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CD4+ T-helper cells play an important role in alloimmune reactions following transplantation by stimulating humoral as well as cellular responses, which might lead to failure of the allograft. CD4+ memory T-helper cells from a previous immunizing event can potentially be reactivated by exposure to HLA mismatches that share T-cell epitopes with the initial immunizing HLA. Consequently, reactivity of CD4+ memory T-helper cells toward T-cell epitopes that are shared between immunizing HLA and donor HLA could increase the risk of alloimmunity following transplantation, thus affecting transplant outcome. In this study, the amount of T-cell epitopes shared between immunizing and donor HLA was used as a surrogate marker to evaluate the effect of donor-reactive CD4+ memory T-helper cells on the 10-year risk of death-censored kidney graft failure in 190 donor/recipient combinations using the PIRCHE-II algorithm. The T-cell epitopes of the initial theoretical immunizing HLA and the donor HLA were estimated and the number of shared PIRCHE-II epitopes was calculated. We show that the natural logarithm-transformed PIRCHE-II overlap score, or Shared T-cell EPitopes (STEP) score, significantly associates with the 10-year risk of death-censored kidney graft failure, suggesting that the presence of pre-transplant donor-reactive CD4+ memory T-helper cells might be a strong indicator for the risk of graft failure following kidney transplantation.

IntroductionCardiovascular disease is the leading cause of death in end-stage renal disease (ESRD) and is strongly associated with vascular calcification. An important driver of vascular calcification is high phosphate levels, but these become lower when patients initiate nocturnal hemodialysis or receive a kidney transplant. However, it is unknown whether nocturnal hemodialysis or kidney transplantation mitigate vascular calcification. Therefore, we compared progression of coronary artery calcification (CAC) between patients treated with conventional hemodialysis, nocturnal hemodialysis, and kidney transplant recipients.MethodsWe measured CAC annually up to 3 years in 114 patients with ESRD that were transplantation candidates: 32 that continued conventional hemodialysis, 34 that initiated nocturnal hemodialysis (≥4x 8 hours/week), and 48 that received a kidney transplant. We compared CAC progression between groups as the difference in square root transformed volume scores per year (ΔCAC SQRV) using linear mixed models. Reference category was conventional hemodialysis.ResultsThe mean age of the study population was 53 ±13 years, 75 (66%) were male, and median dialysis duration was 28 (IQR 12-56) months. Median CAC score at enrollment was 171 (IQR 10-647), which did not differ significantly between treatment groups (P = 0.83). Compared to conventional hemodialysis, CAC progression was non-significantly different in nocturnal hemodialysis -0.10 (95% CI -0.77 to 0.57) and kidney transplantation -0.33 (95% CI -0.96 to 0.29) in adjusted models.ConclusionsNocturnal hemodialysis and kidney transplantation are not associated with significantly less CAC progression compared to conventional hemodialysis during up to 3 years follow-up. Further studies are needed to confirm these findings, to determine which type of calcification is measured with CAC in end-stage renal disease, and whether that reflects cardiovascular risk.

The best treatment for patients with end-stage renal disease is kidney transplantation. Although graft survival rates have improved in the last decades, patients still may lose their grafts partly due to the detrimental effects of donor-specific antibodies (DSA) against human leukocyte antigens (HLA) and to a lesser extent also by antibodies directed against non-HLA antigens expressed on the donor endothelium. Assays to detect anti-HLA antibodies are already in use for many years and have been proven useful for transplant risk stratification. Currently, there is a need for assays to additionally detect multiple non-HLA antibodies simultaneously in order to study their clinical relevance in solid organ transplantation. This study describes the development, technical details and validation of a high-throughput multiplex assay for the detection of antibodies against 14 non-HLA antigens coupled directly to MagPlex microspheres or indirectly via a HaloTag. The non-HLA antigens have been selected based on a literature search in patients with kidney disease or following transplantation. Due to the flexibility of the assay, this approach can be used to include alternative antigens and can also be used for screening of other organ transplant recipients, such as heart and lung.

Individual HLA mismatches may differentially impact graft survival after kidney transplantation. Therefore, there is a need for a reliable tool to define permissible HLA mismatches in kidney transplantation. We previously demonstrated that donor-derived Predicted Indirectly ReCognizable HLA Epitopes presented by recipient HLA class II (PIRCHE-II) play a role in de novo donor-specific HLA antibodies formation after kidney transplantation. In the present Dutch multi-center study, we evaluated the possible association between PIRCHE-II and kidney graft failure in 2,918 donor–recipient couples that were transplanted between 1995 and 2005. For these donors–recipients couples, PIRCHE-II numbers were related to graft survival in univariate and multivariable analyses. Adjusted for confounders, the natural logarithm of PIRCHE-II was associated with a higher risk for graft failure [hazard ratio (HR): 1.13, 95% CI: 1.04–1.23, p = 0.003]. When analyzing a subgroup of patients who had their first transplantation, the HR of graft failure for ln(PIRCHE-II) was higher compared with the overall cohort (HR: 1.22, 95% CI: 1.10–1.34, p

BACKGROUND:Health-related quality of life (HRQOL) is an important outcome measure in patients with end-stage renal disease. HRQOL is assumed to improve with kidney transplantation and also with nocturnal hemodialysis compared to conventional hemodialysis. However, there is no evidence regarding HRQOL to support the optimal treatment choice for patients on nocturnal hemodialysis who hesitate opting for transplantation. We therefore compared HRQOL between patients who were treated with kidney transplantation or nocturnal hemodialysis for one year. METHODS:We assessed HQROL using the Kidney Disease Quality of Life-Short Form questionnaire in a cross-sectional sample of patients who were treated with kidney transplantation (n = 41) or nocturnal hemodialysis (n = 31) for one year. All patients on nocturnal hemodialysis were transplantation candidates. Using linear regression, we compared HRQOL between kidney transplantation and nocturnal hemodialysis, and adjusted for age, sex, dialysis duration, cardiovascular disease, and presence of residual urine production. RESULTS:At one year follow-up, mean age of the study population was 54 ±13 years, and median dialysis duration was 3.2 (IQR 2.1-5.0) years. Kidney transplantation was associated with significantly higher HRQOL on the domain "effects" compared to nocturnal hemodialysis (adjusted difference 12.0 points, 95% CI 3.9; 20.1). There were potentially clinically relevant differences between kidney transplantation and nocturnal hemodialysis on the domains "burden" (adjusted difference 11.1 points, 95% CI -2.6; 24.8), "social support" (adjusted difference 6.2, 95% CI -6.6; 19.1), and the physical composite score (adjusted difference 3.0, 95% CI -2.0; 8.1), but these were not significant. CONCLUSIONS:After kidney transplantation, HRQOL is especially higher on the domain "effects of kidney disease" compared to nocturnal hemodialysis. This can be useful when counseling patients on nocturnal hemodialysis who may opt for transplantation.

In kidney transplantation, survival rates are still partly impaired due to the deleterious effects of donor specific HLA antibodies (DSA). However, not all luminex‐defined DSA appear to be clinically relevant. Further analysis of DSA recognizing polymorphic amino acid configurations, called eplets or functional epitopes, might improve the discrimination between clinically relevant vs. irrelevant HLA antibodies. To evaluate which donor epitope‐specific HLA antibodies (DESAs) are clinically important in kidney graft survival, relevant and irrelevant DESAs were discerned in a Dutch cohort of 4690 patients using Kaplan–Meier analysis and tested in a cox proportional hazard (CPH) model including nonimmunological variables. Pre‐transplant DESAs were detected in 439 patients (9.4%). The presence of certain clinically relevant DESAs was significantly associated with increased risk on graft loss in deceased donor transplantations (p < 0.0001). The antibodies recognized six epitopes of HLA Class I, 3 of HLA‐DR, and 1 of HLA‐DQ, and most antibodies were directed to HLA‐B (47%). Fifty‐three patients (69.7%) had DESA against one donor epitope (range 1–5). Long‐term graft survival rate in patients with clinically relevant DESA was 32%, rendering DESA a superior parameter to classical DSA (60%). In the CPH model, the hazard ratio (95% CI) of clinically relevant DESAs was 2.45 (1.84–3.25) in deceased donation, and 2.22 (1.25–3.95) in living donation. In conclusion, the developed model shows the deleterious effect of clinically relevant DESAs on graft outcome which outperformed traditional DSA‐based risk analysis on antigen level. [ABSTRACT FROM AUTHOR]

In kidney transplantation, donor HLA antibodies are a risk factor for graft loss. Accessibility of donor eplets for HLA antibodies is predicted by the ElliPro score. The clinical usefulness of those scores in relation to transplant outcome is unknown. In a large Dutch kidney transplant cohort, Ellipro scores of pretransplant donor antibodies that can be assigned to known eplets (donor epitope specific HLA antibodies [DESAs]) were compared between early graft failure and long surviving deceased donor transplants. We did not observe a significant Ellipro score difference between the two cohorts, nor significant differences in graft survival between transplants with DESAs having high versus low total Ellipro scores. We conclude that Ellipro scores cannot be used to identify DESAs associated with early versus late kidney graft loss in deceased donor transplants. [ABSTRACT FROM AUTHOR]

A submerged floating tunnel (SFT) can be a promising solution for crossing a deep or wide waterway. This innovative concept however lacks research into its probabilistic design. In this research, the reliability of the tether-stabilized SFT is assessed. A first-order reliability method (FORM) and a Monte Carlo simulation (MCS) are performed for the limit state functions of the most important failure mechanisms. Stochastic variables are chosen so that a target reliability index of 3.8 for a reference period of 50 years is met. The calculated factors from the full probabilistic design are compared with the general recommended partial factors for strength and resistance from Eurocode EN1990. For the strength mechanisms, the calculated factors are smaller than the factors from Eurocode. However, for the equilibrium mechanism, the calculated factor for the unfavorable loading is larger than the factor from Eurocode and should be increased by 10% in order to design a safe enough SFT. [ABSTRACT FROM AUTHOR]

Summary: Kidney transplant candidates are blood group incompatible with roughly one out of three potential living donors. We compared outcomes after ABO‐incompatible (ABOi) kidney transplantation with matched ABO‐compatible (ABOc) living and deceased donor transplantation and analyzed different induction regimens. We performed a retrospective study with propensity matching and compared patient and death‐censored graft survival after ABOi versus ABOc living donor and deceased donor kidney transplantation in a nationwide registry from 2006 till 2019. 296 ABOi were compared with 1184 center and propensity‐matched ABOc living donor and 1184 deceased donor recipients (matching: recipient age, sex, blood group, and PRA). Patient survival was better compared with deceased donor [hazard ratio (HR) for death of HR 0.69 (0.49–0.96)] and non‐significantly different from ABOc living donor recipients [HR 1.28 (0.90–1.81)]. Rate of graft failure was higher compared with ABOc living donor transplantation [HR 2.63 (1.72–4.01)]. Rejection occurred in 47% of 140 rituximab versus 22% of 50 rituximab/basiliximab, and 4% of 92 alemtuzumab‐treated recipients (P < 0.001). ABOi kidney transplantation is superior to deceased donor transplantation. Rejection rate and graft failure are higher compared with matched ABOc living donor transplantation, underscoring the need for further studies into risk stratification and induction therapy [NTR7587, www.trialregister.nl]. [ABSTRACT FROM AUTHOR]

CD4+ T-helper cells play an important role in alloimmune reactions following transplantation by stimulating humoral as well as cellular responses, which might lead to failure of the allograft. CD4+ memory T-helper cells from a previous immunizing event can potentially be reactivated by exposure to HLA mismatches that share T-cell epitopes with the initial immunizing HLA. Consequently, reactivity of CD4+ memory T-helper cells toward T-cell epitopes that are shared between immunizing HLA and donor HLA could increase the risk of alloimmunity following transplantation, thus affecting transplant outcome. In this study, the amount of T-cell epitopes shared between immunizing and donor HLA was used as a surrogate marker to evaluate the effect of donor-reactive CD4+ memory T-helper cells on the 10-year risk of death-censored kidney graft failure in 190 donor/recipient combinations using the PIRCHE-II algorithm. The T-cell epitopes of the initial theoretical immunizing HLA and the donor HLA were estimated and the number of shared PIRCHE-II epitopes was calculated. We show that the natural logarithm-transformed PIRCHE-II overlap score, or Shared T-cell EPitopes (STEP) score, significantly associates with the 10-year risk of death-censored kidney graft failure, suggesting that the presence of pre-transplant donor-reactive CD4+ memory T-helper cells might be a strong indicator for the risk of graft failure following kidney transplantation. [ABSTRACT FROM AUTHOR]

Introduction: Cardiovascular disease is the leading cause of death in end-stage renal disease (ESRD) and is strongly associated with vascular calcification. An important driver of vascular calcification is high phosphate levels, but these become lower when patients initiate nocturnal hemodialysis or receive a kidney transplant. However, it is unknown whether nocturnal hemodialysis or kidney transplantation mitigate vascular calcification. Therefore, we compared progression of coronary artery calcification (CAC) between patients treated with conventional hemodialysis, nocturnal hemodialysis, and kidney transplant recipients. Methods: We measured CAC annually up to 3 years in 114 patients with ESRD that were transplantation candidates: 32 that continued conventional hemodialysis, 34 that initiated nocturnal hemodialysis (≥4x 8 hours/week), and 48 that received a kidney transplant. We compared CAC progression between groups as the difference in square root transformed volume scores per year (ΔCAC SQRV) using linear mixed models. Reference category was conventional hemodialysis. Results: The mean age of the study population was 53 ±13 years, 75 (66%) were male, and median dialysis duration was 28 (IQR 12–56) months. Median CAC score at enrollment was 171 (IQR 10–647), which did not differ significantly between treatment groups (P = 0.83). Compared to conventional hemodialysis, CAC progression was non-significantly different in nocturnal hemodialysis -0.10 (95% CI -0.77 to 0.57) and kidney transplantation -0.33 (95% CI -0.96 to 0.29) in adjusted models. Conclusions: Nocturnal hemodialysis and kidney transplantation are not associated with significantly less CAC progression compared to conventional hemodialysis during up to 3 years follow-up. Further studies are needed to confirm these findings, to determine which type of calcification is measured with CAC in end-stage renal disease, and whether that reflects cardiovascular risk. [ABSTRACT FROM AUTHOR]

Background: Vascular calcification is seen in most patients on dialysis and is strongly associated with cardiovascular mortality. Vascular calcification is promoted by phosphate, which generally reaches higher levels in hemodialysis than in peritoneal dialysis. However, whether vascular calcification develops less in peritoneal dialysis than in hemodialysis is currently unknown. Therefore, we compared coronary artery calcification (CAC), its progression, and calcification biomarkers between patients on hemodialysis and peritoneal dialysis.Methods: We measured CAC in 134 patients who had been treated exclusively with hemodialysis (n = 94) or peritoneal dialysis (n = 40) and were transplantation candidates. In 57 of them (34 on hemodialysis and 23 on peritoneal dialysis), we also measured CAC progression annually up to 3 years and the inactive species of desphospho-uncarboxylated matrix Gla protein (dp-ucMGP), fetuin-A, osteoprotegerin. We compared CAC cross-sectionally with Tobit regression. CAC progression was compared in 2 ways: with linear mixed models as the difference in square root transformed volume score per year (ΔCAC SQRV) and with Tobit mixed models. We adjusted for potential confounders.Results: In the cross-sectional cohort, CAC volume scores were 92 mm3 in hemodialysis and 492 mm3 in peritoneal dialysis (adjusted difference 436 mm3; 95% CI -47 to 919; p = 0.08). In the longitudinal cohort, peritoneal dialysis was associated with significantly more CAC progression defined as ΔCAC SQRV (adjusted difference 1.20; 95% CI 0.09 to 2.31; p = 0.03), but not with Tobit mixed models (adjusted difference in CAC score increase per year 106 mm3; 95% CI -140 to 352; p = 0.40). Peritoneal dialysis was associated with higher osteoprotegerin (adjusted p = 0.02) but not with dp-ucMGP or fetuin-A.Conclusions: Peritoneal dialysis is not associated with less CAC or CAC progression than hemodialysis, and perhaps with even more progression. This indicates that vascular calcification does not develop less in peritoneal dialysis than in hemodialysis. [ABSTRACT FROM AUTHOR]

A submerged floating tunnel (SFT) can be a promising solution for crossing a deep or wide waterway. This innovative concept however lacks research into its probabilistic design. In this research, the reliability of the tether-stabilized SFT is assessed. A first-order reliability method (FORM) and a Monte Carlo simulation (MCS) are performed for the limit state functions of the most important failure mechanisms. Stochastic variables are chosen so that a target reliability index of 3.8 for a reference period of 50 years is met. The calculated factors from the full probabilistic design are compared with the general recommended partial factors for strength and resistance from Eurocode EN1990. For the strength mechanisms, the calculated factors are smaller than the factors from Eurocode. However, for the equilibrium mechanism, the calculated factor for the unfavorable loading is larger than the factor from Eurocode and should be increased by 10% in order to design a safe enough SFT.

Background: Orthodontic treatment can successfully align pathologically migrated teeth and lead to improvement of periodontal stability in patients with periodontitis. Periodontic-orthodontic approaches have gained increasing attention in the past years. Here, we investigated the interest of adults affected by chronic periodontitis in undergoing orthodontic treatment as well as patient-related and tooth-related influence factors.Methods: Periodontal and orthodontic measurements/indices were taken from 115 adult patients with moderate-to-severe periodontitis. The study participants answered a questionnaire investigating patient demographics, quality of life aspects, and their interest in undergoing orthodontic treatment. Correlations between clinical data, questionnaire responses, and this interest were analyzed by means of an age- and sex-adjusted multiple regression model.Results: Two-thirds of the participants were interested in orthodontic therapy and indicated long-term healthy and esthetically appealing teeth as their main motives. A significant correlation was found between subjectively felt impaired dental esthetics and an interest in orthodontic treatment. However, there were no correlations with the severity of periodontitis, tooth alignment, or patient demographics, including sex. Older patients were significantly more often interested in orthodontic treatment. Most participants had never been provided with information about orthodontic treatment options for adults.Conclusions: A considerable number of adult patients with periodontitis were interested in orthodontics to improve tooth alignment. However, severity of periodontitis and tooth misalignment or demographic factors may not be indicative thereof. Therefore, dental practitioners need to be aware of patients wishing to align their teeth and to provide them with the relevant information and, if appropriate, enable interdisciplinary treatment planning. [ABSTRACT FROM AUTHOR]

Background Few studies have evaluated the effect of different immunosuppressive strategies on long-term kidney transplant outcomes. Moreover, as they were usually based on historical data, it was not possible to account for the presence of pretransplant donor-specific human-leukocyte antigen antibodies (DSA), a currently recognized risk marker for impaired graft survival. The aim of this study was to evaluate to what extent frequently used initial immunosuppressive therapies increase graft survival in immunological low-risk patients. Methods We performed an analysis on the PROCARE cohort, a Dutch multicentre study including all transplantations performed in the Netherlands between 1995 and 2005 with available pretransplant serum (n  = 4724). All sera were assessed for the presence of DSA by a luminex single-antigen bead assay. Patients with a previous kidney transplantation, pretransplant DSA or receiving induction therapy were excluded from the analysis. Results Three regimes were used in over 200 patients: cyclosporine (CsA)/prednisolone (Pred) (n  = 542), CsA/mycophenolate mofetil (MMF)/Pred (n  = 857) and tacrolimus (TAC)/MMF/Pred (n  = 811). Covariate-adjusted analysis revealed no significant differences in 10-year death-censored graft survival between patients on TAC/MMF/Pred therapy (79%) compared with patients on CsA/MMF/Pred (82%, P = 0.88) or CsA/Pred (79%, P = 0.21). However, 1-year rejection-free survival censored for death and failure unrelated to rejection was significantly higher for TAC/MMF/Pred (81%) when compared with CsA/MMF/Pred (67%, P <   0.0001) and CsA/Pred (64%, P <   0.0001). Conclusion These results suggest that in immunological low-risk patients excellent long-term kidney graft survival can be achieved irrespective of the type of initial immunosuppressive therapy (CsA or TAC; with or without MMF), despite differences in 1-year rejection-free survival. [ABSTRACT FROM AUTHOR]

Background Pre-transplant donor-specific anti–human leucocyte antigen (HLA) antibodies (DSAs) are associated with impaired kidney graft survival while the clinical relevance of non-donor-specific anti-HLA antibodies (nDSAs) is more controversial. The aim of the present paired kidney graft study was to compare the clinical relevance of DSAs and nDSAs. Methods To eliminate donor and era-dependent factors, a post hoc paired kidney graft analysis was performed as part of a Dutch multicentre study evaluating all transplantations between 1995 and 2005 with available pre-transplant serum samples. Anti-HLA antibodies were detected with a Luminex single-antigen bead assay. Results Among 3237 deceased donor transplantations, we identified 115 recipient pairs receiving a kidney from the same donor with one recipient being DSA positive and the other without anti-HLA antibodies. Patients with pre-transplant DSAs had a significantly lower 10-year death-censored graft survival (55% versus 82%, P=0.0001). We identified 192 pairs with one recipient as nDSA positive (against Class I and/or II) and the other without anti-HLA antibodies. For the patients with nDSAs against either Class I or II, graft survival did not significantly differ compared with patients without anti-HLA antibodies (74% versus 77%, P = 0.79). Only in patients with both nDSAs Class I and II was there a trend towards a lower graft survival (58%, P = 0.06). Lastly, in a small group of 42 recipient pairs, 10-year graft survival in recipients with DSAs was 49% compared with 68% in recipients with nDSAs (P=0.11). Conclusion This paired kidney analysis confirms that the presence of pre-transplant DSAs in deceased donor transplantations is a risk marker for graft loss, whereas nDSAs in general are not associated with a lower graft survival. Subgroup analysis indicated that only in broadly sensitized patients with nDSAs against Class I and II, nDSAs may be a risk marker for graft loss in the long term. [ABSTRACT FROM AUTHOR]

Background: Health-related quality of life (HRQOL) is an important outcome measure in patients with end-stage renal disease. HRQOL is assumed to improve with kidney transplantation and also with nocturnal hemodialysis compared to conventional hemodialysis. However, there is no evidence regarding HRQOL to support the optimal treatment choice for patients on nocturnal hemodialysis who hesitate opting for transplantation. We therefore compared HRQOL between patients who were treated with kidney transplantation or nocturnal hemodialysis for one year. Methods: We assessed HQROL using the Kidney Disease Quality of Life–Short Form questionnaire in a cross-sectional sample of patients who were treated with kidney transplantation (n = 41) or nocturnal hemodialysis (n = 31) for one year. All patients on nocturnal hemodialysis were transplantation candidates. Using linear regression, we compared HRQOL between kidney transplantation and nocturnal hemodialysis, and adjusted for age, sex, dialysis duration, cardiovascular disease, and presence of residual urine production. Results: At one year follow-up, mean age of the study population was 54 ±13 years, and median dialysis duration was 3.2 (IQR 2.1–5.0) years. Kidney transplantation was associated with significantly higher HRQOL on the domain “effects” compared to nocturnal hemodialysis (adjusted difference 12.0 points, 95% CI 3.9; 20.1). There were potentially clinically relevant differences between kidney transplantation and nocturnal hemodialysis on the domains “burden” (adjusted difference 11.1 points, 95% CI -2.6; 24.8), “social support” (adjusted difference 6.2, 95% CI -6.6; 19.1), and the physical composite score (adjusted difference 3.0, 95% CI -2.0; 8.1), but these were not significant. Conclusions: After kidney transplantation, HRQOL is especially higher on the domain “effects of kidney disease” compared to nocturnal hemodialysis. This can be useful when counseling patients on nocturnal hemodialysis who may opt for transplantation. [ABSTRACT FROM AUTHOR]

Individual HLA mismatches may differentially impact graft survival after kidney trans plantation. Therefore, there is a need for a reliable tool to define permissible HLA mismatches in kidney transplantation. We previously demonstrated that donorderived Predicted Indirectly ReCognizable HLA Epitopes presented by recipient HLA class II (PIRCHE-II) play a role in de novo donor-specific HLA antibodies formation after kidney transplantation. In the present Dutch multi-center study, we evaluated the possible association between PIRCHE-II and kidney graft failure in 2,918 donor-recipient couples that were transplanted between 1995 and 2005. For these donors-recipients couples, PIRCHE-II numbers were related to graft survival in univariate and multivariable analyses. Adjusted for confounders, the natural logarithm of PIRCHE-II was associated with a higher risk for graft failure [hazard ratio (HR): 1.13, 95% CI: 1.04-1.23, p = 0.003]. When analyzing a subgroup of patients who had their first transplantation, the HR of graft failure for ln(PIRCHE-II) was higher compared with the overall cohort (HR: 1.22, 95% CI: 1.10-1.34, p < 0.001). PIRCHE-II demonstrated both early and late effects on graft failure in this subgroup. These data suggest that the PIRCHE-II may impact graft survival after kidney transplantation. Inclusion of PIRCHE-II in donor-selection criteria may eventually lead to an improved kidney graft survival. [ABSTRACT FROM AUTHOR]

Protamines are unique sperm-specific proteins that package and protect paternal chromatin until fertilization. A subset of mammalian species expresses two protamines (PRM1 and PRM2), while in others PRM1 is sufficient for sperm chromatin packaging. Alterations of the species-specific ratio between PRM1 and PRM2 are associated with infertility. Unlike PRM1, PRM2 is generated as a precursor protein consisting of a highly conserved N-terminal domain, termed cleaved PRM2 (cP2), which is consecutively trimmed off during chromatin condensation. The carboxyterminal part, called mature PRM2 (mP2), interacts with DNA and together with PRM1, mediates chromatin-hypercondensation. The removal of the cP2 domain is believed to be imperative for proper chromatin condensation, yet, the role of cP2 is not yet understood. We generated mice lacking the cP2 domain while the mP2 is still expressed. We show that the cP2 domain is indispensable for complete sperm chromatin protamination and male mouse fertility. cP2 deficient sperm show incomplete protamine incorporation and a severely altered protamine ratio, retention of transition proteins and aberrant retention of the testis specific histone variant H2A.L.2. During epididymal transit, cP2 deficient sperm seem to undergo ROS mediated degradation leading to complete DNA fragmentation. The cP2 domain therefore seems to be a key aspect in the complex crosstalk between histones, transition proteins and protamines during sperm chromatin condensation. Overall, we present the first step towards understanding the role of the cP2 domain in paternal chromatin packaging and open up avenues for further research.

Light-harvesting concentrators have a high potential to make highly efficient but precious energy converters, such as multijunction photovoltaics, more affordable for everyday applications. They collect sunlight, including diffusively scattered light, on large areas and redirect it to much smaller areas of the highly efficiency solar cells. Among the best current concepts are pools of randomly oriented light-collecting donor molecules that transfer all excitons to few aligned acceptors reemitting the light in the direction of the photovoltaics. So far, this system has only been realized for the 350–550 nm wavelength range, suitable for AlGaInP photovoltaics. This was achieved by using acceptor molecules that aligned during mechanical stretching of polymers together with donors, that stay random in that very same material and procedure. However, until recently, very little was known about the factors that are responsible for the alignability of molecules in stretched polymers and therefore it was difficult to find suitable donors and acceptors, as well as for other spectral ranges. Recently, a structural parameter was introduced with a high predictivity for the alignability of molecules that contain rigid band-like structures or linear aromatic π-systems. However, for light concentrators in more red spectral ranges, molecular systems often contain larger and extended, planar-like π-systems for which the previously reported parameter is not directly applicable. Here, we present a refined prediction parameter also suitable for larger plane-like structures. The new parameter depends on the number of in-plane atoms divided by out-of-plane atoms as determined by computational geometry optimization and additionally the planar aspect ratio for molecules that contain only in-plane atoms. With the help of this parameter, we found a new system that can efficiently collect and redirect light for the second 500–700 nm AlGaAs layer of current world-record multijunction photovoltaics. Similarly, as the previously reported system for the blue-green layer, it has also overall absorption and re-directioning quantum efficiencies close to 80–100%. Both layers, together, already cover about 75% of the energy in the solar spectrum.

Maintenance of metabolic homeostasis requires adaption of gene regulation to the cellular energy state via transcriptional regulators. Here, we identify a role of ceramide synthase (CerS) Schlank, a multiple transmembrane protein containing a catalytic lag1p motif and a homeodomain, which is poorly studied in CerSs, as a transcriptional regulator. ChIP experiments show that it binds promoter regions of lipases lipase3 and magro via its homeodomain. Mutation of nuclear localization site 2 (NLS2) within the homeodomain leads to loss of DNA binding and deregulated gene expression, and NLS2 mutants can no longer adjust the transcriptional response to changing lipid levels. This mechanism is conserved in mammalian CerS2 and emphasizes the importance of the CerS protein rather than ceramide synthesis. This study demonstrates a double role of CerS Schlank as an enzyme and a transcriptional regulator, sensing lipid levels and transducing the information to the level of gene expression.

Summary: Medical waste handlers (MWHs) are at risk of exposure to serious viral infections. No data are available on the prevalence of hepatitis B virus (HBV), hepatitis C virus (HCV) or human immunodeficiency virus (HIV) among MWHs in Libya. During a one-year period (January to December 2004) blood samples from 300 (59 females) MWHs employed by a local contractor in Tripoli and 300 blood samples from non-medical waste handlers (NMWHs) who had no direct or indirect contact with medical waste were examined for HBV, HCV and HIV using enzyme-linked immunosorbent assays. HBV was detected in 7 (2.3%) and 1 (0.3%) and HCV in 8 (2.7%) and 0 (0.0%) of MWHs and NMWHs, respectively. Significant differences were observed in the detection rates of HBV (OR: 7.14; P <0.04) and HCV (OR: undefined; P <0.005) in MWHs when compared with NMWHs. HIV was not detected in both groups. Of the MWHs studied, 21% were immunised against HBV and 7% were trained to handle medical waste. In addition, 99.7% wore overalls, 57.7% thick disposable gloves, 55% boots and 17.7% masks while handling medical waste. In conclusion, prevalence rates of HBV and HCV were significantly higher in MWHs than those in NMWHs examined. Training, immunisation, and post-exposure protection of MWHs, in addition to proper management of medical waste by the health authorities, may significantly reduce the risk of acquiring infectious agents by MWHs in Libya. [Copyright &y& Elsevier]

Mucopolysaccharidosis type II (MPS II) is a lysosomal storage disorder that occurs due to the deficit of the lysosomal enzyme iduronate 2-sulfatase (IDS) that leads to the storage of the glycosaminoglycan heparan- and dermatan-sulfate in all organs and tissues. It is characterized by important clinical features and the severe form presents with a heavy neurological involvement. However, almost nothing is known about the neuropathogenesis of MPS II. To address this issue, we developed a ubiquitous, neuronal, and glial-specific knockdown model in Drosophila melanogaster by using the RNA interference (RNAi) approach. Knockdown of the Ids/CG12014 gene resulted in a significant reduction of the Ids gene expression and enzymatic activity. However, glycosaminoglycan storage, survival, molecular markers (Atg8a, Lamp1, Rab11), and locomotion behavior were not affected. Even strongly reduced, IDS-activity was enough to prevent a pathological phenotype in a MPS II RNAi fruit fly. Thus, a Drosophila MPS II model requires complete abolishment of the enzymatic activity.

The research field on extracellular vesicles (EV) has rapidly expanded in recent years due to the therapeutic potential of EV. Adipose tissue human mesenchymal stem cells (ASC) may be a suitable source for therapeutic EV.A major limitation in the field is the lack of standardization of the challenging techniques to isolate and characterize EV.The aim of our study was to incorporate new controls for the detection and quantification of EV derived from ASC and analyze the applicability and limitations of the available techniques.ASC were cultured in medium supplemented with 5% of vesicles-free fetal bovine serum. The EV were isolated from Conditioned Medium by differential centrifugation with size filtration (0.2 µm). As a control, non-conditioned culture medium was used (Control Medium). To detect EV, electron microscopy, conventional flow cytometry and Western Blot were used. The quantification of the EV was by total protein quantification, Exo-ELISA immunoassay, and Nanosight. Cytokines and growth factors in the EV samples were measured by Multiplex Bead Array Kit. The EV were detected by electron microscope. Total protein measurement was not useful to quantify EV as the Control Medium showed similar protein contents as the EV samples. The Exo-ELISA kits had technical troubles and it was not possible to quantify the concentration of exosomes in the samples. The use of Nanosight enabled quantification and size determination of the EV. It is however not possible to distinguish protein aggregates from EV with this method. The technologies for quantification and characterization of the EV need to be improved. In addition, we detected protein contaminants in the EV samples, which make it difficult to determine the real effect of EV in experimental models. It will be crucial in the future to optimize design novel methods for purification and characterization of EV.

Mesenchymal stem cells (MSC) are present throughout the body and are thought to play a role in tissue regeneration and control of inflammation. MSC can be easily expanded in vitro and their potential as a therapeutic option for degenerative and inflammatory disease is therefore intensively investigated. Whilst it was initially thought that MSC would replace dysfunctional cells and migrate to sites of injury to interact with inflammatory cells, experimental evidence indicates that the majority of administered MSC get trapped in capillary networks and have a short life span. In this review we discuss current knowledge on the migratory properties of endogenous and exogenous MSC and confer on how culture induced modifications of MSC may affect these properties. Finally we will discuss how, despite their limited survival, administered MSC can bring about their therapeutic effects.

Background: Pre-transplant donor-specific anti-human leucocyte antigen (HLA) antibodies (DSAs) are associated with impaired kidney graft survival while the clinical relevance of non-donor-specific anti-HLA antibodies (nDSAs) is more controversial. The aim of the present paired kidney graft study was to compare the clinical relevance of DSAs and nDSAs., Methods: To eliminate donor and era-dependent factors, a post hoc paired kidney graft analysis was performed as part of a Dutch multicentre study evaluating all transplantations between 1995 and 2005 with available pre-transplant serum samples. Anti-HLA antibodies were detected with a Luminex single-antigen bead assay., Results: Among 3237 deceased donor transplantations, we identified 115 recipient pairs receiving a kidney from the same donor with one recipient being DSA positive and the other without anti-HLA antibodies. Patients with pre-transplant DSAs had a significantly lower 10-year death-censored graft survival (55% versus 82%, P=0.0001). We identified 192 pairs with one recipient as nDSA positive (against Class I and/or II) and the other without anti-HLA antibodies. For the patients with nDSAs against either Class I or II, graft survival did not significantly differ compared with patients without anti-HLA antibodies (74% versus 77%, P = 0.79). Only in patients with both nDSAs Class I and II was there a trend towards a lower graft survival (58%, P = 0.06). Lastly, in a small group of 42 recipient pairs, 10-year graft survival in recipients with DSAs was 49% compared with 68% in recipients with nDSAs (P=0.11)., Conclusion: This paired kidney analysis confirms that the presence of pre-transplant DSAs in deceased donor transplantations is a risk marker for graft loss, whereas nDSAs in general are not associated with a lower graft survival. Subgroup analysis indicated that only in broadly sensitized patients with nDSAs against Class I and II, nDSAs may be a risk marker for graft loss in the long term., (© The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

The best treatment for patients with end-stage renal disease is kidney transplantation. Although graft survival rates have improved in the last decades, patients still may lose their grafts partly due to the detrimental effects of donor-specific antibodies (DSA) against human leukocyte antigens (HLA) and to a lesser extent also by antibodies directed against non-HLA antigens expressed on the donor endothelium. Assays to detect anti-HLA antibodies are already in use for many years and have been proven useful for transplant risk stratification. Currently, there is a need for assays to additionally detect multiple non-HLA antibodies simultaneously in order to study their clinical relevance in solid organ transplantation. This study describes the development, technical details and validation of a high-throughput multiplex assay for the detection of antibodies against 14 non-HLA antigens coupled directly to MagPlex microspheres or indirectly via a HaloTag. The non-HLA antigens have been selected based on a literature search in patients with kidney disease or following transplantation. Due to the flexibility of the assay, this approach can be used to include alternative antigens and can also be used for screening of other organ transplant recipients, such as heart and lung.

Background Complement-fixing antibodies against donor HLA are considered a contraindication for kidney transplant. A modification of the IgG single-antigen bead (SAB) assay allows detection of anti-HLA antibodies that bind C3d. Because early humoral graft rejection is considered to be complement mediated, this SAB-based technique may provide a valuable tool in the pretransplant risk stratification of kidney transplant recipients. Methods Previously, we established that pretransplant donor-specific anti-HLA antibodies (DSAs) are associated with increased risk for long-term graft failure in complement-dependent cytotoxicity crossmatch-negative transplants. In this study, we further characterized the DSA-positive serum samples using the C3d SAB assay. Results Among 567 pretransplant DSA-positive serum samples, 97 (17%) contained at least one C3d-fixing DSA, whereas 470 (83%) had non-C3d-fixing DSA. At 10 years after transplant, patients with C3d-fixing antibodies had a death-censored, covariate-adjusted graft survival of 60%, whereas patients with non-C3d-fixing DSA had a graft survival of 64% (hazard ratio, 1.02; 95% confidence interval, 0.70 to 1.48 for C3d-fixing DSA compared with non-C3d-fixing DSA; P =0.93). Patients without DSA had a 10-year graft survival of 78%. Conclusions The C3d-fixing ability of pretransplant DSA is not associated with increased risk for graft failure., (Copyright © 2018 by the American Society of Nephrology.)

Introduction: The intestinal protozoa Entamoeba histolytica, Giardia lamblia, and Cryptosporidium spp. are the causative agents of giardiasis, amebiasis, and cryptosporidiosis, respectively. Adequate knowledge of the geographical distribution of parasites and the demographic variables that influence their prevalence is important for effective control of infection in at-risk populations., Methods: The data were obtained by an English language literature search of Medline and PubMed for papers using the search terms 'intestinal parasites and Libya, G. lamblia and Libya, E. histolytica and Libya and Cryptosporidium and Libya' for the period 2000-2015., Results: The data obtained for the period 2000-2015 showed prevalence rates of 0.8-36.6% (mean 19.9%) for E. histolytica/dispar, 1.2-18.2% (mean 4.6%) for G. lamblia and 0.9-13% (mean 3.4%) for Cryptosporidium spp. among individuals in Libya with gastroenteritis (GE). On the other hand, prevalence rates of 0.8-16.3% (mean 8.3%), 1.8-28.8% (mean 4.8%), and 1.0-2.5% (mean=2.4), respectively, were observed for individuals without GE. The mean prevalence rate of E. histolytica/dispar was significantly higher among individuals with GE compared with those without GE (p<0.0000001, OR=2.74). No significant difference in prevalence rate of the three organisms was found according to gender, but most of infections were observed in children aged 10 years or younger., Conclusion: The reviewed data suggest that E. histolytica, G. lamblia, and Cryptosporidium spp. may play a minor role in GE in Libya. The observed high prevalence rates of E. histolytica/dispar reported from Libya could be due mainly to the non-pathogenic E. dispar and E. moshkovskii. However, more studies are needed in the future using E. histolytica-specific enzyme immunoassays and/or molecular methods to confirm this observation.

The aim of this review is to provide information on the prevalence, clinical syndromes, and antimicrobial resistance and therapy of Aeromonas spp. infections in Arab countries. The data were obtained by an English language literature search from 1995 to 2014 of Medline and PubMed for papers using the search terms "Aeromonas+name of Arab country (i.e. Algeria, Egypt, etc.)". Additional data were obtained from a Google search using the aforementioned terms. The organisms have been reported from diarrheal children, patients with cholera-like diarrhea, an outbreak of acute gastroenteritis and from different types of animals, foods and water source in several Arab countries in the Middle East and North Africa with predominance of A. hydrophila, A. caviae and A. sobria. Using molecular techniques few studies reported genes encoding several toxins from aeromonads isolated from different sources. Among the antimicrobials examined in the present review third generation cephalosporins, fluoroquinolones and aminoglycosides showed excellent activity and can be employed in the treatment of Aeromonas-associated human infections in Arabic countries. Whenever possible, treatment should be guided by the susceptibility testing results of the isolated organism. In the future, studies employing molecular testing methods are required to provide data on circulating genospecies and their modes of transmission in the community, and on their mechanisms of resistance to antimicrobials. Microbiology laboratories and research centers are encouraged to look for these organisms in clinical, food and water sources to attain a better understanding of the public health risks from these organisms in Arab countries., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Resistance to antimicrobial agents is a major health problem that affects the whole world. Providing information on the past state of antimicrobial resistance in Libya may assist the health authorities in addressing the problem more effectively in the future. Information was obtained mainly from Highwire Press (including PubMed) search for the period 1970-2011 using the terms 'antibiotic resistance in Libya', 'antimicrobial resistance in Libya', 'tuberculosis in Libya', and 'primary and acquired resistance in Libya' in title and abstract. From 1970 to 2011 little data was available on antimicrobial resistance in Libya due to lack of surveillance and few published studies. Available data shows high resistance rates for Salmonella species in the late 1970s and has remained high to the present day. High prevalence rates (54-68%) of methicillin-resistant Staphylococcus aureus (MRSA) were reported in the last decade among S. aureus from patients with burns and surgical wound infections. No reports were found of vancomycin-resistant S. aureus (VRSA) or vancomycin-intermediate-resistant S. aureus (VISA) using standard methods from Libya up to the end of 2011. Reported rates of primary (i.e. new cases) and acquired (i.e. retreatment cases) multidrug-resistant tuberculosis (MDR-TB) from the eastern region of Libya in 1971 were 16.6 and 33.3% and in 1976 were 8.6 and 14.7%, in western regions in 1984-1986 were 11 and 21.5% and in the whole country in 2011 were estimated at 3.4 and 29%, respectively. The problem of antibiotic resistance is very serious in Libya. The health authorities in particular and society in general should address this problem urgently. Establishing monitoring systems based on the routine testing of antimicrobial sensitivity and education of healthcare workers, pharmacists, and the community on the health risks associated with the problem and benefits of prudent use of antimicrobials are some steps that can be taken to tackle the problem in the future.

Introduction: Cryptosporidium is the causative agent of cryptosporidiosis. The disease is self-limited in immunocompetent persons but potentially life-threatening in immunocompromised individuals., Methods: The data included in the present review were obtained mainly from a Highwire Press (including PubMed) search for the period 2002-2011., Results: Information on cryptosporidiosis is lacking in some Arab countries; however available data show prevalence rates of <1-43% (mean = 8.7%) of Cryptosporidium infection in diarrheic immunocompetent pediatrics and <1-82% (mean 41%) in immunocompromised patients (including children and adults). Infection rate with Cryptosporidium species among pediatrics in rural and semiurban areas was higher than in urban areas. Cryptosporidium-associated diarrhea occurs mainly in younger children and inversely correlates with age, being more prevalent in children aged 1 year or less, particularly in rural and suburban regions. Although most Arab countries are characterized by a hot summer and a mild winter, infection with Cryptosporidium appears to occur at a higher rate of incidence during the rainy months that are usually associated with the cold season of the year. Contact with animals and contaminated waters are the main modes of transmission of cryptosporidia. Reports of C. hominis from the region indicate that person-to-person transmission is also important. Foreign housekeepers in oil-rich countries may be a source of Cryptosporidium., Conclusion: Cryptosporidium species, mainly C. parvum, are important causes of diarrhea in countries of the Arab world, particularly in children. In addition to educational programs that promote personal, household, as well as food hygiene, improving water treatment processes and protection of treated waters from contamination should be implemented by the health and environmental authorities in each country. More studies employing molecular testing methods are needed in the future to provide data on circulating species/genospecies and subtypes and their modes of transmission in the community.

Stool samples from children < 5 years of age with diarrhea (N = 239) were examined for enteric pathogens using a combination of culture, enzyme-immunoassay, and polymerase chain reaction methods. Pathogens were detected in 122 (51%) stool samples; single pathogens were detected in 37.2% and co-pathogens in 13.8% of samples. Norovirus, rotavirus, and diarrheagenic Escherichia coli (DEC) were the most frequently detected pathogens (15.5%, 13.4%, and 11.2%, respectively); Salmonella, adenovirus, and Aeromonas were detected less frequently (7.9%, 7.1%, and 4.2%). The most commonly detected DEC was enteroaggregative E. coli (5.4%). Resistance to ≥ 3 antimicrobials was observed in 60% (18/30) of the bacterial pathogens. Salmonella resistance to ciprofloxacin (63.1%) has become a concern. Enteric viral pathogens were the most significant causative agents of childhood diarrhea in Tripoli. Bacterial pathogens were also important contributors to pediatric diarrhea. The emergence of ciprofloxacin-resistant Salmonella represents a serious health problem that must be addressed by Libyan health authorities.

Typhoid fever is endemic in the Mediterranean North African countries (Morocco, Algeria, Tunisia, Libya, and Egypt) with an estimated incidence of 10-100 cases per 100,000 persons. Outbreaks caused by Salmonella enterica serovar Typhi are common and mainly due to the consumption of untreated or sewage-contaminated water. Salmonella enterica Paratyphi B is more commonly involved in nosocomial cases of enteric fever in North Africa than expected and leads to high mortality rates among infants with congenital anomalies. Prevalence among travellers returning from this region is low, with an estimate of less than one per 100,000. Although multidrug resistant strains of Salmonella Typhi and Paratyphi are prevalent in this region, the re-emergence of chloramphenicol- and ampicillin-susceptible strains has been observed. In order to better understand the epidemiology of enteric fever in the Mediterranean North African region, population-based studies are needed. These will assist the health authorities in the region in preventing and controlling this important disease.