Lineage-specific detection of residual disease predicts relapse in patients with chronic myeloid leukemia stopping therapy.

ABSTRACT: Patients with chronic myeloid leukemia who are eligible for treatment-free remission (TFR) may still relapse after tyrosine kinase inhibitor (TKI) cessation. There is a need for accurate predictors of outcome to enable patients with a favorable profile to proceed while avoiding futile attempts. Sensitive detection of residual disease in total leukocytes at treatment cessation is associated with relapse but is not highly discriminatory, likely because it is a composite measure of residual leukemia derived from different cell lineages, whereas only some lineages are relevant for relapse. We prospectively measured BCR::ABL1 DNA as a predictive yes/no binary test in 5 cellular fractions from 48 patients meeting conventional criteria for TKI discontinuation. The median BCR::ABL1 DNA level was higher in granulocytes and T cells, but not in other lineages, in patients who relapsed. Among the 40 patients undergoing their first TFR attempt, we defined 3 groups with differing relapse risk: granulocyte-positive group (100%), granulocyte-negative/T-cell-positive group (67%), and granulocyte-negative /T-cell-negative group (25%). These data show the critical importance of lineage-specific assessment of residual disease in the selection of patients who can attempt to achieve TFR with a high expectation of success and, concurrently, defer patients who have a high probability of relapse.

A systems immunology study comparing innate and adaptive immune responses in adults to COVID-19 mRNA and adenovirus vectored vaccines.

Identifying the molecular mechanisms that promote optimal immune responses to coronavirus disease 2019 (COVID-19) vaccination is critical for future rational vaccine design. Here, we longitudinally profile innate and adaptive immune responses in 102 adults after the first, second, and third doses of mRNA or adenovirus-vectored COVID-19 vaccines. Using a multi-omics approach, we identify key differences in the immune responses induced by ChAdOx1-S and BNT162b2 that correlate with antigen-specific antibody and T cell responses or vaccine reactogenicity. Unexpectedly, we observe that vaccination with ChAdOx1-S, but not BNT162b2, induces an adenoviral vector-specific memory response after the first dose, which correlates with the expression of proteins with roles in thrombosis with potential implications for thrombosis with thrombocytopenia syndrome (TTS), a rare but serious adverse event linked to adenovirus-vectored vaccines. The COVID-19 Vaccine Immune Responses Study thus represents a major resource that can be used to understand the immunogenicity and reactogenicity of these COVID-19 vaccines.

The immunotoxicity, but not anti-tumor efficacy, of anti-CD40 and anti-CD137 immunotherapies is dependent on the gut microbiota.

Immune agonist antibodies (IAAs) are promising immunotherapies that target co-stimulatory receptors to induce potent anti-tumor immune responses, particularly when combined with checkpoint inhibitors. Unfortunately, their clinical translation is hampered by serious dose-limiting, immune-mediated toxicities, including high-grade and sometimes fatal liver damage, cytokine release syndrome (CRS), and colitis. We show that the immunotoxicity, induced by the IAAs anti-CD40 and anti-CD137, is dependent on the gut microbiota. Germ-free or antibiotic-treated mice have significantly reduced colitis, CRS, and liver damage following IAA treatment compared with conventional mice or germ-free mice recolonized via fecal microbiota transplant. MyD88 signaling is required for IAA-induced CRS and for anti-CD137-induced, but not anti-CD40-induced, liver damage. Importantly, antibiotic treatment does not impair IAA anti-tumor efficacy, alone or in combination with anti-PD1. Our results suggest that microbiota-targeted therapies could overcome the toxicity induced by IAAs without impairing their anti-tumor activity.

The composition of the gut microbiota following early-life antibiotic exposure affects host health and longevity in later life.

Studies investigating whether there is a causative link between the gut microbiota and lifespan have largely been restricted to invertebrates or to mice with a reduced lifespan because of a genetic deficiency. We investigate the effect of early-life antibiotic exposure on otherwise healthy, normal chow-fed, wild-type mice, monitoring these mice for more than 700 days in comparison with untreated control mice. We demonstrate the emergence of two different low-diversity community types, post-antibiotic microbiota (PAM) I and PAM II, following antibiotic exposure. PAM II but not PAM I mice have impaired immunity, increased insulin resistance, and evidence of increased inflammaging in later life as well as a reduced lifespan. Our data suggest that differences in the composition of the gut microbiota following antibiotic exposure differentially affect host health and longevity in later life.

Pressure ulcer prevalence across Welsh orthopaedic units and community hospitals: surveys based on the European Pressure Ulcer Advisory Panel minimum data set.

The survey used the European Pressure Ulcer Advisory Panel (EPUAP) methodology for the collection of pressure ulcer prevalence data. The orthopaedic survey was conducted across all National Health Service Trusts in Wales between 2 and 6 July 2007 while the community hospital survey covering 25% of all community hospital beds was conducted between 21 April 2008 and 2 May 2008. Data were gathered upon 1196 patients (581, 48.6% within orthopaedic units with 615 located in community hospitals). Of these patients, 81 (13.9%) and 162 (26.7%) had pressure ulcers in orthopaedic and community hospitals, respectively. Where patients presented with multiple pressure ulcers, the most severe pressure ulcer was recorded. Across both surveys, most pressure ulcers were reported to be either category I or II with 91 category I wounds (33 in orthopaedic units and 58 in community hospitals). Severe (categories III and IV) pressure ulcers affected 78 patients (19 in orthopaedic units and 59 in community hospitals). Adoption of the EPUAP pressure ulcer prevalence methods can help achieve consistent data upon pressure ulcer prevalence in different health care organisations and specialities. The adoption of a consistent data collection capture methodology is a clear prerequisite for the compilation of meaningful pressure ulcer prevalence data sets at a national level.

The impact of nurse education on the caring behaviours of nursing students.

This study aimed to ascertain whether nursing students' perceptions of caring behaviours as part of nursing practice change over a three-year, pre-registration, undergraduate nursing course. Students are expected to have a predisposition to care with nurse education nurturing and developing this into professional caring behaviour. However, there is some evidence that this process inures rather than develops these behaviours. This was a quantitative, single cross section survey of two nursing student cohorts from one Higher Education Institution (HEI) in Wales, United Kingdom (UK). There were two sample groups; sample group A were 80 first year students and sample group B were 94 third year students. Students completed a questionnaire incorporating the caring behaviors inventory (CBI) [Wolf, Z.R., Colahan, M., Costello, A., Warwick, F., Ambrose, M.S., Giardino, E.R., 1994. Dimensions of nurse caring. Journal of Nursing Scholarship 26 (2), 107-111]. The key finding was a statistically significant difference in the means in caring behaviours between first years and third years with third years scoring lower than first years. This was exaggerated for those under 26 and increased further for those under 26 with no previous experience of caring. Caring is a core nursing value and a desirable attribute in nursing students, but the educational process seemed to reduce their caring behaviours.

Subcellular curvature at the perimeter of micropatterned cells influences lamellipodial distribution and cell polarity.

This paper employs substrates that are patterned with shapes having well-defined geometric cues to characterize the influence of curvature on the polarization of highly metastatic B16F10 rat melanoma cells. Substrates were patterned using microcontact printing to define adhesive islands of defined shape and size on a background that otherwise prevents cell adhesion. Cells adherent to these surfaces responded to local curvature at the perimeter of the adhesive islands; convex features promoted the assembly of lamellipodia and concave features promoted the assembly of stress filaments. Cells adherent to rectangular shapes displayed a polarized cytoskeleton that increased with the aspect ratio of the shapes. Shapes that combined local geometric cues, by way of concave or convex edges, with aspect ratio were used to understand the additive effects of shape on polarization. The dependence of cell polarity on shape was determined in the presence of small molecules that alter actomyosin contractility and revealed a stronger dependence on contractility for shapes having straight edges, in contrast to those having curved edges. This study demonstrates that the cytoskeleton modulates cell polarity in response to multiple geometric cues in the extracellular environment.

Doing things differently: advantages and disadvantages of Web questionnaires.

For this article, Steve Jones, Fiona Murphy, Mark Edwards and Jane James draw on experiences of delivering a questionnaire to a group of nursing students using the web. Although they encountered problems, this approach to data collection appears to have potential.

Using online questionnaires to conduct nursing research.

This article explores the concept of using online questionnaires to carry out nursing research. It discusses options for nurses who do not have advanced technical IT skills for electronic distribution of survey questionnaires. The general principles of web distribution are explained, and some approaches are evaluated in terms of current access to technology and its ease of use. The article also offers some practical advice for nurse researchers, and examines the advantages and disadvantages of using this new method of data collection, compared with traditional hard copy.

A static-led approach to pressure ulcers: an evaluation after 3 years.

Pressure damage has high cost implications to the patient and care providers. The choice of appropriate equipment to help in the prevention of tissue damage is hampered by extensive choice and little guidance on the most effective product to use. The static-led approach was introduced into Carmarthenshire NHS Trust 3 years ago. This approach simplified the choice of equipment, improving the appropriate usage and reducing expenditure. This article aims to evaluate the approach 3 years after its introduction to determine if the benefits to the patient and the organization still apply.

Pressure area management: a static-led approach.

An increase in expenditure and inappropriate use of pressure-relieving equipment, along with high-prevalence figures, initiated the evaluation of current practice of pressure damage prevention in an acute general hospital. This evaluation started with the organization of a project group, who (after a baseline audit) identified and procured the resources required to introduce and manage an effective pressure damage prevention programme. The investment in high-quality static mattresses for all patients including those who are at high risk of developing pressure damage was based on available clinical evidence. This investment meant a reduction in the amount of dynamic systems needed as many of those patients are at high risk of pressure damage, and are now successfully managed on a static system. The development of a local policy including documentation facilitated regular reassessment of risk level based on a risk assessment tool and clinical rationale. This static-led approach has reduced not only costs but also improved the appropriate allocation of pressure-relieving/reducing equipment. The approach has also simplified the choice of equipment for staff who were previously expected to match patients' needs with varying levels of dynamic mattress efficiency. This article highlights the action taken from the initial identification of a specific need through to the effective implementation, management and monitoring of this innovative practice.

A tool to aid nurses' decision making in relation to dressing selection.

A multidisciplinary formulary group was established to create a standardized approach to wound management throughout Carmarthenshire. It was felt that a tool to aid nurse's decision making in dressing selection might enhance the process of formulary implementation. This article outlines the development of the tool. An action-research approach was chosen to investigate the idea. The project followed a series of cycles consisting of planning, action, data collection and reflection. The first cycle confirmed the need for such a tool. A reference card was produced. As a result of data collected in the second cycle, the card was reproduced with suggested improvements. The improved tool was then evaluated in the third cycle. Minor adjustments and incorporation of the completed Carmarthenshire formulary took place during the fourth cycle. The Carmarthenshire formulary is now in use and accompanied by the reference card.