Genomic surveillance reveals dynamic shifts in the connectivity of COVID-19 epidemics.

The maturation of genomic surveillance in the past decade has enabled tracking of the emergence and spread of epidemics at an unprecedented level. During the COVID-19 pandemic, for example, genomic data revealed that local epidemics varied considerably in the frequency of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lineage importation and persistence, likely due to a combination of COVID-19 restrictions and changing connectivity. Here, we show that local COVID-19 epidemics are driven by regional transmission, including across international boundaries, but can become increasingly connected to distant locations following the relaxation of public health interventions. By integrating genomic, mobility, and epidemiological data, we find abundant transmission occurring between both adjacent and distant locations, supported by dynamic mobility patterns. We find that changing connectivity significantly influences local COVID-19 incidence. Our findings demonstrate a complex meaning of "local" when investigating connected epidemics and emphasize the importance of collaborative interventions for pandemic prevention and mitigation.

Mechanistically Guided Materials Chemistry: Synthesis of Ternary Nitrides, CaZrN2 and CaHfN2.

Recent computational studies have predicted many new ternary nitrides, revealing synthetic opportunities in this underexplored phase space. However, synthesizing new ternary nitrides is difficult, in part because intermediate and product phases often have high cohesive energies that inhibit diffusion. Here, we report the synthesis of two new phases, calcium zirconium nitride (CaZrN2) and calcium hafnium nitride (CaHfN2), by solid state metathesis reactions between Ca3N2 and MCl4 (M = Zr, Hf). Although the reaction nominally proceeds to the target phases in a 1:1 ratio of the precursors via Ca3N2 + MCl4 → CaMN2 + 2 CaCl2, reactions prepared this way result in Ca-poor materials (CaxM2-xN2, x < 1). A small excess of Ca3N2 (ca. 20 mol %) is needed to yield stoichiometric CaMN2, as confirmed by high-resolution synchrotron powder X-ray diffraction. In situ synchrotron X-ray diffraction studies reveal that nominally stoichiometric reactions produce Zr3+ intermediates early in the reaction pathway, and the excess Ca3N2 is needed to reoxidize Zr3+ intermediates back to the Zr4+ oxidation state of CaZrN2. Analysis of computationally derived chemical potential diagrams rationalizes this synthetic approach and its contrast from the synthesis of MgZrN2. These findings additionally highlight the utility of in situ diffraction studies and computational thermochemistry to provide mechanistic guidance for synthesis.

Third-Trimester Ultrasound Diagnosis of Large for Gestational Age and Risk of Cesarean Delivery.

OBJECTIVE: Determine if knowledge of a third-trimester ultrasound diagnosis of large for gestational age (LGA) independently increases the risk of cesarean delivery (CD). STUDY DESIGN: Historical cohort comparing CD rate among patients diagnosed with an LGA fetus on a clinically indicated ultrasound from January 2017 to July 2021 with those without an LGA diagnosis at 34 weeks or later. LGA was defined as an ultrasound-estimated fetal weight greater than or equal to the 90th percentile for the gestational age. Univariate analysis was performed to identify significant confounding variables and was utilized as covariates for binary regression with CD rate as the primary outcome, and adjusted odds ratios (AOR) with 95% confidence intervals (CI) were calculated. Nulliparous term singleton vertex (NTSV) and multiparous CD rates were also compared. RESULTS: There were 447 patients diagnosed with an LGA fetus and 1971 patients without an LGA diagnosis on third-trimester ultrasound. The positive predictive value of LGA diagnosis was 50.1% and the false positive rate was 10.6%. Patients with a diagnosis of LGA had higher AOR of CD (OR 2.11, 95% CI 1.56-2.83), and higher AOR of NTSV CD (OR 1.88, 95% CI 1.14-3.13) compared with those without an LGA diagnosis. There was no difference in the rates of non-medically indicated CD, multiparous primary CD, and attempted and successful TOLAC. CONCLUSION: Our results suggest third-trimester ultrasound diagnosis of LGA independently increases odds of CD, specifically among nulliparous patients, and the potential bias may be one factor contributing to excessive CDs and NTSV CDs.

Synovial Lipomatosis With Extra-articular Extension in the Arthritic Wrist: An Unexpected Diagnosis.

ABSTRACT: Synovial lipomatosis is a rare condition characterized by adipocyte proliferation within joint synovial tissue. It most commonly affects the knee and is typically intra-articular. Only 5 published case reports describe extra-articular synovial lipomatosis of the wrist. We present a case of a sexagenarian patient seen for his wrist arthropathy. His x-ray revealed pan-wrist arthritis and inflammatory soft tissue swelling. The patient was slated for a wrist fusion and Darrach procedure. Following the dorsal skin incision in the operating room, an unusual adipose mass was identified infiltrating all extensor compartments: midcarpal, radiocarpal, and distal radioulnar joints. The mass was excised and sent to pathology prior to proceeding with the slated surgery. Synovial lipomatosis was diagnosed postoperatively based on histopathology. Six weeks postoperatively, the wrist fusion had healed clinically and radiographically, and his pain had improved. There was no evidence of recurrence. Synovial lipomatosis is a rare entity that may imitate multiple other pathologies. It is possible that synovial lipomatosis may represent a secondary occurrence following degenerative articular disease or trauma in older patients. This is the first case report to date describing synovial lipomatosis of the wrist with extra-articular extension in the setting of pan-carpal wrist arthritis.

Verrucous Carcinoma of the Foot: A Single Canadian Center Experience on Diagnosis, Management, and Outcomes.

INTRODUCTION: Verrucous carcinoma (VC) was first described in 1948 by Dr. Ackerman. It is a low-grade cutaneous squamous carcinoma that usually develops in the oral cavity, the anogenital region, and the plantar surface of the foot. Clinically, there is low suspicion for malignancy given the slow growth of VC lesions and their wart-like appearance. Diagnosis can be difficult because of the benign histological appearance with well-differentiated cells and absence of dysplasia. Surgical excision is the only satisfactory form of treatment for plantar VC; however, this becomes difficult given its benign clinical appearance and the pathologic misinterpretation of the lesion as a benign hyperplasia. While there are case reports and retrospective studies of patients with plantar VC in the literature, we present the largest case series of plantar VC within North America, with recurrence despite negative margins. METHODS: We report on all the plantar VC excised between 2014-2023. We report six cases of VC, their treatment, and their outcomes. RESULTS: Six patients obtained a diagnosis of plantar VC by incisional biopsy. All patients underwent excision of their lesions and had negative margins reported on the final pathology. All patients developed nonhealing wounds at the site of their lesion excision; therefore, biopsies were performed to confirm a recurrence. All patients had a recurrence of VC at the initial site. All patients underwent re-excision of the lesions. Despite negative margins again on final pathology, all patients had a subsequent second recurrence. Ultimately, all patients underwent an amputation as definitive management. Each patient had an average of 3 operations. There were 4 different surgeons and different pathologists reporting their findings. CONCLUSIONS: Our experience with plantar VC suggests that an aggressive approach to surgical management is needed. Furthermore, management is optimized with the combined expertise of an experienced dermatopathologist and surgeon. Despite negative margins and repeated excisions, VC lesions recur and invade local tissues to the extent that only amputation of the involved foot has resulted in cure.

Chemokine Oligomers and the Impact of Fondaparinux Binding.

Heparin, a widely used clinical anticoagulant, is generally well-tolerated; however, approximately 1% of patients develop heparin-induced thrombocytopenia (HIT), a serious side effect. While efforts to understand the role of chemokines in HIT development are ongoing, certain aspects remain less studied, such as the stabilization of chemokine oligomers by heparin. Here, we conducted a combined ion mobility-native mass spectrometry study to investigate the stability of chemokine oligomers and their complexes with fondaparinux, a synthetic heparin analog. Collision-induced dissociation and unfolding experiments provided clarity on the specificity and relevance of chemokine oligomers and their fondaparinux complexes with varying stoichiometries, as well as the stabilizing effects of fondaparinux binding.

FAIR enough: Building an academic data ecosystem to make real-world data available for translational research.

The Stanford Population Health Sciences Data Ecosystem was created to facilitate the use of large datasets containing health records from hundreds of millions of individuals. This necessitated technical solutions optimized for an academic medical center to manage and share high-risk data at scale. Through collaboration with internal and external partners, we have built a Data Ecosystem to host, curate, and share data with hundreds of users in a secure and compliant manner. This platform has enabled us to host unique data assets and serve the needs of researchers across Stanford University, and the technology and approach were designed to be replicable and portable to other institutions. We have found, however, that though these technological advances are necessary, they are not sufficient. Challenges around making data Findable, Accessible, Interoperable, and Reusable remain. Our experience has demonstrated that there is a high demand for access to real-world data, and that if the appropriate tools and structures are in place, translational research can be advanced considerably. Together, technological solutions, management structures, and education to support researcher, data science, and community collaborations offer more impactful processes over the long-term for supporting translational research with real-world data.

"Hope is being stirred up": Critical consciousness in gender-based violence interventions.

Gender-based violence (GBV) research in public health has historically paid close attention to gender as a system of oppression, with less attention paid to the intersections between gender and other oppressive systems such as colonialism, white supremacy, and capitalism. In 2019, we adapted and pilot-tested an individual-level evidence-based sexual violence resistance intervention for university-attending women in Eswatini. We conducted a qualitative assessment of our adapted intervention's acceptability and feasibility using a critical pedagogy lens to explore how power operated in delivering an empowerment intervention, using in-depth interviews with intervention participants and facilitators. We analyzed interview transcripts thematically guided by a critical pedagogy framework and organized emergent themes into a concept map with two primary axes: participant-researcher-driven power and proximal-distal determinants. We located participant experiences with the intervention within three quadrants defined by these axes: 1) "Prescriptive," in which the researcher or facilitator primarily controls the content and delivery, with a principal focus on proximal risk reduction strategies; 2) "Solidarity," which emphasizes fostering critical consciousness among facilitators and intervention participants through dialogue, building collective power through participant-driven discussions of individual experiences; and 3) "Liberation," in which participants critically examined the power structures that underpinned their lived experiences, and expressed a desire to transform these in ways the intervention was not designed to address. These three quadrants suggest the existence of a fourth quadrant, "paternalistic," - in which the interventionist seeks to didactically educate participants about structural drivers of their own experience. Our analysis highlights a fundamental tension in the epistemology of GBV research: While there is a clear consensus that 'empowerment' is a necessary component of successful GBV interventions, "liberatory" approaches that cede power to participants are inherently antithetical to the scripted approach typically required for consistent replication in randomized control trials or other 'gold-standard' approaches for post-positivist evidence generation.

Disproportionately High Rates of Burnout Among Disabled Caregivers During the COVID-19 Pandemic.

Background: Burnout is exhaustion caused by exposure to chronic stress. Prior to the COVID-19 pandemic, people with disabilities experienced high levels of burnout due to discrimination, barriers to accessing resources, and lack of accommodations. Caregivers have also experienced high levels of burnout during the COVID-19 pandemic. Background: While researchers have examined burnout among caregivers of disabled children, less research has focused on the experiences of disabled caregivers. We examined the association between caregiver disability and burnout during the pandemic. Methods: We distributed an online survey to caregivers of children enrolled in socially vulnerable elementary and middle schools in San Diego County, California between September and December, 2022. Our survey included demographic questions, questions about pandemic experiences, and a continuous burnout measure. We analyzed survey data to test our hypothesis that caregivers with a disability experienced higher levels of burnout than their non-disabled counterparts during the height of the COVID-19 pandemic. We used multivariable linear regression analysis adjusting for household income and caregiver education level. Results: Disabled caregivers self-reported higher levels of burnout than non-disabled caregivers (B = 0.72; p < 0.001) during the COVID-19 pandemic in bivariate and multivariable analyses. Caregivers with a higher household income (B = 0.04; p = 0.017) and more education (B = 0.13; p = 0.005) also reported higher levels of burnout. Conclusion: The COVID-19 pandemic exacerbated existing difficulties faced by disabled caregivers who often struggle to balance the demands of caregiving with their available resources. Targeted programs and policies are needed to support disabled caregivers during health emergencies that exacerbate existing inequities in access to resources.

Structure and function of Semaphorin-5A glycosaminoglycan interactions.

Integration of extracellular signals by neurons is pivotal for brain development, plasticity, and repair. Axon guidance relies on receptor-ligand interactions crosstalking with extracellular matrix components. Semaphorin-5A (Sema5A) is a bifunctional guidance cue exerting attractive and inhibitory effects on neuronal growth through the interaction with heparan sulfate (HS) and chondroitin sulfate (CS) glycosaminoglycans (GAGs), respectively. Sema5A harbors seven thrombospondin type-1 repeats (TSR1-7) important for GAG binding, however the underlying molecular basis and functions in vivo remain enigmatic. Here we dissect the structural basis for Sema5A:GAG specificity and demonstrate the functional significance of this interaction in vivo. Using x-ray crystallography, we reveal a dimeric fold variation for TSR4 that accommodates GAG interactions. TSR4 co-crystal structures identify binding residues validated by site-directed mutagenesis. In vitro and cell-based assays uncover specific GAG epitopes necessary for TSR association. We demonstrate that HS-GAG binding is preferred over CS-GAG and mediates Sema5A oligomerization. In vivo, Sema5A:GAG interactions are necessary for Sema5A function and regulate Plexin-A2 dependent dentate progenitor cell migration. Our study rationalizes Sema5A associated developmental and neurological disorders and provides mechanistic insights into how multifaceted guidance functions of a single transmembrane cue are regulated by proteoglycans.

Assessing the impact of institutional mistrust on parental endorsement for COVID-19 vaccination among school communities in San Diego County, California.

BACKGROUND: Institutional mistrust has weakened COVID-19 mitigation efforts. Assessing to what extent institutional mistrust impacts parental decision making is important in formulating structural efforts for improving future pandemic response. We hypothesized that institutional mistrust is associated with lower parental endorsement for COVID-19 vaccination. METHODS: We distributed an online survey among parents from schools in areas with high levels of social vulnerability relative to the rest of San Diego County. We defined vaccination endorsement as having a child aged 5 years or older who received at least one COVID-19 vaccine dose or being very likely to vaccinate their child aged 6 months-4 years when eligible. Institutional mistrust reflected the level of confidence in institutions using an aggregate score from 11 to 44. We built a multivariable logistic regression model with potential confounding variables. FINDINGS: Out of 290 parents in our sample, most were female (87.6%), reported their child as Hispanic/Latino (73.4%), and expressed vaccination endorsement (52.1%). For every one-point increase in mistrust score, there was an 8% reduction in the likelihood of participants endorsing vaccination for their child. Other statistically significant correlates that were positively associated with vaccination endorsement included parent vaccination status, child age, parent age, and Hispanic/Latino ethnicity. CONCLUSION: Our study further demonstrates how institutional mistrust hinders public response during health emergencies. Our findings also highlight the importance of building confidence in institutions and its downstream effects on pandemic preparedness and public health. One way that institutions can improve their relationship with constituents is through building genuine partnerships with trusted community figures.

Xylosyltransferase Bump-and-hole Engineering to Chemically Manipulate Proteoglycans in Mammalian Cells.

Mammalian cells orchestrate signalling through interaction events on their surfaces. Proteoglycans are an intricate part of these interactions, carrying large glycosaminoglycan polysaccharides that recruit signalling molecules. Despite their importance in development, cancer and neurobiology, a relatively small number of proteoglycans have been identified. In addition to the complexity of glycan extension, biosynthetic redundancy in the first protein glycosylation step by two xylosyltransferase isoenzymes XT1 and XT2 complicates annotation of proteoglycans. Here, we develop a chemical genetic strategy that manipulates the glycan attachment site of cellular proteoglycans. By employing a tactic termed bump- and-hole engineering, we engineer the two isoenzymes XT1 and XT2 to specifically transfer a chemically modified xylose analogue to target proteins. The chemical modification contains a bioorthogonal tag, allowing the ability to visualise and profile target proteins modified by both transferases in mammalian cells. The versatility of our approach allows pinpointing glycosylation sites by tandem mass spectrometry, and exploiting the chemical handle to manufacture proteoglycans with defined GAG chains for cellular applications. Engineered XT enzymes permit a view into proteoglycan biology that is orthogonal to conventional techniques in biochemistry.

"They Don't See Us": Asian Students' Perceptions of Sexual Violence and Sexual Harassment on Three California Public University Campuses.

Sexual violence and sexual harassment (SVSH) are prevalent among college and university students; however, the experiences of ethnic minority students, especially Asians, are understudied. This study aimed to reduce this gap by exploring Asian students' perceptions of SVSH on three public university campuses in Southern California. We examined their perceptions about the campus environment related to SVSH, attitudes, and behaviors toward help seeking, and utilization of on-campus resources. A total of 23 in-depth interviews were conducted with Asian students enrolled at the three University of California campuses. Thematic coding was conducted to generate main themes and subthemes. Five main themes emerged: (a) SVSH is considered a "taboo" topic in Asian culture and family systems, and Asian student survivors are often reluctant to disclose incidents or seek support services. (b) Students did not feel their campus environments were tailored to understand or meet the sociocultural realities and needs of Asian student survivors. (c) Campus SVSH services and reporting processes were seen as non-transparent. (d) Peers were the major source of support and SVSH information, as opposed to official campus-based resources and training. (e) Survivors often conduct an internal cost-benefit analysis evaluating their decision about whether to report. This study highlights the lack of conversation surrounding SVSH in Asian families, and how the cultural stigma of sex and sexual violence prevented Asian students from receiving knowledge and resources about these topics in their families. Instead of relying on formal campus resources (e.g., Title IX and confidential advocacy services, mental health services), many students turn to their peers for support. Thus, facilitating peer support groups, training university students to support each other through SVSH incidents, and tailoring campus services to the diverse cultural backgrounds of students are key considerations to foster a safe campus environment and prevent SVSH.

Home Groups: Integrating Peer Support and Clinical Care in a Community Mental Health Center.

With peer supporters now comprising one of the most rapidly growing components of the mental health workforce, group interventions that combine their expertise with those of more traditional mental health providers are needed. An example of one such intervention, developed and implemented at a large community mental health center for individuals with serious mental illnesses, is presented. Called a "Home Group" and co-led by peers and clinical psychology interns, this intervention provides unique learning opportunities for peers and trainees and many potential benefits to group members. Vignettes to illustrate the model are presented and the potential therapeutic and empowering aspects of this innovative and promising approach are identified and discussed.

Photoprotection enhanced by red cell wall pigments in three East Antarctic mosses

BACKGROUND: Antarctic bryophytes (mosses and liverworts) are resilient to physiologically extreme environmental conditions including elevated levels of ultraviolet (UV) radiation due to depletion of stratospheric ozone. Many Antarctic bryophytes synthesise UV-B-absorbing compounds (UVAC) that are localised in their cells and cell walls, a location that is rarely investigated for UVAC in plants. This study compares the concentrations and localisation of intracellular and cell wall UVAC in Antarctic Ceratodon purpureus, Bryum pseudotriquetrum and Schistidium antarctici from the Windmill Islands, East Antarctica. RESULTS: Multiple stresses, including desiccation and naturally high UV and visible light, seemed to enhance the incorporation of total UVAC including red pigments in the cell walls of all three Antarctic species analysed. The red growth form of C. purpureus had significantly higher levels of cell wall bound and lower intracellular UVAC concentrations than its nearby green form. Microscopic and spectroscopic analyses showed that the red colouration in this species was associated with the cell wall and that these red cell walls contained less pectin and phenolic esters than the green form. All three moss species showed a natural increase in cell wall UVAC content during the growing season and a decline in these compounds in new tissue grown under less stressful conditions in the laboratory. CONCLUSIONS: UVAC and red pigments are tightly bound to the cell wall and likely have a long-term protective role in Antarctic bryophytes. Although the identity of these red pigments remains unknown, our study demonstrates the importance of investigating cell wall UVAC in plants and contributes to our current understanding of UV-protective strategies employed by particular Antarctic bryophytes. Studies such as these provide clues to how these plants survive in such extreme habitats and are helpful in predicting future survival of the species studied.