Phenotypically Silent Bone Morphogenetic Protein Receptor 2 Mutations Predispose Rats to Inflammation-Induced Pulmonary Arterial Hypertension by Enhancing the Risk for Neointimal Transformation.

BACKGROUND: Bmpr2 (bone morphogenetic protein receptor 2) mutations are critical risk factors for hereditary pulmonary arterial hypertension (PAH) with approximately 20% of carriers developing disease. There is an unmet medical need to understand how environmental factors, such as inflammation, render Bmpr2 mutants susceptible to PAH. Overexpressing 5-LO (5-lipoxygenase) provokes lung inflammation and transient PAH in Bmpr2+/- mice. Accordingly, 5-LO and its metabolite, leukotriene B4, are candidates for the second hit. The purpose of this study was to determine how 5-LO-mediated pulmonary inflammation synergized with phenotypically silent Bmpr2 defects to elicit significant pulmonary vascular disease in rats. METHODS: Monoallelic Bmpr2 mutant rats were generated and found phenotypically normal for up to 1 year of observation. To evaluate whether a second hit would elicit disease, animals were exposed to 5-LO-expressing adenovirus, monocrotaline, SU5416, SU5416 with chronic hypoxia, or chronic hypoxia alone. Bmpr2-mutant hereditary PAH patient samples were assessed for neointimal 5-LO expression. Pulmonary artery endothelial cells with impaired BMPR2 signaling were exposed to increased 5-LO-mediated inflammation and were assessed for phenotypic and transcriptomic changes. RESULTS: Lung inflammation, induced by intratracheal delivery of 5-LO-expressing adenovirus, elicited severe PAH with intimal remodeling in Bmpr2+/- rats but not in their wild-type littermates. Neointimal lesions in the diseased Bmpr2+/- rats gained endogenous 5-LO expression associated with elevated leukotriene B4 biosynthesis. Bmpr2-mutant hereditary PAH patients similarly expressed 5-LO in the neointimal cells. In vitro, BMPR2 deficiency, compounded by 5-LO-mediated inflammation, generated apoptosis-resistant and proliferative pulmonary artery endothelial cells with mesenchymal characteristics. These transformed cells expressed nuclear envelope-localized 5-LO consistent with induced leukotriene B4 production, as well as a transcriptomic signature similar to clinical disease, including upregulated nuclear factor Kappa B subunit (NF-κB), interleukin-6, and transforming growth factor beta (TGF-ß) signaling pathways. The reversal of PAH and vasculopathy in Bmpr2 mutants by TGF-ß antagonism suggests that TGF-ß is critical for neointimal transformation. CONCLUSIONS: In a new 2-hit model of disease, lung inflammation induced severe PAH pathology in Bmpr2+/- rats. Endothelial transformation required the activation of canonical and noncanonical TGF-ß signaling pathways and was characterized by 5-LO nuclear envelope translocation with enhanced leukotriene B4 production. This study offers an explanation of how an environmental injury unleashes the destructive potential of an otherwise silent genetic mutation.

Personalized transcriptome signatures in a cardiomyopathy stem cell biobank.

BACKGROUND: There is growing evidence that pathogenic mutations do not fully explain hypertrophic (HCM) or dilated (DCM) cardiomyopathy phenotypes. We hypothesized that if a patient's genetic background was influencing cardiomyopathy this should be detectable as signatures in gene expression. We built a cardiomyopathy biobank resource for interrogating personalized genotype phenotype relationships in human cell lines. METHODS: We recruited 308 diseased and control patients for our cardiomyopathy stem cell biobank. We successfully reprogrammed PBMCs (peripheral blood mononuclear cells) into induced pluripotent stem cells (iPSCs) for 300 donors. These iPSCs underwent whole genome sequencing and were differentiated into cardiomyocytes for RNA-seq. In addition to annotating pathogenic variants, mutation burden in a panel of cardiomyopathy genes was assessed for correlation with echocardiogram measurements. Line-specific co-expression networks were inferred to evaluate transcriptomic subtypes. Drug treatment targeted the sarcomere, either by activation with omecamtiv mecarbil or inhibition with mavacamten, to alter contractility. RESULTS: We generated an iPSC biobank from 300 donors, which included 101 individuals with HCM and 88 with DCM. Whole genome sequencing of 299 iPSC lines identified 78 unique pathogenic or likely pathogenic mutations in the diseased lines. Notably, only DCM lines lacking a known pathogenic or likely pathogenic mutation replicated a finding in the literature for greater nonsynonymous SNV mutation burden in 102 cardiomyopathy genes to correlate with lower left ventricular ejection fraction in DCM. We analyzed RNA-sequencing data from iPSC-derived cardiomyocytes for 102 donors. Inferred personalized co-expression networks revealed two transcriptional subtypes of HCM. The first subtype exhibited concerted activation of the co-expression network, with the degree of activation reflective of the disease severity of the donor. In contrast, the second HCM subtype and the entire DCM cohort exhibited partial activation of the respective disease network, with the strength of specific gene by gene relationships dependent on the iPSC-derived cardiomyocyte line. ADCY5 was the largest hubnode in both the HCM and DCM networks and partially corrected in response to drug treatment. CONCLUSIONS: We have a established a stem cell biobank for studying cardiomyopathy. Our analysis supports the hypothesis the genetic background influences pathologic gene expression programs and support a role for ADCY5 in cardiomyopathy.

Cost comparison of adverse event management among breast and ovarian cancer patients treated with poly (ADP-ribose) polymerase inhibitors: analysis based on phase 3 clinical trials.

Background: The economic impact of adverse events (AEs) for poly (ADP-ribose) polymerase inhibitors (PARPis) in ovarian or breast cancer has not been widely evaluated. Objective: Compare PARPi-related AE management costs from a US payer perspective. Methods: The frequency of treatment-related grade 3-4 AEs was obtained from published clinical trials of PARPis for the treatment of advanced ovarian cancer (AOC), platinum-sensitive recurrent ovarian cancer (PSROC), and metastatic breast cancer (MBC). AE management costs per patient (2020 USD) per treatment course were calculated by multiplying the AE unit costs by the frequency of AEs for each arm of each trial. Sensitivity analyses were conducted according to the lower and upper limits of the 95% confidence interval for AE rates and unit costs, respectively. Scenarios were also performed to explore the uncertainty of outcomes. Results: Total AE management costs in AOC were: $3,904, olaparib; $5,595, olaparib plus bevacizumab; and $12,215, niraparib. In PSROC, total costs were: $3,894, olaparib; $6,001, rucaparib; and $11,492, niraparib, and in MBC: $3,574, olaparib; and $9,489, talazoparib. Hematological toxicities were the key drivers of AE management costs for PARPis. Conclusions: The main AEs among PARPis were hematological. Olaparib was associated with lower AE costs compared to other PARPis.

Real-world treatment patterns and outcomes in small-cell lung cancer: a systematic literature review.

BACKGROUND: Small-cell lung cancer (SCLC) accounts for 12-15% of lung cancers and is associated with poor survival outcomes and high symptom burden. This study employed a broad, systematic search strategy and timeframe to identify evidence on real-world treatment patterns and outcomes for SCLC outside the USA, including understanding sub-populations such as extensive-stage (ES) or limited-stage (LS) disease. METHODS: Databases (MEDLINE, Embase, and EBM reviews) were searched for journal articles published in the English language between 1 January 2000-1 March 2020 and supplemented by hand searching of conference abstracts and posters presented at conferences between 1 January 2016-1 March 2020 reporting real-world treatment outcomes in patients with SCLC. A targeted clinical guideline review was also completed. RESULTS: One-hundred studies provided quantitative data; 57 were available as full-text articles, whilst the remaining 43 were presented as abstracts or posters. The majority (80 studies, 80%) of included studies reported treatment in the first-line setting, where platinum-based chemotherapy and chemoradiotherapy was the most commonly used treatment strategy, in line with current treatment guidelines in SCLC. First-line treatments were found to have a high response rate; however, most patients relapsed early. No studies reported treatment or outcomes with immune-oncology therapies. Second-line treatment options were very limited, and primarily consisted of either re-treatment with first-line regimen or topotecan, but the prognosis for these patients remained poor. Outcomes were particularly poor amongst those with ES or relapsed disease vs. LS disease. CONCLUSIONS: SCLC treatment patterns and short survival outcomes have remained constant over the previous 20 years. Due to the search timeframe, none of the studies identified reported on the impact of recently approved immune-oncology therapies in SCLC. Further data is needed on the impact of immunotherapies on treatment patterns and real-world outcomes in SCLC.

Patient preferences and experiences regarding thrombopoietin-receptor agonists for immune thrombocytopenia in the United Kingdom and Ireland (TRAPeze UK & IE study).

OBJECTIVES: To establish the experiences with and preferences towards existing thrombopoietin-receptor agonist (TPO-RA) treatments of individuals with immune thrombocytopenia (ITP) in the UK and Ireland, based on treatment attributes. METHODS: Responses from UK and Ireland individuals with ITP were collected in a pan-European online survey (TRAPeze, [Thrombopoietin-Receptor Agonist Patient experience survey]) from 18 September 2020 to 18 February 2021. TRAPeze was a survey of treatment preference regarding TPO-RAs (using a discrete choice experiment design), participant demographics, disease characteristics, treatment history, overall satisfaction with therapy, direct healthcare resource utilization and wider social impact. RESULTS: The survey was completed by 32 UK respondents. Characteristics with the greatest influence on preference towards TPO-RA treatments were method of administration (odds ratio (OR) 5.6, 95% confidence interval (CI) 3.2-10.1) and drug-food interactions (OR 3.2, 95% CI 1.8-5.7). Particularly, participants were more likely to select an oral tablet over a subcutaneous injection (OR 7.4, 95% CI 3.6-15.1) and a treatment without food restrictions rather than with food restrictions (OR 3.6, 95% CI 1.8-6.8). CONCLUSION: This is the first study to quantify the preference of individuals with ITP towards TPO-RA treatment attributes and demonstrates preference for orally administered treatments, without drug-food interactions.

A Review of the Important Role of CYP2D6 in Pharmacogenomics.

Cytochrome P450 2D6 (CYP2D6) is a critical pharmacogene involved in the metabolism of ~20% of commonly used drugs across a broad spectrum of medical disciplines including psychiatry, pain management, oncology and cardiology. Nevertheless, CYP2D6 is highly polymorphic with single-nucleotide polymorphisms, small insertions/deletions and larger structural variants including multiplications, deletions, tandem arrangements, and hybridisations with non-functional CYP2D7 pseudogenes. The frequency of these variants differs across populations, and they significantly influence the drug-metabolising enzymatic function of CYP2D6. Importantly, altered CYP2D6 function has been associated with both adverse drug reactions and reduced drug efficacy, and there is growing recognition of the clinical and economic burdens associated with suboptimal drug utilisation. To date, pharmacogenomic clinical guidelines for at least 48 CYP2D6-substrate drugs have been developed by prominent pharmacogenomics societies, which contain therapeutic recommendations based on CYP2D6-predicted categories of metaboliser phenotype. Novel algorithms to interpret CYP2D6 function from sequencing data that consider structural variants, and machine learning approaches to characterise the functional impact of novel variants, are being developed. However, CYP2D6 genotyping is yet to be implemented broadly into clinical practice, and so further effort and initiatives are required to overcome the implementation challenges and deliver the potential benefits to the bedside.

In vitro and in vivo evaluation of cephalosporins for the treatment of Lyme disease.

BACKGROUND: Lyme disease accounts for >90% of all vector-borne disease cases in the United States and affect ~300,000 persons annually in North America. Though traditional tetracycline antibiotic therapy is generally prescribed for Lyme disease, still 10%-20% of patients treated with current antibiotic therapy still show lingering symptoms. METHODS: In order to identify new drugs, we have evaluated four cephalosporins as a therapeutic alternative to commonly used antibiotics for the treatment of Lyme disease by using microdilution techniques like minimum inhibitory concentration (MIC) and the minimum bactericidal concentration (MBC). We have determined the MIC and MBC of four drugs for three Borrelia burgdorferi s.s strains namely CA8, JLB31 and NP40. The binding studies were performed using in silico analysis. RESULTS: The MIC order of the four drugs tested is cefoxitin (1.25 µM/mL) > cefamandole (2.5 µM/mL), > cefuroxime (5 µM/mL) > cefapirin (10 µM/mL). Among the drugs that are tested in this study using in vivo C3H/HeN mouse model, cefoxitin effectively kills B. burgdorferi. The in silico analysis revealed that all four cephalosporins studied binds effectively to B. burgdorferi proteins, SecA subunit penicillin-binding protein (PBP) and Outer surface protein E (OspE). CONCLUSION: Based on the data obtained, cefoxitin has shown high efficacy killing B. burgdorferi at concentration of 1.25 µM/mL. In addition to it, cefoxitin cleared B. burgdorferi infection in C3H/HeN mice model at 20 mg/kg.

Transfer of communication skills training from workshop to workplace: the impact of clinical supervision.

OBJECTIVE: Recent studies have recognised that the communication skills learned in the training environment are not always transferred back into the clinical setting. This paper reports a study which investigated the potential of clinical supervision in enhancing the transfer process. METHODS: A randomised controlled trial was conducted involving 61 clinical nurse specialists. All attended a 3-day communication skills training workshop. Twenty-nine were then randomised to 4 weeks of clinical supervision, aimed at facilitating transfer of newly acquired skills into practice. Assessments, using real and simulated patients, were carried out before the course, immediately after the supervision period and 3 months later. Interviews were rated objectively using the Medical Interview Aural Rating Scale (MIARS) to assess nurses' ability to use key skills, respond to patient cues and identify patient concerns. RESULTS: Assessments with simulated patients showed that the training programme was extremely effective in changing competence in all three key areas. However, only those who experienced supervision showed any evidence of transfer. Improvements were found in the supervised groups' use of open questions, negotiation and psychological exploration. Whilst neither group facilitated more disclosure of cues or concerns, those in the experimental group responded more effectively to the cues disclosed, reduced their distancing behaviour and increasing their exploration of cues. CONCLUSIONS: The study has shown that whilst training enhances skills, without intervention, it may have little effect on clinical practice. The potential role of clinical supervision as one way of enhancing the clinical effectiveness of communication skills training programmes has been demonstrated. PRACTISE IMPLICATIONS: This study raises questions about the effectiveness of training programmes which do not incorporate a transfer element, and provides evidence to support the need for clinical supervision for clinical nurse specialist.

Identifying the concerns of women undergoing chemotherapy.

This cross-sectional study aimed to identify key concerns of cancer patients receiving in-patient chemotherapy, determine the prevalence of anxiety and depression, and assess whether ward nurses could identify patients' concerns. Thirty-three women on a chemotherapy ward in the northwest of England who had breast, ovarian, cervical or uterine cancer were interviewed using a Concerns Checklist and the Hospital Anxiety and Depression Scale. Patients expressed an average of 10.3 concerns (range: 2-27). Eighty percent of these were not identified by the nurses, who showed a clear bias towards physical symptoms and treatment-related concerns. The nurses were unable to identify the three main concerns in 70% of patients. Twenty-four percent of patients were found to be probable cases of anxiety and/or depression; there was a moderate correlation between the number of concerns and levels of anxiety and depression. Given the body of evidence that lack of identification of concerns leads to unmet needs, increased psychological distress, dissatisfaction with care and possible complaints, this study has provided clear evidence for the need to address this key area of care, and has highlighted the potential of the Concerns Checklist in busy clinical environments.

Managing the difficult consultation.

Patients are more likely to develop psychological problems if their concerns are unresolved and their information needs unmet. However, many health professionals are uncertain how to elicit patients' concerns or tailor information appropriately. These difficulties may also lead to psychological problems for the health professional. Feeling inadequately trained in communication skills has been linked to burnout amongst senior doctors working in cancer. Clinicians find that some consultations are particularly hard to manage; for example, when patients are highly distressed, angry, withdrawn or in denial. Barriers to effective communication are patient-led as well as doctor- or nurse-led but relevant training can help overcome those barriers. The article described one training model that is effective in improving health professionals' skills. Specific strategies are suggested that can help in the more difficult consultations and so enable clinicians to talk to patients about their concerns and worries more freely.

Giving feedback to learners in the practice.

BACKGROUND: Many general practitioners accept vocational registrars and medical students into their practice. Giving feedback to students on their work performance is an essential component of teaching in general OBJECTIVE: This article examines the central role of feedback in the teaching of medical students and registrars and provides practical guidelines on how to provide feedback in the setting of a busy general practice, describes some barriers and pitfalls, and provides a registrar's perspective on what learners see as important. DISCUSSION: For feedback to be effective, it must be given in a supportive environment. Feedback that is specific to the learner performance is highly valued by learners, whereas nonspecific evaluative feedback is less valued. The mentoring relationship between teacher and learner is crucial to giving effective feedback. Learners appreciate a teacher's help identifying any area for improvement, then being given the chance to work out the answers for themselves instead of being told exactly what to do by the more experienced teacher.

A patient-centred approach to defining and assessing interviewing competency.

The inclusion of communication skills as a core competency in health care curricula, has led to the need to define adequacy in this area. Developments in the field of interview analysis have meant that robust and objective ways of assessing interview behaviours are now available; however, these systems in themselves do not provide a model for assessing competency. As adequacy in interviewing is contextually driven, this paper discusses the potential of using patient centeredness to address the issue. It suggests two ways in which patient centeredness may be operationally defined, permitting data available from current rating systems, and from a new system shortly to be available, to be used to assess interviewing competency.

Can oncology nurses treat depression? A pilot project.

BACKGROUND: Depression is a common problem in all medically ill populations. Reported prevalence rates of major depression in patients with cancer are up to 50%. Cancer patients attending primary care and medical outpatient clinics with comorbid major depressive disorder frequently do not receive effective treatment. More effective ways of identifying and treating patients with both cancer and depression are therefore urgently required. AIM: The paper reports a study addressing the question of whether oncology nurses can be trained to take on a greater role in the management of major depression in their patients. METHOD: We developed and piloted an intervention that can be delivered by a specially trained oncology nurse. The intervention is multifaceted and based on a problem-solving model. It requires a widening of the role and expertise of specialist nurses. DISCUSSION: The challenges this role presents to the nurses are discussed. We suggest that they must have a varied work programme that is not exclusively about managing depression, that they require adequate peer support and are likely to be most effective when working as part of a multidisciplinary psycho-oncology team. CONCLUSION: We conclude that it is possible to train selected specialist oncology nurses to manage major depression in patients with cancer in the context of an appropriately constituted multidisciplinary team.

Validation of the Cardiovascular Limitations and Symptoms Profile (CLASP) in chronic stable angina.

PURPOSE: This study aimed to establish the reliability, validity, and sensitivity of the Cardiovascular Limitations and Symptoms Profile (CLASP) in a group of patients with chronic stable angina. METHODS: After 226 patients with angina had been recruited, they were randomly allocated to one of three groups: a 10-week hospital-based angina management program (n = 75; men = 56; age = 60 +/- 8 years), routine care (n = 74; men = 52; age = 61 +/- 7 years), and exercise therapy (n = 77; men = 60; age = 60 +/- 7 years). All the patients were assessed with CLASP on two occasions: at baseline and at 10 weeks. The Sickness Impact Profile (SIP), the Hospital Anxiety and Depression Scale (HADS), and the Sleep Problems Questionnaire (SPQ) also were administered at the same time. RESULTS: Significant positive correlations between the actual number of angina episodes and the CLASP angina subscale scores (r =.60, P <.001) were observed. The CLASP subscale scores for shortness of breath (r = -.36; P <.001) and ankle swelling (r = -.24; P <.001) were significantly correlated with the total treadmill time. The CLASP tiredness subscale score showed a significant positive correlation with the SPQ score (r =.48; P <.001). The CLASP subscale scores were significantly correlated with their corresponding SIP subscale scores: the tiredness score with the sleep and rest score (r =.49; P <.001), the social and leisure score with the recreation and pastimes score (r =.41; P <.001), the home score with the home management score (r =.45; P <.001), and the mobility score with the mobility (r =.37; P <.001) and total treadmill time scores (r = -.49; P <.001). CONCLUSIONS: The findings show CLASP to be a reliable, valid, sensitive measure of health-related quality of life in patients with chronic stable angina. Before it can be recommended for all patients with heart disorders, similar data will be required from other diagnostic groups such as patients with heart failure or those who have sustained an acute myocardial infarction.