Wnt7b acts in concert with Wnt5a to regulate tissue elongation and planar cell polarity via noncanonical Wnt signaling.

Intercellular signaling mediated by evolutionarily conserved planar cell polarity (PCP) proteins aligns cell polarity along the tissue plane and drives polarized cell behaviors during tissue morphogenesis. Accumulating evidence indicates that the vertebrate PCP pathway is regulated by noncanonical, ß-catenin-independent Wnt signaling; however, the signaling components and mechanisms are incompletely understood. In the mouse hearing organ, both PCP and noncanonical Wnt (ncWnt) signaling are required in the developing auditory sensory epithelium to control cochlear duct elongation and planar polarity of resident sensory hair cells (HCs), including the shape and orientation of the stereociliary hair bundle essential for sound detection. We have recently discovered a Wnt/G-protein/PI3K pathway that coordinates HC planar polarity and intercellular PCP signaling. Here, we identify Wnt7b as a ncWnt ligand acting in concert with Wnt5a to promote tissue elongation in diverse developmental processes. In the cochlea, Wnt5a and Wnt7b are redundantly required for cochlear duct coiling and elongation, HC planar polarity, and asymmetric localization of core PCP proteins Fzd6 and Dvl2. Mechanistically, Wnt5a/Wnt7b-mediated ncWnt signaling promotes membrane recruitment of Daple, a nonreceptor guanine nucleotide exchange factor for Gαi, and activates PI3K/AKT and ERK signaling, which promote asymmetric Fzd6 localization. Thus, ncWnt and PCP signaling pathways have distinct mutant phenotypes and signaling components, suggesting that they act as separate, parallel pathways with nonoverlapping functions in cochlear morphogenesis. NcWnt signaling drives tissue elongation and reinforces intercellular PCP signaling by regulating the trafficking of PCP-specific Frizzled receptors.

LIGHT (TNFSF14) Costimulation Enhances Myeloid Cell Activation and Antitumor Immunity in the Setting of PD-1/PD-L1 and TIGIT Checkpoint Blockade.

Coinhibition of TIGIT (T cell immunoreceptor with Ig and ITIM domains) and PD-1/PD-L1 (PD-1/L1) may improve response rates compared with monotherapy PD-1/L1 blockade in checkpoint naive non-small cell lung cancer with PD-L1 expression >50%. TIGIT mAbs with an effector-competent Fc can induce myeloid cell activation, and some have demonstrated effector T cell depletion, which carries a clinical liability of unknown significance. TIGIT Ab blockade translates to antitumor activity by enabling PVR signaling through CD226 (DNAM-1), which can be directly inhibited by PD-1. Furthermore, DNAM-1 is downregulated on tumor-infiltrating lymphocytes (TILs) in advanced and checkpoint inhibition-resistant cancers. Therefore, broadening clinical responses from TIGIT blockade into PD-L1low or checkpoint inhibition-resistant tumors, may be induced by immune costimulation that operates independently from PD-1/L1 inhibition. TNFSF14 (LIGHT) was identified through genomic screens, in vitro functional analysis, and immune profiling of TILs as a TNF ligand that could provide broad immune activation. Accordingly, murine and human bifunctional fusion proteins were engineered linking the extracellular domain of TIGIT to the extracellular domain of LIGHT, yielding TIGIT-Fc-LIGHT. TIGIT competitively inhibited binding to all PVR ligands. LIGHT directly activated myeloid cells through interactions with LTßR (lymphotoxin ß receptor), without the requirement for a competent Fc domain to engage Fcγ receptors. LIGHT costimulated CD8+ T and NK cells through HVEM (herpes virus entry mediator A). Importantly, HVEM was more widely expressed than DNAM-1 on T memory stem cells and TILs across a range of tumor types. Taken together, the mechanisms of TIGIT-Fc-LIGHT promoted strong antitumor activity in preclinical tumor models of primary and acquired resistance to PD-1 blockade, suggesting that immune costimulation mediated by LIGHT may broaden the clinical utility of TIGIT blockade.

Travel Burden as a Measure of Healthcare Access and the Impact of Telehealth within the Veterans Health Administration.

BACKGROUND: Travel is a major barrier to healthcare access for Veteran Affairs (VA) patients, and disproportionately affects rural Veterans (approximately one quarter of Veterans). The CHOICE/MISSION acts' intent is to increase timeliness of care and decrease travel, although not clearly demonstrated. The impact on outcomes remains unclear. Increased community care increases VA costs and increases care fragmentation. Retaining Veterans within the VA is a high priority, and reduction of travel burdens will help achieve this goal. Sleep medicine is presented as a use case to quantify travel related barriers. OBJECTIVE: The Observed and Excess Travel Distances are proposed as two measures of healthcare access, allowing for quantification of healthcare delivery related to travel burden. A telehealth initiative that reduced travel burden is presented. DESIGN: Retrospective, observational, utilizing administrative data. SUBJECTS: VA patients with sleep related care between 2017 and 2021. In-person encounters: Office visits and polysomnograms; telehealth encounters: virtual visits and home sleep apnea tests (HSAT). MAIN MEASURES: Observed distance: distance between Veteran's home and treating VA facility. Excess distance: difference between where Veteran received care and nearest VA facility offering the service of interest. Avoided distance: distance between Veteran's home and nearest VA facility offering in-person equivalent of telehealth service. KEY RESULTS: In-person encounters peaked between 2018 and 2019, and have down trended since, while telehealth encounters have increased. During the 5-year period, Veterans traveled an excess 14.1 million miles, while 10.9 million miles of travel were avoided due to telehealth encounters, and 48.4 million miles were avoided due to HSAT devices. CONCLUSIONS: Veterans often experience a substantial travel burden when seeking medical care. Observed and excess travel distances are valuable measures to quantify this major healthcare access barrier. These measures allow for assessment of novel healthcare approaches to improve Veteran healthcare access and identify specific regions that may benefit from additional resources.

Study protocol to assess de-implementation of the initial provider encounter for diagnosis and treatment of obstructive sleep apnea: the DREAM (Direct Referral for Apnea Monitoring) Project.

BACKGROUND: Obstructive sleep apnea (OSA) is a very common and serious health condition which is highly prevalent among U.S. military Veterans. Because the demand for sleep medicine services often overwhelms the availability of such services, it is necessary to streamline diagnosis and treatment protocols. The goals of this study are to, (1) assess the efficacy of de-implementing the initial provider encounter for diagnosis and treatment of OSA; (2) determine the negative predictive value (NPV) of home sleep apnea testing (HSAT); (3) develop HSAT usage recommendations for various at-risk patient populations. METHODS: This is a large, pragmatic study that will take place in 3 VA sleep medicine programs: San Francisco, CA; Portland, OR; and Pittsburgh, PA. All Veterans referred for new sleep apnea evaluations at these sites will be included in this four-year study. Outcomes will include time from referral for OSA to sleep testing and treatment; positive airway pressure (PAP) treatment adherence measures; patient-reported clinical outcomes and measures of satisfaction; determination of the NPV of HSAT; HSAT usage recommendations for at-risk patient populations. DISCUSSION: The DREAM (Direct Referral for Apnea Monitoring) Project will inform sleep medicine providers and clinical organizations regarding strategies to streamline diagnosis and treatment protocols for OSA. Results of this study should have significant impact on clinical practices and professional guidelines. Trial registration The majority of this project is an observational study of clinical procedures. Therefore, clinical trial registration is not required.

Does Community Outsourcing Improve Timeliness of Care for Veterans With Obstructive Sleep Apnea?

BACKGROUND: Providing timely access to care has been a long-standing priority for the Veterans Affairs Healthcare System. Recent strategies to reduce long wait times have focused on purchasing community care by a fee-for-service model. Whether outsourcing Veterans Affairs (VA) specialty care to the community improves access is unclear. OBJECTIVES: We compared time from referral to treatment among Veterans whose care was provided by VA versus community care purchased by the VA, using obstructive sleep apnea as an example condition. METHODS: This was a retrospective cohort study of Northern California Veterans seeking sleep apnea care through the San Francisco VA Healthcare System between 2012 and 2018. We used multivariable linear regression with propensity score matching to investigate the relationship between time to care delivery and care setting (VA provided vs. VA-purchased community care). A total of 1347 Northern California Veterans who completed sleep apnea testing within the VA and 88 Veterans who completed sleep apnea testing in the community had complete data for analysis. RESULTS: Among Northern California Veterans with obstructive sleep apnea, outsourcing of care to the community was associated with longer time from referral to therapy (mean±SD, 129.6±82.8 d with VA care vs. 252.0±158.8 d with community care, P<0.001) and greater loss to follow-up. CONCLUSIONS: These findings suggest that purchasing community care may lead to care fragmentation and not improve wait times nor improve access to subspecialty care for Veterans.

Rheological stability of carbomer in hydroalcoholic gels: Influence of alcohol type.

OBJECTIVE: The main objective of this paper is to analyse and attempt to understand the nature of rheological changes observed and the dynamics of Carbopol NF 980 hydroalcoholic gels neutralized specifically by triethanol amine (TEA), both as a function of time and alcohol type to probe time stabilities and ageing effects in such carbopol gel systems. The rheological changes and dynamics of 3 carbopol gel systems were observed; the gels included a water-based, ethanol-based, and isopropyl alcohol-based gel. It is hoped that this study shall shed light on the dynamical nature and the microstructural evolution of such networked gel systems, which were maintained under closed isothermal conditions and left completely unperturbed. The experimental results can provide the information necessary to understand and proposes plausible mechanisms guiding this dynamical behaviour in hydroalcoholic carbopol gels. METHODS: A TA instrument mechanical rheometer was used to measure the viscosity and storage and loss modulus, and a pH meter was utilized to determine the changes in each sample over the period. RESULTS: Studying the differences in the gel structures upon initial preparation illustrated that the ethanol and isopropyl alcohol (IPA) gels differed from the water-based gel in terms of viscosity, G', and G″, with the IPA gel displaying the lowest viscosity and moduli values across all shear rates. All the three gel systems exhibited strong shear thinning characteristics and were reminiscent of yield stress type found in colloidal gels. The water-based gel compared to the hydroalcoholic gels was strongly G' dominated, with the magnitude of the difference between G' and G″ observed to be much higher. This reflects that initial formation of the water-based gel structure possesses a much more rigid structure with a high elastic modulus component dominating. This also suggests that the water-based gel structure displayed stronger interactions between the carbopol particles when compared to those of the hydroalcoholic gels. Over the 30-day period, it was observed that the ethanol and water-based gels did not reveal any appreciable viscosity changes, with only an approximate 12% and 7% change from day 1 to 30, respectively. It was observed that the IPA systems' viscosity drastically increased over the period, with an approximately 77% change from day 1 to 30. The water and ethanol-based gels also exhibited very similar rheological behaviour over the entire time period with G' dominating G″. The G″ values of the water and ethanol-based gels decreased slightly at the end of day 30 by 10% and 16%, respectively, while the G' values for each sample remained essentially unchanged, increasing only 0.06% for the water-based gel, and increasing 1.4% for the ethanol-based gel. This further confirms the relatively stable gel structures attained. For the isopropyl gel system, the storage modulus of the system exhibited an average percent increase of approximately 16% from day 1 to day 30, but interestingly the loss modulus varied the least amongst all the gel systems, with only a 3% increase. The increase in G' reflects upon the evolution of a more rigid structure by day 30 for the IPA gel. This observation is clearly consistent with the corresponding increase in viscosity observed in the IPA gel. None of the gels tested displayed a consistent pH over the period. The pH of the hydroalcoholic gels was higher than that of the water-based gel for a majority of the period. The greatest fluctuations in pH were observed for the water and IPA gels, even though the water-based gel had one of the most stable rheological profiles out of the samples tested. The water, ethanol, and IPA gels' pH increased approximately 25%, 6%, and 5%, respectively, from day 1 to day 30. CONCLUSION: The rheological and pH study of the 3 hand sanitizer systems over a 30-day period allowed for rational insights into the plausible reasons responsible for driving the observed rheological changes in these unperturbed systems. For the water-based gel, we hypothesize that the changes observed are due to physical ageing, where the gel structure has evolved over time to eventually progress towards a more stabilized framework structure. The pH of the gel upon formation was on the lower side. Such a lower pH influences the formation of a gel, which is comparatively less swollen and occupies a slightly lesser volume, and thereby points to a much less compacted gel network structure or alternatively, a more fluid structure. If the particles moved around more, the system was not initially in a state of low energy, causing increased particle movement, and in turn, physical ageing. This could be responsible for the development of a physically altered structure over time. The gel structure dynamically attempts to minimize its free energy by becoming more rigid, which has been observed as being manifested in the decrease of both the viscosity and the G″. For the hydroalcoholic gels, we conjecture that ageing observed was a result of chemical ageing, and the alcohol type employed in the preparation is primarily responsible for exhibiting this effect. The polarities of ethyl alcohol and isopropyl alcohol are key to the stabilization of such resultant network structures which get formed because of neutralization. It has been observed in previous studies that with decreasing polarity, there was an increase in the neutralization needed to obtain the development of a structure half as well developed as the final resultant structure. Isopropyl alcohol is a much less polar solvent compared to ethanol and water, and therefore required higher levels of TEA as the base to neutralize the system. We conjecture that the charged TEA cationic species had a greater propensity to get exchanged with bulk solution in the vicinity of the polymer into the bulk solution, and that the pH fluctuation observed indicated a kinetic exchange process over time, causing the viscosity and moduli profiles to increase along with the pH. At this time though, further investigations need to be carried out to truly understand the underlying instability, and thus dynamics for gel systems of this type.

OBJECTIF: L'objectif principal de cet article est d'analyser et de tenter de comprendre la nature des changements rhéologiques observés et la dynamique des gels hydroalcooliques Carbopol NF 980 neutralisés spécifiquement par l'amine triéthanol (TEA), à la fois en fonction du temps et du type d'alcool pour sonder les stabilités temporelles et les effets du vieillissement dans de tels systèmes de gel carbopol. Les changements rhéologiques et la dynamique de 3 systèmes de gel de carbopol ont été observés ; les gels comprenaient un gel à base d'eau, d'éthanol et d'alcool isopropylique. On espère que cette étude éclairera la nature dynamique et l'évolution microstructurale de ces systèmes de gel en réseau, qui ont été maintenus dans des conditions isothermes fermées et laissés complètement imperturbables. Les résultats expérimentaux peuvent fournir les informations nécessaires pour comprendre et proposer des mécanismes plausibles guidant ce comportement dynamique dans les gels hydroalcooliques de carbopol. MÉTHODE: Un rhéomètre TA mécanique a été utilisé pour mesurer la viscosité, le module de stockage et de perte, et un pH-mètre a été utilisé pour déterminer les changements dans chaque échantillon au cours de la période. RÉSULTATS: L'étude des différences dans les structures du gel lors de la préparation initiale a montré que les gels d'éthanol et d'alcool isopropylique (IPA) différaient du gel à base d'eau en termes de viscosité, G' et G'' le gel IPA affichant les valeurs de viscosité et de modules les plus faibles pour tous les taux de cisaillement. Les trois systèmes de gel présentaient de fortes caractéristiques d'amincissement par cisaillement et rappelaient le type de contrainte d'élasticité que l'on trouve dans les gels colloïdaux. Le gel à base d'eau par rapport aux gels hydroalcooliques était fortement dominé par G', l'ampleur de la différence entre G' et G'' présentant une importance beaucoup plus élevée. Cela reflète le fait que la formation initiale de la structure de gel à base d'eau possède une structure beaucoup plus rigide avec un composant de module élastique élevé dominant. Cela suggère également que la structure du gel à base d'eau présentait des interactions plus fortes entre les particules de carbopol par rapport à celles des gels hydroalcooliques. Au cours de la période de 30 jours, il a été observé que l'éthanol et les gels à base d'eau n'ont révélé aucun changement de viscosité appréciable, avec seulement un changement approximatif de 12% et 7% du jour 1 au jour 30, respectivement. Il a été observé que la viscosité des systèmes IPA a considérablement augmenté au cours de la période, avec un changement d'environ 77% du jour 1 au jour 30. Les gels à base d'eau et d'éthanol ont également montré un comportement rhéologique très similaire sur toute la période, G' dominant G''. Les valeurs G'' des gels à base d'eau et d'éthanol ont légèrement diminué à la fin de la journée 30 de 10% et 16%, respectivement, tandis que les valeurs G' pour chaque échantillon sont restées essentiellement inchangées, n'augmentant que de 0,06% pour le gel à base d'eau et augmentant de 1,4% pour le gel à base d'éthanol. Cela confirme en outre les structures de gel relativement stables atteintes. Pour le système de gel isopropylique, le module de stockage du système a montré une augmentation moyenne d'environ 16% du jour 1 au jour 30, mais il est intéressant de noter que le module de perte variait le moins parmi tous les systèmes de gel, avec seulement une augmentation de 3%. L'augmentation de G' reflète l'évolution d'une structure plus rigide au jour 30 pour le gel IPA. Cette observation est clairement cohérente avec l'augmentation correspondante de la viscosité observée dans le gel IPA. Aucun des gels testés n'a montré un pH constant sur la période. Le pH des gels hydroalcooliques était supérieur à celui du gel à base d'eau pendant la majeure partie de la période. Les plus grandes fluctuations de pH ont été observées pour les gels d'eau et d'IPA, même si le gel à base d'eau avait l'un des profils rhéologiques les plus stables parmi les échantillons testés. Le pH de l'eau, de l'éthanol et des gels IPA a augmenté d'environ 25%, 6% et 5%, respectivement, du jour 1 au jour 30. CONCLUSION: L'étude rhéologique et pH des 3 systèmes de désinfectant pour les mains sur une période de 30 jours a permis d'obtenir des informations rationnelles sur les raisons plausibles responsables des changements rhéologiques observés dans ces systèmes non perturbés. Pour le gel à base d'eau, nous émettons l'hypothèse que les changements observés sont dus au vieillissement physique, où la structure du gel a évolué au fil du temps pour éventuellement progresser vers une structure plus stabilisée. Le pH du gel lors de la formation était dans la partie inférieure. Un pH aussi bas influence la formation d'un gel, qui est comparativement moins gonflé et occupe un volume légèrement inférieur, et indique ainsi une structure de réseau de gel beaucoup moins compactée ou autrement dit, une structure plus fluide. Si les particules se déplaçaient davantage, le système n'était pas initialement dans un état de faible énergie, ce qui entraînait une augmentation du mouvement des particules et, à son tour, un vieillissement physique. Cela pourrait être responsable du développement d'une structure physiquement modifiée au fil du temps. La structure du gel tente dynamiquement de minimiser son énergie libre en devenant plus rigide, ce qui a été observé comme se manifestant par la diminution de la viscosité et du G'' Pour les gels hydroalcooliques, nous pensons que le vieillissement observé était le résultat d'un vieillissement chimique, et le type d'alcool utilisé dans la préparation est principalement responsable de cet effet. Les polarités de l'alcool éthylique et de l'alcool isopropylique sont essentielles à la stabilisation de ces structures de réseau résultantes qui se forment en raison de la neutralisation. Il a été observé dans des études antérieures qu'avec la diminution de la polarité, il y avait une augmentation de la neutralisation nécessaire pour obtenir le développement d'une structure à moitié aussi bien développée que la structure résultante finale. L'alcool isopropylique est un solvant beaucoup moins polaire que l'éthanol et l'eau, et nécessitait donc des niveaux plus élevés de TEA comme base pour neutraliser le système. Nous pensons que les espèces cationiques TEA chargées avaient une plus grande propension à être échangées avec une solution en vrac à proximité du polymère, dans la solution en vrac, et que la fluctuation du pH observée indiquait un processus d'échange cinétique au fil du temps, entraînant une augmentation des profils de viscosité et de modules avec le pH. À l'heure actuelle, cependant, des recherches supplémentaires doivent être menées pour vraiment comprendre l'instabilité sous-jacente, et donc la dynamique des systèmes de gel de ce type.

A Low-Cost Beam-Scanning Second Harmonic Generation Microscope with Application for Agrochemical Development and Testing.

A low-cost second harmonic generation (SHG) microscope was constructed, and, for the first time, SHG microscopy was used for imaging agrochemical materials directly on the surface of common commercial crop leaves. The microscope uses a chromatically fixed (1560 nm) femtosecond fiber laser, a commercial 2D galvanometer mirror system, and a PCIe digital oscilloscope card, which together kept total instrument costs under $40 000 (USD), a significant decrease in cost and complexity from common systems (commercial and home-built) using tunable lasers and faster beam-scanning architectures. The figures of merit of the low-cost system still enabled a variety of measurements of agrochemical materials. Following confirmation of largely background-free SHG imaging of common crop leaves (soybean, maize, wheatgrass), SHG microscopy was used to image active ingredient crystallization after solution-phase deposition directly on the leaf surface, including at industrially relevant active ingredient concentrations (<0.05% w/w). Crystallization was also followed in real-time, with differences in crystallization time observed for different application procedures (spraying vs single droplet deposition). A strong dependency of active ingredient crystallization on the substrate was found, with an increased crystallization tendency observed on leaves vs on glass slides. Different crystal habits for the same active ingredient were also observed on different plant species. Finally, a model extended-release formulation was prepared, with a decrease in active ingredient crystallinity observed vs solution-phase deposition. These collective results demonstrate the need for making diagnostic measurements directly on the leaf surface and could help inform the next generation of pesticide products that ensure optimized agricultural output for a growing world population.

Altered trajectories of neurodevelopment and behavior in mouse models of Rett syndrome.

Rett Syndrome (RTT) is a genetic disorder that is caused by mutations in the x-linked gene coding for methyl-CpG-biding-protein 2 (MECP2) and that mainly affects females. Male and female transgenic mouse models of RTT have been studied extensively, and we have learned a great deal regarding RTT neuropathology and how MeCP2 deficiency may be influencing brain function and maturation. In this manuscript we review what is known concerning structural and coinciding functional and behavioral deficits in RTT and in mouse models of MeCP2 deficiency. We also introduce our own corroborating data regarding behavioral phenotype and morphological alterations in volume of the cortex and striatum and the density of neurons, aberrations in experience-dependent plasticity within the barrel cortex and the impact of MeCP2 loss on glial structure. We conclude that regional structural changes in genetic models of RTT show great similarity to the alterations in brain structure of patients with RTT. These region-specific modifications often coincide with phenotype onset and contribute to larger issues of circuit connectivity, progression, and severity. Although the alterations seen in mouse models of RTT appear to be primarily due to cell-autonomous effects, there are also non-cell autonomous mechanisms including those caused by MeCP2-deficient glia that negatively impact healthy neuronal function. Collectively, this body of work has provided a solid foundation on which to continue to build our understanding of the role of MeCP2 on neuronal and glial structure and function, its greater impact on neural development, and potential new therapeutic avenues.

Characterization of Terminal Iron(III)-Oxo and Iron(III)-Hydroxo Complexes Derived from O2 Activation.

O2 activation at nonheme iron centers is a common motif in biological systems. While synthetic models have provided numerous insights into the reactivity of high-valent iron-oxo complexes related to biological processes, the majority of these complexes are synthesized using alternative oxidants. This report describes O2 activation by an iron(II)-triflate complex of the imino-functionalized tris(pyrrol-2-ylmethyl)amine ligand framework, H3[N(piCy)3]. Initial reaction conditions result in the formation of a mixture of oxidation products including terminal iron(III)-oxo and iron(III)-hydroxo complexes. The relevance of these species to the O2 activation process is demonstrated through reactivity studies and electrochemical analysis of the iron(III)-oxo complex.

Defining the structure of undergraduate medical leadership and management teaching and assessment in the UK.

Medical leadership and management (MLM) skills are essential in preventing failings of healthcare; it is unknown how these attitudes can be developed during undergraduate medical education. This paper aims to quantify interest in MLM and recommends preferred methods of teaching and assessment at UK medical schools. Two questionnaires were developed, one sent to all UK medical school faculties, to assess executed and planned curriculum changes, and the other sent to medical students nationally to assess their preferences for teaching and assessment. Forty-eight percent of UK medical schools and 260 individual student responses were recorded. Student responses represented 60% of UK medical schools. 65% of schools valued or highly valued the importance of teaching MLM topics, compared with 93.2% of students. Students' favoured teaching methods were seminars or lectures (89.4%) and audit and quality improvement (QI) projects (77.8%). Medical schools preferred portfolio entries (55%) and presentations (35%) as assessment methods, whilst simulation exercises (76%) and audit reports (61%) were preferred by students. Preferred methods encompass experiential learning or simulation and a greater emphasis should be placed on encouraging student audit and QI projects. The curriculum changes necessary could be achieved via further integration into future editions of Tomorrow's Doctors.

Endovascular fenestration and stenting for renovisceral malperfusion in a pediatric patient with type II Loeys-Dietz syndrome.

A 16-year-old girl with Loeys-Dietz syndrome presented with an acute, complicated type B aortic dissection (AD) with mesenteric and right renal malperfusion owing to a dynamic obstruction. The anatomy of her AD and her genetic aortography were suboptimal for thoracic endovascular aortic repair. Given the concern for anticipated late aortic degeneration and the need for open aortic repair, she underwent successful transfemoral endovascular septal fenestration with stenting of the fenestration into the superior mesenteric artery and additional stenting of the right renal artery. Her renal failure and mesenteric angina resolved, and she was discharged home. Endovascular fenestration provides an elegant solution for AD-associated dynamic malperfusion of aortic branch vessels without compromising future open aortic repairs.

Outcomes of Autologous Versus Irradiated Homologous Costal Cartilage Graft in Rhinoplasty.

Background: Autologous costal cartilage (ACC) and irradiated homologous costal cartilage (IHCC) are commonly used in septorhinoplasty when there is insufficient septal cartilage for grafting. Objective: To assess the surgical outcomes of patients who underwent septorhinoplasty with either ACC or IHCC as measured by rates of infection, resorption, warping, and revision rate. Methods: A retrospective analysis of patients who underwent rhinoplasty with ACC or IHCC at a single academic institution was performed. Demographic data, surgical details, antibiotic use, and outcomes, including surgical duration, infection, resorption, warping, and revision rate, were analyzed using Fisher's exact test, chi-squared test, and logistic regression. Results: One hundred forty-three patients were identified. The median age was 48 years (interquartile range: 35-57.5) and 62.2% (n = 89) were female, 61 patients (42.7%) underwent ACC, and 82 (57.3%) IHCC. Revision rate in both groups was similar (ACC = 14.8%, IHCC = 14.6%; p = 0.98). There was no difference in infection rate (ACC = 4.9%, IHCC = 3.7%; p = 0.71). Postoperative deformity and nasal obstruction were the most common indications for revision surgery. Surgical time was shorter with IHCC (p < 0.01). Mean follow-up time was 26.5 months (±25) for ACC, and 16 months (±12) for IHCC. Conclusions: ACC and IHCC are similar in terms of effectiveness and safety in septorhinoplasty.

Self-Assembled Origami Neural Probes for Scalable, Multifunctional, Three-Dimensional Neural Interface.

Flexible intracortical neural probes have drawn attention for their enhanced longevity in high-resolution neural recordings due to reduced tissue reaction. However, the conventional monolithic fabrication approach has met significant challenges in: (i) scaling the number of recording sites for electrophysiology; (ii) integrating of other physiological sensing and modulation; and (iii) configuring into three-dimensional (3D) shapes for multi-sided electrode arrays. We report an innovative self-assembly technology that allows for implementing flexible origami neural probes as an effective alternative to overcome these challenges. By using magnetic-field-assisted hybrid self-assembly, multiple probes with various modalities can be stacked on top of each other with precise alignment. Using this approach, we demonstrated a multifunctional device with scalable high-density recording sites, dopamine sensors and a temperature sensor integrated on a single flexible probe. Simultaneous large-scale, high-spatial-resolution electrophysiology was demonstrated along with local temperature sensing and dopamine concentration monitoring. A high-density 3D origami probe was assembled by wrapping planar probes around a thin fiber in a diameter of 80∼105 µm using optimal foldable design and capillary force. Directional optogenetic modulation could be achieved with illumination from the neuron-sized micro-LEDs (µLEDs) integrated on the surface of 3D origami probes. We could identify angular heterogeneous single-unit signals and neural connectivity 360° surrounding the probe. The probe longevity was validated by chronic recordings of 64-channel stacked probes in behaving mice for up to 140 days. With the modular, customizable assembly technologies presented, we demonstrated a novel and highly flexible solution to accommodate multifunctional integration, channel scaling, and 3D array configuration.

Lipid-Encapsulated mRNAs Encoding Complex Fusion Proteins Potentiate Antitumor Immune Responses.

Lipid nanoparticle (LNP)-encapsulated mRNA has been used for in vivo production of several secreted protein classes, such as IgG, and has enabled the development of personalized vaccines in oncology. Establishing the feasibility of delivering complex multispecific modalities that require higher-order structures important for their function could help expand the use of mRNA/LNP biologic formulations. Here, we evaluated whether in vivo administration of mRNA/LNP formulations of SIRPα-Fc-CD40L and TIGIT-Fc-LIGHT could achieve oligomerization and extend exposure, on-target activity, and antitumor responses comparable with that of the corresponding recombinant fusion proteins. Intravenous infusion of the formulated LNP-encapsulated mRNAs led to rapid and sustained production of functional hexameric proteins in vivo, which increased the overall exposure relative to the recombinant protein controls by ∼28 to 140 fold over 96 hours. High concentrations of the mRNA-encoded proteins were also observed in secondary lymphoid organs and within implanted tumors, with protein concentrations in tumors up to 134-fold greater than with the recombinant protein controls 24 hours after treatment. In addition, SIRPα-Fc-CD40L and TIGIT-Fc-LIGHT mRNAs induced a greater increase in antigen-specific CD8+ T cells in the tumors. These mRNA/LNP formulations were well tolerated and led to a rapid increase in serum and intratumoral IL2, delayed tumor growth, extended survival, and outperformed the activities of benchmark mAb controls. Furthermore, the mRNA/LNPs demonstrated improved efficacy in combination with anti-PD-L1 relative to the recombinant fusion proteins. These data support the delivery of complex oligomeric biologics as mRNA/LNP formulations, where high therapeutic expression and exposure could translate into improved patient outcomes. SIGNIFICANCE: Lipid nanoparticle-encapsulated mRNA can efficiently encode complex fusion proteins encompassing immune checkpoint blockers and costimulators that functionally oligomerize in vivo with extended pharmacokinetics and durable exposure to induce potent antitumor immunity.

Effect of Preoperative Therapeutic Plasma Exchange With Albumin Replacement Before Kidney Transplant on Intraoperative Coagulation Measured By the Thrombelastograph (TEGR 6s): A Case Report.

Anesthesiologists should be aware of the coagulation implications of therapeutic plasma exchange (TPE) with albumin replacement for desensitization of kidney transplant (KT) recipients. We describe a case where the final preoperative TPE was performed with albumin. A TEGR 6s demonstrated defects in fibrinogen component to clot strength. With surgical oozing noted and the fibrinogen defect, cryoprecipitate was administered. Thereafter, fibrinogen contribution to clot strength normalized, coinciding with clinical hemostasis. With the increased use of TPE to reduce antibodies in KT recipients, visco-elastic testing may assist in the identification of coagulation defects when plasma is not used as replacement fluid.

Sleep disorders among rural Veterans: Relative prevalence, comorbidities, and comparisons with urban Veterans.

PURPOSE: To describe and compare demographic characteristics and comorbidities of rural and urban Veterans diagnosed with sleep disorders, and to evaluate whether rurality is a disparity for sleep care among Veterans. METHODS: Numbers of Veterans with sleep disorders and comorbid conditions were determined using the Department of Veterans Affairs (VA's) Corporate Data Warehouse, a database that contains detailed clinical information for all Veterans who receive VA health care. Comparisons between urban and rural Veterans were conducted for fiscal years (FY) 2010-2021. FINDINGS: The prevalence of diagnosed sleep disorders was similar among rural and urban Veterans from FY2010 to 2021 and increased for both groups during this time period. The prevalence of chronic pulmonary disease, congestive heart failure, and diabetes mellitus was higher for rural Veterans with sleep disorders compared to their urban counterparts. From 2012 to 2021, the percentage of rural Veterans who received sleep care at VA facilities was lower than the percentage of urban Veterans who received VA sleep care during the same time span. CONCLUSIONS: Although rural Veterans exhibited a higher prevalence of 3 comorbid conditions associated with sleep disorders, the prevalence of sleep disorder diagnoses was similar between rural and urban Veterans. Therefore, it is possible that sleep disorders are underdiagnosed among rural Veterans. The fact that rural Veterans received VA sleep care at a lower rate compared to urban Veterans indicates that rurality is a disparity in access to care in this population. VA is addressing this disparity through a variety of programs, including telehealth initiatives.

Veterans Health Administration TeleSleep Enterprise-Wide Initiative 2017-2020: bringing sleep care to our nation's veterans.

STUDY OBJECTIVES: The Veterans Health Administration cares for many veterans with sleep disorders who live in rural areas. The Veterans Health Administration's Office of Rural Health funded the TeleSleep Enterprise-Wide Initiative (EWI) to improve access to sleep care for rural veterans through creation of national telehealth networks. METHODS: The TeleSleep EWI consists of (1) virtual synchronous care, (2) home sleep apnea testing, and (3) REVAMP (Remote Veterans Apnea Management Platform), a patient- and provider-facing web application that enabled veterans to actively engage with their sleep care and sleep care team. The TeleSleep EWI was designed as a hub-and-spoke model, where larger sites with established sleep centers care for smaller, rural sites with a shortage of providers. Structured formative evaluation for the TeleSleep EWI is supported by the Veterans Health Administration's Quality Enhancement Research Initiative and was critical in assessing outcomes and effectiveness of the program. RESULTS: The TeleSleep EWI launched with 7 hubs and 34 spokes (2017) and rapidly expanded to 13 hubs and 63 spokes (2020). The TeleSleep EWI resulted in a significant increase in rural veterans accessing sleep care by utilizing home sleep apnea testing to establish a diagnosis of obstructive sleep apnea and virtual care for follow-up. Rates of virtual care utilization were greater in hubs and spokes participating in the TeleSleep EWI compared with non-EWI sleep programs. Additionally, veterans expressed satisfaction with their virtual care TeleSleep experiences. CONCLUSIONS: The TeleSleep EWI successfully increased sleep care access for rural veterans, promoted adoption of virtual care services, and resulted in high patient satisfaction. CITATION: Chun VS, Whooley MA, Williams K, et al. Veterans Health Administration TeleSleep Enterprise-Wide Initiative 2017-2020: bringing sleep care to our nation's veterans. J Clin Sleep Med. 2023;19(5):913-923.

Tracking B cell responses to the SARS-CoV-2 mRNA-1273 vaccine.

Protective immunity following vaccination is sustained by long-lived antibody-secreting cells and resting memory B cells (MBCs). Responses to two-dose SARS-CoV-2 mRNA-1273 vaccination are evaluated longitudinally by multimodal single-cell analysis in three infection-naïve individuals. Integrated surface protein, transcriptomics, and B cell receptor (BCR) repertoire analysis of sorted plasmablasts and spike+ (S-2P+) and S-2P- B cells reveal clonal expansion and accumulating mutations among S-2P+ cells. These cells are enriched in a cluster of immunoglobulin G-expressing MBCs and evolve along a bifurcated trajectory rooted in CXCR3+ MBCs. One branch leads to CD11c+ atypical MBCs while the other develops from CD71+ activated precursors to resting MBCs, the dominant population at month 6. Among 12 evolving S-2P+ clones, several are populated with plasmablasts at early timepoints as well as CD71+ activated and resting MBCs at later timepoints, and display intra- and/or inter-cohort BCR convergence. These relationships suggest a coordinated and predictable evolution of SARS-CoV-2 vaccine-generated MBCs.

A bioinformatics screen reveals hox and chromatin remodeling factors at the Drosophila histone locus.

BACKGROUND: Cells orchestrate histone biogenesis with strict temporal and quantitative control. To efficiently regulate histone biogenesis, the repetitive Drosophila melanogaster replication-dependent histone genes are arrayed and clustered at a single locus. Regulatory factors concentrate in a nuclear body known as the histone locus body (HLB), which forms around the locus. Historically, HLB factors are largely discovered by chance, and few are known to interact directly with DNA. It is therefore unclear how the histone genes are specifically targeted for unique and coordinated regulation. RESULTS: To expand the list of known HLB factors, we performed a candidate-based screen by mapping 30 publicly available ChIP datasets of 27 unique factors to the Drosophila histone gene array. We identified novel transcription factor candidates, including the Drosophila Hox proteins Ultrabithorax (Ubx), Abdominal-A (Abd-A), and Abdominal-B (Abd-B), suggesting a new pathway for these factors in influencing body plan morphogenesis. Additionally, we identified six other factors that target the histone gene array: JIL-1, hormone-like receptor 78 (Hr78), the long isoform of female sterile homeotic (1) (fs(1)h) as well as the general transcription factors TBP associated factor 1 (TAF-1), Transcription Factor IIB (TFIIB), and Transcription Factor IIF (TFIIF). CONCLUSIONS: Our foundational screen provides several candidates for future studies into factors that may influence histone biogenesis. Further, our study emphasizes the powerful reservoir of publicly available datasets, which can be mined as a primary screening technique.