Citations

AbstractThe purpose of the present study was to measure the effects of gap balancing and resection techniques on migration of a single total knee replacement implant design. A total of 23 patients (24 knees) were recruited on referral to either a surgeon performing gap balancing or a surgeon performing measured resection and followed prospectively. All patients received a fixed bearing, posterior stabilized total knee replacement implant of a single radius femoral component design with cement fixation, and all aspects of care outside of resection technique were identical. Patients underwent radiostereometric analysis (RSA) at 2 weeks (baseline), 6 weeks, 3 months, 6 months, 1 year, and 2 years. Migration of the tibial and femoral components was compared between groups. Tibial component migration was greater at 2 years in the gap balancing group (mean difference = 0.336 mm, p = 0.036), but there was no difference at 1 year. One measured resection and three gap balancing tibial components demonstrated continuous migration > 0.2 mm between years 1 and 2. There was no difference in femoral component migration. Small differences in tibial component migration were found between the gap balancing and measured resection techniques. However, comparing the migration to established predictive thresholds for long-term loosening risk, implants performed with both techniques were found to have equally low revision risk.

INTRODUCTION The human cerebral cortex has undergone an extraordinary increase in size and complexity during mammalian evolution. Cortical cell lineages are specified in the embryo, and genetic and epidemiological evidence implicates early cortical development in the etiology of neuropsychiatric disorders such as autism spectrum disorder (ASD), intellectual disabilities, and schizophrenia. Most of the disease-implicated genomic variants are located outside of genes, and the interpretation of noncoding mutations is lagging behind owing to limited annotation of functional elements in the noncoding genome. RATIONALE We set out to discover gene-regulatory elements and chart their dynamic activity during prenatal human cortical development, focusing on enhancers, which carry most of the weight upon regulation of gene expression. We longitudinally modeled human brain development using human induced pluripotent stem cell (hiPSC)–derived cortical organoids and compared organoids to isogenic fetal brain tissue. RESULTS Fetal fibroblast–derived hiPSC lines were used to generate cortically patterned organoids and to compare oganoids’ epigenome and transcriptome to that of isogenic fetal brains and external datasets. Organoids model cortical development between 5 and 16 postconception weeks, thus enabling us to study transitions from cortical stem cells to progenitors to early neurons. The greatest changes occur at the transition from stem cells to progenitors. The regulatory landscape encompasses a total set of 96,375 enhancers linked to target genes, with 49,640 enhancers being active in organoids but not in mid-fetal brain, suggesting major roles in cortical neuron specification. Enhancers that gained activity in the human lineage are active in the earliest stages of organoid development, when they target genes that regulate the growth of radial glial cells. Parallel weighted gene coexpression network analysis (WGCNA) of transcriptome and enhancer activities defined a number of modules of coexpressed genes and coactive enhancers, following just six and four global temporal patterns that we refer to as supermodules, likely reflecting fundamental programs in embryonic and fetal brain. Correlations between gene expression and enhancer activity allowed stratifying enhancers into two categories: activating regulators (A-regs) and repressive regulators (R-regs). Several enhancer modules converged with gene modules, suggesting that coexpressed genes are regulated by enhancers with correlated patterns of activity. Furthermore, enhancers active in organoids and fetal brains were enriched for ASD de novo variants that disrupt binding sites of homeodomain, Hes1, NR4A2, Sox3, and NFIX transcription factors. CONCLUSION We validated hiPSC-derived cortical organoids as a suitable model system for studying gene regulation in human embryonic brain development, evolution, and disease. Our results suggest that organoids may reveal how noncoding mutations contribute to ASD etiology. Summary of the study, analyses, and main results. Data were generated for iPSC-derived human telencephalic organoids and isogenic fetal cortex. Organoids modeled embryonic and early fetal cortex and show a larger repertoire of enhancers. Enhancers could be divided into activators and repressors of gene expression. We derived networks of modules and supermodules with correlated gene and enhancer activities, some of which were implicated in autism spectrum disorders (ASD).

AbstractBackgroundPast research established that surgery plus adjuvant radiotherapy (S + AR) improves overall survival (OS) in esthesioneuroblastoma (ENB). However, it is unknown if the addition of adjuvant chemotherapy (AC) further improves survival. The primary objective of this study was to compare survival among patients treated with S + AR alone to patients who underwent S + AR + AC.MethodsRetrospective review of patient records.ResultsThirty‐eight patients met inclusion criteria for either S + AR or S + AR + AC treatment groups. The S + AR + AC group contained more patients with Kadish stage D disease, dural invasion, and positive histologic margins postsurgery. All S + AR + AC patients received platinum‐based regimens, combined with etoposide in 67%. OS and recurrence‐free survival did not differ between the two groups, even when restricting the analysis to patients with Kadish stages B and C disease.ConclusionPatients who received platinum‐based AC did not exhibit improved survival compared to S + AR alone. Further investigation, preferably prospective, into the optimal use of systemic therapy in ENB is warranted.

Objective The presence of aortic paravalvular leak (PVL) is associated with lower survival, but a direct comparison of its impact after transcatheter aortic valve replacement (TAVR) versus surgical aortic valve replacement (SAVR) has not been performed. This study sought to determine the differential influence of PVL on survival following TAVR versus SAVR and in patients with varying levels of risk as defined by the Society of Thoracic Surgeons (STS) risk score. Methods Patients with and without postprocedural PVL were identified from 2290 patients undergoing TAVR or SAVR at Mayo Clinic between 2008 and 2014. The primary endpoint was overall survival. Results There were 588 patients with PVL (374 TAVR, 214 SAVR): age 78±11 years, 63% male and mean follow-up of 3±2 years. PVL was trivial/mild in 442 (75%) patients. In propensity-matched analyses (n=86 per group), the overall survival at 1 and 4 years was 93% and 56% vs 89% and 61% in patients with PVL after TAVR versus SAVR, respectively (p=0.43). The presence or degree of PVL severity had no influence on survival of patients with high STS score (≥8%), while the presence of greater than mild PVL predicted worse survival in those with STS score <8%. During the first year after PVL diagnosis, while either improvement or stable PVL grade was seen in the majority of patients, worsening of PVL grade was more common in the TAVR group (19%) versus the SAVR group (4%) (p<0.0001). Conclusions At mid-term follow-up, the presence of PVL was associated with equally unfavourable outcomes following SAVR or TAVR. In patients with high STS risk score, the presence of PVL was not independently associated with increased mortality.

Background We sought to study the prevalence of high‐sensitivity troponin and its association with cardiac structure and outcomes in ambulatory and hospitalized patients with heart failure with a preserved ejection fraction ( HF p EF ). Methods and Results A post hoc analysis utilized data from HF p EF patients: DOSE (Diuretic Optimization Strategies Evaluation) and CARRESS ‐ HF (Cardiorenal Rescue Study in Acute Decompensated Heart Failure) enrolled patients hospitalized with acute HF p EF , and RELAX (Phosphodiesterase‐5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure With Preserved Ejection Fraction) enrolled ambulatory patients with HF p EF . High‐sensitivity troponin I (hs‐TnI) was measured in hospitalized patients at baseline, at 72 to 96 hours, on day 7, and on day 60. In ambulatory patients hs‐TnI was measured at baseline and at week 24. In the ambulatory cohort, correlations between hs‐TnI and cardiac structure and function were assessed. The association between hs‐TnI and a 60‐day composite of emergency room visits, readmissions, and death was assessed for hospitalized patients using multivariable Cox proportional hazard models. The study population included 139 hospitalized and 212 ambulatory patients with HF p EF and hs‐TnI measured at baseline. The median (25th, 75th percentiles) baseline troponin was 17.6 (11.1, 41.0) ng/L in hospitalized patients and 9.5 (5.3, 19.7) ng/L in ambulatory patients ( P <0.001). The prevalence of elevated hs‐TnI (>99% percentile upper reference limit was 86% in hospitalized patients and 53% among ambulatory patients, with stable elevation in ambulatory patients during follow‐up. HF p EF patients with a hs‐TnI above the median were older with worse left ventricular hypertrophy and diastolic dysfunction. Continuously valued hs‐TnI (per doubling) was associated with increased risk of composite end point (adjusted hazard ratio 1.20, 95% confidence interval 1.00‐1.43; P =0.042). Conclusions Hs‐TnI is commonly elevated among both hospitalized and ambulatory patients with HF p EF . Increased hs‐TnI levels are associated with worse cardiac structure and increased risk of adverse events.