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We propose and demonstrate an architecture for fluxonium-fluxonium two-qubit gates mediated by transmon couplers (FTF, for fluxonium-transmon-fluxonium). Relative to architectures that exclusively rely on a direct coupling between fluxonium qubits, FTF enables stronger couplings for gates using noncomputational states while simultaneously suppressing the static controlled-phase entangling rate (ZZ) down to kilohertz levels, all without requiring strict parameter matching. Here, we implement FTF with a flux-tunable transmon coupler and demonstrate a microwave-activated controlled-Z (CZ) gate whose operation frequency can be tuned over a 2-GHz range, adding frequency allocation freedom for FTFs in larger systems. Across this range, state-of-the-art CZ gate fidelities are observed over many bias points and reproduced across the two devices characterized in this work. After optimizing both the operation frequency and the gate duration, we achieve peak CZ fidelities in the 99.85%–99.9% range. Finally, we implement model-free reinforcement learning of the pulse parameters to boost the mean gate fidelity up to 99.922%±0.009%, averaged over roughly an hour between scheduled training runs. Beyond the microwave-activated CZ gate we present here, FTF can be applied to a variety of other fluxonium gate schemes to improve gate fidelities and passively reduce unwanted ZZ interactions.

We develop a class of matrix models that implement and formalize the eigenstate thermalization hypothesis (ETH) and point out that, in general, these models must contain non-Gaussian corrections in order to correctly capture thermal mean-field theory or to capture nontrivial out-of-time-order correlation functions (OTOCs) as well as their higher-order generalizations. We develop the framework of these ETH matrix models and put it in the context of recent studies in statistical physics incorporating higher statistical moments into the ETH ansatz. We then use the ETH matrix model in order to develop a matrix-integral description of Jackiw-Teitelboim (JT) gravity coupled to a single scalar field in the bulk. This particular example takes the form of a double-scaled ETH matrix model with non-Gaussian couplings matching disk correlators and the density of states of the gravitational theory. Having defined the model from the disk data, we present evidence that the model correctly captures the JT+matter theory with multiple boundaries and, conjecturally, at higher genus. This is a shorter companion paper to the work [D. L. Jafferis et al., companion paper, Jackiw-Teitelboim gravity with matter, generalized eigenstate thermalization hypothesis, and random matrices, Phys. Rev. D 108, 066015 (2023).PRVDAQ2470-001010.1103/PhysRevD.108.066015], serving as a guide to the much more extensive material presented there, as well as developing its underpinning in statistical physics.

Abstract WDR5 nucleates the assembly of histone-modifying complexes and acts outside this context in a range of chromatin-centric processes. WDR5 is also a prominent target for pharmacological inhibition in cancer. Small-molecule degraders of WDR5 have been described, but most drug discovery efforts center on blocking the WIN site of WDR5, an arginine binding cavity that engages MLL/SET enzymes that deposit histone H3 lysine 4 methylation (H3K4me). Therapeutic application of WIN site inhibitors is complicated by the disparate functions of WDR5, but is generally guided by two assumptions—that WIN site inhibitors disable all functions of WDR5, and that changes in H3K4me drive the transcriptional response of cancer cells to WIN site blockade. Here, we test these assumptions by comparing the impact of WIN site inhibition versus WDR5 degradation on H3K4me and transcriptional processes. We show that WIN site inhibition disables only a specific subset of WDR5 activity, and that H3K4me changes induced by WDR5 depletion do not explain accompanying transcriptional responses. These data recast WIN site inhibitors as selective loss-of-function agents, contradict H3K4me as a relevant mechanism of action for WDR5 inhibitors, and indicate distinct clinical applications of WIN site inhibitors and WDR5 degraders.

The aims of this study are to describe the use of pharmaceutical venous thromboembolism (pVTE) prophylaxis in patients with traumatic brain injury (TBI) in Europe and study the association of pVTE prophylaxis with outcome. We included 2006 patients ?18 years of age admitted to the intensive care unit from the CENTER-TBI study. VTE events were recorded based on clinical symptoms. Variation between 54 centers in pVTE prophylaxis use was assessed with a multi-variate random-effect model and quantified with the median odds ratio (MOR). The association between pVTE prophylaxis and outcome (Glasgow Outcome Scale-Extended at 6 months) was assessed at center level with an instrumental variable analysis and at patient level with a multi-variate proportional odds regression analysis and a propensity-matched analysis. A time-dependent Cox survival regression analysis was conducted to determine the effect of pVTE prophylaxis on survival during hospital stay. The association between VTE prophylaxis and computed tomography (CT) progression was assessed with a logistic regression analysis. Overall, 56 patients (2%) had a VTE during hospital stay. The majority, 1279 patients (64%), received pVTE prophylaxis, with substantial between-center variation (MOR, 2.7; p?0.001). A moderate association with improved outcome was found at center level (odds ratio [OR], 1.2 [0.7?2.1]) and patient level (multi-variate adjusted OR, 1.4 [1.1?1.7], and propensity adjusted OR, 1.5 [1.1?2.0]), with similar results in subgroup analyses. Survival was higher with the use of pVTE prophylaxis (p?

Abstract Background Despite the important upstream impact policy has on population health outcomes, few studies in implementation science in health have examined implementation processes and strategies used to translate state and federal policies into accessible services in the community. This study examines the policy implementation strategies and experiences of Medicaid programs in three US states that responded to a federal prompt to improve access to evidence-based practice (EBP) substance use disorder (SUD) treatment. Methods Three US state Medicaid programs implementing American Society of Addiction Medicine (ASAM) Criteria-driven SUD services under Section 1115 waiver authority were used as cases. We conducted 44 semi-structured interviews with Medicaid staff, providers and health systems partners in California, Virginia, and West Virginia. Interviews were triangulated with document review of state readiness and implementation plans. The Exploration, Preparation, Implementation, Sustainment Framework (EPIS) guided qualitative theme analysis. The Expert Recommendations for Implementing Change and Specify It criteria were used to create a taxonomy of policy implementation strategies used by policymakers to promote providers’ uptake of statewide EBP SUD care continuums. Results Four themes describe states’ experiences and outcomes implementing a complex EBP SUD treatment policy directive: (1) Medicaid agencies adapted their inner/outer contexts to align with EBPs and adapted EBPs to fit their local context; (2) enhanced financial reimbursement arrangements were inadequate bridging factors to achieve statewide adoption of new SUD services; (3) despite trainings, service providers and managed care organizations demonstrated poor fidelity to the ASAM Criteria; and (4) successful policy adoption at the state level did not guarantee service providers’ uptake of EBPs. States used 29 implementation strategies to implement EBP SUD care continuums. Implementation strategies were used in the Exploration (n=6), Preparation (n=10), Implementation (n=19), and Sustainment (n=6) phases, and primarily focused on developing stakeholder interrelationships, evaluative and iterative approaches, and financing. Conclusions This study enhances our understanding of statewide policy implementation outcomes in low-resource, public healthcare settings. Themes highlight the need for additional pre-implementation and sustainment focused implementation strategies. The taxonomy of detailed policy implementation strategies employed by policymakers across states should be tested in future policy implementation research.

Abstract Despite significant insights into the neural mechanisms of acute placebo responses, less is known about longer-term placebo responses, such as those seen in clinical trials, or their interactions with brain disease. We examined brain correlates of placebo responses in a randomized trial of a then controversial and now disproved endovascular treatment for multiple sclerosis. Patients received either balloon or sham extracranial venoplasty and were followed for 48 weeks. Venoplasty had no therapeutic effect, but a subset of both venoplasty- and sham-treated patients reported a transient improvement in health-related quality of life, suggesting a placebo response. Placebo responders did not differ from non-responders in total MRI T2 lesion load, count or location, nor were there differences in normalized brain volume, regional grey or white matter volume or cortical thickness (CT). However, responders had higher lesion activity. Graph theoretical analysis of CT covariance showed that non-responders had a more small-world-like CT architecture. In non-responders, lesion load was inversely associated with CT in somatosensory, motor and association areas, precuneus, and insula, primarily in the right hemisphere. In responders, lesion load was unrelated to CT. The neuropathological process in MS may produce in some a cortical configuration less capable of generating sustained placebo responses.

Abstract We study Jackiw-Teitelboim gravity with dynamical end of the world branes in asymptotically nearly AdS2 spacetimes. We quantize this theory in Lorentz signature, and compute the Euclidean path integral summing over topologies including dynamical branes. The latter will be seen to exactly match with a modification of the SSS matrix model. The resolution of UV divergences in the gravitational instantons involving the branes will lead us to understand the matrix model interpretation of the Wilsonian effective theory perspective on the gravitational theory. We complete this modified SSS matrix model nonperturbatively by extending the integration contour of eigenvalues into the complex plane. Furthermore, we give a new interpretation of other phases in such matrix models. We derive an effective W(Φ) dilaton gravity, which exhibits similar physics semiclassically. In the limit of a large number of flavors of branes, the effective extremal entropy S 0,eff has the form of counting the states of these branes.

This study reports the X-ray structure of the α1B-adrenergic G protein-coupled receptor bound to an inverse agonist, and unveils key determinants of subtype-selective ligand binding that may help the design of aminergic drugs with fewer side-effects.

Soft X-ray spectromicroscopy at the O K-edge, U N4,5-edges and Ce M4,5-edges has been performed on focused ion beam sections of spent nuclear fuel for the first time, yielding chemical information on the sub-micrometer scale. To analyze these data, a modification to non-negative matrix factorization (NMF) was developed, in which the data are no longer required to be non-negative, but the non-negativity of the spectral components and fit coefficients is largely preserved. The modified NMF method was utilized at the O K-edge to distinguish between two components, one present in the bulk of the sample similar to UO2 and one present at the interface of the sample which is a hyperstoichiometric UO2+x species. The species maps are consistent with a model of a thin layer of UO2+x over the entire sample, which is likely explained by oxidation after focused ion beam (FIB) sectioning. In addition to the uranium oxide bulk of the sample, Ce measurements were also performed to investigate the oxidation state of that fission product, which is the subject of considerable interest. Analysis of the Ce spectra shows that Ce is in a predominantly trivalent state, with a possible contribution from tetravalent Ce. Atom probe analysis was performed to provide confirmation of the presence and localization of Ce in the spent fuel.

Elevated levels of pharmaceuticals, steroid hormones and xenoestrogens (PSHXEs) in the aquatic environment pose a serious threat to the ecological balance. The endocrine disrupting PSHXEs in aquatic systems are linked to several adverse effects like reproductive health impairment, feminization, high mortality rate, decreased biodiversity etc. This study, therefore, sought to investigate the occurrence and the ecological risks posed by some selected PSHXEs and also conduct source apportionment of the PSHXEs in the Ghanaian aquatic environments. A total of 48 samples comprising 24 sediments and water each were taken from six waterbodies in Ghana. The samples were extracted using SPE cartridges for water and QuEChERS-dSPE for sediments. The analyses were done using Shimadzu Prominence UFLC 20A series. Ecological risk assessments were also conducted with the aid of USEPA T.E.S.T., whereas source apportionments were conducted using the APCS-MLR receptor model. Elevated mean total levels of PSHXEs ranging between 12,187 and 52,117 ng/L and 2,022–6,047 ng/g for water and sediment samples respectively were found. The risk quotients (RQ > 1) suggested a high risk posed by PSHXEs in water to organisms at the three trophic levels and also to benthic organisms in sediments of the Ghanaian aquatic environments for a short-term period. The APCS-MLR receptor model suggested three statistically significant sources (p

Human-infecting Cyclospora was recently characterized as three species, two of which (C. cayetanensis and C. ashfordi) are currently responsible for all known human infections in the USA, yet much remains unknown about the genetic structure within these two species. Here, we investigate Cyclospora genotyping data from 2018 through 2022 to ascertain if there are temporal patterns in the genetic structure of Cyclospora parasites that cause infections in US residents from year to year. First, we investigate three levels of genetic characterization: species, subpopulation, and strain, to elucidate annual trends in Cyclospora infections. Next, we determine if shifts in genetic diversity can be linked to any of the eight loci used in our Cyclospora genotyping approach. We observed fluctuations in the abundance of Cyclospora types at the species and subpopulation levels, but no significant temporal trends were identified; however, we found recurrent and sporadic strains within both C. ashfordi and C. cayetanensis. We also uncovered major shifts in the mitochondrial genotypes in both species, where there was a universal increase in abundance of a specific mitochondrial genotype that was relatively abundant in 2018 but reached near fixation (was observed in over 96% of isolates) in C. ashfordi by 2022. Similarly, this allele jumped from 29% to 82% relative abundance of isolates belonging to C. cayetanensis. Overall, our analysis uncovers previously unknown temporal-genetic patterns in US Cyclospora types from 2018 through 2022 and is an important step to presenting a clearer picture of the factors influencing cyclosporiasis outbreaks in the USA.

The search for rocky planet atmospheres with JWST has focused on planets transiting M dwarfs. Such planets have favorable planet-to-star size ratios, enhancing the amplitude of atmospheric features. Since the expected signal strength of atmospheric features is similar to the single-transit performance of JWST, multiple observations are required to confirm any detection. Here, we present two transit observations of the rocky planet GJ 1132 b with JWST NIRSpec G395H, covering 2.8–5.2 μ m. Previous Hubble Space Telescope WFC3 observations of GJ 1132 b were inconclusive, with evidence reported for either an atmosphere or a featureless spectrum based on analyses of the same data set. Our JWST data exhibit substantial differences between the two visits. One transit is consistent with either an H _2 O-dominated atmosphere containing ∼1% CH _4 and trace N _2 O ( ${\chi }_{\nu }^{2}=1.13$ ) or stellar contamination from unocculted starspots ( ${\chi }_{\nu }^{2}=1.36$ ). However, the second transit is consistent with a featureless spectrum. Neither visit is consistent with a previous report of HCN. Atmospheric variability is unlikely to explain the scale of the observed differences between the visits. Similarly, our out-of-transit stellar spectra show no evidence of changing stellar inhomogeneity between the two visits—observed 8 days apart, only 6.5% of the stellar rotation rate. We further find no evidence of differing instrumental systematic effects between visits. The most plausible explanation is an unlucky random noise draw leading to two significantly discrepant transmission spectra. Our results highlight the importance of multivisit repeatability with JWST prior to claiming atmospheric detections for these small, enigmatic planets.

Maternal obesity is a risk factor for pregnancy complications. Obesity caused by a high-fat diet (HFD) may alter maternal glucose/glycogen metabolism. Here, our objective was to investigate whether the placental vasculature is altered via changes in gene expression and glycogen-rich cells using a preclinical mouse model of diet-induced obesity. We subjected female FVB/N mice to one of three feeding regimens: regular chow (RC) given at preconception and during pregnancy (Control); RC given at preconception and then a HFD during pregnancy (HFD-P); or HFD initiated 4 weeks preconception and during pregnancy (HFD-PreCP). Daily food consumption and weekly maternal weights were recorded. Maternal blood glucose levels were measured at preconception and 4 gestational epochs (E6.5-E9.5, E10.5-E12.5, E13.5-E15.5, E16.5-E19.5). At E8.5-E16.5, total RNA in placentas were isolated for gene expression analyses. Placentas were also collected for HE and periodic acid Schiff's (PAS) staining and glycogen content assays. Dams in the HFD-P and HFD-PreCP groups gained significantly more weight than controls. Pre- and antenatal glucose levels were also significantly higher (15%-30%) in HFD-PreCP dams. Expression of several placental genes were also altered in HFD dams compared with controls. Consumption of the HFD also led to phenotypic and morphologic changes in glycogen trophoblasts (GlyTs) and uterine natural killer (uNK) cells. Alterations in vascularity were also observed in the labyrinth of HFD-PreCP placentas, which correlated with decreased placental efficiency. Overall, we observed that a HFD induces gestational obesity in mice, alters expression of placental genes, affects glucose homeostasis, and alters glycogen-positive GlyTs and uNK cells. All these changes may lead to impaired placental vascular development, and thus heighten the risk for pregnancy complications.

Despite the efficacy of tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML), malignant long-term hematopoietic stem cells (LT-HSCs) persist as a source of relapse. However, LT-HSCs are heterogenous and the most primitive, drug-resistant LT-HSC subpopulations are not well characterized. In normal hematopoiesis, self-renewal and long-term reconstitution capacity are enriched within LT-HSCs with low c-Kit expression (c-KITlo). Here, using a transgenic CML mouse model, we found that long-term engraftment and leukemogenic capacity were restricted to c-KITlo CML LT-HSCs. CML LT-HSCs demonstrated enhanced differentiation with expansion of mature progeny following exposure to the c-KIT ligand, stem cell factor (SCF). Conversely, SCF deletion led to depletion of normal LT-HSCs but increase in c-KITlo and total CML LT-HSCs with reduced generation of mature myeloid cells. CML c-KITlo LT-HSCs showed reduced cell cycling and expressed enhanced quiescence and inflammatory gene signatures. SCF administration led to enhanced depletion of CML primitive progenitors but not LT-HSCs after TKI treatment. Human CML LT-HSCs with low or absent c-KIT expression were markedly enriched after TKI treatment. We conclude that CML LT-HSCs expressing low c-KIT levels are enriched for primitive, quiescent, drug-resistant leukemia-initiating cells and represent a critical target for eliminating disease persistence.

Introduction: The epidemiology and prognosis of the isolated traumatic brain injury (TBI) and spinal cord injury (SCI) are well studied. However, the knowledge of the impact of concurrent neurotrauma is very limited. Research questions: To characterize the longitudinal incidence of concurrent TBI and SCI and to investigate their combined impact on clinical care and outcomes, compared to a comparative but isolated SCI or TBI. Materials and methods: Data from 167,793 patients in the Trauma Audit and Research Network (TARN) registry collected in England and Wales between 2008 and 2018 were analysed. Tandem neurotrauma was defined as patients with concurrent TBI and SCI. The patient with isolated TBI or SCI was matched to the patient with tandem neurotrauma using propensity scores. Results: The incidence of tandem neurotrauma increased tenfold between 2008 and 2018, from 0.21 to 2.21 per 100,000 person-years. Patients in the tandem neurotrauma group were more likely to require multiple surgeries, ICU admission, longer ICU and hospital LOS, higher 30-day mortality, and were more likely to be transferred to acute hospitals and rehabilitation or suffer death at discharge, compared to patients with isolated TBI. Likewise, individuals with tandem neurotrauma compared to those with isolated SCI had a higher tendency to receive more than one surgery, ICU admission, longer LOS for ICU and higher mortality either at 30-day follow-up or at discharge. Discussion and conclusions: The incidence of tandem neurotrauma has increased steadily during the past decade. Its occurrence leads to greater mortality and care requirements, particularly when compared to TBI alone. Further investigations are warranted to improve outcomes in tandem neurotrauma.

Planets orbiting M-dwarf stars are prime targets in the search for rocky exoplanet atmospheres. The small size of M dwarfs renders their planets exceptional targets for transmission spectroscopy, facilitating atmospheric characterization. However, it remains unknown whether their host stars’ highly variable extreme-UV radiation environments allow atmospheres to persist. With JWST, we have begun to determine whether or not the most favorable rocky worlds orbiting M dwarfs have detectable atmospheres. Here, we present a 2.8–5.2 μ m JWST NIRSpec/G395H transmission spectrum of the warm (700 K, 40.3× Earth’s insolation) super-Earth GJ 486b (1.3 R _⊕ and 3.0 M _⊕ ). The measured spectrum from our two transits of GJ 486b deviates from a flat line at 2.2 σ − 3.3 σ , based on three independent reductions. Through a combination of forward and retrieval models, we determine that GJ 486b either has a water-rich atmosphere (with the most stringent constraint on the retrieved water abundance of H _2 O > 10% to 2 σ ) or the transmission spectrum is contaminated by water present in cool unocculted starspots. We also find that the measured stellar spectrum is best fit by a stellar model with cool starspots and hot faculae. While both retrieval scenarios provide equal quality fits ( ${\chi }_{\nu }^{2}=1.0$ ) to our NIRSpec/G395H observations, shorter wavelength observations can break this degeneracy and reveal if GJ 486b sustains a water-rich atmosphere.

Takayasu arteritis (TAK) is a rare large-vessel vasculitis that is seen primarily in young females of Asian descent and is infrequently diagnosed in the United States. Pericardial effusion with or without pericarditis as a presenting feature of TAK is rare, with only about five percent of cases of pericarditis attributable to any autoimmune etiology. We present a case of a 22-year-old Caucasian woman who presented with a large, symptomatic pericardial effusion of unclear etiology, who after extensive laboratory workup and imaging to include whole-body positron emission tomography (PET) was diagnosed with TAK. In our patient, the use of whole-body PET showing characteristic hypermetabolism within the aortic arch helped secure our diagnosis while avoiding the need for pericardiocentesis. The patient had rapid symptomatic and radiographic improvement with the use of high-dose oral steroids in addition to colchicine and ibuprofen for her pericarditis and associated pericardial effusion. At follow-up just 1 week after initiation of steroids, only trace effusion was identified on transthoracic echocardiogram.

Landmark-based geometric morphometrics (LGM) is most often used in archaeology to characterize and differentiate groups of artifacts, but it can be used for much more. We demonstrate LGM’s power to uncover new insights by exploring stone-tool allometry, modularity, and integration using a sample of 100 western North American Clovis points. Here, allometry concerns how stone tools change in shape as their size changes through their use-lives, and modularity and integration concern how the constituent parts of a tool work together. We show that Clovis points are surprisingly complex tools. When their blades and hafts are defined technologically, rather than arbitrarily, they unambiguously exhibit allometry, and their hafts and blades are modular and highly integrated. We use these analyses to further explore questions about Clovis points, including the differences between cache and non-cache points. Finally, we use heuristic haft-size categories to examine functional constraints on the shape and size of hafts and blades. This work illustrates the importance of using accurate measurements of point components rather than estimates or proxies, which can lead to unfounded inferences. These analytical approaches and accompanying R code are easily transferable to other research questions of stone-tool use.

The main challenges facing smallholder farmers in sub-Saharan Africa (SSA) are soil fertility decline and climate change, culminating in increased food insecurity. The double effect of climate change and soil fertility decline could be devastating among the poor rural smallholder farmers, who solely depend on rain-fed agriculture with little investment in adaptive mechanisms. Using inorganic fertilizers and careful selection of climate-resilient crops such as sorghum could improve the livelihoods of smallholder farmers through improved soil health and crop yields. However, information on the effects of inorganic fertilizer on sorghum production remains uncertain, especially in SSA. We evaluated the effects of inorganic fertilizers on sorghum yields among smallholder farmers in Western Kenya. We conducted a cross-sectional survey and collected data from 300 smallholder sorghum farmers. We employed a multi-stage sampling procedure to collect data from the specific smallholder farmers from the target population. We employed endogenous switching regression (ESR) modeling to control observed and unobserved bias in predicting the effects of inorganic fertilizer use on productivity. Smallholder farmers applied a limited amount of inorganic fertilizer. We established that hired labor, agricultural training, and farmers' perception of soil erosion were significant positive determinants of inorganic fertilizer use. Location and access to weather forecast information were key negative determinants of inorganic fertilizer use. The use of inorganic fertilizer increased crop yields by 14%. The findings suggested that inorganic amendments could promote food security and improve purchasing power, thus enhancing smallholder farmers' capacity to cope with declining soil fertility and climate change-related challenges. Therefore, agricultural policies targeting improved productivity of smallholder sorghum farmers could enhance inorganic fertilizer use while considering the determinants.

We present the first exoplanet phase-curve measurement made with the JWST NIRSpec instrument, highlighting the exceptional stability of this newly commissioned observatory for exoplanet climate studies. The target, WASP-121b, is an ultrahot Jupiter with an orbital period of 30.6 hr. We analyze two broadband light curves generated for the NRS1 and NRS2 detectors, covering wavelength ranges of 2.70–3.72 μ m and 3.82–5.15 μ m, respectively. Both light curves exhibit minimal systematics, with approximately linear drifts in the baseline flux level of 30 ppm hr ^−1 (NRS1) and 10 ppm hr ^−1 (NRS2). Assuming a simple brightness map for the planet described by a low-order spherical harmonic dipole, our light-curve fits suggest that the phase curve peaks coincide with orbital phases 3.°36 ± 0.°11 (NRS1) and 2.°66 ± 0.°12 (NRS2) prior to mideclipse. This is consistent with the strongest dayside emission emanating from eastward of the substellar point. We measure planet-to-star emission ratios of 3924 ± 7 ppm (NRS1) and 4924 ± 9 ppm (NRS2) for the dayside hemisphere and 136 ± 8 ppm (NRS1) and 630 ± 10 ppm (NRS2) for the nightside hemisphere. The latter nightside emission ratios translate to planetary brightness temperatures of 926 ± 12 K (NRS1) and 1122 ± 10 K (NRS2), which are low enough for a wide range of refractory condensates to form, including enstatite and forsterite. A nightside cloud deck may be blocking emission from deeper, hotter layers of the atmosphere, potentially helping to explain why cloud-free 3D general circulation model simulations systematically overpredict the nightside emission for WASP-121b.

Abstract Invasive non‐native species (INNS) are recognized as a major threat to island biodiversity, ecosystems, and economies globally. Preventing high‐risk INNS from being introduced is the most cost‐effective way to avoid their adverse impacts. We applied a horizon scanning approach to identify potentially INNS in the United Kingdom Overseas Territories (OTs), ranging from Antarctica to the Caribbean, and from the Pacific to the Atlantic. High‐risk species were identified according to their potential for arrival, establishment, and likely impacts on biodiversity and ecosystem function, economies, and human health. Across OTs, 231 taxa were included on high‐risk lists. The highest ranking species were the Asian green mussel (Perna viridis), little fire ant (Wasmannia auropunctata), brown rat (Rattus norvegicus), and mesquite tree (Prosopis juliflora). Shipping containers were identified as the introduction pathway associated with the most species. The shared high‐risk species and pathways identified provide a guide for other remote islands and archipelagos to focus ongoing biosecurity and surveillance aimed at preventing future incursions.

Usage of inefficient and unsafe cookstoves is a cause of significant health losses and injuries in low-income communities. Efforts to develop and disseminate clean cookstoves have concentrated on optimizing thermal and emission performance, but minimal attention was given to safety aspects. Discussions conducted by the ISO TC285 Technical Committee are ongoing on the derivation of a universal biomass cooking stove standard that aims to guide the development and marketing of products that are safe and efficient with clean burning. Under this, cooking stove safety guidelines addressing a range of hazards have been issued to the community of practice. This work critically addressed the current guideline on cooking stove stability by pointing out the inadequacy of the test and suggesting extra tests for an improved rating of a candidate stove. With a pot and fuel introduced to the research, there may be three different failure modes for various pot and stove combinations, which were tipping, sliding, or spilling. The tests were conducted on an inexpensive purposely built “tiltometer” that allowed testing the angles for stove tipping and sliding, as well as cooking pot sliding and spilling failure. The results indicated that tipping angles for a selected list of modern stoves varied widely based on different shapes and masses, from 18° to 72.2°. Also, the performance of the three different failure modes would place the same stove in different tiers by the current safety protocol. Theoretical geometric calculations for the tipping angle were conducted, and the relative errors were within 2.9%–12.7% for the three different orientations. It is suggested that a revision of the interim stove safety standard should be promoted to incorporate the findings of this study.

IntroductionPost-traumatic epilepsy (PTE) is a debilitating chronic outcome of traumatic brain injury (TBI), and neuroinflammation is implicated in increased seizure susceptibility and epileptogenesis. However, how common clinical factors, such as infection, may modify neuroinflammation and PTE development has been understudied. The neurotropic parasite, Toxoplasma gondii (T. gondii) incurably infects one-third of the world’s population. Thus, many TBI patients have a pre-existing T. gondii infection at the time of injury. T. gondii infection results in chronic low-grade inflammation and altered signaling pathways within the brain, and preliminary clinical evidence suggest that it may be a risk factor for epilepsy. Despite this, no studies have considered how a pre-existing T. gondii infection may alter the development of PTE.MethodsThis study aimed to provide insight into this knowledge gap by assessing how a pre-existing T. gondii infection alters susceptibility to, and severity of, pentylenetetrazol (PTZ)-induced seizures (i.e., a surrogate marker of epileptogenesis/PTE) at a chronic stage of TBI recovery. We hypothesized that T. gondii will increase the likelihood and severity of seizures following PTZ administration, and that this would occur in the presence of intensified neuroinflammation. To test this, 6-week old male and female C57BL/6 Jax mice were intraperitoneally injected with 50,000 T. gondii tachyzoites or with the PBS vehicle only. At 12-weeks old, mice either received a severe TBI via controlled cortical impact or sham injury. At 18-weeks post-injury, mice were administered 40 mg/kg PTZ and video-recorded for evaluation of seizure susceptibility. Fresh cortical tissue was then collected for gene expression analyses.ResultsAlthough no synergistic effects were evident between infection and TBI, chronic T. gondii infection alone had robust effects on the PTZ-seizure response and gene expression of markers related to inflammatory, oxidative stress, and glutamatergic pathways. In addition to this, females were more susceptible to PTZ-induced seizures than males. While TBI did not impact PTZ responses, injury effects were evident at the molecular level.DiscussionOur data suggests that a pre-existing T. gondii infection is an important modifier of seizure susceptibility independent of brain injury, and considerable attention should be directed toward delineating the mechanisms underlying this pro-epileptogenic factor.

The National Criticality Experiments Research Center (NCERC) located at the Nevada National Security Site (NNSS) in the Device Assembly Facility (DAF) and operated by Los Alamos National Laboratory (LANL) is the only general purpose critical experiments facility in the United States. Experiments from subcritical to critical and above prompt critical are carried out at NCERC on a regular basis. In recent years, NCERC has become more involved in experiments related to nuclear energy, including the Kilopower/KRUSTY demonstration and the recent Hypatia experiment. Multiple nuclear energy related projects are currently ongoing at NCERC. This paper discusses NCERC’s role in advanced reactor design and how that role may change in the future.

Abstract Floral characters are important for the systematics of the Lauraceae. However, structure and development of the flowers remain poorly known in the family. In this study, we observed the variation and early development of flowers of Beilschmiedia appendiculata, which belongs to the Cryptocarya clade of the family. The results indicate that the shoot apical meristems (SAMs) of the floral buds are enlarged and become a platform for the programmed initiation of the floral organs; floral organs develop basically in an acropetal pattern; phyllotaxis is whorled, initiation of floral primordia within a whorl is asynchronous; floral merosity is extremely variable, for example, dimerous, trimerous, tetramerous, dimerous plus trimerous, and trimerous plus tetramerous. In addition, this species has lost the innermost staminal whorl and glands are not closely associated with stamens of the third staminal whorl, which is unusual in the family Lauraceae. Our new observations broaden our knowledge of the variation of floral structure in Beilschmiedia and pose a fundamental question regarding the ecology underlying the lability of floral organs in B. appendiculata.

PURPOSEUnderdeveloped nations carry the burden of most cervical cancer, yet access to adequate treatment can be challenging. This report assesses the current management of cervical cancer in sub-Saharan Africa to better understand the needs of underdeveloped nations in managing cervical cancer.METHODSA pre- and postsurvey was sent to all centers participating in the Cervical Cancer Research Network's 4th annual symposium. The pre- and postsurvey evaluated human papillomavirus and HIV screening, resources available for workup and/or treatment, treatment logistics, outcomes, and enrollment on clinical trials. Descriptive analyses were performed on survey responses.RESULTSTwenty-nine centers from 12 sub-Saharan countries saw approximately 300 new cases of cervical cancer yearly. Of the countries surveyed, 55% of countries had a human papillomavirus vaccination program and 30% (range, 0%-65%) of women in each region were estimated to have participated in a cervical cancer screening program. In the workup of patients, 43% of centers had the ability to obtain a positron emission tomography and computed tomography scan and 79% had magnetic resonance imaging capabilities. When performing surgery, 88% of those centers had a surgeon with an expertise in performing oncological surgeries. Radiation therapy was available at 96% of the centers surveyed, and chemotherapy was available in 86% of centers. Clinical trials were open at 4% of centers.CONCLUSIONThere have been significant advancements being made in screening, workup, and management of patients with cervical cancer in sub-Saharan Africa; yet, improvement is still needed. Enrollment in clinical trials remains a struggle. Participants would like to enroll patients on clinical trials with Cervical Cancer Research Network's continuous support.

Loss of olfactory function has been commonly reported in SARS-CoV-2 infections. Recovery from anosmia is not well understood. Previous studies showed that sustentacular cells, and occasionally olfactory sensory neurons (OSNs) in the olfactory epithelium (OE), are infected in SARS-CoV-2–infected patients and experimental animals. Here, we show that SARS-CoV-2 infection of sustentacular cells induces inflammation characterized by infiltration of myeloid cells to the olfactory epithelium and variably increased expression of proinflammatory cytokines. We observed widespread damage to, and loss of cilia on, OSNs, accompanied by downregulation of olfactory receptors and signal transduction molecules involved in olfaction. A consequence of OSN dysfunction was a reduction in the number of neurons in the olfactory bulb expressing tyrosine hydroxylase, consistent with reduced synaptic input. Resolution of the infection, inflammation, and olfactory dysfunction occurred over 3–4 weeks following infection in most but not all animals. We also observed similar patterns of OE infection and anosmia/hyposmia in mice infected with other human coronaviruses such as SARS-CoV and MERS-CoV. Together, these results define the downstream effects of sustentacular cell infection and provide insight into olfactory dysfunction in COVID-19–associated anosmia.

Background: Amputation is one of the leading causes of disabilities because of reduced mobility. Without assistive devices specifically prostheses, the quality of life of persons with lower limb amputation (PLLA) further deteriorates. Therefore, prostheses are fundamental to improving their quality of life. Objectives: This study aimed to establish the number of PLLA with or without prosthesis and to determine their socio-economic profile in Rwanda. Method: A descriptive, cross-sectional study was conducted in all sectors of Rwanda. As a result of coronavirus disease 2019 movement restrictions, data collection was carried out through telephone calls with participants to complete the questionnaires. Descriptive, inferential statistics and chi-square test were performed to analyse data using Statistical Package for Social Science (SPSS) 21.0. Results: Of the 3026 participants identified countrywide, 68.8% were males and 60.3% of them did not have any prosthesis (p = 0.003). The majority (62.4%) of those who had prosthetic devices needed repair of their prostheses while 14.8% of participants reported that their prosthetic devices were completely broken and/or damaged (p = 0.604). Among the participants, 63.7% had no source of income and 66.7% had dependents (p ≤ 0.001). Conclusion: The majority of the PLLA in Rwanda did not have prosthetic devices and even those with prostheses did not fully function and thus required repair. Therefore, it adversely affects their livelihood. Contribution: The government should collaborate with stakeholders working with persons with disabilities and implement mechanisms and/or strategies to make prosthetic devices accessible and affordable.

The title compound, [Cu(C9H5N4O)2(C10H9N3)2], was synthesized solvothermally. The complex exhibits a distorted octahedral coordination geometry. The CuII atom is located on an inversion centre. The distorted octahedral CuN6 coordination sphere is composed of bidentate 2,2′-dipyridylamine in the equatorial sites while the axial sites are occupied by 1,1,3,3-tetracyano-2-ethoxypropenide ligands. In the crystal, N—H...N hydrogen bonding results in chains parallel to [010].

Psychosocial and stress-related factors (PSFs), defined as internal or external stimuli that induce biological changes, are potentially modifiable factors and accessible targets for interventions that are associated with adverse pregnancy outcomes (APOs). Although individual APOs have been shown to be connected to PSFs, they are biologically interconnected, relatively infrequent, and therefore challenging to model. In this context, multi-task machine learning (MML) is an ideal tool for exploring the interconnectedness of APOs on the one hand and building on joint combinatorial outcomes to increase predictive power on the other hand. Additionally, by integrating single cell immunological profiling of underlying biological processes, the effects of stress-based therapeutics may be measurable, facilitating the development of precision medicine approaches.ObjectivesThe primary objectives were to jointly model multiple APOs and their connection to stress early in pregnancy, and to explore the underlying biology to guide development of accessible and measurable interventions.Materials and MethodsIn a prospective cohort study, PSFs were assessed during the first trimester with an extensive self-filled questionnaire for 200 women. We used MML to simultaneously model, and predict APOs (severe preeclampsia, superimposed preeclampsia, gestational diabetes and early gestational age) as well as several risk factors (BMI, diabetes, hypertension) for these patients based on PSFs. Strongly interrelated stressors were categorized to identify potential therapeutic targets. Furthermore, for a subset of 14 women, we modeled the connection of PSFs to the maternal immune system to APOs by building corresponding ML models based on an extensive single cell immune dataset generated by mass cytometry time of flight (CyTOF).ResultsJointly modeling APOs in a MML setting significantly increased modeling capabilities and yielded a highly predictive integrated model of APOs underscoring their interconnectedness. Most APOs were associated with mental health, life stress, and perceived health risks. Biologically, stressors were associated with specific immune characteristics revolving around CD4/CD8 T cells. Immune characteristics predicted based on stress were in turn found to be associated with APOs.ConclusionsElucidating connections among stress, multiple APOs simultaneously, and immune characteristics has the potential to facilitate the implementation of ML-based, individualized, integrative models of pregnancy in clinical decision making. The modifiable nature of stressors may enable the development of accessible interventions, with success tracked through immune characteristics.

Cerebral multimodality monitoring (MMM) is, even with a general lack of Class I evidence, increasingly recognized as a tool to support clinical decision-making in the neuroscience intensive care unit (NICU). However, literature and guidelines have focused on unimodal signals in a specific form of acute brain injury. Integrating unimodal signals in multiple signal monitoring is the next step for clinical studies and patient care. As such, we aimed to investigate the recent application of MMM in studies of adult patients with traumatic brain injury (TBI), subarachnoid hemorrhage (SAH), intracerebral hemorrhage (ICH), acute ischemic stroke (AIS), and hypoxic ischemic brain injury following cardiac arrest (HIBI). We identified continuous or daily updated monitoring modalities and summarized the monitoring setting, study setting, and clinical characteristics. In addition, we discussed clinical outcome in intervention studies. We identified 112 MMM studies, including 11 modalities, over the last 7 years (2015–2022). Fifty-eight studies (52%) applied only two modalities. Most frequently combined were ICP monitoring (92 studies (82%)) together with PbtO2 (63 studies (56%). Most studies included patients with TBI (59 studies) or SAH (53 studies). The enrollment period of 34 studies (30%) took more than 5 years, whereas the median sample size was only 36 patients (q1- q3, 20–74). We classified studies as either observational (68 studies) or interventional (44 studies). The interventions were subclassified as systemic (24 studies), cerebral (10 studies), and interventions guided by MMM (11 studies). We identified 20 different systemic or cerebral interventions. Nine (9/11, 82%) of the MMM-guided studies included clinical outcome as an endpoint. In 78% (7/9) of these MMM-guided intervention studies, a significant improvement in outcome was demonstrated in favor of interventions guided by MMM. Clinical outcome may be improved with interventions guided by MMM. This strengthens the belief in this application, but further interdisciplinary collaborations are needed to overcome the heterogeneity, as illustrated in the present review. Future research should focus on increasing sample sizes, improved data collection, refining definitions of secondary injuries, and standardized interventions. Only then can we proceed with complex outcome studies with MMM-guided treatment.

Background: The growth in multi-center neuroimaging studies generated a need for methods that mitigate the differences in hardware and acquisition protocols across sites i.e., scanner effects. ComBat harmonization methods have shown promise but have not yet been tested on all the data types commonly studied with magnetic resonance imaging (MRI). This study aimed to validate neuroCombat, longCombat and gamCombat on both structural and diffusion metrics in both cross-sectional and longitudinal data. Methods: We used a travelling subject design whereby 73 healthy volunteers contributed 161 scans across two sites and four machines using one T1 and five diffusion MRI protocols. Scanner was defined as a composite of site, machine and protocol. A common pipeline extracted two structural metrics (volumes and cortical thickness) and two diffusion tensor imaging metrics (mean diffusivity and fractional anisotropy) for seven regions of interest including gray and (except for cortical thickness) white matter regions. Results: Structural data exhibited no significant scanner effect and therefore did not benefit from harmonization in our particular cohort. Indeed, attempting harmonization obscured the true biological effect for some regions of interest. Diffusion data contained marked scanner effects and was successfully harmonized by all methods, resulting in smaller scanner effects and better detection of true biological effects. LongCombat less effectively reduced the scanner effect for cross-sectional white matter data but had a slightly lower probability of incorrectly finding group differences in simulations, compared to neuroCombat and gamCombat. False positive rates for all methods and all metrics did not significantly exceed 5%. Conclusions: Statistical harmonization of structural data is not always necessary and harmonization in the absence of a scanner effect may be harmful. Harmonization of diffusion MRI data is highly recommended with neuroCombat, longCombat and gamCombat performing well in cross-sectional and longitudinal settings.

Pre-treatment is essential to reduce logistic costs of agricultural residues. This work examined the interactions between pre-treatment conditions and thermo-chemical behaviour on product yields and properties. The effect of pyrolysis operating and briquetting conditions (i.e., temperature, pressure and bean straw-maize cob blend) on yields and properties of pyrolysis products from maize cob, bean straw and blended briquettes were investigated. It was found that briquetting conditions, heating rate and carrier gas flow rate had negligible effects on yields and properties of pyrolysis products. Temperature was the dominant factor that effected the yield and properties of the pyrolysis products. Increasing pyrolysis temperature increased the gas and reduced the char yield. Up to ∼ 45 % of the energy content of the raw material can be stored in smokeless char like material that can be easily transported and used for energy production e.g., household cooking. Pyrolysis of agricultural residues has the potential to reduce harmful particulate emissions whereas the high-water content bio-oil can be used as a binder in briquette production to reduce the pressure and temperature applied.

Low- and middle-income countries around the world are expanding investments in early childhood development (ECD) programs, but few evaluations of ECD programs measure impacts on maternal mental health as well as on other, closely associated psychosocial domains. One reason may be a lack of familiarity with appropriate survey instruments for measuring different aspects of maternal psychosocial well-being among ECD-focused researchers. We identified 478 empirical studies of ECD programs in low- and middle-income countries; 55 of them measure impacts on maternal mental health and related domains. In this article, we identify 22 instruments used to measure maternal depression, stress, anxiety, and other aspects of psychosocial well-being. We provide guidance on the uses of each instrument and examples of country contexts where each has been implemented.

Abstract Laboratory testing used to assess the long-term chemical durability of nuclear waste forms may not be applicable to disposal because the accelerated conditions may not represent disposal conditions. To address this, we examine the corrosion of vitrified archeological materials excavated from the near surface of a ~1500-year old Iron Age Swedish hillfort, Broborg, as an analog for the disposal of vitrified nuclear waste. We compare characterized site samples with corrosion characteristics generated by standard laboratory durability test methods including the product consistency test (PCT), the vapor hydration test (VHT), and the EPA Method 1313 test. Results show that the surficial layer of the Broborg samples resulting from VHT displays some similarities to the morphology of the surficial layer formed over longer timescales in the environment. This work provides improved understanding of long-term glass corrosion behavior in terms of the thickness, morphology, and chemistry of the surficial features that are formed.

Abstract Background Global pandemics like Zika (ZIKV) factor into pregnancy planning and avoidance, yet little is known about how primary care providers (PCPs) incorporate public health guidance into contraceptive counseling. Study objectives include: 1) determining the impact of the ZIKV pandemic on contraceptive counseling changes; and 2) assessing PCP knowledge and practice regarding contraception, ZIKV, and CDC ZIKV guidelines. Methods Study components included: (1) a retrospective review of electronic health records of non-pregnant, reproductive age women presenting for preventive health visits between 2014 and 2017 assessed using interrupted time series analyses (ITSA) to identify changes in documentation of ZIKV risk assessment and contraceptive counseling; and (2) a sequential, cross-sectional study with quantitative surveys and qualitative, semi-structured interviews of PCPs providing preventive care to non-pregnant patients at eight federally qualified health centers in Utah. We performed descriptive analyses on survey data and analyzed qualitative data for dominant themes using a modified Health Belief Model. Results We conducted 6634 chart reviews yielding 9840 visits. The ITSA did not reveal changes in ZIKV risk assessment or contraceptive counseling. Twenty-two out of 40 (55%) eligible providers participated in the provider component. Participants averaged 69 and 81% correct on contraceptive and ZIKV knowledge questions, respectively. Sixty-five percent reported counseling consistent with CDC ZIKV guidelines. Qualitative analysis found providers unlikely to prioritize ZIKV risk assessment in contraceptive counseling for non-pregnant patients. Conclusions PCPs who care for non-pregnant women are knowledgeable about contraception and ZIKV; however, there was no change in ZIKV risk assessment or contraceptive counseling. This stresses the importance of developing strategies to improve guideline uptake.

Understanding which patients will respond to FOLFIRINOX therapy is important for clinical outcome. Here, the authors show that the MIR1307 is increased pancreatic cancer cell lines and inhibition of the microRNA sensitises cells to treatment.’ stratifying patients to achieve the best clinical outcome. Here, the authors show that the MIR1307 is increased in a subgroup of human pancreatic cancers and inhibition of the microRNA in in vitro and in vivo models of pancreatic cancer sensitises cells to treatment.

Abstract Background Accessing subspecialty care is hard for underserved patients in the U.S. Published curricula in underserved medicine for Internal Medicine residents target future-primary care physicians, with unknown impact on future medicine subspecialists. Methods The aim was to retain interest in caring for underserved patients among Internal Medicine residents who plan for subspecialist careers at an urban university hospital. The two-year Underserved Medicine and Public Health (UMPH) program features community-based clinics, evening seminars, reflection assignments and practicum projects for 3–7 Internal Medicine residents per year. All may apply regardless of anticipated career plans after residency. Seven years of graduates were surveyed. Data were analyzed using descriptive statistics. Results According to respondents, UMPH provided a meaningful forum to discuss important issues in underserved medicine, fostered interest in treating underserved populations and provided a sense of belonging to a community of providers committed to underserved medicine. After residency, 48% of UMPH graduates pursued subspecialty training and 34% practiced hospitalist medicine. 65% of respondents disagreed that “UMPH made me more likely to practice primary care” and 59% agreed “UMPH should target residents pursuing subpecialty careers.” Conclusions A curriculum in underserved medicine can retain interest in caring for underserved patients among future-medicine subspecialists. Lessons learned include [1] building relationships with local community health centers and community-practicing physicians was important for success and [2] thoughtful scheduling promoted high resident attendance at program events and avoided detracting from other activities required during residency for subspecialist career paths. We hope Internal Medicine residency programs consider training in underserved medicine for all trainees. Future work should investigate sustainability, whether training results in improved subspecialty access, and whether subspecialists face unique barriers caring for underserved patients. Future curricula should include advocacy skills to target systemic barriers.

Abstract Background Convalescent plasma has been widely used to treat COVID-19 and is under investigation in numerous randomized clinical trials, but results are publicly available only for a small number of trials. The objective of this study was to assess the benefits of convalescent plasma treatment compared to placebo or no treatment and all-cause mortality in patients with COVID-19, using data from all available randomized clinical trials, including unpublished and ongoing trials (Open Science Framework, https://doi.org/10.17605/OSF.IO/GEHFX ). Methods In this collaborative systematic review and meta-analysis, clinical trial registries (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform), the Cochrane COVID-19 register, the LOVE database, and PubMed were searched until April 8, 2021. Investigators of trials registered by March 1, 2021, without published results were contacted via email. Eligible were ongoing, discontinued and completed randomized clinical trials that compared convalescent plasma with placebo or no treatment in COVID-19 patients, regardless of setting or treatment schedule. Aggregated mortality data were extracted from publications or provided by investigators of unpublished trials and combined using the Hartung–Knapp–Sidik–Jonkman random effects model. We investigated the contribution of unpublished trials to the overall evidence. Results A total of 16,477 patients were included in 33 trials (20 unpublished with 3190 patients, 13 published with 13,287 patients). 32 trials enrolled only hospitalized patients (including 3 with only intensive care unit patients). Risk of bias was low for 29/33 trials. Of 8495 patients who received convalescent plasma, 1997 died (23%), and of 7982 control patients, 1952 died (24%). The combined risk ratio for all-cause mortality was 0.97 (95% confidence interval: 0.92; 1.02) with between-study heterogeneity not beyond chance (I2 = 0%). The RECOVERY trial had 69.8% and the unpublished evidence 25.3% of the weight in the meta-analysis. Conclusions Convalescent plasma treatment of patients with COVID-19 did not reduce all-cause mortality. These results provide strong evidence that convalescent plasma treatment for patients with COVID-19 should not be used outside of randomized trials. Evidence synthesis from collaborations among trial investigators can inform both evidence generation and evidence application in patient care.

Abstract Background Anti-N-methyl-d-aspartate receptor encephalitis (anti-NMDARE) is a multi-stage autoimmune-mediated disease associated with a multitude of neuropsychiatric and dysautonomic features. Orofacial dyskinesias are frequently associated with this condition and manifest as abnormal movements of the orofacial musculature. These involuntary movements may result in significant trauma to the oral and maxillofacial complex including the avulsion of the dentition and orofacial lacerations. Case presentation We describe the course of two female patients with anti-NMDARE in whom significant involuntary self-inflicted maxillofacial trauma was suffered despite the use of complex parenteral sedation regimens. The application of traditional maxillomandibular wiring techniques and pharmacologic strategies, including botulinum toxin, to immobilize the mandible were initially unsuccessful. These difficulties led to the fabrication and wire-based fixation of a patient-specific acrylic oral appliance that maintained the mandible in a depressed position and mitigated all lateral and protrusive movements. Discussion and conclusions These cases illustrate the first known successful use of an appliance-based therapy for managing orofacial dyskinesias in the anti-NMDARE patient population through an adaptation of traditional maxillomandibular fixation techniques. This approach eliminated further orofacial trauma and afforded physicians with safer means to manage and assess patients afflicted with this condition during their protracted intensive care unit admissions.

Abstract The Casimir force, a quantum mechanical effect, has been observed in several microelectromechanical system (MEMS) platforms. Due to its extreme sensitivity to the separation of two objects, the Casimir force has been proposed as an excellent avenue for quantum metrology. Practical application, however, is challenging due to attractive forces leading to stiction and device failure, called Casimir pull-in. In this work, we design and simulate a Casimir-driven metrology platform, where a time-delay-based parametric amplification technique is developed to achieve a steady-state and avoid pull-in. We apply the design to the detection of weak, low-frequency, gradient magnetic fields similar to those emanating from ionic currents in the heart and brain. Simulation parameters are selected from recent experimental platforms developed for Casimir metrology and magnetic gradiometry, both on MEMS platforms. While a MEMS offers many advantages to such an application, the detected signal must typically be at the resonant frequency of the device, with diminished sensitivity in the low frequency regime of biomagnetic fields. Using a Casimir-driven parametric amplifier, we report a 10,000-fold improvement in the best-case resolution of MEMS single-point gradiometers, with a maximum sensitivity of 6 Hz/(pT/cm) at 1 Hz. Further development of the proposed design has the potential to revolutionize metrology and may specifically enable the unshielded monitoring of biomagnetic fields in ambient conditions.

The Heterostraci are a subclass of armored jawless vertebrates that were widespread in marginal marine environments around the Old Red Sandstone continent during the late Silurian to Middle Devonian. Although a number of clades have long been recognized, further analysis has been limited by lack of morphological information beyond that afforded by the armor, thus impeding understanding of early vertebrate evolution. Phylogenetic analysis of several heterostracan clades has been carried out previously and we here show an analysis of the family Cyathaspididae in which we prioritize the feature of a single branchial plate as a defining character of the family and reject a number of taxa previously included in analyses of this taxon. This analysis resolves to a single consensus tree showing that the Cyathaspididae is composed of a series of clades that are congruent with the subfamily groupings erected previously: Tolypelepidinae, Irregulareaspidinae, Poraspidinae, Anglaspidinae, and Boothiaspidinae. A trend can be seen from earlier members of the family with a dorsal shield divided into four epitega or growth areas (Asketaspis, Tolypelepis) to the most derived members (Poraspis, Faberaspis) in which the epitega are lost entirely. In addition, the earliest taxa are shown to have possessed shields composed of scale-like elements, which are lost and replaced by continuous ridges in the more derived members. This result supports the hypothesis that the earliest members of the Heterostraci may also have been scale-covered.

Canada’s vast geography, and centralized delivery of cancer care and clinical trials create barriers for trial participation for patients in remote and rural settings. The development and implementation of a framework that enables safe and regulatory compliant trial participation through local healthcare providers would benefit Canadian patients, clinicians, trial sponsors and the health care system. To address this issue, representatives of Canada’s cancer clinical trial community met to identify key challenges and develop recommendations for remote patient participation in trials. A structured literature review identified remote/rural trial delivery models. A panel of expert stakeholders reviewed the models and participated in a workshop to assess health system readiness, identify needed processes, tools and mechanisms, and develop recommendations for a Canadian framework for decentralized clinical trial conduct. The Canadian Remote Access Framework for clinical Trials (CRAFT) represents a risk-based approach used by site investigators to delegate responsibilities for a given trial to satellite health centres within a hub-and-spoke “trial cluster”. The Framework includes specific recommendations to ensure research experience, capacity, regulatory compliance and patient safety. Canada’s cancer care and telemedicine systems can be leveraged to enable broader access to clinical trials for patients who are geographically remote from cancer centres. CRAFT’s risk-based framework is based on other successful models of remote trial patient management and is in the pilot implementation phase in Canada.

Abstract Effective vaccines for human immunodeficiency virus-1 (HIV-1) and hepatitis C virus (HCV) remain a significant challenge for these infectious diseases. Given that the innate immune response is key to controlling the scale and nature of developing adaptive immune responses, targeting natural killer (NK) cells that can promote a T-helper type 1 (Th1)-type immune response through the production of interferon-γ (IFNγ) remains an untapped strategic target for improved vaccination approaches. Here, we investigate metabolic and functional responses of NK cells to simian adenovirus prime and MVA boost vaccination in a cohort of healthy volunteers receiving a dual HCV-HIV-1 vaccine. Early and late timepoints demonstrated metabolic changes that contributed to the sustained proliferation of all NK cells. However, a strong impact of human cytomegalovirus (HCMV) on some metabolic and functional responses in NK cells was observed in HCMV seropositive participants. These changes were not restricted to molecularly defined adaptive NK cells; indeed, canonical NK cells that produced most IFNγ in response to vaccination were equally impacted in individuals with latent HCMV. In summary, NK cells undergo metabolic changes in response to vaccination, and understanding these in the context of HCMV is an important step towards rational vaccine design against a range of human viral pathogens.