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Left ventricular assist devices (LVADs) have been used as a standard treatment option for patients with advanced heart failure. However, these devices are prone to adverse events. Nonsurgical bleeding (NSB) is the most common complication in patients with continuous flow (CF) LVADs. The development of acquired von Willebrand syndrome (AVWS) in CF-LVAD recipients is thought to be a key factor. However, AVWS is seen across a majority of LVAD patients, not just those with NSB. The purpose of this study was to examine the link between acquired platelet defects and NSB in CF-LVAD patients.Blood samples were collected from 62 CF-LVAD patients at pre- and 4 post-implantation timepoints. Reduced adhesion receptor expression (GPIbα and GPVI) and activation of platelets (GPIIb/IIIa activation) were used as markers for acquired platelet defects.Twenty-three patients experienced at least one NSB episode. Significantly higher levels of platelet activation and receptor reduction were seen in the postimplantation blood samples from bleeders compared with non-bleeders. All patients experienced the loss of high molecular weight monomers (HMWM) of von Willebrand Factor (vWF), but no difference was seen between the two groups. Multivariable logistic regression showed that biomarkers for reduced platelet receptor expression (GPIbα and GPVI) and activation (GPIIb/IIIa) have more predictive power for NSB, with the area under curve (AUC) values of 0.72, 0.68, and 0.62, respectively, than the loss of HMWM of vWF (AUC: 0.57).The data from this study indicated that the severity of acquired platelet defects has a direct link to NSB in CF-LVAD recipients.

Noninvasive monitoring of heart allograft health is important to improve clinical outcomes. MicroRNAs (miRs) are promising biomarkers of cardiovascular disease and limited studies suggest they can be used to noninvasively diagnose acute heart transplant rejection.The Genomic Research Alliance for Transplantation (GRAfT) is a multicenter prospective cohort study that phenotyped heart transplant patients from 5 mid-Atlantic centers. Patients who had no history of rejection after transplant were compared to patients with acute cellular rejection (ACR) or antibody-mediated rejection (AMR). Small RNA sequencing was performed on plasma samples collected at the time of an endomyocardial biopsy. Differential miR expression was performed with adjustment for clinical covariates. Regression was used to develop miR panels with high diagnostic accuracy for ACR and AMR. These panels were then validated in independent samples from GRAfT and Stanford University. Receiver operating characteristic curves were generated and area under the curve (AUC) statistics calculated. Distinct ACR and AMR clinical scores were developed to translate miR expression data for clinical use.The GRAfT cohort had a median age of 52 years, with 35% females and 45% Black patients. Between GRAfT and Stanford, we included 157 heart transplant patients: 108 controls and 49 with rejection (50 ACR and 38 AMR episodes). After differential miR expression and regression analysis, we identified 12 miRs that accurately discriminate ACR and 17 miRs in AMR. Independent validation of the miR panels within GRAfT led to an ACR AUC 0.92 (95% confidence interval [CI]: 0.86-0.98) and AMR AUC 0.82 (95% CI: 0.74-0.90). The externally validated ACR AUC was 0.72 (95% CI: 0.59-0.82). We developed distinct ACR and AMR miR clinical scores (range 0-100), a score ≥ 65, identified ACR with 86% sensitivity, 76% specificity, and 98% negative predictive value, for AMR score performance was 82%, 84% and 97%, respectively.We identified novel miRs that had excellent performance to noninvasively diagnose acute rejection after heart transplantation. Once rigorously validated, the unique clinical ACR and AMR scores usher in an era whereby genomic biomarkers can be used to screen and diagnose the subtype of rejection. These novel biomarkers may potentially alleviate the need for an endomyocardial biopsy while facilitating the initiation of targeted therapy based on the noninvasive diagnosis of ACR or AMR.

The HeartWare HVAD System (Medtronic) is a durable implantable left ventricular assist device that has been implanted in approximately 20,000 patients worldwide for bridge to transplant and destination therapy indications. In December 2020, Medtronic issued an Urgent Medical Device Communication informing clinicians of a critical device malfunction in which the HVAD may experience a delay or failure to restart after elective or accidental discontinuation of pump operation. Moreover, evolving retrospective comparative effectiveness studies of patients supported with the HVAD demonstrated a significantly higher risk of stroke and all-cause mortality when compared with a newer generation of a commercially available durable left ventricular assist device. Considering the totality of this new information on HVAD performance and the availability of an alternate commercially available device, Medtronic halted the sale and distribution of the HVAD System in June 2021. The decision to remove the HVAD from commercial distribution now requires the use of the HeartMate 3 left ventricular assist system (Abbott, Inc) if a patient previously implanted with an HVAD requires a pump exchange. The goal of this document is to review important differences in the design of the HVAD and HeartMate 3 that are relevant to the medical management of patients supported with these devices, and to assess the technical aspects of an HVAD-to-HeartMate 3 exchange. This document provides the best available evidence that supports best practices. (J Thorac Cardiovasc Surg 2022;-:1-8).

Background: We previously demonstrated better inflow cannula (IFC) position and reduced pump thrombosis with a centrifugal-flow LVAD (CF-LVAD) compared to an axial-flow device. We hypothesized that implant technique and patient anatomy would affect CF-LVAD IFC positioning and that malposition would impact LV unloading and outcomes. Methods: Pre- and postoperative computed tomography (CT) scans were reviewed for patients with six-month follow-up. Malposition was quantified using angular deviation from an ideal line in two planes. IFC position was compared between conventional sternotomy (CS) and lateral thoracotomy-hemisternotomy (LTHS). The influence of LV end-diastolic dimension (LVEDD), body mass index (BMI), and CT-derived anatomy was determined. LV unloading was assessed by LVAD flow index (FI) and pre- to post-LVAD decrement in mitral regurgitation (MR) and LVEDD. Outcome measures were pump thrombus or stroke (PT/eCVA); 30-day and total heart failure-related readmissions (HFRAs); and survival free of surgery for LVAD dysfunction. Results: One hundred fourteen patients met criteria. Total malposition magnitude was higher for CS than LTHS (p=0.04). Midline-LV apex distance predicted lateral-plane malposition (p=0.04), while apex-LVOT angle predicted both anterior- (p=0.01) and lateral-plane (p=0.04) malposition. Lateral-plane malposition predicted decreased LVAD FI at three (p=0.03) and six (p=0.01) months. Total malposition magnitude predicted increased 30-day HFRAs (p=0.04), while lateral-plane malposition predicted more overall HFRAs (p=0.01). Malposition was not associated with PT/eCVA, changes in MR or LVEDD, or survival free of surgical revision. Conclusions: Patient anatomy and surgical technique were associated with CF-LVAD IFC malposition. In turn, malposition was associated with increased readmissions and decreased LVAD FI.

Background The CTOT-11 (Prevention of Cardiac Allograft Vasculopathy Using Rituximab Therapy in Cardiac Transplantation [Clinical Trials in Organ Transplantation-11]) study was a randomized, placebo-controlled, multicenter, double-blinded clinical trial in nonsensitized primary heart transplant (HTX) recipients. Objectives The study sought to determine whether B cell depletion therapy would attenuate the development of cardiac allograft vasculopathy. Methods A total of 163 HTX recipients were randomized to rituximab 1,000 mg intravenous or placebo on days 0 and 12 post-transplant. Primary outcome was change in percent atheroma volume (PAV) from baseline to 1 year measured by intravascular ultrasound. Secondary outcomes included treated episodes of acute rejection, de novo anti-HLA antibodies (including donor-specific antibodies), and phenotypic differentiation of B cells. Results There were no significant differences at study entry between the rituximab and placebo groups. Paired intravascular ultrasound measures were available at baseline and 1 year in 86 subjects (49 rituximab, 37 placebo). The mean ± SD change in PAV at 12 months was +6.8 ± 8.2% rituximab versus +1.9 ± 4.4% placebo (p = 0.0019). Mortality at 12 months was 3.4% rituximab versus 6.8% placebo (p = 0.47); there were no retransplants or post-transplant lymphoproliferative disorder. The rate of treated rejection was 24.7% rituximab versus 32.4% placebo (p = 0.28). Rituximab therapy effectively eliminated CD20+/CD19+ B cells followed by a gradual expansion of a CD19– cell population in the rituximab-treated group. Conclusions A marked, unexpected increase in coronary artery PAV with rituximab was observed during the first year in HTX recipients. One-year mortality was not impacted; however, longer-term follow-up and mechanistic explanations are required. (Prevention of Cardiac Allograft Vasculopathy Using Rituximab [Rituxan] Therapy in Cardiac Transplantation; NCT01278745)

The Office of the United Nations High Commissioner for Refugees (UNHCR) works increasingly in societies where conflict or human rights violations of massive proportions have very much relativized the notion of rule of law. These are situations in which the basic components of the machinery of protection and justice simply do not exist, or where they do exist, have lost their legitimacy. In terms of practical outcomes for their persecuted, attacked, or terrorized populations, the relevance of rule of law has to be painfully reconstructed, institution by institution, law by law, and capacity by capacity. UNHCR contributes to this effort, because it can make the difference between solutions or protracted exile for refugees, and if refugee issues go unresolved, the prospects for real and lasting peace are much diminished. The article gives a brief overview of recent developments in this area, examines the challenges the UNHCR faces, stresses the importance of prioritizing the reestablishment of the rule of law, and outlines some lessons learned. Particular challenges include competing justice systems, the tensions between “top down” and “bottom up” approaches, and the issues of land rights and the fight against impunity.

It is an unfortunate but true cliche that we live in a seriously troubled world. Turbulence and conflict in many parts of the world from Africa to Iraq and Asia, as well as persecution of peoples because of their ethnicity, politics or religion in countries on all continents continue to be facts of modern day life. We also live in a world the population of which is increasingly mobile, where horizons are ever broader and where the impetus to migrate has its roots in a myriad of social, economic, political and human rights 'push' and 'pull' factors. Conflict, human rights violations, lack of social progress, economic under-privilege and sharp divisions between the 'haves' and the 'have nots' will variously continue to push Sudanese, Uzbeks, Iraqis, Afghans, Sri Lankans, Somalis, Liberians, Chechens, Montagnards and Acehenese, to name but a few groups, towards and across the borders of other countries. These other countries will not only be those which traditionally receive large numbers of refugees. They also include countries with economies in transition, countries on transit routes, and countries where prospects look just that little better. Mobility cannot be prevented. The odds are against this, not least because of the impossibility of policing all the world's borders and the prevalence of people smuggling and trafficking. As far as refugees are concerned, prevention of flight, which denies them their basic security and safety is not only impossible, it is also not permitted under international law. The objective therefore should not be to prevent movement, but to manage better the many sensitive issues at stake, including national security and identity, social harmony and economic progress, in a manner which protects individual rights and State interests, promotes a proper sharing of responsibilities and maximizes the benefits that migration of all sorts can bring to host societies. This paper offers some reflections on the issue of asylum: the challenges of upholding asylum in the context of mixed migration flows; on cooperation and responsibility sharing; and on possible approaches in this regard. The paper reflects upon efforts to devise new approaches, which are being built around regional initiatives situated in countries close to the origin of such flows. These reflections are situated in the context of the major geopolitical changes that have impacted on refugee movements and on the asylum policies of all affected States. In addition, the paper comments on what is lawful and what is doubtfully legitimate from an international protection perspective and suggests possible initiatives to meet States' responsibilities regarding individuals' protection needs, within a framework of rights and law, while respecting the legitimate concerns of States.

Résumé Directeur pour la protection à l'Office du Haut Commissaire des Nations Unies pour les réfugiés, l'auteur brosse un large tableau des activités dévolues au HCR, que résume la notion de « protection » des réfugiés. Après avoir brièvement rappelé l'histoire de la protection internationale des réfugiés, elle examine la question de savoir si la Convention de 1951 relative au statut des réfugiés est toujours à la hauteur pour résoudre les problèmes liés aux migrations de masse qui caractérisent notre époque. Mêime si la Convention de 1951 n'est pas idéale, elle reste le seul traité international reconnu par la quasi-totalité des États pour légitimer le régime de protection des réfugiés. Afin de renforcer cette protection, le HCR a récemment engagé une vaste consultation des États, des organisations non gouvernementales et des réfugiés eux-mêmes pour mieux définir les problèmes et y trouver des solutions dans le contexte actuel. L'auteur est convaincu que cette consultation renforcera la détermination de la communauté internationale à mieux protéger les réfugiés.

List of maps List of tables List of annexes Notes on contributors and editors Foreword Preface Acknowledgments Table of cases Table of treaties and other international instruments List of abbreviations Part 1 Introduction 1.1 Refugee protection today: an overall perspective Volker Turk and Frances Nicholson 1.2 Age and gender dimensions in international refugee law Alice Edwards 1.3 Declaration of the Ministerial Meeting of States Parties to the 1951 Convention and/or its 1967 Protocol Relating to the Status of Refugees Part 2 Non-refoulement (Article 33 of the 1951 Convention) 2.1 The scope and content of the principle of non-refoulement: Opinion Sir Eli Lauterpacht and Daniel Bethlehem 2.2 Summary Conclusions: The principle of non-refoulement 2.3 List of participants Part 3 Illegal Entry (Article 31) 3.1 Article 31 of the 1951 Convention Relating to the Status of Refugees: non-penalization, detention, and protection Guy S. Goodwin-Gill 3.2 Summary Conclusions: Article 31 of the 1951 Convention 3.3 List of participants Part 4 Membership of a Particular Social Group (Article 1A(2)) 4.1 Protected characteristics and social perceptions: an analysis of the meaning of 'membership of a particular social group' T. Alexander Aleinikoff 4.2 Summary Conclusions: membership of a particular social group 4.3 List of participants Part 5 Gender-related Persecution (Article 1A(2)) 5.1 Gender-Related Persecution Rodger Haines QC 5.2 Summary Conclusions: gender-related persecution 5.3 List of participants Part 6 Internal Protection/Relocation/Flight Alternative 6.1 Internal protection/relocation/flight alternative as an aspect of refugee status determination James Hathaway and Michelle Foster 6.2 Summary Conclusions: internal protection/relocation/flight alternative 6.3 List of participants Part 7 Exclusion (Article 1F) 7.1 Current issues in the application of the exclusion clauses Geoff Gilbert 7.2 Summary Conclusions: exclusion from refugee status 7.3 List of participants Part 8 Cessation (Article 1C) 8.1 Cessation of refugee protection Joan Fitzpatrick and Rafael Bonoan 8.2 Summary Conclusions: cessation of refugee status 8.3 List of participants Part 9 Family unity (Final Act, 1951 UN Conference) 9.1 Family unity and refugee protection Kate Jastram and Kathleen Newland 9.2 Summary Conclusions: family unity 9.3 List of participants Part 10 Supervisory Responsibility (Article 35) 10.1 Supervising the 1951 Convention Relating to the Status of Refugees: Article 35 and beyond Walter Kalin 10.2 Summary conclusions: supervisory responsibility 10.3 List of participants Index.

The second day of the expert roundtable addressed the cessation clauses of the 1951 Convention relating to the Status of Refugees, based on two discussion papers, ‘Current Issues in Cessation of Protection under Article 1C of the 1951 Convention and Article I.4 of the 1969 OAU Convention’, by Professor Joan Fitzpatrick and ‘When is International Protection No Longer Necessary? The “Ceased Circumstances” Provisions of the Cessation Clauses: Principles and UNHCR Practice, 1973–99’, by Rafael Bonoan. Participants were also provided with the UNHCR Guidelines on the Application of the Cessation Clauses and written contributions from: the Government of the Netherlands; Judge Bendicht Tellenbach, Swiss Asylum Appeal Commission; and Dr Penelope Mathew, Australian National University. NGO and other input was fed into the process in the course of the discussion. Professor Walter Kalin moderated the discussion. The following Summary Conclusions do not represent the individual views of each participant or necessarily of UNHCR, but reflect broadly the issues emerging from the discussion. State and UNHCR practice with respect to the cessation clauses One of the objectives of the discussion was to understand why, overall, the cessation clauses under the 1951 Convention are little-used provisions by States. There was therefore considerable discussion across the range of issues which impact on the application of the cessation clauses. The emergent focus of the discussion was on the more complex issue of the application of Articles 1C(5) and (6). […]