A matching-adjusted indirect comparison of combination nivolumab plus ipilimumab with BRAF plus MEK inhibitors for the treatment of BRAF-mutant advanced melanoma☆.

BACKGROUND: Approved first-line treatments for patients with BRAF V600-mutant advanced melanoma include nivolumab (a programmed cell death protein 1 inhibitor) plus ipilimumab (a cytotoxic T lymphocyte antigen-4 inhibitor; NIVO+IPI) and the BRAF/MEK inhibitors dabrafenib plus trametinib (DAB+TRAM), encorafenib plus binimetinib (ENCO+BINI), and vemurafenib plus cobimetinib (VEM+COBI). Results from prospective randomized clinical trials (RCTs) comparing these treatments have not yet been reported. This analysis evaluated the relative efficacy and safety of NIVO+IPI versus DAB+TRAM, ENCO+BINI, and VEM+COBI in patients with BRAF-mutant advanced melanoma using a matching-adjusted indirect comparison (MAIC). PATIENTS AND METHODS: A systematic literature review identified RCTs for DAB+TRAM, ENCO+BINI, and VEM+COBI in patients with BRAF-mutant advanced melanoma. Individual patient-level data for NIVO+IPI were derived from the phase III CheckMate 067 trial (BRAF-mutant cohort) and restricted to match the inclusion/exclusion criteria of the comparator trials. Treatment effects for overall survival (OS) and progression-free survival (PFS) were estimated using Cox proportional hazards and time-varying hazard ratio (HR) models. Safety outcomes (grade 3 or 4 treatment-related adverse events) with NIVO+IPI and the comparators were compared. RESULTS: In the Cox proportional hazards analysis, NIVO+IPI showed improved OS compared with DAB+TRAM (HR = 0.53; 95% confidence interval [CI], 0.39-0.73), ENCO+BINI (HR = 0.60; CI, 0.42-0.85), and VEM+COBI (HR = 0.50; CI, 0.36-0.70) for the overall study period. In the time-varying analysis, NIVO+IPI was associated with significant improvements in OS and PFS compared with the BRAF/MEK inhibitors 12 months after treatment initiation. There were no significant differences between NIVO+IPI and BRAF/MEK inhibitor treatment from 0 to 12 months. Safety outcomes favored DAB+TRAM over NIVO+IPI, whereas NIVO+IPI was comparable to VEM+COBI. CONCLUSION: Results of this MAIC demonstrated durable OS and PFS benefits for patients with BRAF-mutant advanced melanoma treated with NIVO+IPI compared with BRAF/MEK inhibitors, with the greatest benefits noted after 12 months.

Optimizing surgery of metaphyseal-diaphyseal fractures of the fifth metatarsal: a cadaveric study on implications of intramedullary screw position, screw parameters and surrounding anatomic structures.

AIMS: Many advocate screw fixation of fractures to the metaphyseal-diaphyseal junction of the fifth metatarsal base, better known as Jones fractures (JF), to facilitate quicker ambulation and return to sport. Maximizing screw parameters based on fifth metatarsal (MT5) anatomy, alongside understanding the anatomic structures compromised by screw insertion, may optimize surgical outcomes. This study aims to (1) correlate the proximity of JF to the peroneus brevis (PB) and plantar fascia (PF) footprints and (2) quantify optimal screw parameters given MT5 anatomy. MATERIALS AND METHODS: 3D CT-scan reconstructions were made of 21 cadaveric MT5s, followed by meticulous mapping of the PB and PF onto the reconstructions. Based on bone length, shape, narrowest intramedullary canal (IMC) diameter, and surrounding anatomy, two traditional debated screw positions were modeled for each reconstruction: (1) an anatomically positioned screw (AP), predicated on maximizing screw length by following the IMC for as long as possible, and (2) a clinically achievable screw (CA), predicated on maximizing screw length without violating the fifth tarso-metatarsal joint or adjacent cuboid bone. Fixation parameters were calculated for all models. RESULTS: The PB and PF extended into the JF site in 29% and 43%, respectively. AP's did not affect PB and PF footprint but required screw entry through the cuboid and fifth tarso-metatarsal joint in all specimens. CA screw entry sites, avoiding the cuboid and fifth tarso-metatarsal joint, partially compromised the PB and PF insertions in 33% and 62% with a median surface loss of 1.6%%(range 0.2-3.2%) and 0.81%%(range 0.05-1.6%), respectively. Mean AP screw length was 64±3.6mm and thread length 49±4.2mm. Mean CA screw length was 48±5.8mm and thread length 28±6.9mm. CONCLUSION: This study underscores the challenges associated with surrounding MT5 anatomy as they relate to optimal JF treatment. Both the extent of JF as well as a clinically achievable positioned screw violate the PB and PF footprints - although the degree to which even partial disruption of these footprints has on outcome remains unclear. To minimize damage to surrounding structures, including the PB and PF footprint, while allowing a screw length approximately two thirds of the metatarsal length, the CA screw position is recommended. This position balances the desire to maximize pull out strength while avoiding cortical penetration or inadvertent fracture site distraction.

Synthesis and 3D Printing of Conducting Alginate-Polypyrrole Ionomers.

Hydrogels composed of calcium cross-linked alginate are under investigation as bioinks for tissue engineering scaffolds due to their variable viscoelasticity, biocompatibility, and erodibility. Here, pyrrole was oxidatively polymerized in the presence of sodium alginate solutions to form ionomeric composites of various compositions. The IR spectroscopy shows that mild base is required to prevent the oxidant from attacking the alginate during the polymerization reaction. The resulting composites were isolated as dried thin films or cross-linked hydrogels and aerogels. The products were characterized by elemental analysis to determine polypyrrole incorporation, electrical conductivity measurements, and by SEM to determine changes in morphology or large-scale phase separation. Polypyrrole incorporation of up to twice the alginate (monomer versus monomer) provided materials amenable to 3D extrusion printing. The PC12 neuronal cells adhered and proliferated on the composites, demonstrating their biocompatibility and potential for tissue engineering applications.

3D hybrid printing platform for auricular cartilage reconstruction.

As scaffolds approach dimensions that are of clinical relevance, mechanical integrity and distribution becomes an important factor to the overall success of the implant. Hydrogels often lack the structural integrity and mechanical properties for use in vivo or handling. The inclusion of a structural support during the printing process, referred to as hybrid printing, allows the implant to retain structure and protect cells during maturation without needing to compromise its biological performance. In this study, scaffolds for the purpose of auricular cartilage reconstruction were evaluated via a hybrid printing approach using methacrylated Gelatin (GelMA) and Hyaluronic acid (HAMA) as the cell-laden hydrogel, Polycaprolactone (PCL) as structural support and Lutrol F-127 as sacrificial material. Furthermore, printing parameters such as nozzle diameter, strand spacing and filament orientation scaffolds were investigated. Compression and bending tests showed that increasing nozzle sizes decrease the compressive modulus of printed scaffolds, with up to 82% decrease in modulus when comparing between a 400 µm and 200 µm sized nozzle tip at the same strand spacing. On the contrary, strand spacing and orientation influences mainly the bending modulus due to the greater porosity and changes in pore size area. Using a 400 µm sized nozzle, scaffolds fabricated have a measured compression and bending modulus in the range similar to the native cartilage. The viability and proliferation of human mesenchymal stem cells delivered within the bioink was not affected by the printing process. Using results obtained from mechanical testing, a scaffold with matching mechanical properties across six distinct regions mimicking the human auricular cartilage can be completed in one single print process. The use of PCL and GelMA-HAMA as structural support and cell-laden hydrogel respectively are an excellent combination to provide tailored mechanical integrity, while maintaining porosity and protection to cells during differentiation.

Managing uncertain recovery for patients nearing the end of life in hospital: a mixed-methods feasibility cluster randomised controlled trial of the AMBER care bundle.

BACKGROUND: The AMBER (Assessment, Management, Best Practice, Engagement, Recovery Uncertain) care bundle is a complex intervention used in UK hospitals to support patients with uncertain recovery. However, it has yet to be evaluated in a randomised controlled trial (RCT) to identify potential benefits or harms. The aim of this trial was to investigate the feasibility of a cluster RCT of the AMBER care bundle. METHODS: This is a prospective mixed-methods feasibility cluster RCT. Quantitative data collected from patients (or proxies if patients lack capacity) were used (i) to examine recruitment, retention and follow-up rates; (ii) to test data collection tools for the trial and determine their optimum timing; (iii) to test methods to identify the use of financial resources; and (iv) to explore the acceptability of study procedures for health professionals and patients. Descriptive statistical analyses and thematic analysis used the framework approach. RESULTS: In total, 894 patients were screened, of whom 220 were eligible and 19 of those eligible (8.6%) declined to participate. Recruitment to the control arm was challenging. Of the 728 patients screened for that arm, 647 (88.9%) were excluded. Overall, 65 patients were recruited (81.3% of the recruitment target of 80). Overall, many were elderly (≥80 years, 46.2%, n = 30, mean = 77.8 years, standard deviation [SD] = 12.3 years). Over half (53.8%) had a non-cancer diagnosis, with a mean of 2.3 co-morbidities; 24.6% patients (n = 16) died during their hospital stay and 35.4% (n = 23) within 100 days of discharge. In both trial arms, baseline IPOS subscale scores identified moderate patient anxiety (control: mean 13.3, SD 4.8; intervention: mean 13.3, SD 5.1), and howRwe identified a good care experience (control: mean 13.1, SD 2.5; intervention: mean 11.5, SD 2.1). Collecting quantitative service use and quality of life data was feasible. No patient participants regarded study involvement negatively. Focus groups with health professionals identified concerns regarding (i) the subjectivity of the intervention's eligibility criteria, (ii) the need to prognosticate to identify potential patients and (iii) consent procedures and the length of the questionnaire. CONCLUSIONS: A full trial of the AMBER care bundle is technically feasible but impractical due to fundamental issues in operationalising the intervention's eligibility criteria, which prevents optimal recruitment. Since this complex intervention continues to be used in clinical care and advocated in policy, alternative research approaches must be considered and tested. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number (ISRCTN) Register, ISRCTN36040085 .

The effects of monoclonal anti-CD47 on RBCs, compatibility testing, and transfusion requirements in refractory acute myeloid leukemia.

BACKGROUND: CD47 is a novel therapeutic target in the treatment of solid-organ and hematologic malignancies. CD47 is also expressed on RBCs. Here, we report our experience of the RBC effects and the impact on blood bank testing and transfusion management in a Phase 1 trial of the humanized anti-CD47 monoclonal antibody Hu5F9-G4 in relapsed or primary refractory acute myeloid leukemia (AML) (NCT02678338). STUDY DESIGN AND METHODS: Nineteen patients with relapsed or primary refractory AML treated across five UK centers were included for analysis. Patients received escalating doses of Hu5F9-G4. Serial laboratory data were collected to evaluate impact on hemoglobin (Hb), markers of hemolysis (bilirubin, lactate dehydrogenase, reticulocyte count), transfusion requirements, and blood compatibility testing. RESULTS: A decline in Hb was observed with drug administration (median Hb change, -1.0 g/dL; range, 0.4-1.6) with associated increase in transfusion requirements. Patients responded to transfusion with a median Hb increment per unit of 1.0 g/dL. RBC agglutination was seen in all cases without associated change in Hb, lactate dehydrogenase, bilirubin, or reticulocyte count. Nine of 19 (47%) patients developed a newly positive antibody screen with a pan-agglutinin identified in plasma. Invalid ABO blood grouping occurred in 4 of 12 (33%) non-group O patients due to anomalous reactivity in the reverse ABO-type results. CONCLUSIONS: Treatment with Hu5F9-G4 in patients with AML resulted in an Hb decline and increased transfusion requirements. Problems with ABO blood typing and compatibility testing were widely observed and should be expected by centers treating recipients of Hu5F9-G4.

Can We Accurately Predict Cost Effectiveness Without Access to Overall Survival Data? The Case Study of Nivolumab in Combination with Ipilimumab for the Treatment of Patients with Advanced Melanoma in England.

BACKGROUND: Nivolumab with ipilimumab (the Regimen) is the first immuno-oncology combination treatment to demonstrate long-term clinical benefit for advanced melanoma patients. We evaluated the cost effectiveness of the Regimen in this population, with and without the availability of overall survival (OS) data. METHODS: A partitioned survival model and a Markov state-transition model were developed to estimate the lifetime costs and benefits of the Regimen versus ipilimumab. These models were built with and without the availability of OS data, as only progression-free survival data were available from the head-to-head, phase III trial against ipilimumab at the time of the National Institute for Health and Care Excellence (NICE) submission. Patient utilities and resource use data were sourced from trial data or the literature. RESULTS: Incremental cost-effectiveness ratios (ICERs) and absolute costs were similar between the models with and without OS data, but the model with OS data generated more than 1 additional quality-adjusted life-year (QALY) across both treatment arms. In both models, based on list prices, the Regimen was the most cost-effective treatment. CONCLUSIONS: The analyses show that the Regimen is a cost-effective treatment for advanced melanoma patients in England, and methods to overcome the lack of OS can give reasonable estimates of QALYs gained and ICERs.

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Rituximab salvage therapy in adults with immune thrombocytopenia: retrospective study on efficacy and safety profiles.

Splenectomy remains the preferred treatment for chronic immune thrombocytopenia (ITP) after corticosteroid failure, despite the risks of despite surgical complications and infection. The aim of this study was to assess the efficacy of and tolerance to rituximab through a retrospective analysis of 35 refractory/relapsing ITP patients treated from 2004 to 2013. The median age of subjects was 46 years (14-80). Rituximab was given at a weekly dose of 375 mg/m(2) for 4 weeks. Median time from diagnosis to first infusion was 17 months (1-362) and follow-up was 47 months (2-133). The overall response rates at 1 and 2 years after the first infusion were 47 and 38 %, with complete response rates of 24 and 25 %, respectively. Median duration of response was 38 months (1-123), with 37 % of patients maintaining a durable response (>1 year). Twenty-nine percent of patients had undergone splenectomy. A durable response after rituximab was more frequently observed in patients undergoing second-line therapy than those in third or later (83 versus 35 %, P = 0.01). Forty-four percent of patients experienced mild hypogammaglobulinaemia after rituximab, and no clinical infection occurred. To conclude, rituximab should be considered as an alternative treatment to splenectomy. Its efficacy and safety profile should lead us to choose this medical option therapy before surgery for ITP patients.

One Health in food safety and security education: A curricular framework.

The challenges of producing and distributing the food necessary to feed an anticipated 9 billion people in developed and developing societies by 2050 without destroying Earth's finite soil and water resources present extremely complex problems that lack simple solutions. The ability of modern societies to adequately address these and other food-related problems will require an educated workforce trained not only in traditional food safety, security, and public health, but also in other areas including food production, sustainable practices, and ecosystem health. To help address the need for such an educated workforce, a curricular framework was developed to assist those tasked with designing education and training for future food systems workers. One sentence summary: A curricular framework for education and training in food safety and security was developed that incorporates One Health concepts.

Effectiveness of the antegrade colonic enema stopper at preventing stomal stenosis: long-term follow-up.

AIM OF THE STUDY: Stomal stenosis is the commonest complication of the antegrade colonic enema (ACE) procedure, reportedly occurring in 25-55% of patients. As such, a simple ACE stopper device (a small silicone plug sited in the ACE conduit between catheterisations) was designed to prevent stenosis. We performed a long-term follow-up study to determine the effectiveness of the stopper device. METHODS: A retrospective case note review was performed of all patients who successfully underwent a primary ACE procedure over an 8.5-year period (January 2002 to June 2010). The inclusion criteria were (i) a minimum of 6 months follow-up, (ii) simple appendicostomy, (iii) caecal/colonic flap. In all patients an ACE stopper was sited in the conduit for at least 4 months and removed only for catheterisation. Data are mean±SEM. MAIN RESULTS: 38 children were included in our study. Mean age at surgery was 9.6±0.5 years. Surgery was performed in 22 patients for incontinence and in 16 for chronic constipation. 31 underwent an appendicostomy and 7 had a caecal/colonic flap; all received an ACE stopper. The mean follow-up was 2.6±0.3 years. Only 3 patients (8%) developed stomal stenosis. The first occurred 6 months postoperatively, resulting from an ACE stopper which was too small and consequently persistently fell out. This conduit required dilatation. The second occurred at 27 months secondary to a stomal infection and required surgical revision. The third occurred 8 months postoperatively for no obvious cause, and was treated with dilation. 1 patient experienced stomal leakage. CONCLUSION: The ACE stopper is a simple yet highly effective method of preventing stomal stenosis. We recommend using the stopper in all ACE patients.

Trends in COPD mortality and in-patient admissions in men & women: evidence of convergence.

Chronic obstructive pulmonary disease (COPD) is one of the leading causes of mortality. Although more prevalent in men, it is anticipated that, due to the convergence in smoking rates, the prevalence rate in women will surpass that of men. There were 14,519 deaths attributable to COPD in the period 2000-2009. Although deaths decreased for both sexes, reduction in deaths was significantly higher among men (test for trend, p<0.01 for men vs. p=0.06 for women). Smoking rates decreased for both sexes from 1980-2009 with the percentage reduction in smoking significantly greater in men (11.5% vs. 7.0%, p<0.001). There has been a convergence in COPD deaths and COPD hospital in-patient discharges for men and women that mirrors the trend in the convergence of male and female smoking rates. This study provides evidence of the need for effective smoking cessation programmes that are targeted at women as well as men.

Risk factors for mesh erosion complicating vaginal reconstructive surgery.

Synthetic mesh erosion is a recognised complication for pelvic floor repair surgery which occurs in 1-10% of patients. Our study aimed to evaluate the different risk factors involved in synthetic mesh erosion complicating vaginal reconstructive surgery at a general district hospital. A retrospective audit of 133 vaginal mesh reconstructive operations at Hinchingbrooke Hospital, Cambridgeshire, UK, was carried out. A total of 14 (10.53%) cases of mesh erosion into the vagina were reported. An increased rate of mesh erosion was associated with concurrent vaginal hysterectomy and previous vaginal reconstructive surgery (p < 0.05, RR 3.222, 95% CI 1.071-9.698 and p < 0.05, RR 4.571, 95% CI 1.58-13.23, respectively). The use of Safil® suture material (polyglycolic acid) was associated with a higher incidence of Gynecare Gynemesh® erosion (p < 0.05, OR = 9, 95% CI 1.073-75.5). It is concluded that this audit has shown the importance of analysing outcomes with all changes of practice, including the change of suture provider.

Risk of Chlamydia trachomatis infection during pregnancy: effectiveness of guidelines-based screening in identifying cases.

Our goal was to define the risk factors for Chlamydia trachomatis (CT) infection among pregnant women at a large urban medical centre. In a retrospective study, clinical records at a US maternity unit from July 2005 through February 2008 were reviewed. The study population included all pregnant women with a singleton newborn of at least 20 weeks gestation and antenatal care information. Logistic regression was used to analyse the association between a positive CT test and demographic, behavioural and prenatal care variables. A total of 2127 women were included in this analysis. The prevalence of CT infection was 4.7%. Cases were more likely to be younger, black and single. Other risk factors included tobacco use and Neisseria gonorrhoeae infection. Our findings suggest that factors other than age may impact upon the diagnosis of CT in pregnant women and that a more comprehensive testing strategy should be considered.

Roles of peroxisome proliferator-activated receptor-alpha and -gamma in the development of non-small cell lung cancer.

Peroxisome proliferator-activated receptor (PPAR)-α and PPARγ participate in cell proliferation and apoptosis. Few studies have simultaneously investigated both PPARα and PPARγ in lung cancers in vivo. The roles of PPARα and -γ were investigated in the development of pulmonary tumors induced in the adult A/J mouse by treatment with 4-(methylnitrosamino)-l-(3-pyridyl)-lbutanone (NNK). Compared with the normal lung tissues, PPARγ expression was much higher in the NNK-induced lung tumor tissues. However, PPARγ transcriptional activity, and the levels of two major endogenous PPARγ ligands, 13-hydroxyoctadecadienoic acid and 15-hydroxyeicosatetraenoic acid, were significantly lower in the NNK-treated lung tissues. The ligand changes in mice were confirmed in human lung cancer tissues. Along with the alteration of PPARγ and its endogenous ligands, the level of PPARα and its activity were increased in the NNK-induced mouse lung tumors. Treatment of mice with the synthetic PPARγ ligand, pioglitazone, significantly inhibited the formation of mouse lung tumors induced by NNK. Our study demonstrated that the reduction of endogenous PPARγ ligands and increased PPARα occurred before the formation of lung tumors, indicating that the molecular changes play a role in lung carcinogenesis. The results suggest that the enhancement of PPARγ activity with its ligands, and the suppression of PPARα with its inhibitors, may prevent the formation of lung tumors, as well as accelerate the therapy of lung cancer. Our findings may also reveal the possibility of using the level of endogenous PPARγ ligands and the activities of PPARγ or PPARα as tumor markers for lung cancer.

Inhibition of thromboxane synthase induces lung cancer cell death via increasing the nuclear p27.

The role of thromboxane in lung carcinogenesis is not clearly known, though thromboxane B2 (TXB(2)) level is increased and antagonists of thromboxane receptors or TXA2 can induce apoptosis of lung cancer cells. p27, an atypical tumor suppressor, is normally sequestered in the nucleus. The increased nuclear p27 may result in apoptosis of tumor cells. We hypothesize that the inhibition of thromboxane synthase (TXS) induces the death of lung cancer cells and that such inhibition is associated with the nuclear p27 level. Our experiment showed that the inhibition of TXS significantly induced the death or apoptosis in lung cancer cells. The activity of TXS was increased in lung cancer. The nuclear p27 was remarkably reduced in lung cancer tissues. The inhibition of TXS caused the cell death and apoptosis of lung cancer cells, likely via the elevation of the nuclear p27 since the TXS inhibition promoted the nuclear p27 level and the inhibition of p27 by its siRNA recovered the cell death induced by TXS inhibition. Collectively, lung cancer cells produce high levels of TXB(2) but their nuclear p27 is markedly reduced. The inhibition of TXS results in the p27-related induction of cell death in lung cancer cells.

In vivo inactivation of MASTL kinase results in thrombocytopenia.

OBJECTIVE: A missense mutation in the microtubule-associated serine/threonine-like kinase gene (MASTL, FLJ14813) on human chromosome 10 was previously linked to a novel form of autosomal dominant inherited thrombocytopenia in a single pedigree. The mutation results in an amino acid change from glutamic acid at position 167 to aspartic acid and segregates perfectly with thrombocytopenic individuals within this extended family. The phenotype is characterized by mild thrombocytopenia with an average platelet count of 60,000 platelets per microliter of blood. We wanted to determine the expression and localization of MASTL, as well as its role in developing thrombocytes using an in vivo model system. MATERIALS AND METHODS: Northern blot analysis allowed us to examine expression patterns. Morpholino knockdown assays in zebrafish (Danio rerio) were employed to determine in vivo contribution to thrombocyte development. Transient expression in baby hamster kidney cells resulted in localization of both the wild-type and E167D mutant forms of MASTL kinase to the nucleus. RESULTS: Northern blot analysis indicates that MASTL messenger RNA is restricted in its expression to hematopoietic and cancer cell lines. A transient knockdown of MASTL in zebrafish results in deficiency of circulating thrombocytes. Transient expression of recombinant MASTL kinase in vitro demonstrates localization to the nucleus. CONCLUSIONS: Functional studies presented here demonstrate a direct relationship between transient knockdown of MASTL kinase gene expression and reduction of circulating thrombocytes in zebrafish. This transient knockdown of MASTL in zebrafish correlates with a decrease in the expression of the thrombopoietin receptor, c-mpl, and the CD41 platelet adhesion protein, GpIIb, but has no effect on essential housekeeping zebrafish gene, EF1alpha.

The acceptability of an information leaflet explaining cardiopulmonary resuscitation policy in the hospice setting: a qualitative study exploring patients' views.

BACKGROUND: Guidelines advise that patients receiving palliative care should be given realistic information about cardiopulmonary resuscitation (CPR) and encouraged to participate in decisions about this. For many patients attending a hospice, CPR is unlikely to be successful because of advanced disease. It is difficult to predict which patients would like to discuss CPR and whether such discussion might cause distress. AIM: This research set out to determine the acceptability and understanding of a patient information leaflet about CPR given to inpatients and day-unit patients in one hospice, and to seek patients' views on communication about resuscitation. METHODS: Semi-structured interviews were carried out with five hospice inpatients and one day-unit patient and analysed using interpretative phenomenological analysis for emergent themes. RESULTS AND CONCLUSIONS: The leaflet was acceptable to the participants but was interpreted in the context of their understanding of their illness and prognosis. The leaflet alone is not a reliable method of communicating resuscitation policy and should be followed up by the opportunity to ask questions, if the patient wishes. Many factors influence patient choices about CPR. Realistic information about prognosis and about the risks and harms of CPR would allow patients to make a better-informed decision. However, if a patient prefers not to talk about their prognosis and end-of-life issues, then this should be respected.