Wearable Alcohol Monitoring Device for the Data-Driven Transcutaneous Alcohol Diffusion Model.

Wearable alcohol monitoring devices demand noninvasive, real-time measurement of blood alcohol content (BAC) reliably and continuously. A few commercial devices are available to determine BAC noninvasively by detecting transcutaneous diffused alcohol. However, they suffer from a lack of accuracy and reliability in the determination of BAC in real time due to the complex scenario of the human skin for transcutaneous alcohol diffusion and numerous factors (e.g., skin thickness, kinetics of alcohol, body weight, age, sex, metabolism rate, etc.). In this work, a transcutaneous alcohol diffusion model has been developed from real-time captured data from human wrists to better understand the kinetics of diffused alcohol from blood to different skin epidermis layers. Such a model will be a footprint to determine a base computational model in larger studies. Eight anonymous volunteers participated in this pilot study. A laboratory-built wearable blood alcohol content (BAC) monitoring device collected all the data to develop this diffusion model. The proton exchange membrane fuel cell (PEMFC) sensor was fabricated and integrated with an nRF51822 microcontroller, LMP91000 miniaturized potentiostat, 2.4 GHz transceiver supporting Bluetooth low energy (BLE), and all the necessary electronic components to build this wearable BAC monitoring device. The %BAC data in real time were collected using this device from these volunteers' wrists and stored in the end device (e.g., smartphone). From the captured data, we demonstrate how the volatile alcohol concentration on the skin varies over time by comparing the alcohol concentration in the initial stage (= 10 min) and later time (= 100 min). We also compare the experimental results with the outputs of three different input profiles: piecewise linear, exponential linear, and Hoerl, to optimize the developed diffusion model. Our results demonstrate that the exponential linear function best fits the experimental data compared to the piecewise linear and Hoerl functions. Moreover, we have studied the impact of skin epidermis thickness within ±20% and demonstrate that a 20% decrease in this thickness results in faster dynamics compared to thicker skin. The model clearly shows how the diffusion front changes within a skin epidermis layer with time. We further verified that 60 min was roughly the time to reach the maximum concentration, Cmax, in the stratum corneum from the transient analysis. Lastly, we found that a more significant time difference between BACmax and Cmax was due to greater alcohol consumption for a fixed absorption time.

Recent Progress and Challenges of Implantable Biodegradable Biosensors.

Implantable biosensors have evolved to the cutting-edge technology of personalized health care and provide promise for future directions in precision medicine. This is the reason why these devices stand to revolutionize our approach to health and disease management and offer insights into our bodily functions in ways that have never been possible before. This review article tries to delve into the important developments, new materials, and multifarious applications of these biosensors, along with a frank discussion on the challenges that the devices will face in their clinical deployment. In addition, techniques that have been employed for the improvement of the sensitivity and specificity of the biosensors alike are focused on in this article, like new biomarkers and advanced computational and data communicational models. A significant challenge of miniaturized in situ implants is that they need to be removed after serving their purpose. Surgical expulsion provokes discomfort to patients, potentially leading to post-operative complications. Therefore, the biodegradability of implants is an alternative method for removal through natural biological processes. This includes biocompatible materials to develop sensors that remain in the body over longer periods with a much-reduced immune response and better device longevity. However, the biodegradability of implantable sensors is still in its infancy compared to conventional non-biodegradable ones. Sensor design, morphology, fabrication, power, electronics, and data transmission all play a pivotal role in developing medically approved implantable biodegradable biosensors. Advanced material science and nanotechnology extended the capacity of different research groups to implement novel courses of action to design implantable and biodegradable sensor components. But the actualization of such potential for the transformative nature of the health sector, in the first place, will have to surmount the challenges related to biofouling, managing power, guaranteeing data security, and meeting today's rules and regulations. Solving these problems will, therefore, not only enhance the performance and reliability of implantable biodegradable biosensors but also facilitate the translation of laboratory development into clinics, serving patients worldwide in their better disease management and personalized therapeutic interventions.

Impact of SARS-CoV-2 ORF6 and its variant polymorphisms on host responses and viral pathogenesis.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) encodes several proteins that inhibit host interferon responses. Among these, ORF6 antagonizes interferon signaling by disrupting nucleocytoplasmic trafficking through interactions with the nuclear pore complex components Nup98-Rae1. However, the roles and contributions of ORF6 during physiological infection remain unexplored. We assessed the role of ORF6 during infection using recombinant viruses carrying a deletion or loss-of-function (LoF) mutation in ORF6. ORF6 plays key roles in interferon antagonism and viral pathogenesis by interfering with nuclear import and specifically the translocation of IRF and STAT transcription factors. Additionally, ORF6 inhibits cellular mRNA export, resulting in the remodeling of the host cell proteome, and regulates viral protein expression. Interestingly, the ORF6:D61L mutation that emerged in the Omicron BA.2 and BA.4 variants exhibits reduced interactions with Nup98-Rae1 and consequently impairs immune evasion. Our findings highlight the role of ORF6 in antagonizing innate immunity and emphasize the importance of studying the immune evasion strategies of SARS-CoV-2.

Impact of SARS-CoV-2 ORF6 and its variant polymorphisms on host responses and viral pathogenesis.

We and others have previously shown that the SARS-CoV-2 accessory protein ORF6 is a powerful antagonist of the interferon (IFN) signaling pathway by directly interacting with Nup98-Rae1 at the nuclear pore complex (NPC) and disrupting bidirectional nucleo-cytoplasmic trafficking. In this study, we further assessed the role of ORF6 during infection using recombinant SARS-CoV-2 viruses carrying either a deletion or a well characterized M58R loss-of-function mutation in ORF6. We show that ORF6 plays a key role in the antagonism of IFN signaling and in viral pathogenesis by interfering with karyopherin(importin)-mediated nuclear import during SARS-CoV-2 infection both in vitro , and in the Syrian golden hamster model in vivo . In addition, we found that ORF6-Nup98 interaction also contributes to inhibition of cellular mRNA export during SARS-CoV-2 infection. As a result, ORF6 expression significantly remodels the host cell proteome upon infection. Importantly, we also unravel a previously unrecognized function of ORF6 in the modulation of viral protein expression, which is independent of its function at the nuclear pore. Lastly, we characterized the ORF6 D61L mutation that recently emerged in Omicron BA.2 and BA.4 and demonstrated that it is able to disrupt ORF6 protein functions at the NPC and to impair SARS-CoV-2 innate immune evasion strategies. Importantly, the now more abundant Omicron BA.5 lacks this loss-of-function polymorphism in ORF6. Altogether, our findings not only further highlight the key role of ORF6 in the antagonism of the antiviral innate immune response, but also emphasize the importance of studying the role of non-spike mutations to better understand the mechanisms governing differential pathogenicity and immune evasion strategies of SARS-CoV-2 and its evolving variants. ONE SENTENCE SUMMARY: SARS-CoV-2 ORF6 subverts bidirectional nucleo-cytoplasmic trafficking to inhibit host gene expression and contribute to viral pathogenesis.

SARS-CoV-2 Causes Lung Infection without Severe Disease in Human ACE2 Knock-In Mice.

The development of mouse models for coronavirus disease 2019 (COVID-19) has enabled testing of vaccines and therapeutics and defining aspects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pathogenesis. SARS-CoV-2 disease is severe in K18 transgenic mice (K18-hACE2 Tg) expressing human angiotensin-converting enzyme 2 (hACE2), the SARS-CoV-2 receptor, under an ectopic cytokeratin promoter, with high levels of infection measured in the lung and brain. Here, we evaluated SARS-CoV-2 infection in hACE2 knock-in (KI) mice that express hACE2 under an endogenous promoter in place of murine ACE2 (mACE2). Intranasal inoculation of hACE2 KI mice with SARS-CoV-2 WA1/2020 resulted in substantial viral replication within the upper and lower respiratory tracts with limited spread to extrapulmonary organs. However, SARS-CoV-2-infected hACE2 KI mice did not lose weight and developed limited pathology. Moreover, no significant differences in viral burden were observed in hACE2 KI mice infected with B.1.1.7 or B.1.351 variants compared to the WA1/2020 strain. Because the entry mechanisms of SARS-CoV-2 in mice remain uncertain, we evaluated the impact of the naturally occurring, mouse-adapting N501Y mutation by comparing infection of hACE2 KI, K18-hACE2 Tg, ACE2-deficient, and wild-type C57BL/6 mice. The N501Y mutation minimally affected SARS-CoV-2 infection in hACE2 KI mice but was required for viral replication in wild-type C57BL/6 mice in a mACE2-dependent manner and augmented pathogenesis in the K18-hACE2 Tg mice. Thus, the N501Y mutation likely enhances interactions with mACE2 or hACE2 in vivo. Overall, our study highlights the hACE2 KI mice as a model of mild SARS-CoV-2 infection and disease and clarifies the requirement of the N501Y mutation in mice. IMPORTANCE Mouse models of SARS-CoV-2 pathogenesis have facilitated the rapid evaluation of countermeasures. While the first generation of models developed pneumonia and severe disease after SARS-CoV-2 infection, they relied on ectopic expression of supraphysiological levels of human ACE2 (hACE2). This has raised issues with their relevance to humans, as the hACE2 receptor shows a more restricted expression pattern in the respiratory tract. Here, we evaluated SARS-CoV-2 infection and disease with viruses containing or lacking a key mouse-adapting mutation in the spike gene in hACE2 KI mice, which express hACE2 under an endogenous promoter in place of murine ACE2. While infection of hACE2 KI mice with multiple strains of SARS-CoV-2 including variants of concern resulted in viral replication within the upper and lower respiratory tracts, the animals did not sustain severe lung injury. Thus, hACE2 KI mice serve as a model of mild infection with both ancestral and emerging SARS-CoV-2 variant strains.

Development of a Macrophage-Based ADCC Assay.

Fc-dependent effector functions are an important determinant of the in vivo potency of therapeutic antibodies. Effector function is determined by the combination of FcRs bound by the antibody and the cell expressing the relevant FcRs, leading to antibody-dependent cellular cytotoxicity (ADCC). A number of ADCC assays have been developed; however, they suffer from limitations in terms of throughput, reproducibility, and in vivo relevance. Existing assays measure NK cell-mediated ADCC activity; however, studies suggest that macrophages mediate the effector function of many antibodies in vivo. Here, we report the development of a macrophage-based ADCC assay that relies on luciferase expression in target cells as a measure of live cell number. In the presence of primary mouse macrophages and specific antibodies, loss of luciferase signal serves as a surrogate for ADCC-dependent killing. We show that the assay functions for a variety of mouse and human isotypes with a model antigen/antibody complex in agreement with the known effector function of the isotypes. We also use this assay to measure the activity of a number of influenza-specific antibodies and show that the assay correlates well with the known in vivo effector functions of these antibodies.

Novel application of electrochemical bipolar exfoliated graphene for highly sensitive disposable label-free cancer biomarker aptasensors.

Label-free aptasensors can be a promising point-of-care biosensor for detecting various cancer diseases due to their selectivity, sensitivity, and lower cost of production and operation. In this study, a highly sensitive aptasensor based on gold-covered polyethylene terephthalate electrodes (PET/Au) decorated with bipolar exfoliated graphene is proposed as a possible contender for disposable label-free aptasensor applications. Bipolar electrochemical exfoliation enables simultaneous exfoliation, reduction, and deposition of graphene nanosheets on prospective electrodes. Our comparative study confirms that the bipolar exfoliated graphene deposited on the negative feeding electrode (i.e., reduced graphene oxide) possesses better electrochemical properties for aptasensing. The optimized aptasensor based on bipolar exfoliated graphene deposited on PET/Au electrodes exhibits a highly sensitive response of 4.07 µA log c -1 (unit of c, pM) which is linear in the range of 0.0007-20 nM, and has a low limit of detection of 0.65 pM (S/N = 3). The aptasensor establishes highly selective performance with a stability of 91.2% after 6 days. This study demonstrates that bipolar electrochemistry is a simple yet efficient technique that could provide high-quality graphene for biosensing applications. Considering its simplicity and efficiency, the BPE technique promises the development of feasible and affordable lab-on-chip and point-of-care cancer diagnosis technologies.

Highly sensitive label-free electrochemical aptasensors based on photoresist derived carbon for cancer biomarker detection.

-Label-free electrochemical aptasensors for cancer biomarker detection can be a promising means for early detection of cancer due to their high sensitivity, selectivity, and stability, and low cost. In this study, a highly sensitive and selective label-free electrochemical aptasensor based on carbon microelectromechanical systems (C-MEMS) was developed for the detection of platelet-derived growth factor-BB (PDGF-BB). The active electrodes of the aptasensors were synthesized via carbonization of SU-8 derived electrodes at high temperatures in an oxygen-free furnace. An oxygen-plasma oxidation treatment was used to functionalize the C-MEMS electrodes, which provided efficient covalent immobilization of amino terminated affinity aptamers. The turn-off and turn-on detection strategies-based on capacitance and resistance measurement, respectively-were employed. The capacitance detection strategies exhibited a wide linear response range of 0.01-50 nM, with a high sensitivity of 3.33 mF cm-2 Logc-1 (unit of c, nM) and a low limit of detection of 7 pM (S/N = 3). The resistance detection strategies exhibited an even wider linear response range of 0.005-50 nM, and a lower limit of detection of 1.9 pM (S/N = 3), with a high sensitivity of 1.65 × 103 Ω Logc-1 (unit of c, nM). Both detection strategies provided high selectivity for PDGF-BB and high stability of 90.34% after 10 days. This research demonstrates that the developed label-free electrochemical C-MEMS based PDGF-BB aptasensor is highly sensitive, selective, and robust. This aptasensor is a promising prospect for the highly demanding task of early detection of cancer biomarkers.

CD25-Targeted IL-2 Signals Promote Improved Outcomes of Influenza Infection and Boost Memory CD4 T Cell Formation.

IL-2 is a pleotropic cytokine with potent pro- and anti-inflammatory effects. These divergent impacts can be directed in vivo by forming complexes of IL-2 and anti-IL-2 mAbs (IL-2C) to target IL-2 to distinct subsets of cells based on their expression of subunits of the IL-2R. In this study, we show that treatment of mice with a prototypical anti-inflammatory IL-2C, JES6-1-IL-2C, best known to induce CD25+ regulatory CD4 T cell expansion, surprisingly causes robust induction of a suite of inflammatory factors. However, treating mice infected with influenza A virus with this IL-2C reduces lung immunopathology. We compare the spectrum of inflammatory proteins upregulated by pro- and anti-inflammatory IL-2C treatment and uncover a pattern of expression that reveals potentially beneficial versus detrimental aspects of the influenza-associated cytokine storm. Moreover, we show that anti-inflammatory IL-2C can deliver survival signals to CD4 T cells responding to influenza A virus that improve their memory fitness, indicating a novel application of IL-2 to boost pathogen-specific T cell memory while simultaneously reducing immunopathology.

Memory CD4 T cell-derived IL-2 synergizes with viral infection to exacerbate lung inflammation.

Defining the most penetrating correlates of protective memory T cells is key for designing improved vaccines and T cell therapies. Here, we evaluate how interleukin (IL-2) production by memory CD4 T cells, a widely held indicator of their protective potential, impacts immune responses against murine influenza A virus (IAV). Unexpectedly, we show that IL-2-deficient memory CD4 T cells are more effective on a per cell basis at combating IAV than wild-type memory cells that produce IL-2. Improved outcomes orchestrated by IL-2-deficient cells include reduced weight loss and improved respiratory function that correlate with reduced levels of a broad array of inflammatory factors in the infected lung. Blocking CD70-CD27 signals to reduce CD4 T cell IL-2 production tempers the inflammation induced by wild-type memory CD4 T cells and improves the outcome of IAV infection in vaccinated mice. Finally, we show that IL-2 administration drives rapid and extremely potent lung inflammation involving NK cells, which can synergize with sublethal IAV infection to promote acute death. These results suggest that IL-2 production is not necessarily an indicator of protective CD4 T cells, and that the lung environment is particularly sensitive to IL-2-induced inflammation during viral infection.

Efficacy and Safety of Pioglitazone Monotherapy in Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis of Randomised Controlled Trials.

Pioglitazone, the only thiazolidinedione drug in clinical practice is under scrutiny due to reported adverse effects, it's unique insulin sensitising action provides rationale to remain as a therapeutic option for managing type 2 diabetes mellitus (T2DM). We conducted a systematic review and meta-analysis comparing pioglitazone monotherapy with monotherapies of other oral antidiabetic drugs for assessing its efficacy and safety in T2DM patients. Mean changes in glycated haemoglobin (HbA1c), and mean changes in fasting blood sugar (FBS) level, body weight (BW) and homeostasis model assessment-insulin resistance (HOMA-IR) were primary and secondary outcomes, respectively. Safety outcomes were changes in lipid parameters, blood pressure and incidences of adverse events. Metafor package of R software and RevMan software based on random-effects model were used for analyses. We included 16 randomised controlled trials. Pioglitazone monotherapy showed equivalent efficacy as comparators in reducing HbA1c by 0.05% (95% CI: -0.21 to 0.11) and greater efficacy in reducing FBS level by 0.24 mmol/l (95% CI: -0.48 to -0.01). Pioglitazone showed similar efficacy as comparators in reducing HOMA-IR (WMD: 0.05, 95% CI: -0.49 to 0.59) and increasing high-density lipoprotein level (WMD: 0.02 mmol/l, 95% CI: -0.06 to 0.10). Improved blood pressure (WMD: -1.05 mmHg, 95% CI: -4.29 to 2.19) and triglycerides level (WMD: -0.71 mmol/l, 95% CI: -1.70 to 0.28) were also observed with pioglitazone monotherapy. There was a significant association of pioglitazone with increased BW (WMD: 2.06 kg, 95% CI: 1.11 to 3.01) and risk of oedema (RR: 2.21, 95% CI: 1.48 to 3.31), though the risk of hypoglycaemia was absolutely lower (RR: 0.51, 95% CI: 0.33 to 0.80). Meta-analysis supported pioglitazone as an effective treatment option for T2DM patients to ameliorate hyperglycaemia, adverse lipid metabolism and blood pressure. Pioglitazone is suggested to prescribe following individual patient's needs. It can be a choice of drug for insulin resistant T2DM patients having dyslipidaemia, hypertension or history of cardiovascular disease.

Lactate biosensing: The emerging point-of-care and personal health monitoring.

Lactate plays a crucial role in the anaerobic metabolic pathway of humans. In situations of oxygen deficit, its production increases; leading to several life-threatening conditions such as hemorrhage, respiratory failure, trauma or ischemia from lactate acidosis. Lactate level detection and point-of-care (POC) monitoring in a fast, accurate and non-invasive manner is ultimately important for many health care applications. Optical and electrochemical techniques are employed in lactate sensing to achieve high sensitivity and selectivity, miniaturization, portability, simplicity, and low cost. To improve the selectivity and sensitivity, two important enzymes, lactate oxidase (LOx) and lactate dehydrogenese (LDH) are employed. Conventional methods for lactate detection are not fast enough to be used in point-of-care or personal health monitoring settings. Moreover, the existing point-of-care lactate sensing tools follow invasive or partially invasive sampling protocols such as finger pricking. In this review, a comprehensive overview of different lactate biosensing devices is presented. Particularly, the state-of-the-art and prospects of wearable, non-invasive lactate sensing from different biofluids are discussed.

Ganoderma lucidum and Auricularia polytricha Mushrooms Protect against Carbofuran-Induced Toxicity in Rats.

The current study aimed to investigate the ameliorative effects of two types of mushrooms, Ganoderma lucidum (GL) and Auricularia polytricha (AP), against carbofuran- (CF) induced toxicity in rats. Male Wistar rats (n = 42) were divided into six equal groups. The rats in the negative control group received oral administration of CF at 1 mg/kg with the normal diet for 28 days. The treatment groups received oral administration of ethanolic extract of GL or AP at 100 mg/kg followed by coadministration of CF at 1 mg/kg with the normal diet for the same experimental period, respectively. In the CF alone treated group, there were significant decreases in the erythrocytic and thrombocytic indices but increases in the concentrations of the total leukocytes, including the agranulocytes. A significant increase in all of the liver function biomarkers except albumin, in lipid profiles except high-density lipoprotein, and in the kidney function markers occurred in the negative control group compared to the rats of the normal control and positive control groups. The coadministration of mushroom extracts significantly ameliorated the toxic effects of the CF. The GL mushroom extract was more efficacious than that of the AP mushroom, possibly due to the presence of high levels of phenolic compounds and other antioxidants in the GL mushroom.

Prospects and Challenges of Volatile Organic Compound Sensors in Human Healthcare.

The chemical signatures of volatile organic compounds (VOCs) in humans can be utilized for point-of-care (POC) diagnosis. Apart from toxic exposure studies, VOCs generated in humans can provide insights into one's healthy and diseased metabolic states, acting as a biomarker for identifying numerous diseases noninvasively. VOC sensors and the technology of e-nose have received significant attention for continuous and selective monitoring of various physiological and pathophysiological conditions of an individual. Noninvasive detection of VOCs is achieved from biomatrices of breath, sweat and saliva. Among these, detection from sweat and saliva can be continuous in real-time. The sensing approaches include optical, chemiresistive and electrochemical techniques. This article provides an overview of such techniques. These, however, have limitations of reliability, precision, selectivity, and stability in continuous monitoring. Such limitations are due to lack of sensor stability and complexity of samples in a multivariate environment, which can lead to false readings. To overcome selectivity barriers, sensor arrays enabling multimodal sensing, have been used with pattern recognition techniques. Stability and precision issues have been addressed through advancements in nanotechnology. The use of various forms of nanomaterial not only enhance sensing performance, but also plays a major role in detection on a miniaturized scale. The rapid growth in medical Internet of Things (IoT) and artificial intelligence paves a pathway for improvements in human theranostics.

Antiphospholipid antibodies in epilepsy: A systematic review and meta-analysis.

BACKGROUND: Autoimmunity is believed to play an important causative role in the pathogenesis of epilepsy. There are evidences for the presence of autoantibodies in patients with epilepsy. To date, many studies have assessed the presence of antiphospholipid antibodies (aPLs) in epilepsy patients, though the relationship has been inconclusive. AIMS: The aim of this systematic review and meta-analysis was to evaluate the presence of aPLs in epileptic patients as compared to healthy controls. METHODS: Five electronic databases (PubMed, Web of Science, Embase, Scopus and Google Scholar) were searched systematically. Study-specific odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using random-effects model. Quality assessment was carried out by using the modified 9-star Newcastle-Ottawa Scale (NOS). L'Abbé plots were generated to visually inspect heterogeneity while publication bias was evaluated via visualization of contour- enhanced funnel plots, and Begg's and Egger's tests. RESULTS: Based on the inclusion criteria, 14 studies were selected involving 1248 epilepsy patients and 800 healthy controls. The majority of epilepsy was categorised as generalised or partial and none had comorbidity with autoimmune diseases. Significant presence of both anticardiolipin (aCL) antibodies (OR: 5.16, 95% CI: 3.21-8.28, p < 0.00001) and anti-ß2- glycoprotein I (anti-ß2-GPI) antibodies (OR: 2.95, 95% CI: 1.07-8.11, p = 0.04) exhibited comorbid association with epilepsy patients as compared to healthy controls. Subgroup analyses revealed that presence of aCL antibodies was more specifically observed in paediatrics (OR: 4.57, 95% CI: 2.57-8.15, p < 0.00001) than adults (OR: 4.24, 95% CI: 1.80-10.01, p = 0.001). The odds of aCL antibody presence was higher in partial epilepsy patients (OR: 7.88, 95% CI: 3.23-19.24, p < 0.00001) than that of generalised (OR: 3.76, 95% CI: 2.15-6.59, p < 0.00001) and in Asian epileptic patients (OR: 9.56, 95% CI: 2.69-33.95, p = 0.0005) than Europeans (OR: 4.35, 95% CI: 2.74-6.92, p < 0.00001). The presence of anti-ß2-GPI antibodies was significant in paediatric (OR: 6.44, 95% CI: 1.39-29.89, p = 0.02) and African population with epilepsies (OR: 10.59, 95% CI: 1.22-92.25, p = 0.03). NOS of the majority of the studies (11/14) indicated a high methodological quality. No substantial heterogeneity was observed either from the quantitative analysis or from the L'Abbé plots while no significant publication bias was detected from funnel plots; Begg's and Egger's tests. CONCLUSION: Since none of the epilepsy subjects exhibited any comorbid autoimmune disorders, significant presence of aCL and anti-ß2-GPI antibodies indicate towards their contribution in immune-mediated general pathogenesis of epilepsy.

Genetic risk factors in thrombotic primary antiphospholipid syndrome: A systematic review with bioinformatic analyses.

BACKGROUND: Antiphospholipid Syndrome (APS) is an autoimmune multifactorial disorder. Genetics is believed to play a contributory role in the pathogenesis of APS, especially in thrombosis development and pregnancy morbidity. In the last 20 years, extensive research on genetic contribution on APS indicates that APS is a polygenic disorder, where a number of genes are involved in the development of its clinical manifestations. AIMS: The aim of this systematic review is to evaluate the genetic risk factors in thrombotic primary APS. Additionally, to assess the common molecular functions, biological processes, pathways, interrelations with the gene encoded proteins and RNA-Seq-derived expression patterns over different organs of the associated genes via bioinformatic analyses. METHODS: Without restricting the year, a systematic search of English articles was conducted (up to 4th September 2017) using Web of Science, PubMed, Scopus, ScienceDirect and Google Scholar databases. Eligible studies were selected based on the inclusion criteria. Two researchers independently extracted the data from the included studies. Quality assessment of the included studies was carried out using a modified New-Castle Ottawa scale (NOS). RESULTS: From an initial search result of 2673 articles, 22 studies were included (1268 primary APS patients and 1649 healthy controls). Twenty-two genes were identified in which 16 were significantly associated with thrombosis in primary APS whereas six genes showed no significant association with thrombosis. Based on the NOS, 14 studies were of high quality while 6 were low quality studies. From the bioinformatic analyses, thrombin-activated receptor activity (q = 6.77 × 10-7), blood coagulation (q = 2.63 × 10-15), formation of fibrin clot (q = 9.76 × 10-10) were the top hit for molecular function, biological process and pathway categories, respectively. With the highest confidence interaction score of 0.900, all of the thrombosis-associated gene encoded proteins of APS were found to be interconnected except for two. Based on the pathway analysis, cumulatively all the genes affect haemostasis [false discovery rate (FDR) = 1.01 × 10-8] and the immune system [FDR = 9.93 × 10-2]. Gene expression analysis from RNA-Seq data revealed that almost all the genes were expressed in 32 different tissues in the human body. CONCLUSION: According to our systematic review, 16 genes contribute significantly in patients with thrombotic primary APS when compared with controls. Bioinformatic analyses of these genes revealed their molecular interconnectivity in protein levels largely by affecting blood coagulation and immune system. These genes are expressed in 32 different organs and may pose higher risk of developing thrombosis anywhere in the body of primary APS patients.

Coexistence of antiphospholipid antibodies and cephalalgia.

Background The occurrence of antiphospholipid antibodies (aPLs) and headache comorbidity in the presence or absence of underlying autoimmune diseases remains unclear. Aim The aim of this review was to summarize the relationship between headache and aPLs based on evidences from cohort studies and case reports, in addition to examining the treatment strategies that resolved headache in aPLs-positive individuals. Methods A comprehensive literature search was conducted through PubMed, ISI Web of Science and Google Scholar. A total of 559 articles were screened and the appropriate articles were selected based on quality and level of evidence. Results Cohort studies (n = 27) from Europe, North America and Asia demonstrated comorbidity of aPLs and headache in antiphospholipid syndrome, systemic lupus erythematosus (SLE) and neuropsychiatric SLE patients. Significantly higher association between migraine and aPLs was observed (n = 170/779; p < 0.0001) in individuals without any underlying diseases. Our analysis of shortlisted case reports (n = 17) showed that a higher frequency of anticardiolipin antibodies were present in subjects with different autoimmune disorders (70.6%). Corticosteroids were highly effective in resolving headache in aPLs-positive individuals. Conclusion Higher frequency of comorbidity between aPLs and headache was observed in healthy individuals and patient cases. Therefore, experimental studies are warranted to evaluate the aPLs-induced pathogenic mechanism of headache.

A Clinical Update and Global Economic Burden of Rheumatoid Arthritis.

BACKGROUND AND OBJECTIVE: Rheumatoid arthritis (RA) is a predominant inflammatory autoimmune disorder. The incidence and prevalence of RA is increasing with considerable morbidity and mortality worldwide. The pathophysiology of RA has become clearer due to many significant research outputs during the last two decades. Many inflammatory cytokines involved in RA pathophysiology and the presence of autoantibodies are being used as potential biomarkers via the use of effective diagnostic techniques for the early diagnosis of RA. Currently, several disease-modifying anti-rheumatic drugs are being prescribed targeting RA pathophysiology, which have shown significant contributions in improving the disease outcomes. DISCUSSION: Even though innovations in treatment strategies and monitoring are helping the patients to achieve early and sustained clinical and radiographic remission, the high cost of drugs and limited health care budgets are restricting the easy access of RA treatment. Both direct and indirect high cost of treatment are creating economic burden for the patients and affecting their quality of life. CONCLUSION: The aim of this review is to describe the updated concept of RA pathophysiology and highlight current diagnostic tools used for the early detection as well as prognosis - targeting several biomarkers of RA. Additionally, we explored the updated treatment options with side effects besides discussing the global economic burden.