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Somatic mutations in non-malignant tissues are selected for because they confer increased clonal fitness. However, it is uncertain whether these clones can benefit organ health. Here, ultra-deep targeted sequencing of 150 liver samples from 30 chronic liver disease patients revealed recurrent somatic mutations. PKD1 mutations were observed in 30% of patients, whereas they were only detected in 1.3% of hepatocellular carcinomas (HCCs). To interrogate tumor suppressor functionality, we perturbed PKD1 in two HCC cell lines and six in vivo models, in some cases showing that PKD1 loss protected against HCC, but in most cases showing no impact. However, Pkd1 haploinsufficiency accelerated regeneration after partial hepatectomy. We tested Pkd1 in fatty liver disease, showing that Pkd1 loss was protective against steatosis and glucose intolerance. Mechanistically, Pkd1 loss selectively increased mTOR signaling without SREBP-1c activation. In summary, PKD1 mutations exert adaptive functionality on the organ level without increasing transformation risk.
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Carcinoma Hepatocelular , Cirrosis Hepática , Neoplasias Hepáticas , Mutación , Canales Catiónicos TRPP , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/metabolismo , Animales , Canales Catiónicos TRPP/genética , Canales Catiónicos TRPP/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/metabolismo , Ratones , Cirrosis Hepática/genética , Cirrosis Hepática/metabolismo , Cirrosis Hepática/patología , Hígado Graso/genética , Hígado Graso/metabolismo , Hígado Graso/patología , Masculino , Serina-Treonina Quinasas TOR/metabolismo , Ratones Endogámicos C57BL , Línea Celular Tumoral , Femenino , Transducción de SeñalRESUMEN
PURPOSE: Atypicalities in the prosodic aspects of speech are commonly considered in clinical assessments of autism. While there is an increasing number of studies using objective measures to assess prosodic deficits, such studies have primarily focused on the intonational and rhythmic aspects of prosody. Little is known about prosodic deficits that are reflected at the segmental level, despite the strong connection between prosody and segmental realization. This study examines the nature of sibilant-vowel coarticulation among male adult native speakers of Cantonese with autism and those without. METHODS: Fifteen Cantonese-speaking autistic (ASD) adults (mean age = 25 years) and 23 neuro-typical (NT) adults (mean age = 20 years) participated. Each participant read aloud 42 syllables with a sibilant onset in carrier phrase. Spectral means and variance, skewness and kurtosis were measured, and regressed by vocalic rounding (rounded vs. unrounded), cohort (ASD vs. NT), sibilant duration, and articulation rate. RESULTS: While neurotypical participants exhibit sibilant-vowel coarticulation that are sensitive to variation in sibilant duration, autistic participants show no sensitivity to segmental temporal changes. CONCLUSION: These findings point to the potential for atypicalities in prosody-segment interaction as an important characteristic of autistic speech.
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Magnesium is ubiquitous in nature. It sits at the origin of the food chain, occupying the center of chlorophyl in plants. In humans, magnesium is critical to diverse molecular and catalytic processes, including energy transfer and maintenance of the genome. Despite its abundance, hypomagnesemia is common and often goes undiagnosed. This is in spite of epidemiologic data linking low magnesium with chronic diseases including diabetes mellitus. Clinically significant hypermagnesemia is encountered less frequently, but the presentation may be dramatic. Advances in molecular biology and the elucidation of the genetic causes of magnesium disorders have enhanced our understanding of their pathophysiology. Treatment approaches are also changing. The repurposing of newer medications, such as sodium/glucose cotransporter 2 inhibitors, offers new therapeutic options. In this review we integrate knowledge in this rapidly evolving field to provide clinicians and trainees with a resource for approaching common clinical scenarios involving magnesium disorders.
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Deficiencia de Magnesio , Magnesio , Humanos , Magnesio/sangre , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéuticoRESUMEN
Patients with inflammatory bowel disease (IBD) are susceptible to colitis-associated cancer (CAC). Chronic inflammation promotes the risk for CAC. In contrast, mucosal healing predicts improved prognosis in IBD and reduced risk of CAC. However, the molecular integration among colitis, mucosal healing, and CAC remains poorly understood. Claudin-2 (CLDN2) expression is upregulated in IBD; however, its role in CAC is not known. The current study was undertaken to examine the role for CLDN2 in CAC. The AOM/DSS-induced CAC model was used with WT and CLDN2-modified mice. High-throughput expression analyses, murine models of colitis/recovery, chronic colitis, ex vivo crypt culture, and pharmacological manipulations were employed in order to increase our mechanistic understanding. The Cldn2KO mice showed significant inhibition of CAC despite severe colitis compared with WT littermates. Cldn2 loss also resulted in impaired recovery from colitis and increased injury when mice were subjected to intestinal injury by other methods. Mechanistic studies demonstrated a possibly novel role of CLDN2 in promotion of mucosal healing downstream of EGFR signaling and by regulation of Survivin expression. An upregulated CLDN2 expression protected from CAC and associated positively with crypt regeneration and Survivin expression in patients with IBD. We demonstrate a potentially novel role of CLDN2 in promotion of mucosal healing in patients with IBD and thus regulation of vulnerability to colitis severity and CAC, which can be exploited for improved clinical management.
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Neoplasias Asociadas a Colitis , Colitis , Enfermedades Inflamatorias del Intestino , Animales , Humanos , Ratones , Claudina-2/genética , Claudina-2/metabolismo , Colitis/inducido químicamente , Colitis/complicaciones , Colitis/genética , Neoplasias Asociadas a Colitis/complicaciones , Neoplasias Asociadas a Colitis/metabolismo , Sulfato de Dextran/toxicidad , Modelos Animales de Enfermedad , Enfermedades Inflamatorias del Intestino/complicaciones , Enfermedades Inflamatorias del Intestino/genética , Enfermedades Inflamatorias del Intestino/metabolismo , Mucosa Intestinal/metabolismo , Ratones Endogámicos C57BL , Survivin/metabolismoRESUMEN
Claudin-2 is a tight junction protein expressed in leaky epithelia where it forms paracellular pores permeable to cations and water. The paracellular pore formed by claudin-2 is important in energy-efficient cation and water transport in the proximal tubules of the kidneys. Mounting evidence now suggests that claudin-2 may modulate cellular processes often altered in disease, including cellular proliferation. Also, dysregulation of claudin-2 expression has been linked to various diseases, including kidney stone disease and renal cell carcinoma. However, the mechanisms linking altered claudin-2 expression and function to disease are poorly understood and require further investigation. The aim of this review is to discuss the current understanding of the role of claudin-2 in kidney function and dysfunction. We provide a general overview of the claudins and their organization in the tight junction, the expression, and function of claudin-2 in the kidney, and the evolving evidence for its role in kidney disease.
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Claudina-2 , Túbulos Renales Proximales , Claudina-2/metabolismo , Túbulos Renales Proximales/metabolismo , Transporte Biológico/fisiología , Riñón/metabolismo , Uniones Estrechas/metabolismo , Agua/metabolismoRESUMEN
Recent studies have revealed great individual variability in cue weighting, and such variation is shown to be systematic across individuals and linked to differences in some general cognitive mechanism. The present study investigated the role of subcortical encoding as a source of individual variability in cue weighting by focusing on English listeners' frequency following responses to the tense/lax English vowel contrast varying in spectral and durational cues. Listeners differed in early auditory encoding with some encoding the spectral cue more veridically than the durational one, while others exhibited the reverse pattern. These differences in cue encoding further correlate with behavioral variability in cue weighting, suggesting that specificity in cue encoding across individuals modulates how cues are weighted in downstream processes.
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Fonética , Percepción del Habla , Humanos , Señales (Psicología) , Acústica del Lenguaje , Percepción del Habla/fisiología , LenguajeRESUMEN
Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the formation of numerous fluid-filled cysts that lead to progressive loss of functional nephrons. Currently, there is an unmet need for diagnostic and prognostic indicators of early stages of the disease. Metabolites were extracted from the urine of patients with early-stage ADPKD (n = 48 study participants) and age- and sex-matched normal controls (n = 47) and analyzed by liquid chromatography-mass spectrometry. Orthogonal partial least squares-discriminant analysis was used to generate a global metabolomic profile of early ADPKD for the identification of metabolic pathway alterations and discriminatory metabolites as candidates of diagnostic and prognostic biomarkers. The global metabolomic profile exhibited alterations in steroid hormone biosynthesis and metabolism, fatty acid metabolism, pyruvate metabolism, amino acid metabolism, and the urea cycle. A panel of 46 metabolite features was identified as candidate diagnostic biomarkers. Notable putative identities of candidate diagnostic biomarkers for early detection include creatinine, cAMP, deoxycytidine monophosphate, various androgens (testosterone; 5-α-androstane-3,17,dione; trans-dehydroandrosterone), betaine aldehyde, phosphoric acid, choline, 18-hydroxycorticosterone, and cortisol. Metabolic pathways associated with variable rates of disease progression included steroid hormone biosynthesis and metabolism, vitamin D3 metabolism, fatty acid metabolism, the pentose phosphate pathway, tricarboxylic acid cycle, amino acid metabolism, sialic acid metabolism, and chondroitin sulfate and heparin sulfate degradation. A panel of 41 metabolite features was identified as candidate prognostic biomarkers. Notable putative identities of candidate prognostic biomarkers include ethanolamine, C20:4 anandamide phosphate, progesterone, various androgens (5-α-dihydrotestosterone, androsterone, etiocholanolone, and epiandrosterone), betaine aldehyde, inflammatory lipids (eicosapentaenoic acid, linoleic acid, and stearolic acid), and choline. Our exploratory data support metabolic reprogramming in early ADPKD and demonstrate the ability of liquid chromatography-mass spectrometry-based global metabolomic profiling to detect metabolic pathway alterations as new therapeutic targets and biomarkers for early diagnosis and tracking disease progression of ADPKD.NEW & NOTEWORTHY To our knowledge, this study is the first to generate urinary global metabolomic profiles from individuals with early-stage ADPKD with preserved renal function for biomarker discovery. The exploratory dataset reveals metabolic pathway alterations that may be responsible for early cystogenesis and rapid disease progression and may be potential therapeutic targets and pathway sources for candidate biomarkers. From these results, we generated a panel of candidate diagnostic and prognostic biomarkers of early-stage ADPKD for future validation.
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Riñón Poliquístico Autosómico Dominante , Humanos , Riñón Poliquístico Autosómico Dominante/diagnóstico , Andrógenos , Biomarcadores/orina , Metabolómica/métodos , Progresión de la Enfermedad , Redes y Vías Metabólicas , Colina , Aminoácidos , Ácidos Grasos , EsteroidesRESUMEN
Phonetic typological studies suggest that syllable duration is inversely correlated with the accompanying tone's approximate average f0, and tones with dynamic f0 movement tend to be in longer syllables rather than shorter ones. Systematic instrumental investigations on tone-duration interaction remain scant, however; existing studies might be confounded as tonal context may impact duration realization due to phonetic constraints on tonal movement. This study investigates the effect of tonal environment on the durational realization of tones in Cantonese, showing that tone-dependent duration variation is governed by the tonal context. Implications of these findings for existing phonetic typology concerning tone-duration interaction are discussed.
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FonéticaRESUMEN
This article describes the use of prognostic, predictive, and response biomarkers that have been developed for autosomal dominant polycystic kidney disease and their use in clinical care or drug development. We focus on biochemical markers that can be assayed in patients' blood and urine and their association with the outcome of decreased glomerular filtration rate. There have been several studies on prognostic biomarkers. The most promising ones have been markers of tubular injury, inflammation, metabolism, or the vasopressin-urinary concentration axis. So far, none have been shown to be superior to kidney volume-based biomarkers. Several biomarkers are additive to kidney volume and genotype in prognostic models, but there have been few direct comparisons between the biochemical markers to identify the best ones. Moreover, there is a lack of uniformity in the statistical tools used to assess and compare biomarkers. There have been few reports of predictive and response biomarkers, and none are suitable surrogate endpoints. The U.S. Food and Drug Administration's Biomarker Qualification Program provides a regulatory pathway to approve biomarkers for use across multiple drug-development programs.
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Enfermedades Renales Poliquísticas , Humanos , Progresión de la Enfermedad , Tasa de Filtración Glomerular , Enfermedades Renales Poliquísticas/diagnóstico , Biomarcadores/metabolismo , PronósticoRESUMEN
New image-derived biomarkers for patients affected by autosomal dominant polycystic kidney disease are needed to improve current clinical management. The measurement of total kidney volume (TKV) provides critical information for clinicians to drive care decisions. However, patients with similar TKV may present with very different phenotypes, often requiring subjective decisions based on other factors (e.g., appearance of healthy kidney parenchyma, a few cysts contributing significantly to overall TKV, etc.). In this study, we describe a new technique to individually segment cysts and quantify biometric parameters including cyst volume, cyst number, parenchyma volume, and cyst parenchyma surface area. Using data from the Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) study the utility of these new parameters was explored, both quantitatively as well as visually. Total cyst number and cyst parenchyma surface area showed superior prediction of the slope of estimated glomerular filtration rate decline, kidney failure and chronic kidney disease stages 3A, 3B, and 4, compared to TKV. In addition, presentations such as a few large cysts contributing significantly to overall kidney volume were shown to be much better stratified in terms of outcome predictions. Thus, these new image biomarkers, which can be obtained automatically, will have great utility in future studies and clinical care for patients affected by autosomal dominant polycystic kidney disease.
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Riñón Poliquístico Autosómico Dominante , Humanos , Riñón Poliquístico Autosómico Dominante/complicaciones , Riñón Poliquístico Autosómico Dominante/diagnóstico por imagen , Progresión de la Enfermedad , Imagen por Resonancia Magnética/métodos , Pronóstico , Riñón/diagnóstico por imagen , Biomarcadores , Tasa de Filtración GlomerularRESUMEN
Brain-derived neurotrophic factor (BDNF) promotes neuronal differentiation and survival and is implicated in the pathogenesis of many neurological disorders. Here, we identified a novel intergenic enhancer located 170 kb from the Bdnf gene, which promotes the expression of Bdnf transcript variants during mouse neuronal differentiation and activity. Following Bdnf activation, enhancer-promoter contacts increase, and the region moves away from the repressive nuclear periphery. Bdnf enhancer activity is necessary for neuronal clustering and dendritogenesis in vitro, and for cortical development in vivo. Our findings provide the first evidence of a regulatory mechanism whereby the activation of a distal enhancer promotes Bdnf expression during brain development.
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Through the analysis of an urban tree inventory with the aid of machine learning, this study brought together different aspects of urban forestry. Urban tree monitoring is essential to successful urban forestry. Transport land use accommodates huge tree stock which requires substantial monitoring efforts. In Hong Kong, more research is needed to take into consideration how monitoring works can be improved in response to variations in tree stand characteristics. This case study aimed to illustrate the usefulness of a large-scale tree survey in mainstreaming future tree monitoring and management in transport land use. A total of 7209 trees were found in a large-scale tree survey conducted in 53 slopes and 52 verges along San Tin Highway in Hong Kong. Dominance by Corymbia citriodora (72%) was observed, especially for the highway verges. Using chi-square tests, significant associations were found between monospecific stands, habitat type, and tree risk rating. A logistic regression model was constructed to predict the occurrence of monoculture. Every metre increase in maximum tree height, the odds of a stand being monospecific would be 1.22 times greater. Stands on verges had 5.26 times greater odds of being monospecific against the slope. The associations and relationships were attributed to the dominance of C. citriodora. By boosting the logistic model, model reliability increased as kappa rose from 0.51 to 0.63, while balanced accuracy improved from 0.72 to 0.85. The occurrence of monospecific stands could be reliably predicted using maximum tree height and habitat type of tree stands. These quantitative findings monitoring can guide urban forest monitoring. Through a better understanding of urban forest structure and composition, future monitoring can aid the mainstreaming of urban forestry in transport planning.
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Monitoreo del Ambiente , Árboles , Hong Kong , Reproducibilidad de los Resultados , Bosques , Agricultura ForestalRESUMEN
Background: Abnormalities in calcium, phosphorus, PTH, vitamin D metabolism, bone, and vascular calcification occur in chronic kidney disease mineral bone disorder (CKD-MBD). Calciphylaxis, involving painful, ulcerative skin lesions, is also a major problem associated with CKD-MBD. There are no quality medical interventions to address these clinical issues. Bone ASARM peptides are strong inhibitors of mineralization and induce hypophosphatemia by inhibiting phosphate uptake from the gut. We hypothesize treatment of CKD-MBD rats with ASARM peptides will reverse hyperphosphatemia, reduce soft-tissue calcification, and prevent calciphylaxis. Methods: To test our hypothesis, we assessed the effects of synthetic ASARM peptide in rats that had undergone a subtotal 5/6th nephrectomy (56NEPHREX), a rodent model of CKD-MBD. All rats were fed a high phosphate diet (2% Pi) to worsen mineral metabolism defects. Changes in serum potassium, phosphate, BUN, creatinine, PTH, FGF23, and calcium were assessed in response to 28 days of ASARM peptide infusion. Also, changes in bone quality, soft-tissue calcification, and expression of gut Npt2b (Slc34a2) were studied following ASARM peptide treatment. Results: Rats that had undergone 56NEPHREX treated with ASARM peptide showed major improvements in hyperphosphatemia, blood urea nitrogen (BUN), and bone quality compared with vehicle controls. Also, ASARM-infused 56NEPHREX rats displayed improved renal, brain, and cardiovascular calcification. Notably, ASARM peptide infusion prevented the genesis of subdermal medial blood vessel calcification and calciphylaxis-like lesions in 56NEPHREX rats compared with vehicle controls. Conclusions: ASARM peptide infusion corrects hyperphosphatemia and improves vascular calcification, renal calcification, brain calcification, bone quality, renal function, and skin mineralization abnormalities in 56NEPHREX rats. These findings confirm our hypothesis and support the utility of ASARM peptide treatment in patients with CKD-MBD.
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Exposure to bio-aerosols such as pollen can lead to adverse health effects. There is a need for a portable and cost-effective device for long-term monitoring and quantification of various types of pollen. To address this need, we present a mobile and cost-effective label-free sensor that takes holographic images of flowing particulate matter (PM) concentrated by a virtual impactor, which selectively slows down and guides particles larger than 6 µm to fly through an imaging window. The flowing particles are illuminated by a pulsed laser diode, casting their inline holograms on a complementary metal-oxide semiconductor image sensor in a lens-free mobile imaging device. The illumination contains three short pulses with a negligible shift of the flowing particle within one pulse, and triplicate holograms of the same particle are recorded at a single frame before it exits the imaging field-of-view, revealing different perspectives of each particle. The particles within the virtual impactor are localized through a differential detection scheme, and a deep neural network classifies the pollen type in a label-free manner based on the acquired holographic images. We demonstrated the success of this mobile pollen detector with a virtual impactor using different types of pollen (i.e., bermuda, elm, oak, pine, sycamore, and wheat) and achieved a blind classification accuracy of 92.91%. This mobile and cost-effective device weighs â¼700 g and can be used for label-free sensing and quantification of various bio-aerosols over extended periods since it is based on a cartridge-free virtual impactor that does not capture or immobilize PM.
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Aprendizaje Profundo , Holografía , Polen , Material Particulado , AerosolesRESUMEN
Introduction: Autosomal dominant polycystic kidney disease (ADPKD) is a progressive genetic kidney disease. Studies of ADPKD presented results using different outcome measures. We aimed to summarize outcomes reported in ADPKD studies, including composite outcomes. Methods: We conducted a systematic review of published studies that included patients with ADPKD and measured kidney-related outcomes. We searched published databases and included all studies regardless of design with at least 100 participants for observational studies. We excluded studies that were limited to dialysis, transplant, or pregnancy outcomes in patients with ADPKD. Results: This review includes data from 175 published articles (49 randomized controlled trials, 2 interventional clinical trials, 30 post hoc analyses, and 94 observational studies). We identified 214 different outcomes, and we categorized them into the 24 main outcome domains. In addition, the review identified 13 articles that reported 9 different composite outcomes. Conclusion: The finding highlights the inconsistency in the outcomes reported by researchers and how they are measured in ADPKD studies. The variability in the outcomes reported supports the need to standardize outcomes in ADPKD studies.
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Autosomal dominant polycystic kidney disease (ADPKD) is a debilitating renal neoplastic disorder with limited treatment options. It is characterized by the formation of large fluid-filled cysts that develop from kidney tubules through abnormal cell proliferation and cyst-filling fluid secretion driven by cAMP-dependent Cl- secretion. We tested the effectiveness of the indazole carboxylic acid H2-gamendazole (H2-GMZ), a derivative of lonidamine, to inhibit these processes using in vitro and in vivo models of ADPKD. H2-GMZ was effective in rapidly blocking forskolin-induced, Cl--mediated short-circuit currents in human ADPKD cells, and it significantly inhibited both cAMP- and epidermal growth factor-induced proliferation of ADPKD cells. Western blot analysis of H2-GMZ-treated ADPKD cells showed decreased phosphorylated ERK and decreased hyperphosphorylated retinoblastoma levels. H2-GMZ treatment also decreased ErbB2, Akt, and cyclin-dependent kinase 4, consistent with inhibition of heat shock protein 90, and it decreased levels of the cystic fibrosis transmembrane conductance regulator Cl- channel protein. H2-GMZ-treated ADPKD cultures contained a higher proportion of smaller cells with fewer and smaller lamellipodia and decreased cytoplasmic actin staining, and they were unable to accomplish wound closure even at low H2-GMZ concentrations, consistent with an alteration in the actin cytoskeleton and decreased cell motility. Experiments using mouse metanephric organ cultures showed that H2-GMZ inhibited cAMP-stimulated cyst growth and enlargement. In vivo, H2-GMZ was effective in slowing postnatal cyst formation and kidney enlargement in the Pkd1flox/flox: Pkhd1-Cre mouse model. Thus, H2-GMZ treatment decreases Cl- secretion, cell proliferation, cell motility, and cyst growth. These properties, along with its reported low toxicity, suggest that H2-GMZ might be an attractive candidate for treatment of ADPKD.NEW & NOTEWORTHY Autosomal dominant polycystic kidney disease (ADPKD) is a renal neoplastic disorder characterized by the formation of large fluid-filled cysts that develop from kidney tubules through abnormal cell proliferation and cyst-filling fluid secretion driven by cAMP-dependent Cl- secretion. This study shows that the lonidamine derivative H2-GMZ inhibits Cl- secretion, cell proliferation, and cyst growth, suggesting that it might have therapeutic value for the treatment of ADPKD.
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Quistes , Enfermedades Renales Poliquísticas , Riñón Poliquístico Autosómico Dominante , Actinas/metabolismo , Animales , Ácidos Carboxílicos/metabolismo , Proliferación Celular , Células Cultivadas , Colforsina/farmacología , Quinasa 4 Dependiente de la Ciclina/metabolismo , Regulador de Conductancia de Transmembrana de Fibrosis Quística/metabolismo , Quistes/metabolismo , Familia de Proteínas EGF/metabolismo , Proteínas de Choque Térmico/metabolismo , Humanos , Indazoles/metabolismo , Indazoles/farmacología , Riñón/metabolismo , Ratones , Enfermedades Renales Poliquísticas/tratamiento farmacológico , Enfermedades Renales Poliquísticas/metabolismo , Riñón Poliquístico Autosómico Dominante/tratamiento farmacológico , Riñón Poliquístico Autosómico Dominante/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptores de Superficie CelularRESUMEN
Importance: Acute kidney injury (AKI) is a heterogeneous syndrome prevalent among hospitalized patients. Personalized risk estimation and risk factor identification may allow effective intervention and improved outcomes. Objective: To develop and validate personalized AKI risk estimation models using electronic health records (EHRs), examine whether personalized models were beneficial in comparison with global and subgroup models, and assess the heterogeneity of risk factors and their outcomes in different subpopulations. Design, Setting, and Participants: This diagnostic study analyzed EHR data from 1 tertiary care hospital and used machine learning and logistic regression to develop and validate global, subgroup, and personalized risk estimation models. Transfer learning was implemented to enhance the personalized model. Predictor outcomes across subpopulations were analyzed, and metaregression was used to explore predictor interactions. Adults who were hospitalized for 2 or more days from November 1, 2007, to December 31, 2016, were included in the analysis. Patients with moderate or severe kidney dysfunction at admission were excluded. Data were analyzed between August 28, 2019, and May 8, 2022. Exposures: Clinical and laboratory variables in the EHR. Main Outcomes and Measures: The main outcome was AKI of any severity, and AKI was defined using the Kidney Disease: Improving Global Outcomes serum creatinine criteria. Performance of the models was measured with area under the receiver operating characteristic curve (AUROC), area under the precision-recall curve, and calibration. Results: The study cohort comprised 76â¯957 inpatient encounters. Patients had a mean (SD) age of 55.5 (17.4) years and included 42 159 men (54.8%). The personalized model with transfer learning outperformed the global model for AKI estimation in terms of AUROC among general inpatients (0.78 [95% CI, 0.77-0.79] vs 0.76 [95% CI, 0.75-0.76]; P < .001) and across the high-risk subgroups (0.79 [95% CI, 0.78-0.80] vs 0.75 [95% CI, 0.74-0.77]; P < .001) and low-risk subgroups (0.74 [95% CI, 0.73-0.75] vs 0.71 [95% CI, 0.70-0.72]; P < .001). The AUROC improvement reached 0.13 for the high-risk subgroups, such as those undergoing liver transplant and cardiac surgery. Moreover, the personalized model with transfer learning performed better than or comparably with the best published models in well-studied AKI subgroups. Predictor outcomes varied significantly between patients, and interaction analysis uncovered modifiers of the predictor outcomes. Conclusions and Relevance: Results of this study demonstrated that a personalized modeling with transfer learning is an improved AKI risk estimation approach that can be used across diverse patient subgroups. Risk factor heterogeneity and interactions at the individual level highlighted the need for agile, personalized care.
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Lesión Renal Aguda , Registros Electrónicos de Salud , Lesión Renal Aguda/diagnóstico , Adulto , Área Bajo la Curva , Creatinina , Humanos , Aprendizaje Automático , Masculino , Persona de Mediana EdadRESUMEN
Speech categories are defined by multiple acoustic dimensions and their boundaries are generally fuzzy and ambiguous in part because listeners often give differential weighting to these cue dimensions during phonetic categorization. This study explored how a listener's perception of a speaker's socio-indexical and personality characteristics influences the listener's perceptual cue weighting. In a matched-guise study, three groups of listeners classified a series of gender-neutral /b/-/p/ continua that vary in VOT and F0 at the onset of the following vowel. Listeners were assigned to one of three prompt conditions (i.e., a visually male talker, a visually female talker, or audio-only) and rated the talker in terms of vocal (and facial, in the visual prompt conditions) gender prototypicality, attractiveness, friendliness, confidence, trustworthiness, and gayness. Male listeners and listeners who saw a male face showed less reliance on VOT compared to listeners in the other conditions. Listeners' visual evaluation of the talker also affected their weighting of VOT and onset F0 cues, although the effects of facial impressions differ depending on the gender of the listener. The results demonstrate that individual differences in perceptual cue weighting are modulated by the listener's gender and his/her subjective evaluation of the talker. These findings lend support for exemplar-based models of speech perception and production where socio-indexical features are encoded as a part of the episodic traces in the listeners' mental lexicon. This study also shed light on the relationship between individual variation in cue weighting and community-level sound change by demonstrating that VOT and onset F0 co-variation in North American English has acquired a certain degree of socio-indexical significance.
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PURPOSE OF REVIEW: Progressive forms of chronic kidney disease (CKD) exhibit kidney inflammation and fibrosis that drive continued nephron loss; however, factors responsible for the development of these common pathologic features remain poorly defined. Recent investigations suggest pathways involved in maintaining urinary phosphate excretion in CKD may be contributing to kidney function decline. This review provides an update on recent evidence linking altered phosphate homeostasis to CKD progression. RECENT FINDINGS: High dietary phosphate intake and increased serum concentrations of fibroblast growth factor 23 (FGF23) both increase urinary phosphate excretion and are associated with increased risk of kidney function decline. Recent investigations have discovered high concentrations of tubular phosphate promote phosphate-based nanocrystal formation that drives tubular injury, cyst formation, and fibrosis. SUMMARY: Studies presented in this review highlight important scientific discoveries that have molded our current understanding of the contribution of altered phosphate homeostasis to CKD progression. The collective observations from these investigations implicate phosphaturia, and the resulting formation of phosphate-based crystals in tubular fluid, as unique risk factors for kidney function decline. Developing a better understanding of the relationship between tubular phosphate handling and kidney pathology could result in innovative strategies for improving kidney outcomes in patients with CKD.