Chronic Refractory Cough (CRC) is a common condition that significantly impairs patients' quality of life. Unfortunately, in many situations patients continue to experience CRC in spite of following ...published guidelines for diagnosis and treatment.
99 patients were referred to National Jewish Health (NJH), a specialty respiratory center for evaluation of CRC (cough ≥ 8 weeks duration). Study duration occurred over 18 months. Intake evaluation for all patients included history, physical examination, spirometry and fiberoptic laryngoscopy. Testing to confirm causes of CRC were performed. Specific therapy for each potential cause was provided. A visual analog cough scale measured cough response.
Ten final diagnostic categories were found in the cohort of 99 patients with CRC: Obstructive sleep apnea (apnea/hypoxia index ≥ 5), rhinosinusitis, Tracheobronchomalacia (≥65% collapse of airway with dynamic expiratory imaging), esophageal dysmotility, gastroesophageal reflux, abnormal swallowing with laryngeal penetration, asthma, COPD, bronchiectasis and paradoxical vocal cord movement. In these patients there were 42 incorrect intake diagnoses and 101 new diagnoses established. Patients with CRC have had multiple diagnoses (3.8 ± 1.6) associated with chronic cough. With directed therapy 71/76 (93%) patients had resolution or improvement in cough symptoms.
Among patients referred to a specialty respiratory center with CRC multiple concomitant diagnoses for cough were common. Certain diagnoses such as OSA and TBM have not been reported in cough guidelines but in this study are commonly associated diagnoses. Targeted therapy for each recognized diagnosis improves patient response.
•Chronic refractory cough is associated with multiple diagnoses.•TBM and OSA are frequently found in patients with CRC.•All potential causes of CRC should be treated.
Despite widespread clinical genetic testing, many individuals with suspected genetic conditions lack a precise diagnosis, limiting their opportunity to take advantage of state-of-the-art treatments. ...In some cases, testing reveals difficult-to-evaluate structural differences, candidate variants that do not fully explain the phenotype, single pathogenic variants in recessive disorders, or no variants in genes of interest. Thus, there is a need for better tools to identify a precise genetic diagnosis in individuals when conventional testing approaches have been exhausted. We performed targeted long-read sequencing (T-LRS) using adaptive sampling on the Oxford Nanopore platform on 40 individuals, 10 of whom lacked a complete molecular diagnosis. We computationally targeted up to 151 Mbp of sequence per individual and searched for pathogenic substitutions, structural variants, and methylation differences using a single data source. We detected all genomic aberrations—including single-nucleotide variants, copy number changes, repeat expansions, and methylation differences—identified by prior clinical testing. In 8/8 individuals with complex structural rearrangements, T-LRS enabled more precise resolution of the mutation, leading to changes in clinical management in one case. In ten individuals with suspected Mendelian conditions lacking a precise genetic diagnosis, T-LRS identified pathogenic or likely pathogenic variants in six and variants of uncertain significance in two others. T-LRS accurately identifies pathogenic structural variants, resolves complex rearrangements, and identifies Mendelian variants not detected by other technologies. T-LRS represents an efficient and cost-effective strategy to evaluate high-priority genes and regions or complex clinical testing results.
Summary
Epidemiologic studies indicate that the risks for major age‐related debilities including coronary heart disease, diabetes, and age‐related macular degeneration (AMD) are diminished in people ...who consume lower glycemic index (GI) diets, but lack of a unifying physiobiochemical mechanism that explains the salutary effect is a barrier to implementing dietary practices that capture the benefits of consuming lower GI diets. We established a simple murine model of age‐related retinal lesions that precede AMD (hereafter called AMD‐like lesions). We found that consuming a higher GI diet promotes these AMD‐like lesions. However, mice that consumed the lower vs. higher GI diet had significantly reduced frequency (P < 0.02) and severity (P < 0.05) of hallmark age‐related retinal lesions such as basal deposits. Consuming higher GI diets was associated with > 3 fold higher accumulation of advanced glycation end products (AGEs) in retina, lens, liver, and brain in the age‐matched mice, suggesting that higher GI diets induce systemic glycative stress that is etiologic for lesions. Data from live cell and cell‐free systems show that the ubiquitin–proteasome system (UPS) and lysosome/autophagy pathway lysosomal proteolytic system (LPS) are involved in the degradation of AGEs. Glycatively modified substrates were degraded significantly slower than unmodified substrates by the UPS. Compounding the detriments of glycative stress, AGE modification of ubiquitin and ubiquitin‐conjugating enzymes impaired UPS activities. Furthermore, ubiquitin conjugates and AGEs accumulate and are found in lysosomes when cells are glycatively stressed or the UPS or LPS/autophagy are inhibited, indicating that the UPS and LPS interact with one another to degrade AGEs. Together, these data explain why AGEs accumulate as glycative stress increases.
Abstract Background Identification of patients at risk of contrast-induced acute kidney injury (CI-AKI) is valuable for targeted prevention strategies accompanying cardiac catheterization. Methods We ...searched MedLine and EMBASE for articles that developed or validated a clinical prediction model for CI-AKI or dialysis after angiography or percutaneous coronary intervention. Random effects meta-analysis was used to pool c-statistics of models. Heterogeneity was explored using stratified analyses and meta-regression. Results We identified 75 articles describing 74 models predicting CI-AKI, 10 predicting CI-AKI and dialysis, and 1 predicting dialysis. Sixty-three developed a new risk model whereas 20 articles reported external validation of previously developed models. Thirty models included sufficient information to obtain individual patient risk estimates; 9 using only preprocedure variables whereas 21 included preprocedural and postprocedure variables. There was heterogeneity in the discrimination of CI-AKI prediction models (median total range in c-statistic 0.78 0.57-0.95; I2 = 95.8%, Cochran Q-statistic P < 0.001). However, there was no difference in the discrimination of models using only preprocedure variables compared with models that included postprocedural variables ( P = 0.868). Models predicting dialysis had good discrimination without heterogeneity (median total range c-statistic: 0.88 0.87-0.89; I2 = 0.0%, Cochran Q-statistic P = 0.981). Seven prediction models were externally validated; however, 2 of these models showed heterogeneous discriminative performance and 2 others lacked information on calibration in external cohorts. Conclusions Three published models were identified that produced generalizable risk estimates for predicting CI-AKI. Further research is needed to evaluate the effect of their implementation in clinical care.
Flue Gas Desulfurization (FGD) gypsum is a byproduct of the coal-fired power plant process commonly used to remove sulfur dioxide emissions from the flue gas. FGD gypsum has numerous industrial, ...agricultural, and environmental applications. This study aimed to explore a novel approach involving the use of FGD gypsum combined with different litter treatments as bedding for broiler production. It focused on performance metrics, including adjusted feed conversion ratio (AFCR) and average body weight (BW), foot pad dermatitis (FPD), and fear response over 5 consecutive flocks. A total of 1,800 one-day-old Ross 708 chicks were randomly assigned to 24 pens (75 birds/pen), divided into 6 treatment groups (4 pens/treatment), with 5 replications and raised until 42 d old (d). Treatments were gypsum that was decaked (D), rotovated (E), and rotovated then windrowed (F) between flocks. Control treatments using pine shavings were decaked (A), rotovated (B), and windrowed postrotovating (C). AFCR, average BW, and mortality were used as a measure of production. Foot pad dermatitis scores were taken on d42 using a scale of 0 (absence), 1 (mild), and 2 (severe). Response to observer and human approach test were used to measure fear response. Data were analyzed as a 2-way ANOVA (Proc Glimmix) for the main effects of bedding type and litter treatment. Means were identified using Tukey's HSD. No effect of bedding type or litter treatment was found for AFCR, BW, or mortality. FPD scores 2 and 1, were higher with pine shavings than gypsum (P = 0.01 and P = 0.01, respectively). While FPD scores 0 were higher for gypsum than the pine shaving (P = 0.01). No difference in fear response was found among birds raised on any of the gypsum litter treatments and any of the pine shaving litter treatments. Overall, the use of gypsum as bedding results in equivalent production and fear response to pine shavings, while increasing FPD quality when compared to pine shaving.
ABSTRACT Recent cosmological hydrodynamical simulations suggest that integral field spectroscopy can connect the high-order stellar kinematic moments h3 (∼skewness) and h4 (∼kurtosis) in galaxies to ...their cosmological assembly history. Here, we assess these results by measuring the stellar kinematics on a sample of 315 galaxies, without a morphological selection, using two-dimensional integral field data from the SAMI Galaxy Survey. Proxies for the spin parameter ( ) and ellipticity ( ) are used to separate fast and slow rotators; there exists a good correspondence to regular and non-regular rotators, respectively, as also seen in earlier studies. We confirm that regular rotators show a strong h3 versus anti-correlation, whereas quasi-regular and non-regular rotators show a more vertical relation in h3 and . Motivated by recent cosmological simulations, we develop an alternative approach to kinematically classify galaxies from their individual h3 versus signatures. Within the SAMI Galaxy Survey, we identify five classes of high-order stellar kinematic signatures using Gaussian mixture models. Class 1 corresponds to slow rotators, whereas Classes 2-5 correspond to fast rotators. We find that galaxies with similar values can show distinctly different signatures. Class 5 objects are previously unidentified fast rotators that show a weak h3 versus anti-correlation. From simulations, these objects are predicted to be disk-less galaxies formed by gas-poor mergers. From morphological examination, however, there is evidence for large stellar disks. Instead, Class 5 objects are more likely disturbed galaxies, have counter-rotating bulges, or bars in edge-on galaxies. Finally, we interpret the strong anti-correlation in h3 versus as evidence for disks in most fast rotators, suggesting a dearth of gas-poor mergers among fast rotators.
We investigate the physical cause of the great range in the ionization level seen in the spectra of narrow-lined active galactic nuclei (AGN). We used a recently developed technique called mean field ...independent component analysis to identify examples of individual Sloan Digital Sky Survey galaxies whose spectra are not dominated by emission due to star formation (SF), which we therefore designate as AGN. We assembled high signal-to-noise ratio (S/N) composite spectra of a sequence of these AGN defined by the ionization level of their narrow-line regions (NLR), and extending down to very low ionization cases. We then used a local optimally emitting cloud (LOC) model to fit emission-line ratios in this AGN sequence, including the weak lines that can be measured only in the co-added spectra. These weak line ratios provide consistency checks on the density, temperature, abundances and ionizing continuum of Seyfert galaxies determined from strong-line ratios. After integrating over a wide range of clouds at different radii and densities, our models indicate that the radial extent of the NLR is the major parameter in determining the position of higher to moderate ionization AGN along our sequence. This provides a physical interpretation for their systematic variation. Higher ionization AGN contain optimally emitting clouds that are more concentrated towards the central continuum source than in lower ionization AGN. Our LOC models indicate that for the special set of objects that lie on our AGN sequence, the ionizing luminosity is anti-correlated with the NLR ionization level, and hence anticorrelated with the radial concentration and actual physical extent of the NLR. A possible interpretation that deserves further exploration is that the ionization sequence might be an age sequence where low ionization objects are older and have systematically cleared out their central regions by radiation pressure. We consider the alternative that our AGN sequence instead represents a mixing curve combining SF and AGN spectra in different proportions, but argue that while many galaxies in fact do have this type of composite spectra, our AGN sequence appears to be a special set of objects with negligible SF excitation.
This paper presents the development and approach of a model-based fault identification and accommodation framework applied to sampled-data controlled distributed energy resources subject to control ...actuator faults. The main objective of the proposed approach is to handle faults that degrade stability as well as performance, while remaining robust to false alarms. The proposed method allows for dual fault detection and estimation, through the use of an embedded system model that minimizes the residual between the estimated and sampled states at each sampling period by adjusting a fault parameter in the embedded model over a past horizon. The resulting fault parameter estimate is then used by the control system to find an optimal fault accommodation strategy by minimizing a predefined performance metric whilst ensuring closed-loop stability. The developed fault accommodation framework is then applied to a simulated model of a solid oxide fuel cell subject to both stability and performance degrading faults in the control actuators. A discussion of some of the practical implementation issues associated with the developed framework is also included.
•A methodology for local monitoring and fault mitigation in DERs is developed.•The methodology integrates data with models to achieve timely fault estimation.•Both stability and performance are considered in the fault accommodation logic.•An application to a solid oxide fuel cell is presented.
Th1 and Th17 T cells are often colocalized in pathological environments, yet Th1-derived IFN-gamma inhibits Th17 cell development in vitro. We explored the physiologic basis of this paradox in ...humans. In this study, we demonstrate increased the number of CD4(+) and CD8(+) IL-17(+) T cells in skin lesions of psoriasis. Furthermore, we show that myeloid APCs potently support induction of IL-17(+) T cells, and that this activity is greatly increased in psoriasis. We tested stimuli that might account for this activity. Th1 cells and IFN-gamma are increased in psoriatic blood and lesional skin. We show that IFN-gamma programs myeloid APCs to induce human IL-17(+) T cells via IL-1 and IL-23. IFN-gamma also stimulates APC production of CCL20, supporting migration of IL-17(+) T cells, and synergizes with IL-17 in the production of human beta-defensin 2, an antimicrobial and chemotactic protein highly overexpressed by psoriatic keratinocytes. This study reveals a novel mechanistic interaction between Th1 and IL-17(+) T cells, challenges the view that Th1 cells suppress Th17 development through IFN-gamma, and suggests that Th1 and IL-17(+) T cells may collaboratively contribute to human autoimmune diseases.
Horseshoe kidneys are one of the most common congenital genitourinary malformations and can increase the complexity of common urologic procedures, especially nephrolithiasis. We present a patient who ...underwent robotic-assisted laparoscopic pyelolithotomy with intracorporeal pyeloscopy and stone basketing to treat a left lower pole stone burden located in a horseshoe kidney. This procedure provided benefits of expanded maneuverability, dexterity, and stability, which resulted in successful elimination of stone burden on post-operative imaging. We believe that robotic-assisted laparoscopic pyelolithotomy with intracorporeal pyeloscopy should be considered as a treatment option in similar cases of complicated nephrolithiasis due to complex renal anatomy.
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