Topological Spin Textures in an Insulating van der Waals Ferromagnet.

Generation and control of topological spin textures constitutes one of the most exciting challenges of modern spintronics given their potential applications in information storage technologies. Of particular interest are magnetic insulators, which due to low damping, absence of Joule heating and reduced dissipation can provide energy-efficient spin-textures platform. Here, it is demonstrated that the interplay between sample thickness, external magnetic fields, and optical excitations can generate a prolific paramount of spin textures, and their coexistence in insulating CrBr3 van der Waals (vdW) ferromagnets. Using high-resolution magnetic force microscopy and large-scale micromagnetic simulation methods, the existence of a large region in T-B phase diagram is demonstrated where different stripe domains, skyrmion crystals, and magnetic domains exist and can be intrinsically selected or transformed to each-other via a phase-switch mechanism. Lorentz transmission electron microscopy unveils the mixed chirality of the magnetic textures that are of Bloch-type at given conditions but can be further manipulated into Néel-type or hybrid-type via thickness-engineering. The topological phase transformation between the different magnetic objects can be further inspected by standard photoluminescence optical probes resolved by circular polarization indicative of an existence of exciton-skyrmion coupling mechanism. The findings identify vdW magnetic insulators as a promising framework of materials for the manipulation and generation of highly ordered skyrmion lattices relevant for device integration at the atomic level.

Understanding the Effect of Curvature on the Magnetization Reversal of Three-Dimensional Nanohelices.

Comprehending the interaction between geometry and magnetism in three-dimensional (3D) nanostructures is important to understand the fundamental physics of domain wall (DW) formation and pinning. Here, we use focused-electron-beam-induced deposition to fabricate magnetic nanohelices with increasing helical curvature with height. Using electron tomography and Lorentz transmission electron microscopy, we reconstruct the 3D structure and magnetization of the nanohelices. The surface curvature, helical curvature, and torsion of the nanohelices are then quantified from the tomographic reconstructions. Furthermore, by using the experimental 3D reconstructions as inputs for micromagnetic simulations, we can reveal the influence of surface and helical curvature on the magnetic reversal mechanism. Hence, we can directly correlate the magnetic behavior of a 3D nanohelix to its experimental structure. These results demonstrate how the control of geometry in nanohelices can be utilized in the stabilization of DWs and control of the response of the nanostructure to applied magnetic fields.

Declining Prevalence of Trichomonas vaginalis Diagnosed by Wet Mount in a Cohort of U.S. Women With and Without HIV.

Background: Women living with HIV (WLWH) are often coinfected with Trichomonas vaginalis (TV), and annual screening is recommended. Our goal was to assess differences in TV prevalence at study entry and over time in enrollment cohorts of the Women's Interagency HIV Study. Methods: In a multisite study, TV was diagnosed by wet mount microscopy. Prevalence was determined across four enrollment waves: 1994-1995, 2001-2002, 2011-2012, and 2013-2015. Generalized estimating equation multivariable logistic regression models assessed changes in visit prevalence across waves after controlling for HIV disease severity and other risks. Results: At 63,824 person-visits (3,508 WLWH and 1,262 women without HIV), TV was diagnosed by wet mount at 1979 visits (3.1%). After multivariable adjustment, HIV status was not associated with TV detection, which was more common among younger women, women with multiple partners, and irregular condom use. All enrollment waves showed a decline in TV detection over time, although p-value for trend did not reach significance for most recent waves. To explore the potential utility of screening among WLWH, we assessed rates of TV detection among women without appreciable vaginal discharge on examination. Initial TV prevalence among asymptomatic women was 3.5%, and prevalence decreased to 0.5%-1% in the most recent wave (2013-2015) (p-trend <0.0001). Conclusions: In this cohort, TV rates are low among WLWH, and HIV does not increase TV risk. Screening may benefit newly diagnosed WLWH, women with risk factors, or those receiving care sporadically but is unlikely to further reduce the low rate of TV among women in care, especially older women without multiple partners. The clinical trials registration number for WIHS is NCT00000797.

Writing and Detecting Topological Charges in Exfoliated Fe5-xGeTe2.

Fe5-xGeTe2 is a promising two-dimensional (2D) van der Waals (vdW) magnet for practical applications, given its magnetic properties. These include Curie temperatures above room temperature, and topological spin textures─TST (both merons and skyrmions), responsible for a pronounced anomalous Hall effect (AHE) and its topological counterpart (THE), which can be harvested for spintronics. Here, we show that both the AHE and THE can be amplified considerably by just adjusting the thickness of exfoliated Fe5-xGeTe2, with THE becoming observable even in zero magnetic field due to a field-induced unbalance in topological charges. Using a complementary suite of techniques, including electronic transport, Lorentz transmission electron microscopy, and micromagnetic simulations, we reveal the emergence of substantial coercive fields upon exfoliation, which are absent in the bulk, implying thickness-dependent magnetic interactions that affect the TST. We detected a "magic" thickness t ≈ 30 nm where the formation of TST is maximized, inducing large magnitudes for the topological charge density (∼6.45 × 1020 cm-2), and the concomitant anomalous (ρxyA,max ≃22.6 µΩ cm) and topological (ρxyu,T 1≃5 µΩ cm) Hall resistivities at T ≈ 120 K. These values for ρxyA,max and ρxyu,T are higher than those found in magnetic topological insulators and, so far, the largest reported for 2D magnets. The hitherto unobserved THE under zero magnetic field could provide a platform for the writing and electrical detection of TST aiming at energy-efficient devices based on vdW ferromagnets.

Pharmacokinetics, Efficacy, and Safety of a SARS-CoV-2 Antibody Treatment in Pediatric Participants: An Open-Label Addendum of a Placebo-Controlled, Randomized Phase 2/3 Trial.

INTRODUCTION: Bamlanivimab and etesevimab (BAM + ETE) are monoclonal antibodies (mAbs) effective in reducing COVID-19-related hospitalizations and all-cause mortality in adult participants at increased risk for severe disease. We present pharmacokinetic (PK), efficacy, and safety results from pediatric participants (< 18 years of age) with COVID-19 who were treated with BAM + ETE. METHODS: In an addendum to the phase 2/3 BLAZE-1 clinical trial (NCT04427501), pediatric participants received open-label weight-based dosing (WBD, n = 94) based on exposure-matching to the authorized dose of BAM + ETE in adult participants. For efficacy and safety assessments, placebo (n = 14) and BAM + ETE (n = 20)-treated adolescent participants (> 12 to < 18 years of age) from the BLAZE-1 trial were included in the overall pediatric population (N = 128). All participants had mild to moderate COVID-19 upon enrollment and ≥ 1 risk factor for severe COVID-19. The primary objective was to characterize the PK of BAM and ETE in the WBD population. RESULTS: The median age of the participants was 11.2 years, 46.1% were female, 57.9% were Black/African American, and 19.7% were Hispanic/Latino. The area under the curve for BAM and ETE in the WBD population was similar to that previously observed in adults. There were no COVID-19-related hospitalizations or deaths. All adverse events (AE) except one were mild or moderate, with one participant reporting a serious AE. CONCLUSION: WBD in pediatric participants achieved similar drug exposures compared to adult participants that received the authorized BAM + ETE dose. The pediatric efficacy and safety data were consistent with adults receiving mAbs for COVID-19. TRIAL REGISTRATION NUMBER: NCT04427501.

Direct observation of magnetic ordering induced via systematic lattice disorder in artificial rhombus spin ices.

It is critical to understand the effect of lattice geometry on the order parameter of a condensed matter system, as it controls phase transitions in such systems. Artificial spin ices (ASIs) are two-dimensional lattices of Ising-like nanomagnets that provide an opportunity to explore such phenomena by lithographically controlling the lattice geometry to observe its influence on magnetic ordering and frustration effects. Here we report a systematic approach to studying the effects of disorder in rhombus ASIs generated from combinations of five vertex motifs. We investigate four geometries characterized by a geometric order parameter, with symmetries ranging from periodic to quasiperiodic to random. Lorentz transmission electron microscopy data indicates magnetic domain behavior depends on chains of strongly-coupled islands in the periodic and sixfold-twinned lattices, while the behavior of the disordered lattice is dominated by vertex motifs with large configurational degeneracy. Utilizing micromagnetic simulations, a quantitative analysis of the lattice energetics showed that the experimental rotationally-demagnetized state of the disordered ASI was closer in energy to the idealized ground state compared to other periodic and twinned ASIs. Our work provides a unique pathway for using degeneracy, magnetic frustration, and order to control the magnetization behavior of designer disordered systems.

Mixed Methods, Implementation Science Evaluation of a Community Health Worker Strategy for HIV Service Engagement in Uganda.

BACKGROUND: A trial found that a community health worker (CHW) strategy using "Health Scouts" improved HIV care uptake and ART coverage. To better understand outcomes and areas for improvement, we conducted an implementation science evaluation. METHODS: Using the RE-AIM framework, quantitative methods included analyses of a community-wide survey (n = 1903), CHW log books, and phone application data. Qualitative methods included in-depth interviews (n = 72) with CHWs, clients, staff, and community leaders. RESULTS: Thirteen Health Scouts logged 11,221 counseling sessions; 2532 unique clients were counseled. 95.7% (1789 of 1891) of residents reported awareness of the Health Scouts. Overall, reach (self-reported receipt of counseling) was 30.7% (580 of 1891). Unreached residents were more likely to be male and HIV seronegative ( P < 0.05). Qualitative themes included the following: (1) reach was promoted by perceived usefulness but deterred by busy client lifestyles and stigma, (2) effectiveness was enabled through good acceptability and consistency with the conceptual framework, (3) adoption was facilitated by positive impacts on HIV service engagement, and (4) implementation fidelity was initially promoted by the CHW phone application but deterred by mobility. Maintenance showed consistent counseling sessions over time. The findings suggested the strategy was fundamentally sound but had suboptimal reach. Future iterations could consider adaptations to improve reach to priority populations, testing the need for mobile health support, and additional community sensitization to reduce stigma. CONCLUSIONS: A CHW strategy to promote HIV services was implemented with moderate success in an HIV hyperendemic setting and should be considered for adoption and scale-up in other communities as part of comprehensive HIV epidemic control efforts. TRIAL REGISTRATION: ClinicalTrials.gov Trial Number NCT02556957.

Optimizing the Dosing Regimen of Cetuximab and Ramucirumab Using the Model-Informed Drug Development Paradigm.

Model-informed drug development (MIDD) is a process that integrates drug exposure-based, biological, and statistical models to enhance the benefit-risk balance in drug development. The US Food and Drug Administration (FDA) MIDD Paired Meeting Pilot Program provides a platform to apply MIDD approaches to drug development and to seek regulatory feedback in a collaborative and streamlined process prior to submission for approval. Eli Lilly and Company (Lilly) participated in the Pilot Program to seek agency alignment to enhance the initial approved dosing regimens of cetuximab (Erbitux; Eli Lilly and Company, Indianapolis, IN) and ramucirumab (Cyramza; Eli Lilly and Company) without conducting additional clinical trials. Here, we describe the overall MIDD strategy at Lilly, the process with the FDA, and the impact of implementing the approach.

Coexistence of Merons with Skyrmions in the Centrosymmetric Van Der Waals Ferromagnet Fe5- x GeTe2.

Fe5- x GeTe2 is a centrosymmetric, layered van der Waals (vdW) ferromagnet that displays Curie temperatures Tc (270-330 K) that are within the useful range for spintronic applications. However, little is known about the interplay between its topological spin textures (e.g., merons, skyrmions) with technologically relevant transport properties such as the topological Hall effect (THE) or topological thermal transport. Here, via high-resolution Lorentz transmission electron microscopy, it is shown that merons and anti-meron pairs coexist with Néel skyrmions in Fe5- x GeTe2 over a wide range of temperatures and probe their effects on thermal and electrical transport. A THE is detected, even at room T, that senses merons at higher T's, as well as their coexistence with skyrmions as T is lowered, indicating an on-demand thermally driven formation of either type of spin texture. Remarkably, an unconventional THE is also observed in absence of Lorentz force, and it is attributed to the interaction between charge carriers and magnetic field-induced chiral spin textures. These results expose Fe5-x GeTe2 as a promising candidate for the development of applications in skyrmionics/meronics due to the interplay between distinct but coexisting topological magnetic textures and unconventional transport of charge/heat carriers.

Prediction of the Renal Organic Anion Transporter 1 (OAT1)- Mediated Drug Interactions for LY404039, the Active Metabolite of Pomaglumetad Methionil.

PURPOSE: The objective of this work was to demonstrate that clinical OAT1-mediated DDIs can be predicted using physiologically based pharmacokinetic (PBPK) modeling. METHODS: LY404039 is a metabotropic glutamate receptor 2/3 agonist and the active moiety of the prodrug pomaglumetad methionil (LY2140023). After oral administration, pomaglumetad methionil is rapidly taken up by enterocytes via PEPT1 and once absorbed, converted to LY404039 via membrane dehydropeptidase 1 (DPEP1). LY404039 is renally excreted by both glomerular filtration and active secretion and in vitro studies showed that the active secretion of LY404039 was mediated by the organic anion transporter 1 (OAT1). Both clinical and in vitro data were used to build a PBPK model to predict OAT1-mediated DDIs. RESULTS: In vitro inhibitory potencies (IC50) of the known OAT inhibitors, probenecid and ibuprofen, were determined to be 4.00 and 2.63 µM, respectively. Subsequently, clinical drug-drug interaction (DDI) study showed probenecid reduced the renal clearance of LY404039 by 30 to 40%. The PBPK bottom-up model, predicted a renal clearance that was approximately 20% lower than the observed one. The middle-out model, using an OAT1 relative activity factor (RAF) of 3, accurately reproduced the renal clearance of LY404039 and pharmacokinetic (PK) changes of LY404039 in the presence of probenecid. CONCLUSIONS: OAT1- mediated DDIs can be predicted using in vitro measured IC50 and PBPK modeling. The effect of ibuprofen was predicted to be minimal (AUC ratio of 1.15) and not clinically relevant.

Improving Research Dissemination to Black Sexual Minority Men: Development of a Community-Led and Theory-Based Dissemination Plan.

Background. Although research dissemination to participants and community stakeholders is a fundamental component of translational research, it rarely occurs. The objective of this study was to create a community-led, theory-based dissemination plan to engage local Black sexual minority men in an active dissemination process throughout a sexual health research study. Method. Seven focus groups (N = 38) were conducted with Black, cisgender sexual minority men aged 18 to 45 years. Findings were analyzed through thematic content analysis guided by McGuire's persuasive communication theory. Findings were used to draft a dissemination plan, which was then reviewed and edited by the study's community advisory board (CAB). The plan continues to be updated in response to community needs through CAB discussions. Results. Participants preferred messages concerning syphilis and other health concerns as well as information on local resources. Preferred sources included researchers working with trusted community organizations and leaders. Preferred channels included community events and social media, implemented with consistency. CAB feedback included expanding the target audience of dissemination efforts as well as the development of ideas for channels (i.e., events) and sources (i.e., community organizations and leaders). Additional revisions occurred in response to the COVID-19 pandemic. Conclusion. Given the continued lack of research dissemination to participant and community stakeholders, the process of developing a community-led, theory-based dissemination plan may benefit and help guide researchers to adopt this practice. It is critical that participant and community stakeholder dissemination become more highly prioritized as we strive for public health improvements and the elimination of health disparities.

Smart capsule for targeted proximal colon microbiome sampling.

The gastrointestinal (GI) tract, particularly the colon region, holds a highly diverse microbial community that plays an important role in the metabolism, physiology, nutrition, and immune function of the host body. Accumulating evidence has revealed that alteration in these microbial communities is the pivotal step in developing various metabolic diseases, including obesity, inflammatory bowel disease (IBD), and colorectal cancer. However, there is still a lack of clear understanding of the interrelationship between microbiota and diet as well as the effectiveness of chemoprevention strategies, including pre and probiotic agents in modifying the colonic microbiota and preventing digestive diseases. Existing methods for assessing these microbiota-diet interactions are often based on samples collected from the feces or endoscopy techniques which are incapable of providing information on spatial variations of the gut microbiota or are considered invasive procedures. To address this need, here we have developed an electronic-free smart capsule that enables site-specific sampling of the gut microbiome within the proximal colon region of the GI tract. The 3D printed device houses a superabsorbent hydrogel bonded onto a flexible polydimethylsiloxane (PDMS) disk that serves as a milieu to collect the fluid in the gut lumen and its microbiome by rapid swelling and providing the necessary mechanical actuation to close the capsule after the sampling is completed. The targeted colonic sampling is achieved by coating the sampling aperture on the capsule with a double-layer pH-sensitive enteric coating, which delays fluid in the lumen from entering the capsule until it reaches the proximal colon of the GI tract. To identify the appropriate pH-responsive double-layer coating and processing condition, a series of systematic dissolution characterizations in different pH conditions that mimicked the GI tract was conducted. The effective targeted microbial sampling performance and preservation of the smart capsule with the optimized design were validated using both realistic in vitro GI tract models with mixed bacteria cultures and in vivo with pigs as an animal model. The results from 16s rRNA and WideSeq analysis in both in vitro and in vivo studies showed that the bacterial population sampled within the retrieved capsule closely matched the bacterial population within the targeted sampling region (proximal colon). Herein, it is envisioned that such smart sampling capsule technology will provide new avenues for gastroenterological research and clinical applications, including diet-host-microbiome relationships, focused on human GI function and health. STATEMENT OF SIGNIFICANCE: The colonic microbiota plays a major role in the etiology of numerous diseases. Extensive efforts have been conducted to monitor the gut microbiome using sequencing technologies based on samples collected from feces or mucosal biopsies that are typically obtained by colonoscopy. Despite the simplicity of fecal sampling procedures, they are incapable of preserving spatial and temporal information about the bacteria through the gastrointestinal (GI) tract. In contrast, colonoscopy is an invasive and impractical approach to frequently assess the effect of dietary and therapeutic intake on the microbiome and their impact on the health of the patient. Here, we developed a non-invasive capsule that enables targeted sampling from the ascending colon, thereby providing crucial information for disease prediction and monitoring.

Thermal Hysteresis and Ordering Behavior of Magnetic Skyrmion Lattices.

The physics of phase transitions in two-dimensional (2D) systems underpins research in diverse fields including statistical mechanics, nanomagnetism, and soft condensed matter. However, many aspects of 2D phase transitions are still not well understood, including the effects of interparticle potential, polydispersity, and particle shape. Magnetic skyrmions are chiral spin-structure quasi-particles that form two-dimensional lattices. Here, we show, by real-space imaging using in situ cryo-Lorentz transmission electron microscopy coupled with machine learning image analysis, the ordering behavior of Néel skyrmion lattices in van der Waals Fe3GeTe2. We demonstrate a distinct change in the skyrmion size distribution during field-cooling, which leads to a loss of lattice order and an evolution of the skyrmion liquid phase. Remarkably, the lattice order is restored during field heating and demonstrates a thermal hysteresis. This behavior is explained by the skyrmion energy landscape and demonstrates the potential to control the lattice order in 2D phase transitions.

Exposure-response relationship of ramucirumab in RANGE, a randomized phase III trial in advanced urothelial carcinoma refractory to platinum therapy.

AIMS: Patients with advanced urothelial carcinoma (UC) who progress after platinum-based chemotherapy have a poor prognosis, and there is a medical need to improve current treatment options. Ramucirumab plus docetaxel significantly improved progression-free survival but not overall survival (OS) in platinum-refractory advanced UC (RANGE trial; NCT02426125). Here, we report the exposure-response (ER) of ramucirumab plus docetaxel using data from the RANGE trial. METHODS: Pharmacokinetic (PK) samples were collected (cycle 1-3, 5, 9 [day 1] and 30 days from treatment discontinuation), and PK data were analysed using population PK (popPK) analysis. The minimum ramucirumab concentration after first dose administration (Cmin,1 , or trough concentration immediately prior to the second dose) was derived by popPK analysis and used as the exposure parameter for ER analysis. Cox proportional hazards regression models and matched case-control analyses were used to evaluate the relationship between Cmin,1 and OS. The Cmin,1 relationship with safety was assessed descriptively. RESULTS: Several poor prognostic factors (ECOG 1, haemoglobin concentration <100 g/L, presence of liver metastases) appeared more frequently in the lower exposure quartiles, suggesting a possible disease-PK interaction. A significant association was identified between Cmin,1 and OS (P = .0108). Higher exposure quartiles were associated with longer survival and smaller hazard ratios compared to placebo. No new exposure-safety trends were observed within the exposure range (ramucirumab 10 mg/kg once every 3 weeks). CONCLUSIONS: This prespecified ER analyses suggests a positive relationship between efficacy and ramucirumab exposure, with an imbalance associated with disease prognostic factors. Further investigation may elucidate a possible disease-PK relationship.

Storytelling to improve healthcare worker understanding, beliefs, and practices related to LGBTQ + patients: A program evaluation.

LGBTQ + persons experience significant health inequities and medical distrust resulting from anti-LGBTQ + bias or cultural incompetence from health care workers (HCW). This program evaluation examined whether storytelling events where LGBTQ + persons shared personal and patient experiences changed HCW understanding, beliefs, and practices related to LGBTQ + patients. Five storytelling events, held biannually in Baltimore, Maryland from 2016 to 2018, were evaluated using post-event surveys, written reflections/notes during the event, and a survey of HCW in a citywide care collaborative focused on HIV prevention and treatment for LGBTQ + persons that did and did not attend a storytelling event. We analyzed surveys to measure differences in understanding, beliefs and practices and used thematic qualitative analysis of written reflections/notes from the storytelling events. 416 persons attended storytelling events; 124(30 %) completed post-event surveys and 449 written reflections/notes were collected. 56 HCW completed post-event surveys; 49(87.5 %) strongly agreed/agreed they better understood LGBTQ + patients. Emergent themes from the 43 HCW written reflections/notes included improved understanding and new approaches for engaging LGBTQ + patients. Among HCW survey respondents (n = 111), attending an event was associated with significant differences in beliefs (p = 0.024) and practices (p = 0.000) related to LGBTQ + patients. Storytelling events may serve as effective tools for increasing HCW's understanding, beliefs and practices. This strategy may ultimately help decrease anti-LGBTQ + bias, reduce medical distrust and lower barriers to HIV prevention/treatment for LGBTQ + persons.

#ProjectPresence: Highlighting black LGBTQ persons and communities to reduce stigma: A program evaluation.

Etiologies of HIV disparities are multifaceted; anti-LGBTQ stigma and social marginalization are contributory factors. A city health department developed a program, #ProjectPresence, exhibiting professional photos of Black LGBTQ persons in public spaces. An academic partner explored the relationship of the program to visibility, anti-LGBTQ stigma and social marginalization of Black LGBTQ persons, i.e. models, directly involved in the program and their perceptions of these relationships more broadly for community members. Brief self-administered surveys and semi-structured, in-depth interviews with #ProjectPresence models (n = 15) were conducted after the program to gather their experiences before, during and after the program. Descriptive analyses of survey responses were conducted using Stata 15.1. Interviews were audio-recorded, transcribed and analyzed in NVivo10 using categorical analysis. Surveys indicated prevalent experiences of enacted stigma (73 %) and perceptions of poor local acceptance of LGBTQ people (53 %). Interviews suggested that the program may have influenced positive individual- and community-level changes by increasing visibility of LGBTQ communities and improving acceptance among non-LGBTQ persons, inspiring personal growth and self-acceptance among models, and providing opportunities to foster new connections among LGBTQ subpopulations. Our findings suggest similar programs may present promising approaches for the reduction of stigma and social marginalization affecting LGBTQ persons and communities.