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1.
Inorg Chem ; 63(8): 3630-3636, 2024 Feb 26.
Artículo en Inglés | MEDLINE | ID: mdl-38359443

RESUMEN

A series of square planar metalloporphyrins (M(TPP), TPP is 5,10,15,20-tetraphenylporphyrin and M(TPFPP), TPFPP is 5,10,15,20-tetrapentafluorophenylporphyrin; M is Zn2+, Ni2+, Pd2+, or Pt2+) with distinct meso-substituents were prepared, and their magneto-optical activity (MOA) was characterized by magnetic circular dichroism (MCD) and magneto-optical rotary dispersion spectroscopy (MORD; also known as Faraday rotation spectroscopy). MOA is crucial in the development of next-generation magneto-optical devices and quantum computing. The data show that the presence of meso-pentafluorophenyl substituents results in significant increase in MOA in comparison to the homologous phenyl group. Differences in the MOA of these metalloporphyrins are rationalized using the Gouterman four-orbital model and pave the way for rational design of improved and tailorable magneto-optical materials.

2.
Planta Med ; 90(1): 13-24, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-37832581

RESUMEN

Glioblastoma is the most frequent primary malignant brain tumor without effective treatment, which makes this work extremely relevant. The study of the bioactive compounds from medicinal plants plays an important role in the discovery of new drugs.This research investigated the constituents of Tapirira guianensis and its antitumor potential (in vitro and in vivo) in glioblastoma. The T. guianensis extracts were characterized by mass spectrometry. The ethyl acetate partition (01ID) and its fractions 01ID-F2 and 01ID-F4 from T. guianensis showed potential antitumor treatment evidenced by selective cytotoxicity for GAMG with IC50 14.1 µg/mL, 83.07 µg/mL, 59.27 µg/mL and U251 with IC50 25.92 µg/mL, 37.3 µg/mL and 18.84 µg/mL. Fractions 01ID-F2 and 01ID-F4 were 10 times more selective when compared to TMZ and 01ID for the two evaluated cell lines. T. guianensis also reduced matrix metalloproteinases 2 - 01ID-F2 (21.84%), 01ID-F4 (29.6%) and 9 - 01ID-F4 (73.42%), ID-F4 (53.84%) activities, and induced apoptosis mainly through the extrinsic pathway. Furthermore, all treatments significantly reduced tumor size (01ID p < 0,01, 01ID-F2 p < 0,01 and 01ID-F4 p < 0,0001) and caused blood vessels to shrink in vivo. The present findings highlight that T. guianensis exhibits considerable antitumor potential in preclinical studies of glioblastoma. This ability may be related to the phenolic compounds and sesquiterpene derivatives identified in the extracts. This study deserves further in vivo research, followed by clinical investigation.


Asunto(s)
Antineoplásicos , Glioblastoma , Plantas Medicinales , Glioblastoma/tratamiento farmacológico , Extractos Vegetales/química , Angiogénesis , Plantas Medicinales/química , Antineoplásicos/farmacología , Apoptosis , Línea Celular Tumoral
3.
Clin Infect Dis ; 72(3): 423-430, 2021 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-31965155

RESUMEN

BACKGROUND: In Melanesia, the prevalence of trachomatous inflammation-follicular (TF) suggests that public health-level interventions against active trachoma are needed. However, the prevalence of trachomatous trichiasis is below the threshold for elimination as a public health problem and evidence of conjunctival infection with trachoma's causative organism (Chlamydia trachomatis [CT]) is rare. Here, we examine the prevalence of ocular infection with CT and previous exposure to CT in three evaluation units (EUs) of Papua New Guinea. METHODS: All individuals aged 1-9 years who were examined for clinical signs of trachoma in 3 Global Trachoma Mapping Project EUs were eligible to take part in this study (N = 3181). Conjunctival swabs were collected from 349 children with TF and tested by polymerase chain reaction to assess for ocular CT infection. Dried blood spots were collected from 2572 children and tested for anti-Pgp3 antibodies using a multiplex assay. RESULTS: The proportion of children with TF who had CT infection was low across all 3 EUs (overall 2%). Anti-Pgp3 seroprevalence was 5.2% overall and there was no association between anti-Pgp3 antibody level and presence of TF. In 2 EUs, age-specific seroprevalence did not increase significantly with increasing age in the 1- to 9-year-old population. In the third EU, there was a statistically significant change with age but the overall seroprevalence and peak age-specific seroprevalence was very low. CONCLUSIONS: Based on these results, together with similar findings from the Solomon Islands and Vanuatu, the use of TF to guide antibiotic mass drug administration decisions in Melanesia should be reviewed.


Asunto(s)
Tracoma , Niño , Preescolar , Chlamydia trachomatis , Humanos , Lactante , Recién Nacido , Melanesia , Papúa Nueva Guinea/epidemiología , Prevalencia , Estudios Seroepidemiológicos , Tracoma/epidemiología
4.
Cell Physiol Biochem ; 55(6): 773-783, 2021 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-34907696

RESUMEN

The importance of Alzheime's Disease (AD) research has never been greater from a worldwide perspective with the disease becoming increasingly prevalent with life expectancy on the rise. One emerging factor that has presented as a serious risk that still requires more research and understanding is the role and effects of Apolipoprotein E4 (ApoE4). When present, individuals are three times more likely to develop AD in their lifetime. This is due to ApoE4's ability to not only increase amyloid beta plaque aggregation ApoE4 also increases hyperphosphorylation of tau causing neurofibrillary tangles. These two factors are the well-known hallmarks for AD, which increase the importance for ApoE4 research as it affects both major aspects. Treatment for AD has always been an issue due to a variety of factors with only a few approved for use today. These approved treatments are only to ease and supress symptoms rather than treating the disease. Dementia symptoms such as memory loss, language problems, motor skills, irritability and paranoia are all symptoms that destroy patient's ability to function in their communities. Inhibiting ApoE4 and reducing its toxic effects is a promising theory that has the ability to extend AD patients' lifespan and prolong capable brain function limiting brain tissue degradation.


Asunto(s)
Enfermedad de Alzheimer/prevención & control , Péptidos beta-Amiloides/antagonistas & inhibidores , Apolipoproteína E4/antagonistas & inhibidores , Inhibidores de la Colinesterasa/uso terapéutico , Células Madre Pluripotentes Inducidas/efectos de los fármacos , Terapia Molecular Dirigida/métodos , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Apolipoproteína E4/metabolismo , COVID-19/metabolismo , COVID-19/prevención & control , COVID-19/virología , Interacciones Huésped-Patógeno/efectos de los fármacos , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Células Madre Pluripotentes Inducidas/virología , SARS-CoV-2/efectos de los fármacos , SARS-CoV-2/fisiología
5.
BMC Med Educ ; 20(1): 437, 2020 Nov 16.
Artículo en Inglés | MEDLINE | ID: mdl-33198737

RESUMEN

BACKGROUND: Medical treatment informed by Precision Medicine is becoming a standard practice for many diseases, and patients are curious about the consequences of genomic variants in their genome. However, most medical students' understanding of Precision Medicine derives from classroom lectures. This format does little to foster an understanding for the potential and limitations of Precision Medicine. To close this gap, we implemented a hands-on Precision Medicine training program utilizing exome sequencing to prepare a clinical genetic report of cadavers studied in the anatomy lab. The program reinforces Precision Medicine related learning objectives for the Genetics curriculum. METHODS: Pre-embalmed blood samples and embalmed tissue were obtained from cadavers (donors) used in the anatomy lab. DNA was isolated and sequenced and illustrative genetic reports provided to the students. The reports were used to facilitate discussion with students on the implications of pathogenic genomic variants and the potential correlation of these variants in each "donor" with any anatomical anomalies identified during cadaver dissection. RESULTS: In 75% of cases, analysis of whole exome sequencing data identified a variant associated with increased risk for a disease/abnormal condition noted in the donor's cause of death or in the students' anatomical findings. This provided students with real-world examples of the potential relationship between genomic variants and disease risk. Our students also noted that diseases associated with 92% of the pathogenic variants identified were not related to the anatomical findings, demonstrating the limitations of Precision Medicine. CONCLUSION: With this study, we have established protocols and classroom procedures incorporating hands-on Precision Medicine training in the medical student curriculum and a template for other medical educators interested in enhancing their Precision Medicine training program. The program engaged students in discovering variants that were associated with the pathophysiology of the cadaver they were studying, which led to more exposure and understanding of the potential risks and benefits of genomic medicine.


Asunto(s)
Anatomía , Educación de Pregrado en Medicina , Estudiantes de Medicina , Anatomía/educación , Cadáver , Curriculum , Humanos , Medicina de Precisión , Análisis de Secuencia de ADN
6.
J Cell Physiol ; 230(5): 1115-27, 2015 May.
Artículo en Inglés | MEDLINE | ID: mdl-25303541

RESUMEN

The present studies determined whether clinically relevant phosphodiesterase 5 (PDE5) inhibitors interacted with a clinically relevant NSAID, celecoxib, to kill tumor cells. Celecoxib and PDE5 inhibitors interacted in a greater than additive fashion to kill multiple tumor cell types. Celecoxib and sildenafil killed ex vivo primary human glioma cells as well as their associated activated microglia. Knock down of PDE5 recapitulated the effects of PDE5 inhibitor treatment; the nitric oxide synthase inhibitor L-NAME suppressed drug combination toxicity. The effects of celecoxib were COX2 independent. Over-expression of c-FLIP-s or knock down of CD95/FADD significantly reduced killing by the drug combination. CD95 activation was dependent on nitric oxide and ceramide signaling. CD95 signaling activated the JNK pathway and inhibition of JNK suppressed cell killing. The drug combination inactivated mTOR and increased the levels of autophagy and knock down of Beclin1 or ATG5 strongly suppressed killing by the drug combination. The drug combination caused an ER stress response; knock down of IRE1α/XBP1 enhanced killing whereas knock down of eIF2α/ATF4/CHOP suppressed killing. Sildenafil and celecoxib treatment suppressed the growth of mammary tumors in vivo. Collectively our data demonstrate that clinically achievable concentrations of celecoxib and sildenafil have the potential to be a new therapeutic approach for cancer.


Asunto(s)
Apoptosis/efectos de los fármacos , Neoplasias/patología , Inhibidores de Fosfodiesterasa 5/farmacología , Pirazoles/farmacología , Sulfonamidas/farmacología , Animales , Autofagia/efectos de los fármacos , Celecoxib , Línea Celular Tumoral , Sinergismo Farmacológico , Estrés del Retículo Endoplásmico/efectos de los fármacos , Femenino , Humanos , Neoplasias Mamarias Experimentales/patología , Ratones Desnudos , Piperazinas , Purinas , Transducción de Señal/efectos de los fármacos , Citrato de Sildenafil
8.
Ir J Med Sci ; 193(2): 677-688, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-37737916

RESUMEN

Cardiac myxomas (CM) are one of the most common benign tumors which are typical in adults with a yearly incidence of 0.5-1 case per million individuals. This review article includes discussions based on existing literature on the role of interleukin interactions in the pathophysiology of cardiac myxoma which can lead to embolic complications, aneurysms, and CNS involvement. The objective of this narrative review was to study the variable clinical presentations of cardiac myxoma, its detection and diagnosis involving multiple modalities like genetic and hematological testing, echocardiography, CT, and MRI, of which transoesophageal echocardiogram shows excellent precision with a 90% to 96% accuracy in diagnosing CM. Individuals with the Carney complex are prone to such neoplasia. Cardiac myxomas are challenging to diagnose due to the ambiguity of their differential with thrombi. Myxomas can also be diagnosed by tumor markers like interleukin-6 and endothelial growth factors. The management of CM includes surgical excision like median sternotomy and robotic minimally invasive surgery. The use of robotic surgery in CM increased from 1.8% in 2012 to 15.1% in 2018. Tumor recurrences are uncommon but can occur due to inadequate surgical resection.


Asunto(s)
Neoplasias Cardíacas , Mixoma , Adulto , Humanos , Recurrencia Local de Neoplasia , Neoplasias Cardíacas/diagnóstico , Neoplasias Cardíacas/cirugía , Neoplasias Cardíacas/patología , Mixoma/complicaciones , Mixoma/diagnóstico , Mixoma/cirugía , Ecocardiografía , Imagen por Resonancia Magnética
9.
Ann Am Thorac Soc ; 21(4): 627-634, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38285910

RESUMEN

Rationale: A recent randomized controlled trial revealed that a multicomponent sepsis transition and recovery (STAR) program delivered through specialized nurse navigators was effective in reducing a composite of 30-day readmission and mortality. Better understanding of patterns of care provided by the STAR program is needed to promote implementation and dissemination of this effective program.Objectives: This study characterizes individual care activities and distinct "packages" of care delivered by the STAR program.Methods: We performed a secondary analysis of data from the intervention arm of the IMPACTS (Improving Morbidity during Post-Acute Care Transitions for Sepsis) randomized controlled trial, conducted at three urban hospitals in the southeastern United States from January 2019 to March 2020. We used a structured data collection process to identify STAR nurse navigator care activities from electronic health record documentation. We then used latent class analysis to identify groups of patients receiving distinct combinations of intervention components. We evaluated differences in patient characteristics and outcomes between groups receiving distinct intervention packages.Results: The 317 sepsis survivors enrolled into the intervention arm of the IMPACTS trial received one or more of nine unique care activities delivered by STAR nurse navigators (care coordination, health promotion counseling, emotional listening, symptom management, medication management, chronic disease management, addressing social determinants of health, care setting advice and guidance, and primary palliative care). Patients received a median of three individual care activities (interquartile range, 2-5). Latent class analysis revealed four distinct packages of care activities delivered to patients with different observable characteristics and different frequency of 30-day readmission and mortality.Conclusions: We identified nine care activities delivered by an effective STAR program and four distinct latent classes or packages of intervention delivery. These results can be leveraged to increase widespread implementation and provide targets to augment future program delivery.


Asunto(s)
Sepsis , Humanos , Sepsis/terapia , Sudeste de Estados Unidos
10.
Ophthalmic Epidemiol ; : 1-8, 2024 Feb 08.
Artículo en Inglés | MEDLINE | ID: mdl-38329811

RESUMEN

PURPOSE: The prevalence of trachomatous inflammation-follicular (TF) in Papua New Guinea (PNG) suggests antibiotic mass drug administration (MDA) is needed to eliminate trachoma as a public health problem but the burden of trichiasis is low. As a result, WHO issued bespoke recommendations for the region. If ≥ 20% of 10-14-year-olds have both any conjunctival scarring (C1 or C2 or C3) and corneal pannus and/or Herbert's pits, MDA should be continued. Equally, if ≥ 5% of that group have both moderate/severe conjunctival scarring (C2 or C3) and corneal pannus and/or Herbert's pits, MDA should be continued. METHODS: We identified 14 villages where > 20% of 1-9-year-olds had TF during baseline mapping undertaken 4 years and 1 month previously. Every child aged 10-14 years in those villages was eligible to be examined for clinical signs of corneal pannus, Herbert's pits and conjunctival scarring. A grading system that built on existing WHO grading systems was used. RESULTS: Of 1,293 resident children, 1,181 (91%) were examined. Of 1,178 with complete examination data, only one (0.08%) individual had concurrent scarring and limbal signs. CONCLUSIONS: The WHO-predefined criteria for continuation of MDA were not met. Ongoing behavioural and environmental improvement aspects of the SAFE strategy may contribute to integrated NTD control. Surveillance methods should be strengthened to enable PNG health authorities to identify future changes in disease prevalence.

11.
Cureus ; 15(10): e47139, 2023 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-38021721

RESUMEN

Methicillin-resistant Staphylococcus aureus (MRSA) is a common hospital-acquired pathogen and can cause a wide spectrum of infections. In recent years, MRSA has emerged as a significant public health concern, particularly in hospitals. Intensive care units (ICUs) and burn units are high-risk areas for hospital-acquired MRSA infections, which can lead to increased morbidity, mortality, and healthcare costs. MRSA exhibits resistance to multiple antibiotics and can cause serious infections, including but not limited to pneumonia, endocarditis, and cutaneous infections, particularly in patients with burn injuries. The prevention and effective management of MRSA infections in both burn patients and those in ICUs is crucial, with strategies like isolation, regular disinfection, and prophylactic intranasal mupirocin. Early diagnosis of MRSA infection and isolation of patients is vital to prevent the spread of MRSA. Implementation of prevention strategies faces many challenges, such as cost, and the most successful infection management practices are still debated. This review has highlighted the substantial concern of MRSA colonization in intensive care and burn units. MRSA poses a significant risk to vulnerable patients, influenced by factors such as compromised immunity and invasive procedures. The prevalence of MRSA colonization varies, influenced by regional factors and infection control practices. Combating MRSA requires a multifaceted approach, including stringent infection control measures and education for healthcare workers and patients. As we move forward, continued research and cooperation are essential to reduce the burden of MRSA in these critical care settings.

12.
BMJ Case Rep ; 16(2)2023 Feb 09.
Artículo en Inglés | MEDLINE | ID: mdl-36759040

RESUMEN

A full-term infant developed stridor, respiratory distress and hypercarbia shortly after birth requiring urgent airway intervention. The patient underwent urgent intubation via rigid bronchoscopy. The diagnosis of congenital subglottic cyst was made. The cyst was decompressed and the patient was extubated the following day. On repeat laryngoscopy 1 month later, there was no residual disease and the patient remained symptom free. Congenital subglottic cysts are extremely rare and the diagnosis can be either missed or misdiagnosed with more common causes of stridor, such as laryngomalacia. Subglottic cysts may cause total airway obstruction and even death if they are large enough and not treated immediately.


Asunto(s)
Obstrucción de las Vías Aéreas , Quistes , Enfermedades de la Laringe , Laringomalacia , Enfermedades Pulmonares Obstructivas , Recién Nacido , Lactante , Humanos , Ruidos Respiratorios/etiología , Enfermedades de la Laringe/complicaciones , Enfermedades de la Laringe/diagnóstico , Enfermedades de la Laringe/cirugía , Laringomalacia/cirugía , Obstrucción de las Vías Aéreas/complicaciones , Laringoscopía/efectos adversos , Quistes/diagnóstico , Quistes/diagnóstico por imagen
13.
Injury ; 52(3): 487-492, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33755550

RESUMEN

AIM: A fracture of the tuberosity is associated with 16% of glenohumeral dislocations. Extension of the fracture into the humeral neck can occur during closed manipulation, leading some to suggest that all such injures should be managed under general anaesthesia in the operating theatre. The purpose of this study was to establish the safety of reduction of glenohumeral dislocations with tuberosity fractures in the emergency department (ED). PATIENTS AND METHODS: We reviewed 188 consecutive glenohumeral dislocations with associated tuberosity fractures identified from a prospective orthopaedic trauma database. Patient demographics, injury details, emergency department management and complications were recorded. The method of reduction, sedation, grade of clinician and outcome were documented. RESULTS: The mean age was 61 years (range 18-96 years) with 79 males and 109 females. The majority of injuries (146, 78%) occurred after a fall from standing height. Closed reduction under sedation in the ED was successful in 162 (86%) cases. Of the remainder, 22 (11%) failed closed reduction under sedation and subsequently went to theatre and 6 (3%) were deemed not suitable for ED manipulation. At presentation 35 (19%) patients had a nerve injury, of which 29 (90%) resolved spontaneously. Two iatrogenic fractures occurred during close manipulation, one in the ED and the other in the operating theatre. Therefore, the risk of iatrogenic propagation of the fracture into the proximal humerus neck was 0.5% if the reduction was performed in the ED, and 1% over-all. More than two attempted reductions predicted a failed ED reduction (P = 0.001). CONCLUSION: Closed reduction of glenohumeral dislocations with associated tuberosity fractures in the ED is safe, with a rate of iatrogenic fracture of 1%. These injuries should be managed by those with appropriate experience only after two adequate radiographic views. In cases where there is ambiguity over the integrity of the humeral neck, reduction should be delayed until multiplanar CT imaging has been obtained.


Asunto(s)
Luxación del Hombro , Fracturas del Hombro , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Servicio de Urgencia en Hospital , Femenino , Humanos , Húmero , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Luxación del Hombro/diagnóstico por imagen , Luxación del Hombro/terapia , Fracturas del Hombro/diagnóstico por imagen , Fracturas del Hombro/cirugía , Adulto Joven
14.
Injury ; 52(4): 1042-1047, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33268080

RESUMEN

BACKGROUND: Percutaneous fixation of Lisfranc injuries is potentially less invasive to traditional open techniques but evidence of any clinical benefit is lacking. The aim of this study is to compare the clinical outcomes of percutaneous reduction and internal fixation (PRIF) of low energy Lisfranc injuries with a matched, control group of patients treated with ORIF. METHODS: Over a seven-year period (2012-2019), 16 consecutive patients with a low energy Lisfranc injury (Myerson B2-type) were treated with PRIF. Patient demographics, injury mechanism and radiological outcomes were recorded within a prospectively maintained database at the institution. This study sample was matched for age, sex and mechanism of injury to a control group of 16 patients with similar low energy Lisfranc injuries (Myerson B2-type) treated with ORIF. Clinical outcome was compared using the American Orthopaedic Foot and Ankle Society (AOFAS) midfoot score and Manchester Oxford Foot Questionnaire (MOXFQ). RESULTS: At a mean follow up of 43 months (95% CI 35.6 - 50.4), both the AOFAS and MOXFQ scores were significantly higher in the PRIF group compared to the control ORIF group (AOFAS 89.1vs 76.4, p=0.03; MOXFQ 10.0 vs 27.6, p=0.03). There were no immediate postoperative complications in either group. There was no radiological evidence of midfoot osteoarthritis in the PRIF group, three patients in the ORIF group developed midfoot osteoarthritis (p=0.2). CONCLUSIONS: PRIF of low energy Lisfranc injures is a safe, minimally invasive technique and is associated with better mid-term clinical outcomes compared to ORIF.


Asunto(s)
Fracturas Óseas , Artrodesis , Estudios de Casos y Controles , Estudios de Seguimiento , Fijación Interna de Fracturas , Fracturas Óseas/diagnóstico por imagen , Fracturas Óseas/cirugía , Humanos , Estudios Retrospectivos , Resultado del Tratamiento
15.
Cancers (Basel) ; 13(9)2021 May 03.
Artículo en Inglés | MEDLINE | ID: mdl-34063683

RESUMEN

Mechanistic in silico models can provide insight into biological mechanisms and highlight uncertainties for experimental investigation. Radiation-induced double-strand breaks (DSBs) are known to be toxic lesions if not repaired correctly. Non-homologous end joining (NHEJ) is the major DSB-repair pathway available throughout the cell cycle and, recently, has been hypothesised to consist of a fast and slow component in G0/G1. The slow component has been shown to be resection-dependent, requiring the nuclease Artemis to function. However, the pathway is not yet fully understood. This study compares two hypothesised models, simulating the action of individual repair proteins on DSB ends in a step-by-step manner, enabling the modelling of both wild-type and protein-deficient cell systems. Performance is benchmarked against experimental data from 21 cell lines and 18 radiation qualities. A model where resection-dependent and independent pathways are entirely separated can only reproduce experimental repair kinetics with additional restraints on end motion and protein recruitment. However, a model where the pathways are entwined was found to effectively fit without needing additional mechanisms. It has been shown that DaMaRiS is a useful tool when analysing the connections between resection-dependent and independent NHEJ repair pathways and robustly matches with experimental results from several sources.

16.
J Immunother Cancer ; 9(10)2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-34607896

RESUMEN

BACKGROUND: Treatment with immune checkpoint inhibitors (ICIs) has been associated with an increased rate of cardiac events. There are limited data on the risk factors that predict cardiac events in patients treated with ICIs. Therefore, we created a machine learning (ML) model to predict cardiac events in this at-risk population. METHODS: We leveraged the CancerLinQ database curated by the American Society of Clinical Oncology and applied an XGBoosted decision tree to predict cardiac events in patients taking programmed death receptor-1 (PD-1) or programmed death ligand-1 (PD-L1) therapy. All curated data from patients with non-small cell lung cancer, melanoma, and renal cell carcinoma, and who were prescribed PD-1/PD-L1 therapy between 2013 and 2019, were used for training, feature interpretation, and model performance evaluation. A total of 356 potential risk factors were included in the model, including elements of patient medical history, social history, vital signs, common laboratory tests, oncological history, medication history and PD-1/PD-L1-specific factors like PD-L1 tumor expression. RESULTS: Our study population consisted of 4960 patients treated with PD-1/PD-L1 therapy, of whom 418 had a cardiac event. The following were key predictors of cardiac events: increased age, corticosteroids, laboratory abnormalities and medications suggestive of a history of heart disease, the extremes of weight, a lower baseline or on-treatment percentage of lymphocytes, and a higher percentage of neutrophils. The final model predicted cardiac events with an area under the curve-receiver operating characteristic of 0.65 (95% CI 0.58 to 0.75). Using our model, we divided patients into low-risk and high-risk subgroups. At 100 days, the cumulative incidence of cardiac events was 3.3% in the low-risk group and 6.1% in the high-risk group (p<0.001). CONCLUSIONS: ML can be used to predict cardiac events in patients taking PD-1/PD-L1 therapy. Cardiac risk was driven by immunological factors (eg, percentage of lymphocytes), oncological factors (eg, low weight), and a cardiac history.


Asunto(s)
Enfermedades Cardiovasculares/inducido químicamente , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Aprendizaje Automático/normas , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad
17.
J Emerg Med ; 36(1): 55-9, 2009 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-18325713

RESUMEN

Duplex ultrasound (US) is used to "rule out" deep venous thrombosis (DVT), but can also diagnose other causes of leg pain or swelling in Emergency Department (ED) patients. Recent literature suggests that US imaging is unnecessary among patients with low or moderate clinical probability of DVT with a normal D-dimer. We attempted to determine the incidence of clinically important incidental findings detected using venous US imaging in patients with suspected lower extremity DVT. We conducted a retrospective chart review of all ultrasounds performed by the non-invasive vascular laboratory on ED patients > 18 years old. Results were classified: normal, DVT, or incidental finding. The latter were classified as clinically significant major findings if the diagnosis led to immediate and specific treatment to prevent morbidity, or clinically significant minor findings. A total of 484 US studies were reviewed; 179 were excluded (arterial studies, penetrating trauma, upper extremity US). Findings among 305 studies were: 238 (78%) normal, 28 (9%) DVT, and 39 (12%) incidental findings. Among 39 incidental findings, 10 were clinically significant major findings and 29 clinically significant minor findings. Clinically significant major findings included: pseudoaneurysm, arterial occlusive disease, vascular graft complication, compartment syndrome, and tumor. Among 38 abnormal US studies that required immediate treatment, DVT comprised 74% (95% confidence interval 59%-85%) and important major incidental findings 26% (95% confidence interval 14%-41%). Among ED patients who underwent US to evaluate leg pain and swelling, 26% of positive studies showed clinically important findings other than DVT. Further research is needed to determine if D-dimer plus a clinical probability tool will include or exclude the patients with clinically significant major findings.


Asunto(s)
Hallazgos Incidentales , Trombosis de la Vena/diagnóstico por imagen , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Servicio de Urgencia en Hospital , Femenino , Productos de Degradación de Fibrina-Fibrinógeno/análisis , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Ultrasonografía , Trombosis de la Vena/sangre , Adulto Joven
18.
PLoS One ; 14(12): e0225216, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31830051

RESUMEN

Microsatellites-a type of short tandem repeat (STR)-have been used for decades as putatively neutral markers to study the genetic structure of diverse human populations. However, recent studies have demonstrated that some microsatellites contribute to gene expression, cis heritability, and phenotype. As a corollary, some microsatellites may contribute to differential gene expression and RNA/protein structure stability in distinct human populations. To test this hypothesis, we investigate genotype frequencies, functional relevance, and adaptive potential of microsatellites in five super-populations (ethnicities) drawn from the 1000 Genomes Project. We discover 3,984 ethnically-biased microsatellite loci (EBML); for each EBML at least one ethnicity has genotype frequencies statistically different from the remaining four. South Asian, East Asian, European, and American EBML show significant overlap; on the contrary, the set of African EBML is mostly unique. We cross-reference the 3,984 EBML with 2,060 previously identified expression STRs (eSTRs); repeats known to affect gene expression (64 total) are over-represented. The most significant pathway enrichments are those associated with the matrisome: a broad collection of genes encoding the extracellular matrix and its associated proteins. At least 14 of the EBML have established links to human disease. Analysis of the 3,984 EBML with respect to known selective sweep regions in the genome shows that allelic variation in some of them is likely associated with adaptive evolution.


Asunto(s)
Etnicidad/genética , Genoma Humano , Genotipo , Repeticiones de Microsatélite , Alelos , Frecuencia de los Genes , Humanos , Polimorfismo de Nucleótido Simple
19.
Br J Ophthalmol ; 103(3): 338-342, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-29793925

RESUMEN

OBJECTIVE: To estimate the prevalence and main causes of blindness and vision impairment in people aged 50 years and older in Papua New Guinea (PNG). DESIGN: National cross-sectional population-based survey in National Capital District (NCD), Highlands, Coastal and Islands regions. METHODS: Adults aged 50 years and above were recruited from 100 randomly selected clusters. Each participant underwent monocular presenting and pinhole visual acuity (VA) assessment and lens examination. Those with pinhole VA<6/12 in either eye had a dilated fundus examination to determine the primary cause of reduced vision. Those with obvious lens opacity were interviewed on barriers to cataract surgery. RESULTS: A total of 4818 adults were examined. The age-adjusted and sex-adjusted prevalence of blindness (VA <3/60), severe vision impairment (SVI, VA <6/60 but ≥3/60), moderate vision impairment (MVI, VA <6/18 but ≥6/60) and early vision impairment (EVI, VA <6/12 but ≥6/18) was 5.6% (95% CI 4.9% to 6.3%), 2.9% (95% CI 2.5% to 3.4%), 10.9% (95% CI 9.9% to 11.9%) and 7.3% (95% CI 6.6% to 8.0%), respectively. The main cause of blindness, SVI and MVI was cataract, while uncorrected refractive error was the main cause of EVI. A significantly higher prevalence of blindness, SVI and MVI occurred in the Highlands compared with NCD. Across all regions, women had lower cataract surgical coverage and spectacle coverage than men. CONCLUSIONS: PNG has one of the highest reported prevalence of blindness globally. Cataract and uncorrected refractive error are the main causes, suggesting a need for increased accessible services with improved resources and advocacy for enhancing eye health literacy.


Asunto(s)
Ceguera/epidemiología , Baja Visión/epidemiología , Personas con Daño Visual/estadística & datos numéricos , Distribución por Edad , Anciano , Anciano de 80 o más Años , Ceguera/diagnóstico , Ceguera/prevención & control , Catarata/epidemiología , Estudios Transversales , Femenino , Accesibilidad a los Servicios de Salud , Necesidades y Demandas de Servicios de Salud , Encuestas Epidemiológicas , Humanos , Masculino , Persona de Mediana Edad , Papúa Nueva Guinea/epidemiología , Prevalencia , Distribución por Sexo , Baja Visión/diagnóstico , Baja Visión/prevención & control , Agudeza Visual
20.
Br J Ophthalmol ; 103(6): 743-747, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-29973367

RESUMEN

BACKGROUND/AIMS: To conduct an assessment of avoidable blindness, diabetes mellitus and diabetic retinopathy (DR) in adults aged 50 years and older in the National Capital District (NCD) region of Papua New Guinea (PNG). METHODS: A cross-sectional population-based survey was performed for which 25 clusters of 50 people aged ≥50 years were randomly selected from the NCD region. The standardised rapid assessment of avoidable blindness (RAAB) with diabetic retinopathy (+DR) methodology was used. Blindness was defined as presenting visual acuity <3/60 in the better eye. Participants were classified as having diabetes if they were known to have diabetes or if their random blood glucose level was ≥200 mg/dL. Dilated fundus examination and Scottish DR grading were performed. RESULTS: In total, 1192 out of 1250 eligible participants (95.4%) were examined. Of these, 7.8% had known or newly diagnosed diabetes. Seventy-one per cent of participants with known diabetes had a blood glucose level ≥200 mg/dL, and 82.9% had never had an ophthalmological examination for DR. Prevalence of DR and/or maculopathy was 46.4%. The age-adjusted and sex-adjusted prevalence of diabetes was estimated at 8.1% (95% CI 5.7% to 10.4%) in the population aged 50 years or older in the NCD region of PNG. CONCLUSIONS: Prevalence of diabetes in adults aged 50 years and older was lower than reported elsewhere in the region, and lower than other RAAB+DR surveys. Despite this, the prevalence of DR is high compared with other RAAB+DR surveys and demonstrates the need for increased awareness and accessibility to eye services for people with diabetes.


Asunto(s)
Ceguera/epidemiología , Retinopatía Diabética/complicaciones , Encuestas Epidemiológicas , Medición de Riesgo/métodos , Agudeza Visual , Distribución por Edad , Anciano , Anciano de 80 o más Años , Ceguera/diagnóstico , Ceguera/etiología , Estudios Transversales , Retinopatía Diabética/diagnóstico , Retinopatía Diabética/epidemiología , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Papúa Nueva Guinea/epidemiología , Prevalencia , Estudios Retrospectivos , Factores de Riesgo
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