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This case presents a somewhat unique and different phenotype of hereditary spastic paraplegia from previously reported kinase D-interacting substrate of 220 kDa (KIDINS220) gene mutation-related disease. We report a unique putative causative heterozygous mutation in KIDINS220 in a pure hereditary spastic paraplegia (HSP) patient expanding the HSP group further. We also deliberate on how our case was different from prior KIDINS220-related pathologies including spastic paraplegia, intellectual disability, nystagmus, and obesity (SINO) syndrome, and the observation of KIDINS220 and aquaporin-4 (AQP4) downregulation in the ventricular ependymal lining of idiopathic normal pressure hydrocephalus (iNPH) patients. These findings warrant further investigations of the biology of KIDINS220. With the advent of new gene editing technologies like Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/CRISPR-associated protein 9 (Cas9), variants such as ours provide an opportunity for targeted precision medicine.
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The phenomenon of climate change has become a global challenge that affects human activities in many ways. Exploring the sustainability and innovativeness of digital education is an important reference for the further implementation of science and education strategies and positive effects on climate change mitigation. This study designed two questionnaires for basic and tertiary education to address variability in education and collected 523 samples for basic education and 412 samples for tertiary education respectively. Using digital teaching practices and digital teaching quality as mediators, structural equation modelling (SEM) was used to examine the impact of digital education on sustainability and innovation in education. Research shows that digital teaching and learning in basic and higher education can significantly contribute to the two-way development of educational sustainability and innovation, through digital teaching and learning practices. Digital teaching practice and digital teaching quality in higher education play a complete mediating role, while basic education only plays a partial mediating role. Higher education emphasizes digital teaching and learning practice processes and teaching quality, and most students hope that online teaching and learning can be further integrated with offline education to form a new model of education. This study will help government departments understand the pedagogical reality of digital education at a deeper level and provide ideas for the subsequent sustainable development and educational innovation of digital teaching. It can also provide new ideas for climate change mitigation and sustainable development.
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BACKGROUND: Enterococcal bacteremia has become prevalent in the recent decade, especially in hospitalized patients. Moreover, the rise in resistance patterns against antibiotic drugs regarding enterococci infection, such as cephalosporins, ampicillin and vancomycin, is prevailing. The major driving force behind this is the incongruous use of antibiotics with a minor contribution from environmental stressors which calls for vigilant and prudent administration of evidence-based antibiotics. METHODS: A retrospective study was conducted from January 1 2017 until December 31 2021, at the tertiary care center, Dr Ziauddin Hospital in Karachi, Pakistan. RESULTS: Our research revealed ampicillin resistance in 87 (63.5%), with an estimated 25 (18.8%) mortality. Male gender 19 (76%) and vancomycin resistance 13 (52%) were associated with increased mortality. Furthermore, appropriate antibiotic therapy reduced the risk of death compared with inappropriate and excessive use of antibiotics 10 (40%) vs. 15 (60%) vs. 20 (80%) respectively. Targeted therapy with amoxicillin/clavulanic acid was associated with lower mortality 1 (4%) and higher discharge rates 34 (32.1%). On Kaplan-Meier survival, targeted therapy with amoxicillin/clavulanic acid was associated with shorter hospital stays and prolonged survival. UTI was found as the most common source of enterococcal bacteremia 57 (41.6%), followed by respiratory 21 (15.3%) and intra-abdominal 13 (9.5%). In 26 (19%) patients, no identifiable source of infection was found. CONCLUSION: Vancomycin resistance and male gender were found independent risk factors for mortality. The use of inappropriate antibiotics significantly increases mortality in these patients. The appropriate antibiotic therapy reduces the risk of death. Furthermore, overuse of antibiotics didn't reduce mortality; instead increased the financial burden and chances of developing multi-drug resistant strains of other organisms by increasing hospital stays of patients.
Subject(s)
Anti-Bacterial Agents , Bacteremia , Health Personnel , Antimicrobial Stewardship , Humans , Bacteremia/drug therapy , Bacteremia/mortality , Anti-Bacterial Agents/therapeutic use , Vancomycin-Resistant Enterococci , Retrospective Studies , Enterococcus/drug effects , Pakistan/epidemiology , Practice Patterns, Physicians'ABSTRACT
Global warming is a life-threatening risk to mankind and its survival; to combat this risk, the considerable contribution of renewable energy cannot be overlooked for sustainable growth globally. The aim of this paper is to scrutinize the threshold level and asymmetric connection among renewable energy consumption, foreign direct investment, financial inclusion, and agricultural productivity in dissimilar regimes of the different income levels of 123 countries from 1995 to 2019 by applying an advance technique PSTR (panel smooth transition regression) model. The PSTR model results imply that the connection between renewable energy consumption and agricultural productivity at all the estimates is non-linear. Moreover, in all countries, there is a positive and significant connection among renewable energy consumption, foreign direct investment, financial inclusion, and agricultural productivity in both low and high regimes, except the carbon emission, which has a negative and significant impact on agricultural productivity. Based on the results of this study, the recommendations are as follows: (i) to increase renewable energy consumption, efficient-energy resources should be used by farmers for the agricultural process; (ii) the dependence on non-renewable energy resources should be minimized and shifted towards natural and renewable resources.
Subject(s)
Carbon Dioxide , Economic Development , Renewable Energy , Internationality , Investments , AgricultureABSTRACT
Cardiovascular disease is one of the leading threats to human lives and its fatality rate still rises gradually year by year. Driven by the development of advanced information technologies, such as big data, cloud computing, and artificial intelligence, remote/distributed cardiac healthcare is presenting a promising future. The traditional dynamic cardiac health monitoring method based on electrocardiogram (ECG) signals only has obvious deficiencies in comfortableness, informativeness, and accuracy under motion state. Therefore, a non-contact, compact, wearable, synchronous ECG and seismocardiogram (SCG) measuring system, based on a pair of capacitance coupling electrodes with ultra-high input impedance, and a high-resolution accelerometer were developed in this work, which can collect the ECG and SCG signals at the same point simultaneously through the multi-layer cloth. Meanwhile, the driven right leg electrode for ECG measurement is replaced by the AgCl fabric sewn to the outside of the cloth for realizing the total gel-free ECG measurement. Besides, synchronous ECG and SCG signals at multiple points on the chest surface were measured, and the recommended measuring points were given by their amplitude characteristics and the timing sequence correspondence analysis. Finally, the empirical mode decomposition algorithm was used to adaptively filter the motion artifacts within the ECG and SCG signals for measuring performance enhancement under motion states. The results demonstrate that the proposed non-contact, wearable cardiac health monitoring system can effectively collect ECG and SCG synchronously under various measuring situations.
Subject(s)
Artificial Intelligence , Wearable Electronic Devices , Humans , Signal Processing, Computer-Assisted , Electrocardiography/methods , HeartABSTRACT
According to the United Nations Agenda, the 2023 sustainable environment is necessary to secure this planet's future; public-private partnerships investment in energy is crucial to sustainable development. The research examines the quantile association between public-private partnership ventures in energy and environmental degradation in ten developing nations, and data is used from January 1998-December 2016. The advanced econometrics quantile-on-quantile regression approach is used to control the issues of heterogeneity and asymmetric relationship. According to the quantile-on-quantile approach, there is a strong positive association between public-private partnerships in energy and environmental degradation in Argentina, Brazil, Bangladesh, and India. But the negative relationship is observed on different quantiles of China, Malaysia, Mexico, Peru, Thailand, and the Philippines. The findings suggest that the world needs to act as a single community and divert its resources toward renewable energy sources to control climate change; also, to accomplish the UN 15-year road map of Agenda 2023 with 17-SDGs; out of these 17 sustainable goals, SDG-7 is related to affordable and clean energy, SDG-11 is about sustainable cities and communities, and SDG-13 focuses on climate action for sustainable development.
Subject(s)
Public-Private Sector Partnerships , Sustainable Development , Cities , Investments , China , Economic Development , Carbon Dioxide/analysis , Renewable EnergyABSTRACT
Inherited muscular abnormalities are debilitating disorders that greatly diminish the quality of life in affected individuals. Mutations in proteins such as dystrophin and caveolin, which together with other proteins form structural connections between the cytoskeleton and the extracellular matrix, are frequently the culprit of muscular dystrophies. In this case report, we describe a patient with a novel pathogenic dystrophin mutation co-existing with a caveolin-3 deletion. While genetically composed of this unique combination, the patient phenotypically presented with a primary clinical manifestation of Duchenne muscular dystrophy (DMD) in contrast to other cases of dual mutations in dystrophin and dystrophin-associated proteins.
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Through the transition of novel ideas, products, technologies, and business models, info-globalization facilitates the flow and expansion of cross-border information and resources. In the meantime, this stimulates the potential of informational globalization and the internet for environmental and other technological advancements, and assists to the realization of cleaner and greener production and consumption. However, prior studies have completely disregarded this facet of globalization. Thus, this novel study evaluates the role of technological innovation (TIN) and information globalization (ING) in predicting ecological footprints (EFP) and carbon emissions (CO2) in the world's top ten greenest economies. Besides, this study also unveils the moderating role of TIN and ING for environmental sustainability. The novel research employs non-parametric causality-in-quantiles approaches on quarterly data from 1994Q1 to 2019Q4 in order to quantify for causality-in-mean and causality-in-variance, since there may be no causation at first moment, but higher-order interdependencies may exist. The findings revealed that TIN and ING possess significant predictive potential for both ecological footprint and carbon emissions, indicating asymmetric predictability over environmental sustainability. Moreover, TIN and ING asserted a significant interaction role when it comes to predicting pollution levels in chosen countries. Overall, it is essential to note that natural resource conservation and pollution mitigation via green and technical innovation become a dilemma since pollution has no boundaries and will always stoke fires beyond them. The provision of financial and R&D assistance, as well as the use of mass and social media to raise awareness not only in their own regions but also in neighboring countries, might contribute to the achievement of SDG 13 and Cope26's ambition of cutting pollution by 2030.
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Inventions , Sustainable Development , Humans , Carbon , Carbon Dioxide , Economic Development , Internationality , Renewable EnergyABSTRACT
This study analyzes the causal connection between financial inclusion and carbon emission in selected South Asian countries through a quantile technique-based linear Granger and non-parametric causality test. The analysis of the study covers quarterly data from 1980 Q1 to 2019 Q4. However, the linear Granger causality assessment outcome does not indicate any causal relationship between financial inclusion and carbon emission. In contrast, results from non-parametric assessment reveal a non-linear connection between the variables. The non-parametric test results of the South Asian countries exhibit that financial inclusion leads to carbon emission, which instigates the deterioration of the environment, except for Bhutan. Subsequently, creating awareness by promoting renewable energy resources is essential while investing in fuel-efficient technology to reduce the dependence on fossil fuels. The results of this study provide significant information to the governments and policymakers in emerging countries to improve financial literacy among people to reduce the risk of global warming by encouraging investment in energy-efficient resources.
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Carbon Dioxide , Economic Development , Humans , Asia, Southern , Carbon Dioxide/analysis , Renewable Energy , CarbonABSTRACT
This study examines long-term connection and short-term dynamics concerning ecological footprint and six independent variables, named fossil fuel consumption, energy consumption, financial depth, trade, GDP, and ICT for Pakistan's duration from 1960 to 2019. The "QARDL-quantile autoregressive distributed lag" technique is used for time series and panel estimation. The QARDL model exhibits the connection between variables over the quantiles range, reflecting varying stages of Pakistan's ecological footprint. The results exhibit noticeable quantile-varying co-integration connection among ecological footprint and six independent variables. The results accentuate the significant influence of energy consumption, strong financial position, economic growth, and ICT technologies on ecological well-being, which assists in understanding short and long-term impact on the environment in Pakistan.
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Carbon Dioxide , Economic Development , Carbon Dioxide/analysis , Fossil Fuels , Pakistan , TechnologyABSTRACT
Ride-sharing services are a sustainable form of the transportation system that needs to be popularized among students by examining the crucial factors that determine the students' behavior to use the innovative service. Therefore, this paper attempts to explore students' behavior regarding the use of ride-sharing services by extending the "Technology Acceptance Model." The expanded model includes the current TAM structures and integrates contextual stimuli that may or may not affect the ride-sharing service's behavior. Moreover, the study focuses on determining the moderating role of perceived risk between the proposed relationships. The paper uses PLS-SEM to analyze the research model and determine the results of the hypotheses. The findings of this research are useful for ride-sharing service providers and policymakers who can promote the services among students by reducing the perceived risks and promoting the environmental benefits of ride-sharing. Furthermore, the limitations of this paper pose future research directions.
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This research examines the impact of the COVID-19 on cryptocurrencies' connectedness by employing two techniques: TVP-VAR-based connectedness and causality in the quantiles. First, the TVP-VAR-based connectedness unveils that cryptocurrencies act as a net receiver and transmitter of shocks, with Bitcoin, Ethereum are the highest transmitters among others. Moreover, the causality-in-quantile test shows that COVID-19 significantly causes spillover connectedness among cryptocurrencies, mainly at the quantiles ranging from 0.1 to 0.8, while an insignificant causal relationship is found in few cases. The study has implications for investors and policymakers.
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Background: Cariprazine, a novel antipsychotic drug, is a partial agonist of dopamine D2/D3 receptors with preferential binding to the D3 receptor. There has been an increasing interest in cariprazine augmentation to clozapine; however, the evidence thus far has been only limited to case reports and case series. Objectives: To evaluate the efficacy and safety of the augmentation of clozapine with cariprazine in patients with sub-optimal treatment response. Methods: Demographic and clinical information of the study population were collected from the electronic records and PANSS scale administered at baseline and 3 months. Tolerability and discontinuation reasons where applicable were also recorded. Results: Ten patients (four men and six women) with a mean age of 36.5 years (rangeâ=â26-45) were included. Reasons for cariprazine initiation included inadequate treatment response, persistent negative symptoms and/or tolerability issues with clozapine or previous augmentation options. Two patients discontinued cariprazine within the first 6 weeks due to restlessness and poor response, respectively. There was a significant reduction in the median total PANSS score from baseline to 3 months (from 59 to 22.5, p < 0.05), median positive PANSS score (from 11.5 to 5.5, p < 0.05) and in the median negative PANSS score (from 15.5 to 3, p < 0.05) which correspond to a 48%, 33.8% and 65.8% mean score reduction, respectively. Conclusion: This is the first pilot study evaluating the effectiveness of clozapine augmentation. The preliminary evidence suggests that this may be a safe and effective practice in patients failing to adequately respond to or tolerate clozapine and/or previous augmentation strategies.
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PURPOSE OF REVIEW: Central nervous system (CNS) lymphomas (CNSLs) have varied clinical presentations which can mimic neuroinflammatory disease, leading to a diagnostic dilemma for clinicians. RECENT FINDINGS: This report describes two patients who initially received a diagnosis of neuroinflammatory disorders but were refractory to treatment over a protracted time course. In both cases, biopsy revealed diffuse large B cell lymphoma (DLBCL) as the final diagnosis. SUMMARY: The analysis of these cases provides an opportunity for increased recognition of CNS lymphomas for earlier diagnosis and treatment. It also calls for increased clinical suspicion for CNSLs in such circumstances. And possibly the search for new biomarker development for identifying and tracking CNSLs.
Subject(s)
Central Nervous System Neoplasms , Lymphoma, Large B-Cell, Diffuse , Biomarkers , Central Nervous System Neoplasms/pathology , Humans , Lymphoma, Large B-Cell, Diffuse/diagnosis , Lymphoma, Large B-Cell, Diffuse/pathology , Neuroinflammatory DiseasesABSTRACT
BACKGROUND: Globally, occupational stress is a common finding among dentists. The present study aimed to assess prevalence of perceived stress among practicing dentists of Karachi, Pakistan, and assess the perceived stress levels according to the professional standing among dental surgeons. METHODS: A cross-sectional survey was conducted using a convenience sampling technique in which 200 dentists from Karachi were recruited. A self-constructed questionnaire was used to collect data, including demographic and professional backgrounds. Stress level assessment was performed using the perceived stress scale (PSS). RESULTS: The response rate was 78.5%. In general, a moderate stress level (mean PSS = 18.35 ± 5.417) appeared in the sample size of 157 dentists, and the prevalence of perceived stress was 86%. The level of perceived stress was significantly lower in groups including 40 years old and above (mean diff; p = - 0.197), Rupees 1 lac (100,000) and more of monthly income (mean diff; p = 0.029), 11 and more years of experience (mean diff; p = 0.001) and Assistant Professor/Associate Professor/Professor (mean diff; p = 0.035). CONCLUSION: All groups representing the senior status of dentists have appeared with lower stress than groups representing the junior status of dentists. Exploratory studies are required to discover an effective coping strategy to deal with occupational stress among the junior dentists of Karachi.
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Occupational Stress , Surgeons , Adult , Cross-Sectional Studies , Dentists , Humans , Surveys and QuestionnairesABSTRACT
PURPOSE: Coronavirus disease 2019 (COVID-19) clinical outcome and disease severity affected by several factors; deterioration of glycemic control is one of them. Therefore, achieving optimum blood glucose parameters is hypothesized for better consequences of COVID-19. However, varying data supporting this hypothesis is available in literature. The intention of this study was to investigate the role of glycemic management on the prognosis of hospitalized COVID-19 patients with varying degrees of severity. METHODS: From April 2020 to January 2021, we carried this retrospective cohort in a clinical care facility in Pakistan. RESULTS: Mortality was lowest in patients with HbA1c of less than 7% (53 mmol/mol) (p < 0.001). Similarly, mortality was found lowest in patients with fasting blood glucose less than 126 mg/dl and random blood glucose less than 160 mg/dl (p < 0.001 in each). In contrast, need for admission in critical care was found highest in patients with HbA1c between 7 and 10% (53-86 mmol/mol) (p 0.002). However, participants with blood glucose levels during fasting greater than 200 mg/dl and random blood glucose levels greater than 250 mg/dl were found to have a greater need for invasive mechanical ventilation. Cox regression hazard showed no difference in risk of death and invasive mechanical ventilation based on previous glycemic control. CONCLUSION: Effective diabetic management is correlated with a considerably lower risk of mortality and invasive mechanical ventilation in COVID-19 cases.
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COVID-19 , Blood Glucose , COVID-19/therapy , Glycated Hemoglobin , Glycemic Control , Humans , Retrospective StudiesABSTRACT
The antioxidant activity and the inhibitory potential of α-amylase of lyophilized hydroethanolic extracts of Conocarpus erectus leaves obtained by ultrasonication were determined. The most potent extract was subjected to ultra-high performance liquid chromatography system equipped with mass spectrometer for metabolite identification. The identified metabolites were docked in α-glucosidase to assess their binding mode. The results revealed that 60% ethanolic extract exhibited highest ferric reducing antioxidant power (4.08 ± 0.187 mg TE/g DE) and α-amylase inhibition (IC50 58.20 ± 1.25 µg/mL. The metabolites like ellagic acid, 3-O-methyl ellagic acid, ferujol, 5, 2 Ì-dihydroxy-6,7,8-trimethyl flavone and kaempferol glucoside were identified in the extract and subjected to molecular docking studies regarding α-amylase inhibition. The comparison of binding affinities revealed 3-O-methyl ellagic acid as most effective inhibitor of α-amylase with binding energy of -14.5911 kcal/mol comparable to that of acarbose (-15.7815 kcal/mol). The secondary metabolites identified in the study may be extended further for functional food development with antidiabetic properties.
Se determinó la actividad antioxidante y el potencial inhibidor de la α-amilasa de extractos hidroetanólicos liofilizados de hojas de Conocarpus erectus obtenidos por ultrasónicación. El extracto más potente se sometió a un sistema de cromatografía líquida de ultra alto rendimiento equipado con un espectrómetro de masas para la identificación de metabolitos. Los metabolitos identificados se acoplaron en α-glucosidasa para evaluar su modo de unión. Los resultados revelaron que el extracto etanólico al 60% exhibió el mayor poder antioxidante reductor férrico (4.08 ± 0.187 mg TE/g DE) e inhibición de la α-amilasa (IC50 58.20 ± 1.25 µg/mL. Los metabolitos como el ácido elágico, 3-O-metil elágico ácido, ferujol, 5, 2 Ì-dihidroxi-6,7,8-trimetil flavona y kaempferol glucósido se identificaron en el extracto y se sometieron a estudios de acoplamiento molecular con respecto a la inhibición de la α-amilasa. La comparación de las afinidades de unión reveló 3-O-metil El ácido elágico como inhibidor más eficaz de la α-amilasa con una energía de unión de -14,5911 kcal/mol comparable a la de la acarbosa (-15,7815 kcal/mol). Los metabolitos secundarios identificados en el estudio pueden ampliarse aún más para el desarrollo funcional de alimentos con propiedades antidiabéticas.
Subject(s)
Plant Extracts/chemistry , alpha-Amylases/antagonists & inhibitors , Myrtales/chemistry , Antioxidants/chemistry , Benzopyrans/analysis , In Vitro Techniques , Plant Extracts/pharmacology , Plant Leaves/chemistry , Molecular Docking Simulation , Antioxidants/pharmacologyABSTRACT
With the development of remote cardiac healthcare, wearable devices for electrocardiogram (ECG) monitoring are stringent requirements to cope with this rapid growth of demands. Due to the advantages of no-contact ECG measuring methods in safety, convenience, and comfortableness, it is more suitable for wearable long-term ECG monitoring than the conventional Ag/AgCl electrodes. The capacitance coupling printed circuit board (PCB) electrode with ultra-high input impedance proposed in this paper can realize non-contact ECG measurement through a multi-layer insulating medium. Then, an eight-channel ECG signal processing circuit is also designed and fabricated. In addition, the following important performance properties of the non-contact ECG measuring system, such as the input impedance, the phase-frequency characteristic, the amplitude-frequency characteristic, the coupling coefficient, and the input short-circuit input noise, were all experimentally measured. The synchronous comparison between the Ag/AgCl electrode and the PCB electrode was also conducted to verify the accuracy of the non-contact measuring method. Finally, the influence of the lead positions, coupling medium parameters, and the body motion states was also experimentally studied. The results demonstrate that the proposed non-contact ECG measuring method based on capacitance coupling PCB electrodes can effectively collect the main components of ECG signals and cardiac rhythm in various situations.
Subject(s)
Electrocardiography , Signal Processing, Computer-Assisted , Electric Capacitance , Electric Impedance , ElectrodesABSTRACT
In nature, plant-insect interactions occur in complex settings involving multiple trophic levels, often with multiple species at each level.1 Herbivore attack of a host plant typically dramatically alters the plant's odor emission in terms of concentration and composition.2,3 Therefore, a well-adapted herbivore should be able to predict whether a plant is still suitable as a host by judging these changes in the emitted bouquet. Although studies have demonstrated that oviposition preferences of successive insects were affected by previous infestations,4,5 the underlying molecular and olfactory mechanisms remain unknown. Here, we report that tobacco hawkmoths (Manduca sexta) preferentially oviposit on Jimson weed (Datura wrightii) that is already infested by a specialist, the three-lined potato beetle (Lema daturaphila). Interestingly, the moths' offspring do not benefit directly, as larvae develop more slowly when feeding together with Lema beetles. However, one of M. sexta's main enemies, the parasitoid wasp Cotesia congregata, prefers the headspace of M. sexta-infested plants to that of plants infested by both herbivores. Hence, we conclude that female M. sexta ignore the interspecific competition with beetles and oviposit deliberately on beetle-infested plants to provide their offspring with an enemy-reduced space, thus providing a trade-off that generates a net benefit to the survival and fitness of the subsequent generation. We identify that α-copaene, emitted by beetle-infested Datura, plays a role in this preference. By performing heterologous expression and single-sensillum recordings, we show that odorant receptor (Or35) is involved in α-copaene detection.
Subject(s)
Coleoptera , Datura , Manduca , Moths , Animals , Datura/metabolism , Female , Herbivory , Insecta , OvipositionABSTRACT
In advanced peripheral arterial disease (PAD), medial arterial calcification is known to inflate the ankle-brachial index. An alternative method of evaluating symptomatic patients is toe-brachial indexes (TBI), where a ratio less than .7 indicates PAD and less than .4 indicates a severe form. The objective of this retrospective analysis was to investigate the association between TBIs less than .7 and angiographically verified PAD. Patients were required to have either a leg angiogram 13 months prior to or 12 months after a 6-minute walk test. Of the 174 included patients, the mean overall TBI was .450. The mean TBI by location was highest at iliac and infra-geniculate with .544 and lowest at supra-geniculate with .372. Infra-geniculate lesions were also the most frequent (n = 46). A TBI less than .4 was found in 47.7% of patients. TBIs greater than .7 were present in 36 patients; however, only 16 had significant angiographic stenosis. In conclusion, the majority of patients with angiographic PAD had a TBI less than .7, especially less than .4. Contrary to suspicion, infra-geniculate lesions were the most common and had the highest TBI.