The quantum model of T-cell activation: Revisiting immune response theories.

Our understanding of the immune response is far from complete, missing out on more detailed explanations that could be provided by molecular insights. To bridge this gap, we introduce the quantum model of T-cell activation. This model suggests that the transfer of energy during protein phosphorylation within T cells is not a continuous flow but occurs in discrete bursts, or 'quanta', of phosphates. This quantized energy transfer is mediated by oscillating cycles of receptor phosphorylation and dephosphorylation, initiated by dynamic 'catch-slip' pulses in the peptide-major histocompatibility complex-T-cell receptor (pMHC-TcR) interactions. T-cell activation is predicated upon achieving a critical threshold of catch-slip pulses at the pMHC-TcR interface. Costimulation is relegated to a secondary role, becoming crucial only when the frequency of pMHC-TcR catch-slip pulses does not meet the necessary threshold for this quanta-based energy transfer. Therefore, our model posits that it is the quantum nature of energy transfer-not the traditional signal I or signal II-that plays the decisive role in T-cell activation. This paradigm shift highlights the importance of understanding T-cell activation through a quantum lens, offering a potentially transformative perspective on immune response regulation.

Spectroscopic investigation and structural simulation in human serum albumin with hydroxychloroquine/Silybum marianum and a possible potential COVID-19 drug candidate.

In this study, the interaction between human serum albumin (HSA) and the hydroxychloroquine/Silybum marianum (HCQ/SM) mixture was investigated using various techniques. The observed high binding constant (Kb) and Stern-Volmer quenching constant (KSV) indicate a strong binding affinity between the HCQ/SM mixture and HSA. The circular dichroism (CD) analysis revealed that HCQ/SM induced conformational changes in the secondary structure of HSA, leading to a decrease in the α-helical content. UV-Vis analysis exhibited a slight redshift, indicating that the HCQ/SM mixture could adapt to the flexible structure of HSA. The experimental results demonstrated the significant conformational changes in HSA upon binding with HCQ/SM. Theoretical studies were carried out using molecular dynamics simulation via the Gromacs simulation package to explore insights into the drug interaction with HSA-binding sites. Furthermore, molecular docking studies demonstrated that HCQ/SM-HSA exhibited favorable docking scores with the receptor (5FUZ), suggesting a potential therapeutic relevance in combating COVID-19 with a value of -6.24 kcal mol-1. HCQ/SM exhibited stronger interaction with both SARS-CoV-2 virus main proteases compared to favipiravir. Ultimately, the experimental data and molecular docking analysis presented in this research offer valuable insights into the pharmaceutical and biological properties of HCQ/SM mixtures when interacting with serum albumin.

Multifaceted functions of chronic inflammation in regulating tumor dormancy and relapse.

Inflammation is a double-edged sword exhibiting multifaceted functions. On one hand, it either induces tumor cell apoptosis, or establishes tumor dormancy by inhibiting tumor cell proliferation; on the other hand, it either facilitates the tumorigenesis process or reawakens dormant tumor cells, resulting in disease recurrences. Each outcome would depend on the balance between type I and type II inflammation as well as the duration of inflammation being acute or chronic. In this essay, we provide a critical review of the empirical evidence suggesting that chronic inflammation, dominated by type I inflammatory cells and cytokines as a result of trauma and microbiome dysbiosis, could facilitate the carcinogenesis process in normal cells and retain nascent transformed cells in a dormant state. On the other hand, an elevated type II inflammation along with inefficient resolution of type I inflammation following trauma or major surgeries could delay the wound healing process and promote the growth and reawakening of dormant tumor cells, resulting in disease recurrences. Finally, cytokines exhibiting type I and II inflammatory functions, simultaneously, tend to promote tumor recurrence when become chronic. Therefore, the risk of reawakening dormant tumor cells should be considered in cancer survivors who experience major surgeries and trauma, or suffer from chronic inflammatory diseases.

Personal Digital Twin: A Close Look into the Present and a Step towards the Future of Personalised Healthcare Industry.

Digital twins (DTs) play a vital role in revolutionising the healthcare industry, leading to more personalised, intelligent, and proactive healthcare. With the evolution of personalised healthcare, there is a significant need to represent a virtual replica for individuals to provide the right type of care in the right way and at the right time. Therefore, in this paper, we surveyed the concept of a personal digital twin (PDT) as an enhanced version of the DT with actionable insight capabilities. In particular, PDT can bring value to patients by enabling more accurate decision making and proper treatment selection and optimisation. Then, we explored the progression of PDT as a revolutionary technology in healthcare research and industry. However, although several research works have been performed for smart healthcare using DT, PDT is still at an early stage. Consequently, we believe that this work can be a step towards smart personalised healthcare industry by guiding the design of industrial personalised healthcare systems. Accordingly, we introduced a reference framework that empowers smart personalised healthcare using PDTs by bringing together existing advanced technologies (i.e., DT, blockchain, and AI). Then, we described some selected use cases, including the mitigation of COVID-19 contagion, COVID-19 survivor follow-up care, personalised COVID-19 medicine, personalised osteoporosis prevention, personalised cancer survivor follow-up care, and personalised nutrition. Finally, we identified further challenges to pave the PDT paradigm toward the smart personalised healthcare industry.

Seroprevalence of SARS-CoV-2 in Guilan Province, Iran, April 2020.

We determined the seroprevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in an affected area in northern Iran in April 2020. Antibodies to SARS-CoV-2 were detected in 528 persons by using rapid tests. Adjusted prevalence of SARS-CoV-2 seropositivity was 22.2% (95% CI 16.4%-28.5%).

Industry 4.0 towards Forestry 4.0: Fire Detection Use Case.

Forestry 4.0 is inspired by the Industry 4.0 concept, which plays a vital role in the next industrial generation revolution. It is ushering in a new era for efficient and sustainable forest management. Environmental sustainability and climate change are related challenges to promote sustainable forest management of natural resources. Internet of Forest Things (IoFT) is an emerging technology that helps manage forest sustainability and protect forest from hazards via distributing smart devices for gathering data stream during monitoring and detecting fire. Stream processing is a well-known research area, and recently, it has gained a further significance due to the emergence of IoFT devices. Distributed stream processing platforms have emerged, e.g., Apache Flink, Storm, and Spark, etc. Querying windowing is the heart of any stream-processing platform which splits infinite data stream into chunks of finite data to execute a query. Dynamic query window-based processing can reduce the reporting time in case of missing and delayed events caused by data drift.In this paper, we present a novel dynamic mechanism to recommend the optimal window size and type based on the dynamic context of IoFT application. In particular, we designed a dynamic window selector for stream queries considering input stream data characteristics, application workload and resource constraints to recommend the optimal stream query window configuration. A research gap on the likelihood of adopting smart IoFT devices in environmental sustainability indicates a lack of empirical studies to pursue forest sustainability, i.e., sustainable forestry applications. So, we focus on forest fire management and detection as a use case of Forestry 4.0, one of the dynamic environmental management challenges, i.e., climate change, to deliver sustainable forestry goals. According to the dynamic window selector's experimental results, end-to-end latency time for the reported fire alerts has been reduced by dynamical adaptation of window size with IoFT stream rate changes.

Local and distant tumor dormancy during early stage breast cancer are associated with the predominance of infiltrating T effector subsets.

BACKGROUND: Although breast cancer mortality is a result of distant recurrences associated with the establishment of tumor dormancy, current clinical practice guidelines recommend a wait and watch approach for tumor recurrences. This is because of our limited understanding of tumor dormancy and insufficient evidence in support of immunological control of tumor dormancy. METHODS: We used FVBN202 transgenic mice expressing rat neu oncogene in the mammary glands, and their parental FVB strain lacking neu expression. These models allowed the detection of tumor dormancy at distant sites using the rat neu protein as a tumor marker. We also used Ki67 for the detection of the indolent and quiescent types of tumor dormancy. Multicolor flow cytometry was used to detect dormant tumor cells and T cell subsets. Co-culture studies were performed to determine the role of T cells in preventing regrowth of dormant cells. RESULTS: We demonstrated that dormant tumor cells were present at the site of primary breast cancer and at distant sites in the lungs and in the liver very early in the course of early stage breast cancer when no distant metastasis was evident. Dormant tumor cells were characterized as neu expressing Ki67- and Ki67low fractions associated with the induction of local immune responses predominated by CD4+ and CD8+ T effector cell subsets. The presence of neu-autoreactive T cells from FVBN202 mice only prevented regrowth of dormant cells. On the other hand, presence of neu-alloreactive anti-tumor T cells in FVB mice prior to tumor challenge resulted in the protection of mice from the dissemination of dormant tumor cells to distant organs. CONCLUSION: Our results suggest that immunotherapeutic targeting of semi-allogeneic mutant neoantigens during tumor dormancy might prevent distant recurrence of the disease.

Prospective comparative study between the effect of CIDEX® OPA and STERRAD NX on the durability of digital flexible ureteroscope.

PURPOSE: We compared the effect of chemical disinfection (CIDEX® OPA) and low-temperature hydrogen peroxide gas plasma (STERRAD NX) on two brand new digital flexible ureteroscope (DFU) (Flex-Xc) using subjective and objective parameters. METHODS: Over 11-month period, all flexible ureteroscopic procedures that fulfill the inclusion criteria were done by two brand new flexible ureteroscopes and were prospectively evaluated. Intraoperative data included total operative time, laser power and duration, stone criteria and subjective evaluation of the procedure as well as visibility and maneuverability scores were reported. The end point of the study was when the scope was deemed by the surgeon as unable to perform the procedure; when leak test is positive. RESULTS: A total of 88 patients were randomized either for the first flexible ureteroscope disinfected using Cidex® OPA (n = 59, 67%) or second ureteroscope sterilized with Sterrad NX (n = 29, 33%). Intraoperative, the first DFU was significantly used with a total operative time of approximately 49 h compared to the second one (p < 0.001). In the same context, laser power parameters were significantly different among the two groups (p = 0.003). The subjective evaluation of the procedure, maneuverability, visibility scores, laser duration, stone burden and post-operative infection rate were statistically insignificant between both groups. At the end point of the study, the deflection in up and downward directions for both DFU were measured. CONCLUSIONS: The durability and longevity of the DFU is strongly related to the sterilization method. Our findings suggest that CIDEX® OPA should prioritize Sterrad in sterilization of DFU.

Cross-cultural adaptation and validation of the Saudi Arabic version of the Knee Injury and Osteoarthritis Outcome Score (KOOS).

The Knee Injury Osteoarthritis Outcome Score (KOOS) is a widely used joint-specific measure employed to evaluate pain, symptoms, activities of daily living, recreational activities, and quality of life in patients with knee osteoarthritis (OA). Although the original KOOS has been translated into many languages, a Saudi Arabic version is not available. This study aimed to culturally adapt and evaluate the psychometric properties of the Saudi Arabic version of the KOOS in patients with knee OA. The original KOOS was translated and adapted into Saudi Arabic version over six stages according to the guidelines suggested by Beaton and recommended by the American Association of Orthopedic Surgeons Outcome Committee. Patients diagnosed with knee OA (n = 136) were recruited to examine the psychometric properties, such as internal consistency that was tested using Cronbach's alpha, test-retest reliability that was analyzed using the intra-class correlation coefficient (ICC2,1), and construct validity that examined by testing the correlations between the new version subscales, Form 36 Health Survey subscales, and the Visual Analog Scale, Spearman's correlation coefficient (rs) was used to measure the correlations. A total of 122 (89.7%) of the 136 participants with knee OA completed the second re-test of new Saudi Arabic version. Excellent internal consistency (Cronbach's alpha = 0.87-0.92) was detected in the subscales of the adapted version, as well as excellent test-retest reliability (ICC2,1 = 0.92-0.94). The pattern of correlation between the subscales of the Saudi Arabic version of the KOOS, SF-36 domains and the Visual Analog Scale for pain supported the construct validity of the adapted version. The Saudi Arabic version of the KOOS was well accepted and exhibited excellent reliability, internal consistency, and construct validity in Saudi patients with knee OA.

Impact of health literacy on diabetes outcomes: a cross-sectional study from Lahore, Pakistan.

OBJECTIVES: To evaluate the functional health literacy of patients with type 2 diabetes in Lahore and its impact on glycaemic control. STUDY DESIGN: A six-month cross-sectional study. METHODS: Health literacy in 204 patients with diabetes was evaluated using a validated questionnaire (Short Test of Functional Health Literacy [s-TOFHLA]). RESULTS: The frequency distribution among various age groups (P = 0.003), education levels (P = 0.0005), socio-economic status levels (P = 0.0005) and glycated haemoglobin (HbA1C) levels (P = 0.0005) differed significantly with health literacy level. The majority of patients with diabetes (86.1%) with poor glycaemic control (HbA1C >9%) had inadequate health literacy and were more likely to have retinopathy (odds ratio = 13.1, P = 0.003). Health literacy levels were not significantly different when compared for antidiabetic therapies (P = 0.234). Significant associations were observed between predictors of glycaemic control (s-TOFHLA score [P = 0.0005], education status [P = 0.0005] and disease risks [P = 0.005]) and HbA1C, level. However, after adjusting for basic characteristics, only s-TOFHLA score had a significant association with HbA1C level (P = 0.001). CONCLUSIONS: These data suggest that inadequate health literacy is potentially associated with poor glycaemic control, and microvascular and macrovascular complications, particularly retinopathy. As such, educational and training programmes should be introduced to improve functional health literacy of patients with diabetes for better glycaemic control.

Trends in the prescribing of topical nasal agents Using an NHS England data base.

OBJECTIVES: Our aim is to present data depicting geographical prescribing trends and expenditure related to topical nasal agent prescriptions across clinical commissioning groups (CCG's) in England. We assess if prescribing trends can act as a surrogate marker for allergic rhinitis (AR) and rhinosinusitis disease burden (RS). DESIGN: NHS England primary care prescriptions dispensed for topical drugs used in nasal allergy (BNF chapter 12.2.1) were accessed using OpenPrescribing beta software. Graphical data over a 5-year period was generated to highlight nationwide trends in prescribing and expenditure. Out of 211 CCG districts, the highest and lowest 40 prescribing rate CCG's were subdivided according to rural/urban output and geographical location to highlight specific regional trends. Two sampled, paired and unpaired t tests of unequal variance were performed to determine the significance of observed trends. RESULTS: The 5-year trend in prescription rate (mean yearly expenditure £40 725 258) for drugs used in nasal allergy marginally increased. Peak prescription was during months of high environmental pollen. Regardless of pollen season (June 2016 vs November 2015), CCG's of urban districts had significantly lower rates of prescribing (P ≤ .001). Amongst the 40 lowest and 40 highest prescribing rate CCG's, prescription rates fell significantly between months of high and low environmental pollen (P ≤ .0001). Regardless of pollen season, rural eastern and eastern coastal districts of England had persistently high rates of prescription. CONCLUSIONS: This study shows marked geographical variation in prescribing for topical nasal agents in England. There is propensity for eastern districts to have higher rates of prescribing in England. Adopting prescribing trends as a surrogate marker for disease burden could allow allergy and endoscopic sinus surgery services to be concentrated to specific regions. This would provide more effective, economical treatment for both AR and RS.

Using large sequencing data sets to refine intragenic disease regions and prioritize clinical variant interpretation.

PURPOSE: Classification of novel variants is a major challenge facing the widespread adoption of comprehensive clinical genomic sequencing and the field of personalized medicine in general. This is largely because most novel variants do not have functional, genetic, or population data to support their clinical classification. METHODS: To improve variant interpretation, we leveraged the Exome Aggregation Consortium (ExAC) data set (N = ~60,000) as well as 7,000 clinically curated variants in 132 genes identified in more than 11,000 probands clinically tested for cardiomyopathies, rasopathies, hearing loss, or connective tissue disorders to perform a systematic evaluation of domain level disease associations. RESULTS: We statistically identify regions that are most sensitive to functional variation in the general population and also most commonly impacted in symptomatic individuals. Our data show that a significant number of exons and domains in genes strongly associated with disease can be defined as disease-sensitive or disease-tolerant, leading to potential reclassification of at least 26% (450 out of 1,742) of variants of uncertain clinical significance in the 132 genes. CONCLUSION: This approach leverages domain functional annotation and associated disease in each gene to prioritize candidate disease variants, increasing the sensitivity and specificity of novel variant assessment within these genes.Genet Med advance online publication 22 September 2016.

Application of Next Generation Sequencing for Diagnostic Testing of Tree Fruit Viruses and Viroids.

Conventional detection of viruses and virus-like diseases of plants is accomplished using a combination of molecular, serological, and biological indexing. These are the primary tools used by plant virologists to monitor and ensure trees are free of known viral pathogens. The biological indexing assay, or bioassay, is considered to be the "gold standard" as it is the only method of the three that can detect new, uncharacterized, or poorly characterized viral disease agents. Unfortunately, this method is also the most labor intensive and can take up to three years to complete. Next generation sequencing (NGS) is a technology with rapidly expanding possibilities including potential applications for the detection of plant viruses. In this study, comparisons are made between tree fruit testing by conventional and NGS methods, to demonstrate the efficacy of NGS. A comparison of 178 infected trees, many infected with several viral pathogens, demonstrated that conventional and NGS were equally capable of detecting known viruses and viroids. Comparable results were obtained for 170 of 178 of the specimens. Of the remaining eight specimens, some discrepancies were observed between viruses detected by the two methods, representing less than 5% of the specimens. NGS was further demonstrated to be equal or superior for the detection of new or poorly characterized viruses when compared with a conventional bioassay. These results validated both the effectiveness of conventional virus testing methods and the use of NGS as an additional or alternative method for plant virus detection.

Improving hearing loss gene testing: a systematic review of gene evidence toward more efficient next-generation sequencing-based diagnostic testing and interpretation.

PURPOSE: With next generation sequencing technology improvement and cost reductions, it has become technically feasible to sequence a large number of genes in one diagnostic test. This is especially relevant for diseases with large genetic and/or phenotypic heterogeneity, such as hearing loss. However, variant interpretation remains the major bottleneck. This is further exacerbated by the lack in the clinical genetics community of consensus criteria for defining the evidence necessary to include genes on targeted disease panels or in genomic reports, and the consequent risk of reporting variants in genes with no relevance to disease. METHODS: We describe a systematic evidence-based approach for assessing gene-disease associations and for curating relevant genes for different disease aspects, including mode of inheritance, phenotypic severity, and mutation spectrum. RESULTS: By applying this approach to clinically available hearing loss gene panels with a total of 163 genes, we show that a significant number (45%) of genes lack sufficient evidence of association with disease and thus are expected to increase uncertainty and patient anxiety, in addition to intensifying the interpretation burden. Information about all curated genes is summarized. Our retrospective analysis of 539 hearing loss cases tested by our previous OtoGenomeV2 panel demonstrates the impact of including genes with weak disease association in laboratory wet-bench and interpretation processes. CONCLUSION: Our study is, to our knowledge, the first to highlight the urgent need for defining the clinical validity of gene-disease relationships for more efficient and accurate clinical testing and reporting.Genet Med 18 6, 545-553.

Evaluation of pesticide residues of organochlorine in vegetables and fruits in Qatar: statistical analysis.

The study aimed to examine the residues of organochlorines pesticides (OCPs) in vegetables and fruits in Qatar. A total of 127 samples was studied. Ninety percent of the imported samples recorded residues above the maximum residue levels (MRLs). The most frequently detected OCP in the samples was heptachlor (found in 75 samples). In the comparisons between the washed and unwashed samples, no significant differences were observed (P > 0.05). However, the effect of washing process with tap water depended on the type of vegetables and fruits.

Incidence of autism in high risk neonatal follow up.

OBJECTIVE: To detect autism spectrum disorder (ASD) cases within the High Risk Neonatal Follow up Program (HRNFP), as an indicator of the prevalence of ASD and associated risk factors in the Kingdom of Saudi Arabia (KSA). METHODS: We conducted this retrospective medical chart review in a tertiary care hospital in Riyadh, KSA. All patients admitted to the HRNFP were seen at 3 years corrected age between January 2012 and December 2013. Patients diagnosed with ASD from the HRNFP were referred to the King Fahad Medical City (KFMC) Autism Program for further assessment. The following potential risk factors for ASD were documented: low birth weight, gestational age less than 33 weeks, and male gender. RESULTS: In 2012, 59 patients were evaluated in the HRNFP. Three cases were diagnosed with ASD, with an ASD incidence rate of 5.1% (95% confidence interval [CI] calculated by adjusted Wald method: 1.2-14.5%). In 2013, 48 patients were evaluated and 2 cases were diagnosed with ASD, with an ASD incidence rate of 4.2% (95% CI: 0.4%-14.8%). The total ASD incidence rate during the 2-year study period was 4.7% (95% CI: 1.7%-10.8%). Factors associated with a higher likelihood of ASD were: male gender, low birth weight, and gestational age less than 33 weeks. CONCLUSION: Compared with the community, the prevalence of ASD was higher in the HRNFP. Further investigation is required to evaluate risk factors.

Sorting out cirrhosis: mechanisms of non-response to hepatitis C therapy.

Although cirrhosis has long been recognized as an important negative predictor of treatment response for hepatitis C virus (HCV) therapy, the mechanisms underlying this association remain relatively poorly understood. Treatment has progressed rapidly with the introduction of highly effective all-oral therapies, with promising outcomes even in patients with advanced cirrhosis. However, even with the new therapies, it is clear that patients with cirrhosis require special attention. Efficacy continues to be somewhat reduced compared to non-cirrhotic patients and safety is an important concern. In this review, we explore the reasons for treatment non-response in patients with cirrhosis. We focus on how cirrhosis impacts on four important areas including drug delivery, drug uptake and metabolism, immune responses and drug toxicity with examples from the clinical and basic literature. Fortunately, as treatment continues to progress, many of the challenges of treating patients with cirrhosis will become less and less problematic.