Donor Gender Research Articles

Female Gender Is Associated with Improved Long-Term Survival Following Allogeneic Hematopoietic Stem Cell Transplant

Introduction: Life expectancy for long-term survivors of allogeneic hematopoietic stem cell transplant (allo-HCT) is significantly lower compared to that of the age-matched general population, despite a relatively low primary disease relapse rate >2 years post-transplant. Long-term transplant-related complications instead account for most mortality in this patient population. These include chronic graft-versus-host disease (cGVHD), infection, organ failure, and secondary cancers. In addition, gender is emerging as a critical determinant of outcome in the immediate post-transplant setting. However, less is known regarding gender effects on outcomes of long-term survivors. We retrospectively investigated the impact of recipient gender and donor-recipient gender mismatch on outcomes of long-term survivors of allo-HCT. Methods: We performed a retrospective analysis using Duke University's Adult Blood and Marrow Transplant database, supplemented by individual patient chart review. Inclusion criteria consisted of long-term survivors of first allo-HCT, excluding syngeneic, between 1995 - 2015 for a hematologic malignancy. A long-term survivor is defined as having been alive with documented follow-up to at least five years following allo-HCT. Patient characteristics were summarized as count (%) for categorical variables and median (interquartile range) for continuous variables. Fisher's exact tests or t-tests were used to compare difference between groups. Overall survival was estimated using the Kaplan-Meier method and multivariable Cox proportional hazard model. Patients who had received cord blood allograft were excluded from donor-recipient gender survival analyses. SAS version 9.4 (SAS Institute, Cary, NC) and R 3.5.0 were used to perform statistical analyses. Results: Over this 20-year period, 1103 patients underwent allo-HCT, with 247 (22%) meeting inclusion criteria. Of these 247, males and females had similar demographic and treatment characteristics (Table 1). However, significantly more deaths after the 5-year landmark occurred in male recipients (Figure 1, p value=0.003). To estimate whether this was due to the general population-wide shorter life expectancy for males, we performed Kaplan-Meier estimates of survival for patients aged < 50 years at transplant and aged ≥ 50 years at transplant, with similar results for both groups (Figure 2, p value=0.006). Interestingly, donor gender did not have a significant impact on overall survival in multivariate analysis (Table 2), and differences in overall survival of donor-recipient gender pairs was driven by patient gender (Figure 3, p value =0.007). A separate multivariate analysis of interaction between donor-recipient gender pairs further demonstrated that significant differences in overall survival were due to patient gender (Table 3). In addition to patient gender, only cGVHD retained significance as a covariate with impact on overall survival in multivariate analysis (Table 2, Table 3). Men experienced slightly higher rates and increased severity of cGVHD, and a greater percentage of cGVHD-related mortality as compared to females, though these findings were not statistically significant (Table 1). Conclusion: In this long-term survival analysis of allo-HCT adult patients, one of the only to include follow-up to 15 years, our results show that women survive significantly longer than men irrespective of their age at transplant. This outcome is independent of other common pre-transplant prognostic indicators such as donor gender or performance status at transplant. Inferior survival for males is consistent with survival outcomes described in another large and fully risk annotated HCT cohort, and in solid organ transplants such as lung and kidney. Gathering evidence suggests a biologic basis for long-term gender-determined outcomes, possibly due to differing rates or severity of cGVHD or sustained alloimmune tolerance in females. Male patients should be counseled on their possible increased long-term risk. Prospective and larger studies are warranted to validate these retrospective clinical results. Disclosures Rizzieri: Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Stemline: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite: Honoraria, Speakers Bureau; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; abbvie: Membership on an entity's Board of Directors or advisory committees; AROG: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Celltrion: Membership on an entity's Board of Directors or advisory committees; Mustang: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees; Acrobiotech: Membership on an entity's Board of Directors or advisory committees.

Mesenchymal Stem Cells (MSCs) Intensify the Impact of KIR Ligand-Mismatching on Acute Graft-Versus-Host Disease Post HSCT in Patients with Acute Myeloid Leukemia but Not with Acute Lymphocytic Leukemia

Objectives: Mesenchymal stem cells (MSCs) and killer cell immunoglobulin-like receptor (KIR) ligand-mismatch, which can trigger the alloreactivity of natural killer (NK) cells, have been shown to be protective for severe acute and chronic graft-versus-host disease (aGVHD, cGVHD) following allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, there are no prospective or retrospective studies exploring their relationship. Here, we investigated the potential influence of KIR matching, MSCs and their coaction on GVHD prophylaxis, overall survival (OS) and relapse rate (RR) of allo-HSCT. Methods: Data from 154 patients with acute myeloid and lymphocytic leukemia treated with allo-HSCT between May 2015 and May 2020 in the transplantation unit of the Fujian Medical University Union Hospital were retrospectively analyzed. The cohort included 93 male patients (60.3%) and 61 female (39.7%), with a median age of 24 years (1-59 years), 104 cases of acute myeloid leukemia (AML; 67.5%) and 50 cases with acute lymphocytic leukemia (ALL; 32.5%). Eighty-one patients (52.6%) underwent MSCs infusion on day+1. The sources of MSCs were human placenta or human bone marrow. MSCs infusion dose ranged from 0.5 to 3x106/kg of recipient weight. KIR genotyping was performed by the PCR-SSO method. The amplicons were quantified on the Luminex 200 flow analyzer and analyzed using the Quick-Type for Lifecodes software for generating KIR data. Cox proportional hazards model and Kaplan-Meier survival curves were used for analysis. Results: At the time of transplantation, 65 cases (42.2%) were in remission, while 89 (57.8%) had active disease. aGVHD occurred in 31 patients (20.1%) and recurrence arose in 21 patients (13.6%), but no significant cGVHD was observed. After adjusting for age, disease-risk, HLA-match, donor gender, conditioning regimen intensity and type of post-grafting GVHD prophylaxis, Cox regression analysis revealed that KIR ligand-matching was associated with an increased risk of aGVHD compared to KIR ligand-mismatching (p=0.023) in AML patients, but KIR ligand-mismatching had no significant effect on aGVHD in ALL patients, and on OS and RR in both AML and ALL patients. MSCs was associated with much lower recurrence rate (RR) (p=0.049), even when the recipients were not in remission at the time of HSCT. Furthermore, MSCs reduced the incidence of aGVHD in both AML and ALL patients, although it did not reach statistical significance (p=0.19). The combination of KIR ligand-mismatching and MSCs infusion significantly suppressed aGVHD occurrence in AML patients (p=0.033). More importantly, MSCs infusion intensified the suppression effect of KIR ligand-mismatching on aGVHD in AML patients (p=0.047). In the KIR ligand-mismatch group, the incidence of aGVHD was 10.3% when patients received MSCs, compared to 25.6% in those who did not. However, combining KIR ligand-mismatch and MSCs injection had no significant effect on aGVHD in ALL patients, or on OS and RR in both AML and ALL patients. Conclusions: KIR ligand-mismatch, MSCs infusion and their combination significantly reduced the risk of aGVHD after allo-HSCT in AML patients. It confirms the relationship between MSCs injection and lower RR. These data provide a clinically applicable strategy where co-transplantation with MSCs and triggering of allo-NK cells by KIR ligand-mismatching can ameliorate aGVHD, thus improving allo-HSCT outcome in AML patients. Disclosures No relevant conflicts of interest to declare.

Replicative senescence and arteriosclerosis after kidney transplantation.

Replicative senescence is associated with telomere shortening. In native kidneys, obtained prior to transplantation, we recently described and validated a significant association between shorter intrarenal telomere length and renal arteriosclerosis. After renal transplantation, animal experiments suggested that ischaemia-reperfusion injury, acute rejection episodes and cytomegalovirus disease associate with accelerated renal allograft senescence. The association between post-transplant events and replicative senescence has not yet been evaluated in a human setting. In a cohort of 134 kidney allograft recipients, we performed protocol-specified renal allograft biopsies at 3 months, 1 year, 2 years and 5 years after transplantation (n = 579 biopsies). We used quantitative real-time polymerase chain reaction to measure intrarenal relative average telomere length (T/S ratio). The association between donor and recipient demographic factors, post-transplant clinical/histological events, renal allograft histological evolution by 5 years post-transplant and intrarenal telomere length at 5 years after transplantation was studied using multiple regression models. At 5 years after transplantation, shorter intrarenal telomere length was associated with male donor gender, older donor age, donor history of hypertension and donor cardiovascular risk, which confirms the associations observed in native kidneys. Recipient characteristics and post-transplant events like delayed graft function, acute rejection episodes, presence of donor-specific antibodies, cytomegalovirus disease and immunosuppressive regimen did not associate with alterations of intrarenal telomere length at 5 years. Independent of donor age and donor cardiovascular risk, intrarenal arteriosclerosis in protocol biopsies obtained at 5 years after transplantation and progressive arteriosclerosis over time after transplantation associated with shorter telomere length, while this was not the case for other histological lesions. Moreover, telomere attrition augments the association between older donor age and the presence of severe arteriosclerosis. In the group with the oldest donor age and shortest telomere length, there was significantly more severe arteriosclerosis (43%) in protocol biopsies at 5 years after transplantation, compared with other combinations (13-28%) (P = 0.001). Intrarenal arteriosclerosis at 5 years after transplantation did not associate with post-transplant clinical events. We demonstrate that intrarenal telomere length at 5 years after transplantation, as a marker for replicative senescence, associates with renal arteriosclerosis and reflects kidney donor characteristics, but not post-transplant events.

IFNL4 and donor selection for matched unrelated donor haematopoietic stem-cell transplantation

IFNL4 and donor selection for matched unrelated donor haematopoietic stem-cell transplantation

Substrate oxidation in primary human skeletal muscle cells is influenced by donor age

Primary human myotubes represent an alternative system to intact skeletal muscle for the study of human diseases related to changes in muscle energy metabolism. This work aimed to study if fatty acid and glucose metabolism in human myotubes in vitro were related to muscle of origin, donor gender, age, or body mass index (BMI). Myotubes from a total of 82 donors were established from three different skeletal muscles, i.e., musculus vastus lateralis, musculus obliquus internus abdominis, and musculi interspinales, and cellular energy metabolism was evaluated. Multiple linear regression analyses showed that donor age had a significant effect on glucose and oleic acid oxidation after correcting for gender, BMI, and muscle of origin. Donor BMI was the only significant contributor to cellular oleic acid uptake, whereas cellular glucose uptake did not rely on any of the variables examined. Despite the effect of age on substrate oxidation, cellular mRNA expression of pyruvate dehydrogenase kinase 4 (PDK4) and peroxisome proliferator–activated receptor gamma coactivator 1 alpha (PPARGC1A) did not correlate with donor age. In conclusion, donor age significantly impacts substrate oxidation in cultured human myotubes, whereas donor BMI affects cellular oleic acid uptake.

SURGICAL COMPLICATIONS IN RENAL TRANSPLANT IN A TERTIARY CENTRE IN PAKISTAN

Introduction: The treatment of choice for patients with end stage renal disease is renal transplantation. Despite improvement in peritoneal dialysis and hemodialysis, renal transplant patients survive much longer after receiving a kidney transplant. This is attributed to improved immunosuppressive regimes and advancement in organ storage and surgical technique. Despite the success of renal transplantation postoperative complications can be expected and are not categorically benign, thus making it a double edged sword. Post-operative complications account for 15% - 17% of all cases and are associated with significant morbidity. Complications of renal transplantation can be classified as pathological or surgical entities. Surgical complications can be categorized as vascular complications (arteries, venous thrombosis, transplant renal arterial stenosis, graft rupture, hematoma, etc.) and Urological complications (ureteral obstruction, VUR, urinary leak and fistula). Knowledge of the incidence of clinical manifestation and management of surgical complication is necessary for all kidney transplant surgeons. Objective: Objective of the study is to evaluate the frequency of surgical complications after renal transplant at SIUT. Material and Methods: This is a retrospective cross sectional/cohort study planned to determine patient with organ survival rates along with post-transplant complications from living donor during 1 year from Jan 2018 to Dec 2018. Case notes of all the patients were evaluated and relevant information were gathered. Result was analyzed for patient and donor gender, age of donor and recipients, cause of ESRD, HLA match, single V/S double/triple renal vessels, ischemia time, use of DJ stent and post-operative surgical complications. Data was analyzed using SPSS version 22. Result: From January 1st to 31st December 2018 total of 300 renal transplants were done. Male to female ratio was 3.1: 1. Most common complication noted in this time period was lymphocele which accounts for 8.6%. Ureteric complication were seen in 2.6% of cases. Wound infection were seen in 2.3% of cases. Three patients were presented with forgotten JJ stents. Immediate vascular complications were seen in 3 cases who required redo vascular anastomosis. Exploration was done in 6% of cases because of hematoma and anuria graft. Two patients had graft nephrectomy because of anastomotic site bleeding. Conclusion: Surgical complications after renal transplant are common even at experienced centers. Familiarity with these complications is of utmost importance as early diagnosis and prompt management increase the long- term graft survival.

PROPENSITY SCORE MATCHED RISK OF BILIARY COMPLICATIONS AFTER LIVER TRANSPLANT AND OUTCOME BY DONOR TYPE

Background: Donation after circulatory death (DCD), donation after brain death (DBD), and living donor (LD) liver transplantation (LT) are three types of donors used in patients with end-stage liver diseases. Each type has unique benefits, risks, and potential complications. In this study, we assess the risk of biliary complications, and their effect on long-term outcome. Methods: We collected data on all consecutive DCD, DBD and LD-LT recipients between 1989 and 2019 from a single center, and used propensity score matching to identify three groups. Patient survival, graft survival, and biliary complications (bile leak, anastomotic (AS) and non-anastomotic strictures (NAS)) were analyzed and compared between groups. Adjusted p-values were calculated using multivariate Cox regression models. Results: We identified 141 DCDs, 3,226 DBD, and 386 LD-LT in our cohort, with significantly different recipient age, gender, etiology of liver disease, Na-Model for End-Stage Liver Disease (MELD), incidence of hepatocellular carcinoma (HCC), and donor age, gender, and cold ischemic time. Propensity score matching allowed correction for all differences except MELD, presence of HCC, and etiology of liver disease. This produced three groups of 138 recipients each. Adjustment for MELD, HCC, and etiology of liver disease was then performed using Cox models. Eighteen LT recipients (4.3%) had arterial complications (thrombosis and stenosis; no difference between groups). Bile leak was identified in 10.1% of DCD-LTs, versus 7.2% of DBD-LTs, and 36.2% of LD-LTs (p-values=0.240 and <0.001, respectively). Anastomotic biliary stricture developed in 28.3% DCD-LTs, versus 18.1% of DBD-LTs, and 43.5% of LD-LTs (p-values=0.038 and 0.006, respectively). Non-anastomotic biliary stricture was present in 15.2% of DCD-LT s, versus 1.4% of DBDs-LT, and 4.3% of LD-LTs (p-values=0.004 and 0.005, respectively). Eighteen patients (4.3%) were retransplanted and there was no significant difference in retransplant rate between groups. LD-LTs free of any biliary complications had the best patient survival whereas DCD-LTs with ≥1 biliary complication (presence of a bile leak and/or AS and/or NAS) had the worst survival (Figure). Among the 21 DCD-LT patients with non-anastomotic strictures, six died, two were retransplanted, three remain stent dependent, and ten were ultimately stent-free. Conclusion: DCD and LD-LT recipients had significantly higher rates of biliary complications. Biliary complications in DCD-LTs had the most significant impact on survival, although two thirds of the recipients with ischemic cholangiopathy could ultimately achieve a favorable outcome.

Pre-transplant HLA Antibodies and Delayed Graft Function in the Current Era of Kidney Transplantation.

Delayed graft function (DGF) occurs in a significant proportion of deceased donor kidney transplant recipients and was associated with graft injury and inferior clinical outcome. The aim of the present multi-center study was to identify the immunological and non-immunological predictors of DGF and to determine its influence on outcome in the presence and absence of human leukocyte antigen (HLA) antibodies. 1,724 patients who received a deceased donor kidney transplant during 2008–2017 and on whom a pre-transplant serum sample was available were studied. Graft survival during the first 3 post-transplant years was analyzed by multivariable Cox regression. Pre-transplant predictors of DGF and influence of DGF and pre-transplant HLA antibodies on biopsy-proven rejections in the first 3 post-transplant months were determined by multivariable logistic regression. Donor age ≥50 years, simultaneous pre-transplant presence of HLA class I and II antibodies, diabetes mellitus as cause of end-stage renal disease, cold ischemia time ≥18 h, and time on dialysis >5 years were associated with increased risk of DGF, while the risk was reduced if gender of donor or recipient was female or the reason for death of donor was trauma. DGF alone doubled the risk for graft loss, more due to impaired death-censored graft than patient survival. In DGF patients, the risk of death-censored graft loss increased further if HLA antibodies (hazard ratio HR=4.75, P < 0.001) or donor-specific HLA antibodies (DSA, HR=7.39, P < 0.001) were present pre-transplant. In the presence of HLA antibodies or DSA, the incidence of biopsy-proven rejections, including antibody-mediated rejections, increased significantly in patients with as well as without DGF. Recipients without DGF and without biopsy-proven rejections during the first 3 months had the highest fraction of patients with good kidney function at year 1, whereas patients with both DGF and rejection showed the lowest rate of good kidney function, especially when organs from ≥65-year-old donors were used. In this new era of transplantation, besides non-immunological factors, also the pre-transplant presence of HLA class I and II antibodies increase the risk of DGF. Measures to prevent the strong negative impact of DGF on outcome are necessary, especially during organ allocation for presensitized patients.

Influence of donor and recipient gender on liver transplantation outcomes in Europe.

The impact of gender and donor/recipient gender mismatch on LT outcomes is controversial. The aim of this study was to compare outcomes of LT in Europe, using the ELTR database, between male and female recipients, including donor/recipient gender mismatch. Recipient, donor and transplant characteristics were compared between male and female patients. Patient survival was compared between groups, and the impact of donor/recipient gender matching as well as donor and recipient anthropometric characteristics were evaluated as potential risk factors for post-LT death/graft loss. A total of 46,334 LT patients were evaluated (70.5% men and 29.5% women). Ten-year survival rate was significantly higher in female than in male recipients (66% vs 59%, P<.0001). At multivariate analysis, adjusted for indication to LT and type of graft, donor/recipient gender mismatch (HR 1.12, 95% CI 1.04-1.2; P=.003), donor age>60years (HR 1.09, 95% CI 1.01-1.18; P=.027) and recipient age (HR 1.02, 95% CI 1.1-1.02; P<.0001) were significantly associated with post-LT lower survival rate in men. Conversely in female recipients, donor BMI>30 (HR 1.32, 95% CI 1.09-1.6; P=.005), donor age>60years (HR 1.15, 95% CI 1.01-1.32; P=.027) and recipient age (HR 1.02, 95% CI 1.01-1.02; P<.0001) were significantly associated with lower post-LT survival rate. Donor/recipient gender mismatch in male recipients and the use of obese donor in female recipients are associated with reduced survival after LT. Therefore, the incorporation of donor and recipient anthropometric quantities in the allocation process should be a matter of further studies, as their matching can significantly influence long-term outcomes.

Lipid ratios as a marker for red blood cell storage quality and as a possible explanation for donor gender differences in storage quality.

Red blood cells that are stored for transfusions as red cell concentrates (RCCs) undergo changes during the storage period, culminating in the lysis of the cells. The goal of this work is to find markers that are linked to high haemolysis, in order to explain the inter-donor variability that is known to occur in storage quality, and also the known differences between RCCs from male and female donors. The relative amounts of lipids at the end of the storage period were compared for one group of low haemolysis samples (24 units, all ≤0·15% haemolysis), and one group of high haemolysis samples (26 units, all ≥0·5% haemolysis). Representative lipids were analysed from different lipid classes, including cholesterol, phosphatidylcholine, phosphatidylethanolamine, sphingomyelin and ceramide. Whole membrane preparations were analysed with one mass spectrometry technique, and lipid extracts were analysed with a second mass spectrometry technique. The ratio of palmitoyl-oleoyl phosphatidylcholine (POPC) to sphingomyelin was different for the high and low haemolysis groups (P=0·0001) and for the RCCs from male and female donors (P=0·0009). The ratio of cholesterol to phospholipids showed only minimal links to haemolysis. Higher relative amounts of sphingomyelin were associated with lower haemolysis, and higher relative amounts of ceramides were associated with increased haemolysis. The level of sphingomyelinase activity and the resulting ratio of sphingomyelin to POPC is proposed as a possible marker for RCC storage quality.

Donor risk factors and recipient clinical impact of positive microbial contamination after bone marrow harvests - a large academic medical center experience

Background & Aim Background Microbial contamination (+MC) is a complication of bone marrow harvestS. However, risk factors for +MC and implications for recipients are not well-defined. Clinical interventions after +MC range from observation to antimicrobial therapy. Methods, Results & Conclusion Methods We report a retrospective review of 91 pediatric and 101 adult related-donor marrow harvests from Jan 2015 to Mar 2019. Harvests were performed at Boston Children's Hospital (pedi) or Brigham & Women's Hospital (adult) under general anesthesia. Donors received no systemic antimicrobials, just topical sterilization. Samples were cultured in BacT systems and incubated for 14 days at 35°C. Results 19.4% of harvested products from pedi and 24.8% from adult donors demonstrated ≥ 1 +MC result. Mean donor age, weight, gender, and volume harvested differed between pedi and adult donors: 12 vs 40yr, 45.2 vs 79.4kg, male 47% vs 65%, and 622 vs 1200mL. 37% and 39% of products underwent manipulation, respectively (Table 1). Mean time to detection was 4.7 and 6.1 days after pedi and adult harvests. 7.5% and 5.0% of harvests, respectively, yielded +MC ≤ 2 days; 11.8% and 5.9% by 5 days after harvest. Organisms isolated were P. acnes (n=29), Coag-negative Staphylococcus (n=13) and one other Propionibacterium species (n=1). We examined potential risk factors for + MC such as length of harvest (invasive harvesting time); donor age, weight and gender; manipulation; and cell yield (Table 2). In pediatric harvests, +MC correlated with donor age (19 vs 10yr, p Response to positive cultures was at attending physician discretion. Only 9.3% of recipients of a +MC marrow had antimicrobial therapy added, with no product-transmitted infection seen. Neutrophil and platelet engraftment did not differ between +MC vs No Growth marrow recipients. Rates of infusion reactions were within historical norms (19% adult and 11% pedi) and not impacted by +MC. Analyses of donor AEs and +MC unrelated donor harvests are ongoing. Conclusions +MCs are common after pediatric and adult donor harvests. Risk factors may include longer harvest time and higher donor weight but are not clearly modifiable. Despite this +MC incidence, medical implications for recipients and donors after +MC with routine skin flora are few.

Chemosensory communication of aggression: women's fine-tuned neural processing of male aggression signals.

The current study is the first to examine the central nervous processing of aggression chemosignals within men and women by means of chemosensory event-related potential (CSERP) analysis. Axillary sweat was collected from 17 men and 17 women participating in a competitive computer game (aggression condition) and playing a construction game (control condition). Sweat samples were pooled with reference to donor gender and condition, and presented to 23 men and 25 women via a constant flow olfactometer. Ongoing electroencephalogram was recorded from 61 scalp locations, CSERPs (P2, P3-1, P3-2) were analysed and neuronal sources calculated (low-resolution electromagnetic tomography, LORETA). Women, especially, showed larger P3-1 and P3-2 amplitudes in response to male as compared with female aggression signals (all p values < 0.01). The peak activation of this effect was related to activity within the dorsomedial prefrontal cortex (Brodmann area 8). As male aggression commonly targets physical harm, the competence of the human brain to sensitively detect male aggression signals is considered to be highly adaptive. The detection of male aggression signals seems to be of higher importance for women than for men. It is suggested that the processing of male aggression signals in women induces an immediate response selection.This article is part of the Theo Murphy meeting issue ‘Olfactory communication in humans’.

Generation of two control iPSC clones NCCSi008-A and NCCSi008-B from an individual of Indian ethnicity.

Two iPSC clones, NCCSi008-A and NCCSi008-B, were generated from a healthy male individual of Indian origin by reprogramming his CD4+ T cells with an integration free Sendai viral vector. The established iPSC clones showed high alkaline phosphatase (ALP) activity, expression of pluripotency markers, a normal male karyotype consistent with the donor gender (46, XY) and has potential for multi-lineage differentiation. These iPSC lines of Indian origin would serve as valuable resources for disease modeling, drug development and screening.

The Impact of Donor Gender on Heart Transplantation Outcomes - A Study of over 60,000 Patients in the United States

The objective of this study was to evaluate the impact of donor gender on heart transplantation outcomes in the United States. From 1987 to March 2019, 63,775 adult patients underwent heart transplantation in the United States, and their data were prospectively collected by the United Network for Organ Sharing (UNOS). Patients without missing data were stratified by donor gender (female, N = 11,474; male, N = 27,509) and donor menopause status (pre-menopause, ages 35-40 years old, N = 1,783; post-menopause, ages 50-55 years old, N = 1,105). The groups were propensity matched 1:1 based on year of surgery, pre-transplant status, wait list time, human leukocyte antigen matching, donor demographics, and allograft ischemic time. Paired t-test, McNemor's tests and Kaplan-Meier survival analyses were performed. The primary endpoint was all cause mortality, and secondary endpoints were postoperative complications. Propensity matching generated 15,506 patients based on donor gender and 1,094 patients based on donor menopause status. Recipients who received female donor hearts were more likely to have acute rejection episodes (630/11.9% vs. 545/10.1%, p = .007) and require post-transplant dialysis (837/10.9% vs. 719/9.3%, p = .001) than those who received male donor hearts. No difference was observed between using female or male donor hearts in the rates of graft failure (551/8.2% vs. 641/9.5%) or stroke (179/2.4% vs. 199/2.6%) (p ≥ .34). Median survival using female vs. male donor hearts was 11.6 vs. 12.1 years (p = .34) with ten-year survival of 56.5% vs. 57.1%, respectively. Recipients who received pre- vs. post-menopausal female donor hearts had similar rates of acute rejection episodes (39/11% vs. 45/12.5%), graft failure (37/7.9% vs. 46/9.9%), stroke (10/1.8% vs. 15/2.8%), or requiring dialysis (67/12.3% vs. 81/14.9%) (p ≥ .09). Median survival using pre- vs. post-menopausal female donor hearts was 11.5 vs. 10.4 years (p = .23) with ten-year survival of 56.7% vs. 51.2%, respectively. Analysis of the UNOS database showed similar median survival using female vs. male donor hearts in adult heart transplantation, irrespective of donor menopause status. Currently, female donor hearts are used far less frequently, thus these results represent an opportunity to maximize usage by better utilization of suitable female donor organs.

A Comparative Single Center Study between Two Decades of Fibrosis in Cardiac Allografts

Fibrous remodeling of the myocardium is regarded as the morphological correlate of deterioration of cardiac function. Fibrosis levels are thought to increase with age. Due to an increased shortage of donor organs during the past decade, number of patients bridged to heart transplantion (HTx) with mechanical unloading of the left ventricle using mechanical circulatory systems(MCS), as well as medium donor age have been significantly increased. The aim of this study was to investigate differences in myocardial fibrosis levels of cardiac allografts, postulating that pre-sensitation and systemic inflammatory response to MCS as well as older age of donors are associated with elevated levels of fibrosis in right ventricular endomyocardial biopsies (EMBs)of cardiac allografts in comparison to those a decade ago. All consecutive surveillance EMBs harvested over two calendar years harvested at a single center separated by a decade (n=101 and n=248, respectively) were analysed for levels of interstitial and perivascular fibrosis using a collagen stain (Sirius red). Fibrosis levels were measured in volume percent using a purpose build software solution (Nikon)under visual control in 12 consective high power fields equalling 1qmm. Statistical analysis (Students t-test, ANOVA,regression analysis) were performed to investigate influence of age and gender of donor, age of recipient at time of HTx, influence of MCS and time of harvesting the biopsy after HTx on fibrosis levels. No relevant variation in fibrosis levels in EMBs between the investigated two different consecutive decades could be demonstrated, although donor age was identified as a statistically significant factor (p= 0.026). Furthermore, no significant statistical difference between gender, time after HTx and no difference between MCS and non-MCS patients could be demonstrated. The results warrant further correlative clinico-pathological investigation in view of heart function of cardiac allografts of older donors and long term outcome of cardiac allografts.

Vasopressor Requirement in Patients Undergoing Ventricular Assist Device Explant and Heart Transplant

Vasoplegia post ventricular assist device (VAD) explant and heart transplantation is a well recognised phenomenon. One potential reason for this is the continuous flow nature of current generation VADs. We were interested in exploring the quantity of vasopressor requirement in patients undergoing heart transplantation between three groups - VAD explant (VE), Non-VAD implant previous sternotomy (PS) and no previous sternotomy (NPS). We included 15 patients in each group for a total of 45 patients. Patients were retrospectively identified from our transplant database. We aimed to include our most recent transplants with 30-day outcome data available. Demographic, operative, and post-operative data was obtained from the medical records, operation reports and ICU charts. Statistical analysis was conducted using SPSS v25. There was no significant difference between the three groups in terms of Gender, Age, BMI, Pre-operative eGFR, Donor Ischaemic time, Donor Gender, Donor age or Donor BMI. Intraop blood transfusions were higher in the PS and VE groups compared to the NPS groups, p<0.01. There was no significant difference amongst the groups in terms of blood products. Median Cardiopulmonary bypass time was significantly higher in the PS (195 minutes IQR 139-239) and VE groups (213 minutes IQR 195-254) compared to the NPS groups, p=0.02. When comparing the VE and PS groups, there was no difference in cardiopulmonary bypass time, p=0.29. Milrinone was significantly higher at 24 hours in the VE group compared to the PS and NPS groups, p=0.02. At 48 hours, the VE group had a significantly higher median Epinephrine (13.5 ml/hr IQR 0-30) compared to the PS group (0 ml/hr IQR 0-6) and Median Milrinone (10 ml/hr IQR 4-12) vs 0 ml/hr (IQR 0-6.5). There was no significant difference amongst the three groups with respect to 30 Day mortality, ICU length of stay, ventilation time or overall hospital length of stay. From our data, we can conclude that the VE group had a higher vasopressor requirement than the NPS and PS groups at 48 Hours. Irrespective of these differences, there did not appear to be any difference in ICU length of stay and overall hospital length of stay amongst the three groups.

The Impact of Donor Tobacco and Marijuana Smoking History on Early and Intermediate-Term Lung Transplant Outcomes

Donor tobacco and marijuana smoking are common in the lung donor pool, with both known to adversely affect post-lung transplant (LTx) outcomes. The intermediate survival outcomes and extent of the interactions of these smoking histories has not been described. DonateLife records and clinical databases were combined, with univariate and multivariate analyses undertaken to clarify the relation between donor tobacco and/or marijuana history and LTx outcomes. Between 2014-2018, 304 LTx were performed from 296 donors, including: A) 140 (46%) donor never smokers; B) 114 (38%) tobacco-light smokers (=<20 pk years) ± marijuana-light smoker (=intermittent use < 5yrs); C) 16 (5.3%) tobacco-heavy smokers (>20pk years) ± marijuana-light smokers; D) 20 (6.6%) marijuana-heavy smokers (= daily use or >5 yrs) + tobacco-light or heavy smokers (n=6 light marijuana only & n= 8 no data resulted not included) (Table 1). Donor smoking type, history and extent varied with donor age & gender. Smoking category adversely impacted 24hrPF ratio. Never smoker A) vs Combination D) were the only categories to show 3yr survival rate difference [P=0.02 by Log-rank (Figure 2), Hazard Ratio: 3.00 (95%CI: 1.17-7.69), P=0.02 by Cox Regression, adjusted for LTx type, diagnosis, and extended donor]. A donor smoking history generally has only a small effect on early and later outcomes. Despite a significantly younger donor age, a combined heavy marijuana and tobacco usage history may have long term consequences that need to be balanced against the risk of no-transplant for an individual waiting list potential recipient.

Outcomes of Heart Transplantation from Hepatitis C Seropositive Donors: An Updated Analysis of the United Network for Organ Sharing Registry

Hepatitis C (HCV) has become readily treatable in the modern era. The use of HCV+ organs for transplant has shown promising results and increases donor availability. This study is an updated analysis of outcomes after HCV+ heart transplantation in the United States. The United Network for Organ Sharing registry was queried for adult patients who received heart transplants from 2015-2018. Excluded multiorgan transplants, incomplete HCV data, and loss to follow-up. HCV status was classified by serology (Ab+ vs Ab-). Median follow-up was 24 months. During the study period, 7529 patients received heart transplants: 136 from HCV Ab+ donors and 7393 from HCV Ab- donors. Seven recipients (5.1%) of HCV Ab+ hearts had HCV+ serology prior to transplant, compared to 129 recipients (1.7%) of HCV Ab- organs (p=0.018). There was no difference in donor age (p=0.489), ejection fraction (p=0.221), gender mismatch (p=0.341), or ABO compatibility (p=0.707). HCV Ab+ transplants involved further travel (mean: 323 vs 149 miles, p<0.001) with longer ischemic times (mean: 3.55 vs 3.03 hours, p<0.001) due to regional variation in use of HCV+ organs. Kaplan Meier analysis showed no effect of HCV status on overall survival (p=0.960), and no difference in graft failure (p=0.700). On multivariate Cox regression, HCV status was not a significant predictor of mortality (HR 0.85, 95% CI 0.47-1.56, p=0.601), while overall mortality was affected by HLA mismatch (HR 1.07, 95% CI 1.00-1.14, p= 0.037), donor age (HR 1.01, 95% CI 1.00-1.02, p=0.002), recipient creatinine (HR 1.07, 95% CI 1.04-1.12, p<0.001), and use of ECMO (HR 3.27, 95% CI 2.08-5.12, p<0.001) or a ventricular assist device (HR 1.23, 95% 1.08-1.41, p=0.003) at the time of transplant. Transplantation of HCV+ donor hearts has demonstrated promising outcomes thus far, with comparable overall survival and graft outcomes. Ongoing investigation is warranted to observe long-term outcomes.

Mitigating Risks of Primary Graft Dysfunction with Antegrade Myocardial Perfusion

Primary Graft Dysfunction (PGD) is the leading cause of early mortality after heart transplantation. Several risk factors of PGD have been identified, including; prolonged warm ischaemic time, advanced donor age, gender mismatch and recipient diabetes mellitus. We adopted a novel method of implantation using "antegrade myocardial perfusion (AMP)" during implantation and compared this to the conventional approach. We obtained the retrospective data retrospectively from the Golden Jubilee National Hospital heart transplant database, ClinicalPortal and CIS databases from January/2012-May/2018. Missing data were obtained from the hard copy case notes. We performed AMP utilising continuous cold blood (4-6°C) antegrade cardioplegia to achieve aortic root pressures of 60-70 mmHg. Leucocyte filer was utilised. The infusion would continue with an LV vent insitu until the left atrial and aortic anastomoses were complete. "Hotshot" warm blood was then infused prior to removal of the cross clamp. Multivariable logistic regression with moderate/severe PGD as the outcome measure. Confounders were adjusted for recipient age, total ischaemic time, bypass time, predicted left ventricular (LV) mass mismatch, recipient diabetes mellitus and donor age. A total of 75 patients were included in this study. 44% (n=33) underwent AMP and 56 % (n=42) had orthotopic heart transplantation with the conventional approach. There was no statistically significant difference in age, gender, incidence of diabetes mellitus, preoperative utilisation of mechanical circulatory support between the AMP and the control group. We found that total ischaemia time was significantly shorter in the AMP cohort (154+/-50.2 vs. 181+/-47.1 min, p=0.018). The rate of postoperative VA ECMO support was significantly lower in the AMP cohort (15% vs. 54%, p<0.001). The rate of moderate-severe PGD was significantly lower in the AMP cohort (21% vs. 69%, p<0.001). The odds ratio of PGD in patients in the historical cohort vs AMP was 4.15 (1.21-14.24). Our implantation technique utilising AMP significantly lowers the rate of moderate and severe PGD when compared to the standard implantation technique employed by the historical cohort.

Determination of the Trace Element Composition of Human Nails

The analysis of human nail samples for trace elements by arc atomic emission spectrometry using a dry residue after acid mineralization has been experimentally examined. The relatively constant concentrations of the determined elements were observed in the course of monitoring for 6–10 months. The cadmium content of a donor increased briefly, and this increase coincided in time with a short change in location. Thus, the possibility of using nails as a source of information on past exposures was confirmed. It was found that the Mg, Cu, and Zn contents of a set of 73 samples from various donors obeyed the normal law, and the Al and Ca contents corresponded to the lognormal law. The influence of the donor gender on the copper content of the nails was revealed; donor smoking affected the lead content (in the latter case, insufficient statistical significance can be due to the small number of smoking donors and the inability to determine the concentration in all samples). Positive correlations were found between the concentrations of a number of elements, in particular, Mg/Ca, Cu/Zn, Cu/Al, Cu/Mg, and Cd/Pb, and a negative correlation was found for Ca/Cd.