RESUMEN
S100A1, a small homodimeric EF-hand Ca2+-binding protein (~21 kDa), plays an important regulatory role in Ca2+ signaling pathways involved in various biological functions including Ca2+ cycling and contractile performance in skeletal and cardiac myocytes. One key target of the S100A1 interactome is the ryanodine receptor (RyR), a huge homotetrameric Ca2+ release channel (~2.3 MDa) of the sarcoplasmic reticulum. Here, we report cryoelectron microscopy structures of S100A1 bound to RyR1, the skeletal muscle isoform, in absence and presence of Ca2+. Ca2+-free apo-S100A1 binds beneath the bridging solenoid (BSol) and forms contacts with the junctional solenoid and the shell-core linker of RyR1. Upon Ca2+-binding, S100A1 undergoes a conformational change resulting in the exposure of the hydrophobic pocket known to serve as a major interaction site of S100A1. Through interactions of the hydrophobic pocket with RyR1, Ca2+-bound S100A1 intrudes deeper into the RyR1 structure beneath BSol than the apo-form and induces sideways motions of the C-terminal BSol region toward the adjacent RyR1 protomer resulting in tighter interprotomer contacts. Interestingly, the second hydrophobic pocket of the S100A1-dimer is largely exposed at the hydrophilic surface making it prone to interactions with the local environment, suggesting that S100A1 could be involved in forming larger heterocomplexes of RyRs with other protein partners. Since S100A1 interactions stabilizing BSol are implicated in the regulation of RyR-mediated Ca2+ release, the characterization of the S100A1 binding site conserved between RyR isoforms may provide the structural basis for the development of therapeutic strategies regarding treatments of RyR-related disorders.
Asunto(s)
Calcio , Microscopía por Crioelectrón , Canal Liberador de Calcio Receptor de Rianodina , Proteínas S100 , Canal Liberador de Calcio Receptor de Rianodina/metabolismo , Canal Liberador de Calcio Receptor de Rianodina/química , Proteínas S100/metabolismo , Proteínas S100/química , Calcio/metabolismo , Animales , Unión Proteica , Sitios de Unión , Modelos Moleculares , Conformación Proteica , HumanosRESUMEN
After two decades of improvements, the current human reference genome (GRCh38) is the most accurate and complete vertebrate genome ever produced. However, no single chromosome has been finished end to end, and hundreds of unresolved gaps persist1,2. Here we present a human genome assembly that surpasses the continuity of GRCh382, along with a gapless, telomere-to-telomere assembly of a human chromosome. This was enabled by high-coverage, ultra-long-read nanopore sequencing of the complete hydatidiform mole CHM13 genome, combined with complementary technologies for quality improvement and validation. Focusing our efforts on the human X chromosome3, we reconstructed the centromeric satellite DNA array (approximately 3.1 Mb) and closed the 29 remaining gaps in the current reference, including new sequences from the human pseudoautosomal regions and from cancer-testis ampliconic gene families (CT-X and GAGE). These sequences will be integrated into future human reference genome releases. In addition, the complete chromosome X, combined with the ultra-long nanopore data, allowed us to map methylation patterns across complex tandem repeats and satellite arrays. Our results demonstrate that finishing the entire human genome is now within reach, and the data presented here will facilitate ongoing efforts to complete the other human chromosomes.
Asunto(s)
Cromosomas Humanos X/genética , Genoma Humano/genética , Telómero/genética , Centrómero/genética , Islas de CpG/genética , Metilación de ADN , ADN Satélite/genética , Femenino , Humanos , Mola Hidatiforme/genética , Masculino , Embarazo , Reproducibilidad de los Resultados , Testículo/metabolismoRESUMEN
BACKGROUND: Multivariable equations are recommended by primary prevention guidelines to assess absolute risk of cardiovascular disease (CVD). However, current equations have several limitations. Therefore, we developed and validated the American Heart Association Predicting Risk of CVD EVENTs (PREVENT) equations among US adults 30 to 79 years of age without known CVD. METHODS: The derivation sample included individual-level participant data from 25 data sets (N=3 281 919) between 1992 and 2017. The primary outcome was CVD (atherosclerotic CVD and heart failure). Predictors included traditional risk factors (smoking status, systolic blood pressure, cholesterol, antihypertensive or statin use, and diabetes) and estimated glomerular filtration rate. Models were sex-specific, race-free, developed on the age scale, and adjusted for competing risk of non-CVD death. Analyses were conducted in each data set and meta-analyzed. Discrimination was assessed using the Harrell C-statistic. Calibration was calculated as the slope of the observed versus predicted risk by decile. Additional equations to predict each CVD subtype (atherosclerotic CVD and heart failure) and include optional predictors (urine albumin-to-creatinine ratio and hemoglobin A1c), and social deprivation index were also developed. External validation was performed in 3 330 085 participants from 21 additional data sets. RESULTS: Among 6 612 004 adults included, mean±SD age was 53±12 years, and 56% were women. Over a mean±SD follow-up of 4.8±3.1 years, there were 211 515 incident total CVD events. The median C-statistics in external validation for CVD were 0.794 (interquartile interval, 0.763-0.809) in female and 0.757 (0.727-0.778) in male participants. The calibration slopes were 1.03 (interquartile interval, 0.81-1.16) and 0.94 (0.81-1.13) among female and male participants, respectively. Similar estimates for discrimination and calibration were observed for atherosclerotic CVD- and heart failure-specific models. The improvement in discrimination was small but statistically significant when urine albumin-to-creatinine ratio, hemoglobin A1c, and social deprivation index were added together to the base model to total CVD (ΔC-statistic [interquartile interval] 0.004 [0.004-0.005] and 0.005 [0.004-0.007] among female and male participants, respectively). Calibration improved significantly when the urine albumin-to-creatinine ratio was added to the base model among those with marked albuminuria (>300 mg/g; 1.05 [0.84-1.20] versus 1.39 [1.14-1.65]; P=0.01). CONCLUSIONS: PREVENT equations accurately and precisely predicted risk for incident CVD and CVD subtypes in a large, diverse, and contemporary sample of US adults by using routinely available clinical variables.
Asunto(s)
Aterosclerosis , Enfermedades Cardiovasculares , Insuficiencia Cardíaca , Adulto , Humanos , Masculino , Femenino , Persona de Mediana Edad , Anciano , Creatinina , Hemoglobina Glucada , American Heart Association , Factores de Riesgo , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/epidemiología , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/epidemiología , Albúminas , Medición de RiesgoRESUMEN
BACKGROUND: Hematuria is an established sign of glomerular disease and can be associated with kidney failure, but there has been limited scientific study of this trait. METHODS: Here, we combined genetic data from the UK Biobank with predicted gene expression and splicing from GTEx kidney cortex samples (n = 65) in a transcriptome-wide association study (TWAS) to identify additional potential biological mechanisms influencing hematuria. RESULTS: The TWAS using kidney cortex identified significant associations for 5 genes in terms of expression and 3 significant splicing events. Notably, we identified an association between the skipping of COL4A4 exon 27, which is genetically predicted by intronic rs11898094 (minor allele frequency 13%), and hematuria. Association between this variant was also found with urinary albumin excretion. We found independent evidence supporting the same variant predicting this skipping event in glomeruli-derived mRNA transcriptomics data (n = 245) from NEPTUNE. The functional significance of loss of exon 27 was demonstrated using the split NanoLuc-based α3α4α5(IV) heterotrimer assay, in which type IV collagen heterotrimer formation was quantified by luminescence. The causal splicing variant for this skipping event is yet to be identified. CONCLUSIONS: In summary, by integrating multiple data types, we identify a potential splicing event associated with hematuria and albuminuria.
RESUMEN
BACKGROUND: Recommendations for apixaban dosing on the basis of kidney function are inconsistent between the US Food and Drug Administration and European Medicines Agency for patients with atrial fibrillation. Optimal apixaban dosing in chronic kidney disease remains unknown. METHODS: With the use of deidentified electronic health record data from the Optum Labs Data Warehouse, patients with atrial fibrillation and chronic kidney disease stage 4/5 initiating apixaban between 2013 and 2021 were identified. Risks of bleeding and stroke/systemic embolism were compared by apixaban dose (5 versus 2.5 mg), adjusted for baseline characteristics by the inverse probability of treatment weighting. The Fine-Gray subdistribution hazard model was used to account for the competing risk of death. Cox regression was used to examine risk of death by apixaban dose. RESULTS: Among 4313 apixaban new users, 1705 (40%) received 5 mg and 2608 (60%) received 2.5 mg. Patients treated with 5 mg apixaban were younger (mean age, 72 versus 80 years), with greater weight (95 versus 80 kg) and higher serum creatinine (2.7 versus 2.5 mg/dL). Mean estimated glomerular filtration rate was not different between the groups (24 versus 24 mL·min-1·1.73 m-2). In inverse probability of treatment weighting analysis, apixaban 5 mg was associated with a higher risk of bleeding (incidence rate 4.9 versus 2.9 events per 100 person-years; incidence rate difference, 2.0 [95% CI, 0.6-3.4] events per 100 person-years; subdistribution hazard ratio, 1.63 [95% CI, 1.04-2.54]). There was no difference between apixaban 5 mg and 2.5 mg groups in the risk of stroke/systemic embolism (3.3 versus 3.0 events per 100 person-years; incidence rate difference, 0.2 [95% CI, -1.0 to 1.4] events per 100 person-years; subdistribution hazard ratio, 1.01 [95% CI, 0.59-1.73]), or death (9.9 versus 9.4 events per 100 person-years; incidence rate difference, 0.5 [95% CI, -1.6 to 2.6] events per 100 person-years; hazard ratio, 1.03 [95% CI, 0.77-1.38]). CONCLUSIONS: Compared with 2.5 mg, use of 5 mg apixaban was associated with a higher risk of bleeding in patients with atrial fibrillation and severe chronic kidney disease, with no difference in the risk of stroke/systemic embolism or death, supporting the apixaban dosing recommendations on the basis of kidney function by the European Medicines Agency, which differ from those issued by the US Food and Drug Administration.
Asunto(s)
Fibrilación Atrial , Embolia , Insuficiencia Renal Crónica , Accidente Cerebrovascular , Humanos , Anciano , Fibrilación Atrial/tratamiento farmacológico , Anticoagulantes/efectos adversos , Resultado del Tratamiento , Accidente Cerebrovascular/epidemiología , Piridonas/efectos adversos , Hemorragia/inducido químicamente , Insuficiencia Renal Crónica/tratamiento farmacológico , Embolia/etiologíaRESUMEN
About 37 million people in the United States have chronic kidney disease, a disease that encompasses diseases of multiple causes. About 10% or more of kidney diseases in adults and about 70% of selected chronic kidney diseases in children are expected to be explained by genetic causes. Despite the advances in genetic testing and an increasing understanding of the genetic bases of certain kidney diseases, genetic testing in nephrology lags behind other medical fields. More understanding of the benefits and logistics of genetic testing is needed to advance the implementation of genetic testing in chronic kidney diseases. Accordingly, the National Kidney Foundation convened a Working Group of experts with diverse expertise in genetics, nephrology, and allied fields to develop recommendations for genetic testing for monogenic disorders and to identify genetic risk factors for oligogenic and polygenic causes of kidney diseases. Algorithms for clinical decision making on genetic testing and a road map for advancing genetic testing in kidney diseases were generated. An important aspect of this initiative was the use of a modified Delphi process to reach group consensus on the recommendations. The recommendations and resources described herein provide support to nephrologists and allied health professionals to advance the use of genetic testing for diagnosis and screening of kidney diseases.
RESUMEN
BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1RA) have cardiovascular benefits in type 2 diabetes, but none of the cardiovascular trials studied atrial fibrillation/atrial flutter (AF) as a primary endpoint. Data from post-marketing surveillance studies remains sparse. OBJECTIVE: To examine the real-world risk of AF comparing GLP-1RA with other non-insulin glucose-lowering agents. DESIGN: Cohort study using de-identified electronic health record data from the Optum Labs Data Warehouse. PARTICIPANTS: Adult patients with diabetes who were newly prescribed add-on non-insulin glucose-lowering agents and were on metformin between 2005-2020. EXPOSURES: New users of GLP-1RA were separately compared with new users of dipeptidyl peptidase-4 inhibitors (DPP4i) and sodium-glucose cotransporter 2 inhibitors (SGLT2i), using 1:1 propensity score matching to adjust for differences in patient characteristics. MAIN MEASURES: The primary outcome was incident AF, defined and captured by diagnosis code for AF. Incidence rate difference (IRD) and hazard ratio (HR) were estimated in the matched cohorts. KEY RESULTS: In the matched cohort of 14,566 pairs of GLP-1RA and DPP4i followed for a median of 3.8 years, GLP-1RA use was associated with a lower risk of AF (IRD, -1.0; 95% CI, -1.8 to -0.2 per 1000 person-years; HR, 0.82; 95% CI, 0.70 to 0.96). In the matched cohort of 9,424 pairs of patients on GLP-1RA and SGLT2i with a median follow-up of 2.9 years, there was no difference in the risk for AF (IRD, 0.4; 95% CI -0.7 to 1.5 per 1000 person-years; HR, 1.12; 95% CI, 0.89 to 1.42). CONCLUSIONS: In this real-word study, GLP-1RA was associated with a lower risk of AF compared with DPP4i, but no difference compared with SGLT2i, suggesting that cardiovascular benefits of GLP-1RA use may extend to prevention for AF in patients with diabetes. Our findings call for future randomized controlled trials to focus on the effects of GLP-1RA on AF prevention.
Asunto(s)
Fibrilación Atrial , Diabetes Mellitus Tipo 2 , Inhibidores de la Dipeptidil-Peptidasa IV , Receptor del Péptido 1 Similar al Glucagón , Hipoglucemiantes , Humanos , Fibrilación Atrial/epidemiología , Fibrilación Atrial/tratamiento farmacológico , Masculino , Femenino , Receptor del Péptido 1 Similar al Glucagón/agonistas , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Persona de Mediana Edad , Anciano , Hipoglucemiantes/uso terapéutico , Hipoglucemiantes/efectos adversos , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Inhibidores de la Dipeptidil-Peptidasa IV/efectos adversos , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Inhibidores del Cotransportador de Sodio-Glucosa 2/efectos adversos , Estudios de Cohortes , Factores de Riesgo , Adulto , Incidencia , Agonistas Receptor de Péptidos Similares al GlucagónRESUMEN
BACKGROUND: Early trials of dihydropyridine calcium channel blockers (DCCBs) suggest a detrimental effect on intraglomerular pressure and an association with albuminuria. OBJECTIVE: We sought to evaluate the associations of DCCB initiation with albuminuria and kidney failure with replacement therapy (KFRT) and to determine whether renin-angiotensin system (RAS) blockade modified these associations. DESIGN: We conducted a target trial emulation study using a new user, active comparator design and electronic health record data from Geisinger Health. PARTICIPANTS: We included patients without severe albuminuria or KFRT who were initiated on a DCCB or thiazide (active comparator) between January 1, 2004, and December 31, 2019. MAIN MEASURES: Using inverse probability of treatment weighting, we performed doubly robust Cox proportional hazards regression to estimate the association of DCCB initiation with incident severe albuminuria (urine albumin to creatinine ratio > 300 mg/g) and KFRT, overall and stratified by RAS blocker use. KEY RESULTS: There were 11,747 and 26,758 eligible patients initiating a DCCB and thiazide, respectively, with a weighted baseline mean age of 60 years, systolic blood pressure of 143 mm Hg, and eGFR of 86 mL/min/1.73 m2, and with a mean follow-up of 8 years. Compared with thiazides, DCCBs were significantly associated with the development of severe albuminuria (hazard ratio [HR], 1.29; 95% confidence interval [CI], 1.16-1.43), with attenuation of risk in the presence of RAS blockade (P for interaction < 0.001). The risk of KFRT was increased among patients without RAS blockade (HR, 1.66; 95% CI, 1.19-2.31), but not with RAS blockade (P for interaction = 0.005). CONCLUSIONS: DCCBs were associated with increased risk of albuminuria and, in the absence of RAS blockade, KFRT. These findings suggest coupling DCCB therapy with RAS blockade may mitigate adverse kidney outcomes.
Asunto(s)
Albuminuria , Bloqueadores de los Canales de Calcio , Humanos , Femenino , Masculino , Persona de Mediana Edad , Bloqueadores de los Canales de Calcio/uso terapéutico , Albuminuria/tratamiento farmacológico , Anciano , Dihidropiridinas/uso terapéutico , Tasa de Filtración Glomerular/efectos de los fármacosRESUMEN
Cardiovascular disease is the leading cause of morbidity and mortality in patients with end-stage kidney disease. Currently, thrice-weekly in-center hemodialysis for 3 to 5 hours per session is the most common therapy worldwide for patients with treated kidney failure. Outcomes with thrice-weekly in-center hemodialysis are poor. Emerging evidence supports the overarching hypothesis that a more physiological approach to administering dialysis therapy, including in the home through home hemodialysis or peritoneal dialysis, may lead to improvement in several cardiovascular risk factors and cardiovascular outcomes compared with thrice-weekly in-center hemodialysis. The Advancing American Kidney Health Initiative, which has a goal of increasing the use of home dialysis, is aligned with the American Heart Association's 2024 mission to champion a full and healthy life and health equity. We conclude that incorporation of interdisciplinary care models to increase the use of home dialysis therapies in an equitable manner will contribute to the ultimate goal of improving outcomes for patients with kidney failure and cardiovascular disease.
Asunto(s)
Enfermedades Cardiovasculares , Sistema Cardiovascular , Fallo Renal Crónico , American Heart Association , Enfermedades Cardiovasculares/terapia , Hemodiálisis en el Domicilio/efectos adversos , Humanos , Fallo Renal Crónico/terapia , Estados UnidosRESUMEN
ALG8 protein-truncating variants (PTVs) have previously been described in patients with polycystic liver disease and in some cases cystic kidney disease. Given a lack of well-controlled studies, we determined whether individuals heterozygous for ALG8 PTVs are at increased risk of cystic kidney disease in a large, unselected health system-based observational cohort linked to electronic health records in Pennsylvania (Geisinger-Regeneron DiscovEHR MyCode study). Out of 174,172 patients, 236 were identified with ALG8 PTVs. Using ICD-based outcomes, patients with these variants were significantly at increased risk of having any kidney/liver cyst diagnosis (Odds Ratio 2.42, 95% confidence interval: 1.53-3.85), cystic kidney disease (3.03, 1.26-7.31), and nephrolithiasis (1.89, 1.96-2.97). To confirm this finding, blinded radiology review of computed tomography and magnetic resonance imaging studies was completed in a matched cohort of 52 thirty-plus year old ALG8 PTV heterozygotes and related non-heterozygotes. ALG8 PTV heterozygotes were significantly more likely to have cystic kidney disease, defined as four or more kidney cysts (57.7% vs. 7.7%), or bilateral kidney cysts (69.2% vs. 15.4%), but not one or more liver cyst (11.5% vs. 7.7%). In publicly available UK Biobank data, ALG8 PTV heterozygotes were at significantly increased risk of ICD code N28 (other disorders of kidney/ureter) (3.85% vs. 1.33%). ALG8 PTVs were not associated with chronic kidney disease or kidney failure in the MyCode study or the UK Biobank data. Thus, PTVs in ALG8 result in increased risk of a mild cystic kidney disease phenotype.
Asunto(s)
Quistes , Hepatopatías , Enfermedades Renales Poliquísticas , Riñón Poliquístico Autosómico Dominante , Humanos , Enfermedades Renales Poliquísticas/patología , Riñón/patología , Quistes/genética , Hepatopatías/diagnóstico , Hepatopatías/epidemiología , Hepatopatías/genética , Riñón Poliquístico Autosómico Dominante/diagnóstico , Riñón Poliquístico Autosómico Dominante/epidemiología , Riñón Poliquístico Autosómico Dominante/genética , GlucosiltransferasasRESUMEN
BACKGROUND: Type 2 diabetes (T2D) is a strong risk factor for cardiovascular (CV) disease. CV outcomes in T2D have generally been improving over time but recent data from the US suggest attenuation of trends in older adults with reversal of trends in younger adults. However, published data are only reported through 2015. OBJECTIVES: To quantify trends over time in CV outcomes from 2001 to 2018, and describe changes over time in health care costs in T2D. METHODS: This retrospective cohort study incorporated data from a regional health insurance plan. Study outcomes included acute myocardial infarction (AMI), ischemic stroke, hemorrhagic stroke, heart failure hospitalization (HFH), percutaneous coronary intervention, coronary artery bypass surgery, and all-cause mortality. Poisson regression estimated rate ratios across the entire 17-year study period (RR17). RESULTS: Among 79,392 T2D members tracked on average 4.1 years, overall trends in AMI (RR17â¯=â¯0.69; 95% CI: 0.64, 0.74), HFH (RR17â¯=â¯0.82; 0.79, 0.86), and all-cause mortality (RR17â¯=â¯0.87; 0.84, 0.91) improved while ischemic stroke (RR17â¯=â¯2.36; 2.16, 2.57) worsened. For AMI, HFH, and all-cause mortality, trends in older age groups were significantly better than in younger age groups (interaction P-values < .001). Health care costs related to pharmaceuticals (+15%/year) and emergency department (ED) visits (>15%/year) increased at faster rates than other utilization metrics (+10%/year). CONCLUSIONS: In T2D, overall trends in most CV outcomes improved but smaller improvements or worsening trends were observed in younger patients. Health care costs accelerated at faster rates for medications and ED visits.
Asunto(s)
Diabetes Mellitus Tipo 2 , Accidente Cerebrovascular Isquémico , Infarto del Miocardio , Humanos , Anciano , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/epidemiología , Estudios Retrospectivos , Infarto del Miocardio/epidemiología , Infarto del Miocardio/terapia , Hospitalización , Costos de la Atención en SaludRESUMEN
The prevalence of obesity in the United States and across the world continues to climb, imparting increased risk of chronic disease. This impact is doubly felt in nephrology because obesity not only increases the risk of chronic kidney disease (CKD) but also exacerbates existing cardiovascular morbidity and mortality. The role of medical weight loss therapy in CKD has been debated, but increasing evidence suggests that intentional weight loss is protective against adverse kidney and cardiovascular outcomes. This may be particularly true with the advent of novel pharmacotherapies taking advantage of the incretin system, resulting in weight loss approaching that seen with surgical interventions. Moreover, these novel therapies have repeatedly demonstrated protective effects on the cardiovascular system. Here, we review the impact of obesity and weight loss on CKD, and the biological basis and clinical evidence for incretin therapy. This perspective provides recommended prescribing practices as a practical tool to engage nephrologists and patients with CKD in the treatment of obesity-related morbidity.
Asunto(s)
Nefrólogos , Insuficiencia Renal Crónica , Humanos , Estados Unidos/epidemiología , Incretinas , Obesidad/complicaciones , Obesidad/tratamiento farmacológico , Obesidad/epidemiología , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/epidemiología , Insuficiencia Renal Crónica/etiología , Pérdida de PesoRESUMEN
RATIONALE & OBJECTIVE: Preeclampsia is a pregnancy-related complication characterized by acute hypertension and end-organ dysfunction. We evaluated the long-term association between preeclampsia and the risk of developing chronic hypertension and kidney disease. STUDY DESIGN: Observational cohort study. SETTING & PARTICIPANTS: 27,800 adults with deliveries in the Geisinger Health System between 1996 and 2019. EXPOSURE: Preeclampsia. OUTCOME: Hypertension, reduced estimated glomerular filtration rate (eGFR)<60mL/min/1.73m2), and albuminuria>300mg/g. ANALYTICAL APPROACH: Propensity-score matching and Cox proportional hazards models to evaluate the association between preeclampsia and incident hypertension, reduced eGFR, and albuminuria. RESULTS: Of 27,800 adults with pregnancies during the study period (mean age, 28 years; 3% Black race), 2,977 (10.7%) had at least 1 pregnancy complicated by preeclampsia. After matching for multiple characteristics, individuals with preeclampsia had a higher risk of developing chronic hypertension (HR, 1.77 [95% CI, 1.45-2.16]), eGFR<60mL/min/1.73m2 (HR, 3.23 [95% CI, 1.64-6.36]), albuminuria (HR, 3.60 [95% CI, 2.38-5.44]), and a subsequent episode of preeclampsia (HR, 24.76 [95% CI, 12.47-48.36]), compared with matched controls without preeclampsia. Overall, postpartum follow-up testing was low. In the first 6 months after delivery, 31% versus 14% of individuals with and without preeclampsia had serum creatinine tests, respectively, and testing for urine protein was the same in both groups, with only 26% having follow-up testing. LIMITATIONS: Primarily White study population, observational study, reliance on ICD codes for medical diagnosis. CONCLUSIONS: Individuals with a pregnancy complicated by preeclampsia had a higher risk of hypertension, reduced eGFR, and albuminuria compared with individuals without preeclampsia. PLAIN-LANGUAGE SUMMARY: Preeclampsia is a significant contributor to perinatal and maternal morbidity and is marked by new-onset hypertension and end-organ damage, including acute kidney injury or proteinuria. To gain insight into the long-term kidney effects of the disease, we compared adults with deliveries complicated by preeclampsia with those without preeclampsia in the Geisinger Health System, while also assessing postpartum testing rates. Our results demonstrate that pregnant individuals with preeclampsia are at a heightened risk for future hypertension, reduced eGFR, and albuminuria, with overall low rates of postpartum testing among both individuals with and without preeclampsia. These findings underscore the need to consider preeclampsia as an important risk factor for the development of chronic kidney disease. Further studies are required to determine optimal postpreeclampsia monitoring strategies.
Asunto(s)
Hipertensión , Preeclampsia , Insuficiencia Renal Crónica , Adulto , Embarazo , Femenino , Humanos , Preeclampsia/epidemiología , Albuminuria , Riñón , Estudios de Cohortes , Insuficiencia Renal Crónica/etiología , Insuficiencia Renal Crónica/complicaciones , Tasa de Filtración Glomerular , Hipertensión/complicaciones , Factores de RiesgoRESUMEN
RATIONALE & OBJECTIVE: The National Kidney Foundation (NKF) launched the first national US kidney disease patient registry, the NKF Patient Network, that is open to patients throughout the continuum of chronic kidney disease (CKD). The Network provides individualized education and will facilitate patient-centered research, clinical care, and health policy decisions. Here, we present the overall design and the results of a feasibility study that was conducted July through December 2020. STUDY DESIGN: Longitudinal observational cohort study of patient-entered data with or without electronic health care record (EHR) linkage in collaboration with health systems. SETTING & PARTICIPANTS: People with CKD, age≥18 years, are invited through their provider, NKF communications, or national outreach campaign. People self-enroll and share their data through a secure portal that offers individualized education and support. The first health system partner is Geisinger. EXPOSURE: Any cause and stage of CKD, including dialysis and kidney transplant recipients. OUTCOME: Feasibility of the EHR data transfer, participants' characteristics, and their perspectives on usability and content. ANALYTICAL APPROACH: Data were collected and analyzed through the registry portal powered by the Pulse Infoframe healthie 2.0 platform. RESULTS: During the feasibility study, 80 participants completed their profile, and 42 completed a satisfaction survey. Mean age was 57.5 years, 51% were women, 83% were White, and 89% were non-Hispanic or Latino. Of the participants, 60% were not aware of their level of estimated glomerular filtration rate and 91% of their urinary albumin-creatinine ratio. LIMITATIONS: Challenges for the Network are lack of awareness of kidney disease for many with CKD, difficulty in recruiting vulnerable populations or those with low digital readiness, and loss to follow-up, all leading to selection bias. CONCLUSIONS: The Network is positioned to become a national and international platform for real-world data that can inform the development of patient-centered research, care, and treatments.
Asunto(s)
Insuficiencia Renal Crónica , Femenino , Humanos , Masculino , Persona de Mediana Edad , Tasa de Filtración Glomerular , Riñón , Pruebas de Función Renal , Sistema de Registros , Insuficiencia Renal Crónica/epidemiología , Insuficiencia Renal Crónica/terapiaRESUMEN
Over the years, many computational strategies have been employed to elucidate reaction networks. One of these methods is accelerated molecular dynamics, which can circumvent the expense required in dynamics to find all reactants and products (local minima) and transition states (first-order saddle points) on a potential energy surface (PES) by using fictitious forces that promote reaction events. The ab initio nanoreactor uses these accelerating forces to study large chemical reaction networks from first-principles quantum mechanics. In the initial nanoreactor studies, this acceleration was done through a piston periodic compression potential, which pushes molecules together to induce entropically unfavorable bimolecular reactions. However, the piston is not effective for discovering intramolecular and dissociative reactions, such as those integral to the decomposition channels of phenyl radical oxidation. In fact, the choice of accelerating forces dictates not only the rate of reaction discovery but also the types of reactions discovered; thus, it is critical to understand the biases and efficacies of these forces. In this study, we examine forces using metadynamics, attractive potentials, and local thermostats for accelerating reaction discovery. For each force, we construct a separate phenyl radical combustion reaction network using solely that force in discovery trajectories. We elucidate the enthalpic and entropic trends of each accelerating force and highlight their efficiency in reaction discovery. Comparing the nanoreactor-constructed reaction networks with literature renditions of the phenyl radical combustion PES shows that a combination of accelerating forces is best suited for reaction discovery.
RESUMEN
Previous research suggests that, despite the commonality of mental illness in the United States, the majority of U.S. individuals with mental illness do not seek treatment. One important factor that contributes to this lack of treatment utilization is mental illness stigma. Such stigma may result, in part, from many individuals in the U.S. underestimating the prevalence of mental illness. To test whether this is the case, 638 adults from across the U.S. completed measures related to perceived prevalence of mental illness, private stigma, perceived public stigma, and help-seeking. Findings indicated participants significantly underestimated the given-year prevalence rate of mental illness. The perceived given-year prevalence rate was significantly correlated with lower private stigma and more positive attitudes towards help-seeking. Personal stigma significantly predicted attitudes towards help-seeking. Findings also suggested that individuals who have received mental health services have a higher perceived prevalence rate of mental illness, as well as lower levels of personal stigma and more positive attitudes towards help-seeking. These findings support the notion that helping the general public recognize the true prevalence rate of mental illness could reduce personal mental illness stigma and facilitate help-seeking behaviors. However, future experimental studies are needed to test this hypothesis.
RESUMEN
Importance: Most studies of autosomal dominant polycystic kidney disease (ADPKD) genetics have used kidney specialty cohorts, focusing on PKD1 and PKD2. These can lead to biased estimates of population prevalence of ADPKD-associated gene variants and their phenotypic expression. Objective: To determine the prevalence of ADPKD and contributions of PKD1, PKD2, and other genes related to cystic kidney disease in a large, unselected cohort. Design, Setting, and Participants: This retrospective observational study used an unselected health system-based cohort in central and northeast Pennsylvania with exome sequencing (enrolled from 2004 to 2020) and electronic health record data (up to October 2021). The genotype-first approach included the entire cohort and the phenotype-first approach focused on patients with ADPKD diagnosis codes, confirmed by chart and imaging review. Exposures: Loss-of-function (LOF) variants in PKD1, PKD2, and other genes associated with cystic kidney disease (ie, ALG8, ALG9, DNAJB11, GANAB, HNF1B, IFT140, SEC61B, PKHD1, PRKCSH, SEC63); likely pathogenic missense variants in PKD1 and PKD2. Main Outcomes and Measures: Genotype-first analysis: ADPKD diagnosis code (Q61.2, Q61.3, 753.13, 753.12); phenotype-first analysis: presence of a rare variant in PKD1, PKD2, or other genes associated with cystic kidney disease. Results: Of 174â¯172 patients (median age, 60 years; 60.6% female; 93% of European ancestry), 303 patients had ADPKD diagnosis codes, including 235 with sufficient chart review data for confirmation. In addition to PKD1 and PKD2, LOF variants in IFT140, GANAB, and HNF1B were associated with ADPKD diagnosis after correction for multiple comparisons. Among patients with LOF variants in PKD1, 66 of 68 (97%) had ADPKD; 43 of 43 patients (100%) with LOF variants in PKD2 had ADPKD. In contrast, only 24 of 77 patients (31.2%) with a PKD1 missense variant previously classified as "likely pathogenic" had ADPKD, suggesting misclassification or variable penetrance. Among patients with ADPKD diagnosis confirmed by chart review, 180 of 235 (76.6%) had a potential genetic cause, with the majority being rare variants in PKD1 (127 patients) or PKD2 (34 patients); 19 of 235 (8.1%) had variants in other genes associated with cystic kidney disease. Of these 235 patients with confirmed ADPKD, 150 (63.8%) had a family history of ADPKD. The yield for a genetic determinant of ADPKD was higher for those with a family history of ADPKD compared with those without family history (91.3% [137/150] vs 50.6% [43/85]; difference, 40.7% [95% CI, 29.2%-52.3%]; P < .001). Previously unreported PKD1, PKD2, and GANAB variants were identified with pedigree data suggesting pathogenicity, and several PKD1 missense variants previously reported as likely pathogenic appeared to be benign. Conclusions and Relevance: This study demonstrates substantial genetic and phenotypic variability in ADPKD among patients within a regional health system in the US.
Asunto(s)
Secuenciación del Exoma , Riñón Poliquístico Autosómico Dominante , Femenino , Humanos , Masculino , Riñón/patología , Mutación , Riñón Poliquístico Autosómico Dominante/genética , Estudios Retrospectivos , Canales Catiónicos TRPP/genética , Persona de Mediana EdadRESUMEN
BACKGROUND: The American Heart Association, in conjunction with the National Institutes of Health, annually reports on the most up-to-date statistics related to heart disease, stroke, and cardiovascular risk factors, including core health behaviors (smoking, physical activity, diet, and weight) and health factors (cholesterol, blood pressure, and glucose control) that contribute to cardiovascular health. The Statistical Update presents the latest data on a range of major clinical heart and circulatory disease conditions (including stroke, congenital heart disease, rhythm disorders, subclinical atherosclerosis, coronary heart disease, heart failure, valvular disease, venous disease, and peripheral artery disease) and the associated outcomes (including quality of care, procedures, and economic costs). METHODS: The American Heart Association, through its Statistics Committee, continuously monitors and evaluates sources of data on heart disease and stroke in the United States to provide the most current information available in the annual Statistical Update. The 2020 Statistical Update is the product of a full year's worth of effort by dedicated volunteer clinicians and scientists, committed government professionals, and American Heart Association staff members. This year's edition includes data on the monitoring and benefits of cardiovascular health in the population, metrics to assess and monitor healthy diets, an enhanced focus on social determinants of health, a focus on the global burden of cardiovascular disease, and further evidence-based approaches to changing behaviors, implementation strategies, and implications of the American Heart Association's 2020 Impact Goals. RESULTS: Each of the 26 chapters in the Statistical Update focuses on a different topic related to heart disease and stroke statistics. CONCLUSIONS: The Statistical Update represents a critical resource for the lay public, policy makers, media professionals, clinicians, healthcare administrators, researchers, health advocates, and others seeking the best available data on these factors and conditions.
Asunto(s)
American Heart Association , Cardiopatías/epidemiología , Cardiopatías/prevención & control , Servicios Preventivos de Salud , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/prevención & control , Comorbilidad , Estado de Salud , Cardiopatías/diagnóstico , Cardiopatías/mortalidad , Humanos , Estilo de Vida , Factores Protectores , Medición de Riesgo , Factores de Riesgo , Conducta de Reducción del Riesgo , Accidente Cerebrovascular/diagnóstico , Accidente Cerebrovascular/mortalidad , Factores de Tiempo , Estados Unidos/epidemiologíaRESUMEN
The 2021 Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for the Management of Blood Pressure in Chronic Kidney Disease (CKD) recommends a target systolic blood pressure under 120 mmHg based on standardized office blood pressure measurement. Here, we examined the potential implications of this new guideline for blood pressure lowering with antihypertensive medication among adults in the United States with CKD compared to the 2012 KDIGO guideline (target blood pressure 130/80 mmHg or under with albuminuria or 140/90 mmHg or under without albuminuria) and the 2017 American College of Cardiology/American Heart Association (target blood pressure under 130/80 mmHg) guideline. Additionally, we determined implications of the 2021 KDIGO guideline for angiotensin converting enzyme inhibitor (ACEi) or angiotensin II-receptor blocker (ARB) use for those with albuminuria (recommended at systolic blood pressure of 120 mmHg or over) compared to the 2012 KDIGO guideline (recommended at blood pressures over 130/80 mmHg). Data were analyzed from 1,699 adults with CKD (estimated glomerular filtration rate 15-59 ml/min/1.73m2 or a urinary albumin-to-creatinine ratio of 30 mg/g or more) in the 2015-2018 National Health and Nutrition Examination Survey and averaged up to three standardized blood pressure measurements. Among adults with CKD, 69.5% were eligible for blood pressure lowering according to the 2021 KDIGO guideline, compared with 49.8% as per 2012 KDIGO or 55.6% as per 2017 American College of Cardiology/American Heart Association guidelines. Among those with albuminuria, 78.2% were eligible for ACEi/ARB use by the 2021 KDIGO guideline compared with 71.0% by the 2012 KDIGO guideline. However, only 39.1% were taking an ACEi/ARB. Thus, our findings highlight opportunities to improve blood pressure management and reduce cardiovascular risk among adults in the United States with CKD.
Asunto(s)
Hipertensión , Insuficiencia Renal Crónica , Adulto , Antagonistas de Receptores de Angiotensina , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Presión Sanguínea , Humanos , Hipertensión/diagnóstico , Hipertensión/tratamiento farmacológico , Hipertensión/epidemiología , Encuestas Nutricionales , Insuficiencia Renal Crónica/diagnóstico , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/epidemiología , Estados Unidos/epidemiologíaRESUMEN
Protein structure determines biological function. Accurately conceptualizing 3D protein/ligand structures is thus vital to scientific research and education. Virtual reality (VR) enables protein visualization in stereoscopic 3D, but many VR molecular-visualization programs are expensive and challenging to use; work only on specific VR headsets; rely on complicated model-preparation software; and/or require the user to install separate programs or plugins. Here we introduce ProteinVR, a web-based application that works on various VR setups and operating systems. ProteinVR displays molecular structures within 3D environments that give useful biological context and allow users to situate themselves in 3D space. Our web-based implementation is ideal for hypothesis generation and education in research and large-classroom settings. We release ProteinVR under the open-source BSD-3-Clause license. A copy of the program is available free of charge from http://durrantlab.com/protein-vr/, and a working version can be accessed at http://durrantlab.com/pvr/.