The particulate guanylyl cyclase A receptor (GC-A), via activation by its endogenous ligands atrial natriuretic peptide (ANP) and b-type natriuretic peptide (BNP), possesses beneficial biological ...properties such as blood pressure regulation, natriuresis, suppression of adverse remodeling, inhibition of the renin-angiotensin-aldosterone system, and favorable metabolic actions through the generation of its second messenger cyclic guanosine monophosphate (cGMP). Thus, the GC-A represents an important molecular therapeutic target for cardiovascular disease and its associated risk factors. However, a small molecule that is orally bioavailable and directly targets the GC-A to potentiate cGMP has yet to be discovered. Here, we performed a cell-based high-throughput screening campaign of the NIH Molecular Libraries Small Molecule Repository, and we successfully identified small molecule GC-A positive allosteric modulator (PAM) scaffolds. Further medicinal chemistry structure-activity relationship efforts of the lead scaffold resulted in the development of a GC-A PAM, MCUF-651, which enhanced ANP-mediated cGMP generation in human cardiac, renal, and fat cells and inhibited cardiomyocyte hypertrophy in vitro. Further, binding analysis confirmed MCUF-651 binds to GC-A and selectively enhances the binding of ANP to GC-A. Moreover, MCUF-651 is orally bioavailable in mice and enhances the ability of endogenous ANP and BNP, found in the plasma of normal subjects and patients with hypertension or heart failure, to generate GC-A-mediated cGMP ex vivo. In this work, we report the discovery and development of an oral, small molecule GC-A PAM that holds great potential as a therapeutic for cardiovascular, renal, and metabolic diseases.
To examine the association between the Centers for Disease Control and Prevention (CDC)'s Social Vulnerability Index (SVI) and COVID-19 incidence among Louisiana census tracts.
An ecological study ...comparing the CDC SVI and census tract-level COVID-19 case counts was conducted. Choropleth maps were used to identify census tracts with high levels of both social vulnerability and COVID-19 incidence. Negative binomial regression with random intercepts was used to compare the relationship between overall CDC SVI percentile and its four sub-themes and COVID-19 incidence, adjusting for population density.
In a crude stratified analysis, all four CDC SVI sub-themes were significantly associated with COVID-19 incidence. Census tracts with higher levels of social vulnerability were associated with higher COVID-19 incidence after adjusting for population density (adjusted RR: 1.52, 95% CI: 1.41-1.65).
The results of this study indicate that increased social vulnerability is linked with COVID-19 incidence. Additional resources should be allocated to areas of increased social disadvantage to reduce the incidence of COVID-19 in vulnerable populations.
To clarify how work and non-work role conflicts are processed and produce psychological change, we propose an integrative theory of work-family conflict (WFC) episode processing. We clarify ...ambiguities around the meaning of WFC, overcome questionable research assumptions, make testable counter-normative predictions, reconcile “levels” and “episodes” WFC conceptions, and explain how WFC can even have a net positive effect for the person. In the model, a trigger event causes a perceived WF role incompatibility and a negative change in core affect, prompting either a scripted response or controlled sensemaking. In the latter, cognitive appraisals and secondary affect ensue, causing a choice of a coping/resolution response. Responses are reinforced/punished, and possibly, consciously evaluated. Episodes end with the potential storage of outputs in long-term memory. State inputs to an episode condition processing and memory storage. Stored episode outputs can thereafter become inputs to future episodes and/or cause longer-term change in role performance, satisfaction, and well-being. After describing these processes, we suggest new directions for WFC research and practice.
•clarifies the definition of WFC as a discrete occurrence of WF incompatibility.•provides precise theoretical description of WFC processing.•models appraisal, resolution, memory instead of treating these as error.•posits successful episode resolution as key mediator vs. frequency or intensity.•suggests several new directions for empirical research and practice.
Abstract
BACKGROUND
Patients recovering from decompressive laminectomy without fusion may require assistance with activities of daily living and physical/occupational therapy upon hospital discharge.
...OBJECTIVE
To examine comorbidities and perioperative characteristics of patients undergoing lumbar decompression for associations with discharge status using a multicenter database.
METHODS
A multicenter database was used for this retrospective cohort analysis. Patients admitted from home with degenerative spine disease for lumbar decompression without fusion were included. Thirty-day outcomes and operative characteristics were compared as a function of patient discharge using chi-square and Wilcoxon Rank Sum tests. Multivariable logistic regression was used to determine factors associated with discharge to a nonhome facility.
RESULTS
Of the 8627 patients included for analysis, 9.7% were discharged to a nonhome facility. On multivariable analysis, age (85+ vs <65, odds ratio OR 13.59), number of levels of decompression (3+ vs 1, OR 1.75), African American race vs Non-Hispanic or Hispanic White (OR 1.87), female vs male gender (OR 1.97), body mass index (BMI) (40+ vs 18.5-24.9, OR 1.74), American Society of Anesthesiologists physical classification status (4 vs 1 or 2, OR 2.35), hypertension (OR 1.29), dependent functional status (OR 3.92), diabetes (OR 1.47), smoking (OR 1.40), hematocrit (<35 vs 35+, OR 1.76), international normalized ratio (≥1.3 vs <1.3, OR 2.32), and operative time (3+ h vs <1 h, OR 5.34) were significantly associated with an increased odds of discharge to nonhome facilities.
CONCLUSION
Preoperative status and operative course variables can influence discharge disposition in lumbar decompression patients. Identifying specific factors that contribute to a greater likelihood of dismissal to skilled facility or rehabilitation unit can further inform both surgeons and patients during preoperative counseling and disposition planning.
Neovascularization is the pathological driver of blinding eye diseases such as retinopathy of prematurity, proliferative diabetic retinopathy, and wet age-related macular degeneration. The loss of ...vision resulting from these diseases significantly impacts the productivity and quality of life of patients, and represents a substantial burden on the health care system. Current standard of care includes biologics that target vascular endothelial growth factor (VEGF), a key mediator of neovascularization. While anti-VGEF therapies have been successful, up to 30% of patients are non-responsive. Therefore, there is a need for new therapeutic targets, and small molecule inhibitors of angiogenesis to complement existing treatments. Apelin and its receptor have recently been shown to play a key role in both developmental and pathological angiogenesis in the eye. Through a cell-based high-throughput screen, we identified 4-aminoquinoline antimalarial drugs as potent selective antagonists of APJ. The prototypical 4-aminoquinoline, amodiaquine was found to be a selective, non-competitive APJ antagonist that inhibited apelin signaling in a concentration-dependent manner. Additionally, amodiaquine suppressed both apelin-and VGEF-induced endothelial tube formation. Intravitreal amodaiquine significantly reduced choroidal neovascularization (CNV) lesion volume in the laser-induced CNV mouse model, and showed no signs of ocular toxicity at the highest doses tested. This work firmly establishes APJ as a novel, chemically tractable therapeutic target for the treatment of ocular neovascularization, and that amodiaquine is a potential candidate for repurposing and further toxicological, and pharmacokinetic evaluation in the clinic.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Decompressive craniectomy (DC) is the definitive neurosurgical treatment for managing refractory malignant cerebral edema and intracranial hypertension due to combat-related severe traumatic brain ...injury (TBI). To date, the long-term outcomes and sequelae of this procedure on host-country national (HCN) populations during Operation Iraqi Freedom (Iraq, 2003-2011), Operation Enduring Freedom (Afghanistan, 2001-2014), and Operation Freedom's Sentinel (Afghanistan, 2015-2021) have not been described, specifically the process and results of delayed custom synthetic cranioplasty. The Joint Trauma System's Clinical Practice Guidelines (JTS-CPG) for severe head injury counsels surgeons to discard the cranial osseous explant when treating coalition service members. Ongoing political and healthcare system instabilities often preclude opportunities for delayed cranioplasty by host-country assets. Various surgical options (such as hinge craniectomy) are inadequate in the setting of complicated cranial comminution from blast or missile injuries, severe cerebral edema, grossly contaminated wounds, complex polytrauma, and tissue devitalization. Delayed cranioplasty with a custom synthetic implant is a viable but logistically challenging alternative. In this retrospective review, the authors present the first patient series describing delayed custom synthetic cranioplasty in an HCN population performed during active military conflict.
Patients were identified through the Joint Trauma System/Theater Medical Data Store, and subgroup analyses were performed to include mechanisms of injury, surgical complications, and clinical outcomes.
Twenty-five patients underwent DC between 2012 and 2020 to treat penetrating, blast, and high-energy closed head injuries per JTS-CPG criteria. The average time from injury to surgery was 1.4 days, although 6 patients received delayed care (3-6 days) due to protracted evacuation from local hospitals. Delayed care correlated with an increased rate of intracranial abscess and empyema. The average time to cranioplasty was 134 days due to a lack of robust mechanisms for patient follow-up, tracking, and access to NATO hospitals. HCN patients who recovered from DC demonstrated overall benefit from custom synthetic cranioplasty, although formal statistical analysis was impeded by a lack of long-term follow-up.
This review demonstrates that cranioplasty with a custom synthetic implant is a safe and feasible treatment for vulnerable HCN patients who survive their index DC surgery. This unique paradigm of care highlights the capabilities of deployed neurosurgical healthcare teams working in partnership with the prosthetics laboratory at Walter Reed National Military Medical Center.
Abstract The aim of this study was to test the hypothesis that diabetes mellitus (DM) is associated with an increased prevalence of chronic low back pain (CLBP) in the general population. We analyzed ...data for 5106 adults (4591 without DM & 515 with diagnosed DM), who were part of the National Health and Nutrition Examination Survey (NHANES) from 2009 through 2010. Adults with DM were older (mean age 54.2 years' vs 42.1 years), more likely to be obese (BMI > 30, 69.5% vs 33.3%), less educated (college or above 44.4% vs 57.3%), had a lower annual income (<$20,000, 16.8% vs 13.4%), were more likely to be a former smoker (31.5% vs 20.9%), less physically active (43.5% vs 59.4%). The prevalence of CLBP was 19.8% in adults with DM vs. 12.9% in adults without DM (age-adjusted OR 1.46; 95% CI, 1.00–1.94, P = 0.050). After the adjustments for CLBP's known risk factors, the association remained significant (OR 1.39; 95% CI, 1.02–1.92, P = 0.041). Adults with DM have a higher prevalence of CLBP. Further research is needed to examine the association and pathophysiology of DM and CLBP as well as the role of shared risk factors. Summary Adults with diabetes have higher prevalence of chronic low back pain (CLBP), and higher odds of CLBP after adjusting for LBP risk factors
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NAD+ is a crucial cellular factor that plays multifaceted roles in wide ranging biological processes. Low levels of NAD+ have been linked to numerous diseases including metabolic ...disorders, cardiovascular disease, neurodegeneration, and muscle wasting disorders. A novel strategy to boost NAD+ is to activate nicotinamide phosphoribosyltransferase (NAMPT), the putative rate-limiting step in the NAD+ salvage pathway. We previously showed that NAMPT activators increase NAD+ levels in vitro and in vivo. Herein we describe the optimization of our NAMPT activator prototype (SBI-0797812) leading to the identification of 1-(4-((4-chlorophenyl)sulfonyl)phenyl)-3-(oxazol-5-ylmethyl)urea (34) that showed far more potent NAMPT activation and improved oral bioavailability.
Background:
The effect of tibiotalar joint line level (TTJL) on patient outcomes following total ankle arthroplasty (TAA) remains unclear. It was previously reported that patients with end-stage ...ankle arthritis have an elevated TTJL compared with nonarthritic ankles, and the TTJL post-TAA remains elevated compared with nonarthritic ankles. The objectives of this study were to (1) propose a reliable radiographic method to measure the TTJL absolute value and (2) determine the effect of TTJL alterations on tibiotalar range of motion (ROM) following TAA.
Methods:
A retrospective review was performed on patients who underwent TAA between January 2018 and April 2021 with a minimum of 1-year postoperative follow-up and complete perioperative ROM radiographs. Radiographic TTJL and ROM measurements were performed by 2 observers. The proposed TTJL measuring technique computes 4 measurements: high, low, center of the talus (center), and center of the axis (axis). Reliability of measurements and correlation between TTJL measurements and ROM were assessed.
Results:
A total of 33 patients were included. Postoperatively, 22 patients had a lowered TTJL compared to 11 patients with an elevated TTJL (2.2 ± 1.3 mm lowered vs 1.9 ± 1.2 mm elevated; P < .0001). Of the 4 TTJL measurements, 3 (low, center, axis) demonstrated a significant positive correlation between lowering the TTJL and improved tibiotalar dorsiflexion and 2 (low, axis) for total ROM (all P < .05). Plantarflexion was not significantly affected by TTJL alterations. Compared to patients with an elevated TTJL, patients with a lowered TTJL had improved tibiotalar dorsiflexion (8.8 vs 2.5 degrees; P = .0015) and total ROM (31.0 vs 22.9 degrees; P = .0191), respectively. The interrater reliability was nearly perfect (intraclass correlation r = 0.96-0.99).
Conclusion:
In this small series, we found that lowering the TTJL level may more closely reestablish the native TTJL and correlates with improved tibiotalar dorsiflexion and total ROM following TAA.
Level of Evidence:
Level IV, case series.
Highlights • Minimally invasive techniques are used in a variety of spine procedures. • Endoscopic discectomy can be either micro-endoscopic or full-endoscopic. • No difference was found in ...complications between endoscopic and open approaches. • Endoscopic approaches are safe and efficacious alternatives to traditional approaches.
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