Paediatric oncologists' perspectives on Strategic solutions to develop Integrated Cancer Palliative Care: feedback intervention theory as an explanatory Framework.

BACKGROUND: Globally, children with cancer often experience delays in palliative care referral or are infrequently referred. Therefore, we conducted a qualitative study to gain insight from paediatric oncologists into what enables or deters palliative care referral. Strategic solutions to develop integrated palliative care was a critical study theme. In this paper, we have explained and interpreted these strategic solutions through the lens of feedback intervention theory. METHODOLOGY: The study findings were interpreted using Kumar's six-step approach that enabled systematic evaluation of a theory's appropriateness and alignment with the researcher's paradigm, methodology, and study findings. It also explained how theory informed analysis and elucidated challenges or the development of new models. The feedback intervention theory appraises the discrepancy between actual and desired goals and provides feedback to improve it. RESULTS: Strategic solutions generated from the study findings were coherent with the aspects elucidated in theory, like coping mechanisms, levels of feedback hierarchy, and factors determining the effect of the feedback intervention on performance. Paediatric oncologists suggested integrating palliative care providers in the team innocuously, improving communication between teams, relabelling palliative care as symptom control, and working with a skilled and accessible palliative care team. The paper proposes an infinite loop model developed from the study, which has the potential to foster integrated palliative care through excellent collaboration and continuous feedback. CONCLUSION: Applying feedback intervention theory can bridge the gap between actual and desired practice for integrated cancer palliative care in paediatric oncology.

Relating different perspectives on how outcomes of behavior influence behavior.

Many researchers have tackled the question of how behavior is influenced by its outcomes. Some have adopted a nonmechanistic (functional) perspective that attempts to describe the influence of outcomes on behavior. Others have adopted a mechanistic (cognitive) perspective that attempts to explain the influence of outcomes on behavior. Orthogonal to this distinction, some have focused on the influence of outcomes that a behavior had in the past, whereas others also consider the influence of outcomes that a behavior might have in the future. In this article, we relate these different perspectives with the goal of reducing misunderstandings and fostering collaborations between researchers who adopt different perspectives on the common question of how behavior is influenced by its outcomes.

Vaginal epithelial dysfunction is mediated by the microbiome, metabolome, and mTOR signaling.

Bacterial vaginosis (BV) is characterized by depletion of Lactobacillus and overgrowth of anaerobic and facultative bacteria, leading to increased mucosal inflammation, epithelial disruption, and poor reproductive health outcomes. However, the molecular mediators contributing to vaginal epithelial dysfunction are poorly understood. Here we utilize proteomic, transcriptomic, and metabolomic analyses to characterize biological features underlying BV in 405 African women and explore functional mechanisms in vitro. We identify five major vaginal microbiome groups: L. crispatus (21%), L. iners (18%), Lactobacillus (9%), Gardnerella (30%), and polymicrobial (22%). Using multi-omics we show that BV-associated epithelial disruption and mucosal inflammation link to the mammalian target of rapamycin (mTOR) pathway and associate with Gardnerella, M. mulieris, and specific metabolites including imidazole propionate. Experiments in vitro confirm that type strain G. vaginalis and M. mulieris supernatants and imidazole propionate directly affect epithelial barrier function and activation of mTOR pathways. These results find that the microbiome-mTOR axis is a central feature of epithelial dysfunction in BV.

Multimodality Cardiac Imaging in COVID.

Infection with SARS-CoV-2, the virus that causes COVID, is associated with numerous potential secondary complications. Global efforts have been dedicated to understanding the myriad potential cardiovascular sequelae which may occur during acute infection, convalescence, or recovery. Because patients often present with nonspecific symptoms and laboratory findings, cardiac imaging has emerged as an important tool for the discrimination of pulmonary and cardiovascular complications of this disease. The clinician investigating a potential COVID-related complication must account not only for the relative utility of various cardiac imaging modalities but also for the risk of infectious exposure to staff and other patients. Extraordinary clinical and scholarly efforts have brought the international medical community closer to a consensus on the appropriate indications for diagnostic cardiac imaging during this protracted pandemic. In this review, we summarize the existing literature and reference major societal guidelines to provide an overview of the indications and utility of echocardiography, nuclear imaging, cardiac computed tomography, and cardiac magnetic resonance imaging for the diagnosis of cardiovascular complications of COVID.

Upregulation of IFN-stimulated genes persists beyond the transitory broad immunologic changes of acute HIV-1 infection.

Chronic immune activation during HIV-1 infection contributes to morbidity and mortality in people living with HIV. To elucidate the underlying biological pathways, we evaluated whole blood gene expression trajectories from before, through acute, and into chronic HIV-1 infection. Interferon-stimulated genes, including MX1, IFI27 and ISG15, were upregulated during acute infection, remained elevated into chronic infection, and were strongly correlated with plasma HIV-1 RNA as well as TNF-α and CXCL10 cytokine levels. In contrast, genes involved in cellular immune responses, such as CD8A, were upregulated during acute infection before reaching a peak and returning to near pre-infection levels in chronic infection. Our results indicate that chronic immune activation during HIV-1 infection is characterized by persistent elevation of a narrow set of interferon-stimulated genes and innate cytokines. These findings raise the prospect of devising a targeted intervention to restore healthy immune homeostasis in people living with HIV-1.

The experiences of family members witnessing the diminishing drinking of a dying relative in hospital: A narrative inquiry.

BACKGROUND: The optimal management of diminishing drinking at the end of life is contentious. Clinicians and family members may understand the phenomenon differently and hold divergent priorities regarding care. Family members can be distressed by diminishing drinking and its management, particularly when in a hospital environment. AIM: To explore the experiences of family members when witnessing the diminishing drinking of a dying relative. DESIGN: A narrative inquiry methodology, derived from pragmatism. SETTING AND PARTICIPANTS: Thirteen recently bereaved family members were recruited through the bereavement services of three UK hospitals. Inclusion criteria included having an adult relative who died in hospital of any diagnosis more than 48 hours from admission and who had had noticeable diminishing drinking. FINDINGS: Participants experienced diminishing drinking as an unfolding process that was part of overall decline. They all believed it to be detrimental. Three groups of responses were identified: promoting, accepting and ameliorating. Supportive measures included offering equipment to support drinking, staff being present and communicating about expectations and care management aims. CONCLUSIONS: There is potential to improve family members' experiences through re-conceptualisation of diminishing drinking aligned to their experiences, supporting family members by listening to their experiences with insight and strengthening their agency within the management of their relatives with diminishing drinking.

Memory T cells possess an innate-like function in local protection from mucosal infection.

Mucosal infections pose a significant global health burden. Antigen-specific tissue-resident T cells are critical to maintaining barrier immunity. Previous studies in the context of systemic infection suggest that memory CD8+ T cells may also provide innate-like protection against antigenically unrelated pathogens independent of T cell receptor engagement. Whether bystander T cell activation is also an important defense mechanism in the mucosa is poorly understood. Here, we investigated whether innate-like memory CD8+ T cells could protect against a model mucosal virus infection, herpes simplex virus 2 (HSV-2). We found that immunization with an irrelevant antigen delayed disease progression from lethal HSV-2 challenge, suggesting that memory CD8+ T cells may mediate protection despite the lack of antigen specificity. Upon HSV-2 infection, we observed an early infiltration, rather than substantial local proliferation, of antigen-nonspecific CD8+ T cells, which became bystander-activated only within the infected mucosal tissue. Critically, we show that bystander-activated CD8+ T cells are sufficient to reduce early viral burden after HSV-2 infection. Finally, local cytokine cues within the tissue microenvironment after infection were sufficient for bystander activation of mucosal tissue memory CD8+ T cells from mice and humans. Altogether, our findings suggest that local bystander activation of CD8+ memory T cells contributes a fast and effective innate-like response to infection in mucosal tissue.

Myocardial Injury on CMR in Patients With COVID-19 and Suspected Cardiac Involvement.

BACKGROUND: Myocardial injury in patients with COVID-19 and suspected cardiac involvement is not well understood. OBJECTIVES: The purpose of this study was to characterize myocardial injury in a multicenter cohort of patients with COVID-19 and suspected cardiac involvement referred for cardiac magnetic resonance (CMR). METHODS: This retrospective study consisted of 1,047 patients from 18 international sites with polymerase chain reaction-confirmed COVID-19 infection who underwent CMR. Myocardial injury was characterized as acute myocarditis, nonacute/nonischemic, acute ischemic, and nonacute/ischemic patterns on CMR. RESULTS: In this cohort, 20.9% of patients had nonischemic injury patterns (acute myocarditis: 7.9%; nonacute/nonischemic: 13.0%), and 6.7% of patients had ischemic injury patterns (acute ischemic: 1.9%; nonacute/ischemic: 4.8%). In a univariate analysis, variables associated with acute myocarditis patterns included chest discomfort (OR: 2.00; 95% CI: 1.17-3.40, P = 0.01), abnormal electrocardiogram (ECG) (OR: 1.90; 95% CI: 1.12-3.23; P = 0.02), natriuretic peptide elevation (OR: 2.99; 95% CI: 1.60-5.58; P = 0.0006), and troponin elevation (OR: 4.21; 95% CI: 2.41-7.36; P < 0.0001). Variables associated with acute ischemic patterns included chest discomfort (OR: 3.14; 95% CI: 1.04-9.49; P = 0.04), abnormal ECG (OR: 4.06; 95% CI: 1.10-14.92; P = 0.04), known coronary disease (OR: 33.30; 95% CI: 4.04-274.53; P = 0.001), hospitalization (OR: 4.98; 95% CI: 1.55-16.05; P = 0.007), natriuretic peptide elevation (OR: 4.19; 95% CI: 1.30-13.51; P = 0.02), and troponin elevation (OR: 25.27; 95% CI: 5.55-115.03; P < 0.0001). In a multivariate analysis, troponin elevation was strongly associated with acute myocarditis patterns (OR: 4.98; 95% CI: 1.76-14.05; P = 0.003). CONCLUSIONS: In this multicenter study of patients with COVID-19 with clinical suspicion for cardiac involvement referred for CMR, nonischemic and ischemic patterns were frequent when cardiac symptoms, ECG abnormalities, and cardiac biomarker elevations were present.

Learning in Individual Organisms, Genes, Machines, and Groups: A New Way of Defining and Relating Learning in Different Systems.

Learning is a central concept in many scientific disciplines. Communication about research on learning is, however, hampered by the fact that different researchers define learning in different ways. In this article, we introduce the extended functional definition of learning that can be used across scientific disciplines. We provide examples of how the definition can be applied to individual organisms, genes, machines, and groups. Using the extended functional definition (a) reveals a heuristic framework for research that can be applied across scientific disciplines, (b) allows researchers to engage in intersystem analyses that relate the behavior and learning of different systems, and (c) clarifies how learning differs from other phenomena such as (changes in) behavior, damaging systems, and programming systems.

Effects on the Affect Misattribution Procedure are strongly moderated by influence awareness.

The Affect Misattribution Procedure (AMP) is used in many areas of psychological science based on the assumption that it not only taps into attitudes and biases but does so without a person's awareness. Across eight preregistered studies (N = 1603) plus meta-analyses, we reexamined the 'implicitness' of AMP effects, and in particular, the idea that people are unaware of the prime's influence on their evaluations. Results indicated that AMP effects and their predictive validity are primarily moderated by a subset of influence-aware trials (within individuals), and high rates of influence awareness (between individuals). Interestingly, an individual's influence-awareness rate on one AMP predicted how they performed on an earlier AMP, even when the two assessed different attitude domains. Taken together, our results suggest that AMP effects are not implicit in the way that has been claimed, a finding that has implications for the procedure, past findings, and theory. All materials and data are available at osf.io/gv7cm.

The enigma of Sir William Robert Wills Wilde (1815-1876).

William Wilde, father of Oscar Wilde, made a significant contribution to ophthalmology and otology. Qualified as a surgeon. educated in statistics and showing sympathy for the Irish population, Wilde was appointed a Commissioner for the 1851 Census, which covered the time of the Irish Famine (1845-1852). Wilde, steeped in Irish mythology, used his knowledge to develop a close rapport with the Irish peasantry. However, his life was a paradox; he supported the British Government's approach to the Famine and at the same time he showed humanity to the Irish peasantry. In his personal life he was implicated in an abortive libel case involving a young female patient who had accused him of rape. Wilde lived as though he had two separate lives: on the one hand the successful surgeon, famine Commissioner and cataloguer of Irish antiquities, and the other a countryman and disciple of Irish mythology. Wilde was highly preceptive especially in his views on the recording of medical data and outcomes in clinical practice. We argue that Wilde was probably unmatched in the variety of his talents but was also perplexing in the various actions he took during his life and that indeed Wilde was an enigma.

Why is William Sharp's name forgotten when his novel method for treating fractures of the Ankle is still used today?

In 1837 Guillaume von Dupuytren (1777-1835) wrote that the innovative method of reducing an ankle fracture by relaxing the calf muscles was due to both William Sharp (1729-1810) and Percivall Pott (1714-1788). While history records the many surgical achievements of Percivall Pott, little is known of William Sharp's contribution. He is probably best known as one of a remarkable family portrayed by Johan Zoffany (1733-1810) and exhibited at the Royal Academy in 1781. We review William Sharp's career and contribution as a surgeon to the treatment of fracture/dislocations of the ankle and ask why his concept is not better known today.

Society for Cardiovascular Magnetic Resonance 2022 Cases of SCMR case series.

"Cases of SCMR" is a case series on the SCMR website (https://www.scmr.org) for the purpose of education. The cases reflect the clinical presentation, and the use of cardiovascular magnetic resonance (CMR) in the diagnosis and management of cardiovascular disease. The 2022 digital collection of cases are presented in this manuscript.

Robert Lawson Tait (1845-1899): The true innovator of aseptic surgery?

Robert Lawson Tait was an original thinker, a surgical innovator, a controversialist and an iconoclast. He made important contributions to surgery, was an eloquent supporter of Darwinian evolution and women in medicine and opposed vivisection. He is probably best remembered for his high-profile opposition to Listerian antisepsis which continued until his death. While Lister went on to receive the country's highest honours and was lauded throughout the world, Tait received much more modest honours and little subsequent recognition by historians. Yet it could be argued that Tait's system rather than Lister's was the basis of modern aseptic surgery. Tait never changed his views on asepsis over his lifetime and relied on surgical cleanliness, which, combined with his extensive clinical experience, enabled him to achieve outcomes as good or better than with antisepsis. By contrast, Listerism evolved over 30 years, claimed to be based on laboratory data and adopted the new discoveries of the germ theory of disease as they emerged. We compare the systems of Tait and Lister, explore the basis of Tait's opposition to Listerian methods and conclude that Tait's thinking underlies modern surgical practice and that he should receive greater acknowledgement for his contribution to the prevention of surgical infections.

Presuppositions, cost-benefit, collaboration, and competency impacts palliative care referral in paediatric oncology: a qualitative study.

BACKGROUND: Although a significant proportion of children with cancer need palliative care, few are referred or referred late, with oncologists and haematologists gatekeeping the referral process. We aimed to explore the facilitators and barriers to palliative care referral. METHODS: Twenty-two paediatric oncologists and haematologists were purposively recruited and interviewed. Data were analysed using reflexive thematic analysis. Findings were interpreted using the critical realist paradigm. RESULTS: Four themes were generated. 1) Oncologists expressed concern about the competency of palliative care teams. Palliative care often symbolised therapeutic failure and abandonment, which hindered referral. Trustworthy palliative care providers had clinical competence, benevolence, and knowledge of oncology and paediatrics. 2) Making a palliative care referral was associated with stigma, navigating illness-related factors, negative family attitudes and limited resources, impeding palliative care referral. 3) There were benefits to palliative care referral, including symptom management and psychosocial support for patients. However, some could see interactions with the palliative care team as interference hindering future referrals. 4) Suggested strategies for developing an integrated palliative care model include evident collaboration between oncology and palliative care, early referral, rebranding palliative care as symptom control and an accessible, knowledgeable, and proactive palliative care team. CONCLUSION: Presuppositions about palliative care, the task of making a referral, and its cost-benefits influenced referral behaviour. Early association with an efficient rebranded palliative care team might enhance integration.

Stable HIV Reservoir Despite Prolonged Low-Dose Mycophenolate to Limit CD4+ T-cell Proliferation.

Background: The HIV reservoir of latently infected CD4+ T cells represents the barrier to cure. CD4+ T-cell proliferation is a mechanism that sustains the reservoir even during prolonged antiretroviral therapy (ART). Blocking proliferation may therefore deplete the reservoir. Methods: We conducted an unblinded, uncontrolled clinical trial of mycophenolate, a T-cell antiproliferative compound, in people with HIV on chronic suppressive ART. Study drug dose selection was based on calibration to an observed ex vivo antiproliferative effect. The primary outcome was clinically significant reduction (>0.25 log10) in the HIV reservoir, measured by total and intact HIV DNA per million T cells in blood over 48 weeks. Results: Five participants enrolled in the trial. Four participants took mycophenolate mofetil (MMF). One had a per-protocol switch to enteric-coated mycophenolate sodium (Myfortic) due to nausea but left the study for personal reasons. One participant developed finger cellulitis, but there were no opportunistic infections. In the 4 participants who completed the protocol, there was no clinically significant reduction in total or intact HIV DNA. There was no change in blood CD4+ T-cell subset composition within the HIV reservoir or the entire CD4+ T-cell population, although total CD4+ T cells decreased slightly in all 4 participants. An ex vivo antiproliferative effect was observed using participant serum obtained 1 hour after dosing, but this effect was severely diminished at drug trough. Conclusions: Mycophenolate given over 48 weeks did not reduce the volume or composition of the HIV reservoir. Clinical Trials registration: NCT03262441.

Surgeon-anatomist to robotic technician? The evolving role of the surgeon over three centuries.

In the 18th century, anatomy was the principal science underlying surgical practice. Over the next three centuries, the scientific basis of surgery changed dramatically. Morbid anatomy led to the understanding of organ-based pathologies that allowed surgeons to remove, reconstruct and in some cases replace internal organs. In the 19th century, the new science of microbiology facilitated antisepsis, then asepsis as surgery progressed from a craft to a scientific discipline. Yet many surgeons believed that surgery was not merely a science but also an art, in which the creativity of the doctor was necessary for progress. Surgical advancement depended on creative individuals with innovative flair, prepared to pioneer often risky procedures in the face of mainstream opposition. The 20th century saw a series of changes that made such individualism more difficult. 'Scientific Management' when applied to surgery decreed that procedures be performed according to predetermined schedules, a drive to uniformity producing better outcomes and diminishing individual variation. Yet inventive individuals continued to produce surgical advances. In the 21st century, moves toward standardisation developed further. The escalating safety culture in surgery moderates the introduction of novel, potentially riskier procedures, while more and more regulation increasingly requires surgeons to adhere to guidelines and protocols, further restricting surgical individualism. Moreover, the role of the individual is further diminished, as surgical care is delivered by teams, both in deciding management in major cases and in the operating theatre. The introduction of robotics into surgery has led to the suggestion that the role of the surgeon may become that of a technician. Will these constraints, and greater patient involvement in decisions, allow tomorrow's surgeons the freedom to innovate? We believe that the pioneering spirit, imagination and flair will not be lost. Tomorrow's surgeons must remain doctors, showing the compassion and empathy that robots cannot provide.

Changes in concentrations of cervicovaginal immune mediators across the menstrual cycle: a systematic review and meta-analysis of individual patient data.

BACKGROUND: Hormonal changes during the menstrual cycle play a key role in shaping immunity in the cervicovaginal tract. Cervicovaginal fluid contains cytokines, chemokines, immunoglobulins, and other immune mediators. Many studies have shown that the concentrations of these immune mediators change throughout the menstrual cycle, but the studies have often shown inconsistent results. Our understanding of immunological correlates of the menstrual cycle remains limited and could be improved by meta-analysis of the available evidence. METHODS: We performed a systematic review and meta-analysis of cervicovaginal immune mediator concentrations throughout the menstrual cycle using individual participant data. Study eligibility included strict definitions of the cycle phase (by progesterone or days since the last menstrual period) and no use of hormonal contraception or intrauterine devices. We performed random-effects meta-analyses using inverse-variance pooling to estimate concentration differences between the follicular and luteal phases. In addition, we performed a new laboratory study, measuring select immune mediators in cervicovaginal lavage samples. RESULTS: We screened 1570 abstracts and identified 71 eligible studies. We analyzed data from 31 studies, encompassing 39,589 concentration measurements of 77 immune mediators made on 2112 samples from 871 participants. Meta-analyses were performed on 53 immune mediators. Antibodies, CC-type chemokines, MMPs, IL-6, IL-16, IL-1RA, G-CSF, GNLY, and ICAM1 were lower in the luteal phase than the follicular phase. Only IL-1α, HBD-2, and HBD-3 were elevated in the luteal phase. There was minimal change between the phases for CXCL8, 9, and 10, interferons, TNF, SLPI, elafin, lysozyme, lactoferrin, and interleukins 1ß, 2, 10, 12, 13, and 17A. The GRADE strength of evidence was moderate to high for all immune mediators listed here. CONCLUSIONS: Despite the variability of cervicovaginal immune mediator measurements, our meta-analyses show clear and consistent changes during the menstrual cycle. Many immune mediators were lower in the luteal phase, including chemokines, antibodies, matrix metalloproteinases, and several interleukins. Only interleukin-1α and beta-defensins were higher in the luteal phase. These cyclical differences may have consequences for immunity, susceptibility to infection, and fertility. Our study emphasizes the need to control for the effect of the menstrual cycle on immune mediators in future studies.