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Maternal Risk Factors Do Not Correlate With AKI in Patients With Congenital Heart Disease (CHD)
No full textPurpose: Acute kidney injury (AKI) is a common complication in children who undergo cardiopulmonary bypass (CPB) and is correlated with longer hospital courses and worse outcomes. Several risk factors exist which increase the risk of AKI in pediatric populations, including premature birth, congenital heart disease (CHD), and prolonged CPB time. Maternal risk factors can impair nephrogenesis in utero, thereby increasing the likelihood for developing AKI. However, it is yet to be shown if maternal risk factors lead to an increased incidence in AKI in pediatric patients with CHD who undergo CPB. We examine the incidence of four maternal risk factors—pre-eclampsia, maternal hypertension, gestational diabetes mellitus, and maternal smoking—in 252 pediatric CHD patients who underwent CPB surgery. The purpose of this project was to examine the incidence and predictors of AKI in pediatric patients who underwent cardiopulmonary bypass (CPB) surgery at our institution. We hypothesize an association between maternal risk factors and AKI incidence in pediatric patients with CHD who underwent CPB surgery. Methods: We performed a retrospective study on 252 patients who underwent CPB for repair of a CHD between March1, 2020, and March 1, 2022. Patients were between ages 0-12 months at time of surgery and received care in the cardiac intensive care unit (CICU). P-value of 0.05 was used to determine statistical significance. NGAL levels and Cystatin C levels were also obtained. Results: Forty-four patients (17.5%) developed AKI by KDIGO criteria, with only 2.4% of those meeting stage 2 or 3 AKI. Fifty-one (24%) patients demonstrated elevated urine NGAL levels after bypass (>125). Eighteen patients (8.4%) had elevated levels of Cystatin C. Pre-eclampsia was not protective in regards to AKI in our population. Maternal smoking, maternal gestational diabetes and maternal hypertension did not correlate with development of AKI in children with CHD undergoing CPB. Conclusion: We found no association between maternal risk factors and AKI incidence in CHD patients undergoing CPB surgery in this cohort. Elevated NGAL levels and Cystatin C levels following CPB did not individually correlate with increased odds of developing AKI
Demonstration of Steroid Atrophy From Chronic Topical Steroid Use in Various Fitzpatrick Skin Types
No full textBackground:
Topical steroids are commonly prescribed first-line medications for various inflammatory and autoimmune dermatologic conditions. Their widespread use raises the importance of proper use. Topical steroids have well-known side effects including skin atrophy, redness, striae, and telangiectasias. These side effects have not been well documented in patients of various skin tones. Primary care clinicians must recognize topical steroid side effects and their appearance in various skin tones. This paper will focus on representing skin atrophy, the most common steroid side effect, in a variety of Fitzpatrick skin types.
Case Presentation:
We present a series of images illustrating skin atrophy after prolonged topical steroid use on various Fitzpatrick skin types. The first case shows Fitzpatrick V skin with areas of erythema, hypopigmentation, and hyperpigmentation on the trunk. The second case presents thin skin with bright erythema and purpuric papules on the upper extremities of Fitzpatrick II skin. A third case showcases symmetric, parallel, linear, maroon dermal scars perpendicular to tension lines in the background of epidermal atrophy circum-anally and on the buttocks of Fitzpatrick IV skin. A fourth case exhibits Fitzpatrick III skin with shiny, thin skin and patches of hypopigmentation and telangiectasias on bilateral cheeks. The fifth case is a Fitzpatrick IV skin type with plaque psoriasis on the lower extremity and a background of skin thinning, hypopigmentation, and visible underlying vasculature from chronic topical steroid use. The final case represents Fitzpatrick VI skin with pyoderma gangrenosum, atrophied skin with overt hypopigmented patches adjacent to a cribriform scar. These cases feature the diverse presentations of skin atrophy on different Fitzpatrick skin types.
Conclusion:
Steroid atrophy is the most common side effect of chronic topical steroid use. Topical steroids are widely used for dermatologic conditions such as atopic dermatitis and plaque psoriasis. Steroids work to quell these inflammatory and autoimmune conditions and are overall tolerated well with proper use. Overuse of topical steroids is common and can cause known side effects of skin atrophy, erythema, striae, and telangiectasias. Recognition of steroid overuse requires knowledge of its presentation in various skin tones. In lighter skin types, atrophy is apparent with visible underlying vasculature and bright red erythema. In darker skin types, atrophy is more subtle and underlying vasculature may appear burgundy or maroon. Awareness of these differences in presentation will allow for quick recognition and immediate cessation of steroid use to prevent further side effects
Structure-Activity Relationship Studies in a Series of 2-Aryloxy-N-(pyrimidin-5-yl)acetamide Inhibitors of SLACK Potassium Channels
No full textEpilepsy of infancy with migrating focal seizures (EIMFS) is a rare, serious, and pharmacoresistant epileptic disorder often linked to gain-of-function mutations in the KCNT1 gene. KCNT1 encodes the sodium-activated potassium channel known as SLACK, making small molecule inhibitors of SLACK channels a compelling approach to the treatment of EIMFS and other epilepsies associated with KCNT1 mutations. In this manuscript, we describe a hit optimization effort executed within a series of 2-aryloxy-N-(pyrimidin-5-yl)acetamides that were identified via a high-throughput screen. We systematically prepared analogs in four distinct regions of the scaffold and evaluated their functional activity in a whole-cell, automated patch clamp (APC) assay to establish structure-activity relationships for wild-type (WT) SLACK inhibition. Two selected analogs were also profiled for selectivity versus other members of the Slo family of potassium channels, of which SLACK is a member, and versus a panel of structurally diverse ion channels. The same two analogs were evaluated for activity versus the WT mouse channel as well as two clinically relevant mutant human channels.This research was funded by the National Institute of Neurological Disorders and Stroke, grant number R33NS109521 (C.D.W. and K.A.E.). Portions of this work have been supported by certain funds managed by Deerfield Management Company, L.P. Funding for theWaveFront Biosciences Panoptic and the Syncropatch 768 PE platform was provided by the Office of The Director (OD) of the National Institutes of Health under the award numbers 1S10OD021734 and 1S10OD021734, respectively. These instruments are housed and maintained in the Vanderbilt Institute of Chemical Biology's High-throughput Screening Center
Consensus Recommendations for Studies of Outflow Facility and Intraocular Pressure Regulation Using Ex Vivo Perfusion Approaches
No full textIntraocular pressure (IOP) elevation is the primary risk factor and currently the main treatable factor for progression of glaucomatous optic neuropathy. In addition to direct clinical and living animal in vivo studies, ex vivo perfusion of anterior segments and whole eyes is a key technique for studying conventional outflow function as it is responsible for IOP regulation. We present well-tested experimental details, protocols, considerations, advantages, and limitations of several ex vivo model systems for studying IOP regulation. These include: (1) perfused whole globes, (2) stationary anterior segment organ culture, (3) perfused human anterior segment organ culture, (4) perfused animal anterior segment organ culture, (5) perfused human corneal rims, and (6) perfused human anterior segment wedges. These methods, with due consideration paid to their strengths and limitations, comprise a set of very strong tools for extending our understanding of IOP regulation.Supported by grants from the National Eye Institute, National Institutes of Health (EY030238 to TSA; EY025721 to TSA; EY010572 to TSA and KEK; EY026048 to TSA and VKR; EY008247 to TSA; EY003279 to TSA; EY021800 to MJK; EY031071 to MJK; EY030501 to ASH; EY033015 to KSN; EY026529 to CMM; EY031631 to YL; EY033961 to YL; EY023242 to YL; EY032960 to YL; EY028671 to YL; EY014800 to DK; EY027920 to DK; EY031817 to DK; EY002423 to DK; EY021205 to RLL; EY026885 to PL; EY033600 to PL; EY034096 to SH; EY022634 to HG; EY025643 to YD; EY026962 to WM; EY031700 to WM; EY033929 to WM; EY036011 to AK); The BrightFocus Foundation; Research to Prevent Blindness; Aerie Pharmaceuticals; Glaukos Corporation; Glaucoma Research Foundation; Western Glaucoma Foundation; Lewis Rudin Glaucoma Prize to MJK); and Allergan by AbbVie. Disclosure: T.S. Acott, None; M.P. Fautsch, None; W. Mao, Arrowhead Pharmaceuticals (C); C.R. Ethier, None; A.S. Huang, None; M.J. Kelley, None; M. Aga, None; S.K. Bhattacharya, None; T. Borras, None; D. Bovenkamp, None; U.R. Chowdhury, None; A.F. Clark, None; M.I. Dibas, None; Y. Du, None; M.H. Elliott, None; J.A. Faralli, None; H. Gong, None; S. Herberg, None; M.A. Johnstone, None; P.L. Kaufman, None; K.E. Keller, None; R.A. Kelly, None; D. Krizaj, None; M.H. Kuehn, None; H.L. Li, None; R. Lieberman, None; S.C. Lin, None; Y. Liu, None; F.S. McDonnell, None; C.M. McDowell, None; G.J. McLellan, None; P. Mzyk, None; K.S. Nair, None; D.R. Overby, None; D.M. Peters, None; V.K. Raghunathan, None; P.V. Rao, None; G.W. Roddy, None; N.A. Sharif, None; M.S. Shim, None; Y. Sun, None; B.R. Thomson, None; C.B. Toris, None; C.E. Willoughby, None; H.F. Zhang, None; T.F. Freddo, None; R. Fuchshofer, None; K.R. Hill, None; A. Karimi, None; K. Kizhatil, None; C.C. Kopcyznski, None; P. Liton, None; G. Patel, None; M. Peng, None; P.P. Pattabiraman, None; G. Prasanna, None; E. Reina-Torres, None; E.G.Samples, None; J.R. Samples, None; C.L. Steel, None; C.A. Strohmaier, None; P. Subramanian, None; C.K. Sugali, None; J. van Batenburg-Sherwood, None; C. Wong, None; H. Youngblood, None; G.S. Zode, None; E. White, None; W.D. Stamer, Non
p21(Waf1/Cip1) Is a Novel Downstream Target of 40S Ribosomal S6 Kinase 2
No full textBackground/Objectives: The ribosomal S6 kinase 2 (S6K2) acts downstream of the mechanistic target of rapamycin complex 1 and is a homolog of S6K1 but little is known about its downstream effectors. The objective of this study was to use an unbiased transcriptome profiling to uncover how S6K2 promotes breast cancer cell survival. Methods: RNA-Seq analysis was performed to identify novel S6K2 targets. Cells were transfected with siRNAs or plasmids containing genes of interest. Western blot analyses were performed to quantify total and phosphorylated proteins. Apoptosis was monitored by treating cells with different concentrations of doxorubicin. Results: Silencing of S6K2, but not S6K1, decreased p21 in MCF-7 and T47D breast cancer cells. Knockdown of Akt1 but not Akt2 decreased p21 in MCF-7 cells whereas both Akt1 and Akt2 knockdown attenuated p21 in T47D cells. While Akt1 overexpression enhanced p21 and partially reversed the effect of S6K2 deficiency on p21 downregulation in MCF-7 cells, it had little effect in T47D cells. S6K2 knockdown increased JUN mRNA and knockdown of cJun enhanced p21. Low concentrations of doxorubicin increased, and high concentrations decreased p21 levels in T47D cells. Silencing of S6K2 or p21 sensitized T47D cells to doxorubicin via c-Jun N-terminal kinase (JNK)-mediated downregulation of Mcl-1. Conclusions: S6K2 knockdown enhanced doxorubicin-induced apoptosis by downregulating the cell cycle inhibitor p21 and the anti-apoptotic protein Mcl-1 via Akt and/or JNK.Z.X. was supported by NIH R01 NS096068, and NIH R01 NS114018
The effects of mosaicism on biological and clinical markers of Alzheimer's disease in adults with Down syndrome
No full textBACKGROUND: Individuals with Down syndrome (DS) are at high risk of early-onset Alzheimer's disease (AD); yet, some 20 percent do not develop any signs of dementia until after 65 years or in their lifetime. Mosaicism could contribute to this phenotypic variation, where some disomic cells could lead to lower levels of gene products from chromosome 21. METHODS: We examined longitudinal neuropsychological and biomarker data from two large studies of DS: the Alzheimer Biomarker Consortium-Down syndrome study (ABC-DS) (n = 357); and a legacy study (n = 468). We assessed mosaicism using karyotyping or GWAS data. Participants had data on plasma AD biomarkers (Abeta(40), Abeta(42), tau, and NfL) and longitudinal cognitive measures. A subset had cerebrospinal fluid biomarkers (Abeta(40), Abeta(42), tau, ptau181, and NfL) and amyloid and tau PET data. FINDINGS: For both cohorts, the prevalence of mosaicism was <10% (ABC-DS: 7.3%; Legacy: 9.6%), and those with mosaicism had lower plasma Abeta(40) and Abeta(42) concentrations. For the older legacy cohort, when compared to those with full trisomy, those with mosaicism had significantly smaller decline in total and annualized neurocognitive scores, and lower incidence and prevalence of dementia. INTERPRETATION: Mosaicism in DS was associated with lower concentrations of plasma Abeta peptides, possibly leading to lower AD risk. However, its clinical impact was less clear in the younger ABC-DC cohort, and a follow-up study is warranted. FUNDING: National Institutes of Health (R01AG014673, P01HD035897, R56AG061837), NIA (U01AG051412, U19AG068054), NICHD, ADRC programs, the Eunice Kennedy Shriver Intellectual and Developmental Disabilities Research Centers Program, and NCATS (UL1TR001873).The Alzheimer's Biomarkers Consortium–Down Syndrome (ABC-DS) is funded by the National Institute on Aging and the National Institute of Child Health and Human Development (U01 AG051406, U01 AG051412, U19 AG068054). In addition, the work contained in this publication was also supported through the additional National Institutes of Health supports: R01 AG014673, P01 HD035897, U54 HD079123, and R56 AG061837; The Alzheimer's Disease Research Centers Program (P50 AG008702, P30 AG062421, P50 AG16537, P50 AG005133, P50 AG005681, P30 AG062715, and P30 AG066519); the Eunice Kennedy Shriver Intellectual and Developmental Disabilities Research Centers Program (U54 HD090256, U54 HD087011, and P50 HD105353); the National Center for Advancing Translational Sciences (UL1 TR001873, UL1 TR002373, UL1 TR001414, UL1 TR001857, Disease and Related Dementias (U24 AG21886); and DS-Connect® (The Down Syndrome Registry) supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), and by NYS through its Office for People with Developmental Disabilities. In Cambridge, UK this research was supported by the NIHR Cambridge Biomedical Research Centre and the Windsor Research Unit, CPFT, Fulbourn Hospital Cambridge, UK. The authors are grateful to the ABC-DS and the legacy study participants, their families and care providers, and the ABC-DS and the legacy research and support staff for their contributions to this study. This manuscript has been reviewed by ABC-DS investigators for scientific content and consistency of data interpretation with previous ABC-DS study publications. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH, the CPFT, the NIHR or the UK Department of Health and Social Care
In Silico Analysis Determining the Binding Interactions of NAD(P)H: Quinone Oxidoreductase 1 and Resveratrol via Docking and Molecular Dynamic Simulations
No full textOBJECTIVE: NAD(P)H: Quinone oxidoreductase1 (NQO1) plays a crucial role in cellular defense against oxidative stress. Overexpression of NQO1 is linked to various cancer pathways. Despite its potential, the actual mechanisms to inhibit NQO1 and increase the efficacy of standard therapeutic options are not yet established. Resveratrol is an anti-cancer polyphenol found in dietary products and red wine. The objective of this investigation is to employ in silico methods to explore how resveratrol interacts with NQO1. MATERIALS AND METHODS: Docking analysis of resveratrol against NQO1 was performed using Glide. The most efficiently docked complex was characterized and analyzed by measuring intermolecular (IM) hydrogen (H)-bonds and binding energy values, additional hydrophobic, and electrostatic interactions. IM interaction between complexed protein and compound was demonstrated using LigPlot+ and the Schrodinger ligand interaction module. Molecular dynamics tools were employed to examine the physical movement of molecules to evaluate how macromolecular structures relate to their functions. RESULTS: The results of this investigation depicted a strong affinity of resveratrol against NQO1 followed by MD simulations (NQO1-resveratrol complex-binding energy: -2.847kcal/mol). Resveratrol's robust binding affinity through docking and molecular dynamic simulations highlights a significant change around 90 ns. The H-bonds number was inversely linked with the resveratrol-NQO1 complex stability. The NQO1-Resveratrol complex displayed dynamic motion, as revealed by porcupine projections, indicating alterations in its movement and flexibility. CONCLUSION: The present in silico analysis suggests a possible alteration in resveratrol's orientation in the protein binding pocket. The findings encourage further investigation, including validation using in vitro and in vivo assays.This work was partially supported by the National Institutes of Health [Award #: 1S21MD012472-01; Award #: 2U54MD006882-06 and the Cancer Prevention and Research Institute of Texas (Award #: RP210046
Potentiation of Sphingolipids and TGF-beta in the human corneal stroma reveals intricate signaling pathway crosstalks
No full textCorneal haze brought on by fibrosis due to insult can lead to partial or complete vision loss. Currently, corneal transplantation is the gold standard for treating severe corneal fibrosis, which comes with the risk of rejection and the issue of donor tissue shortages. Sphingolipids (SPLs) are known to be associated with fibrosis in various tissues and organs, including the cornea. We previously reported that SPLs are tightly related to Transforming Growth Factor beta (TGF-beta) signaling and corneal fibrogenesis. This study aimed to elucidate the interplay of SPLs, specifically sphingosine-1-phosphate (S1P) signaling, and its' interactions with TGF-beta signaling through detailed analyses of the corresponding downstream signaling targets in the context of corneal fibrosis, in vitro. Healthy human corneal fibroblasts (HCFs) were isolated, plated on polycarbonate membranes, and stimulated with a stable Vitamin C derivative. The 3D constructs were treated with either 5 muM sphingosine-1-phosphate (S1P), 5 muM SPHK I(2) (I(2); inhibitor of sphingosine kinase 1, one of the two enzymes responsible for generating S1P in mammalian cells), 0.1 ng/mL TGF-beta1, or 0.1 ng/mL TGF-beta3. Cultures with control medium-only served as controls. All 3D constructs were examined for protein expression of fibrotic markers, SPLs, TGF-betas, and relevant downstream signaling pathways. This data revealed no significant changes in any LTBP (latent TGF-beta binding proteins) expression when stimulated with S1P or I(2). However, LTBP1 was significantly upregulated via stimulation of TGF-beta1 and TGF-beta3, whereas LTBP2 was significantly upregulated only with TGF-beta3 stimulation. Significant downregulation of TGF-beta receptor II (TGF-betaRII) following S1P stimulation but significant upregulation following I(2) stimulation was observed. Following TGF-beta1, S1P, and I(2) stimulation, phospho-SMAD2 (pSMAD2) was significantly downregulated. Furthermore, I(2) stimulation led to significant downregulation of SMAD4. Adhesion/proliferation/transcription regulation targets, SRC, FAK, and pERK 1/2 were all significantly downregulated by exogenous S1P, whereas I(2) only significantly downregulated FAK. Exogenous TGF-beta3 caused significant upregulation of AKT. Interestingly, both I(2) and TGF-beta3 caused significant downregulation of JNK expression. Lastly, TGF-beta1 led to significant upregulation of sphingosine kinase 1 (SphK1) and sphingosine-1-phosphate receptor 3 (S1PR3), whereas TGF-beta3 caused significant upregulation of only SphK1. Together with previously published work from our group and others, S1P inhibition exhibits great potential as an efficacious anti-fibrotic modality in human corneal stromal ECM. The current findings shed further light on a very complex and rather incompletely investigated mechanism, and cement the intricate crosstalk between SPLs and TGF-beta in corneal fibrogenesis. Future studies will dictate the potential of utilizing SPLs/TGF-beta signaling modulators as novel therapeutics in corneal fibrosis.This study was supported by the National Eye Institute (NEI) grant EY031316
Primary care teams' reported actions to improve medication safety: a qualitative study with insights in high reliability organising
No full textBACKGROUND: Our aim was to understand actions by primary care teams to improve medication safety. METHODS: This was a qualitative study using one-on-one, semistructured interviews with the questions guided by concepts from collaborative care and systems engineering models, and with references to the care of older adults. We interviewed 21 primary care physicians and their team members at four primary care sites serving patients with mostly low socioeconomic status in Southwest US during 2019-2020. We used thematic analysis with a combination of inductive and deductive coding. First, codes capturing safety actions were incrementally developed and revised iteratively by a team of multidisciplinary analysts using the inductive approach. Themes that emerged from the coded safety actions taken by primary care professionals to improve medication safety were then mapped to key principles from the high reliability organisation framework using a deductive approach. RESULTS: Primary care teams described their actions in medication safety mainly in making standard-of-care medical decisions, patient-shared decision-making, educating patients and their caregivers, providing asynchronous care separate from office visits and providing clinical infrastructure. Most of the actions required customisation at the individual level, such as limiting the supply of certain medications prescribed and simplifying medication regimens in certain patients. Primary care teams enacted high reliability organisation principles by anticipating and mitigating risks and taking actions to build resilience in patient work systems. The primary care teams' actions reflected their safety organising efforts as responses to many other agents in multiple settings that they could not control nor easily coordinate. CONCLUSIONS: Primary care teams take many actions to shape medication safety outcomes in community settings, and these actions demonstrated that primary care teams are a reservoir of resilience for medication safety in the overall healthcare system. To improve medication safety, primary care work systems require different strategies than those often used in more self-contained systems such as hospital inpatient or surgical services.Support: Funding Source: Agency for Health Care Research and Quality. Project Title: PROMIS Learning Lab: Partnership in Resilience for Medication Safety. Federal Award Identification Number (FAIN): 1R18HS027277- 01. Project Period: 09/30/2019-09/29/2023. Funding Agency: Agency for Healthcare Research and Quality. Program Title: RFA- HS- 18- 001: Patient Safety Learning Laboratories: Pursuing Safety in Diagnosis and Treatment at the Intersection of Design, Systems Engineering, and Health Services Research (R18). COVID supplement: Project Title: Partnership for Medication Safety in Primary Care and Telehealth during COVID- 19 Public Health Crisis. Award Number: 3R18HS027277- 02S1. Budget Period: 01/01/2021-12/31/2021. Funding Agency: Agency for Healthcare Research and Quality. Program Title: PA- 20- 070: Competitive Revision Supplements to Existing AHRQ Health Service Research (HSR) Grants and Cooperative Agreements to Evaluate Health System and Healthcare Professional Responsiveness to COVID- 19
Identifying short term radiographic outcome of bone versus metallic augmented, central screw type baseplate in reverse total shoulder arthroplasty
Get PDFAlthough there are several ways to overcome severe glenoid deficiencies since the inception of Reverse Total Shoulder Arthroplasty (RTSA), treating them can be complicated. Current treatment options used at The Shoulder Center are glenoid bone graft and metallic augmented baseplates, and while both have demonstrated success in restoring the glenohumeral joint line in the recent literature, there remain no consensus guidelines defining the use of one versus the other. This study analyzes differences in efficacy between the two types of augments to evaluate whether profound differences in the incidence of baseplate failure between them exist. Patient demographics, comorbidities, and radiographs were analyzed to examine patient outcomes post-operatively and delineate the ideal augment for patients