The incremental yield of prenatal exome sequencing over chromosome microarray for congenital heart abnormalities: A systematic review and meta-analysis.

OBJECTIVES: To determine the incremental yield of prenatal exome sequencing (PES) over standard testing in fetuses with an isolated congenital heart abnormality (CHA), CHA associated with extra-cardiac malformations (ECMs) and CHA dependent upon anatomical subclassification. METHODS: A systematic review of the literature was performed using MEDLINE, EMBASE, Web of Science and grey literature January 2010-February 2023. Studies were selected if they included greater than 20 cases of prenatally diagnosed CHA when standard testing (QF-PCR/chromosome microarray/karyotype) was negative. Pooled incremental yield was determined. PROSPERO CRD 42022364747. RESULTS: Overall, 21 studies, incorporating 1957 cases were included. The incremental yield of PES (causative pathogenic and likely pathogenic variants) over standard testing was 17.4% (95% CI, 13.5%-21.6%), 9.3% (95% CI, 6.6%-12.3%) and 35.9% (95% CI, 21.0%-52.3%) for all CHAs, isolated CHAs and CHAs associated with ECMs. The subgroup with the greatest yield was complex lesions/heterotaxy; 35.2% (95% CI 9.7%-65.3%). The most common syndrome was Kabuki syndrome (31/256, 12.1%) and most pathogenic variants occurred de novo and in autosomal dominant (monoallelic) disease causing genes (114/224, 50.9%). CONCLUSION: The likelihood of a monogenic aetiology in fetuses with multi-system CHAs is high. Clinicians must consider the clinical utility of offering PES in selected isolated cardiac lesions.

Deep, rapid, and durable prostate-specific antigen decline with apalutamide plus androgen deprivation therapy is associated with longer survival and improved clinical outcomes in TITAN patients with metastatic castration-sensitive prostate cancer.

BACKGROUND: The first interim analysis of the phase III, randomized, double-blind, placebo-controlled, multinational TITAN study demonstrated improved overall survival (OS) and radiographic progression-free survival (rPFS) with apalutamide added to ongoing androgen deprivation therapy (ADT) in patients with metastatic castration-sensitive prostate cancer. The final analysis confirmed improvement in OS and other long-term outcomes. We evaluated prostate-specific antigen (PSA) kinetics and the association between PSA decline and outcomes in patients with metastatic castration-sensitive prostate cancer from TITAN. PATIENTS AND METHODS: Patients received apalutamide (240 mg/day) or placebo plus ADT (1 : 1). This post hoc exploratory analysis evaluated PSA kinetics and decline in relation to rPFS (22.7 months' follow-up) and OS, time to PSA progression, and time to castration resistance (44.0 months' follow-up) in patients with or without confirmed PSA decline using a landmark analysis, the Kaplan-Meier method, and Cox proportional hazards model. RESULTS: One thousand and fifty-two patients (apalutamide, 525; placebo, 527) were enrolled. Best confirmed PSA declines (≥50% or ≥90% from baseline or to ≤0.2 ng/ml) were achieved at any time during the study in 90%, 73%, and 68% of apalutamide-treated versus 55%, 29%, and 32% of placebo-treated patients, respectively. By 3 months of apalutamide treatment, best deep PSA decline of ≥90% or to ≤0.2 ng/ml occurred in 59% and 51% of apalutamide- and in 13% and 18% of placebo-treated patients, respectively. Achievement of deep PSA decline at landmark 3 months of apalutamide treatment was associated with longer OS [hazard ratio (HR) 0.35; 95% confidence interval (CI) 0.25-0.48), rPFS (HR 0.44; 95% CI 0.30-0.65), time to PSA progression (HR 0.31; 95% CI 0.22-0.44), and time to castration resistance (HR 0.38; 95% CI 0.27-0.52) compared with no decline (P < 0.0001 for all). Similar results were observed at landmark 6 and 12 months of apalutamide treatment. CONCLUSIONS: Apalutamide plus ADT demonstrated a robust (rapid, deep, and durable) PSA decline that was associated with improved clinical outcomes, including long-term survival.

Causal somatic mutations in urine DNA from persons with the CLOVES subgroup of the PIK3CA-related overgrowth spectrum.

Congenital lipomatous overgrowth with vascular, epidermal, and skeletal (CLOVES) anomalies and Klippel-Trenaunay (KTS) syndromes are caused by somatic gain-of-function mutations in PIK3CA, encoding a catalytic subunit of phosphoinositide 3-kinase. Affected tissue is needed to find mutations, as mutant alleles are not detectable in blood. Because some patients with CLOVES develop Wilms tumor, we tested urine as a source of DNA for mutation detection. We extracted DNA from the urine of 17 and 24 individuals with CLOVES and KTS, respectively, and screened 5 common PIK3CA mutation hotspots using droplet digital polymerase chain reaction. Six of 17 CLOVES participants (35%) had mutant PIK3CA alleles in urine. Among 8 individuals in whom a mutation had been previously identified in affected tissue, 4 had the same mutant allele in the urine. One study participant with CLOVES had been treated for Wilms tumor. We detected the same PIK3CA mutation in her affected tissue, urine, and tumor, indicating Wilms tumors probably arise from PIK3CA mutant cells in patients with CLOVES. No urine sample from a participant with KTS had detectable PIK3CA mutations. We suggest that urine, which has the advantage of being collected non-invasively, is useful when searching for mutations in individuals with CLOVES syndrome.

Okur-Chung neurodevelopmental syndrome: Eight additional cases with implications on phenotype and genotype expansion.

Okur-Chung syndrome is a neurodevelopmental condition attributed to germline CSNK2A1 pathogenic missense variants. We present 8 unreported subjects with the above syndrome, who have recognizable dysmorphism, varying degrees of developmental delay and multisystem involvement. Together with 6 previously reported cases, we present a case series of 7 female and 7 male subjects, highlighting the recognizable facial features of the syndrome (microcephaly, hypertelorism, epicanthic fold, ptosis, arched eyebrows, low set ears, ear fold abnormality, broad nasal bridge and round face) as well as frequently occurring clinical features including neurodevelopmental delay (93%), gastrointestinal (57%), musculoskeletal (57%) and immunological (43%) abnormalities. The variants reported in this study are evolutionary conserved and absent in the normal population. We observed that the CSNK2A1 gene is relatively intolerant to missense genetic changes, and most variants are within the protein kinase domain. All except 1 variant reported in this cohort are spatially located on the binding pocket of the holoenzyme. We further provide key recommendations on the management of Okur-Chung syndrome. To conclude, this is the second case series on Okur-Chung syndrome, and an in-depth review of the phenotypic features and genomic findings of the condition with suggestions on clinical management.

Metabolomics Study for Identification of Potential Biomarkers of Long-term Survival in Kidney Transplantation Recipients.

BACKGROUND: The recent progress and appropriate use of immunosuppressive drugs have considerably improved the short-term survival in kidney transplantation recipients (KTRs). The development of new strategies to improve long-term survival outcome after kidney transplantation is also becoming important. Although current diagnosis of allograft dysfunction relies on serum creatinine concentration and biopsy, they are nonspecific indicators of allograft function. Therefore, noninvasive, sensitive, and specific biomarkers for the prediction of long-term survival are needed. The aim of this study was to discover potential biomarkers for long-term survival in KTRs through the use of liquid chromatography-tandem mass spectrometry. METHODS: We used the metabolic approach to explore the change of metabolites in the serum of KTRs. Twenty-four KTRs with long-term good survival (LGS) and 10 KTRs with chronic antibody-mediated rejection (CAMR) were included in this study. After quantile normalization with chromatographic data, multivariate statistical analysis was performed. We attempted to analyze metabolic profiling with LGS and CAMR groups. RESULTS: The orthogonal partial least-squares discriminant analysis score plot showed a separation between 2 groups in the principal component. In the corresponding loading plot, 344 metabolites responsible for the separation observed in the score plot were identified (variable influence on projection ≥1.0). We then selected 54 metabolites to compare mass with charge by searching a web database, and 11 compounds were identified. CONCLUSIONS: We found metabolites in serum that differ in LGS and CAMR groups. Further studies are needed to figure out potential metabolomic biomarkers to predict long-term survival in KTRs.

Progression of Osteoporosis After Kidney Transplantation in Patients With End-Stage Renal Disease.

BACKGROUND: This study investigated the prevalence of osteoporosis and the risk factors for its progression in kidney transplant recipients (KTRs). METHODS: Dual energy X-ray absorptiometry was used to prospectively measure changes in bone mineral density (BMD) before kidney transplantation (KT) and 1 year after transplantation in 207 individuals. We also analyzed the risk factors of osteoporosis progression during this period. RESULTS: Prior to KT, the mean BMD score (T-score of the femur neck area) was -2.1 ± 1.2, and the prevalence of osteoporosis was 41.5% (86/207). At 1 year post-transplantation, the mean BMD score significantly decreased to -2.3 ± 1.1 (P < .001), and the prevalence of osteoporosis increased to 47.3% (98/207; P = .277). The BMD score worsened over the study period in 69.1% (143/207) of patients, improved in 24.1% (50/207), and showed no change in 6.8% (14/207). Minimal intact parathyroid hormone (iPTH) improvement after KT was found to be an independent risk factor of osteoporosis progression. CONCLUSIONS: This study demonstrates progressive loss of BMD after KT and sustained secondary hyperparathyroidism might influence the progression of osteoporosis.

Effect of Empagliflozin on Tacrolimus-Induced Pancreas Islet Dysfunction and Renal Injury.

An inhibitor of sodium glucose co-transporter type 2 (SGLT-2) is recommended in type 2 diabetes mellitus (DM) but its use is still undetermined in tacrolimus (TAC)-induced DM. We evaluated the effect of empagliflozin (Em) on TAC-induced pancreatic islet dysfunction and renal injury in an experimental model of TAC-induced DM and in vitro. TAC induced a twofold increase in SGLT-2 expression, while Em decreased SGLT-2 expression and further increased urinary glucose excretion compared to the TAC group. Em reduced hyperglycemia and increased plasma insulin level, pancreatic islet size, and glucose-stimulated insulin secretion compared to the TAC group. In kidney, Em alleviated TAC-induced renal dysfunction and decreased albumin excretion and histological injury compared with the TAC group. Increased oxidative stress and apoptotic cell death by TAC was remarkably decreased with Em in serum and pancreatic and renal tissues. In in vitro study, TAC decreased cell viability and increased reactive oxygen species (ROS) production in both insulin-secreting beta-cell derived (INS-1) and human kidney-2 (HK-2) cell lines. Addition of Em increased cell viability and decreased ROS production in HK-2 but not in INS-1 cell lines. This suggests that Em is effective in controlling TAC-induced hyperglycemia and has direct protective effect on TAC-induced renal injury.

Ureteral Complications in Kidney Transplantation: Analysis and Management of 853 Consecutive Laparoscopic Living-Donor Nephrectomies in a Single Center.

BACKGROUND: We report the incidence and nature of ureteral and surgical complications in our series of 853 consecutive living-donor renal transplants after laparoscopic living-donor nephrectomy. The aim of this study was to analyze the therapeutic approaches to ureteral complications in kidney transplantations and their relationship with recipient outcome. METHODS: The medical records of patients who underwent kidney transplantation from 2000 to 2014 were reviewed retrospectively. After the donor nephrectomies were performed with the use of laparoscopic, hand-assisted laparoscopic, and vesico-ureteral anastomosis, the recipient's ureteral complications were classified according to the mechanism and site of urinary tract involvement: anastomosis stricture, anastomosis leakage, vesico-ureteral reflux, and urolithiasis. RESULTS: Among the 853 cases of kidney transplantation, ureteral complications occurred in 66 patients (7.73%). The most common complication was urinary tract infection caused by vesico-ureteral reflux (n = 24, 2.81%), which was managed with by means of sub-ureteral polydimethylsiloxane injection. The second most common complication was the anastomosis site stricture (n = 23, 2.69%), which was treated by means of ureteral re-implantation or percutaneous nephrostomy. Anastomosis site leakage occurred in 11 patients (1.28%) and was managed by percutaneous nephrostomy with double-J stenting and drainage or ureteral re-implantation. Urolithiasis occurred in 8 patients (0.93%). CONCLUSIONS: There was an 8% rate of recipient ureteral complications at our institution. Of the 66 patients, 46 (5.4%) required surgical repair. The remaining 20 patients with ureteral complications were treated with conservative care or minimally invasive procedures. The keys to successful management of these problems are early diagnosis and prompt reconstruction whenever possible. Most ureteral complications are easily managed with a successful outcome with early intervention.

Impact of Pretransplant Panel-Reactive Antibody Level on Renal Graft Survival in Patients With a Negative Crossmatch and No Donor-Specific Antibody.

BACKGROUND: Patients with high panel-reactive antibody (PRA) levels before transplantation tend to remain on the waiting list longer when considering cadaveric donor transplantation and have worse outcomes than those with lower PRA levels. This study investigated the impact of the pretransplantation PRA level on rejection and graft survival after kidney transplantation in patients with a negative crossmatch (CXM(-)) and no donor-specific antibody (DSA(-)). METHODS: We retrospectively analyzed 513 recipients of kidney allograft treated from January 2009 to April 2013. Those who tested positive on crossmatching, had donor-specific antibodies, were ABO incompatible, or had no PRA level data were excluded (n = 130). The remaining patients were stratified into 3 groups according to their PRA levels: group I, PRA = 0 (314 [80.1%]); group II, PRA ≤50% (27 [7.2%]); and group III, PRA >50% (27 [7.2%]). Graft failure was defined as a return to dialysis, transplant nephrectomy, or death with a functioning kidney. RESULTS: The mean patient follow-up was 30.4 ± 4.6 months. The rejection rate was 20.1% (group I, 18.5% [n = 58] vs group II, 23.8% [n = 10] vs group III, 33.3% [n = 9] [P = .053]). The graft failure rate was 21.7% (group I, 6.4% [n = 20] vs group II. 7.1% [n = 3] vs group III, 7.4% [n = 7] [P = .792]), and the 3-year graft survival rates were 96.3, 92.4, and 92.5%, respectively (P = .851). CONCLUSIONS: The pretransplant PRA level was not significantly associated with graft survival in patients with CXM(-) and DSA(-). However, the rejection rate tended toward significance as the PRA level increased (P = .053).

Clinical Outcome of Simultaneous Native Nephrectomy and Kidney Transplantation in Patients With Autosomal Dominant Polycystic Kidney Disease.

BACKGROUND: End-stage renal disease patients with autosomal dominant polycystic kidney disease may require native nephrectomy for various indications. However, the appropriate timing for nephrectomy in kidney transplantation and its effect on allograft survival have not been fully investigated. METHODS: We retrospectively analyzed 41 kidney transplant recipients with autosomal dominant polycystic kidney disease in whom transplantation was done simultaneously, after, or without native nephrectomy at Seoul St. Mary's hospital between January 1987 and February 2014. We divided patients into 2 groups based on when native nephrectomy was performed: simultaneously (group A, n = 13) and after or without nephrectomy (group B, n = 28), and compared perioperative outcomes, posttransplantation complications, and allograft survival rates. RESULTS: The mean operative time was significantly longer in group A than in group B (6.48 ± 1.84 vs 5.27 ± 0.84 hours; P = .048). The mean numbers of units required for intraoperative blood transfusions were also significantly higher in group A than in group B (3.66 ± 3.43 vs 0.75 ± 0.26 units; P = .018). However, there were no differences between groups in the incidence of acute rejection and other complications such as postoperative bleeding and infectious complications (P > .05, for all). The allograft survival rate also did not differ between groups (P > .05). CONCLUSIONS: Our study showed that patients undergoing simultaneous nephrectomy and kidney transplantations had clinical outcomes, in terms of complications and allograft survival, that were comparable to those in patients undergoing kidney transplantations with or without previous nephrectomy.

Nanoembossed gold nanoshell with a fluorescence-like strong SERS signal.

We present a nanoembossed nanoshell with a new internal location for the formation of strong electromagnetic fields. The internally nanoembossed gold nanoshell (AuNS) is fabricated by electrostatically assembling smaller silica nanoparticles (∼15.7 nm) around the silica core (∼123.6 nm) followed by growing gold nanoseeds on the core in a wet process. FDTD calculations reveal the creation of a strong electromagnetic field (|E/Ein|max = 55 at 633 nm) at sharp edges formed by the contact between the nanoembosses and the silica core. The field formation is supported by measuring the SERS signal of Ru(bpy) encapsulated in the nanoembossing silica nanoparticles. SERS signals as strong as the corresponding fluorescence are obtained. The Raman enhancement factor (EF) is estimated to be up to 10(10) at 633 nm excitation, in addition to a comparable EF at 785 nm laser excitation. The SERS intensity of the nanoembossed nanoshell layer is sufficiently high compared to the outer or the core of the nanoshell. Finally, we fabricate all-in-one nanoparticles with all the three places where the reporter dyes are loaded and acquire the highest SERS intensity to potentially enable bio-medical applications of the nanoembossed AuNS as a sensitive and reliable labeling particle.

Clinical reappraisal of SHORT syndrome with PIK3R1 mutations: toward recommendation for molecular testing and management.

SHORT syndrome has historically been defined by its acronym: short stature (S), hyperextensibility of joints and/or inguinal hernia (H), ocular depression (O), Rieger abnormality (R) and teething delay (T). More recently several research groups have identified PIK3R1 mutations as responsible for SHORT syndrome. Knowledge of the molecular etiology of SHORT syndrome has permitted a reassessment of the clinical phenotype. The detailed phenotypes of 32 individuals with SHORT syndrome and PIK3R1 mutation, including eight newly ascertained individuals, were studied to fully define the syndrome and the indications for PIK3R1 testing. The major features described in the SHORT acronym were not universally seen and only half (52%) had four or more of the classic features. The commonly observed clinical features of SHORT syndrome seen in the cohort included intrauterine growth restriction (IUGR) <10th percentile, postnatal growth restriction, lipoatrophy and the characteristic facial gestalt. Anterior chamber defects and insulin resistance or diabetes were also observed but were not as prevalent. The less specific, or minor features of SHORT syndrome include teething delay, thin wrinkled skin, speech delay, sensorineural deafness, hyperextensibility of joints and inguinal hernia. Given the high risk of diabetes mellitus, regular monitoring of glucose metabolism is warranted. An echocardiogram, ophthalmological and hearing assessments are also recommended.