High-sensitivity troponin in the evaluation of patients with suspected acute coronary syndrome: a stepped-wedge, cluster-randomised controlled trial.

BACKGROUND: High-sensitivity cardiac troponin assays permit use of lower thresholds for the diagnosis of myocardial infarction, but whether this improves clinical outcomes is unknown. We aimed to determine whether the introduction of a high-sensitivity cardiac troponin I (hs-cTnI) assay with a sex-specific 99th centile diagnostic threshold would reduce subsequent myocardial infarction or cardiovascular death in patients with suspected acute coronary syndrome. METHODS: In this stepped-wedge, cluster-randomised controlled trial across ten secondary or tertiary care hospitals in Scotland, we evaluated the implementation of an hs-cTnI assay in consecutive patients who had been admitted to the hospitals' emergency departments with suspected acute coronary syndrome. Patients were eligible for inclusion if they presented with suspected acute coronary syndrome and had paired cardiac troponin measurements from the standard care and trial assays. During a validation phase of 6-12 months, results from the hs-cTnI assay were concealed from the attending clinician, and a contemporary cardiac troponin I (cTnI) assay was used to guide care. Hospitals were randomly allocated to early (n=5 hospitals) or late (n=5 hospitals) implementation, in which the high-sensitivity assay and sex-specific 99th centile diagnostic threshold was introduced immediately after the 6-month validation phase or was deferred for a further 6 months. Patients reclassified by the high-sensitivity assay were defined as those with an increased hs-cTnI concentration in whom cTnI concentrations were below the diagnostic threshold on the contemporary assay. The primary outcome was subsequent myocardial infarction or death from cardiovascular causes at 1 year after initial presentation. Outcomes were compared in patients reclassified by the high-sensitivity assay before and after its implementation by use of an adjusted generalised linear mixed model. This trial is registered with ClinicalTrials.gov, number NCT01852123. FINDINGS: Between June 10, 2013, and March 3, 2016, we enrolled 48 282 consecutive patients (61 [SD 17] years, 47% women) of whom 10 360 (21%) patients had cTnI concentrations greater than those of the 99th centile of the normal range of values, who were identified by the contemporary assay or the high-sensitivity assay. The high-sensitivity assay reclassified 1771 (17%) of 10 360 patients with myocardial injury or infarction who were not identified by the contemporary assay. In those reclassified, subsequent myocardial infarction or cardiovascular death within 1 year occurred in 105 (15%) of 720 patients in the validation phase and 131 (12%) of 1051 patients in the implementation phase (adjusted odds ratio for implementation vs validation phase 1·10, 95% CI 0·75 to 1·61; p=0·620). INTERPRETATION: Use of a high-sensitivity assay prompted reclassification of 1771 (17%) of 10 360 patients with myocardial injury or infarction, but was not associated with a lower subsequent incidence of myocardial infarction or cardiovascular death at 1 year. Our findings question whether the diagnostic threshold for myocardial infarction should be based on the 99th centile derived from a normal reference population. FUNDING: The British Heart Foundation

Estimating the burden of selected non-communicable diseases in Africa: a systematic review of the evidence

Background The burden of non-communicable diseases (NCDs) is rapidly increasing globally, and particularly in Africa, where the health focus, until recently, has been on infectious diseases. The response to this growing burden of NCDs in Africa has been affected owing to a poor understanding of the burden of NCDs, and the relative lack of data and low level of research on NCDs in the continent. Recent estimates on the burden of NCDs in Africa have been mostly derived from modelling based on data from other countries imputed into African countries, and not usually based on data originating from Africa itself. In instances where few data were available, estimates have been characterized by extrapolation and over-modelling of the scarce data. It is therefore believed that underestimation of NCDs burden in many parts of Africa cannot be unexpected. With a gradual increase in average life expectancy across Africa, the region now experiencing the fastest rate of urbanization globally, and an increase adoption of unhealthy lifestyles, the burden of NCDs is expected to rise. This thesis will, therefore, be focussing on understanding the prevalence, and/or where there are available data, the incidence, of four major NCDs in Africa, which have contributed highly to the burden of NCDs, not only in Africa, but also globally. Methods I conducted a systematic search of the literature on three main databases (Medline, EMBASE and Global Health) for epidemiological studies on NCDs conducted in Africa. I retained and extracted data from original population-based (cohort or cross sectional), and/or health service records (hospital or registry-based studies) on prevalence and/or incidence rates of four major NCDs in Africa. These include: cardiovascular diseases (hypertension and stroke), diabetes, major cancer types (cervical, breast, prostate, ovary, oesophagus, bladder, Kaposi, liver, stomach, colorectal, lung and non-Hodgkin lymphoma), and chronic respiratory diseases (chronic obstructive pulmonary disease (COPD) and asthma). From extracted crude prevalence and incidence rates, a random effect meta-analysis was conducted and reported for each NCD. An epidemiological model was applied on all extracted data points. The fitted curve explaining the largest proportion of variance (best fit) from the model was further applied. The equation generated from the fitted curve was used to determine the prevalence and cases of the specific NCD in Africa at midpoints of the United Nations (UN) population 5-year age-group population estimates for Africa. Results From the literature search, studies on hypertension had the highest publication output at 7680, 92 of which were selected, spreading across 31 African countries. Cancer had 9762 publications and 39 were selected across 20 countries; diabetes had 3701 publications and 48 were selected across 28 countries; stroke had 1227 publications and 19 were selected across 10 countries; asthma had 790 publications and 45 were selected across 24 countries; and COPD had the lowest output with 243 publications and 13 were selected across 8 countries. From studies reporting prevalence rates, hypertension, with a total sample size of 197734, accounted for 130.2 million cases and a prevalence of 25.9% (23.5, 34.0) in Africa in 2010. This is followed by asthma, with a sample size of 187904, accounting for 58.2 million cases and a prevalence of 6.6% (2.4, 7.9); COPD, with a sample size of 24747, accounting for 26.3 million cases and a prevalence of 13.4% (9.4, 22.1); diabetes, with a sample size of 102517, accounting for 24.5 million cases and a prevalence of 4.0% (2.7, 6.4); and stroke, with a sample size of about 6.3 million, accounting for 1.94 million cases and a prevalence of 317.3 per 100000 population (314.0, 748.2). From studies reporting incidence rates, stroke accounted for 496 thousand new cases in Africa in 2010, with a prevalence of 81.3 per 100000 person years (13.2, 94.9). For the 12 cancer types reviewed, a total of 775 thousand new cases were estimated in Africa in 2010 from registry-based data covering a total population of about 33 million. Among women, cervical cancer and breast cancer had 129 thousand and 81 thousand new cases, with incidence rates of 28.2 (22.1, 34.3) and 17.7 (13.0, 22.4) per 100000 person years, respectively. Among men, prostate cancer and Kaposi sarcoma closely follows with 75 thousand and 74 thousand new cases, with incidence rates of 14.5 (10.9, 18.0) and 14.3 (11.9, 16.7) per 100000 person years, respectively. Conclusion This study suggests the prevalence rates of the four major NCDs reviewed (cardiovascular diseases (hypertension and stroke), diabetes, major cancer types, and chronic respiratory diseases (COPD and asthma) in Africa are high relative to global estimates. Due to the lack of data on many NCDs across the continent, there are still doubts on the true prevalence of these diseases relative to the current African population. There is need for improvement in health information system and overall data management, especially at country level in Africa. Governments of African nations, international organizations, experts and other stakeholders need to invest more on NCDs research, particularly mortality, risk factors, and health determinants to have evidenced-based facts on the drivers of this epidemic in the continent, and prompt better, effective and overall public health response to NCDs in Africa

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Methods of communicating a primary diagnosis of breast cancer to patients.

Background The method of delivering a diagnosis of breast cancer to women has the potential to impact on their level of interpretation, patient recall and satisfaction. Objectives To assess the effectiveness of different methods when used to communicate a primary diagnosis of breast cancer to women. Search strategy We searched the Cochrane Breast Cancer Group Specialised Register on 7 September 2006, Cochrane Consumers and Communication Group on 27 October 2006, MEDLINE (1966 to present), CINAHL (1982 to present), EMBASE OVID (1980 to present), British Nursing Index (Jan 1984 to present), PsycInfo (1967 to present), Dissertation Abstracts International (2004 to 2006), Library and Info Science Abstracts (LISA) (1969 to present), ISI Web of Knowledge (conference abstracts) and reference lists of articles. Selection criteria We sought randomised controlled trials of women with a histologically confirmed diagnosis of breast cancer being given a diagnosis of primary breast cancer. Trials should also have used one or more of the following methods; face-to-face consultations, written information, telephone consultation, audio or video tapes of consultation. Data collection and analysis Two review authors independently assessed trials for inclusion in the review. Studies were to be assessed using standardised data extraction and quality assessment forms. Main results The search strategies identified 2847 citations overall. A total of 30 citations appeared relevant however there were three duplicates which left 27 articles for further review. Articles reporting the same primary data accounted for 6 of the publications Brown 1997; Brown 1998; Brown 1999; Brown 2000; Hack 2000; Hack 2003 which left 23 original papers to be reviewed for inclusion. Of these, none met the inclusion criteria. Data extraction and assessment of methodological quality was therefore not possible. Authors' conclusions The review question remains unanswered as there were no randomised trials of methods of communicating a diagnosis of breast cancer to women. The authors have considered the possible reasons for the lack of research studies in this area and have considered that it is perhaps unethical to randomise women at such a vulnerable time such as waiting for a diagnosis. The design of ethically sensitive research to examine this topic needs to be explored to inform future practice. As some papers reviewed by the authors related to the first consultation visit, where treatment options are discussed, perhaps a review which focused on the methods of communication at the first consultation visit would provide more reliable evidence for the effectiveness of methods of communication and overcome the ethical dilemmas previously mentioned

Specialist breast care nurses for supportive care of women with breast cancer.

Background Breast Care Nurses (BCNs) are now established internationally, predominantly in well resourced healthcare systems. The role of BCNs has expanded to reflect the diversity of the population in which they work, and the improvements in survival of women with breast cancer. Interventions by BCNs aim to support women and help them cope with the impact of the disease on their quality of life. Objectives To assess the effectiveness of individual interventions carried out by BCN's on quality of life outcomes for women with breast cancer. Search methods We searched the Cochrane Breast Cancer Group Specialised Register and the Cochrane Central Register of Controlled Trials (15 January 2007). We also searched MEDLINE (1966 to September 2006), CINAHL (1982 to September 2006), EMBASE (1980 to September 2006), British Nursing Index (1984 to September 2006), CancerLit (1961 to September 2006), PsycInfo (1967 to September 2006), Library and Info Science Abstracts (LISA) (1969 to September 2006), Dissertation Abstracts International (only available 2005 to September 2006). We contacted authors as appropriate. Selection criteria Randomised controlled trials assessing the effects of interventions carried out by BCN's on quality of life outcomes, for women with breast cancer. Data collection and analysis Two authors independently assessed relevant studies for inclusion and undertook data extraction and quality assessment of included studies. Main results We included five studies, categorised into three groups. Three studies assessing psychosocial nursing interventions around diagnosis and early treatment found that the BCN could affect some components of quality of life, such as anxiety and early recognition of depressive symptoms. However, their impact on social and functional aspects of the disease trajectory was inconclusive. Supportive care interventions during radiotherapy was assessed by one study which showed that specific BCN interventions can alleviate perceived distress during radiotherapy treatment, but did not improve coping skills, mood or overall quality of life. One study assessed nurse-led follow-up interventions in which no statistically significant difference was identified for main demographic variables, satisfaction with care, access to medical care or anxiety and depression. Authors' conclusions There is limited evidence at this time to support the contention that interventions by BCNs assist in the short-term with the recognition and management of psychological distress for women with breast cancer. Further research is required before the impact of BCNs on aspects of quality of life for women with breast cancer can be known

Using a needs assessment tool in breast cancer follow-up

Needs which arise for women with breast cancer are complex and are directly influenced by thier individual experience form diagnosis, through treatment and beyond. The aim of this study is to assess the effectiveness of using a needs assessment tool during a clinical consultation

Parasites reveal movement of bats between the New and Old Worlds

The global distribution of bat taxa indicates that the Atlantic and Pacific Oceans are effective barriers to movement between the Old and New Worlds. For instance, one of the major suborders, Yinpterochiroptera, has an exclusively Old World distribution, and within the other, Yangochiroptera, no species and only five genera are common to both. However, as bats are sometimes blown out to sea, and have colonised isolated islands, occasional natural movement between the New and Old Worlds does appear to be possible. Here we identify new genotypes of a blood parasite, Trypanosoma dionisii, in Old World bats that are closely related to South American strains. Using highly conservative calibration points, divergence of Old and New World strains is estimated to have occurred 3.2-5.0 million years ago (MYA), depending on the method used (upper 95% CL for maximum time 11.4 MYA). The true date of divergence is likely to be considerably more recent. These results demonstrate that taxon-specific parasites can indicate historical movements of their hosts, even where their hosts may have left no lasting phylogenetic footprint. (C) 2012 Elsevier Inc. All rights reserved

Parasites reveal movement of bats between the New and Old Worlds

The global distribution of bat taxa indicates that the Atlantic and Pacific Oceans are effective barriers to movement between the Old and New Worlds. For instance, one of the major suborders, Yinpterochiroptera, has an exclusively Old World distribution, and within the other, Yangochiroptera, no species and only five genera are common to both. However, as bats are sometimes blown out to sea, and have colonised isolated islands, occasional natural movement between the New and Old Worlds does appear to be possible. Here we identify new genotypes of a blood parasite, Trypanosoma dionisii, in Old World bats that are closely related to South American strains. Using highly conservative calibration points, divergence of Old and New World strains is estimated to have occurred 3.2-5.0 million years ago (MYA), depending on the method used (upper 95% CL for maximum time 11.4 MYA). The true date of divergence is likely to be considerably more recent. These results demonstrate that taxon-specific parasites can indicate historical movements of their hosts, even where their hosts may have left no lasting phylogenetic footprint. (C) 2012 Elsevier Inc. All rights reserved

High-sensitivity cardiac troponin and the diagnosis of myocardial infarction in patients with kidney impairment.

The benefit and utility of high-sensitivity cardiac troponin (hs-cTn) in the diagnosis of myocardial infarction in patients with kidney impairment is unclear. Here, we describe implementation of hs-cTnI testing on the diagnosis, management, and outcomes of myocardial infarction in patients with and without kidney impairment. Consecutive patients with suspected acute coronary syndrome enrolled in a stepped-wedge, cluster-randomized controlled trial were included in this pre-specified secondary analysis. Kidney impairment was defined as an eGFR under 60mL/min/1.73m2. The index diagnosis and primary outcome of type 1 and type 4b myocardial infarction or cardiovascular death at one year were compared in patients with and without kidney impairment following implementation of hs-cTnI assay with 99th centile sex-specific diagnostic thresholds. Serum creatinine concentrations were available in 46,927 patients (mean age 61 years; 47% women), of whom 9,080 (19%) had kidney impairment. hs-cTnIs were over 99th centile in 46% and 16% of patients with and without kidney impairment. Implementation increased the diagnosis of type 1 infarction from 12.4% to 17.8%, and from 7.5% to 9.4% in patients with and without kidney impairment (both significant). Patients with kidney impairment and type 1 myocardial infarction were less likely to undergo coronary revascularization (26% versus 53%) or receive dual anti-platelets (40% versus 68%) than those without kidney impairment, and this did not change post-implementation. In patients with hs-cTnI above the 99th centile, the primary outcome occurred twice as often in those with kidney impairment compared to those without (24% versus 12%, hazard ratio 1.53, 95% confidence interval 1.31 to 1.78). Thus, hs-cTnI testing increased the identification of myocardial injury and infarction but failed to address disparities in management and outcomes between those with and without kidney impairment