 550 Ma, providing a robust age for peak metamorphism in the Bras d'Or terrane that supports similar, albeit sparse, ages reported previously from monazite and titanite samples. This metamorphism is coeval with the emplacement of voluminous dioritic to granitic plutons that occur throughout the Bras d'Or terrane and form in an Andean-type continental margin subduction zone. New U-Pb zircon ages presented here from plutons in the northern Bras d'Or terrane, combined with previously published ages, are consistent with subduction-related magmatism and associated metamorphism between ca. 575 and 540 Ma.

Barite is an important industrial mineral used as a weighing agent in fluids during the drilling of oil and natural gas wells, with the majority of United States production originating from Nevada. This paper considers three barite properties at varying stages of development—Rossi, Heavy Spar, and Ann—all located within the northern Nevada barite belt. At all three sites, barite is hosted in the Roberts Mountains allochthon consisting of siliceous sedimentary rocks. Geochemical characterization of waste rock, ore, and process products has been undertaken as part of project development at each site, including 212 acid-base accounting (ABA) analysis and 19 humidity-cell tests operated for up to 114 weeks. This study demonstrates that the presence of barite greatly limits the application of using traditional Sobek-style ABA methods. Barite will undergo incomplete dissolution and extraction in the ABA tests that will result in an overprediction of acid generation for materials that contain barite (i.e., ore and jig by-products). Results indicate use of the net acid generation test to inform waste rock management represents a more reliable indicator of acid generation for these three deposits and potentially also other barite deposits. Potential barite mine sites should continue to be evaluated using the same geochemical testing tools as base metal mines but using those tools in a selective way to achieve balance between regulatory requirements and costs.

The Coldbrook Group and related plutons in the Caledonian Highlands of southern New Brunswick contain voluminous late Ediacaran silicic rocks formed in a magmatic event not recognized in other parts of Avalonia in the northern Appalachian orogen. To better constrain the age and origin of these rocks, we used U–Pb zircon dating by laser ablation inductively coupled plasma mass spectrometry to check for older inherited zircon and obtain trace element data, followed by chemical abrasion isotope dilution thermal ionization mass spectrometry (CA-TIMS) to obtain precise dates. Four silicic samples were dated from the Coldbrook Group, one from the Bonnell Brook pluton, and, for comparison, a felsic lithic-crystal tuff sample from the older arc-related Broad River Group. Overlapping CA-TIMS dates of 551.57 ± 0.23, 551.38 ± 0.24, and 551.70 ± 0.20 Ma for samples from the lower, middle, and upper Coldbrook Group, respectively, and 551.71 ± 0.19 Ma for granite from the Bonnell Brook pluton show that these units crystallized in 760 000 years or less, consistent with a super-eruption event. Rhyolite from the uppermost unit of the Coldbrook Group yielded a younger date of 549.18 ± 0.09 Ma, but the large extent of that unit is consistent with the possibility of a second younger super-eruption. The felsic lithic-crystal tuff sample from the Broad River Group yielded a date of 615.48 ± 0.16 Ma, consistent with previously published dates from that group and associated plutons. Differences in zircon chemistry between the Broad River Group sample and the late Ediacaran samples are consistent with the contrasting subduction-related vs within-plate extensional tectonic settings as suggested by previous studies of whole-rock petrological characteristics of the two age groups.

The MacCodrum Formation is a classical “lower” Cambrian unit in southeastern Cape Breton Island stratigraphy, described since the 1800s. The age of this formation and its correlation with other Avalonian Cambrian units in eastern Newfoundland and southern New Brunswick have remained uncertain through numerous revisions. Here we present U-Pb CA-TIMS ages from an ash bed in the basal part of the MacCodrum Formation in its type-section on MacCodrum Brook that fix the maximum time of deposition at 531.86 ± 0.34 Ma. Organic-walled microfossils sampled throughout the MacCodrum Formation type-section yield acritarch taxa identifying the Asteridium– Comasphaerdium Zone, whereas the first acritarchs of the Skiagia– Fimbriaglomerella Zone appear in the overlying Canoe Brook Formation in other sections. The radiometric age and acritarch zonation place the MacCodrum Formation in the upper Fortunian, Cambrian Stage 2. Among trace fossils in the MacCodrum Formation, the meandering trace fossil Didymaulichnus dailyi comb. nov. is of particular note and morphologically identical to the type material from the lower part of the Ratcliffe Brook Formation in New Brunswick. The new radiometric and biostratigraphic data presented here provide the first firm constraints on the age of the MacCodrum Formation and enable more precise correlation with sections in southern New Brunswick and eastern Newfoundland.

Aims/hypothesis The aim of this work was to investigate the risk of developing chronic kidney disease (CKD) or end-stage kidney disease (ESKD) following a pregnancy complicated by gestational diabetes mellitus (GDM) or pre-existing diabetes among Aboriginal women in the Northern Territory (NT), Australia. Methods We undertook a longitudinal study of linked healthcare datasets. All Aboriginal women who gave birth between 2000 and 2016 were eligible for inclusion. Diabetes status in the index pregnancy was as recorded in the NT Perinatal Data Collection. Outcomes included any stage of CKD and ESKD as defined by ICD-10 coding in the NT Hospital Inpatient Activity dataset between 2000 and 2018. Risk was compared using Cox proportional hazards regression. Results Among 10,508 Aboriginal women, the mean age was 23.1 (SD 6.1) years; 731 (7.0%) had GDM and 239 (2.3%) had pre-existing diabetes in pregnancy. Median follow-up was 12.1 years. Compared with women with no diabetes during pregnancy, women with GDM had increased risk of CKD (9.2% vs 2.2%, adjusted HR 5.2 [95% CI 3.9, 7.1]) and ESKD (2.4% vs 0.4%, adjusted HR 10.8 [95% CI 5.6, 20.8]). Among women with pre-existing diabetes in pregnancy, 29.1% developed CKD (adjusted HR 10.9 [95% CI 7.7, 15.4]) and 9.9% developed ESKD (adjusted HR 28.0 [95% CI 13.4, 58.6]). Conclusions/interpretation Aboriginal women in the NT with GDM or pre-existing diabetes during pregnancy are at high risk of developing CKD and ESKD. Pregnancy presents an important opportunity to identify kidney disease risk. Strategies to prevent kidney disease and address the social determinants of health are needed. Graphical abstract

What is this summary about? This is a plain language summary of a publication describing long-term results from the RESONATE-2 study with up to 8 years of follow-up. The original paper was published in Blood Advances in June 2022. What were the results? Researchers looked at 269 adults with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who had not received any treatment for their CLL/SLL. Study participants were randomly divided into two groups: 136 participants received treatment with a drug called ibrutinib, and 133 participants received treatment with a drug called chlorambucil. Participants in the study were treated and followed for up to 8 years, with results showing that more participants who took ibrutinib (59%) were alive without worsening of their disease at 7 years after starting treatment than participants who took chlorambucil (9%). Almost half of the participants (42%) were able to stay on ibrutinib treatment for up to 8 years. What do the results of the study mean? In people with CLL or SLL, more participants who were taking ibrutinib were alive without worsening of their disease after 7 years compared with participants who took chlorambucil. Clinical Trial Registration: NCT01722487 ( ClinicalTrials.gov ) Clinical Trial Registration: NCT01724346 ( ClinicalTrials.gov )

As autonomous systems become responsible for more complex decisions, it is crucial to consider how these systems will respond in situations wherein they must make potentially controversial decisions without input from users. While previous literature has suggested that users prefer machinelike systems that act to promote the greater good, little research has focused on how the humanlikeness of an agent influences how moral decisions are perceived. We ran two online studies where participants and an automated agent made a decision in an adapted trolley problem. Our results conflicted with previous literature as they did not support the idea that humanlike agents are trusted in a manner analogous to humans in moral dilemmas. Conversely, our study did support the importance for trust of shared moral view between users and systems. Further investigation is necessary to clarify how humanlikeness and moral view interact to form impressions of trust in a system.

Purpose: The phase II CAPTIVATE study investigated first-line treatment with ibrutinib plus venetoclax for chronic lymphocytic leukemia in two cohorts: minimal residual disease (MRD)-guided randomized treatment discontinuation (MRD cohort) and fixed duration (FD cohort). We report tumor debulking and tumor lysis syndrome (TLS) risk category reduction with three cycles of single-agent ibrutinib lead-in before initiation of venetoclax using pooled data from the MRD and FD cohorts. Patients and Methods: In both cohorts, patients initially received three cycles of ibrutinib 420 mg/day then 12 cycles of ibrutinib plus venetoclax (5-week ramp-up to 400 mg/day). Results: In the total population (N = 323), the following decreases from baseline to after ibrutinib lead-in were observed: percentage of patients with a lymph node diameter ≥5 cm decreased from 31% to 4%, with absolute lymphocyte count ≥25 × 109/L from 76% to 65%, with high tumor burden category for TLS risk from 23% to 2%, and with an indication for hospitalization (high TLS risk, or medium TLS risk and creatinine clearance Conclusions: Three cycles of ibrutinib lead-in before venetoclax initiation provides effective tumor debulking, decreases the TLS risk category and reduces the need for hospitalization for intensive monitoring for TLS.

Objectives The objectives of this study were to investigate the occurrence, types and severity of malocclusions in children with speech sound disorder (SSD) persisting after 6 years of age, and to compare these findings to a control group of children with typical speech development (TSD). Methods In total, 105 children were included: 61 with SSD and motor speech involvement (mean age 8:5 ± 2:8 years; range 6:0–16:7 years, 14 girls and 47 boys) and 44 children with TSD (mean age 8:8 ± 1:6; range 6:0–12:2 years, 19 girls and 25 boys). Extra-oral and intra-oral examinations were performed by an orthodontist. The severity of malocclusion was scored using the IOTN-DHC Index. Results There were differences between the SSD and TSD groups with regard to the prevalence, type, and severity of malocclusions; 61% of the children in the SSD group had a malocclusion, as compared to 29% in the TSD group. In addition, the malocclusions in the SSD group were rated as more severe. Functional posterior crossbite and habitual lateral and/or anterior shift appeared more frequently in the SSD group. Class III malocclusion, anterior open bite and scissors bite were found only in the SSD group. Conclusion Children with SSD and motor speech involvement are more likely to have a higher prevalence of and more severe malocclusions than children with TSD.

Zircon grains from metasiltstone beds in the Precambrian Ashburn Formation were dated to constrain the age of the stromatolite Archaeozoon acadiense. The largest group of analyzed grains consists of mostly well-rounded detrital zircon no younger than 1060 Ma with significant peaks at about 1200–1100, 1500, 1800, 2050, and 2700 Ma, as well as a few Mesoarchean ages. A second population of apparently euhedral grains gives ages in the range 680–400 Ma. The distribution of detrital zircon ages along with field relationships suggest that the Ashburn and Martinon formations are proximal and distal parts of the Green Head Group, respectively, and hence a previously reported maximum depositional age of ca. 602 ± 8 Ma for the Martinon Formation also applies to stromatolite in the Ashburn Formation. Paleozoic zircon recovered from the Ashburn Formation cannot be detrital because the rocks were intruded and contact metamorphosed by the Golden Grove Plutonic Suite at ca. 550–525 Ma. The Paleozoic zircon grains were found in four independently processed samples and have also been seen in other studies in the region, showing that they are not due to laboratory contamination. Zircon formed during younger magmatic activity may have been transported in hydrothermal fluids and emplaced into these metasedimentary rocks in veins. A single euhedral zircon recovered from an atypically thick vein gave an age of 659 ± 33 Ma. Hydrothermally transported zircon might provide a window into younger igneous processes for which evidence is not otherwise preserved in this and other areas.

Virtual personal assistants (VPAs) are becoming so widely available that considerations are being made as to whether to begin including them in self-driving vehicles. While research has been done exploring human interactions with single VPAs, there has been a little work exploring human interactions and human mental models with interconnected systems. As companies like Amazon consider whether to integrate Alexa in their self-driving car, research needs to be done to explore whether individual's mental model of these systems is of a single system or if every embodiment of the VPA (e.g., echo) represents a different VPA. Knowing this will allow researchers and practitioners to apply existing models of trust, and predict whether high trust in the Siri that exists in an iPhone will carry over into high (and potentially miscalibrated) trust in Apple's Siri-directed self-driving vehicle. Results indicate that there is not one consistent mental model that users have, and provides the framework for greater exploration into individual differences and the determinants that affect users’ mental model.

Joint and muscle pain, including arthralgia, myalgia, and musculoskeletal pain, are among the common adverse events (AEs) reported for ibrutinib, a once-daily Bruton's tyrosine kinase inhibitor approved for the treatment of various B-cell malignancies, including chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). This pooled analysis from nine clinical trials of ibrutinib in CLL and MCL (

The present review sought to examine and summarise the unique experience of concurrent pain and psychiatric conditions, that is often neglected, within the population of homeless individuals. Furthermore, the review examined factors that work to aggravate pain and those that have been shown to improve pain management. Electronic databases (MEDLINE, EMBASE, psycINFO, and Web of Science) and the grey literature (Google Scholar) were searched. Two reviewers independently screened and assessed all literature. The PHO MetaQAT was used to appraise quality of all studies included. Fifty-seven studies were included in this scoping review, with most of the research being based in the United States of America. Several interacting factors were found to exacerbate reported pain, as well as severely affect other crucial aspects of life that correlate directly with health, within the homeless population. Notable factors included drug use as a coping mechanism for pain, as well as opioid use preceding pain; financial issues; transportation problems; stigma; and various psychiatric disorders, such as post-traumatic stress disorder, depression, and anxiety. Important pain management strategies included cannabis use, Accelerated Resolution Therapy for treating trauma, and acupuncture. The homeless population experiences multiple barriers which work to further impact their experience with pain and psychiatric conditions. Psychiatric conditions impact pain experience and can work to intensify already adverse health circumstances of homeless individuals.

On the sea floor of specific deep ocean environments lie prolific amounts of polymetallic nodules that contain minerals critical to meeting the future energy demands of a growing worldwide population. Polymetallic nodules rich in manganese, nickel, and cobalt spread over millions of square kilometers of abyssal seabed and contain the minerals needed for future energy storage demands. The offshore oil and gas industry seeks to participate in the energy expansion by leveraging its deepwater experience to harvest these nodules. The knowledge and wisdom gained from decades of operating offshore provides significant insight into the development and implementation of the technology needed to address the challenges of deep sea nodule harvesting. The authors describe a design selection tool based on the methods described by Stuart Pugh to select a polymetallic nodule Vertical Transport System. Stuart Pugh, known for his work in product design and development, introduced the Pugh Method in the 1980s. The Pugh Method is a structured and integrated process applied to design development including concept generation, evaluation, and selection. The Vertical Transport System design processes uses the Pugh Method to recommend a candidate design. The evaluation step uses a two groups of company experts who present the concepts (the team), and collectively evaluate (the group) and recommend the best design concept for further development. We apply the method to the case of deep sea mineral recovery operations specifically the design of the Vertical Transportation System. First, the authors introduce the Pugh Method tool, how it works, and how it applies to this specific case. We describe how risks and rewards relate to each selection characteristic used to evaluate the Vertical Transport System concepts. Further, we talk about team selection and the points to consider when assembling the right team to achieve credible results. Next, we describe each concept identifying and recognizing the various technical, operational, and economic selection characteristics, such as size, power consumption, reliability, availability, etc. Finally, we evaluate each concept against the different selection characteristics and discuss the results. The paper concludes with a robust process flow chart describing the selection method for a Vertical Transport System.

Purpose:The phase II CAPTIVATE study investigated first-line treatment with ibrutinib plus venetoclax for chronic lymphocytic leukemia in two cohorts: minimal residual disease (MRD)-guided randomized treatment discontinuation (MRD cohort) and fixed duration (FD cohort). We report tumor debulking and tumor lysis syndrome (TLS) risk category reduction with three cycles of single-agent ibrutinib lead-in before initiation of venetoclax using pooled data from the MRD and FD cohorts.Patients and Methods:In both cohorts, patients initially received three cycles of ibrutinib 420 mg/day then 12 cycles of ibrutinib plus venetoclax (5-week ramp-up to 400 mg/day).Results:In the total population (N = 323), the following decreases from baseline to after ibrutinib lead-in were observed: percentage of patients with a lymph node diameter ≥5 cm decreased from 31% to 4%, with absolute lymphocyte count ≥25 × 109/L from 76% to 65%, with high tumor burden category for TLS risk from 23% to 2%, and with an indication for hospitalization (high TLS risk, or medium TLS risk and creatinine clearance Conclusions:Three cycles of ibrutinib lead-in before venetoclax initiation provides effective tumor debulking, decreases the TLS risk category and reduces the need for hospitalization for intensive monitoring for TLS.

Supplementary Data from Effective Tumor Debulking with Ibrutinib Before Initiation of Venetoclax: Results from the CAPTIVATE Minimal Residual Disease and Fixed-Duration Cohorts

Supplemental Table 1 and Supplemental Figure Legends

Purpose:Clinical trials of venetoclax reported negligible rates of clinical tumor lysis syndrome (TLS) in patients with chronic lymphocytic leukemia (CLL) when using an extended dose escalation schedule. We aimed to understand TLS prophylaxis, rates of select adverse events (AE), and impact of dosing modifications in routine clinical practice.Experimental Design:This retrospective cohort study included 297 CLL venetoclax-treated patients outside of clinical trials in academic and community centers. Demographics, baseline disease characteristics, venetoclax dosing, TLS risk and prophylaxis, and AEs were collected.Results:The group was 69% male, 96% had relapsed/refractory CLL, 45% had deletion chromosome 17p, 84% had unmutated IGHV, 80% received venetoclax monotherapy, and median age was 67. TLS risk was categorized as low (40%), intermediate (32%), or high (28%), and 62% had imaging prior to venetoclax initiation. Clinical TLS occurred in 2.7% of patients and laboratory TLS occurred in 5.7%. Pre-venetoclax TLS risk group and creatinine clearance independently predict TLS development in multivariable analysis. Grade 3/4 AEs included neutropenia (39.6%), thrombocytopenia (29.2%), infection (25%), neutropenic fever (7.9%), and diarrhea (6.9%). Twenty-two patients (7.4%) discontinued venetoclax due to an AE. Progression-free survival was similar regardless of number of dose interruptions, length of dose interruption, and stable venetoclax dose.Conclusions:These data provide insights into current use of venetoclax in clinical practice, including TLS rates observed in clinical practice. We identified opportunities for improved adherence to TLS risk stratification and prophylaxis, which may improve safety.

Purpose:Venetoclax-based therapy is a standard-of-care option in first-line and relapsed/refractory chronic lymphocytic leukemia (CLL). Patient management following venetoclax discontinuation remains nonstandard and poorly understood.Experimental Design:To address this, we conducted a large international study to identify a cohort of 326 patients who discontinued venetoclax and have been subsequently treated. Coprimary endpoints were overall response rate (ORR) and progression-free survival for the post-venetoclax treatments stratified by treatment type [Bruton's tyrosine kinase inhibitor (BTKi), PI3K inhibitor (PI3Ki), and cellular therapies].Results:We identified patients with CLL who discontinued venetoclax in the first-line (4%) and relapsed/refractory settings (96%). Patients received a median of three therapies prior to venetoclax; 40% were BTKi naïve (n = 130), and 81% were idelalisib naïve (n = 263). ORR to BTKi was 84% (n = 44) in BTKi-naïve patients versus 54% (n = 30) in BTKi-exposed patients. We demonstrate therapy selection following venetoclax requires prior novel agent exposure consideration and discontinuation reasons.Conclusions:For BTKi-naïve patients, selection of covalently binding BTKis results in high ORR and durable remissions. For BTKi-exposed patients, covalent BTK inhibition is not effective in the setting of BTKi resistance. PI3Kis following venetoclax do not appear to result in durable remissions. We conclude that BTKi in naïve or previously responsive patients and cellular therapies following venetoclax may be the most effective strategies.See related commentary by Rogers, p. 3501

Supplemental Figure 2: Progression free survival of patients without prior BTKi exposure who had progressed on venetoclax and were then treated with BTKi.

Supplemental Figure 1: Overall survival of entire cohort from initiation of venetoclax.

A large dyke of quartz tholeiitic gabbronorite has been mapped for 59 km in southern New Brunswick, Canada, between Lepreau River in the northeast and Indian Island in the southwest. Scattered outcrops occur along a positive aeromagnetic lineament, providing a dyke strike of N42°E overall (segments N30°E to N72°E), dips of 80° to 90°NNW, and widths of 4 to 30 m. A new 40Ar/39Ar plagioclase age of 201.67 ± 0.35 Ma for the Lepreau River Dyke is similar to dates for the massive North Mountain Basalt in the Fundy Basin to the east. The dyke is associated with the Ministers Island and Christmas Cove dykes, which are indistinguishable in chemistry, petrology, and probable age, and we regard them as segments of the same co-magmatic dyke system. In addition, their petrology is similar to that of the basalts of the adjacent Early Mesozoic Fundy and Grand Manan basins. We propose that the Lepreau River and associated dykes were sources for the regional basin basalts, which in turn are part of the Central Atlantic Magmatic Province (CAMP) that overlaps the Triassic–Jurassic boundary and associated mass extinction event.

BTK inhibitors are an effective therapy for previously untreated patients with CLL but require indefinite duration treatment that can result in cumulative toxicities. Novel combinations of agents that provide deep remissions could allow for fixed duration therapy. Acalabrutinib, unlike ibrutinib, does not inhibit anti-CD20 monoclonal antibody dependent cellular phagocytosis, making it a suitable partner drug to rituximab. Using standard dosing (375mg/m2) of rituximab causes loss of target membrane CD20 immune cells and exhaustion of the finite cytotoxic capacity of the innate immune system. Alternatively, using high frequency, low dose (HFLD), subcutaneous rituximab limits loss of CD20 and allows for self-administration at home by patients. The combination of HFLD rituximab 50mg given twice a week for six cycles of 28 days with the addition of acalabrutinib starting in week 2 was evaluated in a phase II study (#NCT03788291 at clinicaltrials.gov) of 38 patients with treatment naive CLL. Patients achieving a complete response with undetectable MRD after 12 or 24 cycles of acalabrutinib could stop therapy. All patient responded, including one with a complete response with undetectable MRD in the peripheral blood and bone marrow at 12 months who stopped therapy. At a median follow-up of 2.3 years two patients with high-risk features have progressed while on acalabrutinib monotherapy. We conclude that HFLD rituximab in combination with acalabrutinib is an effective and tolerable self-administered home combination that provides a platform to build upon future regimens that may more reliably allow for fixed-duration therapy.

The COVID-19 pandemic has revealed the vulnerability of the modern, global society. With expected waves of future infections by SARS-CoV-2, treatment options for infected individuals will be crucial in order to decrease mortality and hospitalizations. The SARS-CoV-2 main protease is a validated drug target, for which the first inhibitor has been approved for use in patients. To facilitate future work on this drug target, we designed a solid-phase synthesis route towards azapeptide activity-based probes that are capped with a cysteine-reactive electrophile for covalent modification of the active site of Mpro. This design led to the most potent ABP for Mpro and one of the most potent inhibitors reported thus far. We demonstrate that this ABP can be used to visualize Mpro activity and target engagement by drugs in infected cells. ispartof: CHEMICAL SCIENCE vol:14 issue:7 pages:1666-1672 ispartof: location:England status: published

West and East Ganderia in the northern Appalachians and Caledonides, respectively, represent a Gondwanan superterrane situated along the Tornquist margin of Amazonia prior to Furongian drift into the Iapetus Ocean, which opened the Rheic Ocean from west to east. The ocean-facing Penobscot arc-backarc system was established by 515 Ma in West Ganderia. A correlative arc formed at ca. 480 Ma in East Ganderia. In West Ganderia, the Tremadocian Penobscottian orogeny involved closure of the Penobscot backarc basin. Tremadocian Monian tectonism in East Ganderia was mainly related to oblique accretion to East Avalonia and the Megumian Cymru terrane. Penobscottian and late Floian Monian orogenesis led to termination of Early Ordovician arc magmatism, probably due to shallow subduction of buoyant oceanic lithosphere. Early to Middle Ordovician arc-backarc systems were erected on Penobscottian-Monian modified West and East Ganderia. The active edge of West Ganderia accreted diachronously to peri-Laurentia between 475 Ma and 455 Ma, followed by Wenlock to Ludlow Salinic accretion of the inboard Gander margin through closure of the intervening backarc basin. In the Caledonides, East Ganderia and East Avalonia accreted to Laurentia during the correlative Wenlock Scandian orogeny. The Ordovician to Silurian tectonic evolution of Ganderia was markedly non-cylindrical with pronounced partitioning of Salinic-Scandian convergence. Pridoli to Lochkovian closure of the Acadian seaway in the northern Appalachians led to Acadian accretion of West Avalonia to composite Laurentia. Shallow Early Devonian underthrusting of West and East Avalonia beneath Laurentia produced widespread Acadian tectonism and voluminous Early Devonian Acadian magmatism. The Appalachian Meguma terrane formed part of Megumia, which probably formed originally adjacent to East Avalonia and West Africa. The Meguma terrane accreted dextrally to Laurentia during and after the late Emsian to Famennian Neoacadian orogeny, mainly driven by outboard subduction of the Rheic Ocean. No correlative terrane docking took place in the Caledonides.

Microstructures and corresponding properties of compacted powders ultimately depend on the mechanical response of individual particles. In principle, computational simulations can predict the results of powder compaction processes, but the selection of appropriate models for both particle–particle interactions and particle deformations across all relevant length scales remain nontrivial tasks, especially in material systems lacking detailed mechanical property information. The work presented here addresses these issues by conducting uniaxial compressions in situ inside of a scanning electron microscope to characterize the mechanical response of individual micron-sized particles of a molecular crystal, hexanitrohexaazaisowurtzitane (CL-20). This experimental approach enabled the collection of quantitative force and displacement data alongside simultaneous imaging to capture morphology changes. The results reveal information about elastic deformation, yield, plastic deformation, creep, and fracture phenomena. Accordingly, this work demonstrates a generalizable approach for assessing the mechanical response of individual micron-sized molecular crystal particles and utilizing those responses in particle-level models. Graphic abstract

Previous research has shown that the design of robots can impact the level of trust, liking, and empathy that a user feels towards a robot. Additionally, this empathy can have direct impacts on users’ interactions with the system. Existing research has looked at how empathy can influence user willingness to, for example, put the robot in harm’s way or to destroy the robot. However, these studies have been inherently reliant upon narrative driven manipulations, which may result in experimental demands which could have influenced the results. As such, we provide a human-likeness manipulation in order to evaluate the impacts of design which may evoke empathy, on use of robots in high-risk environments. Results indicate no significant difference in robot use between conditions. These results are in conflict with previous research. More research is needed to understand when users are/are not willing to use a robot in a high-risk environment.

Purpose: Thromboembolic events (TE) are the most common complications of myeloproliferative neoplasms (MPN). Clinical parameters, including patient age and mutation status, are used to risk-stratify patients with MPN, but a true biomarker of TE risk is lacking. Protein disulfide isomerase (PDI), an endoplasmic reticulum protein vital for protein folding, also possesses essential extracellular functions, including regulation of thrombus formation. Pharmacologic PDI inhibition prevents thrombus formation, but whether pathologic increases in PDI increase TE risk remains unknown. Experimental Design: We evaluated the association of plasma PDI levels and risk of TE in a cohort of patients with MPN with established diagnosis of polycythemia vera (PV) or essential thrombocythemia (ET), compared with healthy controls. Plasma PDI was measured at enrollment and subjects followed prospectively for development of TE. Results: A subset of patients, primarily those with JAK2-mutated MPN, had significantly elevated plasma PDI levels as compared with controls. Plasma PDI was functionally active. There was no association between PDI levels and clinical parameters typically used to risk-stratify patients with MPN. The risk of TE was 8-fold greater in those with PDI levels above 2.5 ng/mL. Circulating endothelial cells from JAK2-mutated MPN patients, but not platelets, demonstrated augmented PDI release, suggesting endothelial activation as a source of increased plasma PDI in MPN. Conclusions: The observed association between plasma PDI levels and increased risk of TE in patients with JAK2-mutated MPN has both prognostic and therapeutic implications.

In understanding the nature of contrast in the emerging field of neutral helium microscopy, it is important to identify if there is an atom-surface scattering distribution that can be expected to apply broadly across a range of sample surfaces. Here we present results acquired in a scanning helium microscope (SHeM) under typical operating conditions, from a range of surfaces in their native state, i.e. without any specialist sample preparation. We observe diffuse scattering, with an approximately cosine distribution centred about the surface normal. The 'cosine-like' distribution is markedly different from those distributions observed from the well-prepared, atomically pristine, surfaces typically studied in helium atom scattering experiments. Knowledge of the typical scattering distribution in SHeM experiments provides a starting basis for interpretation of topographic contrast in images, as well as a reference against which more exotic contrast mechanisms can be compared.

To determine rates and predictors of postpartum diabetes screening among Aboriginal and/or Torres Strait Islander and non-Indigenous women with gestational diabetes mellitus (GDM).PANDORA is a prospective longitudinal cohort of women recruited in pregnancy. Postpartum diabetes screening rates at 12 weeks (75-g oral glucose tolerance test (OGTT)) and 6, 12 and 18 months (OGTT, glycated haemoglobin [HbAPostpartum screening rates with an OGTT by 12 weeks and 6 months postpartum were lower among Aboriginal and/or Torres Strait Islander women than non-Indigenous women (18% vs. 30% at 12 weeks, and 23% vs. 37% at 6 months, p 0.001). Aboriginal and/or Torres Strait Islander women were more likely to have completed a 6-month HbAGiven very high rates of type 2 diabetes among Aboriginal and Torres Strait Islander women, early postpartum screening with the most feasible test should be prioritised to detect prediabetes and diabetes for intervention.

The cilium acts as an antenna receiving and sending signals, the latter via extracellular vesicles (EVs). In C. elegans and mammals, the Autosomal Dominant Polycystic Kidney Disease (ADPKD) gene products polycystin-1 (PC1) and polycystin-2 (PC2) localize to both cilia and EVs, act in the same genetic pathway, and function in a sensory capacity, suggesting ancient conservation. However, the functions of the polycystins on cilia and EVs remain enigmatic. We used our C. elegans model and endogenously fluorescent-tagged LOV-1/polycystin-1 to study LOV-1 processing, trafficking, transport, EV biogenesis, and function in living animals. Super resolution, real time imaging reveals that LOV-1 is processed into N-terminal (NTM) and C-terminal (CTM) forms via a conserved GPCR proteolytic site (GPS). The LOV-1 NTM is secreted into the extracellular matrix and not localized to ciliary tip EVs. In contrast, LOV-1 CTM and PKD-2 are co-trafficked, co-transported, and co-localized in cilia and on environmentally released ciliary EVs. LOV-1 CTM requires PKD-2 for ciliary EV localization, while PKD-2 localizes to ciliary EVs independent of LOV-1. We find that LOV-1 but not PKD-2 is required for chemosensation of an ascaroside mating pheromone. These findings indicate that the polycystins LOV-1 and PKD-2 function together and independently and provide insight to how cargo is selected and packaged in ciliary EVs.

Trust in automation is an important construct to consider when attempting to predict proper use of automated systems. Automation is being used in increasingly diverse and more complex ways. Previous findings report that trust can be generalized across systems, leading to contagion effects. However, it is unclear in the current literature how users form perceptions of the boundaries between systems. To address this problem, we conducted two experiments in which we considered how perceived similarity, perceived functional relatedness, attributed blame, and attributed responsibility influenced the magnitude of contagion effects for trust. Participants were presented with hypothetical scenarios in which an airplane environment is depicted. We found that participants tended not to have a contagion effect for clearly unrelated components (a farmer and microwave) while showing a contagion effect for those that are related, suggesting that previous findings including contagion effects may not be explained by an anchoring effect. The degree of difference in trust between the success and failure conditions was also predicted by similarity and relatedness of the components. Moving forward, more research should focus on understanding how users form mental models of system boundaries.

The Cambrian syn-rift strata preserved in western Avalonia provide a distinctive example of how unconformity-bounded sequences are diachronous throughout proximal to marginal rift branches. Terreneuvian‒Miaolingian third-order sequences of the Caledonian Highlands, New Brunswick, Canada, reflect a complex interplay among syn-rift tectonic events, denudation pulses, and sea-level fluctuations. Unconformably overlying the early, rift-related volcanosedimentary Coldbrook Group (ca. 560‒550 Ma), the Ratcliffe Brook, Glen Falls, Hanford Brook, and Forest Hills Formations can be subdivided into two transgressive systems tract (TST)‒highstand systems tract (HST) sequences (each ∼10 m.y.) and an incomplete TST sequence that are separated by stratigraphic gaps. They reflect uplift and tilting events affecting the basement, transgressive and drowning surfaces, and condensed sections. Arid to semi-arid climatic episodes are supported by the excellent preservation of mafic to felsic volcanic clasts in non-marine breccias and conglomerates, which are derived from the Ediacaran basement, and the local precipitation of marine gypsum through the evaporation of pore fluids. Early Miaolingian episodes of microbial/shelly carbonate production preserved precipitates of coeval evaporite (gypsum pseudomorphs after drusy mosaics of calcite) and ikaite (glendonitic, star-shaped aggregates and crusts). Both minerals, traditionally considered to be indicators of contrasting climate conditions, potentially co-occur in temperate-water substrates recording high rates of microbial activity. The early rift phases preserved in the western Avalonian rift transect comprise stepwise uplift and unroofing of rift shoulders, which are related to diachronous, angular discordances and paraconformities bounded by syntectonic slope-apron deposits. Facies homogenization was attained during Miaolingian times as a result of generalized flooding, sealing of paleotopographies, and blanketing with monotonous offshore-dominant shales.

Smoking cannabis in medical users is associated with exposure to harmful toxins. It is important to characterize cannabis-use profiles and risk-factors for medical cannabis users who smoke cannabis. 100 members of a medical cannabis dispensary with mental health concerns were interviewed in detail about their cannabis use. Forty seven percent of participants preferred smoking only, 18% preferred vaporizing, 25% preferred both smoking and vaping, and 10% preferred oral ingestion methods. Smokers differed from other users in multiple ways, including a greater preference for THC-dominant chemovars, and more frequent and greater amount of cannabis consumption. Smoking was also associated with greater rates of alcohol use disorder. These results may inform harm-reduction approaches to decrease the number of individuals smoking cannabis and use less harmful methods of medical cannabis ingestion.