Spatiotemporal hierarchical Bayesian analysis to identify factors associated with COVID-19 in suburban areas in Colombia.

Introduction: The pandemic had a profound impact on the provision of health services in Cúcuta, Colombia where the neighbourhood-level risk of Covid-19 has not been investigated. Identifying the sociodemographic and environmental risk factors of Covid-19 in large cities is key to better estimate its morbidity risk and support health strategies targeting specific suburban areas. This study aims to identify the risk factors associated with the risk of Covid-19 in Cúcuta considering inter -spatial and temporal variations of the disease in the city's neighbourhoods between 2020 and 2022. Methods: Age-adjusted rate of Covid-19 were calculated in each Cúcuta neighbourhood and each quarter between 2020 and 2022. A hierarchical spatial Bayesian model was used to estimate the risk of Covid-19 adjusting for socioenvironmental factors per neighbourhood across the study period. Two spatiotemporal specifications were compared (a nonparametric temporal trend; with and without space-time interaction). The posterior mean of the spatial and spatiotemporal effects was used to map the Covid-19 risk. Results: There were 65,949 Covid-19 cases in the study period with a varying standardized Covid-19 rate that peaked in October-December 2020 and April-June 2021. Both models identified an association of the poverty and stringency indexes, education level and PM10 with Covid-19 although the best fit model with a space-time interaction estimated a strong association with the number of high-traffic roads only. The highest risk of Covid-19 was found in neighbourhoods in west, central, and east Cúcuta. Conclusions: The number of high-traffic roads is the most important risk factor of Covid-19 infection in Cucuta. This indicator of mobility and connectivity overrules other socioenvironmental factors when Bayesian models include a space-time interaction. Bayesian spatial models are important tools to identify significant determinants of Covid-19 and identifying at-risk neighbourhoods in large cities. Further research is needed to establish causal links between these factors and Covid-19.

The future direction of the adult heart allocation system in the United States.

Ensuring equitable and fair organ allocation is a central charge of the United Network for Organ Sharing (UNOS) as the Organ Procurement and Transplantation Network (OPTN) through its contract with the Department of Health and Human Services (DHHS). The OPTN/UNOS Board initiated a reassessment of the current allocation system. This paper describes the efforts of the OPTN/UNOS Heart Subcommittee, acting on behalf of the OPTN/UNOS Thoracic Organ Transplantation Committee, to modify the current allocation system. The Subcommittee assessed the limitations of the current three-tiered system, outcomes of patients with status exceptions, emerging ventricular assist device (VAD) population, options for improved geographic sharing and status of potentially disenfranchised groups. They analyzed waiting list and posttransplant mortality rates of a contemporary cohort of patient groups at risk, in collaboration with the Scientific Registry of Transplant Recipients to develop a proposed multi-tiered allocation scheme. This proposal provides a framework for simulation modeling to project whether candidates would have better waitlist survival in the revised allocation system, and whether posttransplant survival would remain stable. The tiers are subject to change, based on further analysis by the Heart Subcommittee and will lead to the development of a more effective and equitable heart allocation system.

Report from a forum on US heart allocation policy.

Since the latest revision in US heart allocation policy (2006), the landscape and volume of transplant waitlists have changed considerably. Advances in mechanical circulatory support (MCS) prolong survival, but Status 1A mortality remains high. Several patient subgroups may be disadvantaged by current listing criteria and geographical disparity remains in waitlist time. This forum on US heart allocation policy was organized to discuss these issues and highlight concepts for consideration in the policy development process. A 25-question survey on heart allocation policy was conducted. Among attendees/respondents were 84 participants with clinical/published experience in heart transplant representing 51 US transplant centers, and OPTN/UNOS and SRTR representatives. The survey results and forum discussions demonstrated very strong interest in change to a further-tiered system, accounting for disadvantaged subgroups and lowering use of exceptions. However, a heart allocation score is not yet viable due to the long-term viability of variables (used in the score) in an ever-developing field. There is strong interest in more refined prioritization of patients with MCS complications, highly sensitized patients and those with severe arrhythmias or restrictive physiology. There is also strong interest in distribution by geographic boundaries modified according to population. Differences of opinion exist between small and large centers.

Heart transplantation in the United States, 1998-2007.

This article highlights trends in heart transplantation from 1998 to 2007, using data from the Organ Procurement and Transplantation Network (OPTN) and the Scientific Registry of Transplant Recipients (SRTR). The number of candidates actively awaiting heart transplantation has declined steadily, from 2525 in 1998 to 1408 in 2007, a 44% decrease. Despite this decline, a larger proportion of patients are listed as either Status 1A or 1B, likely secondary to increased use of mechanical circulatory support. During this time, the overall death rate among patients awaiting heart transplantation fell from 220 to 142 patients per 1000 patient-years at risk; this likely reflects better medical and surgical options for those with end-stage heart failure. This trend was noted across all racial groups, both sexes, all disease etiologies (retransplantation excepted) and all status groups. Recipient numbers were relatively stable over the past decade. In 2007, 2207 transplants were performed, although the proportion of patients transplanted as Status 1A shifted from 34% to 50%. A trend toward transplanting more patients above 65 years of age was seen. Adjusted patient (and graft) survival at 3 months, 1, 5 and 10 years after transplantation has gradually, but significantly, improved during the same period; current patient survival estimates are 93%, 88%, 74% and 55%, respectively.

Expression of cathepsin K is regulated by shear stress in cultured endothelial cells and is increased in endothelium in human atherosclerosis.

Cathepsins, the lysosomal cysteine proteases, are involved in vascular remodeling and atherosclerosis. Genetic knockout of cathepsins S and K in mice has shown to reduce atherosclerosis, although the molecular mechanisms remain unclear. Because atherosclerosis preferentially occurs in arteries exposed to disturbed flow conditions, we hypothesized that shear stress would regulate cathepsin K expression and activity in endothelial cells. Mouse aortic endothelial cells (MAEC) exposed to proatherogenic oscillatory shear (OS, +/- 5 dyn/cm(2) for 1 day) showed significantly higher cathepsin K expression and activity than that of atheroprotective, unidirectional laminar shear stress (LS, 15 dyn/cm(2) for 1 day). Western blot and active-site labeling studies showed an active, mature form of cathepsin K in the conditioned medium of MAEC exposed to OS but not in that of LS. Functionally, MAEC exposed to OS significantly increased elastase and gelatinase activity above that of LS. The OS-dependent elastase and gelatinase activities were significantly reduced by knocking down cathepsin K with small-interfering (si) RNA, but not by a nonsilencing siRNA control, suggesting that cathepsin K is a shear-sensitive protease. In addition, immunohistochemical analysis of atherosclerotic human coronary arteries showed a positive correlation between the cathepsin K expression levels in endothelium and elastic lamina integrity. These findings suggest that cathepsin K is a mechanosensitive, extracellular matrix protease that, in turn, may be involved in arterial wall remodeling and atherosclerosis.

Warfarin therapy does not increase bleeding in patients undergoing heart transplantation.

BACKGROUND: Historically, warfarin has been discontinued or rapidly reversed with fresh frozen plasma in patients awaiting heart transplantation because of concerns regarding excessive bleeding. Because preoperative warfarin may have effects on bleeding after cardiac operations, we reviewed our experience to determine the risks in patients undergoing heart transplantation while maintained on warfarin. METHODS: The records of consecutive adult patients undergoing heart transplantation from January 1996 to December 1998 were reviewed. Preoperative and 24-hour postoperative data were obtained, including patient demographics; hematologic laboratory values; medication use; repeat or primary sternotomy data; allogeneic blood product administration; and chest tube drainage. Multivariate linear and logistic regression analyses were performed using these variables to determine risk factors for bleeding after heart transplantation. RESULTS: Ninety adult patients, mean age 50 years, underwent orthotopic heart transplantation during the 36-month period. No relationships existed between preoperative international normalized ratio (INR, mean = 1.83 +/- 0.1, p = 0.84) or postoperative INR (mean = 2.2 +/- 0.9, p = 0.63) and chest tube drainage (mean = 721 +/- 63 mL). Relationships were observed between total blood product administration and preoperative INR (partial r = 0.30, p = 0.01) and postoperative INR (partial r = -0.37, p = 0.002); however, preoperative INR did not correlate (p = 0.29) when perioperative use of fresh frozen plasma was factored as a covariate. Inverse relationships were evident between postoperative INR and total blood product exposures, as well as transfusions of platelets (partial r = -0.26, p = 0.03), fresh frozen plasma (partial r = -0.28, p = 0.02), and red cells (partial r = -0.25, p = 0.04). CONCLUSIONS: Although we noted no correlations between INR and chest tube output, inverse relationships were observed with transfusion requirements in the first 24 hours after transplantation. Preoperative warfarin may be safely continued in patients awaiting heart transplantation.

A multicenter, randomized, controlled trial of Celsior for flush and hypothermic storage of cardiac allografts.

BACKGROUND: A multicenter, randomized, controlled, open-label trial was conducted to evaluate the safety and efficacy of Celsior when used for flush and hypothermic storage of donor hearts before transplantation. METHODS: Heart transplant recipients were randomized to one of two treatment groups in which donor hearts were flushed and stored in either Celsior or conventional preservation solution(s) (control). Study subjects were followed for 30 days after transplantation. RESULTS: A total of 131 heart transplant recipients were enrolled (Celsior, n = 64; control, n = 67). The treatment groups were evenly distributed in donor and recipient base line characteristics. Graft loss rate was lower in the Celsior group on day 7 (3% versus 9%) and on day 30 (6% versus 13%), but the difference was not statistically significant based on 95% confidence interval analysis. No significant difference was measured between the Celsior and control groups in 7-day patient survival (97% versus 94%) and the proportion of patients with one or more adverse events (Celsior, 88%; control 87%) or serious adverse events (Celsior, 38%; control, 46%). Significantly fewer patients in the Celsior group developed at least one cardiac-related serious adverse event (13% versus 25%). CONCLUSIONS: Celsior was demonstrated to be as safe and effective as conventional solutions for flush and cold storage of cardiac allografts before transplantation.

Flow cytometric detection of HLA-specific antibodies as a predictor of heart allograft rejection.

BACKGROUND: Historically, panel reactive antibody (PRA) analysis to detect HLA antibodies has been performed using cell-based complement-dependent cytotoxicity (CDC) techniques. Recently, a flow cytometric procedure (FlowPRA) was introduced as an alternative approach to detect HLA antibodies. The flow methodology, using a solid phase matrix to which soluble HLA class I or class II antigens are attached is significantly more sensitive than CDC assays. However, the clinical relevance of antibodies detected exclusively by FlowPRAhas not been established. In this study of cardiac allograft recipients, FlowPRA was performed on pretransplant sera with no detectable PRA activity as assessed by CDC assays. FlowPRA antibody activity was then correlated with clinical outcome. METHODS: PRA analysis by anti-human globulin enhanced (AHG) CDC and FlowPRA was performed on sera corresponding to final cross-match specimens from 219 cardiac allograft recipients. In addition, sera collected 3-6 months posttransplant from 91 patients were evaluated. The presence or absence of antibodies was correlated with episodes of rejection and patient survival. A rejection episode was considered to have occurred based on treatment with antirejection medication and/or histology. RESULTS: By CDC, 12 patients (5.5%) had pretransplant PRA >10%. In contrast, 72 patients (32.9%) had pretransplant anti-HLA antibodies detectable by FlowPRA (34 patients with only class I antibodies; 7 patients with only class II antibodies; 31 patients with both class I and class II antibodies). A highly significant association (P<0.001) was observed between pretransplant HLA antibodies detected by FlowPRA and episodes of rejection that occurred during the first posttransplant year. Fifteen patients died within the first year posttransplant. Of nine retrospective flow cytometric cross-matches that were performed, two were in recipients who had no pretransplant antibodies detectable by FlowPRA. Both of these cross-matches were negative. In contrast, five of seven cross-matches were positive among recipients who had FlowPRA detectable pretransplant antibodies. Posttransplant serum specimens from 91 patients were also assessed for antibodies by FlowPRA. Among this group, 58 patients had FlowPRA antibodies and there was a trend (although not statistically significant) for a biopsy documented episode of rejection to have occurred among patients with these antibodies. CONCLUSIONS: Collectively, our data suggest that pre- and posttransplant HLA antibodies detectable by FlowPRA and not AHG-CDC identify cardiac allograft recipients at risk for rejection. Furthermore, a positive donor reactive flow cytometric cross-match is significantly associated with graft loss. Thus, we believe that detection and identification of HLA-specific antibodies can be used to stratify patients into high and low risk categories. An important observation of this study is that in the majority of donor:recipient pairs, pretransplant HLA antibodies were not directed against donor antigens. We speculate that these non-donor-directed antibodies are surrogate markers that correspond to previous T cell activation. Thus, the rejection episodes that occur in these patients are in response to donor-derived MHC peptides that share cryptic determinants with the HLA antigens that initially sensitized the patient.

Effects of donor bone marrow infusion in clinical lung transplantation.

BACKGROUND: We have demonstrated that donor cell chimerism is associated with a lower incidence of obliterative bronchiolitis (OB) in lung recipients, and that donor chimerism is augmented by the infusion of donor bone marrow (BM). We herein report the intermediate results of a trial combining the infusion of donor BM and lung transplantation. METHODS: Clinical and in vitro data of 26 lung recipients receiving concurrent infusion of donor bone marrow (3.0 to 6.0 x 10(8) cells/kg) were compared with those of 13 patients receiving lung transplant alone. RESULTS: Patient survival and freedom from acute rejection were similar between groups. Of the patients whose graft survived greater than 4 months, 5% (1 of 22) of BM and 33% (4 of 12) of control patients, developed histologic evidence of OB (p = 0.04). A higher proportion (but not statistically significant) of BM recipients (7 of 10, 70%) exhibited donor-specific hyporeactivity by mixed lymphocyte reaction assays as compared with the controls (2 of 7, 28%). CONCLUSIONS: Infusion of donor BM at the time of lung transplantation is safe, and is associated with recipients' immune modulation and a lower rate of obliterative bronchiolitis.

An outbreak of hantavirus pulmonary syndrome, Chile, 1997.

An outbreak of 25 cases of Andes virus-associated hantavirus pulmonary syndrome (HPS) was recognized in southern Chile from July 1997 through January 1998. In addition to the HPS patients, three persons with mild hantaviral disease and one person with asymptomatic acute infection were identified. Epidemiologic studies suggested person-to-person transmission in two of three family clusters. Ecologic studies showed very high densities of several species of sigmodontine rodents in the area.

Single-field total lymphoid irradiation in the treatment of refractory rejection after heart transplantation.

Nine heart transplant recipients were treated with single-field total lymphoid irradiation (TLI) for early (<1 year) or late (>1 year) rejection that was refractory to multiple regimens of immunosuppressive therapy. For patients with early rejection (n = 6), the rejection frequency (rejections/patient/month) decreased from pre-TLI of 1.63 to post-TLI of .02 (p < .001), and for patients with late rejection (n = 3), the rejection frequency decreased from pre-TLI of .23 to post-TLI of .05 (p < .02). The reduced rejection frequencies have been maintained for a mean follow-up of 28.6 (8 to 78) months, and adverse events during or late after TLI were uncommon. Single-field TLI is a safe and effective technique in the management of refractory rejection early or late after heart transplantation.

Lung transplantation: a current perspective.

Lung transplantation is a viable therapeutic option for patients with end-stage lung disease. Quality of life and survival are improved for most recipients. Donor availability remains an impediment to widespread application. The development of OB after lung transplantation continues to affect long-term survival. Clinical and basic science research will provide new strategies to further improve results.

Reperfusion injury in single-lung transplant recipients with pulmonary hypertension and emphysema.

BACKGROUND: The early postoperative course of single-lung transplant recipients depends on the recipient's underlying lung pathophysiology and the degree of ischemic-reperfusion injury. We examined the effect of pulmonary hemodynamics and preoperative diagnosis on early allograft function and the effects of pulmonary hemodynamics, allograft blood flow, and chest radiographs on length of mechanical ventilation and intensive care unit length of stay. METHODS: We retrospectively collected data on 30 single-lung transplant recipients, 15 each with pretransplantation pulmonary hypertension and emphysema. Blood flow to the allografts was quantitated by perfusion scans obtained on the first postoperative day. Chest radiographs were graded for reperfusion injury. Pulmonary and hemodynamic data, gas exchange parameters, duration of mechanical ventilation, and intensive care unit stay were recorded. RESULTS: Patients with pulmonary hypertension had a prolonged intensive care unit stay compared with emphysema patients, but pulmonary artery pressures were not quantitatively related to duration of ventilation during the intensive care unit stay. There was no difference in the severity of allograft infiltrate between the emphysema and pulmonary hypertensive patients. The day 1 chest radiograph score was highly predictive of an intensive care unit stay of > or = 7 days, although the threshold score of those with pulmonary hypertension was significantly lower than in emphysema patients. Allograft blood flow and pulmonary hypertension were not contributors to early graft dysfunction. Allograft perfusion decreased with increasing radiographically demonstrated infiltrate in those with emphysema but not in those with pulmonary hypertension. CONCLUSIONS: Elevated allograft blood flow and pressures do not exacerbate radiographically confirmed reperfusion injury. Reperfusion injury is the major cause of early respiratory morbidity after single-lung transplantation. Allograft perfusion in emphysema patients decreases in response to reperfusion injury, but pulmonary hypertension patients remain almost entirely dependent on allograft function, even with severe chest radiograph scores. This may be an important mechanism by which single-lung transplant recipients with emphysema, unlike those with pulmonary hypertension, are able to mitigate the degree of respiratory impairment associated with reperfusion injury.

Improved multiorgan function after prolonged univentricular support.

Eleven cardiac transplant candidates (all male; mean age, 43.3 years) with multiorgan (hepatic, pulmonary, and/or renal) dysfunction were sustained for prolonged periods (> 30 days) with the HeartMate (Thermo Cardiosystems, Inc, Woburn, MA) left ventricular assist device. We evaluated the effect of extended support on end-organ recovery and on the ultimate outcome of cardiac transplantation. In addition to cardiac failure, 9 patients had hepatic dysfunction, 8 had pulmonary dysfunction, and 6 had renal dysfunction (4 of whom required hemodialysis before left ventricular assist device support). Mean duration of support was 115 days (range, 31 to 233 days). All patients underwent successful transplantation; 10 of these patients survived a mean of 24 months. One patient, who had required hemodialysis and ventilatory support during and after support, experienced progressive multiorgan failure and died 7 weeks after transplantation. Two late deaths after transplantation were unrelated to the device. Overall, patients experienced improvement in cardiac functional class status, and most participated in cardiac rehabilitation programs before transplantation. During left ventricular assist device support, hepatic function returned to normal in 8 patients, pulmonary function recovered in 7, and renal function returned to normal in 4. One patient who required hemodialysis underwent renal transplantation after cardiac transplantation and had complete recovery of renal function. In the current era of donor shortages, gravely ill patients can benefit from a strategy of prolonged left ventricular assist device support. This strategy has proved safe, has allowed for reversal of multiorgan dysfunction, and has produced healthier transplant candidates.

Reevaluation of steroid tapering after steroid pulse therapy for heart rejection.

A retrospective analysis was conducted to determine the efficacy and complications resulting from steroid pulse therapy, with or without a steroid taper, in 93 episodes of heart transplant rejection that occurred in 72 patients (58 men, 14 women; mean age, 47.6 years). Each rejection episode was classified according to severity (Texas Heart Institute endomyocardial biopsy scale) and the treatment. Group 1 included 25 episodes of grade 7, 8, 9, or 10 rejection (International Society for Heart Transplantation [ISHT] grade IIIB or IV) that were treated with high-dose methylprednisolone (2.5 to 3.0 gm) and a steroid taper of 1.75 gm over 30 days. Group 2 included 16 episodes of rejection, with the severity of rejection and methylprednisolone pulse therapy being similar to that in group 1, but without a steroid taper. The results of treatment in group 1 were compared with those in group 2. Group 3 included 12 episodes of grade 5, 6, or 7 rejection (ISHT grade IIIA or IIIB) that were treated with moderate-dose methylprednisolone (1.0 to 2.0 gm) and a steroid taper, as described. Group 4 included 40 episodes of rejection, with the severity of rejection and methylprednisolone therapy being similar to that of group 3, but without a steroid taper. The results of treatment in group 3 were compared with those in group 4. No statistically significant differences were found among the groups regarding subsequent episodes of rejection or infection within 3 months of treatment. No statistically significant difference was noted among the groups in the number of rejection episodes requiring additional therapy to control the rejection.(ABSTRACT TRUNCATED AT 250 WORDS)

Successful bridge to heart transplantation with a new left ventricular assist device.

During the last 5 years, a new pneumatically driven left ventricular assist device has been implanted in 18 heart transplantation candidates who required advanced mechanical circulatory support. The mean duration of support was 80 +/- 74 days, and the cumulative support time was 1400 days. Fifteen patients were successfully supported until the time of heart transplantation. As a result of early experience, in which three of four patients died after heart transplantation because their end-organ function failed to recover, subsequent efforts were made to institute support early, before irreversible organ damage occurred. Eleven of the 12 patients in the later experience are currently alive and well at a mean follow-up of 12.6 +/- 7.5 months. No thromboembolic episodes occurred, and minimal anticoagulation was required. Furthermore, patients were able to participate in rehabilitative exercise programs, thus optimizing their transplantation status. Finally, the findings in these patients have shown the feasibility of providing long-term, or even permanent, cardiac assistance.

Heart transplantation after mechanical circulatory support: four years' experience.

To determine the effect of mechanical circulatory support before heart transplantation, we conducted a retrospective analysis of 207 men who underwent staged orthotopic transplantations. Of these patients, 185 (group I) required pharmacologic support before transplantation; 14 (group II) required mechanical circulatory support with an intraaortic balloon pump (duration of support, 1 to 26 days); and eight (group III) required advanced mechanical circulatory support with an implantable left ventricular assist device (duration of support, 19 to 132 days). A comparison of complications after transplantation (infection and rejection), hospitalization, and survival showed that no significant differences existed among the three groups. In each group, respectively, 1-year survival was 80.9%, 77.3%, and 75%, and 2-year survival was 75.7%, 67.7%, and 75%. Based on our experience, patients receiving mechanical circulatory support before transplantation can be expected to have a good outcome. In fact, such support can help to improve their end-organ perfusion, and, thus, their status as heart transplantation candidates. Furthermore, this study shows that advanced mechanical circulatory support is possible even for prolonged periods, with low risk of sudden death. This finding is an important step toward development of a permanent assist device.

Adjuvant native heart surgery during heterotopic heart transplantation: two case reports.

The results of heterotopic heart transplantation may be further improved if repairs on native heart abnormalities are performed just before implantation of the allograft. Such procedures increase the potential for the recipient's own heart to recover function and, thus, to maintain circulation if the heterotopic heart malfunctions or fails. The native hearts of two of our patients, both women, showed signs of greater contractility and ejection after repair and were able to provide adequate circulatory support during periods of donor heart failure. The first patient required ventricular aneurysmectomy and coronary artery bypass grafting, and the second, native mitral valve repair. Moreover, when persistent ventricular fibrillation occurred in the donor heart of the first patient, a donor cardiectomy was performed, and the recipient heart functioned well thereafter. As more adjuvant operations are performed and the results evaluated, we may find that heterotopic operations would be suitable in a greater variety of heart transplant candidates.