An evaluation of classification systems for stillbirth

<p>Abstract</p> <p>Background</p> <p>Audit and classification of stillbirths is an essential part of clinical practice and a crucial step towards stillbirth prevention. Due to the limitations of the ICD system and lack of an international approach to an acceptable solution, numerous disparate classification systems have emerged. We assessed the performance of six contemporary systems to inform the development of an internationally accepted approach.</p> <p>Methods</p> <p>We evaluated the following systems: Amended Aberdeen, Extended Wigglesworth; PSANZ-PDC, ReCoDe, Tulip and CODAC. Nine teams from 7 countries applied the classification systems to cohorts of stillbirths from their regions using 857 stillbirth cases. The main outcome measures were: the ability to retain the important information about the death using the <it>InfoKeep </it>rating; the ease of use according to the <it>Ease </it>rating (both measures used a five-point scale with a score <2 considered unsatisfactory); inter-observer agreement and the proportion of unexplained stillbirths. A randomly selected subset of 100 stillbirths was used to assess inter-observer agreement.</p> <p>Results</p> <p><it>InfoKeep </it>scores were significantly different across the classifications (<it>p </it>≤ 0.01) due to low scores for Wigglesworth and Aberdeen. CODAC received the highest mean (SD) score of 3.40 (0.73) followed by PSANZ-PDC, ReCoDe and Tulip [2.77 (1.00), 2.36 (1.21), 1.92 (1.24) respectively]. Wigglesworth and Aberdeen resulted in a high proportion of unexplained stillbirths and CODAC and Tulip the lowest. While <it>Ease </it>scores were different (<it>p </it>≤ 0.01), all systems received satisfactory scores; CODAC received the highest score. Aberdeen and Wigglesworth showed poor agreement with kappas of 0.35 and 0.25 respectively. Tulip performed best with a kappa of 0.74. The remainder had good to fair agreement.</p> <p>Conclusion</p> <p>The Extended Wigglesworth and Amended Aberdeen systems cannot be recommended for classification of stillbirths. Overall, CODAC performed best with PSANZ-PDC and ReCoDe performing well. Tulip was shown to have the best agreement and a low proportion of unexplained stillbirths. The virtues of these systems need to be considered in the development of an international solution to classification of stillbirths. Further studies are required on the performance of classification systems in the context of developing countries. Suboptimal agreement highlights the importance of instituting measures to ensure consistency for any classification system.</p

Identification of a Sudden Cardiac Death Susceptibility Locus at 2q24.2 through Genome-Wide Association in European Ancestry Individuals

Sudden cardiac death (SCD) continues to be one of the leading causes of mortality worldwide, with an annual incidence estimated at 250,000–300,000 in the United States and with the vast majority occurring in the setting of coronary disease. We performed a genome-wide association meta-analysis in 1,283 SCD cases and >20,000 control individuals of European ancestry from 5 studies, with follow-up genotyping in up to 3,119 SCD cases and 11,146 controls from 11 European ancestry studies, and identify the BAZ2B locus as associated with SCD (P = 1.8×10−10). The risk allele, while ancestral, has a frequency of ∼1.4%, suggesting strong negative selection and increases risk for SCD by 1.92–fold per allele (95% CI 1.57–2.34). We also tested the role of 49 SNPs previously implicated in modulating electrocardiographic traits (QRS, QT, and RR intervals). Consistent with epidemiological studies showing increased risk of SCD with prolonged QRS/QT intervals, the interval-prolonging alleles are in aggregate associated with increased risk for SCD (P = 0.006)

Detection and localization of early- and late-stage cancers using platelet RNA

Cancer patients benefit from early tumor detection since treatment outcomes are more favorable for less advanced cancers. Platelets are involved in cancer progression and are considered a promising biosource for cancer detection, as they alter their RNA content upon local and systemic cues. We show that tumor-educated platelet (TEP) RNA-based blood tests enable the detection of 18 cancer types. With 99% specificity in asymptomatic controls, thromboSeq correctly detected the presence of cancer in two-thirds of 1,096 blood samples from stage I–IV cancer patients and in half of 352 stage I–III tumors. Symptomatic controls, including inflammatory and cardiovascular diseases, and benign tumors had increased false-positive test results with an average specificity of 78%. Moreover, thromboSeq determined the tumor site of origin in five different tumor types correctly in over 80% of the cancer patients. These results highlight the potential properties of TEP-derived RNA panels to supplement current approaches for blood-based cancer screening

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

The role of C1 inhibitor and complement as acute phase reactants: are we missing the diagnosis of hereditary angioedema?

Background C1 inhibitor (C1-INH) and complement 4 (C4) have historically been referred to as positive acute phase reactants, however this has never been evaluated in hereditary angioedema (HAE) patients. Low function of C1-INH and low levels of C4 are important in the diagnosis of HAE type 1 and 2. If C1-INH and/or C4 are significant acute phase reactants, their levels may be falsely “normal” in patients with HAE when measured during times of infection or inflammation resulting in missed or delayed diagnosis. Case presentation We present a case series of four HAE patients who had C4, C1-INH, c-reactive protein (CRP) and ferritin measured at baseline and again during a self-reported upper respiratory tract infection (URTI) or flu-like illness. We did not identify any HAE patients who had a significant change in their C1-INH functional level in the context of a mild infection. However, the C4 level did increase into the normal range on three occasions (2 patients, with 1 patient having elevation during two separate illnesses). Conclusions C1 inhibitor may not be a clinically significant acute phase protein and appears to still be a reliable diagnostic marker of hereditary angioedema, even in times of modest acute inflammation, unlike complement C4 which can be elevated in this setting.Medicine, Faculty ofNon UBCAllergy and Immunology, Division ofHematology, Division ofMedicine, Department ofReviewedFacult

Sex disparities in systemic sclerosis-associated pulmonary arterial hypertension: a cohort study

Abstract Background The impact of male sex as a determinant of health outcomes in systemic sclerosis-associated pulmonary arterial hypertension (SSc-PAH) is controversial. The primary objective of this study was to evaluate the effect of sex on survival in patients with SSc-PAH. The secondary objectives were to evaluate the effect of sex on age of PAH diagnosis, time from SSc diagnosis to PAH diagnosis, and SSc disease manifestations. Methods Sex-based disparities were evaluated in a cohort of SSc-PAH patients with a primary outcome of time from PAH diagnosis to all-cause mortality. Secondary outcomes were differences in age of diagnosis, disease duration, and SSc manifestations. Survival differences were evaluated using Kaplan-Meier and Cox proportional hazard models. Results We identified 378 SSc-PAH (58 males, 320 females) patients, with a female:male ratio of 5.5:1. Males had a shorter mean ± standard deviation time from SSc diagnosis to PAH diagnosis (1.7 ± 14 versus 5.5 ± 14.2 years); shorter PAH duration (3.5 ± 3.1 versus 4.7 ± 4.2 years), increased frequency of renal crisis (19 % versus 8 %, relative risk (RR) 2.33, 95 %CI 1.22, 4.46), interstitial lung disease (67 % versus 48 %, RR 1.41, 95 %CI 1.14, 1.74), and diffuse subtype (40 % versus 22 %, RR 1.84, 95 %CI 1.26, 2.69). Males appeared to have decreased 1-, 2-, 3-, and 5-year survival (83.2 %, 68.7 %, 53.2 %, 45.6 %) compared to females (85.7 %, 75.7 %, 66.4 %, 57.4 %). However, there was no difference in mortality between sexes (HR 1.43 (95 %CI 0.97, 2.13). Conclusions Sex disparities appear to exist in the frequency of PAH, time to PAH diagnosis, PAH disease duration and SSc disease burden. However, male sex does not independently impact SSc-PAH survival

Coronavirus disease 2019 in adults with congenital heart disease: a position paper from the ESC working group of adult congenital heart disease, and the International Society for Adult Congenital Heart Disease.

We are witnessing an unparalleled pandemic caused by the novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) associated with coronavirus disease 2019 (COVID-19). Current data show that SARS-CoV-2 results in mild flu-like symptoms in the majority of healthy and young patients affected. Nevertheless, the severity of COVID-19 respiratory syndrome and the risk of adverse or catastrophic outcomes are increased in patients with pre-existing cardiovascular disease. Patients with adult congenital heart disease (ACHD)-by definition-have underlying cardiovascular disease. Many patients with ACHD are also afflicted with residual haemodynamic lesions such as valve dysfunction, diminished ventricular function, arrhythmias or cyanosis, have extracardiac comorbidities, and face additional challenges regarding pregnancy. Currently, there are emerging data of the effect of COVID-19 on ACHD patients, but many aspects, especially risk stratification and treatment considerations, remain unclear. In this article, we aim to discuss the broad impact of COVID-19 on ACHD patients, focusing specifically on pathophysiology, risk stratification for work, self-isolation, hospitalization, impact on pregnancy, psychosocial health, and longer-term implications for the provision of ACHD care

Recommendations for advance care planning in adults with congenital heart disease: a position paper from the ESC Working Group of Adult Congenital Heart Disease, the Association of Cardiovascular Nursing and Allied Professions (ACNAP), the European Association for Palliative Care (EAPC), and the International Society for Adult Congenital Heart Disease (ISACHD).

Survival prospects in adults with congenital heart disease (CHD), although improved in recent decades, still remain below expectations for the general population. Patients and their loved ones benefit from preparation for both unexpected and predictable deaths, sometimes preceded by a prolonged period of declining health. Hence, advance care planning (ACP) is an integral part of comprehensive care for adults with CHD. This position paper summarizes evidence regarding benefits of and patients' preferences for ACP and provides practical advice regarding the implementation of ACP processes within clinical adult CHD practice. We suggest that ACP be delivered as a structured process across different stages, with content dependent upon the anticipated disease progression. We acknowledge potential barriers to initiate ACP discussions and emphasize the importance of a sensitive and situation-specific communication style. Conclusions presented in this article reflect agreed expert opinions and include both patient and provider perspectives.status: publishe

Recommendations for advance care planning in adults with congenital heart disease: a position paper from the ESC Working Group of Adult Congenital Heart Disease, the Association of Cardiovascular Nursing and Allied Professions (ACNAP), the European Association for Palliative Care (EAPC), and the International Society for Adult Congenital Heart Disease (ISACHD)

Survival prospects in adults with congenital heart disease (CHD), although improved in recent decades, still remain below expectations for the general population. Patients and their loved ones benefit from preparation for both unexpected and predictable deaths, sometimes preceded by a prolonged period of declining health. Hence, advance care planning (ACP) is an integral part of comprehensive care for adults with CHD. This position paper summarizes evidence regarding benefits of and patients' preferences for ACP and provides practical advice regarding the implementation of ACP processes within clinical adult CHD practice. We suggest that ACP be delivered as a structured process across different stages, with content dependent upon the anticipated disease progression. We acknowledge potential barriers to initiate ACP discussions and emphasize the importance of a sensitive and situation-specific communication style. Conclusions presented in this article reflect agreed expert opinions and include both patient and provider perspectives. Keywords: Adult congenital heart disease; Advance care planning

Recommendations for advance care planning in adults with congenital heart disease : a position paper from the ESC Working Group of Adult Congenital Heart Disease, the Association of Cardiovascular Nursing and Allied Professions (ACNAP), the European Association for Palliative Care (EAPC), and the International Society for Adult Congenital Heart Disease (ISACHD)

Survival prospects in adults with congenital heart disease (CHD), although improved in recent decades, still remain below expectations for the general population. Patients and their loved ones benefit from preparation for both unexpected and predictable deaths, sometimes preceded by a prolonged period of declining health. Hence, advance care planning (ACP) is an integral part of comprehensive care for adults with CHD. This position paper summarizes evidence regarding benefits of and patients' preferences for ACP and provides practical advice regarding the implementation of ACP processes within clinical adult CHD practice. We suggest that ACP be delivered as a structured process across different stages, with content dependent upon the anticipated disease progression. We acknowledge potential barriers to initiate ACP discussions and emphasize the importance of a sensitive and situation-specific communication style. Conclusions presented in this article reflect agreed expert opinions and include both patient and provider perspectives. Keywords: Adult congenital heart disease; Advance care planning