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The activation of the NLRP3 inflammasome has been linked to several inflammatory and autoinflammatory diseases. Despite cases of potential hearing improvement in immune-mediated diseases, direct evidence of the efficacy of targeting this mechanism in the inner ear is still lacking. Previously, we discovered that macrophages are associated with Sensorineural Hearing loss (SNHL) in Chronic Suppurative Otitis Media (CSOM), the leading cause of this permanent hearing loss in the developing world and incurring costs of $4 to $11 billion dollars in the United States. However, the underlying mechanism remained unknown. Here, we investigate how macrophages drive permanent hearing loss in CSOM. We first confirmed the occurrence of NLRP3 inflammasome activation in cochlear macrophages in CSOM. We then revealed that Outer Hair Cells (OHCs) were protected in CSOM by macrophage depletion and subsequently confirmed the same protection in the NLRP3 knockout condition. Furthermore, we showed that therapeutic inhibition of NLRP3 inflammasome activation and downstream inhibition of IL-1ß protects OHCs in CSOM. Collectively, our data demonstrates that the main driver for hearing loss in CSOM is NLRP3 inflammasome activation in cochlear macrophages and this is therapeutically targetable, leading the way for the development of interventions to prevent the leading cause of permanent hearing loss and a costly disease in the developed world.
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Cóclea , Inflamasomas , Macrófagos , Ratones Endogámicos C57BL , Proteína con Dominio Pirina 3 de la Familia NLR , Otitis Media Supurativa , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/antagonistas & inhibidores , Animales , Macrófagos/metabolismo , Ratones , Inflamasomas/metabolismo , Cóclea/metabolismo , Cóclea/patología , Enfermedad Crónica , Ratones Noqueados , Masculino , Humanos , Pérdida Auditiva/etiología , Pérdida Auditiva/prevención & control , Femenino , Interleucina-1beta/metabolismo , Modelos Animales de EnfermedadRESUMEN
PURPOSE: Assessing immune-related ocular toxicities from immune checkpoint inhibitors (ICIs) is crucial, though rare. This study, utilizing real-world data, examines the occurrence of ophthalmic immune-related adverse events (irAEs) after ICI treatment and their impact on overall survival. DESIGN: A retrospective cohort study METHODS: Data were obtained from TriNetX, an aggregated electronic health records database. Patients who developed ophthalmic irAEs within 1 year after the first instance of ICI therapy were included. Participants with defined ocular toxicities 6 months before ICI treatment were excluded. Subjects were paired with controls using propensity scores derived from demographics and cancer type. A Cox proportional hazard model was used to determine hazard ratios. A Kaplan-Meier survival function was evaluated with the log-rank test based on the development of ophthalmic irAEs in a 12-month landmark analysis. RESULTS: A cohort of 41,020 patients comprising 57.4% males with a mean age of 65.2±11.9 years was included. The five most prevalent ophthalmic irAEs in this cohort were dry eye syndrome (2%), conjunctivitis (0.87%), blepharitis (0.51%), anterior uveitis (0.39%), and keratitis (0.38%). Dry eye syndrome was the most common irAE among all ICI classes. Subjects taking CTLA-4 inhibitor plus PD-1 inhibitor and CTLA-4 inhibitors had higher rates of anterior uveitis (1.39% and 1.29%, respectively) than PD-1 inhibitors (0.27%) and PD-L1 inhibitors (0.14%) within 1 year after taking ICI. After a 12-month landmark analysis, there was a significant decreased chance of survival for the following categories: any ophthalmic irAE (HR, 1.37; 95% CI, 1.20-1.56; P < 0.0001), neuro-ophthalmic irAE (HR, 1.53; 95% CI, 1.09-2.14; Pâ¯=â¯0.0124), and cornea and ocular surface irAE (HR, 1.34; 95% CI, 1.15-1.56; P < 0.0001). CONCLUSIONS: Ophthalmic irAEs involving the anterior segment are more frequent than the posterior segment, regardless of ICI class. Ophthalmic irAEs may also portend decreased survival. This insight could help guide clinicians aggressively manage irAEs and allow patients to continue ICI therapy despite having ocular issues.
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Chronic suppurative otitis media (CSOM) is a neglected disease that afflicts 330 million people worldwide and is the most common cause of permanent hearing loss among children in the developing world. Previously, we discovered that outer hair cell (OHC) loss occurred in the basal turn of the cochlea and that macrophages are the major immune cells associated with OHC loss in CSOM. Macrophage-associated cytokines are upregulated. Specifically, CCL-2, an important member of the MCP family, is elevated over time following middle ear infection. CCR2 is a common receptor of the MCP family and the unique receptor of CCL2. CCR2 knockout mice (CCR2-/-) have been used extensively in studies of monocyte activation in neurodegenerative diseases. In the present study, we investigated the effect of CCR2 deletion on the cochlear immune response and OHC survival in CSOM. The OHC survival rate was 84 ± 12.5% in the basal turn of CCR2+/+ CSOM cochleae, compared with was 63 ± 19.9% in the basal turn of CCR2-/- CSOM cochleae (p ≤ 0.05). Macrophage numbers were significantly reduced in CCR2-/- CSOM cochleae compared with CCR2+/+ CSOM cochleae (p ≤ 0.001). In addition, CCL7 was upregulated, whereas IL-33 was downregulated, in CCR2-/- CSOM cochleae. Finally, the permeability of the blood-labyrinth barrier in the stria vascularis remained unchanged in CCR2-/- CSOM compared with CCR2+/+ CSOM. Taken together, the data suggest that CCR2 plays a protective role through cochlear macrophages in the CSOM cochlea.
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Células Ciliadas Auditivas Externas , Ratones Noqueados , Otitis Media Supurativa , Receptores CCR2 , Animales , Otitis Media Supurativa/inmunología , Ratones , Receptores CCR2/metabolismo , Receptores CCR2/genética , Células Ciliadas Auditivas Externas/metabolismo , Células Ciliadas Auditivas Externas/patología , Enfermedad Crónica , Macrófagos/inmunología , Macrófagos/metabolismo , Cóclea/metabolismo , Cóclea/patología , Cóclea/inmunología , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Quimiocina CCL2/metabolismo , Quimiocina CCL2/genética , Masculino , FemeninoRESUMEN
Epistaxis is common worldwide otorhinolaryngology emergency presenting as a life-threatening condition especially in resource-constrained hospitals with limited health-care facilities for acceptable management. The aim of this study is to find out the common causes of epistaxis. It was a cross sectional study. It was carried out on 304 patients who presented with epistaxis at tertiary care hospital of Central India (Peoples College of Medical Science & Research Centre, Bhopal). It was found that among 304 participants, maximum number of patients with epistaxis were of age group 21-30 years i.e. 66 (21.71%) with 210 (69.08%) were male and 94 (30.92%) were female. It was found that maximum patients were of nose picking i.e. 113 (37.17%) followed by trauma via accident, assault and fall i.e. 77 (25.33%), followed by hypertension i.e. 49. Epistaxis is a common emergency condition in Otorhinolaryngology. People of all ages can be affected. Hypertension and trauma were the most common etiological/risk factors among the patients in whom etiology was found although in most of the patients etiology could not be found.
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OBJECTIVE: This study aimed to assess the utility of magnetic resonance imaging (MRI) in outpatient evaluation of patients with chronic continuous or recurrent dizziness (CCRD) and determine whether certain patient characteristics, symptoms, or examination findings are associated with diagnostic MRI findings. STUDY DESIGN: Retrospective cohort study. SETTING: Ambulatory center. PATIENTS: 304 patients who received an MRI for CCRD. INTERVENTION: Diagnostic utility of MRI in patients with CCRD. MAIN OUTCOME MEASURE: MRI diagnostic findings in patients with CCRD and associated patient characteristics, symptoms, or examination findings. MATERIALS AND METHODS: In this retrospective analysis, 304 patients who visited an outpatient clinic between 1998 and 2023 and underwent MRI for CCRD, without previously diagnosed neurological abnormalities, were examined. The study investigated the relationship between demographic characteristics, comorbidities, clinical symptoms, and examination findings with diagnostic MRI findings. Univariate analysis was used to identify factors predictive of diagnostic MRI findings. RESULTS: Out of 304 patients, 11 (3.6%; 95% confidence interval [CI], 1.5-5.72%) had diagnostic MRI findings. The most common diagnostic finding (36.4%) was brain metastasis, seen only in patients with previously diagnosed metastatic cancer. Univariate analysis revealed that hypertension (p = 0.004, likelihood ratio [LR] = 2.51), hyperlipidemia (p = 0.004, LR = 2.91), and cancer (p = 0.021, LR = 2.96) were significantly associated with diagnostic MRI findings. Incidental findings were observed in 73 patients (24%; 95% CI, 19.2-28.8%). Outside of cancer patients, six (2.3%; 95% CI, 1.1-5.0%) had diagnostic MRI findings. CONCLUSION: In our study, MRI rarely displayed diagnostic findings in patients with CCRD and normal neurologic examination. However, individuals with hypertension, hyperlipidemia, or cancer were significantly more likely to display positive MRI findings. It is essential to carefully consider the need for MRI when assessing patients with CCRD.
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Mareo , Imagen por Resonancia Magnética , Humanos , Masculino , Femenino , Mareo/diagnóstico por imagen , Persona de Mediana Edad , Estudios Retrospectivos , Anciano , Adulto , Pacientes Ambulatorios , Enfermedad Crónica , Recurrencia , Anciano de 80 o más Años , Neoplasias Encefálicas/diagnóstico por imagenRESUMEN
Laser-induced graphene (LIG) has been emerging as a promising electrode material for supercapacitors due to its cost-effective and straightforward fabrication approach. However, LIG-based supercapacitors still face challenges with limited capacitance and stability. To overcome these limitations, in this work, we present a novel, cost-effective, and facile fabrication approach by integrating LIG materials with candle-soot nanoparticles. The composite electrode is fabricated by laser irradiation on a Kapton sheet to generate LIG material, followed by spray-coating with candle-soot nanoparticles and annealing. Materials characterization reveals that the annealing process enables a robust connection between the nanoparticles and the LIG materials and enhances nanoparticle graphitization. The prepared supercapacitor yields a maximum specific capacitance of 15.1 mF/cm2 at 0.1 mA/cm2, with a maximum energy density of 2.1 µWh/cm2 and a power density of 50 µW/cm2. Notably, the synergistic activity of candle soot and LIG surpasses the performances of previously reported LIG-based supercapacitors. Furthermore, the cyclic stability of the device demonstrates excellent capacitance retention of 80% and Coulombic efficiency of 100% over 10000 cycles.
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BACKGROUND & OBJECTIVES: The purpose of present study is to analyse the distribution and pattern of genetic mutations in PRE-XDR-TB and extensive drug resistant Mycobacterium tuberculosis (XDR-TB) using second-line line probe assay and to compare them with different parameters. METHOD: Sputum, Lymph node aspirate and cold accesses from patients with rifampicin resistant Tuberculosis were subjected to first line and second line Probe Assay (Genotype MTBDRsl by Hain Life Science, Germany) to assess additional drug resistance to fluroquinolones (Levofloxacin & Moxifloxacin) and Aminoglycosides (Amikacin, Ofloxacin and Kanamycin). The genetic mutation pattern was analysed and compared with demographic, clinical and other parameters. RESULTS: The final study population included 123 fluoroquinolone resistant isolates including 14 isolates with additional second line aminoglycosides drug resistance. The most frequent mutation observed among Gyr A drug resistance mutation was D94G (Gyr A MUT3C, 50/123,40%) corresponding to high level resistance to levofloxacin and moxifloxacin. The most frequent wild type mutant among Gyr A gene locus was WT 3 (85/123,69%). The most common mutation among second line aminoglycoside resistant isolates was at eis WT2 (7/14,50%) followed by rrs MUT 2 (4/14,29%). CONCLUSIONS: GyrA MUT3C (Asp94Gly) was the most common mutation in Gyr A gene locus in M. tuberculosis causing high level levofloxacin and moxifloxacin resistance. Patients with Asp94Gly mutation was significantly associated with underweight body mass index (p = 0.026). This study also observed that history of anti-tuberculosis therapy is a risk factor for FQ drug resistance mutations (p < 0.001).
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Antituberculosos , Mutación , Mycobacterium tuberculosis , Humanos , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/efectos de los fármacos , Mycobacterium tuberculosis/aislamiento & purificación , Masculino , Femenino , Adulto , Antituberculosos/farmacología , Antituberculosos/uso terapéutico , Tuberculosis Pulmonar/tratamiento farmacológico , Tuberculosis Pulmonar/microbiología , Persona de Mediana Edad , Tuberculosis Extensivamente Resistente a Drogas/tratamiento farmacológico , Tuberculosis Extensivamente Resistente a Drogas/microbiología , Pruebas de Sensibilidad Microbiana , Fluoroquinolonas/farmacología , Fluoroquinolonas/uso terapéutico , Farmacorresistencia Bacteriana Múltiple/genética , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Tuberculosis Resistente a Múltiples Medicamentos/microbiología , Levofloxacino/farmacología , Levofloxacino/uso terapéutico , Moxifloxacino/uso terapéutico , Moxifloxacino/farmacología , Adulto JovenAsunto(s)
Determinación de la Presión Sanguínea , Humanos , Nueva Zelanda , Determinación de la Presión Sanguínea/instrumentación , Determinación de la Presión Sanguínea/métodos , Instituciones de Salud , Monitores de Presión Sanguínea , Monitoreo Ambulatorio de la Presión Arterial/instrumentación , Monitoreo Ambulatorio de la Presión Arterial/métodosRESUMEN
Background: Nonadherence to medications is a common clinical issue. We describe a case in which weekly visits to assess medication adherence achieved euthyroidism in a patient with persistent primary hypothyroidism and suspected nonadherence to levothyroxine. The patient, however, did not report nonadherence. Case Presentation: A male aged 67 years with multinodular goiter underwent total thyroidectomy for abnormal thyroid nodule biopsy. Surgical pathology revealed papillary thyroid cancer with lymph node metastasis for which he received radioactive iodine treatment. His plasma thyrotropin (TSH) was noted to be 0.28 uIU/mL (reference range 0.35-4.00 uIU/mL) 7 months postsurgery while taking 224 mcg levothyroxine tablets daily. His plasma TSH remained elevated for about 5 years despite titrations of the levothyroxine dosage, counseling, and multiple follow-up visits. A home care nurse was involved in monitoring the patient taking levothyroxine daily and correctly but was unsuccessful. The patient and his son reported taking levothyroxine daily and correctly. The patient was asked to visit the primary care clinic every week for 6 weeks with all his medications. Repeat plasma TSH normalized to 1.01 uIU/mL. The suspected etiology of previously high plasma TSH was nonadherence to levothyroxine, which was discussed in detail with the patient. The patient verbalized understanding, was willing to follow recommendations and ended the weekly clinic visits. Repeat plasma TSH was again high and the patient claimed adherence, but weekly visits to primary care clinic were resumed, and life-threatening consequences of hypothyroidism were discussed with the patient and his son. After 9 weeks of visits, he was noted to have low plasma TSH (0.23 uIU/mL). Conclusions: Weekly visits seem impractical but may help in cases of persistent hypothyroidism in which the patient admits to being or is suspected to be nonadherent to levothyroxine. Knowing their medication use will be checked at weekly clinic visits may motivate the patient to be adherent.
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Living donor liver transplantation (LDLT) needs "Mercedes Benz" or "J-shaped" incision, causing short and long-term complications. An upper midline incision (UMI) is less invasive alternative but technically challenging. Reporting UMI for recipients in LDLT vs. conventional J-shaped incision. Retrospective analysis, July 2021 to December 2022. Peri-operative details and post-transplant outcomes of 115 consecutive adult LDLT recipients transplanted with UMI compared with 140 recipients with J-shaped incision. Cohorts had similar preoperative and intraoperative variables. The UMI group had significant shorter time to ambulation (3 ± 1.6 vs. 3.6 ± 1.3 days, p = 0.001), ICU stay (3.8 ± 1.3 vs. 4.4 ± 1.5 days, p = 0.001), but a similar hospital stay (15.6±7.6 vs. 16.1±10.9 days, p = 0.677), lower incidence of pleural effusion (11.3% vs. 27.1% p = 0.002), and post-operative ileus (1.7% vs. 9.3% p = 0.011). The rates of graft dysfunction (4.3% vs. 8.5% p = 0.412), biliary complications (6.1% vs. 12.1% p = 0.099), 90-day mortality (7.8% vs. 12.1% p = 0.598) were similar. UMI-LDLT afforded benefits such as reduced pleuropulmonary complications, better early post-operative recovery and reduction in scar-related complaints in the medium-term. This is a safe, non-inferior and reproducible technique for LDLT.
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Trasplante de Hígado , Donadores Vivos , Complicaciones Posoperatorias , Humanos , Trasplante de Hígado/métodos , Trasplante de Hígado/efectos adversos , Femenino , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Adulto , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Tiempo de Internación , Resultado del TratamientoRESUMEN
OBJECTIVE: This study aimed to evaluate the prevalence, incidence, and associated demographic factors of chronic suppurative otitis media (CSOM), utilizing a nationwide healthcare claims database. METHODS: This retrospective study utilized outpatient administrative claims data from the IBM MarketScan Research Database from 2007 to 2021. The database (11 246 909 584 claims with 148 147 615 unique patients) includes health data from the private-sector, Medicare/Medicaid, managed care providers, and EMR providers. Included patients had a diagnosis of CSOM based on ICD-9-CM and ICD-10-CM codes. Prevalence and health utilization were estimated by age, gender, and geographic region. RESULTS: In the United States, the estimated CSOM prevalence and incidence was 0.46% and 0.03%, respectively. Among CSOM patients (n = 679 906), mean age (SD) was 8.1 (15.4) years, and 52.8% were male. Most patients (81.1%) were aged 0 to 10 years. CSOM prevalence was lower in females (OR = 0.64, 95% CI 0.64-0.65, P < .001), less common in older age (OR = 0.94, 95% CI 0.94-0.94, P < .001), and highest in the South region (OR = 2.08, 95% CI 2.06-2.09, P < .001). CONCLUSION: Our results show CSOM prevalence (0.46%) is similar to other developed countries. CSOM prevalence was highest in those aged 0 to 10 years, in males and in the South region. Of note, prevalence and cost are likely significantly underestimated given limitations in accurate ICD-CM coding and the exclusion of uninsured patients. Further epidemiological studies are warranted to characterize the impact of CSOM on the US healthcare system.
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Otitis Media Supurativa , Humanos , Otitis Media Supurativa/epidemiología , Estados Unidos/epidemiología , Masculino , Femenino , Enfermedad Crónica/epidemiología , Estudios Retrospectivos , Preescolar , Lactante , Prevalencia , Niño , Adolescente , Adulto , Persona de Mediana Edad , Incidencia , Adulto Joven , Anciano , Recién Nacido , Bases de Datos FactualesRESUMEN
PURPOSE: To ascertain whether the use of ultra-wide-field fluorescein angiography (UWFFA) at baseline visit alters the assessment of disease activity and localization, as well as the management of patients presenting to a tertiary uveitis clinic. DESIGN: Retrospective comparison of diagnostic approaches. METHODS: Baseline visits of 158 patients who presented to the Uveitis Clinic at the Byers Eye Institute at Stanford between 2017 and 2022 were evaluated by 3 uveitis-trained ophthalmologists (I.K., A.B., and H.G.). Each eye had undergone clinical examination along with ultra-wide-field fundus photography (UWFFP) (Optos Plc), spectral-domain optical coherence tomography (SD-OCT, Spectralis Heidelberg, Heidelberg Engineering) and UWFFA (Optos Plc) at the baseline visit. Investigators were asked to successively determine disease activity, localization of disease (anterior, posterior or both), and management decisions based on clinical examination and UWFFP and SD-OCT (Set 1) and Set 1 plus UWFFA (Set 2). The primary outcome was the percentage of eyes whose management changed based on the availability of UWFFA compared with Set 1. RESULTS: The mean age of the patients was 46.9 ± 22.4 years (range, 7-96), and 91 (57.6%) were female. With Set 1 alone, 138 eyes (55.2%) were found to have active disease; localization was anterior in 58 eyes (42.0%), posterior in 53 eyes (38.4%), and anterior + posterior in 27 eyes (19.6%). With Set 2, 169 eyes of 107 patients had active anterior, posterior, or panuveitis. In comparison with Set 1, assessment with Set 2 identified additional 31 eyes (18.3%) with active disease (P = .006) and an additional 31 eyes (18.3%) having disease in both anterior + posterior segments (P < .001). Regarding the primary outcome, management was changed in 68 eyes (27.4%) in Set 2 compared with Set 1. CONCLUSIONS: Baseline UWFFA may alter assessment of disease activity, localization, and management decisions compared with clinical examination with only UWFFP and SD-OCT for eyes with uveitis. Thus, UWFFA may be considered as an essential tool in the evaluation of patients with uveitis at the baseline visit.
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Angiografía con Fluoresceína , Centros de Atención Terciaria , Tomografía de Coherencia Óptica , Uveítis , Humanos , Femenino , Masculino , Estudios Retrospectivos , Angiografía con Fluoresceína/métodos , Persona de Mediana Edad , Tomografía de Coherencia Óptica/métodos , Uveítis/diagnóstico , Adulto , Anciano , Agudeza Visual/fisiología , Adulto Joven , Adolescente , Fondo de OjoAsunto(s)
Desfibriladores , Cardioversión Eléctrica , Paro Cardíaco , Humanos , Cardioversión Eléctrica/métodos , Paro Cardíaco/terapia , Paro Cardíaco/etiología , Masculino , Reanimación Cardiopulmonar/métodos , Fibrilación Ventricular/terapia , Paro Cardíaco Extrahospitalario/terapia , Persona de Mediana EdadRESUMEN
In this paper, the piezoresistive sensitivity is enhanced by applying uniform mechanical stress (MS) on the multi-nanosheet (NS) channels of sub-5 nm junctionless field-effect transistors. The piezoresistivity of the sensing device is boosted by narrowing channel conductivity using low gate biasing and reducing physical channel width, resulting in the maximum (â¼6 times higher) sensitivity observed in the subthreshold regime compared to the ON-state condition. In addition, the sensitivity is extensively increased by â¼30.3% near the threshold voltage with horizontally multi-NS stacking due to the uniform MS distribution on the multi-NS channels, which can sense slight deflection of pressure on the circular diaphragm. These results show that the tunable sensitivity of junctionless multi-channel devices is superior to the inversion mode, a consequence of the less scattering effect, better thermal stability, and low electronic noise.
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The primary event in chemical neurotransmission involves the fusion of a membrane-limited vesicle at the plasma membrane and the subsequent release of its chemical neurotransmitter cargo. The cargo itself is not known to have any effect on the fusion event. However, amphiphilic monoamine neurotransmitters (e.g., serotonin and dopamine) are known to strongly interact with lipid bilayers and to affect their mechanical properties, which can in principle impact membrane-mediated processes. Here, we probe whether serotonin can enhance the association and fusion of artificial lipid vesicles in vitro. We employ fluorescence correlation spectroscopy and total internal reflection fluorescence microscopy to measure the attachment and fusion of vesicles whose lipid compositions mimic the major lipid components of synaptic vesicles. We find that the association between vesicles and supported lipid bilayers is strongly enhanced in a serotonin dose-dependent manner, and this drives an increase in the rate of spontaneous fusion. Molecular dynamics simulations and fluorescence spectroscopy data show that serotonin insertion increases the water content of the hydrophobic part of the bilayer. This suggests that the enhanced membrane association is likely driven by an energetically favorable drying transition. Other monoamines, such as dopamine and norepinephrine, but not other related species, such as tryptophan, show similar effects on membrane association. Our results reveal a lipid bilayer-mediated mechanism by which monoamines can themselves modulate vesicle fusion, potentially adding to the control toolbox for the tightly regulated process of neurotransmission in vivo.
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Membrana Dobles de Lípidos , Simulación de Dinámica Molecular , Serotonina , Membrana Dobles de Lípidos/química , Membrana Dobles de Lípidos/metabolismo , Serotonina/química , Serotonina/metabolismo , Fusión de Membrana , Vesículas Sinápticas/metabolismo , Vesículas Sinápticas/química , Espectrometría de Fluorescencia , Interacciones Hidrofóbicas e HidrofílicasRESUMEN
Blood pressure (BP) measurement is affected by multiple variables which influence clinical management decisions and patient outcomes. Around 24-hour ambulatory blood pressure monitoring (ABPM) avoids incorrect diagnosis of hypertension (HT), and unnecessary treatment and provides the best prediction of cardiovascular (CV) risk. Clinically important phenotypes of HT such as masked HT (masked HT), white coat HT (white coat HT), and nocturnal HT (nocturnal HT) may be missed by not incorporating ambulatory BP monitoring in practice. However, lack of device availability, operational difficulties, and cost remain barriers to its widespread acceptance in India. In this review, we discuss the when, what, who, why, and where (5Ws) relevant to ABPM measurement.
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Monitoreo Ambulatorio de la Presión Arterial , Hipertensión , Humanos , Monitoreo Ambulatorio de la Presión Arterial/métodos , Hipertensión/diagnóstico , Hipertensión Enmascarada/diagnóstico , Hipertensión de la Bata Blanca/diagnóstico , Presión Sanguínea/fisiología , IndiaRESUMEN
Understanding the dynamics of electric-double-layer (EDL) charging in porous media is essential for advancements in next-generation energy storage devices. Due to the high computational demands of direct numerical simulations and a lack of interfacial boundary conditions for reduced-order models, the current understanding of EDL charging is limited to simple geometries. Here, we present a network model to predict EDL charging in arbitrary networks of long pores in the Debye-Hückel limit without restrictions on EDL thickness and pore radii. We demonstrate that electrolyte transport is described by Kirchhoff's laws in terms of the electrochemical potential of charge (the valence-weighted average of the ion electrochemical potentials) instead of the electric potential. By employing the equivalent circuit representation suggested by these modified Kirchhoff's laws, our methodology accurately captures the spatial and temporal dependencies of charge density and electric potential, matching results obtained from computationally intensive direct numerical simulations. Our network model provides results up to six orders of magnitude faster, enabling the efficient simulation of a triangular lattice of five thousand pores in 6 min. We employ the framework to study the impact of pore connectivity and polydispersity on electrode charging dynamics for pore networks and discuss how these factors affect the time scale, energy density, and power density of capacitive charging. The scalability and versatility of our methodology make it a rational tool for designing 3D-printed electrodes and for interpreting geometric effects on electrode impedance spectroscopy measurements.
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BACKGROUND: Empirical use of pharmacogenetic test(PGT) is advocated for many drugs, and resource-rich setting hospitals are using the same commonly. The clinical translation of pharmacogenetic tests in terms of cost and clinical utility is yet to be examined in hospitals of low middle income countries (LMICs). AIM: The present study assessed the clinical utility of PGT by comparing the pharmacogenetically(PGT) guided- versus standard of care(SOC)- warfarin therapy, including the health economics of the two warfarin therapies. METHODS: An open-label, randomized, controlled clinical trial recruited warfarin-receiving patients in pharmacogenetically(PGT) guided- versus standard of care(SOC)- study arms. Pharmacogenetic analysis of CYP2C9*2(rs1799853), CYP2C9*3(rs1057910) and VKORC1(rs9923231) was performed for patients recruited to the PGT-guided arm. PT(Prothrombin Time)-INR(international normalized ratio) testing and dose titrations were allowed as per routine clinical practice. The primary endpoint was the percent time spent in the therapeutic INR range(TTR) during the 90-day observation period. Secondary endpoints were time to reach therapeutic INR(TRT), the proportion of adverse events, and economic comparison between two modes of therapy in a Markov model built for the commonest warfarin indication- atrial fibrillation. RESULTS: The study enrolled 168 patients, 84 in each arm. Per-protocol analysis showed a significantly high median time spent in therapeutic INR in the genotype-guided arm(42.85%; CI 21.4-66.75) as compared to the SOC arm(8.8%; CI 0-27.2)(p < 0.00001). The TRT was less in the PG-guided warfarin dosing group than the standard-of-care dosing warfarin group (17.85 vs. 33.92 days) (p = 0.002). Bleeding and thromboembolic events were similar in the two study groups. Lifetime expenditure was â¹1,26,830 in the PGT arm compared to â¹1,17,907 in the SOC arm. The QALY gain did not differ in the two groups(3.9 vs. 3.65). Compared to SOC, the incremental cost-utility ratio was â¹35,962 per QALY gain with PGT test opting. In deterministic and probabilistic sensitivity analysis, the base case results were found to be insensitive to the variation in model parameters. In the cost-effectiveness-acceptability curve analysis, a 90% probability of cost-effectiveness was reached at a willingness-to-pay(WTP) of â¹ 71,630 well below one time GDP threshold of WTP used. CONCLUSION: Clinical efficacy and the cost-effectiveness of the warfarin pharmacogenetic test suggest its routine use as a point of care investigation for patient care in LMICs.
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Anticoagulantes , Citocromo P-450 CYP2C9 , Economía Farmacéutica , Relación Normalizada Internacional , Vitamina K Epóxido Reductasas , Warfarina , Humanos , Warfarina/economía , Warfarina/administración & dosificación , Warfarina/uso terapéutico , Femenino , Masculino , Persona de Mediana Edad , Citocromo P-450 CYP2C9/genética , Anciano , Vitamina K Epóxido Reductasas/genética , Anticoagulantes/administración & dosificación , Anticoagulantes/economía , Anticoagulantes/uso terapéutico , Pruebas de Farmacogenómica/economía , Adulto , Farmacogenética/economía , Análisis Costo-BeneficioRESUMEN
Nanopore-based sensing platforms have transformed single-molecule detection and analysis. The foundation of nanopore translocation experiments lies in conductance measurements, yet existing models, which are largely phenomenological, are inaccurate in critical experimental conditions such as thin and tightly fitting pores. Of the two components of the conductance blockade, channel and access resistance, the access resistance is poorly modeled. We present a comprehensive investigation of the access resistance and associated conductance blockade in thin nanopore membranes. By combining a first-principles approach, multiscale modeling, and experimental validation, we propose a unified theoretical modeling framework. The analytical model derived as a result surpasses current approaches across a broad parameter range. Beyond advancing our theoretical understanding, our framework's versatility enables analyte size inference and predictive insights into conductance blockade behavior. Our results will facilitate the design and optimization of nanopore devices for diverse applications, including nanopore base calling and data storage.