RESUMEN
Small molecule neurotensin receptor 1 (NTSR1) agonists have been pursued for more than 40 years as potential therapeutics for psychiatric disorders, including drug addiction. Clinical development of NTSR1 agonists has, however, been precluded by their severe side effects. NTSR1, a G protein-coupled receptor (GPCR), signals through the canonical activation of G proteins and engages ß-arrestins to mediate distinct cellular signaling events. Here, we characterize the allosteric NTSR1 modulator SBI-553. This small molecule not only acts as a ß-arrestin-biased agonist but also extends profound ß-arrestin bias to the endogenous ligand by selectively antagonizing G protein signaling. SBI-553 shows efficacy in animal models of psychostimulant abuse, including cocaine self-administration, without the side effects characteristic of balanced NTSR1 agonism. These findings indicate that NTSR1 G protein and ß-arrestin activation produce discrete and separable physiological effects, thus providing a strategy to develop safer GPCR-targeting therapeutics with more directed pharmacological action.
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Conducta Adictiva/metabolismo , Receptores de Neurotensina/metabolismo , beta-Arrestinas/metabolismo , Regulación Alostérica/efectos de los fármacos , Regulación Alostérica/fisiología , Animales , Conducta Adictiva/tratamiento farmacológico , Línea Celular , Femenino , Células HEK293 , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Modelos Animales , Receptores Acoplados a Proteínas G/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Bibliotecas de Moléculas Pequeñas/farmacologíaRESUMEN
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.
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Fármacos Cardiovasculares , Enfermedades Cardiovasculares/metabolismo , GMP Cíclico/metabolismo , Péptidos Natriuréticos/metabolismo , Receptores del Factor Natriurético Atrial , Anciano , Regulación Alostérica , Animales , Fármacos Cardiovasculares/química , Fármacos Cardiovasculares/metabolismo , Fármacos Cardiovasculares/farmacocinética , Fármacos Cardiovasculares/farmacología , Células Cultivadas , Femenino , Células HEK293 , Ensayos Analíticos de Alto Rendimiento , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Miocitos Cardíacos/metabolismo , Receptores del Factor Natriurético Atrial/química , Receptores del Factor Natriurético Atrial/efectos de los fármacos , Receptores del Factor Natriurético Atrial/metabolismoRESUMEN
In Plasmodium, the first two and rate-limiting enzymes of the pentose phosphate pathway, glucose 6-phosphate dehydrogenase (G6PD) and the 6-phosphogluconolactonase, are bifunctionally fused to a unique enzyme named GluPho, differing structurally and mechanistically from the respective human orthologs. Consistent with the enzyme's essentiality for malaria parasite proliferation and propagation, human G6PD deficiency has immense impact on protection against severe malaria, making PfGluPho an attractive antimalarial drug target. Herein we report on the optimized lead compound N-(((2R,4S)-1-cyclobutyl-4-hydroxypyrrolidin-2-yl)methyl)-6-fluoro-4-methyl-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamide (SBI-0797750), a potent and fully selective PfGluPho inhibitor with robust nanomolar activity against recombinant PfGluPho, PvG6PD, and P. falciparum blood-stage parasites. Mode-of-action studies have confirmed that SBI-0797750 disturbs the cytosolic glutathione-dependent redox potential, as well as the cytosolic and mitochondrial H2O2 homeostasis of P. falciparum blood stages, at low nanomolar concentrations. Moreover, SBI-0797750 does not harm red blood cell (RBC) integrity and phagocytosis and thus does not promote anemia. SBI-0797750 is therefore a very promising antimalarial lead compound.
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Antimaláricos , Deficiencia de Glucosafosfato Deshidrogenasa , Malaria Falciparum , Malaria Vivax , Malaria , Antimaláricos/farmacología , Antimaláricos/uso terapéutico , Hidrolasas de Éster Carboxílico , Glucosa/metabolismo , Glucosafosfato Deshidrogenasa/metabolismo , Humanos , Peróxido de Hidrógeno/metabolismo , Malaria Falciparum/tratamiento farmacológico , Malaria Vivax/tratamiento farmacológico , Fosfatos , Plasmodium falciparum/metabolismo , Plasmodium vivaxAsunto(s)
Vacunas contra la COVID-19 , COVID-19 , Inmunogenicidad Vacunal , SARS-CoV-2 , Eficacia de las Vacunas , Humanos , Anticuerpos Neutralizantes/sangre , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , COVID-19/sangre , COVID-19/inmunología , COVID-19/prevención & control , COVID-19/virología , Vacunas contra la COVID-19/inmunología , Vacunas contra la COVID-19/farmacología , Vacunas contra la COVID-19/uso terapéutico , SARS-CoV-2/efectos de los fármacos , SARS-CoV-2/inmunologíaRESUMEN
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.
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Citocinas/metabolismo , Nicotinamida Fosforribosiltransferasa/metabolismo , Urea/farmacología , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Relación Estructura-Actividad , Urea/análogos & derivados , Urea/químicaRESUMEN
The chemokine system plays an important role in mediating a proinflammatory microenvironment for tumor growth in hepatocellular carcinoma (HCC). The CXCR6 receptor and its natural ligand CXCL16 are expressed at high levels in HCC cell lines and tumor tissues and receptor expression correlates with increased neutrophils in these tissues contributing to poor prognosis in patients. Availability of pharmacologcal tools targeting the CXCR6/CXCL16 axis are needed to elucidate the mechanism whereby neutrophils are affected in the tumor environment. We report the discovery of a series of small molecules with an exo-[3.3.1]azabicyclononane core. Our lead compound 81 is a potent (EC50 = 40 nM) and selective orally bioavailable small molecule antagonist of human CXCR6 receptor signaling that significantly decreases tumor growth in a 30-day mouse xenograft model of HCC.
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Receptores CXCR6/antagonistas & inhibidores , Bibliotecas de Moléculas Pequeñas/química , Animales , Compuestos de Azabiciclo/química , Compuestos de Azabiciclo/metabolismo , Compuestos de Azabiciclo/farmacología , Compuestos de Azabiciclo/uso terapéutico , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Evaluación Preclínica de Medicamentos , Femenino , Humanos , Concentración 50 Inhibidora , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Ratones , Ratones Endogámicos NOD , Ratones SCID , Receptores CXCR6/metabolismo , Transducción de Señal/efectos de los fármacos , Bibliotecas de Moléculas Pequeñas/metabolismo , Bibliotecas de Moléculas Pequeñas/farmacología , Bibliotecas de Moléculas Pequeñas/uso terapéutico , Relación Estructura-Actividad , Trasplante HeterólogoRESUMEN
Parasitic infections are likely under-recognized among immigrant populations in the USA. We conducted a cross-sectional study to evaluate if such infections have health impacts among recent immigrants in Chicago and to identify predictive factors for parasitic infections. A total of 133 recent immigrants were enrolled, filling out a standardized medical questionnaire and providing blood and stool samples. Appriximately 12% of subjects (15/125) who provided a blood or stool sample for testing were found to have evidence of current or prior infection with a pathogenic parasite, of which Toxocara spp. (8 subjects, 6.4%) and Strongyloides stercoralis (5 subjects, 4%) were most commonly identified. Parasitic infection was more likely among subjects who had immigrated within the previous 2 years and those with a self-reported history of worms in the stool. The most useful surrogate markers identified for parasitic infections were an elevated immunoglobulin E level (seen in 46.7% (7/15) of subjects with parasitic infections and 20% (22/110) of uninfected individuals, p = 0.04) and the presence of Blastocystis hominis cysts on Ova & Parasite exam (detected in 38.5% (5/13) of subjects with parasitic infections who provided a stool sample and 5.1% (5/98) of uninfected subjects, p = 0.002). Our study found that parasitic infections may be common in recent US immigrants, which highlights an important health disparity among a vulnerable population that merits further study. Additionally, clinical risk factors, symptoms, and laboratory findings traditionally thought to be associated with parasites were commonly found but not predictive of infection in this study population.
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Emigrantes e Inmigrantes/estadística & datos numéricos , Adulto , Animales , Chicago/epidemiología , Estudios Transversales , Heces/parasitología , Femenino , Humanos , Parasitosis Intestinales/sangre , Parasitosis Intestinales/parasitología , Masculino , Persona de Mediana Edad , Parásitos , Prevalencia , Factores de Riesgo , Encuestas y CuestionariosRESUMEN
OBJECTIVES: We quantify and describe emergency department antibiotic discharge prescription dosing errors for pediatric patients in a community hospital health system. METHODS: This was a retrospective chart review evaluating emergency department discharge prescriptions written between July 1, 2014, and June 30, 2015. Pediatric patients who received a prescription for an oral antibiotic were included in error analysis if they had a weight updated in the electronic medical record during the encounter. We used a predefined threshold of +10% variance from the recommended dose to quantify error. Prescriber, environmental, and antibiotic specific data were also collected to identify variables associated with high incidence of error. RESULTS: Among the 1934 prescriptions included in our error analysis, we detected 776 (40%) dosing errors. Of the prescriptions reviewed, 288 (15%) contained an overdosing error and 488 (25%) contained an underdosing error. There were 208 underdosing errors written for amoxicillin to treat acute otitis media. These errors represented 43% of the total underdosing errors and had a greater magnitude of variance from the recommended dose compared with overall underdosing errors. CONCLUSIONS: Underdosing of amoxicillin in acute otitis media was a dosing error that occurred frequently throughout our community health system. Further research is needed to identify the clinical impact these errors have on pediatric patients.
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Antibacterianos/uso terapéutico , Errores de Medicación/estadística & datos numéricos , Alta del Paciente , Pautas de la Práctica en Medicina/estadística & datos numéricos , Antibacterianos/administración & dosificación , Peso Corporal , Niño , Registros Electrónicos de Salud , Servicio de Urgencia en Hospital , Femenino , Hospitales Comunitarios , Humanos , Masculino , North Carolina , Estudios RetrospectivosRESUMEN
Oxidative injury to cardiomyocytes plays a critical role in cardiac pathogenesis following myocardial infarction. Transplantation of stem cell-derived cardiomyocytes has recently progressed as a novel treatment to repair damaged cardiac tissue but its efficacy has been limited by poor survival of transplanted cells owing to oxidative stress in the post-transplantation environment. Identification of small molecules that activate cardioprotective pathways to prevent oxidative damage and increase survival of stem cells post-transplantation is therefore of great interest for improving the efficacy of stem cell therapies. This report describes a chemical biology phenotypic screening approach to identify and validate small molecules that protect human-induced pluripotent stem cell cardiomyocytes (hiPSC-CMs) from oxidative stress. A luminescence-based high-throughput assay for cell viability was used to screen a diverse collection of 48,640 small molecules for protection of hiPSC-CMs from peroxide-induced cell death. Cardioprotective activity of "hit" compounds was confirmed using impedance-based detection of cardiomyocyte monolayer integrity and contractile function. Structure-activity relationship studies led to the identification of a potent class of compounds with 4-(pyridine-2-yl)thiazole scaffold. Examination of gene expression in hiPSC-CMs revealed that the hit compound, designated cardioprotectant 312 (CP-312), induces robust upregulation of heme oxygenase-1, a marker of the antioxidant response network that has been strongly correlated with protection of cardiomyocytes from oxidative stress. CP-312 therefore represents a novel chemical scaffold identified by phenotypic high-throughput screening using hiPSC-CMs that activates the antioxidant defense response and may lead to improved pharmacological cardioprotective therapies.
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Hemo-Oxigenasa 1/metabolismo , Células Madre Pluripotentes Inducidas/efectos de los fármacos , Miocitos Cardíacos/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Sustancias Protectoras/farmacología , Bibliotecas de Moléculas Pequeñas/farmacología , Antioxidantes/farmacología , Biomarcadores/metabolismo , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/metabolismo , Miocitos Cardíacos/metabolismo , Relación Estructura-Actividad , Regulación hacia Arriba/efectos de los fármacosRESUMEN
Hypothalamic CAMKK2 represents a potential mechanism for chemically affecting satiety and promoting weight loss in clinically obese patients. Single-digit nanomolar inhibitors of CAMKK2 were identified in three related ATP-competitive series. Limited optimization of kinase selectivity, solubility, and pharmacokinetic properties were undertaken on all three series, as SAR was often transferrable. Ultimately, a 2,4-diaryl 7-azaindole was optimized to afford a tool molecule that potently inhibits AMPK phosphorylation in a hypothalamus-derived cell line, is orally bioavailable, and crosses the blood-brain barrier. When dosed orally in rodents, compound 4â¯t limited ghrelin-induced food intake.
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Quinasa de la Proteína Quinasa Dependiente de Calcio-Calmodulina/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Administración Oral , Animales , Encéfalo/metabolismo , Quinasa de la Proteína Quinasa Dependiente de Calcio-Calmodulina/genética , Quinasa de la Proteína Quinasa Dependiente de Calcio-Calmodulina/metabolismo , Ingestión de Alimentos/efectos de los fármacos , Ghrelina/farmacología , Enlace de Hidrógeno , Indoles/química , Indoles/metabolismo , Concentración 50 Inhibidora , Ratones , Mutagénesis , Inhibidores de Proteínas Quinasas/metabolismoRESUMEN
IN BRIEF Diabetes has been associated with the incidence of back pain. However, the relationship between markers of diabetes progression and back pain has not been studied. The objective of this study was to correlate clinical and laboratory measures of diabetes disease severity to the presence of back pain to provide insight into the relationship between these conditions. Findings showed that markers of diabetes disease progression were associated with the presence of back pain, suggesting that uncontrolled diabetes may contribute to the development of chronic back pain.
RESUMEN
There was a 13% increase in the number of insured patients in Chicago sexually transmitted disease clinics 1 year after Affordable Care Act implementation. Major disparities in being insured persisted among those at higher risk for sexually transmitted diseases. ABSTRACT: There was a 13% increase in the number of insured patients in Chicago sexually transmitted disease clinics 1 year after Affordable Care Act implementation. Insured patients were more likely to report having access to preventive (65% vs. 36%, P < 0.01) and sick care (72% vs. 44%, P < 0.01). Major disparities in being insured persisted among men, those aged 26 to 45 years, and racial minorities.
Asunto(s)
Accesibilidad a los Servicios de Salud , Cobertura del Seguro , Patient Protection and Affordable Care Act , Enfermedades de Transmisión Sexual/diagnóstico , Adulto , Chicago , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedades de Transmisión Sexual/prevención & control , Encuestas y Cuestionarios , Estados Unidos , Adulto JovenRESUMEN
Acute liver failure (ALF) has been associated with cerebral edema and elevated intracranial pressure (ICP), which may be managed utilizing an ICP monitor. The most feared complication of placement is catastrophic intracranial hemorrhage in the setting of severe coagulopathy. Previous studies reported hemorrhage rates between 3.8-22 % among various devices, with epidural catheters having lower hemorrhage rates and precision relative to subdural bolts and intraparenchymal catheters. We sought to identify institutional hemorrhagic rates of ICP monitoring in ALF and its associated factors in a modern series guided by protocol implantation. Patient records treated for ALF with ICP monitoring at Mayo Clinic in Rochester, MN from 1995 to 2014 were reviewed. Protocalized since 1995, epidural (EP) ICP monitors were first used followed by intraparenchymal (IP) for stage III-IV hepatic encephalopathy. The following variables and outcomes were collected: patient demographics, ICPs and treatment methods, laboratory data, imaging studies, number of days for ICP monitoring, radiographic and symptomatic hemorrhage rates, orthotopic liver transplantation rates, and death. A total of 20 ICP monitors were placed for ALF, 7 EP, and 13 IP. International normalized ratio (INR) at placement of an EP monitor was 2.4 (1.7-3.2) with maximum of 2.7 (2.0-3.6) over the following 2.3 (1-3) days. Mean EP ICP at placement was 36.3 (11-55) and maximum of 43.1 (20-70) mm Hg. INR at placement of an IP monitor was 1.3 (<0.8-3.0) with maximum value of 2.9 (1.6-5.4) over the following 4.2 (2-6) days. Mean IP ICP at placement was 9.9 (2-19) and maximum was 39.8 (11-100) mm Hg. There was one asymptomatic hemorrhage in the EP group (14.3 % hemorrhage rate) and two hemorrhages in the IP group (hemorrhage rate was 15.4 %), both of which were fatal. Overall mortality rate in the EP group was 71.4 % (5/7) with two patients receiving transplantation, and one death in the transplant group. Overall mortality in the IP group was 38.5 % (5/13) with nine liver transplantations; three of the transplanted patients died, including one of the fatal hemorrhages due to monitor placement. Intracranial hypertension is common in patients with ALF with severe hepatic encephalopathy. Monitored patients in both groups experienced elevations of ICP in the setting of intermittent coagulopathy. Severity of coagulopathy did not influence hemorrhage rate. Yet, hemorrhages related to IP monitoring can be catastrophic and may add to the overall mortality.
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Edema Encefálico/fisiopatología , Presión Intracraneal/fisiología , Fallo Hepático Agudo/fisiopatología , Monitorización Neurofisiológica/métodos , Adolescente , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
The exploration of a diarylsulfonamide series of free fatty acid receptor 4 (FFA4/GPR120) agonists is described. This work led to the identification of selective FFA4 agonist 8 (GSK137647A) and selective FFA4 antagonist 39. The in vitro profile of compounds 8 and 39 is presented herein.
Asunto(s)
Receptores Acoplados a Proteínas G/agonistas , Sulfonamidas/farmacología , Animales , Línea Celular , Relación Dosis-Respuesta a Droga , Células HEK293 , Humanos , Insulina/agonistas , Ratones , Estructura Molecular , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/químicaRESUMEN
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.
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Tobillo , Artroplastia de Reemplazo de Tobillo , Humanos , Tobillo/cirugía , Articulación del Tobillo/cirugía , Reproducibilidad de los Resultados , Artroplastia de Reemplazo de Tobillo/métodos , Estudios Retrospectivos , Rango del Movimiento ArticularRESUMEN
PURPOSE: To determine function and complications after reverse total shoulder arthroplasty (RTSA) in obese patients compared with a control group of nonobese patients. METHODS: Between 2005 and 2011, we performed 76 RTSAs in 17 obese, 36 overweight, and 23 normal weight patients, based on World Health Organization body mass index classification. We reviewed the charts for age, sex, body mass index, date of surgery, type of implant, type of incision, length of stay, comorbidities, surgical time, blood loss, American Society of Anesthesiologists score, shoulder motion, scapular notching, and postoperative complications. Complications and outcomes were analyzed and compared between groups. RESULTS: Reverse total shoulder arthroplasty in obese patients was associated with significant improvement in range of motion. Complication rate was significantly greater in the obese group (35%), compared with 4% in the normal weight group. We found no significant differences between scapular notching, surgical time, length of hospitalization, humeral component loosening, postoperative abduction, forward flexion, internal and external rotation, pain relief, or instability between groups. CONCLUSIONS: Our results show that obese patients have significant improvement in motion after RTSA but are at an increased risk for complication. Obesity is not a contraindication to RTSA, but obese patients need to understand fully the increased risk of complication with RTSA. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic III.
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Artroplastia de Reemplazo/métodos , Obesidad/epidemiología , Manguito de los Rotadores/patología , Tendinopatía/epidemiología , Tendinopatía/cirugía , Anciano , Anciano de 80 o más Años , Artroplastia de Reemplazo/efectos adversos , Comorbilidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Rango del Movimiento Articular , Estudios Retrospectivos , Articulación del Hombro/fisiopatologíaRESUMEN
Recent advances in technology can be leveraged to enhance public health research and practice. This study aimed to assess the effects of mobility and policy changes on COVID-19 case growth and the effects of policy changes on mobility using data from Google Mobility Reports, information on public health policy, and COVID-19 testing results. Multiple bivariate regression analyses were conducted to address the study objectives. Policies designed to limit mobility led to decreases in mobility in public areas. These policies also decreased COVID-19 case growth. Conversely, policies that did not restrict mobility led to increases in mobility in public areas and led to increases in COVID-19 case growth. Mobility increases in public areas corresponded to increases in COVID-19 case growth, while concentration of mobility in residential areas corresponded to decreases in COVID-19 case growth. Overall, restrictive policies were effective in decreasing COVID-19 incidence in the Dominican Republic, while permissive policies led to increases in COVID-19 incidence.
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OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
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Edema Encefálico , Craniectomía Descompresiva , Traumatismos Cerrados de la Cabeza , Procedimientos de Cirugía Plástica , Humanos , Edema Encefálico/etiología , Edema Encefálico/cirugía , Craniectomía Descompresiva/métodos , Cráneo/cirugía , Estudios RetrospectivosRESUMEN
Primary amebic meningoencephalitis (PAM) is a rare and lethal infection caused by Naegleria fowleri. We report an epidemiological and environmental investigation relating to a case of PAM in a previously healthy boy age 8 years. An interview of the patient's family was conducted to determine the likely exposure site and to assess risk factors. Data from the United States Geological Survey site at Waterloo, NE, on the Elkhorn River were used to estimate water temperature and streamflow at the time and site of exposure. Data from the National Weather Service were used to estimate precipitation and ambient air temperature at the time and site of exposure. Despite conventional treatment, the patient died 2 days after hospital admission. The patient participated in recreational water activities in the Elkhorn River in northeastern Nebraska 5 days before symptom onset. In the week before exposure, water and ambient air high temperatures reached annual highs, averaging 32.4°C and 35.8°C, respectively. The day before infection, 2.2 cm of precipitation was reported. Streamflow was low (407 ft3/s). Infections in several northern states, including Nebraska, suggest an expanding geographic range of N. fowleri transmission, which may lead to increased incidence of PAM in the United States. Similar environmental investigations at suspected exposure sites of future cases will allow data aggregation, enabling investigators to correlate environmental factors with infection risk accurately.
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Amebiasis , Infecciones Protozoarias del Sistema Nervioso Central , Meningoencefalitis , Naegleria fowleri , Masculino , Humanos , Estados Unidos/epidemiología , Niño , Nebraska , Infecciones Protozoarias del Sistema Nervioso Central/diagnóstico , Infecciones Protozoarias del Sistema Nervioso Central/epidemiología , Agua , Ríos , Meningoencefalitis/epidemiología , Meningoencefalitis/diagnóstico , Amebiasis/epidemiología , Amebiasis/diagnósticoRESUMEN
The recently discovered apelin/APJ system has emerged as a critical mediator of cardiovascular homeostasis and is associated with the pathogenesis of cardiovascular disease. A role for apelin/APJ in energy metabolism and gastrointestinal function has also recently emerged. We disclose the discovery and characterization of 4-oxo-6-((pyrimidin-2-ylthio)methyl)-4H-pyran-3-yl 4-nitrobenzoate (ML221), a potent APJ functional antagonist in cell-based assays that is >37-fold selective over the closely related angiotensin II type 1 (AT1) receptor. ML221 was derived from an HTS of the ~330,600 compound MLSMR collection. This antagonist showed no significant binding activity against 29 other GPCRs, except to the κ-opioid and benzodiazepinone receptors (<50/<70%I at 10 µM). The synthetic methodology, development of structure-activity relationship (SAR), and initial in vitro pharmacologic characterization are also presented.