SARS-CoV-2 variants evolve convergent strategies to remodel the host response.

SARS-CoV-2 variants of concern (VOCs) emerged during the COVID-19 pandemic. Here, we used unbiased systems approaches to study the host-selective forces driving VOC evolution. We discovered that VOCs evolved convergent strategies to remodel the host by modulating viral RNA and protein levels, altering viral and host protein phosphorylation, and rewiring virus-host protein-protein interactions. Integrative computational analyses revealed that although Alpha, Beta, Gamma, and Delta ultimately converged to suppress interferon-stimulated genes (ISGs), Omicron BA.1 did not. ISG suppression correlated with the expression of viral innate immune antagonist proteins, including Orf6, N, and Orf9b, which we mapped to specific mutations. Later Omicron subvariants BA.4 and BA.5 more potently suppressed innate immunity than early subvariant BA.1, which correlated with Orf6 levels, although muted in BA.4 by a mutation that disrupts the Orf6-nuclear pore interaction. Our findings suggest that SARS-CoV-2 convergent evolution overcame human adaptive and innate immune barriers, laying the groundwork to tackle future pandemics.

Evolution of enhanced innate immune evasion by SARS-CoV-2.

The emergence of SARS-CoV-2 variants of concern suggests viral adaptation to enhance human-to-human transmission1,2. Although much effort has focused on the characterization of changes in the spike protein in variants of concern, mutations outside of spike are likely to contribute to adaptation. Here, using unbiased abundance proteomics, phosphoproteomics, RNA sequencing and viral replication assays, we show that isolates of the Alpha (B.1.1.7) variant3 suppress innate immune responses in airway epithelial cells more effectively than first-wave isolates. We found that the Alpha variant has markedly increased subgenomic RNA and protein levels of the nucleocapsid protein (N), Orf9b and Orf6-all known innate immune antagonists. Expression of Orf9b alone suppressed the innate immune response through interaction with TOM70, a mitochondrial protein that is required for activation of the RNA-sensing adaptor MAVS. Moreover, the activity of Orf9b and its association with TOM70 was regulated by phosphorylation. We propose that more effective innate immune suppression, through enhanced expression of specific viral antagonist proteins, increases the likelihood of successful transmission of the Alpha variant, and may increase in vivo replication and duration of infection4. The importance of mutations outside the spike coding region in the adaptation of SARS-CoV-2 to humans is underscored by the observation that similar mutations exist in the N and Orf9b regulatory regions of the Delta and Omicron variants.

SARS-CoV-2 sensing by RIG-I and MDA5 links epithelial infection to macrophage inflammation.

SARS-CoV-2 infection causes broad-spectrum immunopathological disease, exacerbated by inflammatory co-morbidities. A better understanding of mechanisms underpinning virus-associated inflammation is required to develop effective therapeutics. Here, we discover that SARS-CoV-2 replicates rapidly in lung epithelial cells despite triggering a robust innate immune response through the activation of cytoplasmic RNA sensors RIG-I and MDA5. The inflammatory mediators produced during epithelial cell infection can stimulate primary human macrophages to enhance cytokine production and drive cellular activation. Critically, this can be limited by abrogating RNA sensing or by inhibiting downstream signalling pathways. SARS-CoV-2 further exacerbates the local inflammatory environment when macrophages or epithelial cells are primed with exogenous inflammatory stimuli. We propose that RNA sensing of SARS-CoV-2 in lung epithelium is a key driver of inflammation, the extent of which is influenced by the inflammatory state of the local environment, and that specific inhibition of innate immune pathways may beneficially mitigate inflammation-associated COVID-19.

Developing Workforce Skills and Capacity in Telehealth: What LEND Trainees Need to Know.

INTRODUCTION: The COVID-19 pandemic significantly impacted the way health-related services are delivered, rapidly shifting from in-person to telehealth visits. To ensure that future healthcare providers are fully prepared to deliver services to families of youth with neurodevelopmental disabilities (NDD), understanding telehealth's advantages and barriers is vital. To this end, data were gathered to inform the development of a nationally available telehealth curriculum aimed at training future healthcare professionals from the Leadership Education in Neurodevelopmental Disabilities (LEND) network. METHODS: Surveys were sent out nationally to current LEND trainees, practicing healthcare professionals, and family members of youth with NDD in November of 2020. Multiple choice and free response questions were completed and analyzed. A total of N = 208 surveys were completed (88 LEND trainees, 94 practicing professionals, 23 family members). RESULTS: Most survey respondents reported having positive experiences with telehealth. LEND trainees and current healthcare professionals cited increased access to care and engagement as the top benefit of telehealth. Most family members reported using telehealth services (78%) and felt it was superior to in-person visits in terms of location of visit, scheduling, and meeting transportation needs. Trainees and professionals agreed the top barriers to telehealth for families were lack of broadband access and complexity of implementation and use. LEND trainees agreed telehealth basics should be included in LEND curriculum. DISCUSSION: Trainees, professionals, and family members all agreed that knowing the basics of telehealth is essential for effective telehealth service delivery. Emerging healthcare professionals need to understand how those they will be serving engage with technology, their levels of experience in this area, and effective strategies for engaging children and youth with NDD through telehealth. This will bridge the engagement gap many families of children with disabilities face when not meeting in person. Findings from this study contributed to the design of learning materials that currently support LEND trainees across the country in developing these skills.

The application of antimicrobial stewardship knowledge to nursing practice: A national survey of United Kingdom pre-registration nursing students.

AIM: To assess student nurses understanding and skills in the application of antimicrobial stewardship knowledge to practice. DESIGN: Quantitative. METHODS: Cross-sectional survey. RESULTS: Five hundred and twenty three student nurses responded across 23 UK universities. Although students felt prepared in competencies in infection prevention and control, patient-centred care and interprofessional collaborative practice, they felt less prepared in competencies in which microbiological knowledge, prescribing and its effect on antimicrobial stewardship is required. Problem-based learning, activities in the clinical setting and face-to-face teaching were identified as the preferred modes of education delivery. Those who had shared antimicrobial stewardship teaching with students from other professions reported the benefits to include a broader understanding of antimicrobial stewardship, an understanding of the roles of others in antimicrobial stewardship and improved interprofessional working. CONCLUSION: There are gaps in student nurses' knowledge of the basic sciences associated with the antimicrobial stewardship activities in which nurses are involved, and a need to strengthen knowledge in pre-registration nurse education programmes pertaining to antimicrobial management, specifically microbiology and antimicrobial regimes and effects on antimicrobial stewardship. Infection prevention and control, patient-centred care and interprofessional collaborative practice are areas of antimicrobial stewardship in which student nurses feel prepared. Interprofessional education would help nurses and other members of the antimicrobial stewardship team clarify the role nurses can play in antimicrobial stewardship and therefore maximize their contribution to antimicrobial stewardship and antimicrobial management. IMPLICATIONS FOR THE PROFESSION: There is a need to strengthen knowledge from the basic sciences, specifically pertaining to antimicrobial management, in pre-registration nurse education programmes. PATIENT OR PUBLIC CONTRIBUTION: No patient or public contribution. IMPACT: What Problem Did the Study Address? Nurses must protect health through understanding and applying antimicrobial stewardship knowledge and skills (Nursing and Midwifery Council 2018); however, there is no research available that has investigated nurses understanding and skills of the basic sciences associated with the antimicrobial stewardship activities in which they are involved. What Were the Main Findings? There are gaps in student nurses' knowledge of the basic sciences (specifically microbiology and prescribing) associated with the antimicrobial stewardship activities in which nurses are involved. Problem-based learning, and activities in the clinical setting, were reported as useful teaching methods, whereas online learning, was seen as less useful. Where and on Whom Will the Research Have an Impact? Pre-registration nurse education programmes. REPORTING METHOD: The relevant reporting method has been adhered to, that is, STROBE.

The lived experiences of hematology healthcare providers during and beyond the COVID-19 crisis: A qualitative study.

OBJECTIVE: Amid the COVID-19 pandemic, healthcare providers (HCPs) of hematology patients face unique challenges due to the vulnerability of their patients. This study explores the lived experiences of these providers during and beyond the crisis. METHODS: Twenty-one Australian HCPs caring for hematology patients completed semi-structured interviews exploring their experiences and needs during the COVID-19 pandemic, adequacy of support and information provided by healthcare organizations, impact on hematology patients, and the benefits and challenges of telehealth care. Data were analyzed using reflexive thematic analysis. RESULTS: Four themes were identified: (1) Managing an initial state of flux (unsettling uncertainty and fear, unique needs of hematology patients, getting on with the job together); (2) Concerns about care provision (questioning care efficacy, burden of compassion); (3) Disconnect between HCP needs and system-level responses (burnout, isolation, and poor work-life balance, broadcast fatigue, protecting mental health), and; (4) Reflecting on the future (ongoing challenges for hematology patients, higher staff turnover and heavier workloads, innovation in the healthcare field). CONCLUSION: This study sheds light on the challenges that hematology HCPs face during and beyond the COVID-19 crisis, impacting their wellbeing. Addressing these challenges is paramount for the healthcare system at large. Provider-led peer support programs may be beneficial for addressing moral distress and building resilience. Additionally, specific consideration for the ongoing vulnerability of hematology patients could have positive impacts on providers' professional satisfaction.

"Now is the time for institutions to be investing in growing exercise programs as part of standard of care": a multiple case study examining the implementation of exercise oncology interventions.

BACKGROUND: Implementation science seeks to systematically identify determinants, strategies, and outcomes within a causal pathway to help explain successful implementation. This process is applied to evidence-based interventions (EBIs) to improve their adoption, implementation, and sustainment. However, this method has not been applied to exercise oncology services, meaning we lack knowledge about implementing exercise EBIs in routine practice. This study aimed to develop causal pathways from the determinants, strategies (including mechanism of change), and implementation outcomes to explain exercise EBIs implementation in routine cancer care. METHODS: A multiple-case study was conducted across three healthcare sites in Australia. Sites selected had implemented exercise within routine care for people diagnosed with cancer and sustained the delivery of services for at least 12 months. Four data sources informed the study: semi-structured interviews with staff, document reviews, observations, and the Program Sustainability Assessment Tool (survey). Framework analysis was applied to understand the findings. The Implementation Research Logic Model was used to identify commonalities in implementation across sites and develop causal pathways. RESULTS: Two hundred and eighteen data points informed our findings. Across sites, 18 determinants and 22 implementation strategies were consistent. Sixteen determinants and 24 implementation strategies differed across sites and results of implementation outcomes varied. We identified 11 common pathways that when combined, help explain implementation processes. The mechanisms of implementation strategies operating within the pathways included (1) knowledge, (2) skills, (3) secure resources, (4) optimism, and (5) simplified decision-making processes associated with exercise; (6) relationships (social and professional) and support for the workforce; (7) reinforcing positive outcomes; (8) capability to action plan through evaluations and (9) interactive learning; (10) aligned goals between the organisation and the EBI; and (11) consumer-responsiveness. CONCLUSION: This study developed causal pathways that explain the how and why of successful implementation of exercise EBIs in cancer care. These findings can support future planning and optimisation activities by creating more opportunities for people with cancer to access evidence-based exercise oncology services. IMPLICATIONS FOR CANCER SURVIVORS: Understanding how to implement exercise within routine cancer care successfully is important so cancer survivors can experience the benefits of exercise.

Using a LIFE Framework to Develop MCH Leaders.

INTRODUCTION: The Maternal Child Health (MCH) Bureau created MCH Leadership Competencies to support current and future leaders by defining the knowledge and skills necessary to lead in this field. The Michigan-LEND (MILEND) training program developed a 'LIFE. framework', an acronym that stands for Leadership, Interdisciplinary, Family-Professional Partnerships, and Equity, to codify the 12 MCH leadership competencies into an easy to remember and easy to apply structure. This manuscript addresses the question, Does the LIFE framework align with the 12 MCH Leadership Competencies? Our hypothesis is that MI-LEND trainees will demonstrate improvement in their self-assessment of the 12 MCH leadership competencies after completing the MI-LEND program which uses the LIFE framework. METHODS: Data were collected from 24 MI-LEND long-term trainees (> 300 hours) who completed a 100-itemleadership self-assessment questionnaire based on the MCH Navigator at the beginning and the end of the training year. Non-parametric sign tests were used to test the median difference, item by item for each of the questions under each competency. Parametric paired-sample t-tests were used to analyze mean difference, competency by competency when the assumption of normality was met. RESULTS: All basic and advanced-level competencies had a statistically significant improvement between the beginning and end of the training year. The greatest changes were seen in Family-Professional Partnerships, Policy, Interdisciplinary Team Building, MCH Knowledge Base and Critical Thinking - all areas emphasized in the L.I.F.E. DISCUSSION: While the LIFE framework may oversimplify MCH Leadership Competencies, it is an effective mnemonic tool to organize and articulate MCH leadership competencies and could foster consistency across MCH programs.

Finding My Way-Advanced: can a web-based psychosocial intervention improve the mental quality of life for women with metastatic breast cancer vs attention-control? Study protocol of a randomised controlled trial.

BACKGROUND: Women living with metastatic breast cancer (MBC) are at risk of significantly impaired quality of life (QOL), symptom burden, distress and fear of progression, and unmet needs, yet they face barriers to accessing evidence-based psychosocial treatments. Our group therefore developed Finding My Way-Advanced (FMW-A), a web-based self-guided psychosocial program for women with MBC. This study aims to assess its efficacy in improving mental and other QOL domains, distress, fear of progression, unmet needs, and health service utilisation. METHODS: The multi-site randomised controlled trial (RCT) will enrol 370 Australian participants. Eligible participants are adult (18 years +) women diagnosed with MBC, with a life expectancy of 6 months or more, with sufficient English-language literacy to provide informed consent. Participants will be identified, screened and referred from one of 10 Australian sites, or via self-referral in response to advertisements. Participants complete four online questionnaires: prior to accessing their program ('baseline'), 6 weeks later ('post-intervention'), then 3 months and 6 months post-intervention. Consenting participants will be randomised to either FMW-A (intervention), or Breast Cancer Network Australia's (BCNA) online/app resource My Journey (minimal intervention attention-control). This is a single-blind study, with randomisation computer-generated and stratified by site. FMW-A is a 6-module program addressing some of the most common issues experienced by women with MBC, with BCNA control resources integrated within the 'resources' section. All modules are immediately accessible, with an additional booster module released 10 weeks later. The primary outcome is mental QOL; statistical criteria for superiority is defined as a 4-point difference between groups at post-treatment. Secondary outcomes include other QOL domains, distress, fear of progression, health service use, intervention adherence, and user satisfaction. DISCUSSION: This will be the first adequately powered RCT of a self-directed online intervention for women with MBC. If efficacious, FMW-A will help address two national key priorities for management of MBC - enhancing QOL and reducing symptom burden. FMW-A has the potential to address unmet needs and overcome access barriers for this overlooked population, while reducing health system burden. TRIAL REGISTRATION: The study was registered prospectively with the ANZCTR on 29/10/2021. Trial ID ACTRN12621001482853p.  https://anzctr.org.au/Trial/Registration/TrialReview.aspx?id=382714&isReview=true.

Experiences and needs of people with haematological cancers during the COVID-19 pandemic: A qualitative study.

OBJECTIVE: Haematological cancer patients are particularly vulnerable to the effects of COVID-19. In addition to being immunocompromised, pandemic-related travel restrictions have impacted access to treatments and overseas stem cell donations for patients requiring transplantation. Given this vulnerability, people with haematological cancers are at risk of experiencing heightened distress during the pandemic. This study aimed to explore haematological cancer patients' experiences and needs. METHODS: Twenty-four Australian haematological cancer patients completed semi-structured interviews exploring their concerns and worries during the pandemic, impact of pandemic on management of disease, access to information and support, lifestyle changes, and attitudes towards emerging models of healthcare during the pandemic. Interview transcripts were thematically analysed. RESULTS: Four themes reflecting the experiences of haematological cancer patients during the pandemic were identified: 'Fears about contracting COVID-19' (behaviour changes to protect health, impact on daily routine and habits, annoyance at dismissive attitude of others toward COVID-19); 'Reduced sense of connection and support' (reduced social support and access to external support services); 'New challenges' (increased financial hardship, worsened health), and; 'Underlying system and communication issues' (access to trusted information, satisfaction/dissatisfaction with care, navigating telehealth). Participants expressed a need for improved access to support services and trusted information. CONCLUSIONS: The findings emphasise the additional challenges experienced by haematological cancer patients during the COVID-19 pandemic and their impact on daily life. Results point to the importance of validation of increased distress during periods of uncertainty; reinforcing recommendations about high-quality sources of information; and facilitating access to support services when face-to-face care is limited.

Health care workers' perspectives on care for patients with injection drug use associated infective endocarditis (IDU-IE).

BACKGROUND: Despite high morbidity and mortality, patients with injection drug use associated infective endocarditis (IDU-IE) lack standardized care, and experience prolonged hospitalization and variable substance use disorder (SUD) management. Our study's objective was to elicit perspectives of health care workers (HCWs) who deliver care to this population by understanding their perceived patient, provider, and system-level resources and barriers. METHODS: This qualitative study included interviews of HCWs providing care to patients with IDU-IE from January 2017 to December 2019 at a single Midwest academic center. Based on electronic medical record queries to determine high and low rates of referral to SUD treatment, HCWs were selected using stratified random sampling followed by convenience sampling of non-physician HCWs and a patient. Study participants were recruited via email and verbal consent was obtained. The final sample included 11 hospitalists, 3 specialists (including 2 cardiovascular surgery providers), 3 case managers, 2 social workers, 1 nurse, and 1 patient. Qualitative semi-structured interviews explored challenges and resources related to caring for this population. Qualitative Data Analysis (QDA) Minor Lite was used for thematic data using an inductive approach. RESULTS: Three major thematic categories emerged relative to patient-level barriers (e.g., pain control, difficult patient interactions, social determinants of health), provider-level barriers (e.g., inequity, expectations for recovery, varying levels of hope, communication style, prescribing medication for SUD), and system-level barriers (e.g., repeat surgery, placement, resources for SUD and mental health). The need to address underlying SUD was a prominent theme. CONCLUSION: Practical steps we can take to improve treatment for this population include training and coaching HCWs on a more person-centered approach to communication and transparent decision-making around pain management, surgery decisions, and expectations for SUD treatment.

Communicating Actively, Responding Empathically (CARE): Perceptions of Cancer Health Professionals Attending Communication Training Workshops.

Communication skills training is standardly offered to health professionals working in cancer; however, there is no consensus on the precise style or duration of training, which is most effective. This study aimed to examine the experiences of health professionals who had participated in either a 1-day communication skills training workshop focusing on experiential learning or a 2-h workshop in which participants discussed different communication styles demonstrated on purpose-designed videotapes. Twenty health professionals comprising ten from each workshop type participated in a semi-structured interview with an interpretative descriptive design. Participant characteristics were summarised using descriptive statistics. Thematic analysis was conducted. Consistent themes across both groups were the importance of good communication and perceived barriers. All participants strongly endorsed the value of their respective training experience and considered this was due in part to the skill of facilitators and the creation of a supportive learning environment. Role plays were reported to be helpful in promoting skill development, and some participants in the 2-h workshop indicated that they would have liked the opportunity to practice new skills through role play, which was not possible in the short workshop. Participants self-reported increased confidence following both workshops and perceived improvements in delivery of person-centred care. Both the 1-day and the 2-h communication workshops were a positive experience for the groups who attended. The 1-day communication workshop offered an opportunity for experiential learning, which the 2-h group felt would have been worthwhile; however, both groups found value in attending the workshops.

Experiences and unmet needs of family members requested to donate haematopoietic stem cells to an ill relative: findings from a prospective multi-centre study.

BACKGROUND: Despite well-documented physical effects of haematopoietic stem cell (HSC) donation, far less attention has been focused on the psychosocial impact for family donors. This study aimed to better understand the psychosocial aspects of HSC donation by family members, focusing, in particular on their needs for information and supportive care. METHODS: Thirty-one adult HSC family donors from two clinical hospitals were interviewed before, during and 1 month after HSC donation. Interviews explored ambivalence, motivation, perceived pressure, preparedness, the donor-recipient relationship, information and support received and suggestions for improvement. RESULTS: Three main themes about the donation experience were identified: 'call to arms' (focused on the recipient, stressful urgency, making meaning of being a donor, decisional ambivalence), 'proceeding with donation' (living in limbo, unsettling uncertainty, pervasive pain, feeling supported) and 'after the dust settles' (feeling discarded, downplaying role, residual symptoms, dealing with adverse recipient outcomes). Underlying system and communication issues included time for consideration prior to donor work-up, management of confidentiality, information inadequacy and access to support. Donors wanted information about the emotional challenges specific to being a family donor, such as ways in which previous donors coped with recipient death. For donors whose recipient had died, the priority for improved care was follow-up support. CONCLUSION: Our findings emphasise a gap in information and supportive care for family donors and the need for a protocol specifically designed to inform and support family donors before, during and after HSC donation.

Prevalence and correlates of psychological distress, unmet supportive care needs, and fear of cancer recurrence among haematological cancer patients during the COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic has had a disruptive effect on people with haematological cancers, who represent a high-risk population due to the nature of their disease and immunosuppressive treatments. We aimed to identify the psychological impacts of the COVID-19 pandemic on haematology patients and identify correlated factors to inform the development of appropriate supportive interventions. METHODS: Three hundred and ninety-four respondents volunteered their participation in response to a study advertisement distributed online through established haematology groups. Participants completed a self-report online survey exploring wellbeing, psychological distress, unmet supportive care needs, and fear of cancer recurrence. RESULTS: At least 1 in 3 respondents (35%) reported clinical levels of distress and nearly 1 in 3 (32%) identified at least one unmet need. Among respondents in remission (n = 134), clinical fear of cancer recurrence was reported by nearly all (95%). Unmet needs, pre-existing health conditions, younger age, financial concerns, and perceived risk of contracting COVID-19 were the dominant factors contributing to psychological distress during the pandemic. Psychological distress, lost income, perceived inadequate support from care team, perceived risk of contracting COVID-19, and being a woman were significantly associated with unmet needs. Psychological distress and concern about the impact of COVID-19 on cancer management were significantly associated with fear of cancer recurrence among respondents in remission. CONCLUSION: Results highlight the high psychological burden and unmet needs experienced by people with haematological cancers during the COVID-19 pandemic and indicate a need for innovative solutions to rapidly identify distress and unmet needs during, and beyond, pandemic times.

Moderators of intervention efficacy for Finding My Way: A web-based psychosocial intervention for cancer-related distress.

PURPOSE: The present analysis explores whether demographic, psychosocial, or intervention adherence factors moderated treatment efficacy of Finding My Way (FMW), an efficacious self-directed web-based psychosocial program for newly diagnosed curatively treated cancer patients. METHODS: Participants (n = 191) completed a 6-module intervention (n = 94) or attention-control (n = 97) program. Outcome measures were completed at baseline (T0), post-program (T1), 3-month (T2), and 6-month (T3) follow ups. Age, gender, social support, information processing style (monitoring vs blunting), emotion-regulation difficulties, and intervention adherence were examined as potential moderators. RESULTS: Age moderated emotional functioning and general distress at T3 with significant intervention benefits only observed in younger participants; age moderated cognitive functioning at T1, with intervention benefits only found in older participants. Gender moderated helplessness/hopelessness, emotional functioning, and cognitive avoidance at T1 with men benefitting more from receiving the intervention vs control. Monitoring information-processing style moderated cancer distress and anxious preoccupation at T3: higher monitors benefitted more from receiving the intervention vs control. Program adherence moderated global QOL, emotional functioning and social functioning at T2 and T3; cognitive avoidance (T1), anxious preoccupation (T2) and role function (T3), with those who completed more of the program benefitting more if they received the intervention than control. Emotion dysregulation and social support each moderated role function at T2, with those more dysregulated and less socially supported benefitting more if they received the intervention than control. CONCLUSIONS: For select outcomes, FMW is more effective for patients with specific characteristics; these findings can inform future tailoring and targeting of online programs for cancer-distress.

Teaching medical students remotely during a pandemic - what can psychiatry offer?

OBJECTIVE: The clinical teaching of psychiatry to medical students throughout the COVID-19 pandemic has presented opportunities for support, engagement and learning above and beyond usual practice. Like other teaching faculties, we needed to quickly adapt the course material to an online platform. However, for psychiatric teaching, it was also essential to find alternatives to patient interviewing, and to provide support and containment in uncertain times. We aim to describe our philosophical stance and framework for the delivery of our online course. CONCLUSIONS: Key components in the delivery of our modified course were the transition to online learning and assessment, developing a suite of surrogate clinical learning experiences, using simulated patients for online interviewing, and attention to student well-being whilst providing a supportive and contained environment for student learning. Supportive leadership and good communication assisted the teaching staff to deliver the course during COVID-19.

Kinetics of Early Innate Immune Activation during HIV-1 Infection of Humanized Mice.

Human immunodeficiency virus type 1 (HIV-1) infection is associated with aberrant immune activation; however, most model systems for HIV-1 have been used during established infection. Here, we utilize ultrasensitive HIV-1 quantification to delineate early events during the eclipse, burst, and chronic phases of HIV-1 infection in humanized mice. We show that very early in infection, HIV-1 suppresses peripheral type I interferon (IFN) and interferon-stimulated gene (ISG) responses, including the HIV-1 restriction factor IFI44. At the peak of innate immune activation, prior to CD4 T cell loss, HIV-1 infection differentially affects peripheral and lymphoid Toll-like receptor (TLR) expression profiles in T cells and macrophages. This results in a trend toward an altered activation of nuclear factor κB (NF-κB), TANK-binding kinase 1 (TBK1), and interferon regulatory factor 3 (IRF3). The subsequent type I and III IFN responses result in preferential induction of peripheral ISG responses. Following this initial innate immune activation, peripheral expression of the HIV-1 restriction factor SAM domain- and HD domain-containing protein 1 (SAMHD1) returns to levels below those observed in uninfected mice, suggesting that HIV-1 interferes with their basal expression. However, peripheral cells still retain their responsiveness to exogenous type I IFN, whereas splenic cells show a reduction in select ISGs in response to IFN. This demonstrates the highly dynamic nature of very early HIV-1 infection and suggests that blocks to the induction of HIV-1 restriction factors contribute to the establishment of viral persistence.IMPORTANCE Human immunodeficiency virus type 1 (HIV-1) infection is restricted to humans and some nonhuman primates (e.g., chimpanzee and gorilla). Alternative model systems based on simian immunodeficiency virus (SIV) infection of macaques are available but do not recapitulate all aspects of HIV-1 infection and disease. Humanized mice, which contain a human immune system, can be used to study HIV-1, but only limited information on early events and immune responses is available to date. Here, we describe very early immune responses to HIV-1 and demonstrate a suppression of cell-intrinsic innate immunity. Furthermore, we show that HIV-1 infection interacts differently with innate immune responses in blood and lymphoid organs.

Development and usability evaluation of an online self-management intervention for fear of cancer recurrence (iConquerFear).

OBJECTIVE: To develop and evaluate the usability of iConquerFear, an online self-management adaptation of an efficacious face-to-face therapist-delivered treatment for fear of cancer recurrence (FCR). METHODS: iConquerFear development was theory based and person based. Development was guided by Ritterband et al's behaviour change model for internet interventions. iConquerFear end users (cancer survivors) provided iterative feedback in accordance with Yardley et al's person-based approach to maximise engagement and usability. Online focus groups and cognitive interviews were conducted to evaluate the usability of iConquerFear. Discussions were recorded, transcribed verbatim, and thematically analysed. RESULTS: Five online FCR modules were developed. Twenty-three cancer survivors (47% of those eligible) participated; 11/23 (58%) were breast cancer survivors, and average age was 53 years (SD = 10.8). Thematic saturation was reached after six focus groups (n = 16) and seven individual think-aloud interviews. Thematic analysis produced five overarching themes: easy navigation essential; satisfaction and engagement with content; flexible access is key; normalising and empowering; and a useful first step. CONCLUSIONS: Online self-management interventions like iConquerFear have the potential to address the unmet supportive care needs reported by burgeoning numbers of cancer survivors. However, that potential may not be realised unless interventions are rigorously developed and user tested, as benefits are constrained by limited engagement. Themes from the usability testing of iConquerFear highlight the importance of developing flexible, tailored, interactive, and contextual online self-management interventions for people with cancer.

Communicating Actively Responding Empathically (CARE): Comparison of Communication Training Workshops for Health Professionals Working in Cancer Care.

Accessing full-day communication skills training can be challenging for health professionals working in cancer care. This study aimed to examine the effectiveness of Communicating Actively, Responding Empathically (CARE Express), a modified 2-h communication skills training course, across measures of health professional confidence, skills and attitudes. Cancer care health professionals (n = 147) were recruited from allied health, nursing and medical disciplines, using a partial randomisation to allocate to three arms: control, two-hour training (CARE Express) and 1-day training (CARE). Perceived confidence and skills were measured by self-report using a purpose-built scale, and written responses to a challenging clinical encounter were obtained at baseline, post-training and three-months post-training. Attitudes toward psychosocial issues were evaluated with the Physician Belief Scale at baseline and 3 months post-training. No changes were observed in the control group (n = 50) from baseline to 3 months follow-up. Participants in the CARE Express (n = 48) and CARE (n = 49) groups had significant improvement in confidence in identifying/responding to emotions between baseline and 3 months post-training (p < 0.001), as well as their attitude toward psychosocial care (p < 0.001). A significant increase in "acknowledging" responses from baseline to 3 months was also observed for CARE Express and CARE (p < 0.001), with no difference between groups. CARE Express and CARE resulted in changes in confidence in emotional identification/response, psychosocial focus and communication skills maintained at 3 months post-training. Whilst the 1-day workshop has been regarded as gold standard, this study has revealed positive outcomes with a modified 2-h version, thus offering a potential alternate training model.