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1.
J Pediatr ; 271: 114056, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38615943

RESUMEN

OBJECTIVE: To evaluate the prevalence, trends, and factors associated with psychotropic medication use and polypharmacy among children and adolescents initiating intensive behavioral therapy for severe challenging behavior over a 10-year period. STUDY DESIGN: In this retrospective observational study, we examined data from caregiver interviews and patient medical records on the number and types of psychotropic medications prescribed to patients initiating intensive behavioral therapy between January 1, 2013, and December 31, 2022. Trends in medication use and polypharmacy across the 10-year period were analyzed using regression analysis, while differences in demographics and clinical factors for patients with use and polypharmacy were analyzed using nonparametric statistical analysis with odds ratios presented for significant factors. RESULTS: Data from all 302 pediatric patients initiating intensive behavioral therapy across the 10-year period were analyzed. Among all patients and all years, 83.8% were taking at least 1 psychotropic medication and 68.2% experienced polypharmacy. There were no changes in the prevalence of use, mean number of medications taken, or polypharmacy across the 10-year period. Patients diagnosed with attention-deficit/hyperactivity disorder or anxiety disorder, as well as those exhibiting self-injurious behavior had higher use of psychotropic medication and polypharmacy and were taking more medications overall. CONCLUSIONS: Psychotropic medication use and polypharmacy were extremely high for children and adolescents with severe challenging behavior, but use and polypharmacy did not change over the 10-year period of data collection. Further research is needed to establish the generality of these findings to other regions of the US.


Asunto(s)
Terapia Conductista , Polifarmacia , Psicotrópicos , Humanos , Femenino , Masculino , Niño , Psicotrópicos/uso terapéutico , Estudios Retrospectivos , Adolescente , Terapia Conductista/métodos , Problema de Conducta , Preescolar , Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico
2.
J Orthop Surg (Hong Kong) ; 31(3): 10225536231217148, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-38126258

RESUMEN

BACKGROUND: Bicondylar tibial plateau fractures are complex injuries that commonly require surgical repair. Long-term clinical outcome has been associated with discrepancies in leg alignment, instability and condylar width abnormalities. While intuitive, the degree of articular damage at time of injury has not been linked to outcomes in patients with bicondylar tibial plateau fractures. The aim of this study was to quantify percentage of articular surface cross sectional area disruption and assess for correlation between the degree of articular injury and patient reported physical function. METHODS: Retrospective cohort study at two level 1 trauma centers. 57 consecutive patients undergoing surgical repair for bicondylar tibial plateau fractures between 2013 and 2016. MAIN OUTCOME MEASURE: Preoperative CT scans were reviewed, and the percentage of articular surface disruption cross sectional area was calculated. PROMIS® scores were collected from patients at a minimum of 2 years. RESULTS: 57 patients with an average age of 58 ± 14.3 years were included. The average PROMIS® score was 45.5. There was a correlation between percentage of articular surface disruption and total PROMIS® scores (0.4, CI: 0.2-0.5, p = .007) and the physical function of the PROMIS® score (0.4, CI: 0.2-0.6, p < .001). CONCLUSION: Our method for calculating articular surface disruption on CT is a simple, reproducible and accurate method for assessing the degree of articular damage in patients with bicondylar tibial plateau fractures. We found that the percentage of cross-sectional articular surface disruption correlates with patient reported outcomes and physical function.


Asunto(s)
Fracturas de la Tibia , Fracturas de la Meseta Tibial , Humanos , Adulto , Persona de Mediana Edad , Anciano , Estudios Retrospectivos , Fracturas de la Tibia/diagnóstico por imagen , Fracturas de la Tibia/cirugía , Tomografía Computarizada por Rayos X , Fijación Interna de Fracturas/métodos
3.
BMJ Case Rep ; 16(12)2023 Dec 21.
Artículo en Inglés | MEDLINE | ID: mdl-38129090

RESUMEN

A patient in her late 20s presented with severe epigastric pain. A CT scan of the abdomen and pelvis was performed to exclude an upper gastrointestinal perforation. This showed findings of perigastric appendagitis. This is a rare cause of severe upper abdominal pain. The patient was treated with oral and intravenous analgesia medication and discharged the next day. No surgical intervention was required.


Asunto(s)
Cavidad Abdominal , Dolor Abdominal , Femenino , Humanos , Dolor Abdominal/etiología , Abdomen , Tomografía Computarizada por Rayos X/efectos adversos
4.
J Gen Intern Med ; 38(16): 3541-3548, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-37731136

RESUMEN

BACKGROUND: In 2021, the U.S. Preventive Services Task Force (USPSTF) recommended screening for prediabetes and diabetes among adults aged 35-70 years with overweight or obesity. Studying dysglycemia screening in federally qualified health centers (FQHCs) that serve vulnerable patient populations is needed to understand health equity implications of this recommendation. OBJECTIVE: To investigate screening practices among FQHC patients who would be eligible according to the 2021 USPSTF recommendation. DESIGN: Retrospective cohort study analyzing electronic health records from a national network of 282 FQHC sites. PARTICIPANTS: We included 183,329 patients without prior evidence of prediabetes or diabetes, who had ≥ 1 office visit from 2018-2020. MAIN MEASURES: Screening eligibility was based on age and measured body mass index (BMI). The primary outcome, screening completion, was ascertained using hemoglobin A1c or fasting plasma glucose results from 2018-2020. KEY RESULTS: Among 89,543 patients who would be eligible according to the 2021 USPSTF recommendation, 53,263 (59.5%) were screened. Those who completed screening had higher BMI values than patients who did not (33.0 ± 6.7 kg/m2 vs. 31.9 ± 6.2 kg/m2, p < 0.001). Adults aged 50-64 years had greater odds of screening completion relative to younger patients (OR 1.13, 95% CI: 1.10-1.17). Patients from racial and ethnic minority groups, as well as those without health insurance, were more likely to complete screening than White patients and insured patients, respectively. Clinical risk factors for diabetes were also associated with dysglycemia screening. Among patients who completed screening, 23,588 (44.3%) had values consistent with prediabetes or diabetes. CONCLUSIONS: Over half of FQHC patients who would be eligible according to the 2021 USPSTF recommendation were screened. Screening completion was higher among middle-aged patients, those with greater BMI values, as well as vulnerable groups with a high risk of developing diabetes. Future research should examine adoption of the 2021 USPSTF screening recommendation and its impact on health equity.


Asunto(s)
Diabetes Mellitus , Estado Prediabético , Adulto , Persona de Mediana Edad , Humanos , Estado Prediabético/diagnóstico , Estado Prediabético/epidemiología , Etnicidad , Estudios Retrospectivos , Grupos Minoritarios , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/epidemiología , Tamizaje Masivo/métodos
5.
Int J Spine Surg ; 17(2): 258-264, 2023 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-36635064

RESUMEN

BACKGROUND: Anterior cervical corpectomy and fusion (ACCF) is often required to adequately decompress the spinal cord in patients with multilevel cervical spondylosis. Unfortunately, multilevel corpectomy constructs have high rates of early failure and frequently require supplemental posterior fixation. First described in 2003, skip ACCF (sACCF) is defined by corpectomies above and below an intervening vertebral body, which serves as an additional fixation point to augment biomechanical stability. Subsequent studies report high fusion rates and low construct failure rates secondary to superior biomechanical stability. OBJECTIVE: The goal of this study was to demonstrate the safety and efficacy of sACCF in the largest series published to date. METHODS: This study was a retrospective case series of all patients who underwent sACCF at a single institution over a 10-year period. Standard demographic and perioperative data were collected. Outcome data included immediate postoperative complications, long-term reoperation, and pre- and postoperative radiographic parameters. RESULTS: Forty-five patients underwent sACCF: 42 at C4-C6 and 3 at C5-C7. Mean age was 57.5 years. More than half (64.4%) of patients were smokers. Almost all patients were discharged home, the vast majority (82.2%) within 3 days of surgery. Five patients (11.1%) developed complications during the index hospitalization: 2 C5 palsies and 3 medical complications. Three patients (6.7%) developed instrumentation failure requiring anterior revision and supplemental posterior fixation. There were statistically significant increases in C1-C7 (47.8 vs 41.1, P < 0.001) and C2-C7 lordosis (11.1 vs 5.0, P < 0.001) on postoperative radiographs compared with preoperative imaging. Average follow-up was 21.1 months. CONCLUSION: sACCF can be performed safely with complication rates similar to those reported for multilevel anterior cervical discectomy and fusion or adjacent segment ACCF. It should be considered for patients with multilevel cervical pathology for whom an anterior approach is favored. CLINICAL RELEVANCE: sACCF is an effective surgical technique for multilevel cervical decompression and correction of cervical alignment.

6.
World Neurosurg ; 171: 115-123, 2023 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-36584892

RESUMEN

BACKGROUND: Bibliometric analyses of the scientific literature have grown increasingly popular in the past few decades. However, patent bibliometric studies, evaluation of technological literature, have not yet been applied in neurosurgery. OBJECTIVE: To perform a pilot patent bibliometric analysis of the top 100 most cited patents in cranial neurosurgery. METHODS: The Lens was used to query multiple databases, to select the top 100 cranial neurosurgical patents based upon forward patent citations. These were organized into 9 categories based on technological descriptors and were evaluated based on the earliest priority date, year issued, and expiration status, among others. RESULTS: The top 100 most cited patents included technology underlying 3D navigation (n = 31), pharmacology and implants (n = 20), vascular occlusion (n = 5), craniotomy closure (n = 9), focal lesioning and tissue resection (n = 8), brain and systemic cooling (n = 5), neuroendoscopy (n = 8), neuromonitoring and stimulation (6), and technologies improving surgeon performance (n = 8). Ninety-six patents were filed in the United States, 72 were expired, 19 are still active, and 9 were listed as inactive. The highest number of patents was applied for from the mid-1990s to the mid-2000s. Demonstrated trends showed no meaningful correlation between patent rank and earliest priority date (linear trendline y = 0.7107 x -1367.5; R2 = 0.0671), while a very strong correlation was found between patent rank and citations per year (power trendline y = 127.93 x -1.094; R2 = 0.8579). CONCLUSIONS: Patent bibliometrics allow evaluation of neurosurgical advancements from the past and enable subsequent development of cutting-edge technology in the future. The described method is a reproducible and reliable technique for evaluating our field's patent literature.


Asunto(s)
Neurocirugia , Humanos , Estados Unidos , Bibliometría , Procedimientos Neuroquirúrgicos , Publicaciones , Tecnología
7.
World Neurosurg ; 170: e436-e440, 2023 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-36379362

RESUMEN

OBJECTIVE: Spinal cord stimulation is an effective treatment modality for chronic pain. Although percutaneous leads are commonly placed in the outpatient setting, paddle leads are typically implanted in the inpatient setting. Given the substantial cost savings associated with the ambulatory setting, we aimed to demonstrate the feasibility and safety of thoracic paddle lead implantation in a freestanding ambulatory surgery center (ASC). METHODS: Consecutive patients undergoing thoracic paddle lead implantation at a single freestanding ASC from January 2015 to December 2020 were queried. Demographic, perioperative, and outcome data were collected. Primary outcomes were incidence of intraoperative or immediate postoperative complications and need for inpatient transfer. Secondary outcomes included readmission at 30 and 90 days and reoperation at 30 days, 90 days, and 1 year. RESULTS: A total of 46 patients underwent ambulatory thoracic paddle lead implantation over the study period. Two patients (4.3%) suffered an immediate postoperative complication requiring return to surgery at the ASC-one for an epidural hematoma, and one for a flank hematoma. All but one patient (97.8%) were discharged home on the day of surgery. The overall 30- and 90-day readmission rates were 4.3% and 6.5%, respectively. One patient (2.2%) required reoperation for a mechanical complication. No device-related infections were noted during the follow-up period. CONCLUSIONS: Thoracic laminotomy for paddle lead spinal cord stimulator implantation can be performed in a freestanding ASC with complication rates comparable to the hospital setting. Future comparative studies that assess clinical outcomes and cost are necessary to determine the cost-effectiveness of the ambulatory setting.


Asunto(s)
Hematoma Espinal Epidural , Estimulación de la Médula Espinal , Humanos , Procedimientos Quirúrgicos Ambulatorios , Electrodos Implantados/efectos adversos , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Estimulación de la Médula Espinal/efectos adversos , Hematoma Espinal Epidural/etiología , Médula Espinal/cirugía
8.
Front Public Health ; 11: 1277657, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-38164446

RESUMEN

Introduction: Racial and ethnic minority groups and individuals with limited educational attainment experience a disproportionate burden of diabetes. Prediabetes represents a high-risk state for developing type 2 diabetes, but most adults with prediabetes are unaware of having the condition. Uncovering whether racial, ethnic, or educational disparities also occur in the prediabetes stage could help inform strategies to support health equity in preventing type 2 diabetes and its complications. We examined the prevalence of prediabetes and prediabetes awareness, with corresponding prevalence ratios according to race, ethnicity, and educational attainment. Methods: This study was a pooled cross-sectional analysis of the National Health and Nutrition Examination Survey data from 2011 to March 2020. The final sample comprised 10,262 U.S. adults who self-reported being Asian, Black, Hispanic, or White. Prediabetes was defined using hemoglobin A1c and fasting plasma glucose values. Those with prediabetes were classified as "aware" or "unaware" based on survey responses. We calculated prevalence ratios (PR) to assess the relationship between race, ethnicity, and educational attainment with prediabetes and prediabetes awareness, controlling for sociodemographic, health and healthcare-related, and clinical characteristics. Results: In fully adjusted logistic regression models, Asian, Black, and Hispanic adults had a statistically significant higher risk of prediabetes than White adults (PR:1.26 [1.18,1.35], PR:1.17 [1.08,1.25], and PR:1.10 [1.02,1.19], respectively). Adults completing less than high school and high school had a significantly higher risk of prediabetes compared to those with a college degree (PR:1.14 [1.02,1.26] and PR:1.12 [1.01,1.23], respectively). We also found that Black and Hispanic adults had higher rates of prediabetes awareness in the fully adjusted model than White adults (PR:1.27 [1.07,1.50] and PR:1.33 [1.02,1.72], respectively). The rates of prediabetes awareness were consistently lower among those with less than a high school education relative to individuals who completed college (fully-adjusted model PR:0.66 [0.47,0.92]). Discussion: Disparities in prediabetes among racial and ethnic minority groups and adults with low educational attainment suggest challenges and opportunities for promoting health equity in high-risk groups and expanding awareness of prediabetes in the United States.


Asunto(s)
Diabetes Mellitus Tipo 2 , Estado Prediabético , Adulto , Humanos , Estados Unidos/epidemiología , Etnicidad , Estado Prediabético/epidemiología , Diabetes Mellitus Tipo 2/epidemiología , Prevalencia , Encuestas Nutricionales , Estudios Transversales , Grupos Minoritarios , Escolaridad
9.
Int J Mol Sci ; 25(1)2023 Dec 28.
Artículo en Inglés | MEDLINE | ID: mdl-38203602

RESUMEN

Up to 50% of patients with severe congenital heart disease (CHD) develop life-altering neurodevelopmental disability (NDD). It has been presumed that NDD arises in CHD cases because of hypoxia before, during, or after cardiac surgery. Recent studies detected an enrichment in de novo mutations in CHD and NDD, as well as significant overlap between CHD and NDD candidate genes. However, there is limited evidence demonstrating that genes causing CHD can produce NDD independent of hypoxia. A patient with hypoplastic left heart syndrome and gross motor delay presented with a de novo mutation in SMC5. Modeling mutation of smc5 in Xenopus tropicalis embryos resulted in reduced heart size, decreased brain length, and disrupted pax6 patterning. To evaluate the cardiac development, we induced the conditional knockout (cKO) of Smc5 in mouse cardiomyocytes, which led to the depletion of mature cardiomyocytes and abnormal contractility. To test a role for Smc5 specifically in the brain, we induced cKO in the mouse central nervous system, which resulted in decreased brain volume, and diminished connectivity between areas related to motor function but did not affect vascular or brain ventricular volume. We propose that genetic factors, rather than hypoxia alone, can contribute when NDD and CHD cases occur concurrently.


Asunto(s)
Cardiopatías Congénitas , Humanos , Animales , Ratones , Cardiopatías Congénitas/genética , Encéfalo , Ventrículos Cardíacos , Hipoxia , Miocitos Cardíacos , Xenopus , Proteínas Cromosómicas no Histona , Proteínas de Ciclo Celular/genética , Proteínas de Xenopus
10.
J Immunol ; 209(5): 991-1000, 2022 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-36130126

RESUMEN

Akt-1 and Akt-2 are the major isoforms of the serine/threonine Akt family that play a key role in controlling immune responses. However, the involvement of Akt-1 and Akt-2 isoforms in antifungal innate immunity is completely unknown. In this study, we show that Akt2 -/-, but not Akt1 -/-, mice are protected from lethal Candida albicans infection. Loss of Akt-2 facilitates the recruitment of neutrophils and macrophages to the spleen and increases reactive oxygen species expression in these cells. Treating C57BL/6 mice with a specific inhibitor for Akt-2, but not Akt-1, provides protection from lethal C. albicans infection. Our data demonstrate that Akt-2 inhibits antifungal innate immunity by hampering neutrophil and macrophage recruitment to spleens and suppressing oxidative burst, myeloperoxidase activity, and NETosis. We thus describe a novel role for Akt-2 in the regulation of antifungal innate immunity and unveil Akt-2 as a potential target for the treatment of fungal sepsis.


Asunto(s)
Candida albicans , Candidiasis , Proteínas Proto-Oncogénicas c-akt/metabolismo , Animales , Antifúngicos , Ratones , Ratones Endogámicos C57BL , Neutrófilos , Peroxidasa/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Serina/metabolismo , Treonina/metabolismo
11.
Histopathology ; 81(2): 215-227, 2022 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-35543076

RESUMEN

AIMS: Recurrent alterations involving receptor tyrosine or cytoplasmic kinase genes have been described in soft-tissue neoplasms such as infantile fibrosarcoma (IFS) and inflammatory myofibroblastic tumour (IMT). Recent trials and regulatory approvals for targeted inhibitors against the kinase domains of these oncoproteins have allowed for increased use of targeted therapies. We aimed to characterize the histologic features of paediatric mesenchymal neoplasms with kinase alterations treated with targeted inhibitors. METHODS AND RESULTS: Eight patients with tyrosine kinase-altered mesenchymal neoplasms with pre- and posttreatment samples were identified. Tumours occurred in five females and three males with a median age at presentation of 6.5 years. Tumour sites were bone/somatic soft-tissue (n = 5) and viscera (n = 3). Pretreatment diagnoses were: IMT (n = 3), epithelioid inflammatory myofibroblastic sarcoma (n = 1), and descriptive diagnoses (n = 4) such as "kinase-driven spindle cell tumor." Fusions identified were ETV6::NTRK3 (n = 2), TPM3::NTRK1, SEPT7::BRAF, TFG::ROS1, KLC1::ALK, RANBP2::ALK, and MAP4::RAF1. Patients were treated with larotrectinib (n = 3), ALK or ALK/ROS1 inhibitors (n = 3), and MEK inhibitors (n = 2). Posttreatment tumours exhibited a striking decrease in cellularity (7/8) and the presence of collagenous stroma (7/8) with extensive glassy hyalinization (5/8). In two cases, abundant coarse or psammomatous calcifications were seen and in one case prominent perivascular hyalinization was noted. Residual viable tumour was seen in 3/8 cases (<5% in one case, and >75% in 2/8 cases). CONCLUSION: Mesenchymal neoplasms with tyrosine kinase alterations treated with targeted inhibitors show a pathologic response, which includes decreased cellularity and stromal hyalinization. The presence of these features may be helpful in assessing tumour response after targeted therapy.


Asunto(s)
Granuloma de Células Plasmáticas , Sarcoma , Quinasa de Linfoma Anaplásico/genética , Niño , Femenino , Humanos , Masculino , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Tirosina Quinasas/genética , Proteínas Proto-Oncogénicas/genética , Proteínas Tirosina Quinasas Receptoras/genética , Sarcoma/tratamiento farmacológico , Sarcoma/genética , Sarcoma/patología
12.
Plast Reconstr Surg Glob Open ; 10(2): e4085, 2022 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-35141103

RESUMEN

BACKGROUND: The evaluation model of operative competence is based on aggregate tabulations of procedures and end-of-rotation feedback from faculty members. Procedural tabulations do not detail the level of resident involvement in the case, and end of rotation feedback is infrequent and inaccurate due to the necessity of long-term recall. Smart phone-based evaluation systems provide residents with immediate and permanent feedback for surgical encounters. In this study, we examine the feasibility of smart phone-based evaluations in plastic surgery residency. METHODS: This was a 6-month prospective, single institution pilot study at three teaching hospitals, assessing all PGY levels. We utilized our department mobile application (Wayne State University Surgery Department application), which includes intraoperative evaluations based on the Zwisch scale. Prestudy and poststudy surveys were conducted. An unstructured interview of the Clinical Competency Committee provided feedback for the new evaluation tool against the previous evaluation forms. RESULTS: Eleven physicians participated in the study, resulting in 126 encounters and 184 procedures. A 10-question prestudy survey was given with answers ranging from 1 (strongly disagree) to 5 (strongly agree). The Clinical Competency Committee faculty ranked the prestudy resident assessment tool 2.82 of 5, whereas the poststudy survey scored 4.64 of 5. CONCLUSIONS: Residents and faculty both rated the smartphone application as a useful tool for evaluating residents. The success of the application proves its feasibility within plastic surgery residency and may play an important role in rating resident operative competency in the future.

13.
Nat Commun ; 12(1): 6055, 2021 10 18.
Artículo en Inglés | MEDLINE | ID: mdl-34663813

RESUMEN

COVID-19 caused by the SARS-CoV-2 virus has become a global pandemic. 3CL protease is a virally encoded protein that is essential across a broad spectrum of coronaviruses with no close human analogs. PF-00835231, a 3CL protease inhibitor, has exhibited potent in vitro antiviral activity against SARS-CoV-2 as a single agent. Here we report, the design and characterization of a phosphate prodrug PF-07304814 to enable the delivery and projected sustained systemic exposure in human of PF-00835231 to inhibit coronavirus family 3CL protease activity with selectivity over human host protease targets. Furthermore, we show that PF-00835231 has additive/synergistic activity in combination with remdesivir. We present the ADME, safety, in vitro, and in vivo antiviral activity data that supports the clinical evaluation of PF-07304814 as a potential COVID-19 treatment.


Asunto(s)
Tratamiento Farmacológico de COVID-19 , Proteasas 3C de Coronavirus/antagonistas & inhibidores , Inhibidores de Proteasa de Coronavirus/administración & dosificación , Indoles/administración & dosificación , Leucina/administración & dosificación , Pirrolidinonas/administración & dosificación , Adenosina Monofosfato/administración & dosificación , Adenosina Monofosfato/efectos adversos , Adenosina Monofosfato/análogos & derivados , Adenosina Monofosfato/farmacocinética , Alanina/administración & dosificación , Alanina/efectos adversos , Alanina/análogos & derivados , Alanina/farmacocinética , Animales , COVID-19/virología , Chlorocebus aethiops , Coronavirus Humano 229E/efectos de los fármacos , Coronavirus Humano 229E/enzimología , Inhibidores de Proteasa de Coronavirus/efectos adversos , Inhibidores de Proteasa de Coronavirus/farmacocinética , Modelos Animales de Enfermedad , Diseño de Fármacos , Sinergismo Farmacológico , Quimioterapia Combinada , Células HeLa , Humanos , Indoles/efectos adversos , Indoles/farmacocinética , Infusiones Intravenosas , Leucina/efectos adversos , Leucina/farmacocinética , Ratones , Pirrolidinonas/efectos adversos , Pirrolidinonas/farmacocinética , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/efectos de los fármacos , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/enzimología , SARS-CoV-2/efectos de los fármacos , SARS-CoV-2/enzimología , Células Vero
14.
J Biol Chem ; 295(48): 16239-16250, 2020 11 27.
Artículo en Inglés | MEDLINE | ID: mdl-32913128

RESUMEN

The calcium-calmodulin-dependent protein kinase kinase-2 (CaMKK2) is a key regulator of cellular and whole-body energy metabolism. It is known to be activated by increases in intracellular Ca2+, but the mechanisms by which it is inactivated are less clear. CaMKK2 inhibition protects against prostate cancer, hepatocellular carcinoma, and metabolic derangements induced by a high-fat diet; therefore, elucidating the intracellular mechanisms that inactivate CaMKK2 has important therapeutic implications. Here we show that stimulation of cAMP-dependent protein kinase A (PKA) signaling in cells inactivates CaMKK2 by phosphorylation of three conserved serine residues. PKA-dependent phosphorylation of Ser495 directly impairs calcium-calmodulin activation, whereas phosphorylation of Ser100 and Ser511 mediate recruitment of 14-3-3 adaptor proteins that hold CaMKK2 in the inactivated state by preventing dephosphorylation of phospho-Ser495 We also report the crystal structure of 14-3-3ζ bound to a synthetic diphosphorylated peptide that reveals how the canonical (Ser511) and noncanonical (Ser100) 14-3-3 consensus sites on CaMKK2 cooperate to bind 14-3-3 proteins. Our findings provide detailed molecular insights into how cAMP-PKA signaling inactivates CaMKK2 and reveals a pathway to inhibit CaMKK2 with potential for treating human diseases.


Asunto(s)
Proteínas 14-3-3/metabolismo , Quinasa de la Proteína Quinasa Dependiente de Calcio-Calmodulina/metabolismo , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Transducción de Señal , Proteínas 14-3-3/genética , Animales , Células COS , Quinasa de la Proteína Quinasa Dependiente de Calcio-Calmodulina/genética , Línea Celular Tumoral , Chlorocebus aethiops , Proteínas Quinasas Dependientes de AMP Cíclico/genética , Activación Enzimática , Humanos
15.
J Paediatr Child Health ; 56(4): 636-641, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-31821679

RESUMEN

AIM: This study describes an Australian cohort of paediatric Buruli ulcer (BU) patients and compares them with adult BU patients. METHODS: Analysis of a prospective cohort of all BU cases managed at Barwon Health, Victoria, from 1 January 1998 to 31 May 2018 was performed. Children were defined as ≤15 years of age. RESULTS: A total of 565 patients were included: 52 (9.2%) children, 289 (51.2%) adults aged 16-64 years and 224 (39.6%) adults aged ≥65 years. Among children, half were female and the median age was 8.0 years (interquartile range 4.8-12.3 years). Six (11.5%) cases were diagnosed from 2001 to 2006, 14 (26.9%) from 2007 to 2012 and 32 (61.5%) from 2013 to 2018. Compared to adults, children had a significantly higher proportion of non-ulcerative lesions (32.7%, P < 0.001) and a higher proportion of severe lesions (26.9%, P < 0.01). The median duration of symptoms prior to diagnosis was shorter for children compared with adults aged 16-64 years (42 vs. 56 days, P = 0.04). Children were significantly less likely to experience antibiotic complications (6.1%) compared with adults (20.6%, P < 0.001), but had a significantly higher rate of paradoxical reactions (38.8%) compared with adults aged 16-64 (19.2%) (P < 0.001). Paradoxical reactions in children occurred significantly earlier than in adults (median 17 vs. 56 days, P < 0.01). Cure rates were similarly high for children compared to adults treated with antibiotics alone or with antibiotics and surgery. CONCLUSIONS: Paediatric BU cases in Australia are increasing and represent an important but stable proportion of Australian BU cohorts. Compared with adults, there are significant differences in clinical presentation and treatment outcomes.


Asunto(s)
Úlcera de Buruli , Mycobacterium ulcerans , Adolescente , Adulto , Anciano , Antibacterianos/uso terapéutico , Úlcera de Buruli/diagnóstico , Úlcera de Buruli/tratamiento farmacológico , Úlcera de Buruli/epidemiología , Niño , Preescolar , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Victoria/epidemiología , Adulto Joven
17.
J Clin Med ; 8(5)2019 May 06.
Artículo en Inglés | MEDLINE | ID: mdl-31064122

RESUMEN

A paucity of advances in the development of novel therapeutic agents for squamous cell carcinomas of the head and neck, oral cavity (OSCC) and oropharynx, has stagnated disease free survival rates over the past two decades. Although immunotherapies targeted against checkpoint inhibitors such as PD-1 or CTLA-4 are just now entering the clinic for late stage disease with regularity the median improvement in overall survival is only about three months. There is an urgent unmet clinical need to identify new therapies that can be used alone or in combination with current approaches to increase survival by more than a few months. Activation of the apoptotic arm of the unfolded response (UPR) with small molecules and natural products has recently been demonstrated to be a productive approach in pre-clinical models of OSCC and several other cancers. The aim of current study was to perform a high throughput screen (HTS) with a diverse chemical library to identify compounds that could induce CHOP, a component of the apoptotic arm of the UPR. Disulfiram (DSF, also known as Antabuse) the well-known aversion therapy used to treat chronic alcoholism emerged as a hit that could generate reactive oxygen species, activate the UPR and apoptosis and reduce proliferation in OSCC cell cultures and xenografts. A panel of murine embryonic fibroblasts null for key UPR intermediates (e.g., Chop and Atf4) was resistant to DSF suggesting that an intact UPR is a key element of the mechanism regulating the antiproliferative effects of DSF.

18.
J Cyst Fibros ; 18(2): 233-235, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-30224332

RESUMEN

Currently, cystic fibrosis patients require daily nebulized treatments to achieve optimal lung health. Growth of pathogenic bacteria in patient nebulizers is well known, and disinfection guidelines have been established. In this short communication, we sought to discover what effect, if any, repeated nebulization/disinfection cycles had on nebulizer output. We nebulized saline repeatedly after exposure to boiling water, steam, and alcohol disinfection methods. While alcohol disinfection did not affect nebulizer output, boiling water and steam significantly decreased nebulizer output from baseline, 74.1 ±â€¯5.9% (p = 0.022) and steam 63.6 ±â€¯6.5% (p = 0.0048) after 60 cycles respectively. This decrease in nebulizer output could significantly increase the duration of nebulizer treatment time and negatively impact the burden of care on patients with cystic fibrosis.


Asunto(s)
Fibrosis Quística/terapia , Desinfección/métodos , Contaminación de Equipos/prevención & control , Etanol/farmacología , Calor/efectos adversos , Nebulizadores y Vaporizadores/microbiología , Atención al Paciente/instrumentación , Desinfectantes/farmacología , Falla de Equipo , Humanos , Atención al Paciente/métodos , Vapor , Agua
19.
Curr Diab Rep ; 18(11): 104, 2018 09 19.
Artículo en Inglés | MEDLINE | ID: mdl-30229480

RESUMEN

PURPOSE OF REVIEW: Evidence-based treatments for prediabetes can prevent and delay the development of type 2 diabetes in adults. In this review, we propose a framework for population-based diabetes prevention that links screening and prevention activities across key stakeholders. We also discuss gaps in current practice, while highlighting opportunities to improve diabetes screening and prevention efforts population-wide. RECENT FINDINGS: Awareness of diabetes risk is low, and many adults with prediabetes are not identified through existing screening efforts. Accumulating evidence and policies support expansion of the Diabetes Prevention Program (DPP) into clinical and community settings. However, the infrastructure to facilitate referrals and promote data exchange among patients, clinical settings, and community-based DPP programs is lacking. Development of evidence-driven, scalable processes for assessing diabetes risk, screening eligible adults, and delivering preventive treatments are needed to effectively improve the glycemic health of the US adult population.


Asunto(s)
Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/prevención & control , Tamizaje Masivo , Adulto , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/terapia , Humanos , Estilo de Vida , Medición de Riesgo , Estados Unidos
20.
J Gen Intern Med ; 33(7): 1100-1108, 2018 07.
Artículo en Inglés | MEDLINE | ID: mdl-29651678

RESUMEN

BACKGROUND: In 2015, The US Preventive Services Task Force (USPSTF) recommended screening for prediabetes and undiagnosed diabetes (collectively called dysglycemia) among adults aged 40-70 years with overweight or obesity. The recommendation suggests that clinicians consider screening earlier in people who have other diabetes risk factors. OBJECTIVE: To compare the performance of limited and expanded screening criteria recommended by the USPSTF for detecting dysglycemia among US adults. DESIGN: Cross-sectional analysis of survey and laboratory data collected from nationally representative samples of the civilian, noninstitutionalized US adult population. PARTICIPANTS: A total of 3643 adults without diagnosed diabetes who underwent measurement of hemoglobin A1c (A1c), fasting plasma glucose (FPG), and 2-h plasma glucose (2-h PG). MAIN MEASURES: Screening eligibility according to the limited criteria was based on age 40 to 70 years old and overweight/obesity. Screening eligibility according to the expanded criteria was determined by meeting the limited criteria or having ≥ 1 of the following risk factors: family history of diabetes, history of gestational diabetes or polycystic ovarian syndrome, and non-white race/ethnicity. Dysglycemia was defined by A1c ≥ 5.7%, FPG ≥ 100 mg/dL, and/or 2-h PG ≥ 140 mg/dL. KEY RESULTS: Among the US adult population without diagnosed diabetes, 49.7% had dysglycemia. Screening based on the limited criteria demonstrated a sensitivity of 47.3% (95% CI, 44.7-50.0%) and specificity of 71.4% (95% CI, 67.3-75.2%). The expanded criteria yielded higher sensitivity [76.8% (95% CI, 73.5-79.8%)] and lower specificity [33.8% (95% CI, 30.1-37.7%)]. Point estimates for the sensitivity of the limited criteria were lower in all minority groups and significantly different for Asians compared to non-Hispanic whites [29.9% (95% CI, 23.4-37.2%) vs. 49.8% (95% CI, 45.9-53.7%); P < .001]. CONCLUSIONS: Diabetes screening that follows the limited USPSTF criteria will identify approximately half of US adults with dysglycemia. Screening other high-risk subgroups defined in the USPSTF recommendation would improve detection of dysglycemia and may reduce associated racial/ethnic disparities.


Asunto(s)
Comités Consultivos/normas , Tamizaje Masivo/normas , Estado Prediabético/diagnóstico , Estado Prediabético/epidemiología , Servicios Preventivos de Salud/normas , Adulto , Anciano , Glucemia/metabolismo , Estudios Transversales , Femenino , Humanos , Masculino , Tamizaje Masivo/métodos , Persona de Mediana Edad , Encuestas Nutricionales/normas , Estado Prediabético/sangre , Servicios Preventivos de Salud/métodos , Estados Unidos/epidemiología
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