Generation and characterization of a control and patient-derived human iPSC line containing the Hermansky Pudlak type 2 (HPS2) associated heterozygous compound mutation in AP3B1

Induced pluripotent stem cells (iPSCs) were generated from blood outgrowth endothelial cells (BOECs) obtained from a healthy donor and from a patient diagnosed with Hermansky Pudlak Syndrome type 2 (HPS2), caused by compound heterozygous AP3B1 mutations (c.177delA and c.1839-1842delTAGA). BOECs were reprogrammed with a hOKSM self-silencing polycistronic lentiviral vector, where the generated iPSCs showed normal karyotype, expression of pluripotency associated markers and in vitro spontaneous differentiation towards the three germ layers. The generated iPSCs can be used to study HPS2 pathophysiology and the basic functions of AP3B1 protein in different cell types.</p

Prospective observational study of early respiratory management in preterm neonates less than 35 weeks of gestation

Abstract Background Current guidelines for management of respiratory distress syndrome (RDS) recommend continuous positive airway pressure (CPAP) as the primary mode of respiratory support even in the most premature neonates, reserving endotracheal intubation (ETI) for rescue surfactant or respiratory failure. The incidence and timing of ETI in practice is poorly documented. Methods In 27 Level III NICUs in the US (n = 19), Canada (n = 3) and Poland (n = 5), demographics and baseline characteristics, respiratory support modalities including timing of ETI, administration of surfactant and caffeine/other methylxanthines, and neonatal morbidities were prospectively recorded in consecutive preterm neonates following written parental consent. Infants were divided into three groups according to gestational age (GA) at birth, namely 26–28, 29–32 and 33–34 weeks. Statistical comparisons between groups were done using Chi-Square tests. Results Of 2093 neonates (US = 1507, 254 Canada, 332 Poland), 378 (18%) were 26–28 weeks gestational age (GA), 835 (40%) were 29–32 weeks, and 880 (42%) were 33–34 weeks. Antenatal steroid use was 81% overall, and approximately 89% in neonates ≤32 weeks. RDS incidence and use of ventilatory or supplemental oxygen support were similar across all sites. CPAP was initiated in 43% of all infants, being highest in the 29–32-week group, with a lower proportion in other GA categories (p < 0.001). The overall rate of ETI was 74% for neonates 26–28 weeks (42% within 15 min of birth, 49% within 60 min, and 57% within 3 h), 33% for 29–32 weeks (13 16 and 21%, respectively), and 16% for 33–34 weeks (5, 6 and 8%, respectively). Overall intubation rates and timing were similar between countries in all GAs. Rates within each country varied widely, however. Across US sites, overall ETI rates in 26–28-week neonates were 30–60%, and ETI within 15 min varied from 0 to 83%. Similar within 15-min variability was seen at Polish sites (22–67%) in this GA, and within all countries for 29–32 and 33–34-week neonates. Conclusion Despite published guidelines for management of RDS, rate and timing of ETI varies widely, apparently unrelated to severity of illness. The impact of this variability on outcome is unknown but provides opportunities for further approaches which can avoid the need for ETI

The Eritrean Military/National Service Programme: Slavery and the notion of persecution in refugee status determination

Despite the overwhelming evidence of human rights violations within the Eritrean Military/National Service Programme (“MNSP”), adjudication of asylum applications made by Eritreans remains a challenge. Narrow interpretations of “slavery” have created obstacles for protection under the 1951 Convention Relating to the Status of Refugees (“1951 Refugee Convention”). This article discusses MST and Others, the latest Country Guidance case on Eritrea issued by the UK Upper Tribunal Immigration and Asylum Chamber (“UTIAC”), and also the lead case E-5022/2017 of the Swiss Federal Administrative Court (“FAC”), which to a large extent replicated the UTIAC’s approach. The article focuses on how “slavery,” “servitude” and “forced labour” under article 4 of the European Convention on Human Rights (“ECHR”) have been interpreted in the British and Swiss case-law. While both, the British and the Swiss Courts, had recourse to the European Court of Human Rights’ (“ECtHR”) interpretation of article 4(1) ECHR (the right not to be subjected to slavery or servitude), they refused the applicability of international criminal law notions to this provision, and thus to the concept of “persecution” in article 1A(2) of the 1951 Refugee Convention. In doing so, the UTIAC and the FAC set unreasonable requirements to satisfy article 4(1) ECHR. Due to the very limited case-law pertaining to slavery by the ECtHR, the ECHR does not offer an appropriate framework for examining asylum applications of victims of slavery. It is therefore suggested that slavery cases are considered against a wider legal framework, which involves the examination of concepts developed by international criminal law (“ICL”). ICL has indeed developed a significant body of jurisprudence on the interpretation of the international law concept of “slavery” and its application to contemporary situations. The article contrasts the British and Swiss Courts’ position to develop an interpretative approach that connects different areas of international law, including not only international refugee law and international human rights law (“IHRL”), but also ICL. If applied in line with the principle of systemic integration and according to the overall purposes of the 1951 Refugee Convention, this approach would yield consistent results. Ultimately, this article seeks to assist asylum decision-makers and practitioners in the interpretation and application of the refugee definition to asylum applications of persons from Eritrea

Initial invasive or conservative strategy for stable coronary disease

BACKGROUND Among patients with stable coronary disease and moderate or severe ischemia, whether clinical outcomes are better in those who receive an invasive intervention plus medical therapy than in those who receive medical therapy alone is uncertain. METHODS We randomly assigned 5179 patients with moderate or severe ischemia to an initial invasive strategy (angiography and revascularization when feasible) and medical therapy or to an initial conservative strategy of medical therapy alone and angiography if medical therapy failed. The primary outcome was a composite of death from cardiovascular causes, myocardial infarction, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest. A key secondary outcome was death from cardiovascular causes or myocardial infarction. RESULTS Over a median of 3.2 years, 318 primary outcome events occurred in the invasive-strategy group and 352 occurred in the conservative-strategy group. At 6 months, the cumulative event rate was 5.3% in the invasive-strategy group and 3.4% in the conservative-strategy group (difference, 1.9 percentage points; 95% confidence interval [CI], 0.8 to 3.0); at 5 years, the cumulative event rate was 16.4% and 18.2%, respectively (difference, 121.8 percentage points; 95% CI, 124.7 to 1.0). Results were similar with respect to the key secondary outcome. The incidence of the primary outcome was sensitive to the definition of myocardial infarction; a secondary analysis yielded more procedural myocardial infarctions of uncertain clinical importance. There were 145 deaths in the invasive-strategy group and 144 deaths in the conservative-strategy group (hazard ratio, 1.05; 95% CI, 0.83 to 1.32). CONCLUSIONS Among patients with stable coronary disease and moderate or severe ischemia, we did not find evidence that an initial invasive strategy, as compared with an initial conservative strategy, reduced the risk of ischemic cardiovascular events or death from any cause over a median of 3.2 years. The trial findings were sensitive to the definition of myocardial infarction that was used

Health-status outcomes with invasive or conservative care in coronary disease

BACKGROUND In the ISCHEMIA trial, an invasive strategy with angiographic assessment and revascularization did not reduce clinical events among patients with stable ischemic heart disease and moderate or severe ischemia. A secondary objective of the trial was to assess angina-related health status among these patients. METHODS We assessed angina-related symptoms, function, and quality of life with the Seattle Angina Questionnaire (SAQ) at randomization, at months 1.5, 3, and 6, and every 6 months thereafter in participants who had been randomly assigned to an invasive treatment strategy (2295 participants) or a conservative strategy (2322). Mixed-effects cumulative probability models within a Bayesian framework were used to estimate differences between the treatment groups. The primary outcome of this health-status analysis was the SAQ summary score (scores range from 0 to 100, with higher scores indicating better health status). All analyses were performed in the overall population and according to baseline angina frequency. RESULTS At baseline, 35% of patients reported having no angina in the previous month. SAQ summary scores increased in both treatment groups, with increases at 3, 12, and 36 months that were 4.1 points (95% credible interval, 3.2 to 5.0), 4.2 points (95% credible interval, 3.3 to 5.1), and 2.9 points (95% credible interval, 2.2 to 3.7) higher with the invasive strategy than with the conservative strategy. Differences were larger among participants who had more frequent angina at baseline (8.5 vs. 0.1 points at 3 months and 5.3 vs. 1.2 points at 36 months among participants with daily or weekly angina as compared with no angina). CONCLUSIONS In the overall trial population with moderate or severe ischemia, which included 35% of participants without angina at baseline, patients randomly assigned to the invasive strategy had greater improvement in angina-related health status than those assigned to the conservative strategy. The modest mean differences favoring the invasive strategy in the overall group reflected minimal differences among asymptomatic patients and larger differences among patients who had had angina at baseline