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Valbenazine is a highly potent and selective inhibitor of synaptic vesicular monoamine transporter 2. The current therapeutic doses of valbenazine for tardive dyskinesia (TD) are 40, 60, or 80 mg capsules, given orally, once daily (QD). While 40 and 80 mg were investigated in phase 3 KINECT® 3 trial and initially approved, the approval of valbenazine 60 mg was based on the analysis utilizing the Model‐informed drug development (MIDD) approach, facilitated through the US Food and Drug Administration's MIDD Pilot Program. This study aimed to demonstrate the efficacy of 60 mg QD dose through model simulations using an established exposure‐response (E‐R) relationship between valbenazine active metabolite [+]‐α‐dihydrotetrabenazine exposure and the change from baseline in Abnormal Involuntary Movement Scale total score (AIMS‐CFB). A longitudinal E–R model was constructed based on the 40 and 80 mg data from the KINECT 3 trial. The final Emax model adequately predicted dose‐dependent improvement in the primary endpoint and was used to interpolate AIMS‐CFB for 60 mg at week 6. The efficacy of the unstudied 60 mg dose regimen is expected to be within the range of doses studied clinically with predicted mean AIMS‐CFB (95% confidence interval) of −2.69 (−3.30, −2.13) between observed mean AIMS‐CFB for 40 mg of −1.92 and 80 mg of −3.39. Results from this analysis provided the key evidence to establish efficacy of 60 mg QD without the need for an additional clinical trial. The availability of valbenazine 60 mg dose fills an existing medical need for patients with TD who could benefit from this third effective dose. [ABSTRACT FROM AUTHOR]

ABSTRACT Intimate partner violence (IPV) transcends cultural, social and economic boundaries, affecting countless individuals globally. Recovery for IPV survivors is supported by their social networks, yet the readiness of these networks is often poorly understood. This perspective paper proposes an extension to existing network‐oriented IPV support models by integrating a focus on the readiness and well‐being of informal supporters towards the goal of enhancing IPV survivor recovery through effective networks. This paper presents the extended social network‐oriented support model, incorporating the Informal Supporter Readiness Inventory. This tool assesses the readiness of informal supporters, incorporating factors, such as normative and individual beliefs about IPV, and context‐specific factors, to enable identification and targeted assistance where needed. Additionally, the proposed model emphasises the importance of supporting the well‐being of informal supporters, who frequently endure elevated levels of stress, anxiety and depression. By integrating these elements, the extended social network‐oriented support model is designed to help professional supporters foster resilient and sustainable support networks for IPV survivors, with potential applicability across various healthcare disciplines. The extended model underscores the necessity of assessing and fostering both the readiness and well‐being of informal supporters to enhance the recovery journey for IPV survivors. [ABSTRACT FROM AUTHOR]

Aim: How the cerebral metabolic rates of oxygen and glucose utilization (CMRO2 and CMRGlc, respectively) are affected by alterations in arterial PCO2 (PaCO2) is equivocal and therefore was the primary question of this study. Methods: This retrospective analysis involved pooled data from four separate studies, involving 41 healthy adults (35 males/6 females). Participants completed stepwise steady‐state alterations in PaCO2 ranging between 30 and 60 mmHg. The CMRO2 and CMRGlc were assessed via the Fick approach (CBF × arterial‐internal jugular venous difference of oxygen or glucose content, respectively) utilizing duplex ultrasound of the internal carotid artery and vertebral artery to calculate cerebral blood flow (CBF). Results: The CMRO2 was altered by 0.5 mL × min−1 (95% CI: −0.6 to −0.3) per mmHg change in PaCO2 (p < 0.001) which corresponded to a 9.8% (95% CI: −13.2 to −6.5) change in CMRO2 with a 9 mmHg change in PaCO2 (inclusive of hypo‐ and hypercapnia). The CMRGlc was reduced by 7.7% (95% CI: −15.4 to −0.08, p = 0.045; i.e., reduction in net glucose uptake) and the oxidative glucose index (ratio of oxygen to glucose uptake) was reduced by 5.6% (95% CI: −11.2 to 0.06, p = 0.049) with a + 9 mmHg increase in PaCO2. Conclusion: Collectively, the CMRO2 is altered by approximately 1% per mmHg change in PaCO2. Further, glucose is incompletely oxidized during hypercapnia, indicating reductions in CMRO2 are either met by compensatory increases in nonoxidative glucose metabolism or explained by a reduction in total energy production. [ABSTRACT FROM AUTHOR]

Purpose: Abdominal imaging is frequently performed with breath holds or respiratory triggering to reduce the effects of respiratory motion. Diffusion weighted sequences provide a useful clinical contrast but have prolonged scan times due to low signal‐to‐noise ratio (SNR), and cannot be completed in a single breath hold. Echo‐planar imaging (EPI) is the most commonly used trajectory for diffusion weighted imaging but it is susceptible to off‐resonance artifacts. A respiratory resolved, three‐dimensional (3D) diffusion prepared sequence that obtains distortionless diffusion weighted images during free‐breathing is presented. Techniques to address the myriad of challenges including: 3D shot‐to‐shot phase correction, respiratory binning, diffusion encoding during free‐breathing, and robustness to off‐resonance are described. Methods: A twice‐refocused, M1‐nulled diffusion preparation was combined with an RF‐spoiled gradient echo readout and respiratory resolved reconstruction to obtain free‐breathing diffusion weighted images in the abdomen. Cartesian sampling permits a sampling density that enables 3D shot‐to‐shot phase navigation and reduction of transient fat artifacts. Theoretical properties of a region‐based shot rejection are described. The region‐based shot rejection method was evaluated with free‐breathing (normal and exaggerated breathing), and respiratory triggering. The proposed sequence was compared in vivo with multishot DW‐EPI. Results: The proposed sequence exhibits no evident distortion in vivo when compared to multishot DW‐EPI, robustness to B0 and B1 field inhomogeneities, and robustness to motion from different respiratory patterns. Conclusion: Acquisition of distortionless, diffusion weighted images is feasible during free‐breathing with a b‐value of 500 s/mm2, scan time of 6 min, and a clinically viable reconstruction time. [ABSTRACT FROM AUTHOR]

Fire and herbivory have profound effects on vegetation in savanna ecosystems, but little is known about how different herbivore groups influence vegetation dynamics after fire. We assessed the separate and combined effects of herbivory by cattle and wild meso‐ and megaherbivores on postfire herbaceous vegetation cover, species richness, and species turnover in a savanna ecosystem in central Kenya. We measured these vegetation attributes for five sampling periods (from 2013 to 2017) in prescribed burns and unburned areas located within a series of replicated long‐term herbivore exclosures that allow six different combinations of cattle and wild meso‐ and megaherbivores (elephants and giraffes). Vegetation cover (grasses, mainly) and species richness were initially reduced by burning but recovered by 15–27 months after fire, suggesting strong resilience to infrequent fire. However, the rates of recovery differed in plots accessible by different wild and domestic herbivore guilds. Wildlife (but not cattle) delayed postfire recovery of grasses, and the absence of wildlife (with or without cattle) delayed recovery of forbs. Herbivory by only cattle increased grass species richness in burned relative to unburned areas. Herbivory by cattle (with or without wildlife), however, reduced forb species richness in burned relative to unburned areas. Herbivory by wild ungulates (but not cattle) increased herbaceous species turnover in burned relative to unburned areas. Megaherbivores had negligible modifying effects on these results. This study demonstrates that savanna ecosystems are remarkably resilient to infrequent fires, but postfire grazing by cattle and wild mesoherbivores exerts different effects on recovery trajectories of herbaceous vegetation. [ABSTRACT FROM AUTHOR]

In the context of bereavement, little is known about the mechanisms that differentiate normative adjustment patterns from those that may indicate potential psychopathology. This study aimed to replicate and extend previous work by (1) characterizing the trajectories of depressive symptoms from 3 to 12 months after the loss of a spouse, (2) examining whether (a) childhood maltreatment and attachment style predicted distinct depression trajectories, and (b) different depression trajectories were associated with the risk of prolonged grief at 12 months post‐loss. Recently bereaved individuals (N = 175) completed self‐report assessments at 3, 4, 6, and 12‐months post‐loss. Trajectories of depressive symptoms were estimated using group‐based trajectory modelling. Four distinct trajectories of depressive symptoms were identified: (1) resilience (minimal/no depression across time points; 45%), (2) moderate depression‐improved (alleviated to 'mild' by 12 months; 31%), (3) severe depression‐improved (alleviated to 'moderate' by 12 months; 15%), and (4) chronic depression ('severe' symptoms across time points; 9%). Higher childhood maltreatment predicted a greater likelihood of belonging to the 'severe depression‐improved' and 'chronic depression' groups than the 'resilient' and 'moderate depression‐improved' groups. Widow(er)s with higher attachment anxiety were more likely to belong to the 'severe depression‐improved' and 'chronic depression' groups than the 'resilient' group. The trajectory groups with persistent levels of depressive symptoms up until 6 months were more likely to exhibit prolonged grief at 12 months post‐loss. Changes from pre‐loss functioning cannot be estimated. Our findings provide insight into the early identification of post‐loss prolonged grief. [ABSTRACT FROM AUTHOR]

In the realm of high‐throughput screening (HTS), macrocyclic peptide libraries traditionally necessitate decoding tags, essential for both library synthesis and identifying hit peptide sequences post‐screening. Our innovation introduces a tag‐free technology platform for synthesizing cyclic peptide libraries in solution and facilitates screening against biological targets to identify peptide binders through unconventional intramolecular CyClick and DeClick chemistries (CCDC) discovered through our research. This combination allows for the synthesis of diverse cyclic peptide libraries, the incorporation of various amino acids, and facile linearization and decoding of cyclic peptide binder sequences. Our sensitivity‐enhancing derivatization method, utilized in tandem with nano LC‐MS/MS, enables the sequencing of peptides even at exceedingly low picomolar concentrations. Employing our technology platform, we have successfully unearthed novel cyclic peptide binders against a monoclonal antibody and the first cyclic peptide binder of HIV capsid protein responsible for viral infections as validated by microscale thermal shift assays (TSA), biolayer interferometry (BLI) and functional assays. [ABSTRACT FROM AUTHOR]

This study explored the interactions among prenatal stress, child sex, and polygenic risk scores (PGS) for attention‐deficit/hyperactivity disorder (ADHD) on structural developmental changes of brain regions implicated in ADHD. We used data from two population‐based birth cohorts: Growing Up in Singapore Towards healthy Outcomes (GUSTO) from Singapore (n = 113) and Generation R from Rotterdam, the Netherlands (n = 433). Prenatal stress was assessed using questionnaires. We obtained latent constructs of prenatal adversity and prenatal mood problems using confirmatory factor analyses. The participants were genotyped using genome‐wide single nucleotide polymorphism arrays, and ADHD PGSs were computed. Magnetic resonance imaging scans were acquired at 4.5 and 6 years (GUSTO), and at 10 and 14 years (Generation R). We estimated the age‐related rate of change for brain outcomes related to ADHD and performed (1) prenatal stress by sex interaction models, (2) prenatal stress by ADHD PGS interaction models, and (3) 3‐way interaction models, including prenatal stress, sex, and ADHD PGS. We observed an interaction between prenatal stress and ADHD PGS on mean cortical thickness annual rate of change in Generation R (i.e., in individuals with higher ADHD PGS, higher prenatal stress was associated with a lower rate of cortical thinning, whereas in individuals with lower ADHD PGS, higher prenatal stress was associated with a higher rate of cortical thinning). None of the other tested interactions were statistically significant. Higher prenatal stress may promote a slower brain developmental rate during adolescence in individuals with higher ADHD genetic vulnerability, whereas it may promote a faster brain developmental rate in individuals with lower ADHD genetic vulnerability. [ABSTRACT FROM AUTHOR]

Objective: Surgical plume has known potential occupational health hazards. This study compares nanoparticle concentrations in surgical plumes generated between different pediatric tonsillectomy surgical techniques and assesses the efficacy of mitigation measures. Methods: This is a cross‐sectional study performed at a tertiary care academic center. Extracapsular or intracapsular tonsillectomy was performed in 60 patients using four techniques and in 10 additional patients using mitigation measures. Two nanoparticle counters were used to measure particulate concentrations: CPC™ and DiSCmini™. Tonsillectomy techniques included: (1) microdebrider (MD), (2) Bovie with manual suctioning by an assistant (B), (3) Bovie with built‐in smoke evacuation system (BS), and (4) Coblator™ (CB). An additional Yankauer suction was used in the mitigation groups (BSY) and (CBY). Comparative analysis was performed using one‐way ANOVA on ranks and pairwise comparisons between the groups. Results: The mean concentrations (particles/cm3) and coefficient of variants for the DiSCmini particulate counter were MD: 5140 (1.6), B: 30700 (1.5), BS: 25001 (0.8), CB: 54814 (1.7), CBY: 2395 (1.3) and BSY: 11552 (1.0). Mean concentrations for the CPC particulate counter were MD: 1223 (1.4), B: 3405 (0.7), BS: 5002 (0.9), CB: 13273 (1.0), CBY: 1048 (1.2) and BSY: 3046 (0.6). The lowest mean concentrations were noted in cases using MD and the highest in cases using CB. However, after mitigation, CBY had the lowest overall levels. Conclusion: Tonsillectomy technique does impact the levels of nanoparticles emitted within the surgical plume, which may present an occupational hazard for operating room personnel. Level of Evidence: 3 Laryngoscope, 134:2444–2448, 2024 [ABSTRACT FROM AUTHOR]

The goal of this study was to examine what happens to established associations between attention deficit hyperactivity disorder (ADHD) symptoms and cortical surface and thickness regions once we apply inverse probability of censoring weighting (IPCW) to address potential selection bias. Moreover, we illustrate how different factors that predict participation contribute to potential selection bias. Participants were 9‐ to 11‐year‐old children from the Generation R study (N = 2707). Cortical area and thickness were measured with magnetic resonance imaging (MRI) and ADHD symptoms with the Child Behavior Checklist. We examined how associations between ADHD symptoms and brain morphology change when we weight our sample back to either follow‐up (ages 9–11), baseline (cohort at birth), or eligible (population of Rotterdam at time of recruitment). Weights were derived using IPCW or raking and missing predictors of participation used to estimate weights were imputed. Weighting analyses to baseline and eligible increased beta coefficients for the middle temporal gyrus surface area, as well as fusiform gyrus cortical thickness. Alternatively, the beta coefficient for the rostral anterior cingulate decreased. Removing one group of variables used for estimating weights resulted in the weighted regression coefficient moving closer to the unweighted regression coefficient. In addition, we found considerably different beta coefficients for most surface area regions and all thickness measures when we did not impute missing covariate data. Our findings highlight the importance of using inverse probability weighting (IPW) in the neuroimaging field, especially in the context of mental health‐related research. We found that including all variables related to exposure‐outcome in the IPW model and combining IPW with multiple imputations can help reduce bias. We encourage future psychiatric neuroimaging studies to define their target population, collect information on eligible but not included participants and use inverse probability of censoring weighting (IPCW) to reduce selection bias. [ABSTRACT FROM AUTHOR]

T helper 2 (Th2) cells stochastically express from the Il4 locus but it has not been determined whether allelic expression is linked or independent. Here, we provide evidence that alleles are independently activated and inactivated. We compared Il4 locus expression in T cells from hemizygous IL‐4 reporter mice in culture and in vivo following exposure to type 2 immunogens. In culture, Il4 alleles had independent, heritable expression probabilities. Modeling showed that in co‐expressors, dual allele transcription occurs for only short periods, limiting per‐cell mRNA variation in individual cells within a population of Th2 cells. In vivo profiles suggested that early in the immune response, IL‐4 output was derived predominantly from single alleles, but co‐expression became more frequent over time and were tuned by STAT6, supporting the probabilistic regulation of Il4 alleles in vivo among committed IL‐4 producers. We suggest an imprinted probability of expression from individual alleles with a short transcriptional shutoff time controls the magnitude of T cell IL‐4 output, but the amount produced per allele is amplified by STAT6 signaling. This form of regulation may be a relevant general mechanism governing cytokine expression. [ABSTRACT FROM AUTHOR]

Parasitoid wasp larvae engage in intense interspecific competition when sharing a host insect, with lethal consequences for the losers. Larval parasitoid competition is generally thought to be resolved by physical traits, such as enlarged mandibles. Although solitary parasitoid larvae are typically superior competitors against gregarious larvae, such physical traits are unlikely to be effective against large numbers of competitors. Larval competition may instead be mediated by maternal factors that increase the survival of offspring facing interspecific competition, thus increasing parental fitness.When laying eggs inside a host, many female parasitoids also inject oviposition fluids that are known to suppress host immune responses, permitting successful offspring development. We explored whether the oviposition fluids of two wasp species in the genus Cotesia (Cotesia rubecula, a strong competitor that almost always wins interspecific competition against a weaker competitor, Cotesia glomerata) might also represent maternal factors that improve the interspecific competitive ability of their offspring.We demonstrate that injections of both venom and calyx fluid from C. rubecula can inhibit egg hatching and larval development of C. glomerata. Venom from C. rubecula decreased C. glomerata egg development by 2.7 times, and calyx fluid injections caused deformities in 23% of developing C. glomerata. In contrast, reciprocal injections of the oviposition fluids from C. glomerata did not inhibit the development of C. rubecula.Our results show that maternal factors can improve the interspecific competitive ability of parasitoid larvae, challenging the previous assumptions that larval competition was resolved primarily through physical combat or larval secretions. [ABSTRACT FROM AUTHOR]

The impressive capabilities of living organisms arise from the way autonomy is materialized by their bodies. Across scales, living beings couple computational or cognitive intelligence with physical intelligence through body morphology, material multifunctionality, and mechanical compliance. While soft robotics has advanced the design and fabrication of physically intelligent bodies, the integration of information‐processing capabilities for computational intelligence remains a challenge. Consequently, perception and control limitations have constrained how soft robots are built today. Progress toward untethered autonomy will require deliberate convergence in how the field codevelops new materials, fabrication methods, and control strategies for soft robots. Here, a new perspective is put forward: that researchers should use tasks alone to impose material and information constraints on soft robot design. A conceptual framework is proposed for a task‐first design paradigm that sidesteps limitations imposed by control strategies. This framework allows emergent synergies between material and information processing properties of soft matter to be readily exploited for task‐capable agents. Particular attention is paid to the scale dependence of solutions. Finally, an outlook is presented on emerging research opportunities for achieving autonomy in future soft robots as large as elephant trunks and as small as paramecia. [ABSTRACT FROM AUTHOR]

Objectives: To describe the use of customized and custom tracheostomies at our institution, and to identify trends in patient presentation and tracheostomy design. Methods: A retrospective review was conducted for patients at our institution for whom a customized or custom tracheostomy tube was ordered between January 2011 and July 2021. Customized tracheostomy tubes allow for a small selection of alterations to trach design, such as cuff length and flange type. Custom tracheostomies have a unique design created by tracheostomy tube engineers in collaboration with the clinical provider, and are built specifically for a single patient. Results: A total of 235 patients were included, of whom 220 (93%) received customized tracheostomies and 15 custom (7%). The most common indications for customized tracheostomy were tracheal or stomal breakdown on a standard tracheostomy (n = 73, 33%) and ventilation difficulties (n = 61, 27%). The most frequent customization was shaft length (n = 126, 57%). The most common indication for custom tracheostomies was a persistent air leak on a standard or customized trach (n = 9) and the most frequent designs were custom cuffs (n = 8), flanges (n = 4), and anteriorly curved shafts (n = 4). Patients treated with a customized tracheostomy had a 5‐year overall survival of 75.3%, compared to 51.4% for custom. Conclusion: These are the first cohorts of pediatric patients with customized and custom tracheostomies to be described. Modifications to tracheostomies, in particular shaft length and cuff design, can address common complications of extended tracheostomy, and may help improve ventilation in the most challenging cases. Level of Evidence: 4 Laryngoscope, 134:452–458, 2024 [ABSTRACT FROM AUTHOR]

Passive hyperthermia causes cerebral hypoperfusion primarily from heat‐induced respiratory alkalosis. However, despite the cerebral hypoperfusion, it is possible that the mild alkalosis might help to attenuate cerebral inflammation. In this study, the cerebral exchange of extracellular vesicles (microvesicles), which are known to elicit pro‐inflammatory responses when released in conditions of stress, were examined in hyperthermia with and without respiratory alkalosis. Ten healthy male adults were heated passively, using a warm water‐perfused suit, up to core temperature + 2°C. Blood samples were taken from the radial artery and internal jugular bulb. Microvesicle concentrations were determined in platelet‐poor plasma via cells expressing CD62E (activated endothelial cells), CD31+/CD42b− (apoptotic endothelial cells), CD14 (monocytes) and CD45 (pan‐leucocytes). Cerebral blood flow was measured via duplex ultrasound of the internal carotid and vertebral arteries to determine cerebral exchange kinetics. From baseline to poikilocapnic (alkalotic) hyperthermia, there was no change in microvesicle concentration from any cell origin measured (P‐values all >0.05). However, when blood CO2 tension was normalized to baseline levels in hyperthermia, there was a marked increase in cerebral uptake of microvesicles expressing CD62E (P = 0.028), CD31+/CD42b− (P = 0.003) and CD14 (P = 0.031) compared with baseline, corresponding to large increases in arterial but not jugular venous concentrations. In a subset of seven participants who underwent hypercapnia and hypocapnia in the absence of heating, there was no change in microvesicle concentrations or cerebral exchange, suggesting that hyperthermia potentiated the CO2/pH‐mediated cerebral uptake of microvesicles. These data provide insight into a potential beneficial role of respiratory alkalosis in heat stress. Key points: The hyperthermia‐induced hyperventilatory response is observed in most humans, despite causing potentially harmful reductions in cerebral blood flow.We tested the hypothesis that the respiratory‐induced alkalosis is associated with lower circulating microvesicle concentrations, specifically in the brain, despite the reductions in blood flow.At core temperature + 2°C with respiratory alkalosis, microvesicles derived from endothelial cells, monocytes and leucocytes were at concentrations similar to baseline in the arterial and cerebral venous circulation, with no changes in cross‐brain microvesicle kinetics.However, when core temperature was increased by 2°C with CO2/pH normalized to resting levels, there was a marked cerebral uptake of microvesicles derived from endothelial cells and monocytes. The CO2/pH‐mediated alteration in cerebral microvesicle uptake occurred only in hyperthermia.These new findings suggest that the heat‐induced hyperventilatory response might serve a beneficial role by preventing potentially inflammatory microvesicle uptake in the brain. [ABSTRACT FROM AUTHOR]

Hydrophobic hydration, whereby water spontaneously structures around hydrophobic and amphiphilic molecules, plays a key role in the process of surfactant micelle formation and micellar oil solubilization. Using vibrational Raman multivariate curve resolution spectroscopy, we characterized changes in the hydrophobic hydration occurring within nonionic alkylphenol ethoxylate surfactant Tergitol NP‐12 micelles as a function of oil solubilization. We report trends in the changes of hydrophobic hydration depending on the chain length of the oil as well as the presence of a halogen atom in the oil chemical structure. Changes in hydrophobic hydration directly correlate to changes in the physical properties of the micellar solution, including cloud point and micelle hydrodynamic diameter. We compare hydrophobic hydration of Tergitol NP‐12 to nonionic linear alkyl ethoxylate surfactant Makon TD‐12 and ionic sodium dodecyl sulfate and observe similar trends; the molecular structure of the oil has the largest impact on the hydrophobic hydration. We believe these studies contribute to a fundamental understanding of the importance of hydrophobic hydration in surfactant and oil aggregates, especially as it relates to micellar oil solubilization, and provide insight into how the molecular solubilizate can impact micellar structure, size, and stability. [ABSTRACT FROM AUTHOR]

CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats)-Cas9 (CRISPR associated protein 9) is a programmable gene editing tool with a promising potential for cancer gene therapy. This therapeutic function is enabled in the present study via the non-covalent delivery of CRISPR ribonucleic protein (RNP) by cationic glucosamine/PEI-derived graphene quantum dots (PEI-GQDs) that aid in overcoming physiological barriers and tracking genes of interest. PEI-GQD/RNP complex targeting the tumor protein 53 (TP53) gene mutation overexpressed in ~50% of cancers successfully produces its double-stranded breaks in solution and in prostate cancer (PC-3) cells. Restoring this cancer "suicide" gene can promote cellular repair pathways and lead to cancer cell apoptosis. Its repair to the healthy form performed by simultaneous PEI-GQD delivery of CRISPR RNP and a gene repair template leads to a successful therapeutic outcome: 40% apoptotic cancer cell death, while having no effect on non-cancerous (HeK293) cells. The translocation of PEI-GQD/RNP complex into PC-3 cell cytoplasm is tracked via GQD intrinsic fluorescence, while enhanced green fluorescent protein (EGFP)-tagged RNP is detected in the cell nucleus, showing the successful detachment of the gene editing tool upon internalization. Using GQDs as non-viral delivery and imaging agents for CRISPR-Cas9 RNP sets the stage for image-guided cancer-specific gene therapy. [ABSTRACT FROM AUTHOR]

We examined two assumptions of the modified rebreathing technique for the assessment of the ventilatory central chemoreflex (CCR) and cerebrovascular CO2 reactivity (CVR), hypothesizing: (1) that rebreathing abolishes the gradient between the partial pressures of arterial and brain tissue CO2 [measured via the surrogate jugular venous PCO2${P_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$ and arterial PCO2${P_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$ difference (Pjv‐aCO2)] and (2) rebreathing eliminates the capacity of CVR to influence the Pjv‐aCO2 difference, and thus affect CCR sensitivity. We also evaluated these variables during two separate dynamic end‐tidal forcing (ETF) protocols (termed: ETF‐1 and ETF‐2), another method of assessing CCR sensitivity and CVR. Healthy participants were included in the rebreathing (n = 9), ETF‐1 (n = 11) and ETF‐2 (n = 10) protocols and underwent radial artery and internal jugular vein (advanced to jugular bulb) catheterization to collect blood samples. Transcranial Doppler ultrasound was used to measure middle cerebral artery blood velocity (MCAv). The Pjv‐aCO2 difference was not abolished during rebreathing (6.2 ± 2.6 mmHg; P < 0.001), ETF‐1 (9.3 ± 1.5 mmHg; P < 0.001) or ETF‐2 (8.6 ± 1.4 mmHg; P < 0.001). The Pjv‐aCO2 difference did not change during the rebreathing protocol (−0.1 ± 1.2 mmHg; P = 0.83), but was reduced during the ETF‐1 (−3.9 ± 1.1 mmHg; P < 0.001) and ETF‐2 (−3.4 ± 1.2 mmHg; P = 0.001) protocols. Overall, increases in MCAv were associated with reductions in the Pjv‐aCO2 difference during ETF (−0.095 ± 0.089 mmHg cm−1 s−1; P = 0.001) but not during rebreathing (−0.028 ± 0.045 mmHg · cm−1 · s−1; P = 0.067). These findings suggest that, although the Pjv‐aCO2 is not abolished during any chemoreflex assessment technique, hyperoxic hypercapnic rebreathing is probably more appropriate to assess CCR sensitivity independent of cerebrovascular reactivity to CO2. Key points: Modified rebreathing is a technique used to assess the ventilatory central chemoreflex and is based on the premise that the rebreathing method eliminates the difference between arterial and brain tissue PCO2${P_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$. Therefore, rebreathing is assumed to isolate the ventilatory response to central chemoreflex stimulation from the influence of cerebral blood flow.We assessed these assumptions by measuring arterial and jugular venous bulb PCO2${P_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$ and middle cerebral artery blood velocity during modified rebreathing and compared these data against data from another test of the ventilatory central chemoreflex using hypercapnic dynamic end‐tidal forcing.The difference between arterial and jugular venous bulb PCO2${P_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$ remained present during both rebreathing and end‐tidal forcing tests, whereas middle cerebral artery blood velocity was associated with the PCO2${P_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$ difference during end‐tidal forcing but not rebreathing.These findings offer substantiating evidence that clarifies and refines the assumptions of modified rebreathing tests, enhancing interpretation of future findings. [ABSTRACT FROM AUTHOR]

The cerebral vasculature manages oxygen delivery by adjusting arterial blood in‐flow in the face of reductions in oxygen availability. Hypoxic cerebral vasodilatation, and the associated hypoxic cerebral blood flow reactivity, involve many vascular, erythrocytic and cerebral tissue mechanisms that mediate elevations in cerebral blood flow via micro‐ and macrovascular dilatation. This contemporary review focuses on in vivo human work – with reference to seminal preclinical work where necessary – on hypoxic cerebrovascular reactivity, particularly where recent advancements have been made. We provide updates with the following information: in humans, hypoxic cerebral vasodilatation is partially mediated via a – likely non‐obligatory – combination of: (1) nitric oxide synthases, (2) deoxygenation‐coupled S‐nitrosothiols, (3) potassium channel‐related vascular smooth muscle hyperpolarization, and (4) prostaglandin mechanisms with some contribution from an interrelationship with reactive oxygen species. And finally, we discuss the fact that, due to the engagement of deoxyhaemoglobin‐related mechanisms, reductions in O2 content via haemoglobin per se seem to account for ∼50% of that seen with hypoxic cerebral vasodilatation during hypoxaemia. We further highlight the issue that methodological impediments challenge the complete elucidation of hypoxic cerebral reactivity mechanisms in vivo in healthy humans. Future research is needed to confirm recent advancements and to reconcile human and animal findings. Further investigations are also required to extend these findings to address questions of sex‐, heredity‐, age‐, and disease‐related differences. The final step is to then ultimately translate understanding of these mechanisms into actionable, targetable pathways for the prevention and treatment of cerebral vascular dysfunction and cerebral hypoxic brain injury. [ABSTRACT FROM AUTHOR]

Introduction: It is unclear how much physical activity (PA) people with fibromyalgia (PwF) engage in. We conducted a meta‐analysis to examine PA levels in PwF and compared levels with age‐ and gender‐matched controls and between objective and subjective assessments. Methods: Embase, PubMed and CINAHL Plus were searched by two independent reviewers from inception till 3 January 2023 using the keywords: 'fibromyalgia' OR 'fibrositis' AND 'physical activity' OR 'exercise' OR 'sports'. A random effects meta‐analysis adjusting for publication bias was conducted. Results: Across 22 studies, there were 5997 (5956 women) PwF (median age = 44 years). After trim and fill adjustment, PwF spent a mean of 4.0 (95% CI = 2.3–5.8) min/day in vigorous PA, 67.5 (95% CI = 35.4–99.6) min/day in moderate intensity PA and 270.5 (95% CI = 99.6–441.4) min/day in light PA. Only 37.7% (95% CI = 18.7–61.5) of PwF achieved the public PA recommendation of 150 min of moderate to vigorous PA per week. PwF walked 5663.7 (95% CI = 4493.5–6833.9) steps per day, which is below the 6000 steps per day recommendation. PwF spent 39.0 min/day (95% CI = 22.8–55.1, p < 0.001) less in PA than healthy controls, while MET‐minutes per week is 1324.7 (95 % CI = 237.6–2411.7, p = 0.017) lower. There were no significant differences between subjective and objective PA assessments (p = 0.69). Conclusion: Our data demonstrate that the majority of PwF are still insufficiently physically active to obtain significant health benefits. Future clinical PA interventions specifically targeting the prevention of physical inactivity in PwF and engaging physically inactive PwF to become physically active are warranted. [ABSTRACT FROM AUTHOR]

The introduction of model‐based dose calculation algorithms (MBDCAs) in brachytherapy provides an opportunity for a more accurate dose calculation and opens the possibility for novel, innovative treatment modalities. The joint AAPM, ESTRO, and ABG Task Group 186 (TG‐186) report provided guidance to early adopters. However, the commissioning aspect of these algorithms was described only in general terms with no quantitative goals. This report, from the Working Group on Model‐Based Dose Calculation Algorithms in Brachytherapy, introduced a field‐tested approach to MBDCA commissioning. It is based on a set of well‐characterized test cases for which reference Monte Carlo (MC) and vendor‐specific MBDCA dose distributions are available in a Digital Imaging and Communications in Medicine—Radiotherapy (DICOM‐RT) format to the clinical users. The key elements of the TG‐186 commissioning workflow are now described in detail, and quantitative goals are provided. This approach leverages the well‐known Brachytherapy Source Registry jointly managed by the AAPM and the Imaging and Radiation Oncology Core (IROC) Houston Quality Assurance Center (with associated links at ESTRO) to provide open access to test cases as well as step‐by‐step user guides. While the current report is limited to the two most widely commercially available MBDCAs and only for 192Ir‐based afterloading brachytherapy at this time, this report establishes a general framework that can easily be extended to other brachytherapy MBDCAs and brachytherapy sources. The AAPM, ESTRO, ABG, and ABS recommend that clinical medical physicists implement the workflow presented in this report to validate both the basic and the advanced dose calculation features of their commercial MBDCAs. Recommendations are also given to vendors to integrate advanced analysis tools into their brachytherapy treatment planning system to facilitate extensive dose comparisons. The use of the test cases for research and educational purposes is further encouraged. [ABSTRACT FROM AUTHOR]

Insect herbivores simultaneously experience bottom‐up effects of plant defensive chemistry and the top‐down effects of natural enemies. At the intersection of these effects are herbivore immune systems, herbivore traits that have largely been overlooked in studies of plant‐insect interactions. Most previous studies have demonstrated compromised immunity of herbivores that feed on plants with higher defensive chemistry. Many studies have used embedded microfilaments or silica beads as proxies for parasitoid eggs. Yet, parasitoids may evade or suppress host immune responses by injecting venom and calyx fluid, or through modifications of their egg surface structure, necessitating studies that include all three trophic levels to obtain a complete picture of how plant traits may modulate herbivore immunity.Here, we examined the effect of host plant species that differ in glucosinolate (anti‐herbivore compounds produced by plants in the Brassicaceae) concentrations on the immune status of an herbivore and its consequences for two species of parasitoids with different life history traits.We found that larvae of the butterfly Pieris rapae that fed on field mustard Brassica rapa, which contain 52‐fold higher glucosinolate concentrations than collards B. oleracea, attained lower body weights and experienced prolonged development to adulthood.Yet, caterpillars that fed on B. rapa had enhanced cellular immunity, as measured by total and differential haemocyte counts as well as melanization capacity, compared to larvae that fed on B. oleracea.In turn, the likelihood that at least some eggs in clutches of the gregarious endoparasitoid Cotesia glomerata would be encapsulated, leading to a reduction in brood size, were three times greater when their host caterpillars fed on B. rapa compared to B. oleracea.Interestingly, eggs of the solitary endoparasitoid Cotesia rubecula were rarely encapsulated irrespective of the host plant on which their host caterpillar fed. Therefore, our results suggest that plant defence metabolites can influence the expression of herbivore immunity, but the effectiveness of this response strongly depends on the identity of the parasitoid and its ability to evade the caterpillar immune response, and possibly the evolution of these trophic interactions in non‐native systems. Read the free Plain Language Summary for this article on the Journal blog. [ABSTRACT FROM AUTHOR]

Introduction: Understanding the correlates of sedentary behavior (SB) is important in the development of interventions which reduce and interrupt SB in people with fibromyalgia (PwF). This systematic review aimed to investigate the correlates of SB in PwF using the socio‐ecological model. Methods: Three databases (Embase, CINAHL and PubMed) were search from inception until July 21, 2022 using "sedentary" or different types of SB and "fibromyalgia" or "fibrositis" as keywords. The data collected was then analyzed using summary coding. Results: Out of 23 SB correlates retrieved from 7 reports (n = 1698), no correlates were consistently reported (ie, reported in 4 or more studies). Higher pain intensity was the most commonly reported barrier for reducing/interrupting SB (reported in 3 reports). Other reported barriers to reducing/interrupting SB were experiencing physical and mental fatigue, a more severe disease impact, and a lack of motivation to be physically active (all reported in 1 study). A better experienced social and physical functioning and more vitality were facilitators for reducing/interrupting SB (all reported in 1 study). To date, in PwF no correlates of SB at the interpersonal, environmental and policy levels have been explored. Conclusion: Research on correlates of SB in PwF is still in its infancy. The current preliminary evidence suggests that clinicians should consider physical and mental barriers when aiming to reduce or interrupt SB in PwF. Further research on modifiable correlates at all levels of the socio‐ecological model is required to inform future trials aiming to modify SB in this vulnerable population. [ABSTRACT FROM AUTHOR]

EMC1 encodes subunit 1 of the endoplasmic reticulum (ER) membrane protein complex (EMC), a transmembrane domain insertase involved in membrane protein biosynthesis. Variants in EMC1 are described as a cause of global developmental delay, hypotonia, cortical visual impairment, and commonly, cerebral atrophy on MRI scan. We report an individual with severe global developmental delay and progressive cerebellar atrophy in whom exome sequencing identified a heterozygous essential splice‐site variant in intron‐3 of EMC1 (NM_015047.3:c.287‐1G>A). Whole genome sequencing (WGS) identified a deep intronic variant in intron‐20 of EMC1 (NM_015047.3:c.2588‐771C>G) that was poorly predicted by in silico programs to disrupt pre‐mRNA splicing. Reverse Transcription‐PCR (RT‐PCR) revealed stochastic activation of a pseudo‐exon associated with the c.2588‐771C>G variant and mis‐splicing arising from the c.287‐1G>A variant. This case highlights the utility of WGS and RNA studies to identify and assess likely pathogenicity of deep intronic variants and expands the genotypic and phenotypic spectrum of EMC1‐related disorders. [ABSTRACT FROM AUTHOR]

High‐altitude (HA) hypoxia may alter the structural–functional integrity of the neurovascular unit (NVU). Herein, we compared male lowlanders (n = 9) at sea level (SL) and after 14 days acclimatization to 4300 m (chronic HA) in Cerro de Pasco (CdP), Péru (HA), against sex‐, age‐ and body mass index‐matched healthy highlanders (n = 9) native to CdP (lifelong HA). Venous blood was assayed for serum proteins reflecting NVU integrity, in addition to free radicals and nitric oxide (NO). Regional cerebral blood flow (CBF) was examined in conjunction with cerebral substrate delivery, dynamic cerebral autoregulation (dCA), cerebrovascular reactivity to carbon dioxide (CVRCO2) and neurovascular coupling (NVC). Psychomotor tests were employed to examine cognitive function. Compared to lowlanders at SL, highlanders exhibited elevated basal plasma and red blood cell NO bioavailability, improved anterior and posterior dCA, elevated anterior CVRCO2 and preserved cerebral substrate delivery, NVC and cognition. In highlanders, S100B, neurofilament light‐chain (NF‐L) and T‐tau were consistently lower and cognition comparable to lowlanders following chronic‐HA. These findings highlight novel integrated adaptations towards regulation of the NVU in highlanders that may represent a neuroprotective phenotype underpinning successful adaptation to the lifelong stress of HA hypoxia. Key points: High‐altitude (HA) hypoxia has the potential to alter the structural–functional integrity of the neurovascular unit (NVU) in humans.For the first time, we examined to what extent chronic and lifelong hypoxia impacts multimodal biomarkers reflecting NVU structure and function in lowlanders and native Andean highlanders.Despite lowlanders presenting with a reduction in systemic oxidative–nitrosative stress and maintained cerebral bioenergetics and cerebrovascular function during chronic hypoxia, there was evidence for increased axonal injury and cognitive impairment.Compared to lowlanders at sea level, highlanders exhibited elevated vascular NO bioavailability, improved dynamic regulatory capacity and cerebrovascular reactivity, comparable cerebral substrate delivery and neurovascular coupling, and maintained cognition. Unlike lowlanders following chronic HA, highlanders presented with lower concentrations of S100B, neurofilament light chain and total tau.These findings highlight novel integrated adaptations towards the regulation of the NVU in highlanders that may represent a neuroprotective phenotype underpinning successful adaptation to the lifelong stress of HA hypoxia. [ABSTRACT FROM AUTHOR]

Introduction: In 1999, a set of highly accurate Polynesian-specific equations to estimate adult body fat from non-invasive field measures of age, sex, height, and weight (Equation 1), age, sex, height, weight, and bioelectrical impedance analysis (BIA) resistance (Equation 2), and age, sex, height, weight, and the sum of two skinfold thicknesses (Equation 3) were published. The purpose of this study was to evaluate the performance of the equation-based estimators in a sample of Samoan adults recruited 20 years later between 2017 and 2019. Methods: Age, sex, height, weight, BIA resistance, skinfold thickness, and fat mass as measured using dual energy x-ray absorptiometry (DXA) were available for 432 Samoan adults (mean age 50.9 years, 56% female) seen in 2017/2019. We compared equation-derived fat mass and DXA-derived fat mass using scatterplots and Pearson correlation coefficients. We then updated the equation coefficient estimates in a training set (2/3 of the sample) and evaluated the performance of the updated equations in a testing set (the remaining 1/3 of the sample). Results: Equation-derived fat mass was strongly correlated with DXA-derived fat mass for Equation (1) (r² = 0.95, n = 432), Equation (2) (r² = 0.97, n = 425), and Equation (3) (r² = 0.95, n = 426). Updating the equation coefficient estimates resulted in mostly similar coefficients and nearly identical testing set performance for Equation (1) (r² = 0.96, n = 153), Equation (2) (r² = 0.98, n = 150), and Equation (3) (r² = 0.96, n = 150). Conclusions: The Polynesian-specific body fat estimation equations remained stable despite changing social and environmental factors and marked increase in obesity prevalence in Samoa. [ABSTRACT FROM AUTHOR]

The role of precipitation efficiency (PE)—the fraction of column‐integrated condensate that reaches the surface as rain—in the global temperature response to CO2 rise is yet to be quantified. Here we employ 36 limited‐domain cloud resolving models (CRMs) from the Radiative‐Convective Equilibrium Model Intercomparison Project and find that they strongly imply higher PE at warmer temperatures. We then analyze 35 general circulation models (GCMs) from the Coupled Model Intercomparison Project Phase 6 and find that increasing PE is associated with tropical circulation slowdown and greater eastern equatorial Pacific warming. These changes trigger pan‐tropical positive cloud feedback through stratiform anvil cloud reduction and stratocumulus suppression, resulting in higher Effective Climate Sensitivity (ECS). We find that in 24 of 35 GCMs matching the CRMs in simulating increasing PE with greenhouse warming, mean ECS is 1 K higher than in PE‐decreasing GCMs. Thus, further constraining PE sensitivity to temperature could reduce uncertainty over future climate projections. Plain Language Summary: Precipitation efficiency (PE) is the ratio of precipitation to cloud condensate. Evidence from the great majority of cloud‐resolving models and many earth system models support higher PE with warming. With higher PE, more cloud condensate leaves the atmosphere as precipitation, reducing cloud cover and optical thickness. As PE is tightly linked to the latent heat release of tropical convection, an atmosphere with high PE and a weak circulation can release the same latent heat as its counterpart with low PE and strong circulation. Increasing PE is robustly correlated with pan‐tropical positive cloud feedback in the equatorial Pacific, namely thinner stratiform anvil clouds in the west and suppressed stratocumulus cloud cover in the east. Hence, quantifying PE change is critical for climate projections. Key Points: Cloud‐resolving models indicate increasing precipitation efficiency with global warmingHigh precipitation efficiency implies a weak Walker circulation, eastern tropical Pacific warming, and positive tropical cloud feedbackAll 4 K or higher climate sensitivity climate models project increasing precipitation efficiency [ABSTRACT FROM AUTHOR]

In response to different cellular stresses, the transcription factor p53 undergoes different dynamics. p53 dynamics, in turn, control cell fate. However, distinct stresses can generate the same p53 dynamics but different cell fate outcomes, suggesting integration of dynamic information from other pathways is important for cell fate regulation. To determine how MAPK activities affect p53‐mediated responses to DNA breaks and oxidative stress, we simultaneously tracked p53 and either ERK, JNK, or p38 activities in single cells. While p53 dynamics were comparable between the stresses, cell fate outcomes were distinct. Combining MAPK dynamics with p53 dynamics was important for distinguishing between the stresses and for generating temporal ordering of cell fate pathways. Furthermore, cross‐talk between MAPKs and p53 controlled the balance between proliferation and cell death. These findings provide insight into how cells integrate signaling pathways with distinct temporal patterns of activity to encode stress specificity and drive different cell fate decisions. Synopsis: In single pancreatic cells responding to oxidative stress, JNK dynamics regulate an early trigger of cell death, p53 controls late maintenance of cell cycle arrest, and p38 controls a switch between JNK‐ and p53‐dependent cell fate.Simultaneous tracking of p53 levels and either ERK, JNK, or p38 activity is performed in single pancreatic cells responding to DNA breaks or oxidative stress.Sequential pulsing of JNK activity within a short timeframe is associated with the triggering of cell death.p53 is not required for short‐term cell death but is required for long‐term cell cycle arrest.p38 regulates the switch from JNK‐dependent cell death and p53‐dependent cell cycle arrest. [ABSTRACT FROM AUTHOR]

Background: Peer connections in school classrooms play an important role in social–emotional development and mental health. However, research on the association between children's peer relationships and white matter connections in the brain is scarce. We studied associations between peer relationships in the classroom and white matter structural connectivity in a pediatric population‐based sample. Methods: Bullying and victimization, as well as rejection and acceptance, were assessed in classrooms in 634 children at age 7. White matter microstructure (fractional anisotropy (FA), mean diffusivity (MD)) was measured with diffusion tensor imaging at age 10. We examined global metrics of white matter microstructure and used Tract‐Based Spatial Statistics (TBSS) for voxel‐wise associations. Results: Peer victimization was associated with higher global FA and lower global MD and peer rejection was associated with lower global MD; however, these associations did not remain after multiple testing correction. Voxel‐wise TBSS results for peer victimization and rejection were in line with global metrics both in terms of direction and spatial extent of the associations, with associated voxels (pFWE <.05) observed throughout the brain (including corpus callosum, corona radiata, sagittal stratum and superior longitudinal fasciculi). Conclusions: Although based only on cross‐sectional data, the findings could indicate accelerated white matter microstructure maturation in certain brain areas of children who are victimized or rejected more often. However, repeated measurements are essential to unravel this complex interplay of peer connections, maturation and brain development over time. [ABSTRACT FROM AUTHOR]

New Findings: What is the central question of this study?What are the contributions of shear stress and adrenergic tone to brachial artery vasodilatation during hypercapnia?What is the main finding and its importance?In healthy young adults, shear‐mediated vasodilatation does not occur in the brachial artery during hypercapnia, as elevated α₁‐adrenergic activity typically maintains vascular tone and offsets distal vasodilatation controlling flow. We aimed to assess the shear stress dependency of brachial artery (BA) responses to hypercapnia, and the α₁‐adrenergic restraint of these responses. We hypothesized that elevated shear stress during hypercapnia would cause BA vasodilatation, but where shear stress was prohibited (via arterial compression), the BA would not vasodilate (study 1); and, in the absence of α₁‐adrenergic activity, blood flow, shear stress and BA vasodilatation would increase (study 2). In study 1, 14 healthy adults (7/7 male/female, 27 ± 4 years) underwent bilateral BA duplex ultrasound during hypercapnia (partial pressure of end‐tidal carbon dioxide, +10.2 ± 0.3 mmHg above baseline, 12 min) via dynamic end‐tidal forcing, and shear stress was reduced in one BA using manual compression (compression vs. control arm). Neither diameter nor blood flow was different between baseline and the last minute of hypercapnia (P = 0.423, P = 0.363, respectively) in either arm. The change values from baseline to the last minute, in diameter (%; P = 0.201), flow (ml/min; P = 0.234) and conductance (ml/min/mmHg; P = 0.503) were not different between arms. In study 2, 12 healthy adults (9/3 male/female, 26 ± 4 years) underwent the same design with and without α₁‐adrenergic receptor blockade (prazosin; 0.05 mg/kg) in a placebo‐controlled, double‐blind and randomized design. BA flow, conductance and shear rate increased during hypercapnia in the prazosin control arm (interaction, P < 0.001), but in neither arm during placebo. Even in the absence of α₁‐adrenergic restraint, downstream vasodilatation in the microvasculature during hypercapnia is insufficient to cause shear‐mediated vasodilatation in the BA. [ABSTRACT FROM AUTHOR]

Childhood ear infections are highly prevalent and diagnosed with the otoscope, a simple tool that illuminates and magnifies the eardrum to subjectively assess color, translucency and presence of any middle ear fluid. Frequently, however, this view is obstructed by cerumen, complicating clinician assessment and appropriate and effective management. An optical coherence tomography (OCT)‐otoscope capable of capturing both depth‐resolved OCT images and digital color surface images was used to compare OCT against otoscopy for imageability and readability despite cerumen obstruction. Image data were collected from 26 human subjects and read by 12 blinded clinicians and 5 blinded OCT experts. An average of 64.6% of otoscopy views were obstructed. For cases with >75% otoscopy view obstruction, OCT imageability was 84.6%, while otoscopy imageability was 37.5%, excluding complete obstruction cases. OCT‐otoscopy is a promising technology to improve practical middle ear assessment despite the presence of obstructions that frequently render current diagnostic assessments ineffective. [ABSTRACT FROM AUTHOR]

The assessment of left ventricular (LV) contractility in animal models is useful in various experimental paradigms, yet obtaining such measures is inherently challenging and surgically invasive. In a cross‐species study using small and large animals, we comprehensively tested the agreement and validity of multiple single‐beat surrogate metrics of LV contractility against the field‐standard metrics derived from inferior vena cava occlusion (IVCO). Fifty‐six rats, 27 minipigs and 11 conscious dogs underwent LV and arterial catheterization and were assessed for a range of single‐beat metrics of LV contractility. All single‐beat metrics were tested for the various underlying assumptions required to be considered a valid metric of cardiac contractility, including load‐independency, sensitivity to inotropic stimulation, and ability to diagnose contractile dysfunction in cardiac disease. Of all examined single‐beat metrics, only LV maximal pressure normalized to end‐diastolic volume (EDV), end‐systolic pressure normalized to EDV, and the maximal rate of rise of the LV pressure normalized to EDV showed a moderate‐to‐excellent agreement with their IVCO‐derived reference measure and met all the underlying assumptions required to be considered as a valid cardiac contractile metric in both rodents and large‐animal models. Our findings demonstrate that single‐beat metrics can be used as a valid, reliable method to quantify cardiac contractile function in basic/preclinical experiments utilizing small‐ and large‐animal models Key points: Validating and comparing indices of cardiac contractility that avoid caval occlusion would offer considerable advantages for the field of cardiovascular physiology.We comprehensively test the underlying assumptions of multiple single‐beat indices of cardiac contractility in rodents and translate these findings to pigs and conscious dogs.We show that when performing caval occlusion is unfeasible, single‐beat metrics can be utilized to accurately quantify cardiac inotropic function in basic and preclinical research employing various small and large animal species.We report that maximal left‐ventricular (LV)‐pressure normalized to end‐diastolic volume (EDV), LV end‐systolic pressure normalized to EDV and the maximal rate of rise of the LV pressure waveform normalized to EDV are the best three single‐beat metrics to measure cardiac inotropic function in both small‐ and large‐animal models. [ABSTRACT FROM AUTHOR]

Although the COVID‐19 lockdowns in 2020 had some environmental benefits, the pandemic's impact on the global economy has also had conservation repercussions, especially in biodiverse nations. Ecuador, which is heavily reliant on petroleum, agricultural exports, and ecotourism, experienced a rise in poverty in response to pandemic shutdowns. In this study, we sought to quantify levels of illegal timber extraction and poaching before and after the start of COVID‐19 lockdowns throughout two protected areas (Reserva Jama Coaque [JCR] and Bosque Seco Lalo Loor [BSLL]) in the endangered Pacific Forest of Ecuador. We analyzed chainsaw and gunshot acoustic data recorded from devices installed in the forest canopy from December 2019 to March 2020 and October 2020 to March 2021. Results from generalized linear mixed effects models indicated less chainsaw activity before lockdowns (βpost.lockdown = 0.568 ± 0.266 SE, p‐value =.030), although increased average rainfall also seemed to negatively affect chainsaw activity (βavg.rainfall = −0.002 ± 0.0006 SE, p‐value =.003). Gunshots were too infrequent to conduct statistical models; however, 87% of gunshots were detected during the 'lockdown' period. Observational data collected by rangers from these protected areas also noted an increase in poaching activities beginning mid to late 2020 and persisting into 2021. These results add to the steadily growing literature indicating an increase in environmental crime, particularly in biodiverse nations, catalyzed by COVID‐19‐related economic hardships. Identifying areas where environmental crime increased during pandemic lockdowns is vital to address both socioeconomic drivers and enforcement deficiencies to prevent further biodiversity loss and disease outbreaks and to promote ecosystem resilience. Our study also demonstrates the utility of passive acoustic monitoring to detect illegal resource extraction patterns, which can inform strategies such as game theory modeling for ranger patrol circuits and placement of real‐time acoustic detection technologies to monitor and mitigate environmental crimes. [ABSTRACT FROM AUTHOR]

Theory predicts that egg load and foraging activity of insects should be positively related. Species that emerge with a low initial egg load and mature additional eggs as they age may limit initial foraging activity to avoid egg limitation. Similarly, females, which deplete their egg supply through oviposition, should decrease activity immediately afterwards and then increase activity as new eggs are matured.The authors used activity monitors to measure daily locomotor activity separately from exposure to host cues with the stink bug egg parasitoid, Trissolcus japonicus. The authors measured activity and egg load as newly emerged wasps aged and tested whether egg depletion from oviposition would reduce activity.Parasitoid activity increased with age in parallel with egg maturation, with both egg load and activity reaching their maximum about 6–7 days after emergence. Newly emerged wasps began activity later in the day and had lower activity intensity compared with older individuals. When given host experience, females that had laid many offspring, and had thus depleted their egg loads, unexpectedly increased their activity for up to 3 days.The present study results challenge the generally accepted positive relationship between foraging activity and egg load, suggesting that this relationship may be secondary to host patch quality. The authors provide evidence that host patch quality can influence not only within‐patch but also between‐patch foraging activity.Plastic responses in activity patterns may allow parasitoids to better exploit rich host environments while minimising foraging costs and decreasing likelihood of egg limitation in low‐quality environments. [ABSTRACT FROM AUTHOR]

Purpose: Active learning engages students via interaction for deeper understanding and retention. A global pandemic resulted in an abrupt mid‐semester transition from in‐person to virtual learning. This study examined student reporting on active learning before and after this transition. Methods: First‐year DDS candidates took an anonymous survey, reflecting on three Spring (January–April) 2020 courses (lecture‐style, small‐group case‐based, and pre‐clinical). Survey questions included: (1) basic demographics, (2) reporting frequency (1–Never, 2–Rarely, 3–Sometimes, 4–Often, 5–Always) of active learning elements from a pre‐set list before/after the shift to online learning, and (3) Likert‐style questions regarding effects on active learning and learning environment preference. Results: The traditional lecture course manifested two active learning activities in the category Sometimes prior to the transition to virtual; one of those activities (question and answer) experienced the most significant difference (p < 0.0001) in frequency change. The small group, case‐based course incorporated nine activities in‐person in the category Sometimes; although small significant differences (p ≤ 0.05) in frequency were noted for five of those activities between virtual and in‐person, these differences may have not have made a difference in practice. The pre‐clinical course incorporated four activities in the category Sometimes pre‐transition, with no significant differences detected in frequency. Students slightly leaned toward preferring in‐person for the small‐group and pre‐clinical courses, but had no preference for the traditional lecture course. Conclusions: Course structure may correlate more with student experience of the frequency of active learning activities and preference for in‐person versus virtual environment than the environment itself. [ABSTRACT FROM AUTHOR]

Simulation models of multi‐sector systems are increasingly used to understand societal resilience to climate and economic shocks and change. However, multi‐sector systems are also subject to numerous uncertainties that prevent the direct application of simulation models for prediction and planning, particularly when extrapolating past behavior to a nonstationary future. Recent studies have developed a combination of methods to characterize, attribute, and quantify these uncertainties for both single‐ and multi‐sector systems. Here, we review challenges and complications to the idealized goal of fully quantifying all uncertainties in a multi‐sector model and their interactions with policy design as they emerge at different stages of analysis: (a) inference and model calibration; (b) projecting future outcomes; and (c) scenario discovery and identification of risk regimes. We also identify potential methods and research opportunities to help navigate the tradeoffs inherent in uncertainty analyses for complex systems. During this discussion, we provide a classification of uncertainty types and discuss model coupling frameworks to support interdisciplinary collaboration on multi‐sector dynamics (MSD) research. Finally, we conclude with recommendations for best practices to ensure that MSD research can be properly contextualized with respect to the underlying uncertainties. Key Points: Uncertainty is an inherent part of multi‐sector systems analysisApproaches to addressing uncertainty involve deliberate tradeoffsBest practices involve standardizing communication and improving transparency [ABSTRACT FROM AUTHOR]

Myopathy, lactic acidosis, and sideroblastic anemia 2 (MLASA2) is an autosomal recessive mitochondrial disorder caused by pathogenic variants in YARS2. YARS2 variants confer heterogeneous phenotypes ranging from the full MLASA syndrome to a clinically unaffected state. Symptom onset is most common in the first decade of life but can occur in adulthood and has been reported following intercurrent illness. Early death can result from respiratory muscle weakness and cardiomyopathy. We report a case of MLASA2 with compound heterozygous YARS2 pathogenic variants; a known pathogenic nonsense variant [NM_001040436.3:c.98C>A (p.Ser33Ter)] and a likely pathogenic missense variant not previously associated with disease [NM_001040436.3:c.948G>T (p.Arg316Ser)]. The proband initially presented with a relatively mild phenotype of myopathy and lactic acidosis. During pregnancy, anemia emerged as an additional feature and in the postpartum period she experienced severe decompensation of cardiorespiratory function. This is the first reported case of pregnancy‐related complications in a patient with YARS2‐related mitochondrial disease. This case highlights the need for caution and careful counseling when considering pregnancy in mitochondrial disease, due to the risk of disease exacerbation and pregnancy complications. [ABSTRACT FROM AUTHOR]

Recent attention to pneumatically pressurized mechanical metamaterials has identified opportunity for large shape change and mechanical properties adaptation through the collective exploitation of reconfigurable internal structures and enclosed cavities. Yet, many of these ideas are found to act in smooth, continuous ways at moderate rate. This research explores a new class of bimodal, hierarchical mechanical metamaterials that exemplify rapid change of mechanical behavior by exploiting pneumatic pressure as a means to cross bifurcation. A lattice structure with periodic square cavities is presented as a model metamaterial to highlight important design considerations and mechanical behavior. An analytical model is formed to delineate the multimodal boundaries in a high‐dimensional parameter space, while numerical simulations and experiments confirm the presence of each modal characteristic. The studies reveal the high rate of change afforded by this embodiment of pressurized mechanical metamaterials and confirm the origin lay in harnessing elastic instability. Extensions to the idea are compared against the Kutzbach–Grübler criteria to articulate how other metamaterial networks may be leveraged in this way. The outcomes of this research may inspire methods for high‐rate shape and properties change via multimodal mechanical metamaterial assemblies, such as for soft robotic platforms. [ABSTRACT FROM AUTHOR]