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BACKGROUND: Cardiomyocyte growth is coupled with active protein synthesis, which is one of the basic biological processes in living cells. However, it is unclear whether the unfolded protein response transducers and effectors directly take part in the control of protein synthesis. The connection between critical functions of the unfolded protein response in cellular physiology and requirements of multiple processes for cell growth prompted us to investigate the role of the unfolded protein response in cell growth and underlying molecular mechanisms. METHODS: Cardiomyocyte-specific inositol-requiring enzyme 1α (IRE1α) knockout and overexpression mouse models were generated to explore its function in vivo. Neonatal rat ventricular myocytes were isolated and cultured to evaluate the role of IRE1α in cardiomyocyte growth in vitro. Mass spectrometry was conducted to identify novel interacting proteins of IRE1α. Ribosome sequencing and polysome profiling were performed to determine the molecular basis for the function of IRE1α in translational control. RESULTS: We show that IRE1α is required for cell growth in neonatal rat ventricular myocytes under prohypertrophy treatment and in HEK293 cells in response to serum stimulation. At the molecular level, IRE1α directly interacts with eIF4G and eIF3, 2 critical components of the translation initiation complex. We demonstrate that IRE1α facilitates the formation of the translation initiation complex around the endoplasmic reticulum and preferentially initiates the translation of transcripts with 5' terminal oligopyrimidine motifs. We then reveal that IRE1α plays an important role in determining the selectivity and translation of these transcripts. We next show that IRE1α stimulates the translation of epidermal growth factor receptor through an unannotated terminal oligopyrimidine motif in its 5' untranslated region. We further demonstrate a physiological role of IRE1α-governed protein translation by showing that IRE1α is essential for cardiomyocyte growth and cardiac functional maintenance under hemodynamic stress in vivo. CONCLUSIONS: These studies suggest a noncanonical, essential role of IRE1α in orchestrating protein synthesis, which may have important implications in cardiac hypertrophy in response to pressure overload and general cell growth under other physiological and pathological conditions.

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Background: International guidelines recommend the use of local therapy (LT) to limited progression in patients with epidermal growth factor receptor (EGFR)-mutated advanced non-small cell lung cancer (NSCLC). However, the use of LT before disease progression has not been extensively analyzed. This meta-analysis evaluates the efficacy and safety of administering additional LT in conjunction with first-line EGFR-tyrosine kinase inhibitors (TKIs) before disease progression in patients with EGFR-mutated advanced NSCLC. Methods: We systematically searched PubMed, Embase, and the Cochrane Library for studies published up until May 31, 2023. The LT group consisted of patients who received first-line EGFR-TKIs in conjunction with additional LT, while the TKI group comprised participants treated with first-line EGFR-TKIs alone. Studies comparing the survival outcomes of the LT and TKI groups were included in this analysis. The primary outcomes were progression-free survival (PFS) and overall survival (OS). This review was registered on PROSPERO (registration number CRD42023439913). Results: Among the 11 investigated studies covering 1,313 patients, the LT modalities included radiotherapy, surgery, and ablation therapy, which accounted for 91%, 27%, and 27% of the studies, respectively. The pooled hazard ratios of median PFS and OS were 0.34 [95% confidence interval (CI): 0.22-0.53; P<0.001] and 0.42 (95% CI: 0.36-0.48; P<0.001), respectively, which indicated significant benefits for the LT group compared to the TKI group. There was no significant difference between the LT and TKI groups (P=0.473) regarding the incidence of grade 3 or higher adverse events. Conclusions: This study suggests that the strategic use of additional LT before disease progression is a promising approach for the treatment of EGFR-mutated advanced NSCLC.

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Synthesis of new anticancer candidates with protein kinases inhibitory potency is a major goal of pharmaceutical science and synthetic research. This current work represents the synthesis of a series of substituted benzoate-thiazolidinones. Most prepared thiazolidinones were evaluated in vitro for their potential anticancer activity against three cell lines by MTT assay, and they found to be more effective against cancer cell lines with no harm toward normal cells. Thiazolidinones 5 c and 5 h were further evaluated to be kinase inhibitors against EGFR showing effective inhibitory impact (with IC50 value; 0.2±0.009 and 0.098±0.004 µM, for 5 c and 5 h, respectively). Furthermore, 5 c and 5 h have effects on cell cycle and apoptosis induction capability in HepG2 cell lines by DNA-flow cytometry analysis and annexin V-FITC apoptosis assay, respectively. The results showed that they have effect of disrupting the cell cycle and causing cell mortality by apoptosis in the treated cells. Moreover, molecular docking studies showed better binding patterns for 5 c and 5 h with the active site of the epidermal growth factor receptor (EGFR) protein kinase (PDB code 1M17). Finally, toxicity risk and physicochemical characterization by Osiris method was performed on most of the compounds, revealing excellent properties as possible drugs.

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Recombinant adeno-associated virus (rAAV) is an extremely attractive vector in the in vivo delivery of gene therapy as it is safe and its genome is simple. However, challenges including low permissiveness to specific cells and restricted tissue specificity have hindered its clinical application. Based on the previous studies, epidermal growth factor receptor-protein tyrosine kinase (EGFR-PTK) negatively regulated rAAV transduction, and EGFR-positive cells were hardly permissive to rAAV transduction. We constructed a novel rAAV-miRNA133b vector, which co-expressed miRNA133b and transgene, and investigated its in vivo and in vitro transduction efficiency. Confocal microscopy, live-cell imaging, pharmacological reagents and labelled virion tracking were used to analyse the effect of miRNA133b on rAAV2 transduction and the underlying mechanisms. The results demonstrated that miRNA133b could promote rAAV2 transduction and the effects were limited to EGFR-positive cells. The increased transduction was found to be a direct result of decreased rAAV particles degradation in the cytoplasm and enhanced second-strand synthesis. ss-rAAV2-miRNA133b vector specifically increased rAAV2 transduction in EGFR-positive cells or tissues, while ss-rAAV2-Fluc-miRNA133b exerted an antitumor effect. rAAV-miRNA133b vector might emerge as a promising platform for delivering various transgene to treat EGFR-positive cell-related diseases, such as non-small-cell lung cancer.

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BACKGROUND AND AIM: Unexplained recurrent pregnancy loss has been a a challenging research task to experts since there is no explicit pathophysiological mechanism and therefore, the treatment remains elusive. Immunological imbalance and morphological abnormalities are under investigation. This study aims to evaluate the implication of MMP-2, MMP-9, EGFR, and IL-8 in recurrent pregnancy loss cases. MATERIALS & METHODS: The study was carried out through comparison among two groups; the unexplained miscarriage group which consisted of 22 women, and the control group consisted of 18 women, who had electively terminated their pregnancies. Both groups were in the first trimester of gestation. The specimens included the trophoblast, decidua basalis, and decidua parietalis. The study was conducted via immunohistochemical methods. Antibodies were used against MMP-2, MMP-9, EGFR, and IL-8. The results were presented at a contingency table and were statistically analyzed with the Chi-Square Test (X2). RESULTS: There were remarkable disparities in some cases in the comparison of the two groups. MMP-9 was detected significantly high in recurrent pregnancy loss (RPL) cases, both on trophoblastic and decidual specimens (p-value < .00001), MMP-2 displayed no difference among the two groups (mild to moderate detection on trophoblast and almost negative on decidual tissues). EGFR was highly detected in trophoblastic tissue (p-value = .014). IL-8 detection was particularly different in both trophoblast and decidua parietalis of the two groups (p-value < .01). CONCLUSION: The study revealed both morphological and immunological dysregulations that might participate in the RPL pathogenesis.

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Introduction: Colon cancer impacts the lives of Kansans and those across the United States. Epidermal growth factor receptor (EGFR) inhibitors, such as panitumumab and cetuximab, have gained popularity as first-line treatment for stage 4 colon cancer despite their toxicities and have been used by clinicians in later lines of therapy. EGFR inhibitors have been proven to be an efficacious first-line treatment for stage 4 colon cancer, but no study has investigated outcomes comparing EGFR inhibitors as first-line treatment to its use as second- or third-line treatment. This study investigated EGFR inhibitor therapy estimated overall survival when used as first-, second-, and third-line treatment for stage 4 colon cancer. Methods: A retrospective review was done for patients with stage 4 colon cancer who underwent EGFR inhibitor treatment at a large academic center from November 2007 to August 2021. The patients were stratified into five groups by the line in which they received the EGFR inhibitor treatment. A log-rank test was used to analyze the groups, and the median survival for each group was determined. Results: A total of 68 patients were reviewed; 18 received first-line, 23 received second-line, 18 received third-line, 6 received fourth-line, and 3 received sixth-line treatment with an EGFR inhibitor. Fourth- and sixth-line therapies were excluded due to small patient size. There was no significant difference in estimated survival time between any of the lines. Median survival of the therapies was found. Conclusions: There was no statistical difference in survival between the first-, second-, or third-line groups, which may provide justification for its use as a second- or third-line therapy.

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Endometrial metastasis from the lung primary remains is rare. Moreover, the literature only contains case reports of endometrial metastasis from the primary lung cancer. An 83-year-old female patient presented with postmenopausal uterine bleeding and anemia. Endometrial thickening was detected using transvaginal ultrasound and endometrial curettage was performed. Histopathology revealed adenocarcinoma infiltration on an endometrial polyp surface. On histologic examination, high-grade serous carcinoma and clear cell carcinoma diagnoses were initially considered. The tumor cells were immunohistochemically negative for Wilms' tumor 1 and wild-type for p53 expression; however, it was positive for Napsin A. Primary lung adenocarcinoma (LUAD) metastasis was also included in the differential diagnosis. Thyroid transcription factor 1 was positive, whereas paired box gene 8 (Pax8) was negative in tumor cells. Primary LUAD metastasis was diagnosed since a lung mass was radiologically confirmed. Furthermore, epidermal growth factor receptor-exon 19 mutation was detected by molecular analysis. In addition to the clinical and morphological features, this case report emphasizes the importance of multiple immunohistochemical panel applications for the correct diagnosis.

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OBJECTIVE: This study aimed to identify novel genetic variants in the CR2 extracellular domain of the epidermal growth factor receptor (EGFR) in healthy individuals and patients with six different types of adenocarcinoma, in Arabian peninsula populations. It also aimed to investigate the effects of these variants on the EGFR structure and their eventual relevance to tumorigenesis. RESULTS: We detected seven new EGFR genetic variants in 168 cancer patients and 114 controls. A SNP rs374670788 was more frequent in bladder cancer but not significantly associated to. However, a missense mutation (V550M) was significantly associated to colon, ovary, lung, bladder and thyroid cancer samples (p < 0.05). Three mutations (H590R, E602K and T605T) were found in the heterozygous form only in colon cancer patients. Genomic analysis of the synonymous mutation (G632G) showed that the T/A genotype could be associated to thyroid cancer in Arab patients (p < 0.05). An additional novel SNP rs571064657 was observed in control individuals. Computational analysis of the genetic variants revealed a reduction in the stabilization of the EGFR tethered form for both V550M and the common R521K variant with low energetic state (- ∆∆G). Molecular interactions analysis suggested that these mutations might affect the receptor's function and promote tumorigenesis.

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BACKGROUND AND OBJECTIVES: Walking while talking is a dual cognitive-motor task that predicts frailty, falls, and cognitive decline in the general elderly population. Adults with CKD have gait abnormalities during usual walking. It is unknown whether they have greater gait abnormalities and cognitive-motor interference during walking while talking. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Community-dwelling, nondisabled adults (n=330) ≥65 years of age underwent quantitative gait analysis, including walking while talking. Differences in walking-while-talking performance by CKD status were evaluated, and relative changes between walking-while-talking and walking alone performance were computed to quantify cognitive-motor interference (dual-task cost). Associations were tested using multivariable linear spline regression models, and independent gait domains were derived using factor analysis. CKD was defined as an eGFR<60 ml/min per 1.73 m2. RESULTS: CKD was present in 134 (41%) participants. Participants with CKD had slower gait speed along with various gait cycle abnormalities during walking while talking: among those with CKD, every 10-ml/min per 1.73 m2 lower eGFR was associated with 3.3-cm/s (95% confidence interval, 0.4 to 6.1) slower gait speed, 1.8-cm (95% confidence interval, 0.6 to 3.0) shorter step length, 1.1% (95% confidence interval, 0.6 to 1.7) less time in the swing phase, and 1.4% (95% confidence interval, 0.5 to 2.3) greater time in double support after multivariable adjustment. When comparing walking while talking with walking alone, every 10-ml/min per 1.73 m2 lower eGFR was associated with 1.8% (95% confidence interval, 0.5 to 3.2) greater decrease in time in the swing phase and 0.9% (95% confidence interval, 0.2 to 1.5) greater increase in time in the stance phase. Factor analysis identified three walking-while-talking domains and three dual-task cost domains: eGFR was associated specifically with the rhythm domain for both walking-while-talking and dual-task cost. Every 10-ml/min per 1.73 m2 lower eGFR was associated with a poorer performance of 0.2 SD (95% confidence interval, 0.1 to 0.3) for walking while talking and 0.2 SD (95% confidence interval, 0.03 to 0.3) for dual-task cost. CONCLUSIONS: During walking while talking, CKD is associated with gait abnormalities, possibly due to increased cognitive-motor interference.

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The selection of colorectal cancer patients for anti-epidermal growth factor receptor (EGFR) antibody therapy is based on the determination of their RAS mutation status-a strongly negative predictive factor-since the protein target, EGFR, is not a reliable predictor of therapeutic response. In this study, we revisited the EGFR protein issue using a cohort of 90 patients with KRAS exon2 wild-type colorectal cancer who have been treated with cetuximab therapy. Twenty-nine of these patients had metastatic tissue available for analysis. The level of EGFR protein expression in the patients was determined by immunohistochemistry and evaluated by H-score (HS) methodology. Progression-free survival (PFS) and overall survival (OS) of the patients were determined according to the EGFR-HS ranges of both the primary and metastatic tissues using Kaplan-Meyer statistics. In the case of primary tumors, EGFR scores lower than HS = 200 were associated with significantly longer OS. In the case of metastatic tissues, all levels lower than the EGFR-HS range chosen were associated with significantly longer OS. These results are explained by the fact that metastatic tissues rarely maintained the expression levels of the primary tumors. On the other hand, high EGFR expression levels in either primary tumors or metastatic tissues were associated with multiple metastatic disease. This suggests a negative prognostic role of EGFR expression. However, in a multivariate analysis, one-sidedness remained a strong independent predictive factor of survival. Previous studies demonstrated that the EGFR expression level depends on sidedness. Therefore, a subgroup analysis of the left- and right-sided cases was performed on both primary and metastatic tissues. In the case of metastic tissues, an analysis confirmed a better OS in low EGFR protein-expressing cases than in high EGFR protein-expressing cases. Collectively, these data suggest that EGFR protein expression is another negative predictive factor of the efficacy of cetuximab therapy of KRAS exon2 wild-type colorectal cancer.

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BACKGROUND AND OBJECTIVES: Metabolic acidosis is a frequent manifestation of sickle cell disease but the mechanisms and determinants of this disorder are unknown. Our aim was to characterize urinary acidification capacity in adults with sickle cell disease and to identify potential factors associated with decreased capacity to acidify urine. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Among 25 adults with sickle cell disease and an eGFR of ≥60 ml/min per 1.73 m2 from a single center in France, we performed an acute acidification test after simultaneous administration of furosemide and fludrocortisone. A normal response was defined as a decrease in urinary pH <5.3 and an increase in urinary ammonium excretion ≥33 µEq/min at one or more of the six time points after furosemide and fludrocortisone administration. RESULTS: Of the participants (median [interquartile range] age of 36 [24-43] years old, 17 women), 12 had a normal and 13 had an abnormal response to the test. Among these 13 participants, nine had normal baseline plasma bicarbonate concentration. Plasma aldosterone was within the normal range for all 13 participants with an abnormal response, making the diagnosis of type 4 tubular acidosis unlikely. The participants with an abnormal response to the test were significantly older, more frequently treated with oral bicarbonate, had a higher plasma uric acid concentration, higher hemolysis activity, lower eGFR, lower baseline plasma bicarbonate concentration, higher urine pH, lower urine ammonium ion excretion, and lower fasting urine osmolality than those with a normal response. Considering both groups, the maximum urinary ammonium ion excretion was positively correlated with fasting urine osmolality (r2=0.34, P=0.002), suggesting that participants with sickle cell disease and lower urine concentration capacity have lower urine acidification capacity. CONCLUSIONS: Among adults with sickle cell disease, impaired urinary acidification capacity attributable to distal tubular dysfunction is common and associated with the severity of hyposthenuria. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2019_12_10_CJN07830719.mp3.

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BACKGROUND AND OBJECTIVES: Delayed graft function is related to ischemia-reperfusion injury and may be complement dependent. We previously reported from a randomized, placebo-controlled trial that treatment with C1 esterase inhibitor was associated with a shorter duration of delayed graft function and higher eGFR at 1 year. Here, we report longer-term outcomes from this trial. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This is a post hoc analysis of a phase 1/2, randomized, controlled trial enrolling 70 recipients of deceased donor kidney transplants at risk for delayed graft function (NCT02134314). Subjects were randomized to receive C1 esterase inhibitor 50 U/kg (n=35) or placebo (n=35) intraoperatively and at 24 hours. The cumulative incidence functions method was used to compare graft failure and death over 3.5 years. eGFR slopes were compared using a linear mixed effects model. RESULTS: Three deaths occurred among C1 esterase inhibitor-treated patients compared with none receiving placebo. Seven graft failures developed in the placebo group compared with one among C1 esterase inhibitor-treated recipients; the cumulative incidence of graft failure was lower over 3.5 years among C1 esterase inhibitor-treated recipients compared with placebo (P=0.03). Although no difference in eGFR slopes was observed between groups (P for group-time interaction =0.12), eGFR declined in placebo-treated recipients (-4 ml/min per 1.73 m2 per year; 95% confidence interval, -8 to -0.1) but was stable in C1 esterase inhibitor-treated patients (eGFR slope: 0.5 ml/min per 1.73 m2 per year; 95% confidence interval, -4 to 5). At 3.5 years, eGFR was 56 ml/min per 1.73 m2 (95% confidence interval, 42 to 70) in the C1 esterase inhibitor group versus 35 ml/min per 1.73 m2 (95% confidence interval, 21 to 48) in the placebo group, with an estimated mean eGFR difference of 21 ml/min per 1.73 m2 (95% confidence interval, 2 to 41 ml/min per 1.73 m2). CONCLUSIONS: Treatment of patients at risk for ischemia-reperfusion injury and delayed graft function with C1 esterase inhibitor was associated with a lower incidence of graft failure.

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Right- and left-sided colorectal cancers (RSCRC and LSCRC, respectively) are different developmentally, genetically and prognostically. Clinical data also indicate that they respond differently to anti-EGFR therapies. The role of EGFR protein expression in KRAS wild type colorectal cancer is also controversial. Here we have used a cohort of anti-EGFR antibody treated KRAS-wild type colorectal cancer patients (n = 97) to analyse the prognostic role of EGFR protein expression in relation to sidedness. In our cohort EGFR copy number, determined by FISH, was not associated with the level of EGFR protein, assessed by immunohistochemistry and measured by H-scoring. There was a significantly higher EGFR H-score detected in RSCRC as compared to LSCRC in primary tumors (p = 0.04). Furthermore, in a proportion of cases (n = 31) metastatic tissues were also available and their analysis also found a significantly higher EGFR H-score in metastases of RSCRC compared to LSCRC (p = 0.018). Kaplan Meyer survival analysis demonstrated that anti-EGFR antibody therapies were more effective in case of LSCRC compared to RSCRC. Although in case of progression-free survival data just indicated a trend (p = 0.065), in case of overall survival the difference was significant favouring LSCRC (p = 0.047). These data demonstrated for the first time that the EGFR protein expression is significantly higher in KRAS wild type RSLCL as compared to LSCRC. Meanwhile it is somewhat unexpected that the lower EGFR protein expression was found to be associated with better efficacy of anti-EGFR antibody therapies of colorectal cancer, the finding of which must be further validated.

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BACKGROUND AND OBJECTIVES: Low eGFR is known to be associated with frailty, but the association between the longitudinal decline of eGFR and incident frailty in older persons remains to be determined. The objective of this study was to investigate whether a fast decline on eGFR would be associated with incident frailty. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Community dwellers, aged ≥70, were included in this secondary analysis of the 5-year Multidomain Alzheimer Preventive Trial (MAPT). eGFR was calculated using CKD-Epidemiology Collaboration equation at baseline and at 6, 12, and 24 months. The lowest quartile of eGFR slope (-4.1 ml/min per 1.73 m2 per yr) defined a fast decline. The frailty phenotype (unintentional weight loss, exhaustion, low physical activity, slow gait, low handgrip strength assessed with a 0-5 score, where higher is worse; a score ≥3 defines frailty) was assessed at baseline, 6, 12, 24, 36, 48, and 60 months. Cox models were used to test the association between fast eGFR decline and incident frailty. RESULTS: A total of 833 participants were frail neither at baseline nor at 2 years and had appropriate follow-up data. Median (IQR) baseline eGFR was 73 (61-84) ml/min per 1.73 m2. Frailty occurred in 95 (11%) participants between 24 and 60 months. Among them, 31/207 (15%) had fast eGFR decline between baseline and 24 months, and 64/626 (10%) did not. In a Cox model adjusted for demographic variables, cardiovascular comorbidity, C-reactive protein, and baseline eGFR, a fast eGFR decline was associated with incident frailty (HR 1.67, 95% CI 1.03 to 2.71). Sensitivity analyses provided consistent findings. CONCLUSIONS: In community-dwelling older adults with relatively preserved baseline eGFR, a fast eGFR decline is associated with incident frailty.

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BACKGROUND AND OBJECTIVES: Metabolic syndrome is a cluster of risk factors associated with CKD. By studying the genetic and environmental influences on how traits of metabolic syndrome correlate with CKD, the understanding of the etiological relationships can be improved. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: From the population-based TwinGene project within the Swedish Twin Registry, 4721 complete twin pairs (9442 European ancestry participants) were included in this cross-sectional twin study. Metabolic syndrome-related continuous traits were measured, and the binary components as well as the status of metabolic syndrome were defined according to the National Cholesterol Education Program-Adult Treatment Panel III. The eGFR was calculated by cystatin C-based equations from the CKD epidemiology collaboration group, and CKD was defined by eGFR<60 ml/min per 1.73 m2. Genetic and environmental contributions to the correlations between traits of metabolic syndrome and CKD were estimated by using twin-based bivariate structural equation models. RESULTS: The correlation between metabolic syndrome and eGFR-defined CKD was 0.16 (95% confidence interval [95% CI], 0.12 to 0.20), out of which 51% (95% CI, 12% to 90%) was explained by genes, whereas 15% (95% CI, 0% to 42%) and 34% (95% CI, 16% to 52%) was explained by the shared and nonshared environment, respectively. The genetic and environmental correlations between metabolic syndrome and CKD were 0.29 (95% CI, 0.07 to 0.51) and 0.27 (95% CI, 0.13 to 0.41), respectively. For the correlation between abdominal obesity and eGFR, 69% (95% CI, 10% to 100%) was explained by genes and 23% (95% CI, 5% to 41%) was explained by environment. The genetic correlation between abdominal obesity and eGFR was -0.30 (95% CI, -0.54 to -0.06), whereas the environmental correlation was -0.14 (95% CI, -0.22 to -0.06). CONCLUSIONS: Both genes and environment contribute to the correlation between metabolic syndrome and eGFR-defined CKD. The genetic contribution is particularly important to the correlation between abdominal obesity and eGFR.

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BACKGROUND AND OBJECTIVES: Poor identification of individuals with CKD is a major barrier to research and appropriate clinical management of the disease. We aimed to develop and validate a pragmatic electronic (e-) phenotype to identify patients likely to have CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The e-phenotype was developed by an expert working group and implemented among adults receiving in- or outpatient care at five healthcare organizations. To determine urine albumin (UA) dipstick cutoffs for CKD to enable use in the e-phenotype when lacking urine albumin-to-creatinine ratio (UACR), we compared same day UACR and UA results at four sites. A sample of patients, spanning no CKD to ESKD, was randomly selected at four sites for validation via blinded chart review. RESULTS: The CKD e-phenotype was defined as most recent eGFR <60 ml/min per 1.73 m2 with at least one value <60 ml/min per 1.73 m2 >90 days prior and/or a UACR of ≥30 mg/g in the most recent test with at least one positive value >90 days prior. Dialysis and transplant were identified using diagnosis codes. In absence of UACR, a sensitive CKD definition would consider negative UA results as normal to mildly increased (KDIGO A1), trace to 1+ as moderately increased (KDIGO A2), and ≥2+ as severely increased (KDIGO A3). Sensitivity, specificity, and diagnostic accuracy of the CKD e-phenotype were 99%, 99%, and 98%, respectively. For dialysis sensitivity was 94% and specificity was 89%. For transplant, sensitivity was 97% and specificity was 91%. CONCLUSIONS: The CKD e-phenotype provides a pragmatic and accurate method for EHR-based identification of patients likely to have CKD.

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BACKGROUND AND OBJECTIVES: Older adults with CKD are at high risk of falls and disability. It is not known whether gait abnormalities contribute to this risk. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Quantitative and clinical gait assessments were performed in 330 nondisabled community-dwelling adults aged ≥65 years. CKD was defined as an eGFR <60 ml/min per 1.73 m2. Cox proportional hazards models were created to examine fall risk. RESULTS: A total of 41% (n=134) of participants had CKD. In addition to slower gait speed, participants with CKD had gait cycle abnormalities including shorter stride length and greater time in the stance and double-support phases. Among people with CKD, lower eGFR was independently associated with the severity of gait cycle abnormalities (per 10 ml/min per 1.73 m2 lower eGFR: 3.6 cm [95% confidence interval (95% CI), 1.4 to 5.8] shorter stride length; 0.7% [95% CI, 0.3 to 1.0] less time in swing phase; 1.1% [95% CI, 0.5 to 1.7] greater time in double-support phase); these abnormalities mediated the association of lower eGFR with slower gait speed. On clinical gait exam, consistent with the quantitative abnormalities, short steps and marked swaying or loss of balance were more common among participants with CKD, yet most had no identifiable gait phenotype. A gait phenotype defined by any of these abnormal signs was associated with higher risk of falls among participants with CKD: compared with people without CKD and without the gait phenotype, the adjusted hazard ratio was 1.72 (95% CI, 1.06 to 2.81) for those with CKD and the phenotype; in comparison, the adjusted hazard ratio was 0.71 (95% CI, 0.40 to 1.25) for people with CKD but without the phenotype (P value for interaction of CKD status and gait phenotype =0.01). CONCLUSIONS: CKD in older adults is associated with quantitative gait abnormalities, which clinically manifest in a gait phenotype that is associated with fall risk.

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BACKGROUND AND OBJECTIVES: Oral sodium zirconium cyclosilicate (formerly ZS-9) binds and removes potassium via the gastrointestinal tract. Sodium zirconium cyclosilicate-associated restoration and maintenance of normokalemia and adverse events were evaluated in a two-part, open label, phase 3 trial. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In the correction phase, adult outpatients with plasma potassium ≥5.1 mmol/L (i-STAT Point-of-Care) received sodium zirconium cyclosilicate 10 g three times daily for 24-72 hours until normokalemic (potassium =3.5-5.0 mmol/L). Qualifying participants entered the ≤12-month maintenance phase and received sodium zirconium cyclosilicate 5 g once daily titrated to maintain normokalemia without dietary or medication restrictions. Prespecified primary end points were restoration of normal serum potassium values (3.5-5.0 mmol/L) during the correction phase and maintenance of serum potassium ≤5.1 mmol/L during the maintenance phase. Adverse events were assessed throughout. RESULTS: Of 751 participants, 746 (99%) achieved normokalemia during the correction phase (mean serum potassium =4.8 mmol/L; 95% confidence interval, 4.7 to 4.8) and entered the maintenance phase; 466 (63%) participants completed the 12-month trial. Participants were predominantly white, men, and age ≥65 years old; 74% had an eGFR<60 ml/min per 1.73 m2, and 65% used renin-angiotensin-aldosterone system inhibitors. Mean time on sodium zirconium cyclosilicate was 286 days. Mean daily sodium zirconium cyclosilicate dose was 7.2 g (SD=2.6). Over months 3-12, mean serum potassium was 4.7 mmol/L (95% confidence interval, 4.6 to 4.7); mean serum potassium values ≤5.1 and ≤5.5 mmol/L were achieved by 88% and 99% of participants, respectively. Of 483 renin-angiotensin-aldosterone system inhibitor users at baseline, 87% continued or had their dose increased; 11% discontinued. Among 263 renin-angiotensin-aldosterone system inhibitor-naïve participants, 14% initiated renin-angiotensin-aldosterone system inhibitor therapy. Overall, 489 (66%) participants experienced adverse events during the maintenance phase, and 22% experienced a serious adverse event. Of eight (1%) deaths, none were considered related to sodium zirconium cyclosilicate. Nine (1%) and 34 (5%) participants experienced serum potassium <3.0 and 3.0-3.4 mmol/L, respectively. CONCLUSIONS: After achieving normokalemia, individualized once daily sodium zirconium cyclosilicate was associated with maintenance of normokalemia without substantial renin-angiotensin-aldosterone system inhibitor changes for ≤12 months.

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BACKGROUND: Endothelial growth factor receptor (EGFR) mutations are an essential driver of personalized therapy for patients with lung cancer and are detected in approximately 15% of Caucasian and 50% of Asian patients. EGFR tyrosine kinase inhibitors have been developed and used for this set of patients. T790M mutation in exon 20 is usually associated with secondary resistance to EGFR tyrosine kinase inhibitors therapy but is also present in treatment-naïve patients. The frequency for baseline T790M mutation varies from 4 to 35% according to the detection method used. Newer techniques have yielded higher rates, but concerns about false-positive results have been raised. Compound mutations account for 4-14% of all EGFR-mutated tumors, with no studies yet to provide a frequency rate for T790M + 19 deletion association due to the small number of cases. However, there are reports that pretreatment T790M + L858R association is significantly more frequent compared to T790M + exon 19 deletion mutations. Diagnostic challenges, current knowledge on the subject, and therapeutic decisions are discussed. CASE PRESENTATION: We present the case of a 43-year-old Hispanic woman, a treatment-naïve patient, with metastasized lung cancer adenocarcinoma harboring a T790M deletion along with the classic 19 mutation. The initial symptoms were monoparesis of her left leg, associated with hyperreflexia, and hypoesthesia. In the absence of third-generation tyrosine kinase inhibitors, a platinum-based therapy was initiated with no response and she died 4 months after diagnosis. CONCLUSIONS: Osimertinib seems to be a suitable therapy for treatment-naïve patients with sensitizing and resistant compound EGFR mutations. More studies regarding the clinical characteristics of these patients and the appropriate management of this condition are needed to provide the highest standard of care.

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BACKGROUND AND OBJECTIVES: Nontargeted metabolomics can measure thousands of low-molecular-weight biochemicals, but important gaps limit its utility for biomarker discovery in CKD. These include the need to characterize technical and intraperson analyte variation, to pool data across platforms, and to outline analyte relationships with eGFR. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Plasma samples from 49 individuals with CKD (eGFR<60 ml/min per 1.73 m2 and/or ≥1 g proteinuria) were examined from two study visits; 20 samples were repeated as blind replicates. To enable comparison across two nontargeted platforms, samples were profiled at Metabolon and the Broad Institute. RESULTS: The Metabolon platform reported 837 known metabolites and 483 unnamed compounds (selected from 44,953 unknown ion features). The Broad Institute platform reported 594 known metabolites and 26,106 unknown ion features. Median coefficients of variation (CVs) across blind replicates were 14.6% (Metabolon) and 6.3% (Broad Institute) for known metabolites, and 18.9% for (Metabolon) unnamed compounds and 24.5% for (Broad Institute) unknown ion features. Median CVs for day-to-day variability were 29.0% (Metabolon) and 24.9% (Broad Institute) for known metabolites, and 41.8% for (Metabolon) unnamed compounds and 40.9% for (Broad Institute) unknown ion features. A total of 381 known metabolites were shared across platforms (median correlation 0.89). Many metabolites were negatively correlated with eGFR at P<0.05, including 35.7% (Metabolon) and 18.9% (Broad Institute) of known metabolites. CONCLUSIONS: Nontargeted metabolomics quantifies >1000 analytes with low technical CVs, and agreement for overlapping metabolites across two leading platforms is excellent. Many metabolites demonstrate substantial intraperson variation and correlation with eGFR.

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