Dominant-negative variant in SLC1A4 causes an autosomal dominant epilepsy syndrome.

SLC1A4 is a trimeric neutral amino acid transporter essential for shuttling L-serine from astrocytes into neurons. Individuals with biallelic variants in SLC1A4 are known to have spastic tetraplegia, thin corpus callosum, and progressive microcephaly (SPATCCM) syndrome, but individuals with heterozygous variants are not thought to have disease. We identify an 8-year-old patient with global developmental delay, spasticity, epilepsy, and microcephaly who has a de novo heterozygous three amino acid duplication in SLC1A4 (L86_M88dup). We demonstrate that L86_M88dup causes a dominant-negative N-glycosylation defect of SLC1A4, which in turn reduces the plasma membrane localization of SLC1A4 and the transport rate of SLC1A4 for L-serine

Acute kidney injury in patients treated with immune checkpoint inhibitors

Background: Immune checkpoint inhibitor-associated acute kidney injury (ICPi-AKI) has emerged as an important toxicity among patients with cancer. Methods: We collected data on 429 patients with ICPi-AKI and 429 control patients who received ICPis contemporaneously but who did not develop ICPi-AKI from 30 sites in 10 countries. Multivariable logistic regression was used to identify predictors of ICPi-AKI and its recovery. A multivariable Cox model was used to estimate the effect of ICPi rechallenge versus no rechallenge on survival following ICPi-AKI. Results: ICPi-AKI occurred at a median of 16 weeks (IQR 8-32) following ICPi initiation. Lower baseline estimated glomerular filtration rate, proton pump inhibitor (PPI) use, and extrarenal immune-related adverse events (irAEs) were each associated with a higher risk of ICPi-AKI. Acute tubulointerstitial nephritis was the most common lesion on kidney biopsy (125/151 biopsied patients [82.7%]). Renal recovery occurred in 276 patients (64.3%) at a median of 7 weeks (IQR 3-10) following ICPi-AKI. Treatment with corticosteroids within 14 days following ICPi-AKI diagnosis was associated with higher odds of renal recovery (adjusted OR 2.64; 95% CI 1.58 to 4.41). Among patients treated with corticosteroids, early initiation of corticosteroids (within 3 days of ICPi-AKI) was associated with a higher odds of renal recovery compared with later initiation (more than 3 days following ICPi-AKI) (adjusted OR 2.09; 95% CI 1.16 to 3.79). Of 121 patients rechallenged, 20 (16.5%) developed recurrent ICPi-AKI. There was no difference in survival among patients rechallenged versus those not rechallenged following ICPi-AKI. Conclusions: Patients who developed ICPi-AKI were more likely to have impaired renal function at baseline, use a PPI, and have extrarenal irAEs. Two-thirds of patients had renal recovery following ICPi-AKI. Treatment with corticosteroids was associated with improved renal recovery

Gene characteristics predicting missense, nonsense and frameshift mutations in tumor samples

Abstract Background Because driver mutations provide selective advantage to the mutant clone, they tend to occur at a higher frequency in tumor samples compared to selectively neutral (passenger) mutations. However, mutation frequency alone is insufficient to identify cancer genes because mutability is influenced by many gene characteristics, such as size, nucleotide composition, etc. The goal of this study was to identify gene characteristics associated with the frequency of somatic mutations in the gene in tumor samples. Results We used data on somatic mutations detected by genome wide screens from the Catalog of Somatic Mutations in Cancer (COSMIC). Gene size, nucleotide composition, expression level of the gene, relative replication time in the cell cycle, level of evolutionary conservation and other gene characteristics (totaling 11) were used as predictors of the number of somatic mutations. We applied stepwise multiple linear regression to predict the number of mutations per gene. Because missense, nonsense, and frameshift mutations are associated with different sets of gene characteristics, they were modeled separately. Gene characteristics explain 88% of the variation in the number of missense, 40% of nonsense, and 23% of frameshift mutations. Comparisons of the observed and expected numbers of mutations identified genes with a higher than expected number of mutations– positive outliers. Many of these are known driver genes. A number of novel candidate driver genes was also identified. Conclusions By comparing the observed and predicted number of mutations in a gene, we have identified known cancer-associated genes as well as 111 novel cancer associated genes. We also showed that adding the number of silent mutations per gene reported by genome/exome wide screens across all cancer type (COSMIC data) as a predictor substantially exceeds predicting accuracy of the most popular cancer gene predicting tool - MutsigCV

One-Year Outcomes of the Multi-Center StudY to Transplant Hepatitis C-InfeCted kidneys (MYTHIC) Trial

Transplanting kidneys from hepatitis C virus (HCV) viremic donors into HCV-negative patients (HCV D-RNA-positive/R-negative) has evolved from experimental to “standard-of-care” at many centers. Nevertheless, most data derive from single centers and provide only short-term follow-up. The Multicenter Study to Transplant Hepatitis C-Infected Kidneys (MYTHIC) study was a multicenter (7 sites) trial of HCV D-RNA-positive/R-negative kidney transplantation (KT) followed by 8 weeks of glecaprevir/pibrentasvir (G/P) initiated 2 to 5 days post-KT. Prespecified outcomes included probability of KT (vs. matched waitlist comparators) and 1-year safety outcomes, allograft function, and survival. Among 63 enrolled patients, 1-year cumulative incidence of KT was approximately 3.5-fold greater for the MYTHIC cohort versus 2055 matched United Network for Organ Sharing (UNOS) comparators who did not opt-in to receive a kidney from an HCV-viremic donor (68% vs. 19%, P < 0.0001). Of 30 HCV D-RNA-positive/R-negative KT recipients, all achieved HCV cure. None developed clinically significant liver disease or HCV-related kidney injury. Furthermore, 1-year survival was 93% and 1-year graft function was excellent (median creatinine 1.17; interquartile range [IQR]: 1.02–1.38 mg/dl). There were 4 cases of cytomegalovirus (CMV) disease among 10 CMV-negative patients transplanted with a kidney from an HCV-viremic/CMV-positive donor. The 1-year findings from this multicenter trial suggest that opting-in for HCV-viremic KT offers can increase probability of KT with excellent 1-year outcomes. Trial Registration: NCT03781726 [Display omitted

Acute kidney injury in patients treated with immune checkpoint inhibitors.

Immune checkpoint inhibitor-associated acute kidney injury (ICPi-AKI) has emerged as an important toxicity among patients with cancer. We collected data on 429 patients with ICPi-AKI and 429 control patients who received ICPis contemporaneously but who did not develop ICPi-AKI from 30 sites in 10 countries. Multivariable logistic regression was used to identify predictors of ICPi-AKI and its recovery. A multivariable Cox model was used to estimate the effect of ICPi rechallenge versus no rechallenge on survival following ICPi-AKI. ICPi-AKI occurred at a median of 16 weeks (IQR 8-32) following ICPi initiation. Lower baseline estimated glomerular filtration rate, proton pump inhibitor (PPI) use, and extrarenal immune-related adverse events (irAEs) were each associated with a higher risk of ICPi-AKI. Acute tubulointerstitial nephritis was the most common lesion on kidney biopsy (125/151 biopsied patients [82.7%]). Renal recovery occurred in 276 patients (64.3%) at a median of 7 weeks (IQR 3-10) following ICPi-AKI. Treatment with corticosteroids within 14 days following ICPi-AKI diagnosis was associated with higher odds of renal recovery (adjusted OR 2.64; 95% CI 1.58 to 4.41). Among patients treated with corticosteroids, early initiation of corticosteroids (within 3 days of ICPi-AKI) was associated with a higher odds of renal recovery compared with later initiation (more than 3 days following ICPi-AKI) (adjusted OR 2.09; 95% CI 1.16 to 3.79). Of 121 patients rechallenged, 20 (16.5%) developed recurrent ICPi-AKI. There was no difference in survival among patients rechallenged versus those not rechallenged following ICPi-AKI. Patients who developed ICPi-AKI were more likely to have impaired renal function at baseline, use a PPI, and have extrarenal irAEs. Two-thirds of patients had renal recovery following ICPi-AKI. Treatment with corticosteroids was associated with improved renal recovery

Obesity, inflammatory and thrombotic markers, and major clinical outcomes in critically ill patients with COVID‐19 in the US

Objective This study aimed to determine whether obesity is independently associated with major adverse clinical outcomes and inflammatory and thrombotic markers in critically ill patients with COVID‐19. Methods The primary outcome was in‐hospital mortality in adults with COVID‐19 admitted to intensive care units across the US. Secondary outcomes were acute respiratory distress syndrome (ARDS), acute kidney injury requiring renal replacement therapy (AKI‐RRT), thrombotic events, and seven blood markers of inflammation and thrombosis. Unadjusted and multivariable‐adjusted models were used. Results Among the 4,908 study patients, mean (SD) age was 60.9 (14.7) years, 3,095 (62.8%) were male, and 2,552 (52.0%) had obesity. In multivariable models, BMI was not associated with mortality. Higher BMI beginning at 25 kg/m2 was associated with a greater risk of ARDS and AKI‐RRT but not thrombosis. There was no clinically significant association between BMI and inflammatory or thrombotic markers. Conclusions In critically ill patients with COVID‐19, higher BMI was not associated with death or thrombotic events but was associated with a greater risk of ARDS and AKI‐RRT. The lack of an association between BMI and circulating biomarkers calls into question the paradigm that obesity contributes to poor outcomes in critically ill patients with COVID‐19 by upregulating systemic inflammatory and prothrombotic pathways