African Americans have a heightened risk of developing chronic and end-stage kidney disease, an association that is largely attributed to two common genetic variants, termed G1 and G2, in the APOL1 ...gene. Direct evidence demonstrating that these APOL1 risk alleles are pathogenic is still lacking because the APOL1 gene is present in only some primates and humans; thus it has been challenging to demonstrate experimental proof of causality of these risk alleles for renal disease. Here we generated mice with podocyte-specific inducible expression of the APOL1 reference allele (termed G0) or each of the risk-conferring alleles (G1 or G2). We show that mice with podocyte-specific expression of either APOL1 risk allele, but not of the G0 allele, develop functional (albuminuria and azotemia), structural (foot-process effacement and glomerulosclerosis) and molecular (gene-expression) changes that closely resemble human kidney disease. Disease development was cell-type specific and likely reversible, and the severity correlated with the level of expression of the risk allele. We further found that expression of the risk-variant APOL1 alleles interferes with endosomal trafficking and blocks autophagic flux, which ultimately leads to inflammatory-mediated podocyte death and glomerular scarring. In summary, this is the first demonstration that the expression of APOL1 risk alleles is causal for altered podocyte function and glomerular disease in vivo.
Eating and swallowing are complex behaviors involving volitional and reflexive activities of more than 30 nerves and muscles. They have two crucial biologic features: food passage from the oral ...cavity to stomach and airway protection. The swallowing process is commonly divided into oral, pharyngeal, and esophageal stages, according to the location of the bolus. The movement of the food in the oral cavity and to the oropharynx differs depending on the type of food (eating solid food versus drinking liquid). Dysphagia can result from a wide variety of functional or structural deficits of the oral cavity, pharynx, larynx, or esophagus. The goal of dysphagia rehabilitation is to identify and treat abnormalities of feeding and swallowing while maintaining safe and efficient alimentation and hydration.
Coding variants in apolipoprotein L1 (APOL1), termed G1 and G2, can explain most excess kidney disease risk in African Americans; however, the molecular pathways of APOL1-induced kidney dysfunction ...remain poorly understood. Here, we report that expression of G2 APOL1 in the podocytes of Nphs1rtTA/TRE-G2APOL1 (G2APOL1) mice leads to early activation of the cytosolic nucleotide sensor, stimulator of interferon genes (STING), and the NLR family pyrin domain-containing 3 (NLRP3) inflammasome. STING and NLRP3 expression was increased in podocytes from patients with high-risk APOL1 genotypes, and expression of APOL1 correlated with caspase-1 and gasdermin D (GSDMD) levels. To demonstrate the role of NLRP3 and STING in APOL1-associated kidney disease, we generated transgenic mice with the G2 APOL1 risk variant and genetic deletion of Nlrp3 (G2APOL1/Nlrp3 KO), Gsdmd (G2APOL1/Gsdmd KO), and STING (G2APOL1/STING KO). Knockout mice displayed marked reduction in albuminuria, azotemia, and kidney fibrosis compared with G2APOL1 mice. To evaluate the therapeutic potential of targeting NLRP3, GSDMD, and STING, we treated mice with MCC950, disulfiram, and C176, potent and selective inhibitors of NLRP3, GSDMD, and STING, respectively. G2APOL1 mice treated with MCC950, disulfiram, and C176 showed lower albuminuria and improved kidney function even when inhibitor treatment was initiated after the development of albuminuria.
Nearly 60% of patients who are intubated in intensive care units (ICUs) experience dysphagia after extubation, and approximately 50% of them aspirate. Little is known about dysphagia recovery time ...after patients are discharged from the hospital.
To determine factors associated with recovery from dysphagia symptoms after hospital discharge for acute respiratory distress syndrome (ARDS) survivors who received oral intubation with mechanical ventilation.
This is a prospective, 5-year longitudinal cohort study involving 13 ICUs at four teaching hospitals in Baltimore, Maryland. The Sydney Swallowing Questionnaire (SSQ), a 17-item visual analog scale (range, 0-1,700), was used to quantify patient-perceived dysphagia symptoms at hospital discharge, and at 3, 6, 12, 24, 36, 48, and 60 months after ARDS. An SSQ score greater than or equal to 200 was used to indicate clinically important dysphagia symptoms at the time of hospital discharge. Recovery was defined as an SSQ score less than 200, with a decrease from hospital discharge greater than or equal to 119, the reliable change index for SSQ score. Fine and Gray proportional subdistribution hazards regression analysis was used to evaluate patient and ICU variables associated with time to recovery accounting for the competing risk of death.
Thirty-seven (32%) of 115 patients had an SSQ score greater than or equal to 200 at hospital discharge; 3 died before recovery. All 34 remaining survivors recovered from dysphagia symptoms by 5-year follow-up, 7 (23%) after 6 months. ICU length of stay was independently associated with time to recovery, with a hazard ratio (95% confidence interval) of 0.96 (0.93-1.00) per day.
One-third of orally intubated ARDS survivors have dysphagia symptoms that persist beyond hospital discharge. Patients with a longer ICU length of stay have slower recovery from dysphagia symptoms and should be carefully considered for swallowing assessment to help prevent complications related to dysphagia.
Abstract Needham DM, Korupolu R, Zanni JM, Pradhan P, Colantuoni E, Palmer JB, Brower RG, Fan E. Early physical medicine and rehabilitation for patients with acute respiratory failure: a quality ...improvement project. Objectives To (1) reduce deep sedation and delirium to permit mobilization, (2) increase the frequency of rehabilitation consultations and treatments to improve patients' functional mobility, and (3) evaluate effects on length of stay. Design Seven-month prospective before/after quality improvement project. Setting Sixteen-bed medical intensive care unit (MICU) in academic hospital. Participants 57 patients mechanically ventilated 4 days or longer. Intervention A multidisciplinary team focused on reducing heavy sedation and increasing MICU staffing to include full-time physical and occupational therapists with new consultation guidelines. Main Outcome Measures Sedation and delirium status, rehabilitation treatments, functional mobility. Results Compared with before the quality improvement project, benzodiazepine use decreased markedly (proportion of MICU days that patients received benzodiazepines 50% vs 25%, P =.002), with lower median daily sedative doses (47 vs 15mg midazolam equivalents P =.09 and 71 vs 24 mg morphine equivalents P =.01). Patients had improved sedation and delirium status (MICU days alert 30% vs 67%, P <.001 and not delirious 21% vs 53%, P =.003). There were a greater median number of rehabilitation treatments per patient (1 vs 7, P <.001) with a higher level of functional mobility (treatments involving sitting or greater mobility, 56% vs 78%, P =.03). Hospital administrative data demonstrated that across all MICU patients, there was a decrease in intensive care unit and hospital length of stay by 2.1 (95% confidence interval: 0.4–3.8) and 3.1 (0.3–5.9) days, respectively, and a 20% increase in MICU admissions compared with the same period in the prior year. Conclusions Using a quality improvement process, intensive care unit delirium, physical rehabilitation, and functional mobility were markedly improved and associated with decreased length of stay.
Understanding bolus flow patterns in swallowing (rheology, the study of flow) is fundamental to assessment and treatment of dysphagia. These patterns are complex and poorly understood. A liquid ...swallow is typically biphasic, including air, so the actual bolus has both liquid and gas phases. We report a novel observation of annular two-phase flow (a ring of liquid around a core of air) as thin liquids passed through the upper esophageal sphincter (UES). Dynamic CT was performed on 27 healthy asymptomatic volunteers swallowing liquid barium in a semi-reclining position. Each subject swallowed 3, 10, and 20 ml of either thin (14 subjects) or thick liquid (13 subjects). Sagittal and axial images were analyzed. Flow patterns in the UES were assessed on cross-sectional images. Annular flow was seen in the majority of subjects with thin liquid but few with thick liquid swallows. The percentage of Annular flow during UES opening was 3 ml 58%, 10 ml 58%, 20 ml 56% in thin and 3 ml 0%, 10 ml 4%, 20 ml 1% in thick. Annular flow was usually observed from the second or third frames after onset of UES opening. The other pattern, Plug flow was seldom seen with thin but was typical with thick liquid swallows. Annular flow was the most common pattern for thin liquids (but not thick liquids) passing through the UES. Annular flow has been defined as a liquid continuum adjacent to the channel wall with a gas continuum (core) in the center of the channel. The two regions are demarcated by a gas–liquid interface. Annular flow is typical for two-phase gas–liquid flow in a vertical or inclined channel. It results from the interaction of viscosity with cohesive and adhesive forces in the two phases. We infer that the difference in flow pattern between thin liquid–air and thick liquid–air boluses resulted from the differing magnitudes of viscous forces.
BACKGROUND:Millions of patients are discharged from intensive care units annually. These intensive care survivors and their families frequently report a wide range of impairments in their health ...status which may last for months and years after hospital discharge.
OBJECTIVES:To report on a 2-day Society of Critical Care Medicine conference aimed at improving the long-term outcomes after critical illness for patients and their families.
PARTICIPANTS:Thirty-one invited stakeholders participated in the conference. Stakeholders represented key professional organizations and groups, predominantly from North America, which are involved in the care of intensive care survivors after hospital discharge.
DESIGN:Invited experts and Society of Critical Care Medicine members presented a summary of existing data regarding the potential long-term physical, cognitive and mental health problems after intensive care and the results from studies of postintensive care unit interventions to address these problems. Stakeholders provided reactions, perspectives, concerns and strategies aimed at improving care and mitigating these long-term health problems.
MEASUREMENTS AND MAIN RESULTS:Three major themes emerged from the conference regarding(1) raising awareness and education, (2) understanding and addressing barriers to practice, and (3) identifying research gaps and resources. Postintensive care syndrome was agreed upon as the recommended term to describe new or worsening problems in physical, cognitive, or mental health status arising after a critical illness and persisting beyond acute care hospitalization. The term could be applied to either a survivor or family member.
CONCLUSIONS:Improving care for intensive care survivors and their families requires collaboration between practitioners and researchers in both the inpatient and outpatient settings. Strategies were developed to address the major themes arising from the conference to improve outcomes for survivors and families.
Abstract Purpose The aim of this study was to describe the frequency, physiologic effects, safety, and patient outcomes associated with traditional rehabilitation therapy in patients who require ...mechanical ventilation. Materials and Methods Prospective observational report of consecutive patients ventilated 4 or more days and eligible for rehabilitation in a single medical intensive care unit (ICU) during a 13-week period was conducted. Results Of the 32 patients who met the inclusion criteria, only 21 (66%) received physician orders for evaluation by rehabilitation services (physical and/or occupational therapy). Fifty rehabilitation treatments were provided to 19 patients on a median of 12% of medical ICU days per patient, with deep sedation and unavailability of rehabilitation staff representing major barriers to treatment. Physiologic changes during rehabilitation therapy were minimal. Joint contractures were frequent in the lower extremities and did not improve during hospitalization. In 53% and 79% of initial ICU assessments, muscle weakness was present in upper and lower extremities, respectively, with a decreased prevalence of 19% and 43% at hospital discharge, respectively. New impairments in physical function were common at hospital discharge. Conclusions This pilot project illustrated important barriers to providing rehabilitation to mechanically ventilated patients in an ICU and impairments in strength, range of motion, and functional outcomes at hospital discharge.
Interstitial fibrosis (IF), tubular atrophy (TA) and interstitial inflammation (II) are known determinants of progression of renal disease. Standardized quantification of these features could add ...value to current classification of glomerulopathies.
We studied 315 participants in the Nephrotic Syndrome Study Network (NEPTUNE) study, including biopsy-proven minimal change disease (MCD = 98), focal segmental glomerulosclerosis (FSGS = 121), membranous nephropathy (MN = 59) and IgA nephropathy (IgAN = 37). Cortical IF, TA and II were quantified (%) on digitized whole-slide biopsy images, by five pathologists with high inter-reader agreement (intra-class correlation coefficient >0.8). Tubulointerstitial messenger RNA expression was measured in a subset of patients. Multivariable Cox proportional hazards models were fit to assess association of IF with the composite of 40% decline in estimated glomerular filtration rate (eGFR) and end-stage renal disease (ESRD) and separately as well, and with complete remission (CR) of proteinuria.
IF was highly correlated with TA (P < 0.001) and II (P < 0.001). Median IF varied by diagnosis: FSGS 17, IgAN 21, MN 7, MCD 1 (P < 0.001). IF was strongly correlated with baseline eGFR (P < 0.001) and proteinuria (P = 0.002). After adjusting for clinical pathologic diagnosis, age, race, global glomerulosclerosis, baseline proteinuria, eGFR and medications, each 10% increase in IF was associated with a hazard ratio of 1.29 (P < 0.03) for ESRD/40% eGFR decline, but was not significantly associated with CR. A total of 981 genes were significantly correlated with IF (|r| > 0.4, false discovery rate (FDR) < 0.01), including upstream regulators such as tumor necrosis factor, interferon gamma (IFN-gamma), and transforming growth factor beta 1 (TGF-B1), and signaling pathways for antigen presentation and hepatic fibrosis.
The degree of IF is associated with risk of eGFR decline across different types of proteinuric glomerulopathy, correlates with inflammatory and fibrotic gene expression, and may have predictive value in assessing risk of progression.
The application of deep learning for automated segmentation (delineation of boundaries) of histologic primitives (structures) from whole slide images can facilitate the establishment of novel ...protocols for kidney biopsy assessment. Here, we developed and validated deep learning networks for the segmentation of histologic structures on kidney biopsies and nephrectomies. For development, we examined 125 biopsies for Minimal Change Disease collected across 29 NEPTUNE enrolling centers along with 459 whole slide images stained with Hematoxylin & Eosin (125), Periodic Acid Schiff (125), Silver (102), and Trichrome (107) divided into training, validation and testing sets (ratio 6:1:3). Histologic structures were manually segmented (30048 total annotations) by five nephropathologists. Twenty deep learning models were trained with optimal digital magnification across the structures and stains. Periodic Acid Schiff-stained whole slide images yielded the best concordance between pathologists and deep learning segmentation across all structures (F-scores: 0.93 for glomerular tufts, 0.94 for glomerular tuft plus Bowman’s capsule, 0.91 for proximal tubules, 0.93 for distal tubular segments, 0.81 for peritubular capillaries, and 0.85 for arteries and afferent arterioles). Optimal digital magnifications were 5X for glomerular tuft/tuft plus Bowman’s capsule, 10X for proximal/distal tubule, arteries and afferent arterioles, and 40X for peritubular capillaries. Silver stained whole slide images yielded the worst deep learning performance. Thus, this largest study to date adapted deep learning for the segmentation of kidney histologic structures across multiple stains and pathology laboratories. All data used for training and testing and a detailed online tutorial will be publicly available.
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