Severe neurocognitive and growth disorders due to variation in THOC2, an essential component of nuclear mRNA export machinery

Highly conserved TREX-mediated mRNA export is emerging as a key pathway in neuronal development and differentiation. TREX subunit variants cause neurodevelopmental disorders (NDDs) by interfering with mRNA export from the cell nucleus to the cytoplasm. Previously we implicated four missense variants in the X-linked THOC2 gene in intellectual disability (ID). We now report an additional six affected individuals from five unrelated families with two de novo and threematernally inherited pathogenic or likely pathogenic variants in THOC2 extending the genotypic and phenotypic spectrum. These comprise three rare missense THOC2 variants that affect evolutionarily conserved amino acid residues and reduce protein stability and two with canonical splice-site THOC2 variants that result in C-terminally truncated THOC2 proteins.We present detailed clinical assessment and functional studies on a de novo variant in a female with an epileptic encephalopathy and discuss an additional four families with rare variants in THOC2 with supportive evidence for pathogenicity. Severe neurocognitive features, including movement and seizure disorders, were observed in this cohort. Taken together our data show that even subtle alterations to the canonical molecular pathways such asmRNAexport, otherwise essential for cellular life, can be compatible with life, but lead to NDDs in human

Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR)25–75 mL/min per 1·73 m 2 of body surface area, and a urine albumin-to-creatinine ratio (UACR)of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders)were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days)or end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure)in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325)or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%)of 1325 patients in the atrasentan group and 105 (7·9%)of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR]0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%)of 1325 patients in the atrasentan group and 34 (2·6%)of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%)patients in the atrasentan group and 52 (3·9%)in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding: AbbVie

Center-Level Variation in Transplant Rates Following the Heart Allocation Policy Change.

Importance: Wide state-level variability in waiting list outcomes have been noted for patients listed for heart transplant in the US, but little is known regarding center-level transplant rates since the heart allocation policy change. Objective: To evaluate center-level transplant rates following the recent allocation policy change for heart transplant. Design, Setting, and Participants: This cohort study used data from the United Network for Organ Sharing database from October 18, 2015, to March 1, 2020, for a nationwide analysis of transplant centers in the US. Transplant candidates were stratified into 2 time cohorts, with era 1 denoting the 3-year period before the policy change (October 18, 2018), and era 2 representing the 500-day period after the policy change but before the beginning of the COVID-19 pandemic. Data were analyzed from May to June 2021. Exposure: The heart allocation policy change enacted on October 18, 2018. Main Outcomes and Measures: Competing risk regression for waiting list outcomes was performed to calculate adjusted era 1 and era 2 center-level transplant rates. Rates were compared across regions and states, as well as within organ procurement organizations. Pearson correlation coefficient was used to assess center-level factors associated with era 2 transplant rates. Results: Of 15 940 transplant candidates included for analysis, 5063 (median [IQR] age, 56 [45-63] years; 1385 women [27.4%]) comprised the era 2 cohort. The proportion of patients with temporary mechanical circulatory support increased between era 1 and era 2 (extracorporeal membrane oxygenation, 2.00% vs 3.42%; percutaneous ventricular assist device, 0.66% vs 1.86%; intra-aortic balloon pump, 5.21% vs 13.10%). The adjusted mean center-level likelihood of transplant increased after the rule change (from 48.1% in era 1 to 78.0% in era 2). Significant variation in transplant rates was observed across regions and states even among centers with shared organ procurement organizations. The largest absolute difference in transplant rates was 27.1% for 2 centers belonging to the same organ procurement organization. Centers with higher transplant volumes in era 2 and with a greater proportion of candidates with intra-aortic balloon pump were observed to have higher transplant rates. Conclusions and Relevance: Despite sharing organ supply and having a small geographical distance, these findings suggest that intercenter disparities in the likelihood of transplant have persisted following the heart allocation policy change. Further work is necessary to ensure equitable allocation of organs in heart transplant

Association of chronic kidney disease with perioperative outcomes following acute lower limb revascularization.

BACKGROUND: There is a paucity of data examining the impact of advancing chronic kidney disease stages on outcomes following revascularization for acute limb ischemia. The present study examined the association of chronic kidney disease with in-hospital mortality, amputation, and resource utilization following revascularization for acute limb ischemia using a nationally representative cohort. METHODS: The 2016-2018 National Inpatient Sample was queried to identify all adult hospitalizations with lower extremity acute limb ischemia requiring surgical and/or endovascular interventions. Patients were grouped according to the presence of chronic kidney disease and its severity: no chronic kidney disease, chronic kidney disease 1-3 (chronic kidney disease stages 1 through 3), chronic kidney disease 4-5 (chronic kidney disease stages 4 through 5), and end-stage renal disease. Multivariable logistic and linear models were used to evaluate association of chronic kidney disease stage with outcomes of interest. RESULTS: Of an estimated 82,610 patients meeting study criteria, 14.8% had chronic kidney disease (chronic kidney disease 1-3: 63.4%, chronic kidney disease 4-5: 12.1%, end-stage renal disease: 24.5%). Compared to those with chronic kidney disease, chronic kidney disease patients were on average older, were more frequently female, and had a higher median Elixhauser Comorbidity Index. Increasing severity of chronic kidney disease was associated with a stepwise increase in unadjusted mortality rates (4.7% in no chronic kidney disease to 12.6% in end-stage renal disease, P &lt; .001). Following risk adjustment, only end-stage renal disease was associated with increased odds of mortality (adjusted odds ratio 3.10, 95% confidence interval 2.28-4.22) and limb amputation (adjusted odds ratio 1.99, 95% confidence interval 1.59-2.48) compared to patients with no chronic kidney disease. Similarly, advancing chronic kidney disease stage conferred increased odds of prolonged length of stay and greater hospitalization costs. CONCLUSION: Advanced renal dysfunction demonstrated inferior perioperative outcomes and greater health care expenditures in the study population. These findings imply that quality improvement efforts in acute limb ischemia revascularization should target patients with chronic kidney disease 4-5 and end-stage renal disease

Incidence and Outcomes of Laryngeal Complications Following Adult Cardiac Surgery: A National Analysis.

Laryngeal complications (LCs) following cardiac operations contribute to increased morbidity and resource utilization. Using a nationally representative cohort of cardiac surgical patients, we characterized the incidence of LC as well as its associated clinical and financial outcomes. All adults undergoing coronary artery bypass grafting and/or valvular operations were identified using the 2010-2017 Nationwide Readmissions Database. International Classification of Diseases 9th and 10th Revision diagnosis codes were used to identify LC. Trends were analyzed using a rank-based, non-parametric test (nptrend). Multivariable linear and logistic regressions were used to evaluate risk factors for LC, and its impact on mortality, complications, resource use and 30-day non-elective readmissions. Of an estimated 2,319,628 patients, 1.7% were diagnosed with perioperative LC, with rising incidence from 1.5% in 2010 to 1.8% in 2017 (nptrend &lt; 0.001). After adjustment, female sex [adjusted odds ratio 1.08, 95% confidence interval (CI) 1.04-1.12], advancing age, and multi-valve procedures (1.51, 95% CI 1.36-1.67, reference: isolated CABG) were associated with increased odds of LC. Despite no risk-adjusted effect on mortality, LC was associated with increased odds of pneumonia (2.88, 95% CI 2.72-3.04), tracheostomy (4.84, 95% CI 4.44-5.26), and readmission (1.32, 95% CI 1.26-1.39). In addition, LC was associated with a 7.7-day increment (95% CI 7.4-8.0) in hospitalization duration and $24,200 (95% CI 23,000-25,400) in attributable costs. The present study found LC to be associated with increased perioperative sequelae and resource utilization. The development and application of active screening protocols for post-surgical LC are warranted to increase early detection and reduce associated morbidity

Ticagrelor in patients with diabetes and stable coronary artery disease with a history of previous percutaneous coronary intervention (THEMIS-PCI) : a phase 3, placebo-controlled, randomised trial

Background: Patients with stable coronary artery disease and diabetes with previous percutaneous coronary intervention (PCI), particularly those with previous stenting, are at high risk of ischaemic events. These patients are generally treated with aspirin. In this trial, we aimed to investigate if these patients would benefit from treatment with aspirin plus ticagrelor. Methods: The Effect of Ticagrelor on Health Outcomes in diabEtes Mellitus patients Intervention Study (THEMIS) was a phase 3 randomised, double-blinded, placebo-controlled trial, done in 1315 sites in 42 countries. Patients were eligible if 50 years or older, with type 2 diabetes, receiving anti-hyperglycaemic drugs for at least 6 months, with stable coronary artery disease, and one of three other mutually non-exclusive criteria: a history of previous PCI or of coronary artery bypass grafting, or documentation of angiographic stenosis of 50% or more in at least one coronary artery. Eligible patients were randomly assigned (1:1) to either ticagrelor or placebo, by use of an interactive voice-response or web-response system. The THEMIS-PCI trial comprised a prespecified subgroup of patients with previous PCI. The primary efficacy outcome was a composite of cardiovascular death, myocardial infarction, or stroke (measured in the intention-to-treat population). Findings: Between Feb 17, 2014, and May 24, 2016, 11 154 patients (58% of the overall THEMIS trial) with a history of previous PCI were enrolled in the THEMIS-PCI trial. Median follow-up was 3·3 years (IQR 2·8–3·8). In the previous PCI group, fewer patients receiving ticagrelor had a primary efficacy outcome event than in the placebo group (404 [7·3%] of 5558 vs 480 [8·6%] of 5596; HR 0·85 [95% CI 0·74–0·97], p=0·013). The same effect was not observed in patients without PCI (p=0·76, p interaction=0·16). The proportion of patients with cardiovascular death was similar in both treatment groups (174 [3·1%] with ticagrelor vs 183 (3·3%) with placebo; HR 0·96 [95% CI 0·78–1·18], p=0·68), as well as all-cause death (282 [5·1%] vs 323 [5·8%]; 0·88 [0·75–1·03], p=0·11). TIMI major bleeding occurred in 111 (2·0%) of 5536 patients receiving ticagrelor and 62 (1·1%) of 5564 patients receiving placebo (HR 2·03 [95% CI 1·48–2·76], p<0·0001), and fatal bleeding in 6 (0·1%) of 5536 patients with ticagrelor and 6 (0·1%) of 5564 with placebo (1·13 [0·36–3·50], p=0·83). Intracranial haemorrhage occurred in 33 (0·6%) and 31 (0·6%) patients (1·21 [0·74–1·97], p=0·45). Ticagrelor improved net clinical benefit: 519/5558 (9·3%) versus 617/5596 (11·0%), HR=0·85, 95% CI 0·75–0·95, p=0·005, in contrast to patients without PCI where it did not, p interaction=0·012. Benefit was present irrespective of time from most recent PCI. Interpretation: In patients with diabetes, stable coronary artery disease, and previous PCI, ticagrelor added to aspirin reduced cardiovascular death, myocardial infarction, and stroke, although with increased major bleeding. In that large, easily identified population, ticagrelor provided a favourable net clinical benefit (more than in patients without history of PCI). This effect shows that long-term therapy with ticagrelor in addition to aspirin should be considered in patients with diabetes and a history of PCI who have tolerated antiplatelet therapy, have high ischaemic risk, and low bleeding risk

Alirocumab and cardiovascular outcomes after acute coronary syndrome

BACKGROUN