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Research question: What implications for policy and practice can be derived from outcomes and trends observed across 8 years of a surrogacy programme in two UK-regulated IVF centres (London, Cardiff)?\ud Design: Retrospective cohort study analysing surrogacy treatments undertaken between 2014 and September 2021.\ud Results: Surrogacy continues to rise in popularity in the UK despite the inability of those supporting safe and professional practice to advertise to recruit surrogates. In two IVF centres regulated by the Human Fertilisation and Embryology Authority (HFEA), both the number of surrogacy treatments and the proportion of those undertaken on behalf of same-sex male intended parents increased year on year in the period studied. From a cohort of 108 surrogates, 71 babies were born to 61 surrogates (with five pregnancies ongoing) by February 2022. No statistically significant difference in live birth rates (LBR) was observed between the heterosexual couples and same-sex male couples. Sample sizes of single and transgender intended parents were too small (n < 5) to compare. The use of vitrified oocytes in surrogacy treatments has increased year on year, while fresh oocyte use has declined since peaking in 2019. There was no significant difference in LBR between fresh and vitrified oocyte usage across the cohort.\ud Conclusions: The number of surrogacy treatments steadily increased, with clear evidence that the proportion of same-sex male couples accessing surrogacy is a major contributor to this growth. Vitrified/warmed oocyte use now outstrips the use of fresh oocytes in the surrogacy treatment cycles studied here. The results represent a strong basis for supporting the liberalization of regulatory reform expected to be introduced in the UK later in 2022.

As SARS-CoV-2 continues to spread and evolve, detecting emerging variants early is critical for public health interventions. Inferring lineage prevalence by clinical testing is infeasible at scale, especially in areas with limited resources, participation, or testing and/or sequencing capacity, which can also introduce biases1–3. SARS-CoV-2 RNA concentration in wastewater successfully tracks regional infection dynamics and provides less biased abundance estimates than clinical testing4,5. Tracking virus genomic sequences in wastewater would improve community prevalence estimates and detect emerging variants. However, two factors limit wastewater-based genomic surveillance: low-quality sequence data and inability to estimate relative lineage abundance in mixed samples. Here we resolve these critical issues to perform a high-resolution, 295-day wastewater and clinical sequencing effort, in the controlled environment of a large university campus and the broader context of the surrounding county. We developed and deployed improved virus concentration protocols and deconvolution software that fully resolve multiple virus strains from wastewater. We detected emerging variants of concern up to 14 days earlier in wastewater samples, and identified multiple instances of virus spread not captured by clinical genomic surveillance. Our study provides a scalable solution for wastewater genomic surveillance that allows early detection of SARS-CoV-2 variants and identification of cryptic transmission.

Background Systemic lupus erythematosus (SLE) is a chronic, autoimmune disease characterized by abnormal B-cell activation and the presence of autoantibodies, which can result in organ damage. Lupus nephritis (LN) is the most common severe organ manifestation of SLE and may result in impaired kidney function. However, there is limited research on the health-related quality of life (HRQoL) burden amongst patients with LN. The objective of this systematic literature review was to assess the HRQoL, fatigue and health utilities associated with LN. Methods A structured literature search (GSK Study 212980) of the MEDLINE and Embase databases was conducted in July 2019 and updated September 2021. Relevant international congress abstracts from 2016 to 2021 were searched, and gray literature searches and keyword-based searches in PubMed, Google, and Google Scholar were also conducted. Results were screened according to predefined criteria and data on the outcomes of interest were extracted. A quantitative analysis was conducted to supplement the narrative review, to provide 36-item Short Form survey (SF-36) estimates, and to determine variation by prognostic factors. Results Of 1155 articles identified, 26 studies for a total of 3440 patients were included. Patients with LN showed poorer HRQoL and more fatigue than healthy controls/the general population, although these were similar between patients with SLE with and without LN. HRQoL was worse in patients with LN Class III/IV or with active disease. Fatigue was generally reported as the most burdensome symptom and was associated with lower HRQoL and increased treatment dissatisfaction. During induction treatment, HRQoL and fatigue were improved with mycophenolate mofetil versus cyclophosphamide. HRQoL improved over time with treatment amongst patients with active LN. Very limited data were identified assigning utilities to health states for cost-effectiveness analysis. Nine studies were considered for quantitative analysis of baseline SF-36 scores. The analysis suggested that LN has a significant impact across all SF-36 domains, with the lowest scores in the general health perceptions and role-physical domains and physical component summary. Conclusions There is a large HRQoL burden in patients with LN, in particular regarding symptoms of fatigue. Future research should focus on investigating fatigue severity and health utilities in LN.

Globally, biosimilars are expected to play a key role in lowering healthcare costs and providing increased patient access to biological therapies. Given this, and in line with the European Union and World Health Organization, many emerging nations have adapted and established biosimilar regulatory guidelines. Emerging nations present a lucrative market for biosimilar development and commercialization, yet they also pose unique challenges. A thorough understanding of the unique attributes of emerging markets in relation to biosimilars is needed to promote their successful uptake in low- and middle-income countries.This article highlights the opportunities and challenges that emerging markets represent in terms of biosimilar uptake. A comprehensive analysis of biosimilar uptake in European countries, where biosimilars have gained significant market share, was carried out to identify policies that can enhance market penetration in emerging nations.Implementation of pricing and procurement policies, as well as provider and patient confidence in biosimilar efficacy, are key factors in their uptake. Due to the high cost of biosimilar development, incentivizing domestic companies with the biosimilar manufacturing capability to produce these drugs will be helpful in ensuring a sustainable biosimilar market and a steady supply chain.

Aim To assess the influence of gender and age on different parameters of alveolar bone loss using orthopantomogram. Materials and methods Eighty subjects were enrolled in the study (20 dentulous and 60 completely edentulous), fulfilling the inclusion and exclusion criteria. Completely edentulous subjects were divided into four groups (15 males and 15 females above 60 years) and (15 males and 15 females below 60 years). Dentulous group comprised 20 subjects (10 males and 10 females) between 41 and 75 years. After taking panoramic radiographs, vertical as well as horizontal reference lines were drawn. The parameters used for evaluation included mandibular cortical index (MCI), inferior mandibular cortical width (MCW), panoramic mandibular index (PMI), alveolar bone loss (ABL), and height of bone at first premolar (Hp) and first molar (Hm) of the mandible. Results There was significant association between MCI and age for females with C2 and C3 categories being more common with advancing age. MCW was stable in all groups, except in females above 60 years of age. PMI and ABL were nonsignificant for age and gender. Although the average values of bone height (Hm and Hp) for males were higher than those of females, the results were statistically insignificant. Conclusion Panoramic radiographic measurements could provide much valuable information and could help in evaluating patients with a low bone mineral density (BMD) with a few limitations. Clinical significance Dental professionals could screen the patients through panoramic radiographs taken during routine clinical examination, which could help in identifying patients with a low BMD so that further treatment could be initiated early and thus to prevent a pathologic fracture.

β-arrestins (βarrs) play multifaceted roles in the function of G protein-coupled receptors (GPCRs). βarrs typically interact with phosphorylated C-terminal tail (C tail) and transmembrane core (TM core) of GPCRs. However, the effects of the C tail- and TM core-mediated interactions on the conformational activation of βarrs have remained elusive. Here, we show the conformational changes for βarr activation upon the C tail- and TM core-mediated interactions with a prototypical GPCR by nuclear magnetic resonance (NMR) spectroscopy. Our NMR analyses demonstrated that while the C tail-mediated interaction alone induces partial activation, in which βarr exists in equilibrium between basal and activated conformations, the TM core- and the C tail-mediated interactions together completely shift the equilibrium toward the activated conformation. The conformation-selective antibody, Fab30, promotes partially activated βarr into the activated-like conformation. This plasticity of βarr conformation in complex with GPCRs engaged in different binding modes may explain the multifunctionality of βarrs., β-arrestins commonly bind to two distinct elements in GPCRs: the phosphorylated carboxyl terminal tail (C tail) and the cytoplasmic face of the transmembrane region (TM core). Here, the authors use methyl-TROSY NMR measurements to characterise the interactions between β-arrestin 1 (βarr1) and a GPCR and observe that C tail-mediated interaction with a GPCR alone induces the partial activation of βarr1, whereas the TM core- and C tail-mediated interactions together stabilize the activated conformation of βarr1.

PURPOSE This study was undertaken to analyze our cohort of patients with vulvar cancer, the factors affecting their survival, and to review published Indian literature. MATERIALS AND METHODS A prospectively maintained database of 18 patients with vulvar cancer who were amenable to up-front surgery and treated between 2013 and 2021 was analyzed. Patients were studied and evaluated for clinicopathological features, risk factors, stage of disease, surgical modalities, and disease outcome. This study critiques the 16 studies identified in the English literature relating to vulvar carcinoma from 1996 to 2021 from India. RESULTS The mean age of our patients was 63.7 years. All 18 patients underwent up-front radical surgery with primary closure. Postoperative histology was squamous cell carcinoma with negative margins in all and lymph-vascular space involvement negative in 17 of 18 patients. Of the 10 patients who underwent inguinofemoral lymphadenectomy, four patients had positive lymph nodes. The estimated mean survival was 61.6 months. We reviewed the Indian literature for over 25 years. As the majority of patients presented with a locally advanced stage of the disease, the primary mode of treatment was chemoradiotherapy. Lymph node positivity and lack of appropriate management at relapse increased the risk of poor survival. CONCLUSION This review clearly emphasizes the unmet need for more prospective multicentric trials not only to increase our understanding about the disease but also to define better treatment protocols for various stages of the disease, thereby improving disease-free and overall survival.

Studies from high-income countries report associations of preeclampsia (PE) with reduced cognitive function and adverse behavioural outcomes in children. We examined these associations in Indian children aged 5-7 years. Children of mothers with PE (n=74) and without PE (non-PE; n=234) were recruited at delivery at Bharati Hospital, Pune, India. The cognitive performance was assessed using 3 core tests from the Kaufman Assessment Battery and additional tests including Verbal fluency, Kohs block design, and Coding A (from Wechsler Intelligence Scale for Children). The parent-reported Strengths and Difficulties Questionnaire (SDQ) was used to assess children’s behavioral characteristics. Scores were compared between children from PE and non-PE groups, and associations analyzed further using regression models, adjusted for potential confounders. After adjusting for age, sex, socio-economic status and maternal education, children of PE mothers had lower Kohs block design scores (adjusted odds ratio per score category 0.57, [95% CI 0.34-0.96] p=0.034; 0.62 [95%CI (0.36, 1.07), p=0.09 on further adjustment for birth weight and gestation) compared to children of mothers without PE. In the SDQ, there was a lower prevalence of abnormal ‘conduct problem’ scores in PE group than non-PE group (OR=0.33, 95% CI 0.13-0.83, p=0.018, in the fully adjusted model); there were no differences for other behavioral domains. This preliminary study in Indian children suggests that fetal exposure to maternal PE may have an adverse impact on visuo-spatial performance but does not adversely affect behavior. Further studies with larger sample sizes are essential to understand effects of maternal PE on cognitive/behavioral outcomes in children.

Lung transplant is increasingly performed for the treatment of end-stage lung disease. As the number of lung transplants and transplant centers continues to rise, radiologists will more frequently participate in the care of patients undergoing lung transplant, both before and after transplant. Potential donors and recipients undergo chest radiography and CT as part of their pretransplant assessment to evaluate for contraindications to transplant and to aid in surgical planning. After transplant, recipients undergo imaging during the postoperative hospitalization and also in the long-term outpatient setting. Radiologists encounter a wide variety of conditions leading to end-stage lung disease and a myriad of posttransplant complications, some of which are unique to lung transplantation. Familiarity with these pathologic conditions, including their imaging findings and their temporal relationship to the transplant, is crucial to accurate radiologic interpretation. Knowledge of the surgical techniques and expected postoperative appearance prevents confusing normal posttransplant imaging findings with complications. A basic understanding of the indications, contraindications, and surgical considerations of lung transplant aids in imaging interpretation and protocoling and also facilitates communication between radiologists and transplant physicians. Despite medical and surgical advances over the past several decades, lung transplant recipients currently have an average posttransplant life expectancy of only 6.7 years. As members of the transplant team, radiologists can help maximize patient survival and hopefully increase posttransplant life expectancy and quality of life in the coming decades.

The study focused on the medicinal properties of citrus fruits and their ability to synthesize silver nanoparticles. As the resistance against the modern antibiotic agents is on increase, finding new and effective natural antibiotic agents is the need of the modern era. Similarly, bio-synthesis of nanoparticles is also being encouraged for eco-friendly reasons. Due to remarkable medicinal and industrial applications of silver nanoparticles (AgNPs), citrus fruit juice is used to reduce silver ions for the green synthesis of AgNPs. Phytochemical analysis revealed the presence of various constituents which impart antibacterial property to citrus fruits, analyzed against four pathogenic bacteria. Also, citrus fruit juice exhibits radical scavenging activity because of these constituents. Further, the AgNPs synthesized using citrus fruits were characterized using Ultra-Violet Visible (UV-VIS) spectroscopy, Fourier Transform Infrared (FTIR) spectroscopy and Transmission Electron Microscopy (TEM) to study the shape and size of the AgNPs. Anticancer activity of AgNPs was also evaluated against Colo-205 cell lines and found to inhibit 37.9% growth of cell lines at the concentration of 10 μg/ml. Hence, synthesized AgNPs can be used effectively against cancer cell lines in combination with other anti-cancer agents.

Breakthrough infections with SARS-CoV-2 Delta variant have been reported in doubly-vaccinated recipients and as re-infections. Studies of viral spread within hospital settings have highlighted the potential for transmission between doubly-vaccinated patients and health care workers and have highlighted the benefits of high-grade respiratory protection for health care workers. However the extent to which vaccination is preventative of viral spread in health care settings is less well studied. Here, we analysed data from 118 vaccinated health care workers (HCW) across two hospitals in India, constructing two probable transmission networks involving six HCWs in Hospital A and eight HCWs in Hospital B from epidemiological and virus genome sequence data, using a suite of computational approaches. A maximum likelihood reconstruction of transmission involving known cases of infection suggests a high probability that doubly vaccinated HCWs transmitted SARS-CoV-2 between each other and highlights potential cases of virus transmission between individuals who had received two doses of vaccine. Our findings show firstly that vaccination may reduce rates of transmission, supporting the need for ongoing infection control measures even in highly vaccinated populations, and secondly we have described a novel approach to identifying transmissions that is scalable and rapid, without the need for an infection control infrastructure.

The B.1.617.2 (Delta) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first identified in the state of Maharashtra in late 2020 and spread throughout India, outcompeting pre-existing lineages including B.1.617.1 (Kappa) and B.1.1.7 (Alpha)1. In vitro, B.1.617.2 is sixfold less sensitive to serum neutralizing antibodies from recovered individuals, and eightfold less sensitive to vaccine-elicited antibodies, compared with wild-type Wuhan-1 bearing D614G. Serum neutralizing titres against B.1.617.2 were lower in ChAdOx1 vaccinees than in BNT162b2 vaccinees. B.1.617.2 spike pseudotyped viruses exhibited compromised sensitivity to monoclonal antibodies to the receptor-binding domain and the amino-terminal domain. B.1.617.2 demonstrated higher replication efficiency than B.1.1.7 in both airway organoid and human airway epithelial systems, associated with B.1.617.2 spike being in a predominantly cleaved state compared with B.1.1.7 spike. The B.1.617.2 spike protein was able to mediate highly efficient syncytium formation that was less sensitive to inhibition by neutralizing antibody, compared with that of wild-type spike. We also observed that B.1.617.2 had higher replication and spike-mediated entry than B.1.617.1, potentially explaining the B.1.617.2 dominance. In an analysis of more than 130 SARS-CoV-2-infected health care workers across three centres in India during a period of mixed lineage circulation, we observed reduced ChAdOx1 vaccine effectiveness against B.1.617.2 relative to non-B.1.617.2, with the caveat of possible residual confounding. Compromised vaccine efficacy against the highly fit and immune-evasive B.1.617.2 Delta variant warrants continued infection control measures in the post-vaccination era., A study of SARS-CoV-2 variants examining their transmission, infectivity, and potential resistance to therapies provides insights into the biology of the Delta variant and its role in the global pandemic.

Background The world has been battling several vector-borne diseases since time immemorial. Socio-economic marginality, precipitation variations and human behavioral attributes play a major role in the proliferation of these diseases. Lockdown and social distancing have affected social behavioral aspects of human life and somehow impact on the spread of vector borne diseases. This article sheds light into the relationship between COVID-19 lockdown and global dengue burden with special focus on India. It also focuses on the interconnection of the COVID-19 pandemic (waves 1 and 2) and the alteration of human behavioral patterns in dengue cases. Methods We performed a systematic search using various resources from different platforms and websites, such as Medline; Pubmed; PAHO; WHO; CDC; ECDC; Epidemiology Unit Ministry of Health (Sri Lanka Government); NASA; NVBDCP from 2015 until 2021. We have included many factors, such as different geographical conditions (tropical climate, semitropic and arid conditions); GDP rate (developed nations, developing nations, and underdeveloped nations). We also categorized our data in order to conform to COVID-19 duration from 2019 to 2021. Data was extracted for the complete duration of 10 years (2012 to 2021) from various countries with different geographical region (arid region, semitropic/semiarid region and tropical region). Results There was a noticeable reduction in dengue cases in underdeveloped (70–85%), developing (50–90%), and developed nations (75%) in the years 2019 and 2021. The dengue cases drastically reduced by 55–65% with the advent of COVID-19 s wave in the year 2021 across the globe. Conclusions At present, we can conclude that COVID-19 and dengue show an inverse relationship. These preliminary, data-based observations should guide clinical practice until more data are made public and basis for further medical research.

Introduction: Biosimilar medicines have transformed the healthcare landscape by providing improved access to life-saving medicines at a lower cost. Biosimilars are a distinct category of biologic t...

PRCIS Yogic pranayama and diaphragmatic breathing are potential adjunctive therapies for patients with glaucoma; however, they are not substitutes for medicine or eye drops. PURPOSE Currently, medical or surgical lowering of intraocular pressure is the only therapeutic approach for treating primary open-angle glaucoma. Intraocular pressure maintenance is influenced by autonomic activity (sympathetic and parasympathetic). "Yogic pranayama" and "diaphragmatic breathing" are exercises that can affect autonomic activity by stimulating a wakeful hypometabolic state of parasympathetic dominance. We aimed to assess the effect of yogic pranayama and diaphragmatic breathing on intraocular pressure to determine whether it can be recommended for individuals with established glaucoma in combination with glaucoma medication as an adjuvant therapy. MATERIALS AND METHODS In this prospective, randomized trial, 90 patients with primary open-angle glaucoma (180 eyes, age: above 40 y) were assigned to either the control or yogic pranayama and diaphragmatic breathing exercise group. In the latter group, yogic pranayama and diaphragmatic breathing were practiced daily for 6 months. We measured the intraocular pressure at presentation and subsequently after 1, 3, and 6 months. RESULTS Compared with the wait-list group, the yogic pranayama and diaphragmatic breathing exercise group had significantly lowered intraocular pressure (right eye: 20.85±3.39 to 14.90±2.86 mm Hg; left eye: 20.30±4.12 to 14.25±3.85 mm Hg; P

Purpose: To evaluate the outcomes of combined microincision phacoemulsification with sutureless transpupillary silicone oil (SO) removal using an irrigation probe of bimanual irrigation/aspiration. Methods: We conducted a single-center retrospective study, including patients who had undergone phacoemulsification with transpupillary removal of SO, which had been used for intraocular tamponade after a previous pars plana vitrectomy. Outcome measures were corrected distance visual acuity (CDVA), refractive error, intraocular pressure (IOP), and endothelial cell count (ECC) evaluated preoperatively and postoperatively at 3-month follow-up. Any intraoperative or postoperative complications, duration of surgery, and final retinal status at 3 months were also noted. Results: Seventy-four eyes (74 patients) were analyzed. The mean interval between SO placement and cataract surgery was 4.73 months (standard deviation [SD]: 1.02). CDVA improved in 66 (89.2%) eyes and remained the same in 8 (10.8%) eyes (P < 0.001). The mean postoperative spherical equivalent was −0.96D (SD: 0.75) at 3 months (P < 0.001). There was a significant drop in IOP from 15.08 mmHg (SD: 2.67) preoperatively to 11.64 mmHg (SD: 2.02) postoperatively (P < 0.001). The average ECC loss was only 5.7% at 3 months postoperatively. The mean surgical duration was 17.20 min (SD: 7.02). One patient had retinal redetachment and required resurgery. At 3 months, the retina was attached in all patients. Conclusion: Combined microincision phacoemulsification with transpupillary passive SO removal using irrigation probe of bimanual irrigation/aspiration is a safe, effective, and less invasive technique that offers the main advantage of reduced surgical trauma, and should be reserved for patients with a stable retina, not requiring additional surgical intervention.

Objectives To describe the histologic features that are helpful in the diagnosis of the rare bronchiolar adenomas/ciliated muconodular papillary tumors (BAs/CMPTs) during intraoperative consultation. Methods Multi-institutional retrospective review of frozen sections of 18 BAs/CMPTs. Results In 14 of 18 cases, BA/CMPT was the primary reason for sublobar lung resection, and in 4 cases, BA/CMPT was an incidental finding intraoperatively for resections performed for carcinoma in other lobes. There were 11 proximal-type/classic BAs/CMPTs and 7 distal-type/nonclassic BAs/CMPTs. Only 3 (16.7%) of 18 were correctly diagnosed at the time of frozen section, all of which were proximal type/classic. The remainder were diagnosed as adenocarcinoma (n = 7); invasive mucinous adenocarcinoma (n = 1); non–small cell lung carcinoma (n = 1); cystic mucinous neoplasm, favor adenocarcinoma (either mucinous or colloid type) (n = 1); favor adenocarcinoma, cannot exclude CMPT (n = 1); atypical proliferation (n = 2); mucinous epithelial proliferation (n = 1); and mucous gland adenoma (n = 1). Conclusions BA/CMPT can potentially be misdiagnosed as carcinoma during intraoperative consultation. On retrospective review of the frozen sections, the presence of the following may help to avoid misdiagnosis: a mixture of bland ciliated columnar cells, mucinous cells, and, most important, a basal cell layer, as well as a lack of necrosis, significant atypia, and mitoses.

Myiasis is the invasion of living animal tissue by fly larvae. Orbital tissue infestation involvement occurs in 5% of all myiasis cases and is potentially destructive. Infection by Chrysomya bezziana is very rare in clinical practice. A 65-year-old woman with history of left eye evisceration presented to the emergency department due to a creeping sensation in the left eye socket and underwent medical and surgical treatment for C. bezziana ophthalmomyiasis. A systematic review was performed to identify ophthalmomyiasis cases caused by C. bezziana published in PubMed and Embase until December 2019. C. bezziana can cause major destruction to both vital and non-vital tissues. It should be treated promptly to prevent extensive damage and life-threatening conditions. This report provides an overview of the epidemiology, causes, risk factors, diagnosis, and treatment options that could assist clinicians in diagnosis and management of this condition.

Bovine mastitis has become a significant economic importance for the dairy industry. Concerns regarding poor milk quality and emergence of bacterial resistance have necessitated to develop an alternative therapeutic approach to antibiotics for the treatment of mastitis. Saturated medium-chain fatty acids (MCFAs) and essential oils (EOs) are known natural antimicrobials, but their combined effect has not been investigated extensively. The objective of the present investigation was to examine the bactericidal effect of various combined treatments of eight EOs and three saturated MCFAs to inactivate predominant mastitis pathogens, including Staphylococcus aureus ATCC 29213; Escherichia coli ATCC 25922; Klebsiella pneumoniae ATCC 27736 and Streptococcus agalactiae ATCC 27956. The minimum inhibitory concentration (MIC) values confirmed that all the tested pathogens were variably susceptible to both EOs and saturated MCFAs. Among essential oils, carvacrol (CAR), trans-cinnamaldehyde (TC) and thymol (TM) showed the highest inhibitory activity at concentration 0·38–1·32 mg/mL. Carvacrol exhibited effective additive antibacterial activity in combined treatment with octanoic acid (OA) in terms of its fractional inhibitory index (0·63–0·88) and time-kill effect in reducing about 6 log CFU/mL bacterial cells in less than 5 min. The effort was also made to elucidate the mechanism of antibacterial action of CAR and OA against selected mastitis pathogens by observing changes in cell microstructure, permeability and integrity of cell membrane and their membrane potential. After adding CAR and OA at MIC level, there were obvious changes in cell morphology, leakage of small electrolytes and macromolecules at the initial few hours of treatment i.e. within 1–2 h were observed. Our results indicated that CAR and OA could be evaluated as alternatives or adjuncts to antibiotics as intramammary infusion or topical application to treat bovine mastitis, significantly improving the microbiological safety of milk.

The sudden outbreak of COVID-19 has been responsible for several deaths across the globe. Due to its high contagious nature, it spreads from one human to another very quickly. Now it becomes a global public health threat with no approved treatments. In silico techniques can accelerate the drug development process. Our research aimed to identify the novel drugs for inhibition of Main protease (Mpro) enzyme of COVID-19 by performing in silico approach. In this context, a library consisting of 3180 FDA-approved drugs from ‘the ZINC database’ was used to identify novel drug candidates against ‘the Mpro’ of SARS-CoV-2. Initially, the top 10 drugs out of 3180 drugs were selected by molecular docking according to their binding score. Among 10 selected drugs; seven drugs that showed binding with Mpro enzyme residue Glu166 were subjected to100 ns Molecular dynamics (MD) simulation. Out of seven compounds, four namely, ZINC03831201, ZINC08101052, ZINC01482077, and ZINC03830817 were found significant based on MD simulation results. Furthermore, RMSD, RMSF, RG, SASA, PCA, MMPBSA (for last 40 ns) were calculated for the 100 ns trajectory period. Currently, the world needs potent drugs in a short period and this work suggests that these four drugs could be used as novel drugs against COVID-19 and it also provides new lead compounds for further in vitro, in vivo, and ongoing clinical studies against SARS-CoV-2. Communicated by Ramaswamy H. Sarma

Over the past three decades, biotherapeutics have transformed health care by offering effective treatments for complex diseases that were otherwise difficult to deal withThis article aims to review unsuccessful regulatory filings for biosimilar approval.We have focused on regulatory submissions to EMA and FDA. Key shortcomings of the filings that failed to receive approval have been identified and discussed.

The whole world is facing a great challenging time due to Coronavirus disease (COVID-19) caused by SARS-CoV-2. Globally, more than 14.6 M people have been diagnosed and more than 595 K deaths are reported. Currently, no effective vaccine or drugs are available to combat COVID-19. Therefore, the whole world is looking for new drug candidates that can treat the COVID-19. In this study, we conducted a virtual screening of natural compounds using a deep-learning method. A deep-learning algorithm was used for the predictive modeling of a CHEMBL3927 dataset of inhibitors of Main protease (Mpro). Several predictive models were developed and evaluated based on R2, MAE MSE, RMSE, and Loss. The best model with R2=0.83, MAE = 1.06, MSE = 1.5, RMSE = 1.2, and loss = 1.5 was deployed on the Selleck database containing 1611 natural compounds for virtual screening. The model predicted 500 hits showing the value score between 6.9 and 3.8. The screened compounds were further enriched by molecular docking resulting in 39 compounds based on comparison with the reference (X77). Out of them, only four compounds were found to be drug-like and three were non-toxic. The complexes of compounds and Mpro were finally subjected to Molecular dynamic (MD) simulation for 100 ns. The MMPBSA result showed that two compounds Palmatine and Sauchinone formed very stable complex with Mpro and had free energy of −71.47 kJ mol−1 and −71.68 kJ mol−1 respectively as compared to X77 (−69.58 kJ mol−1). From this study, we can suggest that the identified natural compounds may be considered for therapeutic development against the SARS-CoV-2. Communicated by Ramaswamy H. Sarma

Agonist stimulation of G protein-coupled receptors (GPCRs) typically leads to phosphorylation of GPCRs and binding to multifunctional proteins called β-arrestins (βarrs). The GPCR-βarr interaction critically contributes to GPCR desensitization, endocytosis, and downstream signaling, and GPCR-βarr complex formation can be used as a generic readout of GPCR and βarr activation. Although several methods are currently available to monitor GPCR-βarr interactions, additional sensors to visualize them may expand the toolbox and complement existing methods. We have previously described antibody fragments (FABs) that recognize activated βarr1 upon its interaction with the vasopressin V2 receptor C-terminal phosphopeptide (V2Rpp). Here, we demonstrate that these FABs efficiently report the formation of a GPCR-βarr1 complex for a broad set of chimeric GPCRs harboring the V2R C terminus. We adapted these FABs to an intrabody format by converting them to single-chain variable fragments (ScFvs) and used them to monitor the localization and trafficking of βarr1 in live cells. We observed that upon agonist simulation of cells expressing chimeric GPCRs, these intrabodies first translocate to the cell surface, followed by trafficking into intracellular vesicles. The translocation pattern of intrabodies mirrored that of βarr1, and the intrabodies co-localized with βarr1 at the cell surface and in intracellular vesicles. Interestingly, we discovered that intrabody sensors can also report βarr1 recruitment and trafficking for several unmodified GPCRs. Our characterization of intrabody sensors for βarr1 recruitment and trafficking expands currently available approaches to visualize GPCR-βarr1 binding, which may help decipher additional aspects of GPCR signaling and regulation.

Purpose To determine the efficacy of the femtosecond laser with integrated anterior segment optical coherence tomography (AS-OCT) for the detection of posterior capsular dehiscence in posterior polar cataracts (PPCs). To evaluate the safety of phacoemulsification in these eyes undergoing femtosecond laser-assisted cataract surgery (FLACS). Setting Centre For Sight Group of Eye Hospitals, a chain of tertiary eyecare hospitals in India. Design Prospective interventional case series. Methods The study included eyes with PPCs undergoing FLACS using the CATALYS femtosecond platform. Real-time OCT guidance was used to image the posterior capsule (PC), which was then classified as intact or dehiscent. The femtosecond laser was used for the creation of capsulotomy, nuclear fragmentation, and corneal incisions. In all eyes, the posterior offset (distance between the posterior extent of nucleotomy and the PC) was increased to enable a thick epinuclear cushion. Intraoperative status of the PC was noted, and the specificity and the sensitivity of AS-OCT to detect a preexisting posterior capsular defect was determined. Results The cohort included 50 eyes (40 patients), in which a posterior capsular discontinuity on AS-OCT was observed in 7 eyes (14%). Five (10%) of these 7 eyes developed an intraoperative posterior capsular rent (PCR) A sensitivity and negative predictive value of 100% was noted. No case of nucleus drop was noted. Conclusions Femtosecond laser with integrated AS-OCT is a relevant and helpful tool to detect and increase the safety in preexisting posterior capsular dehiscence, alerting the surgeon ahead of phacoemulsification.

Quality of biotherapeutic products is of paramount importance for ensuring patient safety. Analytical tools that can facilitate rapid quality assessment of the therapeutic product at the point of care are very much in demand. In this article, we apply chemometrics based analysis of Raman spectra towards quantitative prediction of protein aggregation in lyophilized biotherapeutic products. Two commercially available therapeutic proteins, erythropoietin (EPO) and human growth hormone (HGH), have been used to demonstrate the applicability of the proposed approach. Thermally induced protein aggregation was monitored by size exclusion chromatography as well as Raman spectroscopy with a 785 nm wavelength laser. Partial least square (PLS) regression was used to analyse the Raman spectra and create a model for quantitative determination of aggregate. Satisfactory performance was observed with both EPO and HGH with R2 of 0.91 and 0.94, cross-validation correlation coefficient of 0.85 and 0.89, and Root Mean Square Error computed from cross calibration (RMSEcv) of 5.25 and 1.92, respectively. The developed approach can enable rapid and accurate assessment of aggregation in lyophilized samples of biotherapeutic products. The study also demonstrates novel use of Raman spectroscopy for protein quantification through a vial.

COVID-19 is a highly contagious disease, which has human-to-human transmission through droplet and contact. It is commonly manifested as fever, dry cough, myalgia, and dyspnoea; the severity of this disease may range from mild, severe to a critical-illness. Currently, there is no definitive treatment or vaccine for COVID-19. The only proven form of management is isolation and supportive care. Therefore, nurses have a pivotal role to play in its management. This evidence-based comprehensive literature review provides the role of nurses in the management of patients with COVID-19, which starts from the initial assessment and triaging, sample collection, care of patients with mild-to-moderate symptoms, care of the critically-ill patient, and care of the dead body.

Coronavirus disease-2019 (COVID-19), associated with the outbreak of deadly virus originating in Wuhan, China, is now a global health emergency and a matter of serious concern. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is rapidly spreading worldwide, and WHO declared the outbreak of this disease a pandemic on March 11, 2020. Though some of the countries have succeeded in slowing down the rate of the spread of this pandemic, most the countries across the globe are still continuing to experience an increasing trend in the growth and spread of this deadly disease. Hence, in the current scenario, is has now become essential to control and finally irradicate this deadly disease using an effective vaccine. One can expect the prominent role of already available antivirals, antibodies and anti-inflammatory drugs in the market, in this pandemic. Immunomodulatory and biological therapeutics are also in the high expectations to combat COVID-19. RNA based vaccines might be more advantageous over traditional vaccines, to deal with the pandemic threat. Aiming towards this direction, clinical trials for SARS-CoV-2 vaccine are currently underway all across the globe. Currently, about 150 health related organizations and research labs are in the progress for the evolution of COVID-19 vaccines, globally. The initial aim of these clinical trials is to assess vaccine's safety, which is tested in Phase I/II/III studies where the primary outcomes typically examine the frequency of adverse effects. The vaccine is about to undergo phase III testing in several countries such as India, USA, South Africa, Brazil and England. US Government, under Operation Wrap Speed is even ready to sponsor three candidates, namely-The University of Oxford and AstraZeneca's AZD1222; Moderna's mRNA-1273; and Pfizer and BioNTech's BNT162 for Phase III trials.

Aim To test the effectiveness of nurse-led dietary diabetes insipidus (DI) bundle on the severity of postoperative fluid imbalance in pituitary region tumours. Design Blinded randomized controlled trial. Methods Patients aged 18-65 operated for sellar-suprasellar tumours in an Indian tertiary care centre were enrolled through total enumeration sampling and underwent randomization with allocation concealment during Sep 2018-Feb 2019. Pre-operative DI, postoperative ventilation, renal failure or decompensated diabetes mellitus were excluded. Patients in the intervention group received a nurse-led DI bundle (validated by three Delphi rounds) with four dietary components: intake of only water during thirst and avoidance of the following-added salt, high-protein foods and caffeinated drinks. Treating clinicians and the investigator assessing outcome were blinded about enrolment. Urine output, serum sodium, vasopressin requirement and hospital stay were assessed as primary outcomes. The outcome measures were monitored daily till the 6th postoperative day. Analyses were performed on 'intention-to-treat' basis, irrespective of compliance. Independent t-test and Chi-square test were used. Results Of the initial 63 patients, 50 fulfilling criteria were randomized to two groups and assessed over six days yielding 150 patient-days per group. There were no significant baseline differences between groups. The mean daily urine output was significantly lower in the DI bundle group than in control, both overall and among endonasal operated pituitary adenomas [3000.09(462.7) vs. 4095.71(896.4)ml & 2987.14(419.5) vs. 4064.73(1051)ml], with the greatest difference on the second postoperative day. Though hypernatraemia in controls became most prominent during days 2-3 and resolved in a week, it was significantly lower in the intervention group (12.7% vs. 30.7% overall, 11.4% vs. 29.4% endonasal adenomas). The need for vasopressin analogues and hospital stay were also significantly lower with DI bundle (p Conclusion This is probably the first ever report of dietary DI bundle among operated pituitary patients, which seem to flatten the DI trend with significant benefits in polyuria, hypernatraemia, vasopressin requirement and hospital stay. Trial registration CTRI/2018/07/015127 of ICMR. Impact The nurse-led dietary DI bundle has effectively reduced the severity of DI among operated pituitary patients with significant benefits in polyuria, hypernatraemia, vasopressin requirement and hospital stay. Its implementation is simple and easy to carry out, especially in resource-constrained institutions, where continuous monitoring and repeated serum sodium estimation are difficult.

Biosimilars hold the potential to be an integral healthcare component that can significantly improve affordability and thereby accessibility of the otherwise expensive biotherapeutic products. Regulators, payors, and policymakers, each have a major role to play in successful adoption of biosimilars. One of the issues that has been a point of frequent discussion is that of interchangeability of biosimilars.This article aims to review the position that the major regulatory bodies have taken on interchangeability of biosimilars. Key issues that remain are also discussed. Adalimumab and etanercept have been chosen as real-world case studies to demonstrate interchangeability considerations. The need for gaining global harmonization on interchangeability is highlighted.A global harmonization on the interchangeability can likely accelerate biosimilar adoption and result in better accessibility to biologics. Experience gained with real-world studies supports switching to biosimilars from originators however post-marketing pharmacovigilance should be in place to assess the risk-benefit profile of biosimilars in the long run.

With the world threatened by a second surge in the number of Coronavirus cases, there is an urgent need for the development of effective treatment for the novel coronavirus (COVID-19). Recently, global attention has turned to preliminary reports on the promising anti-COVID-19 effect of histamine H2-receptor antagonists (H2RAs), most especially Famotidine. Therefore, this study was designed to exploit a possible molecular basis for the efficacy of H2RAs against coronavirus. Molecular docking was performed between four H2RAs, Cimetidine, Famotidine, Nizatidine, Ranitidine, and three non-structural proteins viz. NSP3, NSP7/8 complex, and NSP9. Thereafter, a 100 ns molecular dynamics simulation was carried out with the most outstanding ligands to determine the stability. Thereafter, Famotidine and Cimetidine were subjected to gene target prediction analysis using HitPickV2 and eXpression2Kinases server to determine the possible network of genes associated with their anti-COVID activities. Results obtained from molecular docking showed the superiority of Famotidine and Cimetidine compared to other H2RAs with a higher binding affinity to all selected targets. Molecular dynamic simulation and MMPBSA results revealed that Famotidine as well as Cimetidine bind to non-structural proteins more efficiently with high stability over 100 ns. Results obtained suggest that Famotidine and Cimetidine could be a viable option to treat COVID-19 with a mechanism of action that involves the inhibition of viral replication through the inhibition of non-structural proteins. Therefore, Famotidineand Cimetidine qualify for further study as a potential treatment for COVID-19., Graphical Abstract Communicated by Ramaswamy H. Sarma

Background Drug Resistant Tuberculosis (DR-TB) is an emergent issue in the recent decades. Multidrug resistant (MDR-TB) and Extensive drug resistant (XDR-TB) tuberculosis are the common type of DR-TB. Psychological issues like depression and anxiety are common among the chronic illnesses like tuberculosis. This study aimed at estimating the prevalence of depression and anxiety among these patients. Methods Our study is conducted in a tertiary care teaching hospital in North India. This study aimed at identifying the prevalence of depression and anxiety among the drug resistant tuberculosis patients attending DOTS clinic. The depression and anxiety were screened using PHQ-9 and HAM-A inventories. Binomial and multinomial regression analysis were done to identifying the predictors of depression and anxiety. Results The prevalence rate of depression in MDR-TB and XDR-TB is 68% and 78% respectively. The prevalence of anxiety is 54% in MDR-TB and 66% in XDR-TB respectively in our study. Duration of illness and literacy were the significant predictors of depression and anxiety. Conclusion Patients with DR-TB faces huge psychological burden and this study highlighted the toll of depression and anxiety among them. Adequate screening, identification and treatment for these disorders among DR-TB patients at their earlier treatment stage helps in improving the adherence to treatment and functionality.

Delhi, the national capital of India, experienced multiple severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreaks in 2020 and reached population seropositivity of >50% by 2021. During April 2021, the city became overwhelmed by COVID-19 cases and fatalities, as a new variant, B.1.617.2 (Delta), replaced B.1.1.7 (Alpha). A Bayesian model explains the growth advantage of Delta through a combination of increased transmissibility and reduced sensitivity to immune responses generated against earlier variants (median estimates: 1.5-fold greater transmissibility and 20% reduction in sensitivity). Seropositivity of an employee and family cohort increased from 42% to 87.5% between March and July 2021, with 27% reinfections, as judged by increased antibody concentration after a previous decline. The likely high transmissibility and partial evasion of immunity by the Delta variant contributed to an overwhelming surge in Delhi.

Abstract: The coronavirus pandemic hit the world lately and caused acute respiratory syndrome in humans. The causative agent of the disease was soon identified by scientists as SARS-CoV-2 and later called a novel coronavirus by the general public. Due to the severity and rapid spread of the disease, WHO classifies the COVID-19 pandemic as the 6th public health emergency even after taking efforts like worldwide quarantine and restrictions. Since only symptomatic treatment is available, the best way to control the spread of the virus is by taking preventive measures. Various types of antigen/antibody detection kits and diagnostic methods are available for the diagnosis of COVID-19 patients. In recent years, various phytochemicals and repurposing drugs showing a broad range of anti-viral activities with different modes of actions have been identified. Repurposing drugs such as arbidol, hydroxychloroquine, chloroquine, lopinavir, favipiravir, remdesivir, hexamethylene amiloride, dexamethasone, tocilizumab, interferon-β, and neutralizing antibodies exhibit in vitro anti-coronaviral properties by inhibiting multiple processes in the virus life cycle. Various research groups are involved in drug trials and vaccine development. Plant-based antiviral compounds such as baicalin, calanolides, curcumin, oxymatrine, matrine, and resveratrol exhibit different modes of action against a wide range of positive/negative sense-RNA/DNA virus, and future researches need to be conducted to ascertain their role and use in managing SARS-CoV-2. Thus this article is an attempt to review the current understanding of COVID- 19 acute respiratory disease and summarize its clinical features with their prospective control and various aspects of the therapeutic approach.

Aim In-depth 'One Health' risk assessment of extraintestinal pathogenic Escherichia coli (ExPEC) strains carrying the traits of urinary tract infection, sepsis, meningitis and avian colibacillosis in poultry of India. Methods and results A total of 230 E. coli isolates were recovered from chicken samples representing the different sources (faeces vs caeca), stages (poultry farms vs retails butcher shop) or environments (rural vs urban) of poultry in India. Among all poultry-origin E. coli isolates, 49 (21·1%) strains were identified as ExPEC possessing multiple virulence determinants regardless of their association with any specific phylogenetic lineages. Of particular, potentially virulent ExPEC pathotypes, that is, uropathogenic E.coli (UPEC, 20·4%), avian pathogenic E. coli (APEC, 34·6%), septicaemia-associated E. coli (SEPEC, 47·0%) and neonatal meningitis-causing E.39 coli (NMEC, 2·0%) were also detected among all ExPEC strains. Conclusions Our study is the first to assess ExPEC strains circulating in the different settings of poultry in India and significantly demonstrates their potential ability to cause multiple extraintestinal infections both in humans and animals. Significance and impact of the study The data of our study are in favour of the possibility that poultry-origin putative virulent ExPEC pathotypes consequently constitute a threat risk to 'One Health' or for food safety and a great concern for poultry production of India.

We propose a technique for combined femto laser-assisted cataract surgery (FLACS) and limited vitrectomy from the pars-plana site for optimization of surgical results in subluxated cataracts. FLACS creates a free-floating, customised capsulotomy, minimizes stress on compromised zonules, and prechops the nucleus, effectively reducing the ultrasonic power as well as the forces required to chop the nucleus. The area of zonular dehiscence creates a direct communication between the irrigation fluid and the anterior vitreous, leading to its hydration. Trans-limbal vitrectomy creates a continuum between the liquefied vitreous and the main wound, leading to further vitreous loss, and exaggeration of the zonular weakness, while pars-plana vitrectomy avoids this by cutting the liquefied vitreous, near its attachment, thereby preventing further hydration and causing lesser stress to the zonules. A combination of these procedures, along with a capsule support device, gives favorable surgical outcomes in moderate to severe subluxations.

Background and Objective: Glossopharyngeal nerve block (GNB) technique has been used as alternative of treatment of cancer and noncancer pain of the oral cavity. The objective of the study is to compare the two approaches (extraoral and intraoral) of GNB in patients of carcinoma of the tongue in terms of efficacy, duration, and complications. Materials and Methods: This was a prospective comparative randomized study over a period of 1 year. Fifty patients of either sex of ASA physical status and 2, between 21 and 70 years of age, suffering from carcinoma of the tongue, were selected. The patients were randomly divided into two groups. Group I received 4 mL of 0.5% bupivacaine combined with 40 mg, of triamcinolonacetonide by extraoral approach of GNB, and Group II received the same amount of drug by intraoral approach of GNB. Hemodynamic parameters, degree of pain relief using visual analog scale (VAS), number of attempts, effect on quality of life (QOL), and complication were noted during the performance of GNB. Results: Demographic profile in both groups was comparable. Rate of complication and number of attempts to complete intervention were higher in Group I, which was found to be statistically significant. However, mean VAS scores in Group I were significantly higher as compared to those in Group II during most of the study period starting from the 1st follow-up at 30 min to the 2nd month postintervention (P Conclusion: The intraoral approach of GNB was better with respect to pain control and improvement in QOL whereas the rate of complication and number of attempts was lower in extraoral approach of GNB.

β‐arrestins (βarrs) are key regulators of G protein‐coupled receptor (GPCR) signaling and trafficking, and their knockdown typically leads to a decrease in agonist‐induced ERK1/2 MAP kinase activation. Interestingly, for some GPCRs, knockdown of βarr1 augments agonist‐induced ERK1/2 phosphorylation although a mechanistic basis for this intriguing phenomenon is unclear. Here, we use selected GPCRs to explore a possible correlation between the spatial positioning of receptor phosphorylation sites and the contribution of βarr1 in ERK1/2 activation. We discover that engineering a spatially positioned double‐phosphorylation‐site cluster in the bradykinin receptor (B(2)R), analogous to that present in the vasopressin receptor (V(2)R), reverses the contribution of βarr1 in ERK1/2 activation from inhibitory to promotive. An intrabody sensor suggests a conformational mechanism for this role reversal of βarr1, and molecular dynamics simulation reveals a bifurcated salt bridge between this double‐phosphorylation site cluster and Lys(294) in the lariat loop of βarr1, which directs the orientation of the lariat loop. Our findings provide novel insights into the opposite roles of βarr1 in ERK1/2 activation for different GPCRs with a direct relevance to biased agonism and novel therapeutics.

Background and objectiveBirth weight and post-natal growth are important predictors of adult health. Preeclampsia (PE) is associated with low birth weight and may have long term effects on the health of the children. The current study aims to compare anthropometry and blood pressure between children of mothers with and without PE in an Indian cohort.MethodsWe studied children born to women with (PE; n = 211) and without preeclampsia (non-PE; n = 470) at Bharati Hospital, Pune, India. Anthropometry and blood pressure were measured in children at 3–7 years of age. Weight and height Z-scores were calculated using the WHO 2006 growth reference. Independent t-tests were used to compare means between the two groups, and associations between preeclampsia and child outcomes were analyzed using multiple linear regression, adjusting for potential confounders.ResultsWeight and height Z-scores (p = 0.04 and 0.008), and subscapular skinfold thickness (p = 0.03) were higher among children of PE compared with children of non-PE mothers. Systolic blood pressure was also higher in children of PE mothers (1.70 mmHg [95% CI 0.05, 2.90] p = 0.006). BMI and diastolic blood pressure did not differ between groups. In regression models adjusted for newborn weight and gestational age, current age and sex, and maternal height, BMI and socio-economic status, children of PE mothers had higher weight Z-score (0.27 SD [95%CI 0.06, 0.48] p = 0.01), height Z-score (0.28 SD [95%CI 0.09, 0.47] p = 0.005), and subscapular skinfold thickness (0.38 mm [95%CI 0.00, 0.76] p = 0.049). A trend for higher systolic blood pressure (1.59 mmHg [95%CI -0.02, 3.20] p = 0.053) in the children was also observed in the adjusted model. The difference in systolic blood pressure was attenuated after adjusting further for the child’s weight and height (1.09 mmHg [95%CI -0.48, 2.67] p = 0.17). There was no evidence of differences in effects between boys and girls.ConclusionChildren of PE mothers were taller and heavier, and had higher systolic blood pressure, partly explained by their increased body size, than children of non-PE mothers. In utero exposure to preeclampsia may increase the risk of future cardiovascular disease.

With the rapid development of nanotechnology, much has been anticipated with silver nanoparticles (AgNPs) due to their extensive industrial and commercial applications. However, it has raised concerns over environmental safety and human health effects. In this study, AgNPs were bio-fabricated using aqueous extract of Microchaete and their medical applications like antioxidant, anti-proliferative, and apoptosis were done. The biosynthesis of AgNPs was continuously followed by UV–vis spectrophotometric analysis. The physiochemical properties like shape, size, crystallinity, and polydispersity of the nanoparticles were determined by Scanning Electron Microscopy (SEM) along with EDX, Transmission Electron Microscope (TEM), Atomic Force Microscope (AFM), dynamic light scattering (DLS), and X-Ray Diffraction (XRD). Biosynthesized 7.0 nm sized AgNPs with the crystalline structure (crystalline size 4.8 nm) having a hydrodynamic diameter of 38.74 ± 2.6 nm was achieved due to the involvement of reducing agents present in the cyanobacterial extract. The IC50 values of the AgNPs were evaluated as 75 µg/ml and 79.41 µg/ml with HepG2 and MCF-7 cell lines. Different in-vitro cellular assays investigated in the present study exhibited antioxidant, anti-proliferative, and apoptotic activities. Probably delayed apoptosis in HepG2 and MCF-7 is due to better antioxidant activities of Microchaete based AgNPs.

Context.—The adoption of digital capture of pathology slides as whole slide images (WSI) for educational and research applications has proven utility.Objective.—To compare pathologists' primary diagnoses derived from WSI versus the standard microscope. Because WSIs differ in format and method of observation compared with the current standard glass slide microscopy, this study is critical to potential clinical adoption of digital pathology.Design.—The study enrolled a total of 2045 cases enriched for more difficult diagnostic categories and represented as 5849 slides were curated and provided for diagnosis by a team of 19 reading pathologists separately as WSI or as glass slides viewed by light microscope. Cases were reviewed by each pathologist in both modalities in randomized order with a minimum 31-day washout between modality reads for each case. Each diagnosis was compared with the original clinical reference diagnosis by an independent central adjudication review.Results.—The overall major discrepancy rates were 3.64% for WSI review and 3.20% for manual slide review diagnosis methods, a difference of 0.44% (95% CI, −0.15 to 1.03). The time to review a case averaged 5.20 minutes for WSI and 4.95 minutes for glass slides. There was no specific subset of diagnostic category that showed higher rates of modality-specific discrepancy, though some categories showed greater discrepancy than others in both modalities.Conclusions.—WSIs are noninferior to traditional glass slides for primary diagnosis in anatomic pathology.

The recent outbreak of SARS-CoV-2 disease, also known as COVID-19, has emerged as a pandemic. The unavailability of specific therapeutic drugs and vaccines urgently demands sincere efforts for drug discovery against COVID-19. The main protease (Mpro) of SARS-CoV-2 is a critical drug target as it plays an essential role in virus replication. Therefore for the identification of potential inhibitors of SARS-CoV-2 Mpro, we applied a structure-based virtual screening approach followed by molecular dynamics (MD) study. A library of 686 phytochemicals was subjected to virtual screening which resulted in 28 phytochemicals based on binding energy. These phytochemicals were further subjected to drug-likeness and toxicity analysis, which resulted in seven drug-like hits. Out of seven, five phytochemicals viz., Mpro-Dehydrtectol (-10.3 kcal/mol), Epsilon-viniferin (-8.6 kcal/mol), Peimisine (-8.6 kcal/mol), Gmelanone (-8.4 kcal/mol), and Isocolumbin (-8.4 kcal/mol) were non-toxic. Consequently, these phytochemicals are subjected to MD, post MD analysis, and MM/PBSA calculations. The results of 100 ns MD simulation, RMSF, SASA, Rg, and MM/PBSA show that Epsilon-viniferin (-29.240 kJ/mol), Mpro-Peimisine (-43.031 kJ/mol) and Gmelanone (-13.093 kJ/mol) form a stable complex with Mpro and could be used as potential inhibitors of SARS-CoV-2 Mpro. However, further investigation of these inhibitors against Mpro receptor of COVID-19 is needed to validate their candidacy for clinical trials. Communicated by Ramaswamy H. Sarma

β-Arrestins (βarrs) are multifunctional intracellular proteins with an ability to directly interact with a large number of cellular partners including the G protein-coupled receptors (GPCRs). βarrs contribute to multiple aspects of GPCR signaling, trafficking and downregulation. Considering the central involvement of GPCR signaling in the onset and progression of diverse types of cancers, βarrs have also emerged as key players in the context of investigating cancer phenotypes, and as potential therapeutic targets. In this chapter, we first provide a brief account of structure and function of βarrs and then highlight recent discoveries unfolding novel functional attributes of βarrs in breast cancer. We also underscore the recent paradigms of modulating βarr functions in cellular context and potential therapeutic opportunities going forward.

β-Arrestins (βarrs) critically regulate G-protein-coupled receptor (GPCR) signaling and trafficking. βarrs have two isoforms, βarr1 and βarr2. Receptor phosphorylation is a key determinant for the binding of βarrs, and understanding the intricate details of receptor-βarr interaction is the next frontier in GPCR structural biology. The high-resolution structure of active βarr1 in complex with a phosphopeptide derived from GPCR has been revealed, but that of βarr2 remains elusive. Here, we present a 2.3-A crystal structure of βarr2 in complex with a phosphopeptide (C7pp) derived from the carboxyl terminus of CXCR7. The structural analysis of C7pp-bound βarr2 reveals key differences from the previously determined active conformation of βarr1. One of the key differences is that C7pp-bound βarr2 shows a relatively small inter-domain rotation. Antibody-fragment-based conformational sensor and hydrogen/deuterium exchange experiments further corroborated the structural features of βarr2 and suggested that βarr2 adopts a range of inter-domain rotations.

Chemokine receptors form a major sub-family of G protein-coupled receptors (GPCRs) and they are involved in a number of cellular and physiological processes related to our immune response and regulation. A better structural understanding of ligand-binding, activation, signaling and regulation of chemokine receptors is very important to design potentially therapeutic interventions for human disorders arising from aberrant chemokine signaling. One of the key limitations in probing the structural details of chemokine receptors is the availability of large amounts of purified, homogenous and fully functional chemokine ligands, and the commercially available products, are not affordable for in-depth structural studies. Moreover, production of uniformly isotope-labeled chemokines, for example, suitable for NMR-based structural investigation, also remains challenging. Here, we have designed a streamlined approach to express and purify the human chemokine CCL7 as well as its15N-,15N/13C-,2H/15N/13C-isotope-labeled derivatives, at milligram levels usingE. coliexpression system. Purified CCL7 not only maintains a well-folded three-dimensional structure as analyzed using circular dichroism and1H/15N NMR but it also induces coupling of heterotrimeric G-proteins and β-arrestins for selected chemokine receptors in cellular system. Our strategy presented here may be applicable to other chemokines and therefore, provide a potentially generic and cost-effective approach to produce chemokines in large amounts for functional and structural studies.

Objective: To compare the recently proposed Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) with the four-tiered reporting system (FTRS) followed at our institute. Methods: Parotid gland fine-needle aspirates reported over a period of 5 years were analysed. These aspirates had been placed into 4 categories according to the FTRS: unsatisfactory (UNS), no evidence of malignancy/negative (NEG), inconclusive for malignancy (INC), and diagnostic for malignancy/positive (POS). Aspirates with follow-up histopathology were then categorized according to the MSRSGC as follows: non-diagnostic, non-neoplastic, atypia of unde­termined significance (AUS), neoplasm, suspicious for malignancy, and malignant. The risk of malignancy (ROM) was calculated. Results: A total of 893 parotid region aspirates were evaluated and histopathology was available for 190 cases (21%). ROM in MSRSGC groups, namely non-diagnostic, non-neoplastic, AUS, neoplasm, suspicious for malignant neoplasm, and malignant, was 44, 8, 0, 12, 81 and 100%, respectively. ROM in FTRS groups, namely UNS, NEG, INC, and POS, was 45, 13, 67 and 100%, respectively. Conclusions: MSRGC and FTRS are comparable with respect to the ROM across groups. Compared to FTRS, the further subcategorisation of the non-malignant group, the use of specific nomenclature, and the reproducibility of MSRGC provide proper risk stratification, thereby guiding better management and resulting in improved patient care.