Violence against physicians working in public tertiary care hospital of Bangladesh: a facility-based cross-sectional study.

BACKGROUND: Violence against physicians in the workplace is a prevalent global issue, and Bangladesh is no exception. Such violence significantly disrupts healthcare delivery and the attainment of universal health coverage. This study aimed to comprehensively evaluate the prevalence, nature and associated risk factors of workplace violence (WPV) against physicians in Bangladesh. METHODS: This descriptive cross-sectional study was conducted at a public tertiary care hospital involving 441 physicians with a minimum tenure of 6 months. Data were gathered through a structured self-reported questionnaire, and statistical analyses were performed by using SPSS V.25. RESULTS: Out of the surveyed physicians, 67.3% (n=297) reported experiencing violence, categorised as 84.5% psychological, 13.5% physical and 2% sexual in nature. Predominant forms of psychological violence included bullying (48.8%) and threats (40.1%). The mean age of exposed physicians was 32.5±4.3 (SD) years. Those working in the emergency unit (45.8%), surgery and allied departments (54.2%), engaging in rotating shift work (70%), morning shifts (59.6%) and postgraduate trainees (68%) were frequently subjected to violence. Factors significantly associated with WPV included placement in surgery and allied departments (p<0.001), working rotating shifts (p<0.001), marital status (p=0.011) and being a male physician (p=0.010). Perpetrators were primarily identified as relatives of patients (66%). Working in rotating shifts (adjusted OR(AOR):2.6, 95% CI:1.2 to 5.4) and surgery and allied departments (AOR:5.7, 95% CI:3.4 to 9.8) emerged as significant risk factors of violence against physicians. CONCLUSION: A higher proportion of physicians at the early to mid-level stages of their careers, especially those in rotating shifts and surgery-related departments, reported incidence of WPV. Urgent intervention from policy-makers and healthcare entities is imperative to implement preventive measures. Strengthening security measures, establishing antiviolence policies and providing comprehensive training programmes are crucial steps towards ensuring a safer work environment for healthcare professionals.

Liquid Biopsy Snapshots of Key Phosphoproteomic Pathways in Lung Cancer Patients for Diagnosis and Therapy Monitoring.

Phosphorylation is a post-translational modification in proteins that changes protein conformation and activity for regulating signal transduction pathways. This mechanism is frequently impaired in lung cancer, resulting in permanently active constitutive phosphorylation to initiate tumor growth and/or reactivate pathways in response to therapy. We developed a multiplexed phosphoprotein analyzer chip (MPAC) that enables rapid (detection time: 5 min) and sensitive (LOD: 2 pg/µL) detection of protein phosphorylation and presents phosphoproteomic profiling of major phosphorylation pathways in lung cancer. We monitored phosphorylated receptors and downstream proteins involved in mitogen-activated protein kinase (MAPK) and PI3K/AKT/mTOR pathways in lung cancer cell line models and patient-derived extracellular vesicles (EV). Using kinase inhibitor drugs in cell line models, we found that the drug can inhibit the phosphorylation and/or activation of the kinase pathway. We then generated a phosphorylation heatmap by EV phosphoproteomic profiling of plasma samples isolated from 36 lung cancer patients and 8 noncancer individuals. The heatmap showed a clear difference between the noncancer and cancer samples and identify the specific proteins that are activated in the cancer samples. Our data also showed that MPAC could monitor immunotherapy responses by assessment of the phosphorylation states of the proteins, particularly for PD-L1. Finally, with a longitudinal study, we found that the phosphorylation levels of the proteins were indicative of a positive response to therapy. We believe that this study will lead to personalized treatment by providing a better understanding of the active and resistant pathways and will provide a tool for selecting combined and targeted therapies for precision medicine.

Toward Precision Deposition of Conductive Charge-Transfer Complex Crystals Using Nanoelectrochemistry.

The lack of understanding for precise synthesis and assembly of nano-entities remains a major challenge for nanofabrication. Electrocrystallization of a charge-transfer complex (CTC), tetrathiafulvalene bromide (TTF)Br, is studied on micro/nanoelectrodes for precision deposition of functional materials. The study reveals new insights into the entire CTC electrocrystallization process from the initial nanocluster nucleation to the final elongated crystals with hollow ends grown from the working electrode to the neighboring receiving electrode. On microelectrodes, the number of nucleation sites is reduced to one by lowering the applied overpotential or precursor concentration. Certain current-time transients exhibit significant induction periods prior to stable nucleus growth. The induction regime contains small fluctuating current spikes consistent with stochastic formation of precritical nanoclusters with lifetimes of 0.1-30 s and sizes of 20-160 nm. Electrochemical analyses further reveal rate, size distribution, and formation/dissipation dynamics of the nanoclusters. Crystal growth of (TTF)Br is further studied on triangular nanoelectrode patterns with thickness of 5-500 nm, which shows a mass-transfer-controlled process applicable for precision deposition of functional (TTF)Br crystals. This study, for the first time, establishes CTC nanoelectrochemistry as a platform technology for precise deposition of conductive crystal assemblies spanning the source and drain electrode for sensing applications.

Efficacy of limited antiviral treatment, testing, hospitalization, and social distancing for COVID-19 pandemic.

The control measures of a pandemic must be cautiously evaluated, especially when resources are "limited". A model of COVID-19 transmission dynamics is applied to assess the impact of antiviral treatment, testing, hospitalization, and social distancing. Under the assumption of "unlimited" resources, five control strategies involving social distancing, testing, hospitalization, and antiviral treatment are tested. Then these "optimal" policies are sought in the case of limited resources on behalf of a COVID-19 pandemic scenario. The amplitude of peak epidemics will often be minimized by executing strategies from the beginning of a pandemic, spreading the epidemics' greatest impact over a longer time frame. Therefore, the timing and potency of control measures can reduce the pressure on the system during the top of the epidemic through the pandemic, decreasing the pressure on the healthcare infrastructure. In case of limited access to antiviral supplies, the role of testing, hospitalization, and social distancing strategies is emphasized in this study.

Optimal control for COVID-19 pandemic with quarantine and antiviral therapy.

In the absence of a proper cure for the disease, the recent pandemic caused by COVID-19 has been focused on isolation strategies and government measures to control the disease, such as lockdown, media coverage, and improve public hygiene. Mathematical models can help when these intervention mechanisms find some optimal strategies for controlling the spread of such diseases. We propose a set of nonlinear dynamic systems with optimal strategy including practical measures to limit the spread of the virus and to diagnose and isolate infected people while maintaining consciousness for citizens. We have used Pontryagin's maximum principle and solved our system by the finite difference method. In the end, several numerical simulations have been executed to verify the proposed model using Matlab. Also, we pursued the resilience of the parameters of control of the nonlinear dynamic systems, so that we can easily handle the pandemic situation.

Liquid-Metal-Assisted Deposition and Patterning of Molybdenum Dioxide at Low Temperature.

Molybdenum dioxide (MoO2), considering its near-metallic conductivity and surface plasmonic properties, is a great material for electronics, energy storage devices and biosensing. Yet to this day, room-temperature synthesis of large area MoO2, which allows deposition on arbitrary substrates, has remained a challenge. Due to their reactive interfaces and specific solubility conditions, gallium-based liquid metal alloys offer unique opportunities for synthesizing materials that can meet these challenges. Herein, a substrate-independent liquid metal-based method for the room temperature deposition and patterning of MoO2 is presented. By introducing a molybdate precursor to the surrounding of a eutectic gallium-indium alloy droplet, a uniform layer of hydrated molybdenum oxide (H2MoO3) is formed at the interface. This layer is then exfoliated and transferred onto a desired substrate. Utilizing the transferred H2MoO3 layer, a laser-writing technique is developed which selectively transforms this H2MoO3 into crystalline MoO2 and produces electrically conductive MoO2 patterns at room temperature. The electrical conductivity and plasmonic properties of the MoO2 are analyzed and demonstrated. The presented metal oxide room-temperature deposition and patterning method can find many applications in optoelectronics, sensing, and energy industries.

Phosphoprotein Biosensors for Monitoring Pathological Protein Structural Changes.

Current biotechnological developments are driving a significant shift towards integrating proteomic analysis with landmark genomic, methylomic, and transcriptomic data to elucidate functional effects. For the majority of proteins, structure and function are closely intertwined. Post-translational protein modifications (e.g., phosphorylation) leading to aberrantly active structures can originate a wide variety of pathological conditions, including cancer. Analysis of protein structure variants is thus integral to the identification of clinically actionable targets and the design of novel disease diagnosis and therapy approaches. However, it is still challenging to interrogate subtle structural changes of proteins in a rapid and cost-effective manner with current tools. This review primarily compiles the latest biosensing techniques for protein structural analysis.

Reading Conformational Changes in Proteins with a New Colloidal-Based Interfacial Biosensing System.

Many biological events such as mutations or aberrant post-translational modifications can alter the conformation and/or folding stability of proteins and their subsequent biological function, which may trigger the onset of diseases like cancer. Evaluating protein folding is hence crucial for the diagnosis of these diseases. Yet, it is still challenging to detect changes in protein folding, especially if they are subtle, in a simple and highly sensitive manner with the current assays. Herein, we report a new colloidal-based interfacial biosensing approach for qualitative and quantitative profiling of various types of changes in protein folding; from denaturation to variant conformations in native proteins, such as protein activation via mutations or phosphorylation. The approach is based on the direct interfacial interaction of proteins freely available in solution with added tannic-acid-capped gold nanoparticles, to interrogate their folding status in their solubilized form. We found that under the optimized conditions, proteins can modulate colloids solvation according to their folding or conformational status, which can be visualized in a single step, by the naked eye, with minimal protein input requirements (limit of detection of 1 ng/µL). Protein folding detection was achieved regardless of protein topology and size without using conformation-specific antibodies and mutational analysis, which are the most common assays for sensing malfunctioning proteins. The approach showed excellent sensitivity, superior to circular dichroism, for the detection of the very subtle conformational changes induced by activating mutations and phosphorylation in epidermal growth factor receptor (EGFR) and extracellular signal-regulated kinase (ERK) proteins. This enabled their detection even in complex samples derived from lung cancer cells, which contained up to 95% excess of their wild-type forms. A broader clinical translation was shown via monitoring the action of conformation-restoring drugs, such as tyrosine kinase inhibitors, on EGFR conformation and its downstream protein network, using the ERK protein as a surrogate.

An exosomal- and interfacial-biosensing based strategy for remote monitoring of aberrantly phosphorylated proteins in lung cancer cells.

It is a well-known phenomenon that cancer cells release key biological information such as DNA, RNA or proteins into body fluids (e.g., blood, urine or saliva). The analysis of these molecules-often encapsulated within nanovesicules called exosomes-is highly attractive, because it could replace current surgical biopsies, which are painful, costly and potentially risky for patients. For example, current strategies in lung cancer diagnosis involve genetic analyses from tumour tissues to detect the presence of underlying DNA mutations, known to alter the phosphorylation status and function of proteins. This information is used to direct therapy, as aberrantly phosphorylated proteins are the main targets of current drugs such as Tyrosine Kinase Inhibitors (TKIs). An alternative and less invasive strategy would be the remote analysis of these phospho-proteins by isolating them from cancer-derived exosomes. This would allow evaluating not only their phosphorylation status at diagnosis, but also the timely restoration of protein phosphorylation levels during therapy with TKIs. Yet, this proteomic approach remains vastly unexplored. Herein, we demonstrate that key lung cancer phosphoproteins, such as EGFR and ERK, are expressed in lung cancer exosomes and we outline a new exosomal proteomic-based approach for their fast and convenient detection. This approach, which could complement current genetic analysis for lung cancer detection, easily detects the phosphorylation status of lung cancer exosomal proteins within minutes after their extraction, bringing hope of circumventing the need for tissue biopsy and costly and cumbersome DNA sequencing techniques. It exploits the fact that phosphorylation induces protein conformational changes, which in turn alter protein's ability to effectively interact with bare gold surfaces. This leads to phosphorylated and non-phosphorylated protein isoforms displaying different gold-adsorption profiles. Using single-use and inexpensive, gold (Au) screen-printed electrodes (SPEs), we demonstrate the successful detection of aberrantly phosphorylated EGFR and ERK protein isoforms derived from lung cancer cell exosomes with a sensitivity down to 15 ng µL-1 in samples with up to 90% excess of their non-phosphorylated (wild-type) forms. We further show the applicability of this strategy for monitoring the action of Tyrosine Kinase Inhibitors over time. We believe that this non-invasive technique will open up new avenues for facilitating cancer diagnosis and time-point monitoring of therapeutic responses.

Interfacial nano-mixing in a miniaturised platform enables signal enhancement and in situ detection of cancer biomarkers.

Interfacial biosensing performs the detection of biomolecules at the bare-metal interface for disease diagnosis by comparing how biological species derived from patients and healthy individuals interact with bare metal surfaces. This technique retrieves clinicopathological information without complex surface functionalisation which is a major limitation of conventional techniques. However, it is still challenging to detect subtle molecular changes by interfacial biosensing, and the detection often requires prolonged sensing times due to the slow diffusion process of the biomolecules towards the sensor surface. Herein, we report on a novel strategy for interfacial biosensing which involves in situ electrochemical detection under the action of an electric field-induced nanoscopic flow at nanometre distance to the sensing surface. This nanomixing significantly increases target adsorption, reduces sensing time, and enables the detection of small molecular changes with enhanced sensitivity. Using a multiplex electrochemical microdevice that enables nanomixing and in situ label-free electrochemical detection, we demonstrate the detection of multiple cancer biomarkers on the same device. We present data for the detection of aberrant phosphorylation in the EGFR protein and hypermethylation in the EN1 gene region. Our method significantly shortens the assay period (from 40 min and 20 min to 3 minutes for protein and DNA, respectively), increases the sensitivity by up to two orders of magnitude, and improves detection specificity.

Detection of aberrant protein phosphorylation in cancer using direct gold-protein affinity interactions.

Protein phosphorylation is one of the most prominent post-translational mechanisms for protein regulation, which is frequently impaired in cancer. Through the covalent addition of phosphate groups to certain amino-acids, the interactions of former residues with nearby amino-acids are drastically altered, resulting in major changes of protein conformation that impacts its biological function. Herein, we report that these conformational changes can also disturb the protein's ability to interact with and adsorb onto bare gold surfaces. We exploited this feature to develop a simple electrochemical method for detecting the aberrant phosphorylation of EGFR protein in several lung cancer cell lines. This method, which required as low as 10ng/µL (i.e., 50ng) of purified EGFR protein, also enabled monitoring cell sensitivity to tyrosine kinase inhibitors (TKI) - a common drug used for restoring the function of aberrantly phosphorylated proteins in lung cancer. The reported strategy based on direct gold-protein affinity interactions avoids the conventional paradigm of requiring a phospho-specific antibody for detection and could be a potential alternative of widely used mass spectrometry.