Delayed kidney graft function in simultaneous pancreas‐kidney transplant recipients is associated with early pancreas allograft failure

Delayed graft function (DGF) is a common complication associated with significant untoward effects in kidney‐alone transplantation. The incidence and outcomes following kidney delayed graft function (K‐DGF) among patients undergoing simultaneous pancreas‐kidney (SPK) transplantation are less certain. We analyzed SPK recipients transplanted at our center between January 1994 and December 2017. A total of 632 recipients fulfilled the selection criteria, including 69 (11%) with K‐DGF and 563 without. The incidence of K‐DGF was significantly higher in recipients of organs from older donors and donation after circulatory death (DCD). The presence of K‐DGF was significantly associated with an increased risk of pancreas graft failure during the first 90 days (n = 9, incidence rate [IR] 2.45/100 person‐months), but not with late pancreas failure (n = 32, IR 0.84/100 person‐months), kidney graft failure, or patient death. Although DCD was associated with K‐DGF, it was not associated with either pancreas (hazard ratio [HR] 0.91, 95% CI 0.58‐1.44, P = .69) or kidney (HR 1.09, 95% CI 0.66‐1.82, P = .74) graft failure after adjustment for potential confounders. We found K‐DGF to be a significant risk factor for pancreas graft failure but not kidney graft failure, with the major risk period being early (<90 days) posttransplant, and the major donor risk factor being older donor age.     

The cost‐effectiveness and budgetary impact of a dolutegravir‐based regimen as first‐line treatment of HIV infection in India

Introduction

Dolutegravir (DTG)‐based antiretroviral therapy (ART) is recommended for first‐line HIV treatment in the US and Europe. Efavirenz (EFV)‐based regimens remain the standard of care (SOC) in India. We examined the clinical and economic impact of DTG‐based first‐line ART in the setting of India's recent guidelines change to treating all patients with HIV infection regardless of CD4 count.

Methods

We used a microsimulation of HIV disease, the Cost‐Effectiveness of Preventing AIDS Complications (CEPAC)‐International model, to project outcomes in ART‐naive patients under two strategies: (1) SOC: EFV/tenofovir disoproxil fumarate (TDF)/lamivudine (3TC); and (2) DTG: DTG + TDF/3TC. Regimen‐specific inputs, including virologic suppression at 48 weeks (SOC: 82% vs. DTG: 90%) and annual costs ($98 vs. $102), were informed by clinical trial data and other sources and varied widely in sensitivity analysis. We compared incremental cost‐effectiveness ratios (ICERs), measured in $/year of life saved (YLS), to India's per capita gross domestic product ($1600 in 2015). We compared the budget impact and HIV transmission effects of the two strategies for the estimated 444,000 and 916,000 patients likely to initiate ART in India over the next 2 and 5 years.

Results

Compared to SOC, DTG improved 5‐year survival from 76.7% to 83.0%, increased life expectancy from 22.0 to 24.8 years (14.0 to 15.5 years, discounted), averted 13,000 transmitted HIV infections over 5 years, increased discounted lifetime care costs from $3040 to $3240, and resulted in a lifetime ICER of $130/YLS, less than 10% of India's per capita GDP in 2015. DTG maintained an ICER below 50% of India's per capita GDP as long as the annual three‐drug regimen cost was ≤$180/year. Over a 2‐ or 5‐year horizon, total undiscounted outlays for HIV‐related care were virtually the same for both strategies.

Conclusions

A generic DTG‐based regimen is likely to be cost‐effective and should be recommended for initial therapy of HIV infection in India.

     

Efficacy of anthracycline/taxane‐based neo‐adjuvant chemotherapy on triple‐negative breast cancer in BRCA1/BRCA2 mutation carriers

This study aims to estimate the pathologic complete response (pCR) rate after neo‐adjuvant chemotherapy and to compare disease‐free survival (DFS) and overall survival (OS) between pCR and non‐pCR groups of patients with triple‐negative breast cancer (TNBC) and deleterious BRCA1 or BRCA2 mutation. We carried out a retrospective analysis of 53 patients including 46 BRCA1, 6 BRCA2, and 1 combined BRCA1 and BRCA2 mutation. All patients had been diagnosed with triple‐negative breast cancer (TNBC) between 1997 and 2014. Neo‐adjuvant therapy consisted of regimens that were based on anthracycline or an anthracycline‐taxane doublet. DFS included any relapse or second cancer. The Kaplan‐Meier method and the log‐rank test were used to compare pCR and non‐pCR groups. A pCR was observed in 23 (42.6% [95% CI, 29.2%‐56.8%]) of the TNBC included. The pCR rate was 38.3% [95% CI, 26%‐55%] among BRCA1 mutation carriers, and 66% among the 6 BRCA2 mutation carriers. Median follow‐up was 4.4 years (range 0.62‐16.2 years) and did not differ between the groups (P = .25). Fifteen relapses and six second cancers were recorded during the follow‐up period. Eleven deaths occurred, all of which were in the non‐pCR group. DFS (P < .01) and OS (P < .01) were significantly better in the pCR group than the non‐pCR group. This study shows a high pCR rate after neo‐adjuvant therapy in BRCA‐mutated triple‐negative breast cancer, and the survival results confirm the prognostic value of pCR in this group. These outcomes should be considered as a basis of comparison to be used by future studies about new therapies in this domain.     

Liver transplantation with deceased ABO‐incompatible donors is life‐saving but associated with increased risk of rejection and post‐transplant complications

ABO‐incompatible (ABOi) liver transplantation (LT) with deceased donor organs is performed occasionally when no ABO‐compatible (ABOc) graft is available. From 1996 to 2011, 61 ABOi LTs were performed in Oslo and Gothenburg. Median patient age was 51 years (range 13–75); 33 patients were transplanted on urgent indications, 13 had malignancy‐related indications, and eight received ABOi grafts for urgent retransplantations. Median donor age was 55 years (range 10–86). Forty‐four patients received standard triple immunosuppression with steroids, tacrolimus, and mycophenolate mofetil, and forty‐four patients received induction with IL‐2 antagonist or anti‐CD20 antibody. Median follow‐up time was 29 months (range 0–200). The 1‐, 3‐, 5‐, and 10‐year Kaplan–Meier estimates of patient survival (PS) and graft survival (GS) were 85/71%, 79/57%, 75/55%, and 59/51%, respectively, compared to 90/87%, 84/79%, 79/73%, and 65/60% for all other LT recipients in the same period. The 1‐, 3‐, 5‐, and 10‐year GS for A₂ grafts were 81%, 67%, 62%, and 57%, respectively. In conclusion, ABOi LT performed with non‐A₂ grafts is associated with inferior graft survival and increased risk of rejection, vascular and biliary complications. ABOi LT with A₂ grafts is associated with acceptable graft survival and can be used safely in urgent cases.     

Modelling the variation in skin‐test tuberculin reactions,post‐mortem lesion counts and case pathology in tuberculosis‐exposed cattle: Effects of animal characteristics,histories and co‐infection

Correctly identifying bovine tuberculosis (bTB ) in cattle remains a significant problem in endemic countries. We hypothesized that animal characteristics (sex, age, breed), histories (herd effects, testing, movement) and potential exposure to other pathogens (co‐infection; BVDV , liver fluke and Mycobacterium avium reactors) could significantly impact the immune responsiveness detected at skin testing and the variation in post‐mortem pathology (confirmation) in bTB ‐exposed cattle. Three model suites were developed using a retrospective observational data set of 5,698 cattle culled during herd breakdowns in Northern Ireland. A linear regression model suggested that antemortem tuberculin reaction size (difference in purified protein derivative avium [PPD a ] and bovine [PPD b ] reactions) was significantly positively associated with post‐mortem maximum lesion size and the number of lesions found. This indicated that reaction size could be considered a predictor of both the extent (number of lesions/tissues) and the pathological progression of infection (maximum lesion size). Tuberculin reaction size was related to age class, and younger animals (<2.85 years) displayed larger reaction sizes than older animals. Tuberculin reaction size was also associated with breed and animal movement and increased with the time between the penultimate and disclosing tests. A negative binomial random‐effects model indicated a significant increase in lesion counts for animals with M. avium reactions (PPD b− PPD a <  0) relative to non‐reactors (PPD b− PPD a =  0). Lesion counts were significantly increased in animals with previous positive severe interpretation skin‐test results. Animals with increased movement histories, young animals and non‐dairy breed animals also had significantly increased lesion counts. Animals from herds that had BVDV ‐positive cattle had significantly lower lesion counts than animals from herds without evidence of BVDV infection. Restricting the data set to only animals with a bTB visible lesion at slaughter (n  = 2471), an ordinal regression model indicated that liver fluke‐ infected animals disclosed smaller lesions, relative to liver fluke‐negative animals, and larger lesions were disclosed in animals with increased movement histories.     

Long‐term outcomes in patients with obesity and renal disease after sleeve gastrectomy

Morbid obesity is a barrier to kidney transplant in patients with end‐stage renal disease (ESRD). Laparoscopic sleeve gastrectomy (SG) is an increasingly considered intervention, but the safety and long‐term outcomes are uncertain. We reviewed prospectively collected data on patients with ESRD and chronic kidney disease (CKD) undergoing SG from 2011 to 2018. There were 198 patients with ESRD and 45 patients with CKD (stages 1‐4) who met National Institutes of Health guidelines for bariatric surgery and underwent SG; 72% and 48% achieved a body mass index of ≤ 40 and ≤ 35 kg/m², respectively. The mean percentages of total weight loss and excess weight loss were 18.9 ± 10.8% and 38.2 ± 20.3%, respectively. SG reduced hypertension (85.8% vs 52.1%), decreased antihypertensive medication use (1.6 vs 1.0) (P < .01 each), and reduced incidence of diabetes (59.6% vs 32.5%, P < .01). Of the 71 patients with ESRD who achieved a body mass index of ≤ 40 kg/m², 45 were waitlisted and received a kidney transplant, whereas 10 remain on the waitlist. Mortality rate after SG was 1.8 per 100 patient‐years, compared with 7.3 for non‐SG. Patients with stage 3a or 3b CKD exhibited improved glomerular filtration rate (43.5 vs 58.4 mL/min, P = .01). In conclusion, SG safely improves transplant candidacy while providing significant, sustainable effects on weight loss, reducing medical comorbidities, and possibly improving renal function in stage 3 patients.     

Different risk factor profiles distinguish early‐onset from late‐onset BKV‐replication

Two of three reactivations of latent BKV‐infection occur within the first 6 months after renal transplantation. However, a clear differentiation between early‐onset and late‐onset BKV‐replication is lacking. Here, we studied all kidney transplant recipients (KTRs) at our single transplant center between 2004 and 2012. A total of 103 of 862 KTRs were diagnosed with BK viremia (11.9%), among which 24 KTRs (2.8%) showed progression to BKV‐associated nephropathy (BKVN). Sixty‐seven KTRs with early‐onset BKV‐replication (65%) and 36 KTRs with late‐onset BKV‐replication (35%) were identified. A control group of 598 KTRs without BKV‐replication was used for comparison. Lymphocyte‐depleting induction, CMV‐reactivation, and acute rejection increased the risk of early‐onset BKV‐replication (P < 0.05). Presensitized KTRs undergoing renal retransplantation were those at increased risk of late‐onset BKV‐replication (P < 0.05). Among KTRs with BK viremia, higher doses of mycophenolate increased the risk of progression to BKVN (P = 0.004). KTRs with progression to BKVN showed inferior allograft function (P < 0.05). KTRs with late‐onset BK viremia were more likely not to recover to baseline creatinine after BKV‐replication (P = 0.018). Our data suggest different risk factors in the pathogenesis of early‐onset and late‐onset BKV‐reactivation. While a more intensified immunosuppression is associated with early‐onset BKV‐replication, a chronic inflammatory state in presensitized KTRs may contribute to late‐onset BKV‐replication.     

Comparison of sperm morphology and nuclear sperm quality in SPATA16‐ and DPY19L2‐mutated globozoospermic patients

The aim of this study was to compare the sperm morphology and nuclear sperm quality (sperm aneuploidy and DNA fragmentation) in two groups of globozoospermic patients: DPY19L2‐mutated patients (n = 6) and SPATA16‐mutated patients (n = 2). Results for these two groups were also compared to a group of fertile men (n = 25). Fluorescence in situ hybridisation was performed for chromosomes X, Y and 18. Sperm DNA fragmentation was evaluated by TUNEL assay. Sanger sequencing was performed for mutations screening of DPY19L2 and SPATA16 genes. Sperm analysis revealed a classic phenotype of total globozoospermia in DPY19L2‐mutated group and a particular phenotype characterised by a predominance of double/multiple round‐headed (39.00 ± 4.2%) and multi‐tailed spermatozoa (26.00 ± 16.97%) in SPATA16‐mutated group. FISH analysis showed a significantly higher aneuploidy rate in globozoospermic patients compared to controls (p < 0.05), and a higher rate was observed in SPATA16‐mutated group compared to DPY19L2‐mutated group (p < 0.05). DNA fragmentation index was significantly higher in globozoospermic men compared to controls (p < 0.001), and there is no statistically significant difference between the two globozoospermic groups. We showed that SPATA16 defects could be associated with an abnormal meiosis leading to a particular morphological sperm defect of double/multiple round‐headed and multi‐flagella and a higher sperm aneuploidy rate than in case of DPY19L2‐defects in classic globozoospermia.     

Profiling non‐HLA antibody responses in antibody‐mediated rejection following heart transplantation

Antibody‐mediated rejection (AMR) driven by the development of donor‐specific antibodies (DSA) directed against mismatched donor human leukocyte antigen (HLA) is a major risk factor for graft loss in cardiac transplantation. Recently, the relevance of non‐HLA antibodies has become more prominent as AMR can be diagnosed in the absence of circulating DSA. Here, we assessed a single‐center cohort of 64 orthotopic heart transplant recipients transplanted between 1994 and 2014. Serum collected from patients with ≥ pAMR1 (n = 43) and non‐AMR (n = 21) were tested for reactivity against a panel of 44 non‐HLA autoantigens. The AMR group had a significantly greater percentage of patients with elevated reactivity to autoantigens compared to non‐AMR (P = .002) and healthy controls (n = 94, P < .0001). DSA‐positive AMR patients exhibited greater reactivity to autoantigens compared to DSA‐negative (P < .0001) and AMR patients with DSA and PRA > 10% were identified as the subgroup with significantly elevated responses. Reactivity to 4 antigens, vimentin, beta‐tubulin, lamin A/C, and apolipoprotein L2, was significantly different between AMR and non‐AMR patients. Moreover, increased reactivity to these antigens was associated with graft failure. These results suggest that antibodies to non‐HLA are associated with DSA‐positive AMR although their specific role in mediating allograft injury is not yet understood.     

Risk of Fracture in Primary Aldosteronism: A Population‐Based Cohort Study

Primary aldosteronism (PA) is associated with increased urinary calcium excretion and osteoporosis prevalence. We studied the long‐term effect of hyperaldosterone on fracture risk and possible risk mitigation via treatments, by comparing PA patients and their essential hypertension (EH) counterparts extracted by propensity score match. We used a longitudinal population database from the Taiwan National Health Insurance, and used a validated algorithm to identify PA patients diagnosed in 1997–2010. Our sample included 2533 PA patients, including 921 patients with aldosterone‐producing adenoma (APA). Our methods for assessing excessive fracture risk included multivariable Cox regression and the competing risk regression. The incidence rate of fracture at any site was 14.4 per 1000 person‐years for PA, and 11.2 per 1000 person‐years for APA. In contrast, the incidence rate of fracture at any site was 8.3 per 1000 person‐years in EH controls for PA, and 6.5 per 1000 person‐years in EH controls for APA. Mineralocorticoid receptor antagonist (MRA) treatment might be associated with higher risk of osteoporotic fracture in the whole female PA cohort (subdistribution hazard ratio [SHR] = 2.12, p = 0.008) as well as female APA patients (SHR = 1.15, p = 0.049). As to fracture at any site, MRA treatment was also associated with higher risk; the SHR was 1.88 (p < 0.001) in the whole female PA cohort, and 2.17 (p = 0.019) in female APA patients. PA is tightly associated with higher risk of bone fracture, even in the case where the competing risk of death was controlled. Particularly, female PA patients treated with MRA were confronted with significantly higher risk in bone fracture than their EH controls. © 2017 American Society for Bone and Mineral Research.     

MRI‐Guided Breast Needle Core Biopsies: Pathologic Features of Newly Diagnosed Malignancies

Magnetic resonance imaging (MRI) of the breast is used for select groups of patients. MRI‐guided breast core needle biopsies performed over a 3‐year period were retrospectively reviewed to determine the incidence and types of cancers found and to correlate the cancers with the MRI findings and the indication for the study. Patients were stratified based on indication for MRI examination including, evaluation of disease extent in patients with current ipsilateral carcinoma, surveillance for recurrence of prior ipsilateral carcinoma, as a problem‐solving method and for screening high‐risk patients. The high‐risk screening group included those with family history (with or without germline mutations), prior chest wall radiation, and contralateral breast carcinoma (current or prior). Four‐hundred and forty‐five biopsies were performed on 386 patients. The majority of biopsies (79%) were benign. Biopsies demonstrating ductal carcinoma in situ (DCIS) and invasive carcinoma were more likely to present as nonmass‐like and mass‐forming enhancements respectively, but with only 52% specificity. The highest rate of malignancy (44%) was seen in the least frequently biopsied patient group (n = 25), those with prior ipsilateral carcinoma. Conversely, the most frequently biopsied group (n = 283), the high‐risk screening group, demonstrated the lowest malignancy rate (16%). Within this group, most malignant cases were invasive carcinomas (n = 27), 67% of which were small (≤1 cm), well or moderately differentiated with a good prognostic receptor profile (estrogen receptor positive, human epidermal growth factor receptor 2 negative), and lacked nodal macrometastases. The remaining malignant cases in the high‐risk screening group were DCIS with or without microinvasion (n = 18), 78% of which demonstrated high nuclear grade. Overall, enhancement pattern did not correlate with the likelihood of or type of malignancy. The most common types of carcinomas identified by screening were small estrogen receptor positive invasive tumors and high grade DCIS.     

Modified donor lymphocyte infusion‐associated acute graft‐versus‐host disease after haploidentical T‐cell‐replete hematopoietic stem cell transplantation: incidence and risk factors

We performed a study to investigate the profile of donor lymphocyte infusion (DLI)‐associated acute graft‐versus‐host disease (GVHD) in haploidentical T‐cell‐replete hematopoietic stem cell transplantation (HSCT). A total of 124 patients receiving modified DLI after haploidentical T‐cell‐replete HSCT were enrolled. The cumulative incidence of DLI‐associated acute GVHD was 53.2% for grades II–IV and 28.4% for grades III–IV. The duration of GVHD prophylaxis after DLI was the only risk factor for DLI‐associated grades III–IV acute GVHD (p < 0.05). The cumulative incidence of grades III–IV acute GVHD in patients with prophylaxis more than six, four to six, two to four, and <2 wk were 9.3%, 14.4%, 31.6%, and 49.5%, respectively (p = 0.018). Furthermore, DLI‐associated grades III–IV acute GVHD was the only risk factor for overall survival (p = 0.038, OR   = 2.869) and transplant‐related mortality (p = 0.018, OR = 3.296) but not a risk factor for relapse after DLI (p = 0.840). This study confirms for the first time that the duration of GVHD prophylaxis after DLI is the only risk factor for the development of grades III–IV acute GVHD. Donor lymphocyte infusion with prophylaxis more than six wk was associated with a lower incidence of grades III–IV acute GVHD.     

Allograft outcome following repeat transplantation of patients with non‐adherence‐related first kidney allograft failure: a population cohort study

Nonadherence is an important risk factor for premature allograft failure after kidney transplantation, but outcomes after re‐transplantation remain uncertain. Using data from the Australian and New Zealand Dialysis and Transplant registry, the associations between causes of first allograft failure and acute rejection‐related and non‐adherence‐related allograft failure following re‐transplantation were examined using competing risk analyses, treating the respective alternative causes of allograft failure and death with functioning graft as competing events. Fifty‐nine of 2450 patients (2%) lost their first allografts from nonadherence. Patients who lost their first kidney allograft from nonadherence were younger at the time of first kidney allograft failure but waited longer for a second allograft (>5 years: 54% vs. 20%, P < 0.001) compared with other causes. Compared with patients who lost their first allograft from causes other than nonadherence, the adjusted subdistribution hazard ratio (HR and 95% CI) for acute rejection‐related second allograft failure was 0.58 (0.08, 4.07; P = 0.582) for patients with allograft failure attributed to nonadherence and was 6.30 (1.34, 29.67; P = 0.020) for non‐adherence‐related second allograft failure. In this cohort of transplant recipients who have received second allografts, first allograft failure secondary to nonadherence was associated with a marginally greater risk of allograft failure attributed to nonadherence in subsequent transplantation.     

Effectiveness of a colonoscopic screening programme in first‐degree relatives of patients with colorectal cancer

Aim The study aimed to assess the diagnostic yield of a colonoscopy screening programme in first‐degree relatives of colorectal cancer (CRC) patients and to identify factors associated with advanced neoplasia. Method We conducted a cross‐sectional study. Individual characteristics, family trees and colonoscopy findings of asymptomatic first‐degree relatives of CRC patients were collected. The findings were classified into cancer (invasive carcinoma and/or non‐invasive high‐grade neoplasia), high‐risk adenomas (≥ 10 mm and/or a villous component) and low‐risk adenomas (tubular < 10 mm). The dependent variable was the presence of advanced neoplasia, defined as cancer and/or high‐risk adenoma. Results Two hundred and sixty‐three relatives (147 females), 50.0 ± 11.5 (range, 25–75) years of age, agreed to participate out of a total of 618 who were invited (acceptance rate 42.5%). Index cases were diagnosed at 63.8 ± 12.4 (range, 37–88) years of age. The closest familial relationship was parent/offspring in 168 (63.9%) participants and sibling in 95 (36.1%) participants; 14.8% had three or more relatives with CRC/cancer associated with Lynch syndrome, and two or more affected generations were identified in 24.0%. Advanced neoplasia was found in 56 (21.3%) participants. Of these, invasive cancer, non‐invasive high‐grade neoplasia and high‐risk adenomas were detected in five (1.9%), six (2.3%) and 45 (17.1%) participants, respectively. Low‐risk adenomas were detected in 20 (7.6%) participants. Male sex (odds ratio, 2.59; P = 0.003) and sibling relationship (odds ratio, 2.74; P = 0.001) were independently associated with advanced neoplasia. Conclusion We detected advanced neoplasia in a considerable number of participants. Our data support colonoscopy screening in first‐degree relatives of patients with CRC at an earlier age than in the medium‐risk population. Male sex and sibling relationship were predictors of advanced neoplasia.     

Risk of Colorectal Carcinoma in Post‐Liver Transplant Patients: A Systematic Review and Meta‐analysis

Liver transplant patients (LTx) have an increased risk for developing de novo malignancies, but for colorectal cancer (CRC) this risk is less clear. We aimed to determine whether the CRC risk post‐LTx was increased. A systematic search was performed in MEDLINE and Cochrane databases to identify studies published between 1986 and 2008 reporting on the risk of CRC post‐LTx. The outcomes were (1) CRC incidence rate (IR per 100 000 person‐years (PY)) compared to a weighted age‐matched control population using SEER and (2) relative risk (RR) for CRC compared to the general population. If no RR data were available, the RR was estimated using SEER. Twenty‐nine studies were included. The overall post‐LTx IR was 119 (95% CI 88–161) per 100 000 PY. The overall RR was 2.6 (95% CI 1.7–4.1). The non‐primary sclerosing cholangitis (PSC) IR was 129 per 100 000 PY (95% CI 81–207). Compared to SEER (71 per 100 000 PY), the non‐PSC RR was 1.8 (95% CI 1.1–2.9). In conclusion, the overall transplants and the subgroup non‐PSC transplants have an increased CRC risk compared to the general population. However, in contrast to PSC, non‐PSC transplants do not need an intensified screening strategy compared to the general population until a prospective study further defines recommendations.     

10 years of prophylaxis with nebulized liposomal amphotericin B and the changing epidemiology of Aspergillus spp. infection in lung transplantation

The aim of this study was to assess the outcome and tolerability of prophylactic nebulized liposomal amphotericin B (n‐LAB) in lung transplant recipients (LTR) and the changing epidemiology of Aspergillus spp. infection and colonization . We performed an observational study including consecutive LTR recipients (2003–2013) undergoing n‐LAB prophylaxis lifetime. A total of 412 patients were included (mean postoperative follow‐up 2.56 years; IQR 1.01–4.65). Fifty‐three (12.8%) patients developed 59 Aspergillus spp. infections, and 22 invasive aspergillosis (overall incidence 5.3%). Since 2009, person‐time incidence rates of Aspergillus spp. colonization and infection decreased (2003–2008, 0.19; 2009–2014, 0.09; P = 0.0007), but species with reduced susceptibility or resistance to amphotericin significantly increased (2003–2008, 38.1% vs 2009–2014, 58.1%; P = 0.039). Chronic lung allograft dysfunction (CLAD) was associated with Aspergillus spp. colonization and infection (HR 24.4, 95% CI 14.28–41.97; P = 0.00). Only 2.9% of patients presented adverse effects, and 1.7% required discontinuation. Long‐term administration of prophylaxis with n‐LAB has proved to be tolerable and can be used for preventing Aspergillus spp. infection in LTR. Over the last years, the incidence of Aspergillus spp. colonization and infection has decreased, but species with reduced amphotericin susceptibility or resistance are emerging. CLAD is associated with Aspergillus spp. colonization and infection.     

Selection of normal spermatozoa with a vacuole‐free head (x6300) improves selection of spermatozoa with intact DNA in patients with high sperm DNA fragmentation rates

Intracytoplasmic morphologically selected sperm injection (IMSI, 6300× magnification with Nomarski contrast) of a normal spermatozoon with a vacuole‐free head could improve the embryo's ability to grow to the blastocyst stage and then implant. However, the most relevant indications for IMSI remain to be determined. To evaluate the potential value of IMSI for patients with a high degree of sperm DNA fragmentation (n = 8), different types of spermatozoa were analysed in terms of DNA fragmentation. Motile normal spermatozoa with a vacuole‐free head selected at 6300× magnification had a significantly lower mean DNA fragmentation rate (4.1 ± 1.1%, n = 191) than all other types of spermatozoa: non‐selected spermatozoa (n = 8000; 26.1 ± 1.5% versus 4.1 ± 1.1%; P < 0.005), motile spermatozoa (n = 444; 20.8 ± 2.7% versus 4.1 ± 1.1%; P < 0.001) and motile, normal spermatozoa selected at 200× magnification (n = 370; 18.7 ± 2.7% versus 4.1 ± 1.1%; P < 0.001) and then motile, morphometrically normal spermatozoa with anterior vacuoles (n = 368; 15.9 ± 2.9% versus 4.1 ± 1.1%; P < 0.05) or posterior vacuoles (n = 402; 22.5 ± 3.6% versus 4.1 ± 1.1%; P < 0.001) selected at 6300× magnification. For patients with high sperm DNA fragmentation rates, selection of normal spermatozoa with a vacuole‐free head (6300×) yields the greatest likelihood of obtaining spermatozoa with non‐fragmented DNA.     

Primary preventive cardioverter‐defibrillator implantation (Pro‐ICD) in patients awaiting heart transplantation. A prospective,randomized, controlled 12‐year follow‐up study

The aim of this study was to evaluate whether short‐term primary preventive cardioverter‐defibrillator (ICD) implantation as bridge to heart transplantation (HTX) provides any survival benefit. Thirty‐three patients awaiting HTX were randomized to either conventional therapy (control group) or primary preventive ICD implantation (ICD group). Fourteen patients had ischemic cardiomyopathy (ICM) and 19 patients had dilated cardiomyopathy (DCM). Sixteen patients were randomized to the ICD group and 17 patients were randomized to the control group. Twenty patients (61%) were transplanted after a waiting time of 10 ± 9 months. The remaining 13 patients (39%) were not transplanted because of clinical improvement (n = 5), cerebral hemorrhage (n = 3), or death (n = 5). On the waiting list, 3 ICD patients with DCM developed slow VTs without ICD intervention, two patients with ICM (6%) had fast VT terminated by the ICD, and no arrhythmic death was observed. After 11.9 years (median), 13 of 20 HTX patients (65%) and 5 of 13 non‐HTX patients (38%) were alive. Survivors had a higher LVEF (22 ± 6 vs. 17 ± 4%, P = 0.0092) and a better exercise capacity (75 ± 29 vs. 57 ± 24 Watt, P = 0.0566) at baseline as compared to nonsurvivors. This study may not support the general use of primary preventive ICDs as a short‐term bridge to heart transplantation.     

Combined liver‐kidney transplantation for children with autosomal recessive polycystic kidney disease (ARPKD): indication and outcome

In ARPKD, mutations in the PKHD1 gene lead to remodeling of the kidneys and liver. These may result in progressive liver fibrosis with portal hypertension requiring combined liver and kidney transplantation (CLKT). There is currently no consensus on the indication for CLKT and data on long‐term outcomes are scarce. We analyzed in detail the pretransplant liver symptomatology, laboratory and ultrasound data, histological studies, and genotypes in eight patients undergoing CLKT. The median age was 10.1 years (range 1.7–16) and median follow‐up was 4.6 years (range 1.1–8.9). All patients had clinical signs of portal hypertension and abnormal ultrasound findings. Congenital hepatic fibrosis was present in all pretransplant biopsies (6 out of 8 patients) and in all explanted livers. All patients survived; liver and kidney graft survival was 72% and 88%, respectively. Liver and kidney function were stable in all patients with a median eGFR of 70 ml/min/1.73 m² (range 45–108 ml/min/1.73 m²). Height‐SDS improved significantly after 12, 24, and 36 months (P = 0.016, 0.022 and 0.018 respectively). The indication for CLKT remains challenging and controversial. A favorable outcome for patients with ARPKD can be achieved by using the degree of portal hypertension, longitudinal ultrasound examinations, and preoperative liver histology as parameters for CLKT.     

Transplantation of solid organ recipients shedding Epstein‐Barr virus DNA pre‐transplant: A prospective study

Epstein‐Barr virus (EBV) poses a significant threat to patient and graft survival post‐transplant. We hypothesized that recipients who shed EBV at transplant had less immunologic control of the virus and hence were more likely to have active EBV infection and disease post‐transplant. To test this hypothesis, we conducted a 5‐year prospective study in primary solid organ transplant recipients. We measured EBV DNA in oral washes and blood samples by quantitative PCR before transplant and periodically thereafter for up to 4 years. Pre‐transplant samples were available from 98 subjects. EBV DNA was detected pre‐transplant in 32 of 95 (34%) and 5 of 93 subjects (5%) in oral wash and blood, respectively. Recipients with and without detectable pre‐transplant EBV DNA were not significantly different demographically and had no significant difference in patient and graft survival (P = .6 for both comparisons) or post‐transplant EBV viremia‐free survival (P = .8). There were no cases of EBV‐related disease or post‐transplant lymphoproliferative disorder (PTLD) in any of the patients with detectable EBV DNA pre‐transplant. In conclusion, detectable EBV DNA pre‐transplant was not associated with differences in patient/graft survival, post‐transplant EBV viremia, or EBV‐related diseases including PTLD.