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Topological whirls or ‘textures’ of spins such as magnetic skyrmions represent the smallest realizable emergent magnetic entities1–5. They hold considerable promise as robust, nanometre-scale, mobile bits for sustainable computing6–8. A longstanding roadblock to unleashing their potential is the absence of a device enabling deterministic electrical readout of individual spin textures9,10. Here we present the wafer-scale realization of a nanoscale chiral magnetic tunnel junction (MTJ) hosting a single, ambient skyrmion. Using a suite of electrical and multimodal imaging techniques, we show that the MTJ nucleates skyrmions of fixed polarity, whose large readout signal—20–70% relative to uniformly magnetized states—corresponds directly to skyrmion size. The MTJ exploits complementary nucleation mechanisms to stabilize distinctly sized skyrmions at zero field, thereby realizing three non-volatile electrical states. Crucially, it can electrically write and delete skyrmions to both uniform states with switching energies 1,000 times lower than the state of the art. Here, the applied voltage emulates a magnetic field and, in contrast to conventional MTJs, it reshapes both the energetics and kinetics of the switching transition, enabling deterministic bidirectional switching. Our stack platform enables large readout and efficient switching, and is compatible with lateral manipulation of skyrmionic bits, providing the much-anticipated backbone for all-electrical skyrmionic device architectures9,10. Its wafer-scale realizability provides a springboard to harness chiral spin textures for multibit memory and unconventional computing8,11.

The accumulation of nitrogen compounds in shrimp farming water and effluent presents a major challenge. Ammonia is a form of nitrogen that limits shrimp growth due to its potential toxicity and effects on shrimp health and water quality. This study is aimed at identifying promising bioremediators from shrimp pond sludge to mitigate ammonia levels in both culture water and wastewater and at determining major bacterial communities in sludge using metagenomic analysis. A sludge sample was collected from a shrimp pond in Selangor, Malaysia, to isolate potential ammonia-removing bacteria. Out of 64 isolated strains, Bacillus flexusSS2 showed the highest growth in synthetic basal media (SBM) containing ammonium sulfate at a concentration of 70 mg/L as the sole nitrogen source. The strain was then incubated in SBM with varying pH levels and showed optimal growth at pH 6.5–7. After 24 h of incubation, B. flexusSS2 reduced the ammonia concentration from an initial concentration of 5 to 0.01 mg/L, indicating a 99.61% reduction rate, which was highest in SBM at pH 7. Moreover, the strain showed ammonia removal ability at concentrations ranging from 5 to 70 mg/L. Metagenomic analysis revealed that Proteobacteria was the most abundant phylum in the sludge, followed by Cyanobacteria, Actinobacteria, Chloraflexi, Firmicutes, and Campilobacterota. Bacillus flexusSS2 belongs to the Bacillota phylum and has the potential to serve as a bioremediator for removing ammonia from shrimp culture water and wastewater.

Eukaryotic innate immune systems use pattern recognition receptors to sense infection by detecting pathogen-associated molecular patterns, which then triggers an immune response. Bacteria have similarly evolved immunity proteins that sense certain components of their viral predators, known as bacteriophages1–6. Although different immunity proteins can recognize different phage-encoded triggers, individual bacterial immunity proteins have been found to sense only a single trigger during infection, suggesting a one-to-one relationship between bacterial pattern recognition receptors and their ligands7–11. Here we demonstrate that the antiphage defence protein CapRelSJ46in Escherichia colican directly bind and sense two completely unrelated and structurally different proteins using the same sensory domain, with overlapping but distinct interfaces. Our results highlight the notable versatility of an immune sensory domain, which may be a common property of antiphage defence systems that enables them to keep pace with their rapidly evolving viral predators. We found that Bas11 phages harbour both trigger proteins that are sensed by CapRelSJ46during infection, and we demonstrate that such phages can fully evade CapRelSJ46defence only when both triggers are mutated. Our work shows how a bacterial immune system that senses more than one trigger can help prevent phages from easily escaping detection, and it may allow the detection of a broader range of phages. More generally, our findings illustrate unexpected multifactorial sensing by bacterial defence systems and complex coevolutionary relationships between them and their phage-encoded triggers.

BackgroundMultiple tobacco and e-cigarette product (MTEP) use, the concurrent use of two or more different types of tobacco and/or e-cigarettes products, is common among young people in the US. Changes in patterns of MTEP use among US youth between 2014 and 2020 were identified and the determinants of MTEP use were examined.MethodsFour years of repeated cross-sectional data from the US National Youth Tobacco Survey of middle and high school students from grade 6 to 12 (Ntotal=77 402). Multigroup latent class analysis (LCA) was applied to the data series to allow for simultaneous identification of MTEP use patterns between 2014 and 2020. Logistic regression was used to predict class membership on demographic and tobacco-related variables.FindingsOver the 7-year period, LCA identified three patterns: minimal/non-users (MNU: ~89.8%), mostly occasional e-cigarette and cigarette users (MOEC: ~9%) and polytobacco users (POLY: ~1.2%). From 2014 to 2020, MNU increased from 86.4% to 92% (p<0.05), while MOEC and POLY decreased from 11.2% to 7.9% and from 2.4% to 0.1%, respectively. The probability of regular e-cigarette use increased from 0 to 2.3% among MNU, 6% to 31.9% among MOEC and 29.6% to 67.6% among POLY (p<0.05). In binomial logistic regression, being male, in high school, non-heterosexual, living with someone who uses tobacco at home, having cognitive difficulties, having lower perceptions of tobacco’s danger and exposure to tobacco marketing were associated with greater odds of MOEC and POLY than MNU.ConclusionsThere was an increase in regular e-cigarette use in all three classes, but a corresponding decrease in the proportion of MTEP use. Public health interventions to discourage uptake of e-cigarettes, such as tighter restrictions on marketing to minors, are warranted and there is a need to consider disparities in the determinants of MTEP use.

Aims:Hospital readmissions due to recurrent fluid overload in diabetes and diabetic kidney disease can be avoided with evidence-based interventions. We aimed to identify at-risk patients who can benefit from these interventions by developing risk prediction models for readmissions for fluid overload in people living with diabetes and diabetic kidney disease. Methods:This was a single-center retrospective cohort study of 1,531 adults with diabetes and diabetic kidney disease hospitalized for fluid overload, congestive heart failure, pulmonary edema, and generalized edema between 2015 and 2017. The multivariable regression models for 30-day and 90-day readmission for fluid overload were compared with the LACE score for discrimination, calibration, sensitivity, specificity, and net reclassification index (NRI). Results:Readmissions for fluid overload within 30 days and 90 days occurred in 8.6% and 17.2% of patients with diabetes, and 8.2% and 18.3% of patients with diabetic kidney disease, respectively. After adjusting for demographics, comorbidities, clinical parameters, and medications, a history of alcoholism (HR 3.85, 95% CI: 1.41–10.55) and prior hospitalization for fluid overload (HR 2.50, 95% CI: 1.26–4.96) were independently associated with 30-day readmission in patients with diabetic kidney disease, as well as in individuals with diabetes. Additionally, current smoking, absence of hypertension, and high-dose intravenous furosemide were also associated with 30-day readmission in individuals with diabetes. Prior hospitalization for fluid overload (HR 2.43, 95% CI: 1.50–3.94), cardiovascular disease (HR 1.44, 95% CI: 1.03–2.02), eGFR ≤45 mL/min/1.73 m2(HR 1.39, 95% CI: 1.003–1.93) was independently associated with 90-day readmissions in individuals with diabetic kidney disease. Additionally, thiazide prescription at discharge reduced 90-day readmission in diabetic kidney disease, while the need for high-dose intravenous furosemide predicted 90-day readmission in diabetes. The clinical and clinico-psychological models for 90-day readmission in individuals with diabetes and diabetic kidney disease had better discrimination and calibration than the LACE score. The NRI for the clinico-psychosocial models to predict 30- and 90-day readmissions in diabetes was 22.4% and 28.9%, respectively. The NRI for the clinico-psychosocial models to predict 30- and 90-day readmissions in diabetic kidney disease was 5.6% and 38.9%, respectively. Conclusion:The risk models can potentially be used to identify patients at risk of readmission for fluid overload for evidence-based interventions, such as patient education or transitional care programs to reduce preventable hospitalizations.

Substance use disorders are common and costly psychiatric disorders. According to the 2016 National Survey on Drug Use and Health (NSDUH), an estimated 51.3 million Americans aged 12 or older [...]

ABSTRACT The potential applications of fiber reinforced polymer (FRP) composites as concrete confinement in retrofitting existing concrete columns and in the construction of new high-performance composite columns have received significant [...]

ABSTRACT Accurate prediction of stress-strain relationship of concrete is of vital importance to accurately predict the overall structural behavior of reinforced concrete members. The various types of concrete that are [...]

ABSTRACT Confinement of high-strength concrete (HSC) columns with fiber reinforced polymer (FRP) composites has been receiving increasing research attention due to the advantageous engineering properties offered by the composite system. [...]

ObjectiveSmoking remains prevalent in many countries despite rigorous tobacco control strategies. The use of Swedish snus, a type of low-nitrosamine smokeless tobacco, has been promoted as a tobacco harm reduction strategy.Data sources and study selectionThree databases were searched for studies that assessed the effectiveness of snus in promoting smoking abstinence. A total of 28 studies were reviewed (5 randomised controlled trials (RCTs), 7 longitudinal and 16 cross-sectional studies).Data extractionSeparate meta-analyses were conducted by study type, pooling effect estimates where outcome measures and design were sufficiently comparable. Study details and quality assessment (Risk of Bias 2 for RCTs, Newcastle-Ottawa Scale for observational studies) are provided for each study.Data synthesisWhile the meta-analysis of RCTs did not show a significant association between snus use and smoking cessation (risk ratio (RR)=1.33, 95% CI 0.71 to 2.47 and RR=0.62, 95% CI 0.27 to 1.41), the results of the meta-analysis of longitudinal cohort studies (RR=1.38, 95% CI 1.05 to 1.82, p=0.022) and cross-sectional studies (OR=1.87, 95% CI 1.29 to 2.72, p=0.001) indicated that use of snus was associated with an increased likelihood of quitting or having quit smoking. There was significant heterogeneity in the cross-sectional studies, and leave-one-out analysis indicated that the longitudinal cohort results were driven by one study. Most studies examined were subject to an elevated risk of bias.ConclusionThere is weak evidence for the use of snus for smoking cessation. Better RCTs and longitudinal studies are needed; meanwhile, existing cessation aids may be better placed than snus to promote abstinence.

Device-independent quantum key distribution (DIQKD) enables the generation of secret keys over an untrusted channel using uncharacterized and potentially untrusted devices1–9. The proper and secure functioning of the devices can be certified by a statistical test using a Bell inequality10–12. This test originates from the foundations of quantum physics and also ensures robustness against implementation loopholes13, thereby leaving only the integrity of the users’ locations to be guaranteed by other means. The realization of DIQKD, however, is extremely challenging—mainly because it is difficult to establish high-quality entangled states between two remote locations with high detection efficiency. Here we present an experimental system that enables for DIQKD between two distant users. The experiment is based on the generation and analysis of event-ready entanglement between two independently trapped single rubidium atoms located in buildings 400 metre apart14. By achieving an entanglement fidelity of ℱ≥0.892(23)and implementing a DIQKD protocol with random key basis15, we observe a significant violation of a Bell inequality of S= 2.578(75)—above the classical limit of 2—and a quantum bit error rate of only 0.078(9). For the protocol, this results in a secret key rate of 0.07 bits per entanglement generation event in the asymptotic limit, and thus demonstrates the system’s capability to generate secret keys. Our results of secure key exchange with potentially untrusted devices pave the way to the ultimate form of quantum secure communications in future quantum networks.

One of the lessons that can be learned from past experiences in building mission-critical Internet systems include the need for a clear definition of the development objective. Other useful tips include the use of an incremental and iterative model, the organization around processes and life cycles, the application of process improvement and reengineering, the utilization of parallel development teams and the adaptation of the model.

The polo-box domain (PBD) of Plk1 is a promising target for cancer therapeutics. We designed and synthesized novel phosphorylated macrocyclic peptidomimetics targeting PBD based on acyclic phosphopeptide PMQSpTPL. The inhibitory activities of 16eon Plk1-PBD is >30-fold higher than those of PMQSpTPL. Both 16aand 16epossess excellent selectivity for Plk1-PBD over Plk2/3-PBD. Analysis of the cocrystal structure of Plk1-PBD in complex with 16areveals that the 3-(trifluoromethyl)benzoyl group in 16ainteracts with Arg516 through a π-stacking interaction. This π-stacking interaction, which has not been reported previously, provides insight into the design of novel and potent Plk1-PBD inhibitors. Furthermore, 16h, a PEGlyated macrocyclic phosphopeptide derivative, induces Plk1 delocalization and mitotic failure in HeLa cells. Also, the number of phospho-H3-positive cells in a zebrafish embryo increases in proportion to the amount of 16a. Collectively, the novel macrocyclic peptidomimetics should serve as valuable templates for the design of potent and novel Plk1-PBD inhibitors.

IMPORTANCE: Vaping products were initially designed to deliver nicotine as a tobacco cigarette substitute (eg, electronic cigarettes) but are now frequently used to deliver psychoactive substances, such as cannabis and its derivatives. Large, nationally representative surveys, such as Monitoring the Future, found that approximately 1 in 3 grade-12 students vaped cannabis in 2018 alone. OBJECTIVE: To summarize the findings of epidemiological studies that reported the global prevalence of cannabis vaping in adolescents by survey year and school grades. DATA SOURCES: PubMed, PsycINFO, Scopus, and Web of Science were searched systematically on August 19, 2020, for studies published globally between January 1, 2003, and August 19, 2020. STUDY SELECTION: Publications that reported the prevalence of cannabis vaping in adolescents in the general population were included. DATA EXTRACTION AND SYNTHESIS: Study characteristics and prevalence estimates were extracted from each article. Random-effects meta-analysis based on the DerSimonian and Laird method and meta-regression were performed on lifetime, 12-month, and 30-day prevalence estimates. Meta-regression was also conducted using survey year and school grades as moderators. MAIN OUTCOMES AND MEASURES: Prevalence of cannabis vaping. RESULTS: Seventeen studies met the eligibility criteria (n = 198 845 adolescents). Although no restrictions were imposed on study location, all 17 studies were from the US and Canada. Across all school grades, the pooled prevalence increased for lifetime use (6.1% in 2013-2016 to 13.6% in 2019-2020), use in the past 12 months (7.2% in 2017-2018 to 13.2% in 2019-2020), and use in the past 30 days (1.6% in 2013-2016 to 8.4% in 2019-2020). Heterogeneity across studies was large. The limited evidence from studies using similar survey and study designs suggested that adolescents’ preference for cannabis products other than dried herbs, which usually contain higher Δ9-tetrahydrocannabinol levels, may have shifted over time. CONCLUSIONS AND RELEVANCE: The findings of this study suggest that the prevalence of cannabis vaping has increased among adolescents in the US and Canada and that more effective preventive and response measures are required. TRIAL REGISTRATION: PROSPERO Identifier: CRD42020219644

BackgroundIdentifying patients with BRCAmutations is clinically important to inform on the potential response to treatment and for risk management of patients and their relatives. However, traditional referral routes may not meet clinical needs, and therefore, mainstreaming cancer genetics has been shown to be effective in some high-income and high health-literacy settings. To date, no study has reported on the feasibility of mainstreaming in low-income and middle-income settings, where the service considerations and health literacy could detrimentally affect the feasibility of mainstreaming.MethodsThe Mainstreaming Genetic Counselling for Ovarian Cancer Patients (MaGiC) study is a prospective, two-arm observational study comparing oncologist-led and genetics-led counselling. This study included 790 multiethnic patients with ovarian cancer from 23 sites in Malaysia. We compared the impact of different method of delivery of genetic counselling on the uptake of genetic testing and assessed the feasibility, knowledge and satisfaction of patients with ovarian cancer.ResultsOncologists were satisfied with the mainstreaming experience, with 95% indicating a desire to incorporate testing into their clinical practice. The uptake of genetic testing was similar in the mainstreaming and genetics arm (80% and 79%, respectively). Patient satisfaction was high, whereas decision conflict and psychological impact were low in both arms of the study. Notably, decisional conflict, although lower than threshold, was higher for the mainstreaming group compared with the genetics arm. Overall, 13.5% of patients had a pathogenic variant in BRCA1or BRCA2,and there was no difference between psychosocial measures for carriers in both arms.ConclusionThe MaGiC study demonstrates that mainstreaming cancer genetics is feasible in low-resource and middle-resource Asian setting and increased coverage for genetic testing.

AbstractIn past iterations of ecclesiastical historical writings and teachings, there has not always been sufficient acknowledgment of the encounters between Christians and their religious Others. This article is an exercise in diachronic comparative interreligious encounter: a Muslim-Christian engagement in the eighth century CE and a Jewish-Christian epistolary exchange in the seventeenth century CE. The former took place in Baghdad in the court of a caliph, whereas the latter took place between individuals in London and the Hague, between Baruch Spinoza and Henry Oldenburg. While it might be tempting to highlight the narratives of conversion away from one religion into another—whether from Christianity to Islam, Christianity to Judaism, or vice versa—in current historiography, it also seems that quotidian realities of interreligious exchange often do not lead to such conversions, and yet leave the participants better informed and further enlightened about the practice and pursuit of their own religion. The following two accounts are neither triumphalist nor tragic. Patriarch Timothy and Caliph al-Mahdī's exchange in eighth-century Baghdad shows the degree to which divine identity and Christian apophasismattered. The letter exchanges between Spinoza and his interlocutors also show the degree to which divine mystery as ontological demarcator for both the doctrine of the Trinity and corresponding Christology, as well as Spinoza's repudiation of both, mattered. Lastly, these two examples of interreligious engagements show a pathway of encounter which does not dismiss or cancel the religious Other.

Emergency departments (EDs) often serve vulnerable populations who may lack primary care and have suffered disproportionate COVID-19 pandemic effects. Comparing patients having and lacking a regular source of medical care and other ED patient characteristics, we assessed COVID-19 vaccine hesitancy, reasons for not wanting the vaccine, perceived access to vaccine sites, and willingness to get the vaccine as part of ED care.

Purpose: Regulatory convergence and cooperation among medical product regulatory authorities are essential to delivering safe and efficacious products quickly to patients. The COVID-19 pandemic highlights the urgent need for streamlined regulatory approval processes—which can be achieved in part through regulatory convergence and cooperation—both to accelerate availability of COVID-19 vaccines, treatments and diagnostics and to maintain the availability of the existing medical products unrelated to COVID-19. Methods: The Asia–Pacific Economic Cooperation (APEC) Life Sciences Innovation Forum (LSIF) established the Regulatory Harmonization Steering Committee (RHSC) in 2008 to advance regulatory convergence among APEC’s 21 member economies. Key performance indicators (KPIs) were developed in 2018 to measure convergence. Results: This paper reports survey results collected from KPI tracking in March 2020 from medical product regulatory authorities in all 21 APEC economies concerning areas of regulatory practice in which they could converge and cooperate. For example, from 2008 to 2020, there was a 14.3% increase in the number of APEC member economy regulatory authorities sharing Good Manufacturing Practices (GMP) Certificates and a 28% increase in the number of regulatory authorities accepting multisite licenses in that same period. In addition, this paper explores how APEC economies could realize a maximum level of regulatory convergence and cooperation. Conclusions: Convergence efforts within APEC can accelerate availability of medical products including that related to COVID-19 vaccines, treatments and diagnostics, while maintaining the availability of the existing medical products unrelated to COVID-19 vaccines and treatment. New KPIs and capability building are to be considered to enable a new era of innovation ushered in by COVID-19.

We determine the percentage of diagnosed and undiagnosed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection among a sample of US emergency department (ED) health care personnel before July 2020.

Supplemental Digital Content is available in the text.

The prevalent model for cataract formation in the eye lens posits that damaged crystallin proteins form light-scattering aggregates. The a-crystallins are thought to counteract this process as chaperones by sequestering misfolded crystallin proteins. In this scenario, chaperone pool depletion would result in lens opacification. Here we analyze lenses from different mouse strains that develop early-onset cataract due to point mutations in a-, ß-, or ?-crystallin proteins. We find that these mutant crystallins are unstable in vitro; in the lens, their levels are substantially reduced, and they do not accumulate in the water-insoluble fraction. Instead, all the other crystallin proteins, including the a-crystallins, are found to precipitate. The changes in protein composition and spatial organization of the crystallins observed in the mutant lenses suggest that the imbalance in the lenticular proteome and altered crystallin interactions are the bases for cataract formation, rather than the aggregation propensity of the mutant crystallins.

ObjectivesAdolescents and young adults (AYAs) face difficulties accessing sexual and reproductive health services. These difficulties were exacerbated for a variety of reasons by the COVID-19 pandemic. We document strategies and outcomes implemented at an urban youth sexual health clinic in Florida that allowed uninterrupted provision of services while protecting against spread of COVID-19.MethodsThe plan–do–study–act (PDSA) model was used to implement COVID-19 interventions designed to allow continued service delivery while protecting the health and safety of staff and patients. This method was applied to clinic operations, community referral systems and community outreach to assess and refine interventions within a quick-paced feedback loop.ResultsDuring the COVID-19 pandemic, changes made via PDSA cycles to clinical/navigation services, health communications and youth outreach/engagement effectively responded to AYA needs. Although overall numbers of youth served decreased, all youth contacting the clinic for services were able to be accommodated. Case finding rates for chlamydia, gonorrhoea, syphilis and HIV were similar to pre-pandemic levels.ConclusionsQuality improvement PDSA initiatives at AYA sexual health clinics, particularly those for underserved youth, can be used to adapt service delivery when normal operating models are disrupted. The ability for youth sexual health clinics to adapt to a changing healthcare landscape will be crucial in ensuring that under-resourced youth are able to receive needed services and ambitious Ending the HIV Epidemic goals are achieved.

Extreme phenotypes of OSA have not been systematically defined.

Radical ring‐opening polymerization (rROP) reaction of cyclic ketene acetals (CKA) is an interesting route to biodegradable polymers. Contrary to their tremendous potential, fundamental understanding of their reaction kinetics and thermodynamics is still limited. We present experimental and theoretical investigations for rROP reactions of CKA to systematically elucidate the effects of monomer ring sizes on the homopolymerization. We aim to provide insights on the structural‐reactivity relationship of CKA by studying the thermodynamics and kinetics of the forward ring‐opening propagation reactions and key side reactions, namely ring‐retained propagation and radical back‐biting reaction leading to branching. Experimental results show that for the CKA with smaller ring sizes, significant amount of ring‐retained side products are formed when up to 90% of the monomers are converted. However, for the larger ring sizes (7 and 8 membered), almost complete ring‐opening polymerization with <1% of ring‐retained products are formed. Density functional theory (DFT) calculations show that kinetic effects from the collision frequency dominate in differentiating between ring‐opening propagation, ring‐retained propagation, and backbiting. The results corroborate well with experiments and reports in the literature. Our systematic study from the first principle and experimental validation provide insights into CKA rROP to apply radical polymerization to generate biodegradable polymers. The ring size of the monomer profoundly affects the reactivity and the structure of the polymers. Experiment results show that cyclic ketene acetals (CKA) with smaller ring sizes have a significant amount of ring‐retained side products compared with their counterparts with larger ring sizes. The study reveals clues on the type of monomers and reaction conditions to adopt for introducing degradability in radical polymers.

Human laboratory paradigms are a pillar in medication development for alcohol use disorders (AUD). Neuroimaging paradigms, in which individuals are exposed to cues that elicit neural correlates of alcohol craving (e.g., mesocorticolimbic activation), are increasingly utilized to test the effects of AUD medications. Elucidation of the translational effects of these neuroimaging paradigms on human laboratory paradigms, such as self‐administration, is warranted. The current study is a secondary analysis examining whether alcohol cue–induced activation in the ventral striatum is predictive of subsequent alcohol self‐administration in the laboratory. Non–treatment‐seeking heavy drinkers of East Asian descent (n= 41) completed a randomized, placebo‐controlled, double‐blind, crossover experiment on the effects of naltrexone on neuroimaging and human laboratory paradigms. Participants completed 5 days of study medication (or placebo); on day 4, they completed a neuroimaging alcohol taste cue–reactivity task. On the following day (day 5), participants completed a 60‐minute alcohol self‐administration paradigm. Multilevel Cox regressions indicated a significant effect of taste cue–elicited ventral striatum activation on latency to first drink, Wald χ2= 2.88, p= 0.05, such that those with higher ventral striatum activation exhibited shorter latencies to consume their first drink. Similarly, ventral striatum activation was positively associated with total number of drinks consumed, F(1, 38) = 5.90, p= 0.02. These effects were significant after controlling for alcohol use severity, OPRM1 genotype, and medication. Other potential regions of interest (anterior cingulate, thalamus) were not predictive of self‐administration outcomes. Neuroimaging alcohol taste cue paradigms may be predictive of laboratory paradigms such as self‐administration. Elucidation of the relationships among different paradigms will inform how these paradigms may be used synergistically in experimental medicine and medication development. Among heavy drinkers, alcohol taste cue‐elicited ventral striatum activation is positively associated with total number of drinks consumed in subsequent oral alcohol self‐administration. Depicted above, ventral striatum activation is also negatively associated with latency to first drink (seconds) during alcohol self‐administration. Ventral striatum median‐split (SA_VSmed; 0 = below median, 1 = above median) is for visualization purposes only; a continuous ventral striatum activity variable was used in analyses. Results are significant after controlling for OPRM1, alcohol use severity, and medication.

Hypertension is a highly common condition with well-established adverse consequences. Ambulatory blood pressure monitoring has repeatedly been shown to better predict cardiovascular outcomes and mortality, compared to single office visit blood pressure. Non-dipping of sleep-time blood pressure is an independent marker for increased cardiovascular risk. We review blood pressure variability and the challenges of blood pressure monitoring during sleep. Although pathological sleep such as obstructive sleep apnea has been associated with non-dipping of sleep-time blood pressure, blood pressure is not routinely measured during sleep due to lack of unobtrusive blood pressure monitoring technology. Second, we review existing noninvasive continuous blood pressure monitoring technologies. Lastly, we propose including sleep-time blood pressure monitoring during sleep studies and including sleep studies in patients undergoing ambulatory blood pressure monitoring.

The DNAJ-PKAc fusion kinase is a defining feature of fibrolamellar carcinoma (FLC). FLC tumors are notoriously resistant to standard chemotherapies, with aberrant kinase activity assumed to be a contributing factor. By combining proximity proteomics, biochemical analyses, and live-cell photoactivation microscopy, we demonstrate that DNAJ-PKAc is not constrained by A-kinase anchoring proteins. Consequently, the fusion kinase phosphorylates a unique array of substrates, including proteins involved in translation and the anti-apoptotic factor Bcl-2-associated athanogene 2 (BAG2), a co-chaperone recruited to the fusion kinase through association with Hsp70. Tissue samples from patients with FLC exhibit increased levels of BAG2 in primary and metastatic tumors. Furthermore, drug studies implicate the DNAJ-PKAc/Hsp70/BAG2 axis in potentiating chemotherapeutic resistance. We find that the Bcl-2 inhibitor navitoclax enhances sensitivity to etoposide-induced apoptosis in cells expressing DNAJ-PKAc. Thus, our work indicates BAG2 as a marker for advanced FLC and a chemotherapeutic resistance factor in DNAJ-PKAc signaling scaffolds.

In the early months of the coronavirus disease 2019 (COVID-19) pandemic and before vaccine availability, there were concerns that infected emergency department (ED) health care personnel could present a threat to the delivery of emergency medical care. We examined how the pandemic affected staffing levels and whether COVID-19 positive staff were potentially infectious at work in a cohort of US ED health care personnel in 2020.

A ‘twin-field’ repeater-less protocol has enabled an experimental demonstration of secure quantum key distribution over a 511-km long-haul optical fibre link.

The glass-transition temperature (Tg) of a polymer–nanoparticle composite system is strongly dependent on the local segmental dynamics of the polymers. These dynamics, in turn, are dependent on the types of interfacial interactions that exist between the nanoparticle and the polymers. In this work, we investigate the magnitude of Tgchange with respect to the polymer–nanoparticle interactions by performing molecular dynamics simulations for a full-atomistic model of poly(vinyl alcohol) (PVA)–silica nanocomposites. Our segmental dynamics analysis and potential of mean force calculations indicate that the strong binding interaction between the hydroxylated-silica surface and the poly(vinyl alcohol) (PVA) is able to induce an increase in the Tgof the composite system with respect to the bulk PVA polymer system. While we expect that the Tgof the system will increase with an increasing amount of hydrogen bonds arising from the increasing surface hydroxylation, the trend of increasing Tgreaches a maximum when the surface is about 75% hydroxylated. Beyond 75% hydroxylation, we see a drop in the Tg. The detailed analysis of the interfacial hydrogen-bonding counts, strengths, and radial distributions sheds light on the underlying factors that induce the drop in the Tgbeyond 75% hydroxylation. We found that the competition between inter-PVA–silanol and intra-silanol–silanol interactions is the key factor that contributes to the drop in Tg. Our results allude to the fact that the count and strengths of the different kinds of hydrogen bonds in a polymer–nanocomposite system can be modulated to enable the optimization of the Tgchange desired for specific applications.

In the past 50 years, there have been two major changes that are of methodological and consequential importance to the McHargian land-use suitability analysis (LUSA): increasing evidence of non-stationarity of global and regional ecological conditions and increasing availability of high-resolution spatial–temporal earth observation data. For 50 years, the McHargian LUSA has been an important analysis tool for designers and planners for both regional conservation planning and development. McHarg’s LUSA is a decision support tool that reduces the dimensions of spatial–temporal data. This makes the technique relevant beyond decision support to spatial identification and prediction of areas of socio-ecological opportunity, risk, and priority. In this article, I use a set of recent studies relating to agricultural LUSA to reveal relationships between the traditional McHargian LUSA and related spatial–temporal research methods that are adapting to more data and non-stationary ecological conditions. Using a classification based on descriptive, predictive, and prescriptive research activities, I organize these related methods and illustrate how linkages between research activities can be used to assimilate more kinds of spatial “big data,” address non-stationarity in socio-ecological systems, and suggest ways to enhance decision-making and collaboration between planners and other sciences.

To compare the return of bladder function and genitourinary complications after type C1 robotic nerve-sparing radical hysterectomy (C1-RRH) to type C2 robotic radical hysterectomy (C2-RRH) in gynecologic cancers.

Despite a rich literature on human laboratory paradigms of subjective response (SR) to alcohol, craving for alcohol, and alcohol self‐administration, few studies have examined the interplay across these 3 constructs. The present study addresses this gap in the literature by examining the interplay between SR, craving, and self‐administration in the human laboratory. Data were culled from a medication study (NCT02026011) in which heavy drinking participants of East Asian ancestry completed 2 double‐blinded and counterbalanced experimental sessions. In each experimental session, participants received a priming dose of intravenous (IV) alcohol to a target breath alcohol concentration (BrAC) of 0.06 g/dl and measures of SR (stimulation and sedation) and alcohol craving were collected across rising BrACs. The IV alcohol challenge was immediately followed by a 1‐hour alcohol self‐administration period. Mixed model analyses found a positive and significant relationship between the slope of stimulation and the slope of craving during the alcohol challenge. The relationship between sedation and craving, however, was not significant. The slope of craving during the alcohol challenge significantly predicted a higher number of mini‐drinks consumed and lower latency to first drink. Further, mediation analyses found that craving was a significant mediator of the relationship between stimulation and total number of mini‐drinks consumed, but the same pattern was not found for sedation. Insofar as alcohol self‐administration represents the end point of interest for a host of experimental and clinical research questions, the present study suggests that alcohol craving represents a more proximal predictor of self‐administration than measures of alcohol‐induced stimulation. It is recommended that human laboratory models interpret measures of SR and craving in light of their relative predictive utility for drinking outcomes.

Learned fear often relapses after extinction, suggesting that extinction training generates a new memory that coexists with the original fear memory; however, the mechanisms governing the expression of competing fear and extinction memories remain unclear. We used activity-dependent neural tagging to investigate representations of fear and extinction memories in the dentate gyrus. We demonstrate that extinction training suppresses reactivation of contextual fear engram cells while activating a second ensemble, a putative extinction engram. Optogenetic inhibition of neurons that were active during extinction training increased fear after extinction training, whereas silencing neurons that were active during fear training reduced spontaneous recovery of fear. Optogenetic stimulation of fear acquisition neurons increased fear, while stimulation of extinction neurons suppressed fear and prevented spontaneous recovery. Our results indicate that the hippocampus generates a fear extinction representation and that interactions between hippocampal fear and extinction representations govern the suppression and relapse of fear after extinction.

Brief interventions have empirical support for acutely reducing alcohol use among non–treatment‐seeking heavy drinkers. Neuroimaging techniques allow for the examination of the neurobiological effect of behavioral interventions, probing brain systems putatively involved in clinical response to treatment. Few studies have prospectively evaluated whether psychosocial interventions attenuate neural cue reactivity that in turn reduces drinking in the same population. This study aimed to examine the effect of a brief intervention on drinking outcomes, neural alcohol cue reactivity, and the ability of neural alcohol cue reactivity to prospectively predict drinking outcomes. Non–treatment‐seeking heavy drinking participants were randomized to receive a brief interview intervention (n= 22) or an attention‐matched control (n= 24). Immediately following the intervention or control, participants underwent a functional magnetic resonance imaging scan comprised of the alcohol taste cues paradigm. Four weeks after the intervention (or control), participants completed a follow‐up visit to report on their past‐month drinking. Baseline and follow‐up percent heavy drinking days (PHDD) were calculated for each participant. There was no significant effect of the brief intervention on PHDDat follow‐up or on modulating neural activation to alcohol relative to water taste cues. There was a significant association between neural response to alcohol taste cues and PHDDacross groups (Z> 2.3, p < 0.05), such that individuals who had greater neural reactivity to alcohol taste cues in the precuneus and prefrontal cortex (PFC) had fewer PHDDat follow‐up. This study did not find an effect of the brief intervention on alcohol use in this sample, and the intervention was not associated with differential neural alcohol cue reactivity. Nevertheless, greater activation of the precuneus and PFC during alcohol cue exposure predicted less alcohol use prospectively suggesting that these neural substrates subserve the effects of alcohol cues on drinking behavior. This study examined the effect of a brief intervention on drinking outcomes, neural alcohol cue reactivity, and the ability of neural alcohol cue reactivity to prospectively predict drinking outcomes. Findings indicate no significant effect of the brief intervention on drinking outcomes or on neural alcohol cue reactivity. There was a significant association between neural response to alcohol cues and drinking outcomes, such that individuals with greater precuneus neural reactivity to alcohol cues had less heavy drinking days at follow‐up.