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Crimean-Congo hemorrhagic fever virus (CCHFV) is transmitted predominantly through the bite of infected Hyalomma ticks, yet the earliest events at the vector–host–virus interface in human skin remain largely undefined. This review synthesizes current knowledge of human cutaneous structure and immunity, tick feeding biology, and salivary immunomodulation to propose how local skin responses may shape systemic outcomes of CCHFV disease. We detail the roles and permissiveness of major skin-resident and infiltrating cell types, including keratinocytes, melanocytes, Langerhans cells, dermal dendritic cells, monocytes/macrophages, fibroblasts, granulocytes, T cells, B cells, NK cells, and innate lymphoid cells, in antiviral defense and as potential early targets or carriers of CCHFV. Emphasis is placed on how tick saliva components reprogram the cutaneous microenvironment, alter interferon, complement, inflammasome, and cytokine pathways, and may enable saliva-assisted transmission and viral dissemination from the dermis. We highlight mounting evidence from other arboviruses demonstrating that the skin can act as both a barrier and a major amplifying organ, and we extrapolate testable hypotheses on how early cutaneous immune dynamics might influence CCHFV severity and hemorrhagic manifestations. Finally, we outline key knowledge gaps that, if answered, may inform the development of vaccines and therapeutics that harness cutaneous immunity to block systemic spread.

Colorado tick fever virus (CTFV) is an emerging Coltivirus belonging to the Reoviridae family and Spinareoviridae subfamily which can cause severe disease in humans. Several strains of CTFV have been previously described in the literature, including S6‐14‐03 (CTFV‐Ca), and the coltivirus‐type species, CTFV‐Florio. Following recent full genome sequencing, CTFV‐Ca is proposed to be a unique species within the Coltivirus genus rather than a serotype of CTFV‐Florio. CTFV‐Ca is closely related to human pathogenic coltiviruses, suggesting characterization is necessary to assess its pathogenic potential. We compared the ability of CTFV‐Florio and CTFV‐Ca to infect and proliferate within human dermal microvascular endothelial cells (HMEC‐1s) and detailed the potential immune responses during infection. Our results indicate that, like CTFV‐Florio, CTFV‐Ca is capable of infecting and proliferating within human endothelial cells (ECs). However, CTFV‐Ca is less efficient than CTFV‐Florio in our assays. Using RT‐qPCR gene arrays, we identified 41 genes that are significantly upregulated (> 2‐fold) upon infection including various proinflammatory cytokines and chemokines. Among the differentially upregulated genes, CTFV‐Florio typically induced a stronger response including on each occasion where significant differences were observed between the viruses. We also found both CTFV‐Florio and CTFV‐Ca capable of inducing proinflammatory responses at posttranslational levels as evidenced by significantly increased secretions of IFN‐β, IL‐6, IL‐8, and MCP‐1. Finally, we observed both increased EC permeability and death during CTFV‐Florio and CTFV‐Ca infection. These data describe for the first time a prospective antiviral response of human ECs to CTFV‐Ca infection and suggest that CTFV‐Ca can infect and stimulate potent antiviral and proinflammatory responses similar to the pathogenic Coltivirus‐type species, CTFV‐Florio.

Lone Star virus (LSV) is a newly characterized arbovirus with pathogenic potential. Recently, several tick-borne viruses have emerged as medically and agriculturally important, indicating that more robust surveillance is necessary. However, no published detection methods are available to identify and monitor LSV in vitro. Here, this limitation was addressed by the development and validation of two SYBR green-based RT-qPCRs for the detection and quantification of LSV. For these assays, specific primers were developed for the M and S segments of the viral genome. The assays are highly reproducible, with both assays having an overall intra-assay and interassay Coefficient of Variation (CV) of less than 3%. The limit of detection of both assays was fewer than ten copies/μL of the viral genome. All off-target detection surpassed the cut-off cycle (Co) when tested for specificity against 11 other tick-, mosquito-, and sandfly-borne viruses. Furthermore, 143 ticks were tested with the developed assays, with no ticks testing positive for the presence of LSV. These results demonstrate that the developed assays are specific, sensitive, and reproducible methods of detection and quantification that can be applied to monitor and combat this potentially emerging tick-borne virus.

Prostate cancer is a clinically heterogeneous disease, ranging from indolent asymptomatic disease to very aggressive metastatic and life threatening forms of the disease. Distant metastasis represents the major lethal cause of prostate cancer. The most critical clinical challenge in the management of the patients is identifying those individuals at risk of developing metastatic disease. To understand the molecular mechanisms of prostate cancer metastasis and identify markers with metastatic potential, we have analyzed protein expression in two syngeneic prostate cancer cells lines PC3-N2 and PC3-ML2 using isobaric tags for relative and absolute quantitation labeling and multi-dimensional protein identification technology liquid chromatography matrix assisted laser desorption ionization tandem mass spectrometry. PC3-N2 is lowly metastatic while PC3-ML2 highly metastatic. A total of 1,756 proteins were identified in the analyses with 130 proteins showing different expression levels (p<0.01) in the two cell lines. Out of these, 68 proteins were found to be significantly up-regulated while 62 are significantly down-regulated in PC3-ML2 cells compared with PC3-N2 cells. The upregulation of plectin and vimentin which were the most significantly differentially expressed were validated by Western blot and their functional relevance with respect to invasion and migration was determined by siRNA gene silencing. To our knowledge, this study is the first to demonstrate that up-regulation of vimentin and plectin expression positively correlates with the invasion and metastasis of androgen-independent PCA.

Background Relationship-based, whole person care is foundational to quality general practice. Previous research has identified several characteristics of deep General Practitioner (GP)-patient relationships and their association with improved patient concordance, satisfaction and perceived health outcomes. Psychological attachment theory has been used to understand therapeutic relationships, but has only been explored to a limited extent in the general practice context. Additionally, evolving changes in sociocultural and commercial practice contexts may threaten relationship-based care. In view of this, we aimed to explore the nature and experience of deep GP-patient relationships, as identified by patients, from GP and patient perspectives. Methods Semi-structured interview design. An initial survey assessed patients’ perceived depth of their relationship with their GP, using the Health Care Provider Attachment Figure Survey and Patient-Doctor Depth of Relationship Scale. Patients who reported a deep relationship, and their GPs, were purposively selected for individual interviews exploring their experience of these relationships. A post-interview survey assessed interviewees’ attachment styles, using the Modified and Brief Experiences in Close Relationships Scale. Patient interviewees also rated the patient-centredness of their GP’s clinic using the Person-Centred Primary Care Measure. Transcripts were analysed using thematic analysis. Results Thirteen patients and five GPs were interviewed. Four themes characterised deep relationships: the ‘professional’; human connection; trust; and ‘above and beyond’. Patient, GP and practice team all contributed to their cultivation. Conclusions We present a revised conceptual framework of deep GP-patient relationships. Deep relationships come to the fore in times of patient trouble. Like attachment relationships, they provide a sense of safety, caring and support for patients experiencing vulnerability. They can stretch GP boundaries and capacity for self-care, but also provide joy and vocational satisfaction. Patients may not always desire or need deep relationships with their GP. However, findings highlight the importance of enabling and cultivating these for times of patient hardship, and challenges of doing so within current healthcare climates.

Addressing major global environmental and social challenges requires transformation of the private sector. Small- to medium-sized enterprises (SMEs) constitute 90% of private organisations globally, resulting in calls for research into the strategic roles SMEs can play in shaping sustainable futures through adopting sustainable business models (SBMs). The purpose of our study is to understand the factors that allow SMEs to successfully adopt SBMs. We used an exploratory qualitative approach drawing on interviews with SMEs implementing SBMs. Our findings extend contemporary insights by revealing the important role of the external support (‘enabling’) environment, and identifying—potentially transformative—capabilities that can help steer SMEs’ transitions to SBMs. These include persistence, tenacity, flexibility, adaptability, and a willingness to learn and fail. They enable SMEs to successfully operate in times of uncertainty and rapid changes in the external environment, and respond to new requirements through changes to their business models.

Background Evidence-based quality improvement (QI) interventions and strategies often require adaptation before implementation in new settings. The goal of this study was to describe the adaptation process of QI strategies from an evidence-based cardiovascular initiative, previously tested in community-based primary care clinics, for use in worksite health centers (WHC). Participating WHCs were located at large manufacturing plants. The adapted QI strategies were offered as part of the Healthy Hearts in Manufacturing initiative. Methods Our team followed the ADAPT-ITT framework to adapt the QI strategies for twelve randomly selected WHCs. Meetings were held with WHC leaders, and semi-structured interviews were conducted with WHC clinicians and staff to understand current workflows and identify contextual factors that could help or hinder the implementation of the QI strategies. Data were analyzed using qualitative content analysis. Adaptations were then identified and developed by clinical experts and a practice facilitator, with input from an Advisory Panel. Proposed adaptations were shared with WHC leaders and clinicians for feedback before implementation protocols were finalized. Results Phase 1 (Assessment) showed that manufacturing communities had high rates of heart disease and its risk factors. Four QI interventions from the Million Hearts campaign were selected for implementation using evidence-based QI strategies during Phase 2 (Decision). Phase 3 (Administration) revealed helpful implementation factors, including strong patient-clinician relationships and leadership support, as well as hindering factors, including deficiencies of electronic health records systems, high staff turnover, and poor patient adherence to treatment. These factors informed the Phase 4 (Production) development of implementation materials, for example, tailored blood pressure measurement protocols and patient educational tools. During Phase 5 (Topical experts), clinicians and WHC leaders provided feedback on the adaptations, which were then integrated in Phase 6 (Integration) into a flexible implementation protocol for the practice facilitator. The final phase (Testing) is ongoing. Conclusion This study describes the adaptation process of a primary care cardiovascular QI initiative to meet the unique clinical settings of WHCs. The findings suggest that with contextual adaptation of QI strategies, WHCs have the potential to implement evidence-based interventions to improve cardiovascular care, providing insights for future initiatives in non-traditional clinical care settings.

As organisms age, they often accumulate protein aggregates that are thought to be toxic, potentially leading to age‐related diseases. This accumulation of protein aggregates is partially attributed to a failure to maintain protein homeostasis. A variety of genetic factors have been linked to longevity, but how these factors also contribute to protein homeostasis is not completely understood. In order to understand the relationship between aging and protein aggregation, we tested how a gene that regulates lifespan and age‐dependent locomotor behaviors, p38 MAPK (p38Kb), influences protein homeostasis as an organism ages. We find that p38Kb regulates age‐dependent protein aggregation through an interaction with starvin, a regulator of muscle protein homeostasis. Furthermore, we have identified Lamin as an age‐dependent target of p38Kb and starvin. We find that p38 MAPK (p38Kb) regulates age‐dependent protein homeostasis through an interaction with the BAG protein, starvin. In addition, we find that Lamin Dm0, a homologue of the aging gene Lamin A/C, is a target of p38Kb and stv for degradation during aging.

Background: Bat velocity, attack angle, and vertical angle are common variables that coaches and players want to evaluate during their baseball or softball swing. Objective: The purpose of this study was to investigate and validate a baseball bat handle sensor against motion capture using recreational baseball and softball athletes for bat velocity, attack angle, and vertical angle. Methods: This single visit cross-sectional experimental design study utilized eighteen recreational baseball and softball players (ten males and eight females, age: 20.70 ± 1.69 years, height: 170.74 ± 5.69 cm, weight: 77.97 ± 12.30 kg) were recruited. Bat velocity, attack angle, and vertical angle from the bat handle sensor and 12-camera motion capture system were collected and compared using a two-tailed paired t-test. Results: Differences were statistically significant, showing that 95% of the time, the bat handle sensor overestimated the bat velocity by 1.92 to 2.77 m/s, underestimated the attack angle by -3.46 to -1.96º, and overestimated the vertical angle by 1.64 to 3.21º, compared to the motion capture system. Conclusion: The bat velocity and vertical angle were overestimated, while the attack angle was underestimated by the bat sensor. The information presented in this study can be viable information for coaches and players when utilizing the baseball bat handle sensor technology for training, practice, or in-game situations.

The unfolding COVID-19 pandemic, and the unprecedented social and economic costs it has inflicted, provide an important opportunity to scrutinize the interplay between the resilience of small and medium-sized enterprises (SMEs) and the resilience of the communities they are embedded in. In this article, we articulate the specific ways that SMEs play a crucial, and underappreciated role in building resilience to human and natural hazards, and provide new opportunities to accelerate the adoption of sustainability practices through the configuration of ‘enabling ecosystems’ geared towards promoting sustainability in the private sector. We argue that capacity-building and experimentation are not only required within companies, but also throughout this emerging supportive ecosystem of policies, resources (i.e. finance, materials, skills), governance actors, and intermediaries to adequately focus investment, technical capabilities and innovation. Ultimately, we call for a new transdisciplinary action research agenda that centers on SMEs as pivotal actors and amplifiers of community resilience; while recognizing that these firms are themselves in need of support to secure their own capacity to respond to, and transform in light of, crises. This research program calls for recognizing and applying the lessons that the pandemic presents to the urgent need for accelerated climate action. This will be enabled by developing more targeted approaches to collaborative capacity-building activities in SMEs that feed into experimentation and allow for the accelerated adoption of deliberate and strategic resilient business practices and models.