Once daily cediranib and weekly paclitaxel to prevent malignant bowel obstruction in at-risk patients with platinum-resistant ovarian cancer (CEBOC): a single-arm, phase II safety trial.

OBJECTIVE: Cytotoxic chemotherapy for ovarian cancer can be augmented by co-administration of vascular endothelial growth factor inhibitors but these are contraindicated in patients with bowel obstruction due to the risk of gastrointestinal perforation. We evaluated the safety and feasibility of paclitaxel plus cediranib to treat patients with platinum-resistant ovarian cancer at risk of malignant bowel obstruction. METHODS: A phase II trial included eligible patients between March 2018 and February 2021, identified by clinical symptoms and radiographic risk factors for malignant bowel obstruction. Cediranib (20 mg/day) was added to paclitaxel (70 mg/m2/week) within 9 weeks of starting paclitaxel if pretreatment bowel symptoms had improved. The primary endpoint was the number of patients treated for ≥5 days with cediranib that were free of grade 3-5 gastrointestinal perforation or fistula. Secondary endpoints were hospitalization for bowel obstruction, grade ≥3 adverse events, treatment compliance assessed by relative dose intensity, objective response, progression-free survival, and overall survival. RESULTS: Thirty patients were recruited. Of these, 12 received paclitaxel alone and 17 received paclitaxel and cediranib in combination. One patient died before starting treatment. No patient developed a grade 3-5 gastrointestinal perforation or fistula (one sided 95% confidence interval (CI) upper limit 0.16). One patient required hospitalization for bowel obstruction but recovered with conservative management. The most common cediranib-related grade ≥3 adverse events were fatigue (3/17), diarrhorea (2/17), and hypomagnesemia (2/17). Relative dose intensity for paclitaxel was 90% (interquartile range (IQR) 85-100%; n=29) and for cediranib 88% (IQR 76-93%; n=17). The objective response in patients who received paclitaxel and cediranib was 65.0% (one complete and 10 partial responses). Median progression-free survival was 6.9 months (95% CI 4.4-11.5 months; n=17) and overall survival was 19.4 months (95% CI 10.1-20.4 months; n=17). Median follow-up was 12.4 months (8.9-not reached; n=17). CONCLUSIONS: The unexpectedly high withdrawal rate during paclitaxel alone, before introducing cediranib, meant we were unable to definitely conclude that paclitaxel plus cediranib did not cause gastrointestinal perforation or fistula. The regimen was however tolerated. TRIAL REGISTRATION NUMBER: EudraCT 2016-004618-93.

Medical student perceptions of autism education: A qualitative study.

Background: The global prevalence of autism is reported to be at least 1% and is rising. Autistic people have a range of comorbidities resulting in a high use of health services. Doctors of nearly all specialties are likely to encounter autistic people in their practice. Autistic people report dissatisfactory care and encounter disproportionately worse health-related outcomes than non-autistic people, which in part has been attributed to a lack of skill and awareness in the medical workforce. At present, autism education is not always included in undergraduate medical curricula. In England, the Department of Health and Social Care has mandated that autism education should be included in all undergraduate medical curricula but current evidence relating to the delivery and receipt of autism education is poor. A greater understanding of medical student perceptions of autism education is required to inform curriculum development. This qualitative study sought to explore the perceptions of autism education in final year medical students at a medical school in South-East England by 1) assessing their perceived preparedness to care for autistic people once they have graduated from medical school and 2) determining their perceived acceptability of a new undergraduate education programme, Time for Autism (TfA). Materials and methods: A purposeful sample of ten final-year medical students were recruited. Students completed in-depth, individual interviews. Data was analysed using thematic analysis. Results: Four key themes were identified: Learning environment, Exposure, Relevance and Curricular priority. The findings of this study indicate that medical students perceived greatest value in autism education when it was directly relevant to developing preparedness for practice. Value was influenced by the perceived curricular priority attached to autism education. The new autism programme, Time for Autism was perceived to add relevance and priority to autism education in the existing curriculum in this medical school setting. Discussion: The study findings shed new light on medical education literature, emphasising the importance of congruence between the provision of autism education and the prioritisation of autism education within the curriculum. Consideration of relevance and curricular priority can be used to support the development of autism education in future medical curricula.

Sexually transmitted infections in suspected child sexual abuse.

Making associations between sexually transmitted infections (STIs) and child sexual abuse can be controversial. To contribute to the paucity of research in this field, this service evaluation aims to (1) define the prevalence of STIs in children aged 0-13 years seen at a regional Children's Sexual Assault Referral Centre, (2) determine whether sexual transmission is the most likely mode of transmission for diagnosed STIs, (3) identify factors affecting application of STI screening and (4) assess follow-up. Methods consisted of retrospective analysis of an anonymous database for all patients seen between 1 July 2016 and 1 July 2019. Of 241 children seen, 114/241 (47.3%) received STI screening and 10/114 (8.8%) tested positive (4.1% of children seen overall). No asymptomatic child was diagnosed with an STI. Sexual transmission was the most likely mode of transmission based on child disclosure and physical examination findings for 6/10 children diagnosed with an STI.

The realities and expectations of community involvement in COVID-19 research: a Consumer Reference Group perspective.

BACKGROUND: Older adults have been disproportionately impacted by the COVID-19 pandemic. COVID-19 restrictions such as stay at home orders and physical distancing measures have been implemented to reduce older adults' risk of infection, however, such measures can have negative effects on older adults' mental health and social wellbeing. In 2020, the research team received funding as part of an Australian COVID-19 research grants program to investigate how services can better meet the mental health and social support needs of older adults during COVID-19. A Consumer Reference Group (CRG) was established to provide a community perspective on all research activities. MAIN BODY: The CRG comprised of eight older adults aged 65 years and older living in Western Australia. Two members of the CRG were involved in the initial grant proposal, and one member worked for a not-for-profit organisation that provides support and advocacy for older adults. The CRGs role was to provide consumer and community perspectives on the research design, advise on study materials, facilitate links between consumers, the community, and researchers, and advocate on behalf of consumers and the community. The CRG was encouraged to reflect on the research project, their contributions, and the outcomes obtained. In this commentary, we document the CRGs contributions to the project, and record their reflections, including what went well, what were some challenges, the realities of conducting research during COVID-19, and lessons learnt. CONCLUSION: The CRG were active participants in the research process. They shared their perspectives and made important contributions to the project. Through collaboration with the CRG, we were able to reach four key messages, underpinned by consumers lived experiences, that were used to co-develop knowledge translation products. These were disseminated to service providers and older adults.

Since the start of the COVID-19 pandemic, health and social measures have been introduced to reduce the spread of the virus, including lockdowns, physical distancing, and mask mandates. Older adults (aged 60 years and older) are considered particularly vulnerable to COVID-19 and have therefore faced some of the greatest restrictions to reduce their risk of infection. These restrictions can have a negative effect on older adults social and emotional wellbeing. In 2020 the research team received funding to investigate how services could better meet the mental health and social support needs of older Australians during the pandemic. To enable a community perspective on all research activities, a Consumer Reference Group (CRG) of eight older adults living in Western Australia was established. Two of the eight CRG members were involved in the initial grant proposal. The CRG's role was to share their thoughts on the research design, study materials, and to provide links to and advocate for consumers and the community. This commentary reports reflections from the CRC on what went well, what some of the challenges were, the realities of conducting this research during COVID-19, and what lessons were learnt. Through collaboration with the CRG key messages for the research project were reached and used to inform infographics, which were then disseminated to inform service delivery providers and older adults of the research outcomes.

Developing undergraduate autism education for medical students: a qualitative study.

BACKGROUND: Autistic adults and children experience considerable health inequalities and have high rates of premature mortality, hospital admissions and emergency department visits. This is in part due to a lack of autism awareness in the healthcare and social care workforce. A new educational programme, Time for Autism (TfA), for medical students is being developed to address this challenge. This qualitative study was undertaken to support the development of the new programme in order to (1) understand the medical care experiences of parents of autistic children and (2) assess their views on the acceptability of the new TfA programme and willingness to be involved. METHODS: A convenience sample of 11 parents of autistic children were recruited across the South of England. The ages of the autistic children ranged from 3 to 17 years. Semistructured interviews were completed between October and December 2019. Interview transcripts were analysed using thematic analysis. RESULTS: Three key themes were identified: diagnosis, experiences of doctors and TfA considerations. There was support for and willingness to take part in a dedicated autism education programme for medical students, and constructive feedback to inform and improve its delivery. CONCLUSION: The findings from this study provide insights into the medical care experiences of parents/carers of autistic children. Understanding how parents/carers of autistic children would like medical care to be improved can be used to develop TfA and other autism programmes. Parental/carer support for the development of and involvement in an autism medical education programme enhances the feasibility of the new programme.

Olaparib maintenance versus placebo monotherapy in patients with advanced non-small cell lung cancer (PIN): A multicentre, randomised, controlled, phase 2 trial.

Background: Impaired double strand DNA repair by homologous repair deficiency (HRD) leads to sensitivity to poly ADP ribose polymerase (PARP) inhibition. Poly-ADP ribose polymerase (PARP) inhibitors target HRD to induce synthetic lethality and are used routinely in the treatment of BRCA1 mutated ovarian cancer in the platinum-sensitive maintenance setting. A subset of non-small cell lung cancers (NSCLCs) harbour impaired DNA double strand break repair. We therefore hypothesised that patients with metastatic non-small cell lung cancer exhibiting partial responses to platinum doublet-based chemotherapy, might enrich for impaired HRD, rendering these tumours more sensitive to inhibition of PARP inhibition by olaparib. Methods: The Olaparib Maintenance versus Placebo Monotherapy in Patients with Advanced Non-Small Cell Lung Cancer trial (PIN) was a multicentre double-blind placebo controlled randomised phase II screening trial. This study was conducted at 23 investigative hospital sites in the UK. Patients had advanced (stage IIIB/IV) squamous (Sq) or non-squamous (NSq) NSCLC, and had to be chemo-naive, European Cooperative Oncology Group (ECOG) performance status 0-1. Prior immunotherapy with a PD1 or PDL1 inhibitor was allowed. Patients could be registered for PIN prior to (stage 1), or after (stage 2) initiation of induction chemotherapy. If any tumour shrinkage was observed (any shrinkage of RECIST target lesions), following a minimum of 3 cycles of platinum doublet chemotherapy, patients were randomised 1:1 using a centralised online system, to either olaparib (300 mg twice daily by mouth in 21-day cycles) or placebo, which was continued until disease progression, or unacceptable toxicity. Intention to treat (ITT) analyses of the primary endpoint included all randomised participants. Per protocol (PP) safety analysis included all participants who received at least one dose of study drug. Primary endpoint was progression-free survival (PFS), with a one-sided p-value of 0.2 to demonstrate statistical significance. Hazard ratios (HR) for PFS were both unadjusted and adjusted for the randomisation balancing factors (smoking status and histology). The trial was registered with ClinicalTrials.gov (NCT01788332) and EudraCT (2012-003383-51). Findings: A total of 940 patients were assessed for stage 1 eligibility of whom 263 were registered between Feb 24, 2014 and Nov 7, 2017. 194 patients were excluded prior to stage 2 (no tumour shrinkage or unevaluable) and 70 were randomised; 32 (46%) to Olaparib and 38 (54%) to placebo. 4% (3/70) of patients randomised had a CR and 96% (67/70) had a PR (or other evidence of tumour response/mixed stable) during induction therapy. A total of 36 patients were registered in stage 2 only, i.e., post induction therapy. Intention to treat (ITT) unadjusted analysis showed a PFS hazard ratio (HR) of 0.83 (one-sided 80% CI upper limit 1.03, one-sided unadjusted log rank test p-value=0.23). ITT Cox-adjusted model showed a HR 0.73 (one-sided 80% CI upper limit 0.91, one sided p-value 0.11). Adverse events were reported in 31/32 subjects (97%) in the olaparib arm and 38/38 (100%) in the placebo group. The most commonly reported adverse events in the olaparib group were fatigue (20/31; 65%), nausea (17/31; 55%), anaemia (15/31; 48%) and dyspnea (13/31; 42%). In the placebo group the most common adverse events were fatigue (25/38; 66%), coughing (22/38; 58%), dyspnea (15/38; 39%) and nausea (11/38; 29%). There were no treatment-related deaths. Interpretation: PFS was longer in the olaparib arm, but this did not reach statistical significance. When the PFS HR was adjusted for smoking status and histology, a significant difference at the one-sided 0.2 level was observed, suggesting that tumour control may be achieved for chemosensitive NSCLC treated with PARP monotherapy. We speculate that this signal may be driven by a molecular subgroup harbouring HRD. Funding: This study was funded between AstraZeneca CRUK, National Cancer Research Institute, and Cancer Research UK Feasibility Study Committee.

Hinge disulfides in human IgG2 CD40 antibodies modulate receptor signaling by regulation of conformation and flexibility.

Antibodies protect from infection, underpin successful vaccines and elicit therapeutic responses in otherwise untreatable cancers and autoimmune conditions. The human IgG2 isotype displays a unique capacity to undergo disulfide shuffling in the hinge region, leading to modulation of its ability to drive target receptor signaling (agonism) in a variety of important immune receptors, through hitherto unexplained molecular mechanisms. To address the underlying process and reveal how hinge disulfide orientation affects agonistic activity, we generated a series of cysteine to serine exchange variants in the hinge region of the clinically relevant monoclonal antibody ChiLob7/4, directed against the key immune receptor CD40. We report how agonistic activity varies with disulfide pattern and is afforded by the presence of a disulfide crossover between F(ab) arms in the agonistic forms, independently of epitope, as observed in the determined crystallographic structures. This structural "switch" affects directly on antibody conformation and flexibility. Small-angle x-ray scattering and ensemble modeling demonstrated that the least flexible variants adopt the fewest conformations and evoke the highest levels of receptor agonism. This covalent change may be amenable for broad implementation to modulate receptor signaling in an epitope-independent manner in future therapeutics.

Special Issue "Antibody Engineering for Cancer Immunotherapy".

Since the approval of Rituximab in the late 1990s, the first chimeric monoclonal antibody for the treatment of non-Hodgkin lymphoma, antibody engineering for cancer immunotherapy has become a rapidly growing field, with almost 50 antibody therapeutics approved in the USA and EU and hundreds undergoing testing in clinical trials [...].

An Examination of Factors Associated With Student Resiliency.

BACKGROUND: Student resiliency, success, and retention are top priorities for nursing programs. PURPOSE: The purpose of the cross-sectional descriptive study was to identify factors associated with the resiliency level and physical and mental health of nursing students. METHODS: A cross-sectional descriptive study design was used with a convenience sample of 199 nursing students from organizations that comprise the Community Patient Safety Coalition Nursing Research Consortium. Resiliency was measured with the Connor Davidson Resiliency Scale. Physical and mental health was measured with the Patient Reported Outcomes Measurement Information System Global Health Short Form. RESULTS: Most of the nursing students in the sample were female (92%), White (94%), and in BSN programs (74.4%). Students had low resiliency (P < .0001) and low physical and mental health (P < .0001) compared with the general population. CONCLUSIONS: Student resilience was positively correlated to self-perception of physical and mental health.

A Descriptive Study of Resiliency and Health in Practicing Nurses.

OBJECTIVES: The aim of this study was to identify the degree of resilience and self-perceived physical and mental health in practicing nurses. BACKGROUND: Stressors and challenges of everyday demands influence resilience and well-being in acute care nurses. METHODS: Nurses were surveyed using the Connor-Davidson Resilience Scale and PROMIS Global Health. One sample t test compared the study group to the general population mean of resiliency, physical and mental health scores. Linear regression analysis identified factors associated with resiliency. RESULTS: Of the 859 practicing nurses in the sample, most were female and White, had a BSN or associate of science in nursing degree (55.2%, 30.0%) and more than 10 years of experience (57.1%), and worked in direct patient care (77.0%). Nurses had low resiliency (P < .0001) and physical health (P = .0037). Well-being factors included 2 or more missed days/shifts in 3 months (P < .001), thoughts of quitting (P = .003), and perceptions that workload was too much (P < .001). CONCLUSIONS: Self-perceived physical and mental health was significantly associated with the degree of resilience.

Identifying Patient Strengths Instruments and Examining Their Relevance for Chronic Disease Management: A Systematic Review.

INTRODUCTION: Most health care focuses on patients' deficits to encourage behavior change. A strengths-based approach, which relies on identifying patient strengths, has great potential to facilitate behavior change for chronic disease management. Little is known about instruments used to assess patient strengths. We conducted a systematic review to identify validated instruments that assess personal strengths by using a theory elaboration approach. METHODS: We searched 8 databases including Web of Science, Cumulative Index of Nursing and Allied Health (CINAHL), and PsycINFO (through July 2019) to identify peer reviewed, English-language studies that described strength-based instruments. Thereafter, we evaluated the validity and reliability of the instruments according to 18 Scientific Advisory Committee of the Medical Outcome Trust (SACMOT) criteria, and used an inductive, iterative editing process to identify constructs measured by the instruments. RESULTS: We identified 26 instruments that met our inclusion criteria. The instruments were validated in various clinical and nonclinical populations. Only 4 instruments met most of the SACMOT criteria for validation. We extracted 91 unique constructs that fell into 3 domains: inner strengths (49), external strengths (13), and personality constructs (29). CONCLUSION: A limited number of reliable and valid instruments are available to assess strengths for the adult population, particularly for clinical populations. Internal strengths can be leveraged to improve patient health; however, the development and validation of additional instruments to capture personal strengths is necessary to examine the multilevel influence of external strengths on individual behaviors and well-being.

Depicting "the system": How structural racism and disenfranchisement in the United States can cause dynamics in community violence among males in urban black communities.

BACKGROUND: A complex system of factors interacting across time shapes community violence. It is not well understood how features of persons, institutions and communities interact as a "system" to produce escalating community violence. We aimed to integrate theoretical and experiential knowledge among young African-American urban males to develop a concept model of key causal structures driving dynamics of community violence escalation over time in a context of historical racism. METHODS: We analyzed three published sources (two documentary films and one ethnography) containing lived experience perspectives on community violence escalation among African American males in three U.S. cities experiencing civil unrest due to structural racism. Qualitative descriptive analysis identified features in three key thematic categories: racialized policies and practices, economic and social disenfranchisement, and intrapsychic factors. We used causal loop diagramming, a system dynamics method designed for depicting dynamic hypotheses about the system structure producing observed trends over time, to represent the dynamic relationships among identified individual and community variables. RESULTS: The concept model contained key feedback structures capable of generating exponential growth in violence - providing detailed dynamic hypotheses about how violence can beget more violence ("violence escalation") within a community. Referred to as reinforcing feedback loops, these dynamics involved development of kill-or-be-killed norms, civil unrest emerging from racially oppressive policies, internalizing the code of the streets to seek outward displays of power, and processes that get one "stuck" or not able to break out of the system of violence. CONCLUSIONS: Qualitative system dynamics methods offered an approach to uncover and hypothesize the complex, dynamic relationships between variables shaping violence escalation trends. The resulting causal loop diagram hypothesized dynamic mechanisms capable of creating and perpetuating racial disparities in community violence escalation, that can be tested in future research to inform action to break observed cycles of community violence.

Consolidated Framework for Collaboration Research derived from a systematic review of theories, models, frameworks and principles for cross-sector collaboration.

Cross-sector collaboration is needed to address root causes of persistent public health challenges. We conducted a systematic literature review to identify studies describing theories, models, frameworks and principles for cross-sector collaboration and synthesized collaboration constructs into the Consolidated Framework for Collaboration Research (CFCR). Ninety-five articles were included in the review. Constructs were abstracted from articles and grouped into seven domains within the framework: community context; group composition; structure and internal processes; group dynamics; social capital; activities that influence or take place within the collaboration; activities that influence or take place within the broader community; and activities that influence or take place both in the collaboration and in the community. Community engagement strategies employed by collaborations are discussed, as well as recommendations for using systems science methods for testing specific mechanisms of how constructs identified in the review influence one another. Researchers, funders, and collaboration members can use the consolidated framework to articulate components of collaboration and test mechanisms explaining how collaborations function. By working from a consolidated framework of collaboration terms and using systems science methods, researchers can advance evidence for the efficacy of cross-sector collaborations.

Isotype Switching Converts Anti-CD40 Antagonism to Agonism to Elicit Potent Antitumor Activity.

Anti-CD40 monoclonal antibodies (mAbs) comprise agonists and antagonists, which display promising therapeutic activities in cancer and autoimmunity, respectively. We previously showed that epitope and isotype interact to deliver optimal agonistic anti-CD40 mAbs. The impact of Fc engineering on antagonists, however, remains largely unexplored. Here, we show that clinically relevant antagonists used for treating autoimmune conditions can be converted into potent FcγR-independent agonists with remarkable antitumor activity by isotype switching to hIgG2. One antagonist is converted to a super-agonist with greater potency than previously reported highly agonistic anti-CD40 mAbs. Such conversion is dependent on the unique disulfide bonding properties of the hIgG2 hinge. This investigation highlights the transformative capacity of the hIgG2 isotype for converting antagonists to agonists to treat cancer.

Asking young Aboriginal people who use illicit drugs about their healthcare preferences using audio-computer-assisted self-interviewing.

INTRODUCTION AND AIMS: Substance use significantly contributes to increasing the disease burden experienced by young Aboriginal and Torres Strait Islander (Aboriginal) Australians. Little is known about the primary healthcare needs of young Aboriginal people who use drugs. The aim of this study was to pilot Audio Computer Assisted Self-Interviewing (ACASI) as a method of asking young Aboriginal people who use illicit drugs about their health concerns and service preferences, in inner-Sydney, New South Wales. DESIGN AND METHODS: We employed a sequential mixed methods exploratory study design. Qualitative data was collected using a focus group and in-depth interviews. These findings informed the development of the ACASI survey, which asked questions on substance use, health concerns, health service usage, barriers and preferences for services. Recruitment sites included youth and health services. Qualitative results were analysed thematically, and survey results using descriptive statistics. RESULTS: Eight people participated in the focus group and two in in-depth interviews. Of the 38 survey respondents, 68% reported illicit drug use. Reported barriers to service access included waiting time and services seeming unfriendly or not understanding Aboriginal people. Participants expressed preferences for Aboriginal-friendly health services that provide internet access, literacy skill development and opportunities to learn about Aboriginal culture. Participants found the ACASI survey user-friendly. DISCUSSION AND CONCLUSIONS: This is the first report describing health concerns and service preferences of young Aboriginal people who use illicit drugs. The ACASI survey appears to be an appropriate and efficient approach to giving a voice to young Aboriginal people.

How does measurement of platelet P-selectin compare with other methods of measuring platelet function as a means of determining the effectiveness of antiplatelet therapy?

Measurement of P-selectin on activated platelets as a means of measuring platelet function utilizing the technology described here has the advantage of not requiring immediate access to specialist equipment and expertise. Blood samples are activated, fixed, stored, and transported to a central laboratory for flow cytometric analysis. Here we have compared P-selectin with other more traditional approaches to measuring platelet function in blood and/or platelet-rich plasma (PRP) from patients with acute coronary syndromes on treatment for at least 1 month with either aspirin and clopidogrel or aspirin with prasugrel. The comparators were light transmission aggregometry (LTA), VerifyNow and Multiplate aggregometry (for determining the effects of aspirin) and LTA, VerifyNow and Multiplate together with the BioCytex VASP phosphorylation assay (for the P2Y12 antagonists). The P-selectin Aspirin Test revealed substantial inhibition of platelet function in all but three of 96 patients receiving aspirin with clopidogrel and in none of 51 patients receiving aspirin and prasugrel. The results were very similar to those obtained using LTA. There was only one patient with high residual platelet aggregation and low P-selectin expression. The same patients identified as "non-responders" to aspirin also presented with the highest residual platelet activity as measured using the VerifyNow system, although not quite as well separated from the other values. With the Multiplate test only one of these patients clearly stood out from the others. The results obtained using the P-selectin P2Y12 Test in 102 patients taking aspirin and clopidogrel were similar to the more traditional approaches in that a wide scatter of results was obtained. Generally, high values seen with the P-selectin P2Y12 Test were also high with the LTA, VerifyNow, Multiplate, and BioCytex VASP P2Y12 Tests. Similarly, low residual platelet function using the P2Y12 test was seen irrespective of the testing procedure used. However, there were differences in some patients. Prasugrel was always more effective than clopidogrel in inhibiting platelet function with none of 56 patients (P-selectin and VerifyNow), only 2 of 56 patients (Multiplate) and only 3 of 56 patients (Biocytex VASP) demonstrating high on-treatment residual platelet reactivity (HRPR) defined using previously published cut-off values. The exception was LTA where there were 11 of 56 patients with HRPR. It remains to be seen which experimental approach provides the most useful information regarding outcomes after adjusting therapies in treated patients.

Complex Interplay between Epitope Specificity and Isotype Dictates the Biological Activity of Anti-human CD40 Antibodies.

Anti-CD40 monoclonal antibodies (mAbs) that promote or inhibit receptor function hold promise as therapeutics for cancer and autoimmunity. Rules governing their diverse range of functions, however, are lacking. Here we determined characteristics of nine hCD40 mAbs engaging epitopes throughout the CD40 extracellular region expressed as varying isotypes. All mAb formats were strong agonists when hyper-crosslinked; however, only those binding the membrane-distal cysteine-rich domain 1 (CRD1) retained agonistic activity with physiological Fc gamma receptor crosslinking or as human immunoglobulin G2 isotype; agonistic activity decreased as epitopes drew closer to the membrane. In addition, all CRD2-4 binding mAbs blocked CD40 ligand interaction and were potent antagonists. Thus, the membrane distal CRD1 provides a region of choice for selecting CD40 agonists while CRD2-4 provides antagonistic epitopes.

A Spiritual Care Toolkit: An evidence-based solution to meet spiritual needs.

AIMS AND OBJECTIVES: To determine differences between baseline spiritual perspectives of nurses, patients and their families and examine the effectiveness of a spiritual care (SC) toolkit as an intervention to facilitate meeting spiritual needs of hospitalised patients and families. BACKGROUND: Provision of SC by nurses in the acute care environment is an issue of high priority for patients. Nurses report lack of time, comfort, training, cultural knowledge and mobilisation of resources as obstacles to SC delivery. Evidence points to positive patient outcomes and patient satisfaction, yet few studies include interventions to help nurses meet spiritual needs of patients and families. DESIGN: Descriptive and quasi-experimental design. METHODS: Patients, family members (n = 132) and nurses (n = 54) were administered SC surveys while hospitalised on two acute care units of a Midwest hospital system in the United States. Population represented patients suffering acute, chronic and terminal illness. Data collected over a 13-week period examined relationships between the groups spiritual perspectives and the effectiveness of a SC toolkit intervention. RESULTS: Significant differences between nurse-patient and nurse-family groups were found, whereas no significant differences existed between patient-family groups. A pretest-posttest revealed the SC toolkit aided in overcoming obstacles to nurses' SC delivery. Patients and their family members found the SC toolkit helpful. CONCLUSIONS: Findings suggest an evidence-based SC toolkit has the propensity to help nurses meet spiritual needs of hospitalised patients and families. However, successful implementation and sustainability require organisational support, funding for resources and SC training for staff. RELEVANCE TO CLINICAL PRACTICE: A SC toolkit supplied with culturally sensitive faith resources supporting what patients and families value, believe and practice can be easily customised and implemented by any healthcare organisation in the world. Further investigation of SC toolkit effectiveness using multiple sites is recommended.

The Use of Anti-CD40 mAb in Cancer.

Immunomodulatory monoclonal antibody (mAb) therapy is at the forefront of developing cancer therapeutics with numerous targeted agents proving highly effective in selective patients at stimulating protective host immunity, capable of eradicating established tumours and leading to long-term disease-free states. The cell surface marker CD40 is expressed on a range of immune cells and transformed cells in malignant states whose signalling plays a critical role in modulating adaptive immune responses. Anti-CD40 mAb therapy acts via multiple mechanisms to stimulate anti-tumour immunity across a broad range of lymphoid and solid malignancies. A wealth of preclinical research in this field has led to the successful development of multiple anti-CD40 mAb agents that have shown promise in early-phase clinical trials. Significant progress has been made to enhance the engagement of antibodies with immune effectors through their interactions with Fcγ receptors (FcγRs) by the process of Fc engineering. As more is understood about how to best optimise these agents, principally through the fine-tuning of mAb structure and choice of synergistic partnerships, our ability to generate robust, clinically beneficial anti-tumour activity will form the foundation for the next generation of cancer therapeutics.

Understanding Discourse on Work and Job-Related Well-Being in Public Social Media.

We construct a humans-in-the-loop supervised learning framework that integrates crowdsourcing feedback and local knowledge to detect job-related tweets from individual and business accounts. Using data-driven ethnography, we examine discourse about work by fusing language-based analysis with temporal, geospational, and labor statistics information.