Search

Umer Anayyat,1 Faiza Ahad,1 Tobias Achu Muluh,1 Syed Aqib Ali Zaidi,1 Faiza Usmani,2 Hua Yang,1 Mengqing Li,1 Hammad Ali Hassan,3 Xiaomei Wang1 1Department of Physiology, School of Basic Medical Sciences, Health Sciences Center, Shenzhen University Medical School, Shenzhen University, Shenzhen, Guangdong, 518055, People’s Republic of China; 2Department of Biotechnology, University of Karachi, Karachi, Pakistan; 3Department of Cell Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, USACorrespondence: Xiaomei Wang, Department of Physiology, School of Basic Medical Sciences, Health Sciences Center, Shenzhen University Medical School, Shenzhen University, Shenzhen, Guangdong, 518055, People’s Republic of China, Tel +86-13544234361, Email xmwang@szu.edu.cnAbstract: A novel and rapid therapeutic approach is the treatment of human breast cancer by enhancing the host’s immune system. In initial findings, program death one (PD-1) and program cell death ligand one (PD-L1) showed positive results towards solid tumors, but tumor relapse and drug resistance are the major concerns. Breast cancer therapy has been transformed by the advent of immune checkpoint blockades (ICBs). Triple-negative breast cancers (TNBCs) have exhibited enduring responses to clinical usage of immune checkpoint inhibitors (ICBs) like atezolizumab and pembrolizumab. Nonetheless, a notable proportion of individuals with TNBC do not experience advantages from these treatments, and there is limited comprehension of the resistance mechanisms. Another approach to overcome resistance is cancer stem cells (CSCs), as these cells are crucial for the initiation and growth of tumors in the body. Various cancer vaccines are created using stem cells (dendritic, whole cell, bacterial) and focus primarily on targeting tumor-related antigens. The ultimate objective of cancer vaccines is to immunize the patients by active artificial immunity against cancer, though. In this review, we primarily focused on existing immunotherapeutic options, immune checkpoint blockers, the latest progress in understanding the molecular mechanisms underlying resistance to immune checkpoint inhibitors (ICBs), advanced strategies to overcome resistance to ICBs, cancer stem cell antigens and molecular markers, ongoing clinical trials for BCs and cancer vaccines for breast cancer.Keywords: breast cancer, cancer stem cell, immunotherapy, cancer therapy

This paper presents the results of variation in column spacing of a tube in its outer periphery concerning structural drift and cost optimization. For high rise structures, tubular framing and outrigger braced frames are considered as the most appropriate solution economically. In recent past not must study has been focused on the tubular frame in its columns spacing and span length. In this research, a simple square plan structure has been considered with different heights of 30, 40, and 50 story buildings. Six different framing systems of the tubular structure have been developed with different column spacing in each and employed to each high-rise structure. Concrete strength and steel yield strength has been taken as a fixed value for every model. Several models were developed with these combinations and the drift and structural safety have been optimized by reducing the cross-section sizes in each system. Seismic analysis has been carried out to evaluate the effects of varying column spacing in each tube. The comparison of all the employed systems was carried out and cost analysis has been made. Observations have been taken from drift, base shear, and cost analysis of each framing system of the tube, and certain results were concluded for structures with different height.

Nida Salman Yazdani,1 Kaniz Amna Haider,2 Amna Khan,2 Syed Ali Jaffar Zaidi,2 Akbar Rajani,1 Imran Nisar,2 Fyezah Jehan,2 Zahra Hoodbhoy2 1Research and Programs, VITAL Pakistan Trust, Karachi, Pakistan; 2Department of Paediatrics and Child Health, the Aga Khan University, Karachi, PakistanCorrespondence: Zahra Hoodbhoy, Aga Khan University, Stadium Road PO Box 3500, Karachi, 74800, Pakistan, Tel +92-3343481179, Email zahra.hoodbhoy@aku.eduPurpose: To understand pregnant women’s experience with midwifery-led antenatal care services using the Respectful Maternity Care charter in primary health centers in Karachi, Pakistan.Methods: This cross-sectional study was at Rehri Goth and Ibrahim Hyderi, two peri-urban communities in Karachi, Pakistan, where women receive antenatal care services. All pregnant women in their third trimester who consented during the study period were included. The participants were asked about access to care, antenatal care experience, person-centered approach, and general satisfaction with the facility using a pre-designed questionnaire. These themes were mapped onto the universal Respectful Maternity Care charter. Descriptive statistics were used to summarize the findings in each of these themes. Multivariable logistic regression techniques to determine the relationship between the dependent and independent variables.Results: There were 904 women who agreed to participate in this study during January to December 2021. Majority of the women (94%, n=854) were satisfied with the operating hours and cleanliness. More than 90% of the women reported positive experiences regarding privacy, respectful treatment by midwives, and non-discriminatory care. However, 40% (n=362) of the women reported not receiving adequate information and informed consent before a medical procedure, while 65% (n=587) reported poor counseling for birth preparedness. Maternal age, women’s occupation, women’s education, and parity were found to be significantly associated with respect provided, satisfaction with counseling and the consent process.Conclusion: This study reported satisfaction of pregnant women with the facility’s ambiance, respect, and care; however, poor communication skills regarding consent and antenatal counseling were reported. The findings suggest the need for more efficient strategies, such as regular respectful maternity care and technical training to strengthen midwife-patient interactions and enhance overall satisfaction, thus improving maternal and newborn outcomes.Keywords: antenatal care, patient satisfaction, Respectful Maternity Care, Pakistan

Abstract The Public Health Resource Network is an innovative distance-learning course in training, motivating, empowering and building a network of health personnel from government and civil society groups. Its aim is to build human resource capacity for strengthening decentralized health planning, especially at the district level, to improve accountability of health systems, elicit community participation for health, ensure equitable and accessible health facilities and to bring about convergence in programmes and services. The question confronting health systems in India is how best to reform, revitalize and resource primary health systems to deliver different levels of service aligned to local realities, ensuring universal coverage, equitable access, efficiency and effectiveness, through an empowered cadre of health personnel. To achieve these outcomes it is essential that health planning be decentralized. Districts vary widely according to the specific needs of their population, and even more so in terms of existing interventions and available resources. Strategies, therefore, have to be district-specific, not only because health needs vary, but also because people's perceptions and capacities to intervene and implement programmes vary. In centrally designed plans there is little scope for such adaptation and contextualization, and hence decentralized planning becomes crucial. To undertake these initiatives, there is a strong need for trained, motivated, empowered and networked health personnel. It is precisely at this level that a lack of technical knowledge and skills and the absence of a supportive network or adequate educational opportunities impede personnel from making improvements. The absence of in-service training and of training curricula that reflect field realities also adds to this, discouraging health workers from pursuing effective strategies. The Public Health Resource Network is thus an attempt to reach out to motivated though often isolated health workers. It interacts with, and works to empower, health personnel within the government health system as well as civil society, to meaningfully participate in and strengthen decentralized planning processes and outcomes. Structured as an innovative distance-learning course spread over 12 to 18 months of coursework and contact programmes, the Public Health Resource Network comprises 14 core modules and five optional courses. The technical content and contact programmes have been specifically developed to build perspectives and technical knowledge of participants and provide them with a variety of options that can be immediately put into practice within their work environments and everyday roles. The thematic areas of the course modules range from technical knowledge related to maternal and child health and communicable and noncommunicable diseases; programmatic and systemic knowledge related to health planning, convergence, health management and public-private partnerships; to perspective-building knowledge related to mainstreaming gender issues and community participation. Currently the Public Health Resource Network has been launched in four states of India – Chhattisgarh, Jharkhand, Bihar and Orissa – in its first phase, and reaches out to more than 500 participants with diverse backgrounds. The initiative has received valuable support from central and state government departments of health, state training institutes, the National Rural Health Mission – the current comprehensive health policy in the country – and leading civil society organizations.

The present paper is a contribution to the building blocks of an investment model within the framework of an integrated macroeconomic model of an Islamic economy. Investment behavior in the model is guided by an Islamicethical value system and profit-sharing financial contracts. The typical firm’s investment decision is believed to emerge from a dynamic inter-temporal maximization exercise within an infinite time horizon. The method of Calculus of Variations is applied to arrive at the optimal investment and employment criteria for the firm. The result is then incorporated into a macroeconomic model to study the behavior of key endogenous variables like national income and the rate of profit-share. Comparative statics exercised within a general equilibrium framework reveal the potency of monetary policy but the neutrality of fiscal policy with respect to output and employment. Introduction The past decade has witnessed a tremendous outpouring of interest as well as effort in the formalization of economic models based on profit-sharing financial arrangements as an Islamic alternative to the conventional interestbased economic system. Several macroeconomic models for interest-free economies have been proposed (Anwar 1987; Habibi 1987; Metwally 1981 & 1983). The rigor of an integrated approach to such macroeconomic modelhg depends on the rigor of the component models, namely, the consumption, investment, monetary, and fiscal relationships. Economists have written extensively on different aspects of consumer behavior in Islamic societies. Kahf (1978) and Khan (1984), among others, have contributed to the conceptual and analytical formulation of the consumption function under ...

The Third Seminar on Islamic Economics, held under the sponsorship of the International Institute of Islamic Thought (IIIT) and the Association of Muslim Social Scientists (AMSS), took on an international character with delegates in attendance from as far east as Malaysia, Egypt, and Saudi Arabia in addition to participants from Canada and the United States. This year's theme for the conference, "Resource Mobilization and Investment in an Islamic Framework;' evoked considerable interest among both academicians and practitioners of the Islamic economic reform movement. Evidence of this interest was seen in the large number of research papers received on the subject although, regrettably, funding limitations prevented many a scholar from participating in the meetings. The first day's sessions opened with brief remarks from Sayyid M. Syeed, general secretary of the AMSS, and Zaidi Sattar, program director for the seminar. Their remarks, while highlighting the significant strides made in the past decade in research on Islamic economics, pointed to the substantial financial and logistical constraints that remain in the advancement of future research in the area. IIIT and AMSS were commended for their past role in this endeavor, and hopes were expressed for a more vigorous role in the future. The highlight of the opening session was the thoughtful inaugural address by Taha Jabir al ‘Alwani, President, IIIT, who emphasized the importance of the “human” element in the organization and management of economic resources as “. . . man is both intellect ready for thought, and hands ready for action.” Citing from the Holy Qur’an and the works of Islamic scholars, he stressed that Islamic thought has much to offer in the emancipation of the ummah from the debilitating influence of colonialism. Development of the mind, he argued, is as critical to a society’s growth process as is the development of economic resources ...

This study presents the clinical outcomes of using inhouse prepared fibrin glue for controlling gingival bleeding in patients with inherited bleeding disorders (IBD). The objective of the study was to assess the reduction in transfusion days and improvement in compliance for dental evaluation over a one-year period in a low-to-middle-income country. The quasiexperimental pilot study included 40 IBD patients with gingival bleeding. These were divided into two groups: Group A received fibrin glue (n=20), while Group B did not (n=20). The study compared outcome metrics, including the number of treatment days and blood components transfused, using non-parametric tests with a significance threshold of p<0.05. Results showed that Group A required fewer blood components (n=154) as compared to Group B (n=204) (p<0.001). Patients in Group A with Glanzmann thrombasthenia (GT) had a shorter treatment duration (one day) than those in group B (three days) (p<0.01). In conclusion, the application of fibrin glue effectively managed intractable gingival bleeding in IBD patients.

Chimeric antigen receptor T-cells, known as CAR-T cells, represent a promising breakthrough in the realm of adoptive cell therapy. These T-cells are genetically engineered to carry chimeric antigen receptors that specifically target tumors. They have achieved notable success in the treatment of blood-related cancers, breathing new life into this field of medical research. However, numerous obstacles limit chimeric antigen receptors T-cell therapy's efficacy, such as it cannot survive in the body long. It is prone to fatigue and exhaustion, leading to difficult tumor elimination and repeated recurrence, affecting solid tumors and hematological malignancies. The challenges posed by solid tumors, especially in the context of the complex solid-tumor microenvironment, require specific strategies. This review outlines recent advancements in improving chimeric antigen receptors T-cell therapy by focusing on the chimeric antigen receptors protein, modifying T-cells, and optimizing the interaction between T-cells and other components within the tumor microenvironment. This article aims to provide an extensive summary of the latest discoveries regarding CAR-T cell therapy, encompassing its application across various types of human cancers. Moreover, it will delve into the obstacles that have emerged in recent times, offering insights into the challenges faced by this innovative approach. Finally, it highlights novel therapeutic options in treating hematological and solid malignancies with chimeric antigen receptors T-cell therapies., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Molecularly imprinted polymer (MIP)-based electrochemical sensors have been extensively researched due to their higher sensitivity, quick response, and operational ease. To develop more advanced sensing devices with enhanced properties, MIPs have been integrated with two-dimensional (2D) layered materials such as transition metal dichalcogenides (TMDs) and MXenes. These 2D materials have unique electronic properties and an extended surface area, making them promising sensing materials that can improve the performance of MIPs. In this review article, we describe the methods used for the synthesis of TMDs and MXenes integrated MIP-based electrochemical sensors. Furthermore, we have provided a critical review of a wide range of analytes determined through the application of these electrochemical sensors. We also go over the influence of TMDs and MXenes on the binding kinetics and adsorption capacity which has enhanced binding recognition and sensing abilities. The combination of TMDs and MXenes with MIPs shows promising synergy in the development of highly efficient recognition materials. In the future, these sensors could be explored for a wider range of applications in environmental remediation, drug delivery, energy storage, and more. Finally, we address the challenges and future perspectives of using TMDs and MXenes integrated MIPs. We conclude with a focus on future development and the scope of integrating these materials in sensing technology.

Background: The basilic vein transposition is a brachio basilic arteriovenous fistula (AVF) made after the mobilization and transferring of basilic vein to the ventral aspect of arm inside a subcutaneous pocket by direct dissection. The procedure can be performed either in single stage or two stages. This study compares the clinical efficacy and long term utility of single-stage and two-stage basilic vein transposition among patients of renal failure and to evaluate failure rate, primary patency rates, and postoperative complications., Method: Patients who underwent basilic vein transposition at Sindh Institute of Urology and Transplantation, Karachi from January 2021 to December 2021 were retrospectively reviewed. Patients were divided into two groups according to single stage or two-stage procedure. After the surgical procedure, assessment of fistula maturation and surveillance were undertaken using ultrasound and physical examination. Patients were requested to visit the out-patient clinic for assessment of fistula patency and post-operative complications at regular intervals of 3, 6, and 12 months respectively., Result: During the 12 months' interval, 82 (39.04%) basilic vein transpositions were performed in single-stage and 128 (60.95%) were two-staged transposition. In our analysis we have found that as compared to single stage, two-stage basilic vein transpositions showed significantly better primary patency rates (76.82% vs 96%; p -value 0.000) and required less interventions for maintaining fistula patency. More post-operative sequelae were noted in the single stage version of the procedure as compared to the two stage procedure., Conclusion: Two stage procedure of basilic vein transposition is found to have better patency rate and lesser post-surgical complications. However, a matched cohort prospective study is still needed to further strengthen the conclusion., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Acquired immune deficiency syndrome (UNAIDS) has risen as the serious public health problem across the world. Knowledge about HIV/AIDS is the cornerstone for prevention and treatment. Research is needed to explore the attitude and the effect of different demographic, geographic, and socioeconomic and media exposure factors on males knowledge about HIV in Pakistan. In this study, latest secondary data are used from Pakistan Demographic and Health Survey 2017-18. Sample results show that the majority of the respondents (70%) have knowledge about AIDS. Regression Modeling reveals that man's knowledge about HIV/AIDS is associated with age, place of residence, educational level, wealth index, ethnicity and media exposure factors. Males of age group 35-39, with higher education, belonging to Pukthon ethnicity, having exposure to mass media on a daily basis and belonging to richest wealth quintile has high Knowledge of HIV/AIDS. For example, the regression model predicts that men between the ages of 35 and 39 from Islamabad who live in urban areas, have higher education, are of Pukhtoon ethnicity, are the head of the household, belong to the richest quintile, work in professional occupations, and use media exposure factors on a daily basis would have probability of 97% of having knowledge of HIV/AIDS. But there is still need to focus to increase the men's knowledge of HIV/AIDS.

Small interfering RNA (siRNA) is a potential method of gene silencing to target specific genes. Although the U.S. Food and Drug Administration (FDA) has approved multiple siRNA-based therapeutics, many biological barriers limit their use for treating diseases. Such limitations include challenges concerning systemic or local administration, short half-life, rapid clearance rates, nonspecific binding, cell membrane penetration inability, ineffective endosomal escape, pH sensitivity, endonuclease degradation, immunological responses, and intracellular trafficking. To overcome these barriers, various strategies have been developed to stabilize siRNA, ensuring their delivery to the target site. Chemical modifications implemented with nucleotides or the phosphate backbone can reduce off-target binding and immune stimulation. Encapsulation or formulation can protect siRNA from endonuclease degradation and enhance cellular uptake while promoting endosomal escape. Additionally, various techniques such as viral vectors, aptamers, cell-penetrating peptides, liposomes, and polymers have been developed for delivering siRNA, greatly improving their bioavailability and therapeutic potential., (© 2023. BioMed Central Ltd., part of Springer Nature.)

In this work, a simple and facile method was developed to achieve controlled oxidation and enhance the surface area of MXene nanosheets and their utilization in the efficient sensing of ascorbic acid (AA or vitamin C). After etching of MAX phase to MXene via the MILD technique, controlled flash oxidation was carried out in the open air environment for 1.5 h, followed by flocculation of oxidized MXene nanosheets by using H 2 SO 4 , consequently achieving crumpled MXene possessing anatase phase, porosity, and improved surface area as revealed and confirmed by SEM, TEM, Raman, and BET analysis results. The as-prepared crumpled MXene was coated over a glassy carbon electrode (GCE) and used to determine AA successfully via cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS), and differential pulse voltammetry (DPV) with a linear concentration range of 300 μM to 0.005 μM with a detection limit (LOD) of 2 nM (2.8 % RSD and S/N = 3). The developed electrochemical sensor was used to determine the AA in various actual samples such as juice, urine, serum, and erythrocytes spiked with AA with excellent recoveries in the 94-103 % range. The sensor also demonstrated excellent reproducibility (~1 % RSD for five repetitive assays) and a shelf life of nearly one month with a negligible decrease in response. Furthermore, it lost only 10 % of its response for the next ten days. It also showed satisfactory selectivity toward AA in the presence of other similar compounds, including uric acid (UA), dopamine (DA), and glucose., Competing Interests: Declaration of competing interest The authors declare that they have no known competing interests., (Copyright © 2023 Elsevier B.V. All rights reserved.)

A new generation of dual-target μ opioid receptor (MOR) agonist/dopamine D 3 receptor (D 3 R) antagonist/partial agonists with optimized physicochemical properties was designed and synthesized. Combining in vitro cell-based on-target/off-target affinity screening, in silico computer-aided drug design, and BRET functional assays, we identified new structural scaffolds that achieved high affinity and agonist/antagonist potencies for MOR and D 3 R, respectively, improving the dopamine receptor subtype selectivity (e.g., D 3 R over D 2 R) and significantly enhancing central nervous system multiparameter optimization scores for predicted blood-brain barrier permeability. We identified the substituted trans -(2 S ,4 R )-pyrrolidine and trans -phenylcyclopropyl amine as key dopaminergic moieties and tethered these to different opioid scaffolds, derived from the MOR agonists TRV130 ( 3 ) or loperamide ( 6 ). The lead compounds 46 , 84 , 114, and 121 have the potential of producing analgesic effects through MOR partial agonism with reduced opioid-misuse liability via D 3 R antagonism. Moreover, the peripherally limited derivatives could have therapeutic indications for inflammation and neuropathic pain.

Background: Food insecurity (FI) is at a steep risk, especially in low middle-income countries. FI is further compounded in areas that experience environmental and economic instability, thus a reassessment in such critical times is required for burden estimation and to propose targeted interventions., Aims: The objectives of this study were to assess the prevalence of, and sociodemographic factors associated with FI, as well as the coping strategies utilized in response to FI in peri-urban communities in Karachi, Pakistan., Methods: We conducted a cross-sectional survey from November-December 2022 on 400 households in four peri-urban communities in Karachi, Pakistan. The Household Food Insecurity Access Scale (HFIAS) and reduced Coping Strategies Index (rCSI) questionnaire were used to assess FI. A Poisson regression was used to assess associations between sociodemographic factors and FI., Results: The overall prevalence of FI was found to be 60.2% ( n  = 241) of which 33.8% ( n  = 135) were severely food insecure. Age, women's and breadwinners' education, women's occupation, and parity were significantly associated with FI. Participants reported relying on less expensive foods (44%) and borrowing food or help from others (35%) as the most common coping strategies overall in the FI households., Conclusion: With more than half the households facing FI and adopting severe measures to cope in these communities, it is pivotal to design and test interventions that can withstand economic and climate catastrophes and help ensure a safety need for food security for the most vulnerable.

The peptide hormone angiotensin II regulates blood pressure mainly through the type 1 angiotensin II receptor AT 1 R and its downstream signaling proteins G q and β-arrestin. AT 1 R blockers, clinically used as antihypertensive drugs, inhibit both signaling pathways, whereas AT 1 R β-arrestin-biased agonists have shown great potential for the treatment of acute heart failure. Here, we present a cryo-electron microscopy (cryo-EM) structure of the human AT 1 R in complex with a balanced agonist, Sar 1 -AngII, and G q protein at 2.9 Å resolution. This structure, together with extensive functional assays and computational modeling, reveals the molecular mechanisms for AT 1 R signaling modulation and suggests that a major hydrogen bond network (MHN) inside the receptor serves as a key regulator of AT 1 R signal transduction from the ligand-binding pocket to both G q and β-arrestin pathways. Specifically, we found that the MHN mutations N111 3.35 A and N294 7.45 A induce biased signaling to G q and β-arrestin, respectively. These insights should facilitate AT 1 R structure-based drug discovery for the treatment of cardiovascular diseases., (© 2023 The Authors.)

Urbanization and a massive population boom have immensely increased the solid wastes (SWs) generation and are expected to reach 3.40 billion tons by 2050. In many developed and emerging nations, SWs are prevalent in both major and small cities. As a result, in the current context, the reusability of SWs through various applications has taken on added importance. Carbon-based quantum dots (Cb-QDs) and their many variants are synthesized from SWs in a straightforward and practical method. Cb-QDs are a new type of semiconductor that has attracted the interest of researchers due to their wide range of applications, which include everything from energy storage, chemical sensing, to drug delivery. This review is primarily focused on the conversion of SWs into useful materials, which is an essential aspect of waste management for pollution reduction. In this context, the goal of the current review is to investigate the sustainable synthesis routes of carbon quantum dots (CQDs), graphene quantum dots (GQDs), and graphene oxide quantum dots (GOQDs) from various types SWs. The applications of CQDs, GQDs, and GOQDs in the different areas are also been discussed. Finally, the challenges in implementing the existing synthesis methods and future research directions are highlighted., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

This meta-analysis aims to compare high-flow nasal cannula (HFNC) and conventional oxygen therapy (COT) post-extubation in pediatric cardiac surgical patients. The present meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Two authors independently searched three electronic databases including PubMed, Embase, and the Cochrane Library to identify relevant articles published in English from inception to February 2023. Searching was conducted using keywords and medical subject headings (MeSH), which included "conventional oxygen therapy," "high-flow nasal cannula," "extubation," "pediatrics," and "cardiac surgery." Our primary outcome was extubation failure defined as the need for reintubation within 24 to 72 hours after planned extubation. Secondary outcomes assessed in this meta-analysis included partial pressure of arterial oxygen (PaO2), partial pressure of arterial carbon dioxide (PaCO2), and the ratio of PaO2 and FiO2 (fraction of inspired oxygen). A total of three studies were included in the meta-analysis, with a total of 227 patients.  No significant difference was found between the two groups (the HFNC group and the COT group) in terms of reintubation (RR: 0.88, 95% CI: 0.34, 2.30, p-value: 0.80). Pooled meta-analysis showed that PaO2 was significantly greater in patients receiving HFNC at six hours (MD: 33.73, 95% CI: 18.33, 49.14, p-value<0.001), at 12 hours (MD: 44.90, 95% CI: 28.59, 61.22, p-value<0.001) and at 24 hours (MD: 43.53, 95% CI: 29.16, 57.91, p-value<0.001) of extubation. PaCO2 was significantly lower in patients receiving HFNC at six hours (MD: -5.40, 95% CI: -7.94, -2.85, p-value<0.001) and at 12 hours (MD: -5.93, 95% CI: -9.78, -2.09, p-value<0.001) of extubation. However, no significant difference was reported between the two groups after 24 hours of extubation (MD: -0.84, 95% CI: -9.04, 7.37, p-value: 0.84) and PaO2/FiO2 was significantly greater in patients receiving HFNC at six hours (MD: 64.14, 95% CI: 36.10, 92.17, p-value<0.001), at 12 hours (MD: 70.73, 95% CI: 20.46, 121.01, p-value<0.001) and at 24 hours (MD: 82.18, 95% CI: 50.03, 114.32, p-value<0.001) of intubation. In conclusion, the meta-analysis revealed that compared with COT, HFNC significantly increased PaO2 and the ratio of PaO2 to FiO2, and decreased PaCO2. No significant differences were observed in the rate of reintubation between the two groups. This is the first meta-analysis comparing HFNC and COT in pediatric cardiac surgical patients., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Karedath et al.)

Mu-opioid receptor (µOR) agonists such as fentanyl have long been used for pain management, but are considered a major public health concern owing to their adverse side effects, including lethal overdose 1 . Here, in an effort to design safer therapeutic agents, we report an approach targeting a conserved sodium ion-binding site 2 found in µOR 3 and many other class A G-protein-coupled receptors with bitopic fentanyl derivatives that are functionalized via a linker with a positively charged guanidino group. Cryo-electron microscopy structures of the most potent bitopic ligands in complex with µOR highlight the key interactions between the guanidine of the ligands and the key Asp 2.50 residue in the Na + site. Two bitopics (C5 and C6 guano) maintain nanomolar potency and high efficacy at G i subtypes and show strongly reduced arrestin recruitment-one (C6 guano) also shows the lowest G z efficacy among the panel of µOR agonists, including partial and biased morphinan and fentanyl analogues. In mice, C6 guano displayed µOR-dependent antinociception with attenuated adverse effects, supporting the µOR sodium ion-binding site as a potential target for the design of safer analgesics. In general, our study suggests that bitopic ligands that engage the sodium ion-binding pocket in class A G-protein-coupled receptors can be designed to control their efficacy and functional selectivity profiles for G i , G o and G z subtypes and arrestins, thus modulating their in vivo pharmacology., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Over the last decades, molecularly imprinted polymers (MIPs) have emerged as selective synthetic receptors that have a selective binding site for specific analytes/target molecules. MIPs are synthetic analogues to the natural biological antigen-antibody system. Owing to the advantages they exhibit, such as high stability, simple synthetic procedure, and cost-effectiveness, MIPs have been widely used as receptors/sensors for the detection and monitoring of a variety of analytes. Moreover, integrating electrochemical sensors with MIPs offers a promising approach and demonstrates greater potential over traditional MIPs. In this review, we have compiled the methods and techniques for the production of MIP-based electrochemical sensors along with the applications of reported MIP sensors for a variety of analytes. A comprehensive in-depth analysis of recent trends reported on picomolar (pM/10 -12 M)) and beyond picomolar concentration LOD (≥pM) achieved using MIPs sensors is reported. Finally, we discuss the challenges faced and put forward future perspectives along with our conclusion.

Despite their high analytical performance, conventional analytical biosensor devices are usually difficult to handle, time-consuming, bulky and expensive. As a result, their applications remain restricted to resource-limited environments. In particular, the transportation of conventional analytical equipment is challenging for the proper in-situ point of need (PON)/point of care (POC) detection of biomolecules. In this context, smartphones, the most widely utilized cutting-edge mobile gadgets, continue to be a favored option because of their ease of portability and revolutionary sensing capabilities. On the other hand, aptamers are molecular recognition units consisting of nucleic acids with highly sensitive and selective recognition capabilities towards their respective targets. The coupling of smartphones with aptamers have led the development of advanced, user-friendly, portable, and cost-effective in-situ PON/POC biosensors for the detection of biomolecules. Such sensors are well-suited for a variety of applications, including food safety, environmental monitoring, and disease diagnostics. Herein, for the first time, achievements made between 2017 and 2022 in the concept and design of the smartphone-enabled aptasensors for biosensing applications are reviewed. The review covers different fabrication strategies and the discussion of several operating systems, underlying programs, and related software. At the end, the important merits, challenges, and future prospects of smart phone-driven aptasensors are presented. This report intends to assist scientists and engineers in comprehending the fabrication of smartphone-based aptasensors and their underlying sensing principles, as well as stimulating the future developments in the direction of affordable, portable, simple, and readily available sensing devices., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Current therapies for treatment of proliferative retinopathy focus on retinal neovascularization (RNV) during advanced disease and can trigger adverse side-effects. Here, we have tested a new strategy for limiting neurovascular injury and promoting repair during early-stage disease. We have recently shown that treatment with a stable, pegylated drug form of the ureohydrolase enzyme arginase 1 (A1) provides neuroprotection in acute models of ischemia/reperfusion injury, optic nerve crush, and ischemic stroke. Now, we have determined the effects of this treatment on RNV, vascular repair, and retinal function in the mouse oxygen-induced retinopathy (OIR) model of retinopathy of prematurity (ROP). Our studies in the OIR model show that treatment with pegylated A1 (PEG-A1), inhibits pathological RNV, promotes angiogenic repair, and improves retinal function by a mechanism involving decreased expression of TNF, iNOS, and VEGF and increased expression of FGF2 and A1. We further show that A1 is expressed in myeloid cells and areas of RNV in retinal sections from mice with OIR and human diabetic retinopathy (DR) patients and in blood samples from ROP patients. Moreover, studies using knockout mice with hemizygous deletion of A1 show worsened RNV and retinal injury, supporting the protective role of A1 in limiting the OIR-induced pathology. Collectively, A1 is critically involved in reparative angiogenesis and neuroprotection in OIR. Pegylated A1 may offer a novel therapy for limiting retinal injury and promoting repair during proliferative retinopathy., (© 2022. The Author(s).)

Background: Acute Leukaemia is a malignant disorder characterized by an abnormal proliferation of immature cells, called blasts. Classically, acute leukaemia is classified into acute myeloid leukaemia and acute lymphoblastic leukaemia depending on the lineage of the immature cells. Objective of the study was to evaluate the clinical presentations, analyze the haematologic parameters at time of diagnosis and assess the post-induction status in newly diagnosed ALL patients. This cross-sectional study was conducted in the Department of Haematology, Armed Forces Institute of Pathology, Rawalpindi from June to November 2019., Methods: A total of 55 newly diagnosed ALL patients were recruited including children, adults and elderly. Detailed medical history and physical findings were noted. Haematologic parameters were documented. Each patient was treated as per standard protocol and remission induction status was determined on day 29 of treatment., Results: The median age of the study cohort of 55 newly diagnosed ALL patients was 8.5 years. Males were 37 (67.3%) and females were 18 (32.7%) with a male to female ratio of 2:1. Paediatric group included 31 (56.4%) patients. Nine (16.4%) patients were in the adult group and 15 (27.3%) in the elderly age group. The time from onset of symptoms to diagnosis of acute lymphoblastic leukaemia was 98.87±79.21 days. Fever was the most common symptom but body aches were common among paediatric group while pallor was the most common sign. Mean WBC was 29.1±27.9 x109/l, Hb was 8.1±2.9 g/dl and platelet count was 60±41.8 x109/l B-acute lymphoblastic leukaemia was more common than T-acute lymphoblastic leukaemia. A total of 52 patients were assessed on day 29 to evaluate for post-induction remission status. The remission rate of our cohort of patients was 82.7%., Conclusions: Most of the patients were in paediatric age group and remission rate was better in this age group compared to elderly population. B-ALL was associated with good response to induction chemotherapy while patients with BCR-ABL1 gene rearrangement did not respond well to treatment. Identification of prognostic features at diagnosis will further help our clinicians to predict outcomes of the disease.

Background: The genetic polymorphisms (rs708035, rs3844283) of Interleukin-1 receptor associated kinases 2 (IRAK2) is involved in the NFκB regulatory pathway. The frequencies of IRAK2 gene are unknown in Pakistani population. Therefore, the study was designed to examine the association of targeted single nucleotide polymorphism(s) in IRAK2 gene of RA patients., Methodology: The study participants were selected by ACR/EULAR 2010 standards. After ethical approval, the blood samples of patients and healthy controls were collected for the extraction of DNA followed by the amplification of targeted polymorphism(s) via Tetra-primer Amplification Refractory Mutation System (T-ARMS PCR). Desired products were observed via agarose gel electrophoresis., Results: The allele frequency of wild type A and C is frequent among patients and mutant T and G is frequent among controls. The rs708035 showed significant protective association while rs3844283 was found to be associated with risk of RA. Genetic model associations were applied to determine the role of genotypes. In combination analyses of alleles revealed AC haplotype was found to be associated with risk and TG provide protection against RA. Moreover, targeted SNPs were found to be in 61% Linkage Disequilibrium among the targeted population., Conclusions: Current study revealed the protective and risk association of targeted SNPs (rs708035, rs3844283). Study might be beneficial as it provides baseline data regarding targeted SNPs and their role in the disease progression. This could be served as potential biomarker for diagnostic purpose and effectively utilized in precision medicine approach., Competing Interests: The authors have declared that no competing interests exist.

Arginase 1 (A1) is the enzyme that hydrolyzes the amino acid, L-arginine, to ornithine and urea. We have previously shown that A1 deletion worsens retinal ischemic injury, suggesting a protective role of A1. In this translational study, we aimed to study the utility of systemic pegylated A1 (PEG-A1, recombinant human arginase linked to polyethylene glycol) treatment in mouse models of acute retinal and brain injury. Cohorts of WT mice were subjected to retinal ischemia-reperfusion (IR) injury, traumatic optic neuropathy (TON) or brain cerebral ischemia via middle cerebral artery occlusion (MCAO) and treated with intraperitoneal injections of PEG-A1 or vehicle (PEG only). Drug penetration into retina and brain tissues was measured by western blotting and immunolabeling for PEG. Neuroprotection was measured in a blinded fashion by quantitation of NeuN (neuronal marker) immunolabeling of retina flat-mounts and brain infarct area using triphenyl tetrazolium chloride (TTC) staining. Furthermore, ex vivo retina explants and in vitro retina neuron cultures were subjected to oxygen-glucose deprivation (OGD) followed by reoxygenation (R) and treated with PEG-A1. PEG-A1 given systemically did not cross the intact blood-retina/brain barriers in sham controls but reached the retina and brain after injury. PEG-A1 provided neuroprotection after retinal IR injury, TON and cerebral ischemia. PEG-A1 treatment was also neuroprotective in retina explants subjected to OGD/R but did not improve survival in retinal neuronal cultures exposed to OGD/R. In summary, systemic PEG-A1 administration is neuroprotective and provides an excellent route to deliver the drug to the retina and the brain after acute injury., (Copyright © 2021 Elsevier Inc. All rights reserved.)

A variety of neurodegenerative disorders including Parkinson's disease are due to fibrillation in amyloidogenic proteins. The development of therapeutics for these disorders is a topic of extensive research as effective treatments are still unavailable. The present study establishes that n -acetylneuraminic acid (Neu5ac) inhibits the amyloid fibrillation of hen egg-white lysozyme (HEWL) and α-synuclein (SYN), as observed using various biophysical techniques and cellular assays. Neu5ac inhibits the amyloid formation in both proteins, as suggested from the reduction in the ThT fluorescence and remnant structures in transmission electron microscopy micrographs observed in its presence. In HEWL fibrillation, Neu5ac decreases the hydrophobicity and resists the transition of the α-helix to a β-sheet, as observed by an ANS binding assay, circular dichroism (CD) spectra, and Fourier transform infrared measurements, respectively. Neu5ac stabilizes the states that facilitate the amyloid formation in HEWL and SYN, as demonstrated by an enhanced intrinsic fluorescence in its presence, which is further confirmed by an increase in T m obtained from differential scanning calorimetry thermograms and an increase in the near-UV CD signal for HEWL with Neu5ac. However, the increase in stability is not a manifestation of Neu5ac binding to amyloid facilitating (partially folded or native) states of both proteins, as verified by isothermal titration calorimetry and fluorescence binding measurements. Besides, Neu5ac also attenuates the cytotoxicity of amyloid fibrils, as evaluated by a cell toxicity assay. These findings provide mechanistic insights into the Neu5ac action against amyloid fibrillation and may establish it as a plausible inhibitor molecule against neurodegenerative disorders.

The structure of the human kappa opioid receptor (KOR) in complex with the long-acting antagonist JDTic was solved crystallographically in 2012 and, along with structures of other opioid receptors, revolutionized our understanding of opioid system function and pharmacology. More recently, active state KOR structure was also determined, giving important insights into activation mechanisms of the receptor. In this review, we will discuss how the understanding of atomistic structures of KOR established a key platform for deciphering details of subtype and functional selectivity of KOR-targeting ligands and for discovery of new chemical probes with potentially beneficial pharmacological profiles., (© 2021. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

MXene, a novel class of 2-dimensional transition metal carbides has evolved as a promising material for various applications owing to its outstanding characteristics such as hydrophilicity, high electrical conductivity, surface area, and attractive topological structure. MXenes can form dispersion in common solvents and constitute composite with other nanomaterials, which can be utilized as effective transducers for molecular sensing. MXene-modified support materials, thus provide an intriguing platform for immobilization of target molecules onto their surface. The literature reveals that it has been increasingly utilized in the sensing of diverse types of analytes including glucose, pharmaceuticals, metals and dyes, cancer markers, pesticides, neurotransmitters, small valuable molecules, and so on. In this review, we summarize the recent updates in the MXene modified materials for sensing. For the convenience of our audience, we have distributed the analytes into categories and discussed them comprehensively. Not only we present the synthesis approach, electrochemical properties and surface chemistry of MXenes but also discussed briefly the current challenges and an outlook for future research in the related area.

Linkers are emerging as a key component in regulating the pharmacology of bitopic ligands directed toward G-protein coupled receptors (GPCRs). In this study, the role of regio- and stereochemistry in cyclic aliphatic linkers tethering well-characterized primary and secondary pharmacophores targeting dopamine D 2 and D 3 receptor subtypes (D 2 R and D 3 R, respectively) is described. We introduce several potent and selective D 2 R ( rel - trans -16b ; D 2 R K i = 4.58 nM) and D 3 R ( rel - cis -14a ; D 3 R K i = 5.72 nM) agonists while modulating subtype selectivity in a stereospecific fashion, transferring D 2 R selectivity toward D 3 R via inversion of the stereochemistry around these cyclic aliphatic linkers [e.g., (-)-(1 S ,2 R )-43 and (+)-(1 R ,2 S )-42 ]. Pharmacological observations were supported with extensive molecular docking studies. Thus, not only is it an innovative approach to modulate the pharmacology of dopaminergic ligands described, but a new class of optically active cyclic linkers are also introduced, which can be used to expand the bitopic drug design approach toward other GPCRs.

Type 2 diabetes mellitus (T2DM) is an alarmingly rising disorder characterized mainly by insulin resistance and hyperglycemia. Due to the impairment of glucose homeostasis, most subjects present with elevated serum glucose levels, which can lead to several complications, including hospitalizations and even death. Diet quality and quantity are at the heart of its pathogenesis; hence, for the management of this condition, a technique known as intermittent fasting (IF) has been an area of interest for researchers. Different fasting regimens, including alternate-day fasting, religious fasting, and time-restricted fasting, have proven to be of strategic importance for glycemic control due to their physiologic effects. According to case studies and randomized trials, therapeutic fasting has been shown to reverse insulin resistance, resulting in the discontinuance of insulin therapy while maintaining blood sugar levels. Studies on IF have demonstrated their efficacy in glycemic control and other metabolic parameters, including reducing visceral fat and controlling inflammatory mediators and markers such as C-reactive protein (CRP) and interleukin-6 (IL-6), but control in obesity is its most significant effect as it acts as a risk factor for T2DM. Several case studies have shown a reduction in elevated hemoglobin A1c (HbA1c) levels in subjects after fasting, which some believe is due to sirtuin-6 (SIRT6) proteins. SIRT6 proteins are believed to be responsible for blood glucose homeostasis and insulin resistance reversal by increasing its sensitivity. This family of proteins is increased after fasting; hence, further research in this area will help researchers better understand its mechanism of action and potential therapeutic effects on T2DM. With an alarming increase in the incidence of T2DM around the world, a cost-effective strategy is required to control the disease with easy patient compliance, and IF might prove to be the solution., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Saeed et al.)

Recently, alternative therapies are gaining popularity in the treatment of epilepsy. The present study aimed to find out the antiepileptic potential of quercetin, catechin, and kaempferol. In vivo and in silico experiments were conducted to investigate their therapeutic potential. 25 mg/kg/day of pentylenetetrazole was administered for 4 weeks after epilepsy was induced in the rats; this was followed by the behavioral studies and histological analysis of rat brain slices. Binding affinities of kaempferol, quercetin, and catechin were assessed by performing in silico studies. Kaempferol, quercetin, and catechin were found to have the highest binding affinity with the synaptic vesicle 2A (SV2A) protein, comparable to standard levetiracetam (LEV). The mRNA levels of SV2A, as well as the expression of TNF, IL 6, IL 1 beta, NFkB, IL 1Ra, IL 4, and IL 10, were investigated using qPCR. Our results indicate for the first time that SV2A is also a transporter of understudied phytoflavonoids, due to which a significant improvement was observed in epileptic parameters. The mRNA levels of SV2A were found to be significantly elevated in the PF-treated rats when compared with those of the control rats with epilepsy. Additionally, downregulation of the pro-inflammatory cytokines and upregulation of the anti-inflammatory cytokines were also noted in the PF-treated groups. It is concluded that kaempferol, quercetin, and catechin can effectively decrease the epileptic seizures in our chronic epilepsy rat model to a level that is comparable to the antiepileptic effects induced by levetiracetam drug., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ahmed, Khan, Ali Zaidi and Muhammad.)

The need for safer pain-management therapies with decreased abuse liability inspired a novel drug design that retains μ-opioid receptor (MOR)-mediated analgesia, while minimizing addictive liability. We recently demonstrated that targeting the dopamine D 3 receptor (D 3 R) with highly selective antagonists/partial agonists can reduce opioid self-administration and reinstatement to drug seeking in rodent models without diminishing antinociceptive effects. The identification of the D 3 R as a target for the treatment of opioid use disorders prompted the idea of generating a class of ligands presenting bitopic or bivalent structures, allowing the dual-target binding of the MOR and D 3 R. Structure-activity relationship studies using computationally aided drug design and in vitro binding assays led to the identification of potent dual-target leads ( 23 , 28 , and 40 ), based on different structural templates and scaffolds, with moderate (sub-micromolar) to high (low nanomolar/sub-nanomolar) binding affinities. Bioluminescence resonance energy transfer-based functional studies revealed MOR agonist-D 3 R antagonist/partial agonist efficacies that suggest potential for maintaining analgesia with reduced opioid-abuse liability.

Safoof-e-Pathar phori (SPP) is an Unani poly-herbomineral formulation, which has for a long time been used as a medicine due to its antiurolithiatic activity, as per the Unani Pharmacopoeia. This powder formulation is prepared using six different plant/mineral constituents. In this study, we explored the antiurolithiatic and antioxidant potentials of SPP (at 700 and 1,000 mg/kg) in albino Wistar rats with urolithiasis induced by 0.75% ethylene glycol (EG) and 1% ammonium chloride (AC). Long-term oral toxicity studies were performed according to the Organization for Economic Co-operation and Development (OECD) guidelines for 90 days at an oral dose of 700 mg/kg of SPP. The EG urolithiatic toxicant group had significantly higher levels of urinary calcium, serum creatinine, blood urea, and tissue lipid peroxidation and significantly ( p < 0.001 vs control) lower levels of urinary sodium and potassium than the normal control group. Histopathological examination revealed the presence of refractile crystals in the tubular epithelial cell and damage to proximal tubular epithelium in the toxicant group but not in the SPP treatment groups. Treatment of SPP at 700 and 1,000 mg/kg significantly ( p < 0.001 vs toxicant) lowered urinary calcium, serum creatinine, blood urea, and lipid peroxidation in urolithiatic rats, 21 days after induction of urolithiasis compared to the toxicant group. A long-term oral toxicity study revealed the normal growth of animals without any significant change in hematological, hepatic, and renal parameters; there was no evidence of abnormal histology of the heart, kidney, liver, spleen, or stomach tissues. These results suggest the usefulness of SPP as an antiurolithiatic and an antioxidant agent, and long-term daily oral consumption of SPP was found to be safe in albino Wistar rats for up to 3 months. Thus, SPP may be safe for clinical use as an antiurolithiatic formulation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ahmad, Khan, Ashraf, Ahmad, Daud Ali, Ansari, Kamal, Wahab, Zaidi, Mujeeb and Ahmad.)

The molecular imprinting polymers (MIPs) have shown their potential in various applications including pharmaceuticals, chemical sensing and biosensing, medical diagnosis, and environmental related issues, owing to their artificial selective biomimetic recognition ability. Despite the challenges posed in the imprinting and recognition of biomacromolecules, the use of MIP for the imprinting of large biomolecular oragnism such as viruses is of huge interest because of the necessity of early diagnosis of virus-induced diseases for clinical and point-of-care (POC) purposes. Thus, many fascinating works have been documented in which such synthetic systems undoubtedly explore a variety of potential implementations, from virus elimination, purification, and diagnosis to virus and bacteria-borne disease therapy. This study is focused comprehensively on the fabrication strategies and their usage in many virus-imprinted works that have appeared in the literature. The drawbacks, challenges, and perspectives are also highlighted.

Adolescents are an increasing proportion of low and middle-income country populations. Their coming of age is foundational for health behaviour, as well as social and productive citizenship. We mapped intervention areas for adolescent sexual and reproductive health, including HIV, mental health and violence prevention to sectors responsible for them using a framework that highlights settings, roles and alignment. Out of 11 intervention areas, health is the lead actor for one, and a possible lead actor for two other interventions depending on the implementation context. All other interventions take place outside of the health sector, with the health sector playing a range of bilateral, trilateral supporting roles or in several cases a minimal role. Alignment across the sectors varies from indivisible, enabling or reinforcing to the other extreme of constraining and counterproductive. Governance approaches are critical for brokering these varied relationships and interactions in multisectoral action for adolescent health, to understand the context of such change and to spark, sustain and steer it., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Objective. Neural modulation is a fundamental tool for understanding and treating neurological and psychiatric diseases. However, due to the high-dimensional space, subject-specific responses, and variability within each subject, it is a major challenge to select the stimulation parameters that have the desired effect. Data-driven optimization provides a range of different algorithms and tools for addressing this challenge, but each of these algorithms has specific strengths and limitations, and therefore must be carefully designed for a given neural modulation problem. Here we present a framework for designing data-driven optimization algorithms for neural modulation. Approach. We develop this framework using an optogenetic medial septum stimulation model, where the goal is to find the stimulation parameters that modulate hippocampal gamma power to a desired value. This framework proceeds in four steps: (a) collecting stimulation data, (b) creating high-throughput simulation models, (c) prototyping a range of different data-driven optimization algorithms and evaluating their performance, and (d) deploying the best performing algorithm in vivo. Main results. Following this framework, we prototype and design an algorithm specifically for finding the medial septum optogenetic stimulation parameters that maximize hippocampal gamma power. Building on this, we then change our objective function to find the stimulation parameters that modulate gamma to a specific setpoint, use the framework to understand and anticipate the results before deploying in vivo. Significance. We show that this framework can be used to design an effective optimization solution for a specific neural modulation problem, and discuss how it can potentially be applied beyond the optogenetic medial septum stimulation model., (© 2021 IOP Publishing Ltd.)

Controlling receptor functional selectivity profiles for opioid receptors is a promising approach for discovering safer analgesics; however, the structural determinants conferring functional selectivity are not well understood. Here, we used crystal structures of opioid receptors, including the recently solved active state kappa opioid complex with MP1104 , to rationally design novel mixed mu (MOR) and kappa (KOR) opioid receptor agonists with reduced arrestin signaling. Analysis of structure-activity relationships for new MP1104 analogs points to a region between transmembrane 5 (TM5) and extracellular loop (ECL2) as key for modulation of arrestin recruitment to both MOR and KOR. The lead compounds, MP1207 and MP1208, displayed MOR/KOR Gi-partial agonism with diminished arrestin signaling, showed efficient analgesia with attenuated liabilities, including respiratory depression and conditioned place preference and aversion in mice. The findings validate a novel structure-inspired paradigm for achieving beneficial in vivo profiles for analgesia through different mechanisms that include bias, partial agonism, and dual MOR/KOR agonism., Competing Interests: RU RU have filed a provisional patent on MP1207 and related molecules. TC, SG, BV, AF, SS, AA, AV, MN, SB, EK, VL, SE, CS, AH, JS, JJ No competing interests declared, SZ SZ has filed a provisional patent on MP1207 and related molecules. YP YXP is a co-founder of Sparian biosciences. JM JM has filed a provisional patent on MP1207 and related molecules. BR BLR has filed a provisional patent on MP1207 and related molecules. GP GWP is a co-founder of Sparian biosciences. GWP have filed a provisional patent on MP1207 and related molecules. VK VK has filed a provisional patent on MP1207 and related molecules. SM SM, (© 2021, Uprety et al.)

LA-PTH is a long-acting parathyroid hormone (PTH) peptide analogue in preclinical development for hypoparathyroidism (HP). Like native PTH, LA-PTH contains a methionine at position 8 (Met8) that is predicted to be critical for function. We assessed the impact of Met oxidation on the functional properties of LA-PTH and control PTH ligands. Oxidation of PTH(1-34) resulted in marked (~20-fold) reductions in binding affinity on the PTH receptor-1 (PTHR1) in cell membranes, similarly diminished potency for 3',5'-cyclic AMP signaling in osteoblastic cell lines (SaOS-2 and UMR106), and impaired efficacy for raising blood calcium in mice. Surprisingly, oxidation of LA-PTH resulted in little or no change in these functional responses. The signaling potency of oxidized-LA-PTH was, however, reduced approximately 40-fold compared to LA-PTH in cells expressing a PTHR1 construct that lacks the N-terminal extracellular domain (ECD). Molecular modeling revealed that while Met8 of both LA-PTH and PTH(1-34) is situated within the orthosteric ligand-binding pocket of the receptor's transmembrane domain bundle (TMD), the Met8 sidechain position is shifted for the 2 ligands so that on Met8 oxidation of PTH(1-34), steric clashes occur that are not seen with oxidized LA-PTH. The findings suggest that LA-PTH and PTH(1-34) engage the receptor differently in the Met8-interaction environment of the TMD bundle, and that this interaction environment can be allosterically influenced by the ECD component of the ligand-receptor complex. The findings should be useful for the future development of novel PTH-based peptide therapeutics for diseases of bone and mineral ion metabolism., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: COVID-19 is a novel disease caused by SARS-CoV-2., Methods: We conducted a retrospective evaluation of patients admitted with COVID-19 to one site in March 2020. Patients were stratified into 3 groups: survivors who did not receive mechanical ventilation (MV), survivors who received MV, and those who received MV and died during hospitalization., Results: There were 140 hospitalizations; 22 deaths (mortality rate 15.7%), 83 (59%) survived and did not receive MV, 35 (25%) received MV and survived; 18 (12.9%) received MV and died. Thee mean age of each group was 57.8, 55.8 and 72.7 years, respectively (P = .0001). Of those who received MV and died, 61% were male (P = .01). More than half the patients (n = 90, 64%) were African American. First measured d-dimer >575.5 ng/mL, procalcitonin > 0.24 ng/mL, lactate dehydrogenase >445.6 units/L, and brain natriuretic peptide (BNP) >104.75 pg/mL had odds ratios of 10.5, 5, 4.5 and 2.9, respectively for MV (P < .05 for all). Peak BNP >167.5 pg/mL had an odds ratio of 6.7 for inpatient mortality when mechanically ventilated (P = .02)., Conclusions: Age and gender may impact outcomes in COVID-19. D-dimer, procalcitonin, lactate dehydrogenase and BNP may serve as early indicators of disease trajectory., (Copyright © 2020 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.)

Microbial contaminations and infections are hazardous and pose crucial concerns for humans. They result in severe morbidity and mortality around the globe. Even though dish-culturing, polymerase chain reaction (PCR), an enzyme-linked immunosorbent assay (ELISA) exhibits accurate and reliable detection of bacteria but these methods are time-consuming, laborious, and expensive. This warrants early detection and quantification of bacteria for timely diagnosis and treatment. Bacteria imprinting ensures a solution for selective and early detection of bacteria by snagging them inside their imprinted cavities. This review provides an insight into MIPs based bacterial detection strategies, challenges, and future perspectives.

Cancer is the one of the fatal and dreaded disease responsible for huge number of morbidity and mortality across the globe. It is expected that the global burden will increase to 21.7 million fresh cancer cases as compared to present estimate of 18.1 million cancer cases in addition to nearly 9.6 million cancer deaths worldwide. In response to cancerous or certain benign conditions; specific type of tumor or cancer markers (biomarkers) are produced at much higher levels which are secreted into the urine, blood, stool, tumor or other tissues. Therefore, the efficient and early detection of cancer biomarkers is necessary which can offer a reliable way for cancer patient screening and diagnosis. This process not only helps in the evaluation of pathogenic processes but also the prognosis of different cancers and pharmacological responses to therapeutic interventions are secured. Over the past several years, electrochemical detection methods have proved to be the most attractive methods among many, due to the advantages, such as simple instrumentation, portability, low cost and high sensitivity. Furthermore, the modifications of these electrochemical immunosensors by utilizing various types of nanomaterials enable these systems to detect trace amount of target tumor markers. Hence, herein, we intend to review the selective works on electrochemical detection of various biomarkers using wide range of nanomaterials with a particular focus on graphene., Competing Interests: Declaration of competing interest The authors have no conflict of interest., (Copyright © 2019 Elsevier B.V. All rights reserved.)