Long-term,prolonged-release tacrolimus-based immunosuppression in de novo kidney transplant recipients: 5-year prospective follow-up of the ADHERE study patients

The objectives of this study were to assess long-term graft survival, patient survival, renal function, and acute rejections in de novo kidney transplant recipients, treated with once-daily prolonged-release tacrolimus-based therapy. The study was a 5-year non-interventional prospective follow-up of patients from the ADHERE study, a Phase IV 12-month open-label assessment of patients randomized to receive prolonged-release tacrolimus in combination with mycophenolate mofetil (MMF) (Arm 1) or sirolimus (Arm 2). From 838 patients in the randomized study, 587 were included in the long-term follow-up, of whom 510 completed the study at year 5. At 1 year post-transplant, graft and patient survival rates were 93.0% and 97.8%, respectively, and at 5 years were 84.0% and 90.8%, respectively. Cox proportional hazards analysis showed no association between graft loss, initial randomized treatment arm, donor age, donor type, or sex. The 5-year acute rejection-free survival rate was 77.4%, and biopsy-confirmed acute rejection-free survival rate was 86.0%. Renal function remained stable over the follow-up period: mean ± SD eGFR 4-variable modification diet in renal disease formula (MDRD4) was 52.3 ± 21.6 ml/min/1.73 m² at 6 months and 52.5 ± 23.0 ml/min/1.73 m² at 5 years post-transplant. These findings support the role of long-term once-daily prolonged-release tacrolimus-based immunosuppression, in combination with sirolimus or MMF, for renal transplant recipients in routine clinical practice.     

Girl Child Marriage and Its Effect on Fertility in Pakistan: Findings from Pakistan Demographic and Health Survey, 2006–2007

Child marriage (before 18 years) is prevalent in Pakistan, which disproportionately affects young girls in rural, low income and low education households. Our study aims to determine the association between early marriage and high fertility and poor fertility health indicators among young women in Pakistan beyond those attributed to social vulnerabilities. Nationally representative data from Pakistan Demographic and Health Survey, 2006–2007, a cross-sectional observational survey, were limited to ever-married women aged 20–24 years (n = 1,560; 15 % of 10,023) to identify differences in poor fertility outcomes [high fertility (three or more childbirths); rapid repeat childbirth (<24 months between births); unwanted pregnancy (any ever); pregnancy termination (any stillbirth, miscarriage or abortion ever)] by early (<18) versus adult (≥18) age at marriage. Associations between child marriage and fertility outcomes were assessed by calculating adjusted odds ratios (AORs) using logistic regression models after controlling for demographics, social equity indicators (education, wealth index, rural residence), contraception use, marriage duration and culture-specific factors (husband’s desire for more children, son preference). Overall, 50 % of ever-married women aged 20–24 years in Pakistan were married before the age of 18 years. Girl child marriage was significantly (p < 0.001) associated with low social equity indicators (poverty, rural residence, and no formal education). Adjusted logistic regression models showed that girl child marriage was significantly associated with high fertility (AOR 6.62; 95 % CI 3.53–12.43), rapid repeat childbirth (AOR 2.88; 95 % CI 1.83–4.54), unwanted pregnancy (AOR 2.90; 95 % CI 1.75–4.79), and pregnancy termination (AOR 1.75; 95 % CI 1.10–2.78). Girl child marriage affects half of all ever-married women aged 20–24 years in Pakistan, and increases their risk for high fertility and poor fertility health indicators, highlighting the need of increasing the age of marriage among women in Pakistan. Efforts to eliminate girl child marriage by strict law enforcement, promoting civil, sexual and reproductive health rights for women can help eliminate girl child marriage in Pakistan.     

Under-Five Child Mortality and Morbidity Associated with Consanguineous Child Marriage in Pakistan: Retrospective Analysis using Pakistan Demographic and Health Surveys, 1990–91, 2006–07, 2012–13

Objective To assess the combined effect of consanguineous and child marriages (CCM) on children health, which has not previously been explored, either globally or locally. Methods We analyzed secondary data from a series of cross-sectional, nationally representative Pakistan Demographic and Health Surveys 1990–91, 2006–07, and 2012–13. A total of 5406 mothers with 10,164 children were included in the analysis. Child health was assessed by variables such as history of diarrhea, acute respiratory infection (ARI), ARI with fever, Under-5 child mortality (U5CM) and small-size birth (SSB). Associations among variables were assessed by calculating unadjusted Odd Ratios (OR) and adjusted OR (AOR). Results A majority (n?=?6,247, 61%) of the births were to mothers having CCM as compare to non-CCM (3917, 39%). There was a significant association between CCM and U5CM during 1990–91 (AOR 1.24, 95% CI 1.03–1.49) and 2006–07 (AOR 1.25, 95% CI 1.05–1.51), and infant mortality in 1990–91 (AOR 1.39, 95% CI 1.05–1.85) and 2006–07 (AOR 1.61, 95% CI 1.17–2.21). A significant association was also found between CCM and SSB infants in the period 2006–07 (AOR 1.19, 95% CI 1.01–1.42) and 2012–13 (AOR 1.22, 95% CI 1.02–1.46). We noted no effect of CCM on diarrhea, ARI, and ARI with fever. Conclusion CCM increases the likelihood of U5CM, infant mortality and SSB infants. Further quantitative and qualitative research should be conducted to assess the effects of environmental, congenital and genetic factors on the health of children born to mothers in CCM.     

Comparative pharmacokinetics of tacrolimus in stable pediatric allograft recipients converted from immediate‐release tacrolimus to prolonged‐release tacrolimus formulation

This study was a Phase II, open‐label, multicenter, single‐arm, cross‐over study comparing the pharmacokinetics (PK) of tacrolimus in stable pediatric kidney, liver, or heart allograft recipients converted from immediate‐release tacrolimus (IR‐T) to prolonged‐release tacrolimus (PR‐T). In Days ?30 to ?1 of screening period, patients received their IR‐T‐based regimen; during Days 1‐7, patients received study IR‐T (same dose as screening). On Day 7, the first 24‐hours PK profile was taken; patients were then converted to PR‐T (1 mg:1 mg), with a second 24‐hours PK profile taken on Day 14. The primary end‐point was tacrolimus area under the blood concentration–time curve over 24 hours (AUC₂₄); secondary end‐points were maximum concentration C_maxand concentration at 24 hours C₂₄. The predefined similarity interval for confidence intervals (CIs) of least squares mean (LSM) ratios was 80%‐125%. The PK analysis set comprised 74 pediatric transplant recipients (kidney, n = 45; liver, n = 28; heart, n = 1). PR‐T:IR‐T LSM ratio (90% CI) was similar overall for AUC₂₄, _max, and C₂₄, and for kidney and liver recipients for AUC₂₄ (LSM ratio, kidney 91.8%; liver 104.1%) and C₂₄ (kidney 90.5%; liver 89.9%). Linear relationship was similar between AUC₂₄ and C₂₄, and between PR‐T and IR‐T (rho 0.89 and 0.84, respectively), suggesting that stable pediatric transplant recipients can be converted from IR‐T to PR‐T at the same total daily dose, using the same therapeutic drug monitoring method.     

Structural Lattice Topology and Material Optimization for Battery Protection in Electric Vehicles Subjected to Ground Impact Using Artificial Neural Networks and Genetic Algorithms

A critical external interference that often appears to pose a safety issue in rechargeable energy storage systems (RESS) for electric vehicles (EV) is ground impact due to stone impingement. This study aims to propose the new concept of the sandwich for structural battery protection using a lattice structure configuration for electric vehicle applications. The protective geometry consists of two layers of a twisted-octet lattice structure. The appropriate lattice structure was selected through topology and material optimization using an artificial neural network (ANN), genetic algorithms (GA), and multi-objective optimization with technique for order of preference by similarity to ideal solution (TOPSIS) methods. The optimization variables are the lattice structure relative density, ρ¯, angle, θ, and strength of the materials, σy. Numerical simulations were used to model the dynamic impact loading on the structures due to a conical stone mass of 0.77 kg traveling at 162 km/h. The two-layer lattice structure configuration appears to be suitable for the purposes of RESS protection. The optimum configuration for battery protection is a lattice structure with an angle of 66°, relative density of 0.8, and yield strength of 41 MPa. This optimum configuration can satisfy the safety threshold of battery-shortening deformation. Therefore, the proposed lattice structure configuration can potentially be implemented for electric vehicle applications to protect the battery from ground impact.     

Efficacy and safety of prolonged‐release tacrolimus in stable pediatric allograft recipients converted from immediate‐release tacrolimus – a Phase 2, open‐label,single‐arm,one‐way crossover study

There are limited clinical data regarding prolonged‐release tacrolimus (PR‐T) use in pediatric transplant recipients. This Phase 2 study assessed the efficacy and safety of PR‐T in stable pediatric kidney, liver, and heart transplant recipients (aged ≥5 to ≤16 years) over 1 year following conversion from immediate‐release tacrolimus (IR‐T), on a 1:1 mg total‐daily‐dose basis. Endpoints included the incidence of acute rejection (AR), a composite endpoint of efficacy failure (death, graft loss, biopsy‐confirmed AR, and unknown outcome), and safety. Tacrolimus dose and whole‐blood trough levels (target 3.5–15 ng/ml) were also evaluated. Overall, 79 patients (kidney, n = 48; liver, n = 29; heart, n = 2) were assessed. Following conversion, tacrolimus dose and trough levels remained stable; however, 7.6–17.7% of patients across follow‐up visits had trough levels below the target range. Two (2.5%) patients had AR, and 3 (3.8%) had efficacy failure. No graft loss or deaths were reported. No new safety signals were identified. Drug‐related treatment‐emergent adverse events occurred in 28 patients (35.4%); most were mild, and all resolved. This study suggests that IR‐T to PR‐T conversion is effective and well tolerated over 1 year in pediatric transplant recipients and highlights the importance of therapeutic drug monitoring to maintain target tacrolimus trough levels.     

Block Copolymer Synthesis via a Combination of ATRP and RAFT Using Click Chemistry

Block copolymer synthesis via a combination of ATRP and RAFT using click chemistry is reported for the first time. A RAFT agent with a terminal propargyl group (PTTC) was synthesized and was used to polymerize butyl acrylate and gave quantitative monomer conversion. Azide‐terminated p(tbA) was obtained by ATRP followed by reaction with sodium azide. Later, using CuBr‐PMDETA as catalyst via click chemistry, p(tBA)_(ATRP) and p(BA)_(RAFT) were reacted to get a block copolymer of p(tBA)_(ATRP)‐b‐p(BA)_(RAFT). Further, a total of 24 block copolymers were made by reacting four azido functional polymers with six propargyl functional polymers to obtain block copolymers via click chemistry.