Implications of genetic variations, differential gene expression, and allele-specific expression on metformin response in drug-naïve type 2 diabetes.

PURPOSE: Metformin is widely used to treat type 2 diabetes mellitus (T2DM) individuals. Clinically, inter-individual variability of metformin response is of significant concern and is under interrogation. In this study, a targeted exome and whole transcriptome analysis were performed to identify predictive biomarkers of metformin response in drug-naïve T2DM individuals. METHODS: The study followed a prospective study design. Drug-naïve T2DM individuals (n = 192) and controls (n = 223) were enrolled. T2DM individuals were administered with metformin monotherapy and defined as responders and non-responders based on their glycated haemoglobin change over three months. 146 T2DM individuals were used for the final analysis and remaining samples were lost during the follow-up. Target exome sequencing and RNA-seq was performed to analyze genetic and transcriptome profile. The selected SNPs were validated by genotyping and allele specific gene expression using the TaqMan assay. The gene prioritization, enrichment analysis, drug-gene interactions, disease-gene association, and correlation analysis were performed using various tools and databases. RESULTS: rs1050152 and rs272893 in SLC22A4 were associated with improved response to metformin. The copy number loss was observed in PPARGC1A in the non-responders. The expression analysis highlighted potential differentially expressed targets for predicting metformin response (n = 35) and T2DM (n = 14). The expression of GDF15, TWISTNB, and RPL36A genes showed a maximum correlation with the change in HbA1c levels. The disease-gene association analysis highlighted MAGI2 rs113805659 to be linked with T2DM. CONCLUSION: The results provide evidence for the genetic variations, perturbed transcriptome, allele-specific gene expression, and pathways associated with metformin drug response in T2DM.

Relooking the monkeypox virus during this present outbreak: epidemiology to therapeutics and vaccines.

OBJECTIVE: The recent monkeypox disease outbreak is another significant threat during the ongoing COVID-19 pandemic. This viral disease is zoonotic and contagious. The viral disease outbreak is considered the substantial infection possessed by the Orthopoxvirus family species after the smallpox virus' obliteration, a representative of the same family. It has potentially threatened the Republic of Congo's regions and certain African subcontinent zones. Although repeated outbreaks have been reported in several parts of the world, as conferred from the epidemiological data, very little is explored about the disease landscape. Thus, here we have reviewed the current status of the monkeypox virus along with therapeutic options available to humanity. MATERIALS AND METHODS: We have accessed and reviewed the available literature on the monkeypox virus to highlight its epidemiology, pathogenicity, virulence, and therapeutic options available. For the review, we have searched different literature and database such as PubMed, PubMed Central, Google Scholar, Web of Science, Scopus, etc., using different keywords such as "monkeypox", "Orthopox", "smallpox", "recent monkeypox outbreak", "therapeutic strategies", "monkeypox vaccines", etc. This review has included most of the significant references from 1983 to 2022. RESULTS: It has been reported that the monkeypox virus shows a remarkable similarity with smallpox during the ongoing outbreak. Sometimes, it creates considerable confusion due to misdiagnosis and similarity with smallpox. The misdiagnosis of the disease should be immediately corrected by rendering some cutting-edge techniques especially intended to isolate the monkeypox virus. The pathophysiology and the histopathological data imply the immediate need to design effective therapeutics to confer resistance against the monkeypox virus. Most importantly, the potential implications of the disease are not given importance due to the lack of awareness programs. Moreover, specific evolutionary evidence is crucial for designing effective therapeutic strategies that confer high resistance, particularly against this species. CONCLUSIONS: The review focuses on a brief overview of the recent monkeypox virus outbreak, infection biology, epidemiology, transmission, clinical symptoms, and therapeutic aspects. Such an attempt will support researchers, policymakers, and healthcare professionals for better treatment and containment of the infection caused by the monkeypox virus.

Idiopathic subglottic stenosis in Saskatchewan Hutterite population.

BACKGROUND: By studying the odds of developing idiopathic subglottic stenosis in the isolated and genetically unique Hutterite population, this study sought to strengthen the hypothesis that an underlying genetic predisposition may exist for its development. METHODS: A retrospective chart review examined the medical records of all adult patients treated for idiopathic subglottic stenosis in Saskatchewan between 2008 and 2018. Cases were segregated into Hutterite and non-Hutterite. RESULTS: Four out of 36 cases of idiopathic subglottic stenosis occurred among Hutterites. The odds of a Hutterite developing idiopathic subglottic stenosis are 21.89 times higher than for non-Hutterites. Positive family history was only observed in the Hutterite population. CONCLUSION: The study strengthens the hypothesis that genetics may play a role in the aetiology of idiopathic subglottic stenosis by demonstrating that the genetically and socially unique Hutterites are more likely to develop this rare disease. This study is the first to demonstrate that a specific subpopulation is at a higher risk for developing idiopathic subglottic stenosis.

A systematic review on SARS-CoV-2 remission: an emerging challenge for its management, treatment, immunization strategies, and post-treatment guidelines.

The COVID-19 disease caused by severe acute respiratory syndrome coronavirus -2 (SARS-CoV-2) has posed as a major health concern for people all across the globe. Along with the increasing confirmed patients being readmitted with complaints for fever, cough, cold, the effective monitoring of 'relapse' of the SARS-CoV-2 virus in the previously discharged patients have become the next area of focus. However, availability of limited data on reactivation of SARS-CoV-2 makes the disease prognosis as well as the effective control of re-infection an immense challenge. Prompted by these challenges, we assessed the possibility of re-infection in discharged patients and the risk of the transmission, proficiency of RT-PCR results and approximate period required for the quarantine, and the real challenges for the development of vaccine. In the present review, the published literature on all the possible cases of re-infection from February to July were reported, thereby selected 142 studies from a hub of overall 669 studies after full text screening. The incomplete virus clearance, poor sensitivity of the present diagnostic testing, emergence of mutant strains, insufficient mucus collection from the throat swab etc., are some of the possible causes of re-infection. The new protocols for management of COVID-19 discharged patients should be revised in the guidelines.

COVID-19 vaccines and vaccination program for aging adults.

OBJECTIVE: COVID-19 vaccines have developed quickly, and vaccination programs have started in most countries to fight the pandemic. The aging population is vulnerable to different diseases, also including the COVID-19. A high death rate of COVID-19 was noted from the vulnerable aging population. A present scenario regarding COVID-19 vaccines and vaccination program foraging adults had been discussed. MATERIALS AND METHODS: This paper reviews the current status and future projections till 2050 of the aging population worldwide. It also discusses the immunosenescence and inflammaging issues facing elderly adults and how it affects the vaccinations such as influenza, pneumococcal, and herpes zoster. RESULTS: This paper recommends clinical trials for all approved COVID-19 vaccines targeting the elderly adult population and to project a plan to develop a next-generation COVID-19 vaccine. CONCLUSIONS: The review has mapped the COVID-19 vaccination status from the developed and developing countries for the elderly population. Finally, strategies to vaccinate all elderly adults globally against COVID-19 to enhance longevity has been suggested.

Evaluation of molecular interaction, physicochemical parameters and conserved pattern of SARS-CoV-2 Spike RBD and hACE2: in silico and molecular dynamics approach.

OBJECTIVE: Recent pandemic virus SARS-CoV-2 is a global warning for the healthcare system. The spike protein of virus SARS-CoV-2 is significant because of two reasons. Firstly, the spike protein of this virus binds with the human ACE2 (hACE2) receptor. Secondly, it has several antigenic regions that might be targeted for vaccine development. However, the structural analytical data for the spike protein of this virus is not available. MATERIALS AND METHODS: Here, we performed an analysis to understand the structural two subunits of S glycoprotein (S gp) of SARS-CoV-2. Further, an analysis of secondary structure components and the tertiary structure analysis of RBD was carried out. We also performed molecular interaction analysis between S gp of this virus and hACE2 as well as between SARS-CoV S gp and hACE2 to compare the binding properties of these two viruses. RESULTS: We noted that the molecular interaction of SARS-CoV-2 S gp and hACE2 form eleven hydrogen bonds, while the molecular interaction of SARS-CoV S gp and hACE2 receptor form seven hydrogen bonds, indicating that the molecular interaction of SARS-CoV-2 S gp and hACE2 receptor is more stable than SARS-CoV S gp and hACE2 receptor. The pairwise sequence alignment of S gp SARS-CoV and SARS-CoV-2 shows several conserved residues of these two proteins. Besides, conserved pattern analysis of SARS-CoV-2 S gp and hACE2 revealed the presence of several highly conserved regions for these two proteins. The molecular dynamics simulation shows a stable interplay between SARS-CoV-2 S gp with the hACE2 receptor. CONCLUSIONS: The present study might help determine the SARS-CoV-2 virus entrance mechanism into the human cell. Moreover, the understanding of the conserved regions may help in the process of therapeutic development from the infection of the deadly virus.

Mainstreaming Barahnaja cultivation for food and nutritional security in the Himalayan region.

Selective production of input intensive crops in the present scenario have resulted in productivity stagnation or even decline due to excessive usage of chemicals, affecting the farmers economically. Sustainable agriculture is the way to increase agricultural productivity and economic prosperity by protecting all natural resources. It maintains a balance of soil fertility with crop productivity and nutritional quality. The mixed cropping systems followed earlier in different regions according to their tradition, climatic zone, soil and water conditions were climate-smart approaches to sustainable food production based on practical experiences over the years of old generations. The life style changes, imbalance in farming system in last 70 years and demand for more food as well as declining land resources resulted in intensive agriculture. Besides, least returns and less demand of ethnic crops gave more preference to major staple food crops. Barahnaja is a traditional orphan crops based mixed cropping system practiced in Himalayan region due to its sustainability and assured crop harvest during erratic weather conditions. This traditional farming method is an exemplary scientific approach to derive innovations with respect to productivity, quality, plant soil interactions and organic agriculture. The main focus of the review is to substantiate the characteristics of the traditional mixed cropping system by describing the advantages of the system and opportunities for scientific innovation towards new knowledge and sustainability.

Conceptualization of functional single nucleotide polymorphisms of polycystic ovarian syndrome genes: an in silico approach.

PURPOSE: Polycystic ovarian syndrome (PCOS) is a multi-faceted endocrinopathy frequently observed in reproductive-aged females, causing infertility. Cumulative evidence revealed that genetic and epigenetic variations, along with environmental factors, were linked with PCOS. Deciphering the molecular pathways of PCOS is quite complicated due to the availability of limited molecular information. Hence, to explore the influence of genetic variations in PCOS, we mapped the GWAS genes and performed a computational analysis to identify the SNPs and their impact on the coding and non-coding sequences. METHODS: The causative genes of PCOS were searched using the GWAS catalog, and pathway analysis was performed using ClueGO. SNPs were extracted using an Ensembl genome browser, and missense variants were shortlisted. Further, the native and mutant forms of the deleterious SNPs were modeled using I-TASSER, Swiss-PdbViewer, and PyMOL. MirSNP, PolymiRTS, miRNASNP3, and SNP2TFBS, SNPInspector databases were used to find SNPs in the miRNA binding site and transcription factor binding site (TFBS), respectively. EnhancerDB and HaploReg were used to characterize enhancer SNPs. Linkage Disequilibrium (LD) analysis was performed using LDlink. RESULTS: 25 PCOS genes showed interaction with 18 pathways. 7 SNPs were predicted to be deleterious using different pathogenicity predictions. 4 SNPs were found in the miRNA target site, TFBS, and enhancer sites and were in LD with reported PCOS GWAS SNPs. CONCLUSION: Computational analysis of SNPs residing in PCOS genes may provide insight into complex molecular interactions among genes involved in PCOS pathophysiology. It may also aid in determining the causal variants and consequently contributing to predicting disease strategies.

Diabetes and COVID-19: a major challenge in pandemic period?

OBJECTIVE: Diabetes is a lifestyle disease and it has become an epidemic worldwide in recent decades. In the ongoing COVID-19 pandemic situation, diabetes has become a serious health concern since large numbers of patients are vulnerable to die from the virus. Thus, diabetic patients affected by COVID-19 cause a major health crisis now. Reports show that large occurrence of diabetes makes it a serious comorbidity in COVID-19 patients. MATERIALS AND METHODS: It is crucial to understand how COVID-19 affects diabetes patients. This paper has reviewed published literature extensively to understand the pattern, importance, care, and medication. RESULTS: This review summarizes the association between COVID-19 and diabetes in terms of susceptibility for pneumonia and other diseases. It also discusses the harshness of COVID-19 with diabetes populations and immunological impacts. It further adds the ACE2 receptor role in diabetes with COVID-19 patients. CONCLUSIONS: Finally, this paper illustrates different types of diabetes management techniques, such as blood glucose management, self-management, mental health management, and therapeutic management. It also summarizes the current knowledge about diabetic patients with COVID-19 to fight this pandemic.

BCG as a game-changer to prevent the infection and severity of COVID-19 pandemic?

The impact of COVID-19 is changing with country wise and depend on universal immunization policies. COVID-19 badly affects countries that did not have universal immunization policies or having them only for the selective population of countries (highly prominent population) like Italy, USA, UK, Netherland, etc. Universal immunization of BCG can provide great protection against the COVID-19 infection because the BCG vaccine gives broad protection against respiratory infections. BCG vaccine induces expressions of the gene that are involved in the antiviral innate immune response against viral infections with long-term maintenance of BCG vaccine-induced cellular immunity. COVID-19 cases are reported very much less in the countries with universal BCG vaccination policies such as India, Afghanistan, Nepal, Bhutan, Bangladesh, Israel, Japan, etc. as compared to without BCG implemented countries such as the USA, Italy, Spain, Canada, UK, etc. BCG vaccine provides protection for 50-60 years of immunization, so the elderly population needs to be revaccinated with BCG. Several countries started clinical trials of the BCG vaccine for health care workers and elderly people. BCG can be uses as a prophylactic treatment until the availability of the COVID-19 vaccine.

SARS-CoV-2 causing pneumonia-associated respiratory disorder (COVID-19): diagnostic and proposed therapeutic options.

SARS-CoV-2 is responsible for the outbreak of severe respiratory illness (COVID-19) in Wuhan City, China and is now spreading rapidly throughout the world. The prompt outbreak of COVID-19 and its quick spread without any controllable measure defines the severity of the situation. In this crisis, a collective pool of knowledge about the advancement of clinical diagnostic and management for COVID-19 is a prerequisite. Here, we summarize all the available updates on the multidisciplinary approaches for the advancement of diagnosis and proposed therapeutic strategies for COVID-19. Moreover, the review discusses different aspects of the COVID-19, including its epidemiology; incubation period; the general clinical features of patients; the clinical features of intensive care unit (ICU) patients; SARS-CoV-2 infection in the presence of co-morbid diseases and the clinical features of pediatric patients infected with the SARS-CoV-2. Advances in various diagnostic approaches, such as the use of real-time polymerase chain reaction (RT-PCR), chest radiography, and computed tomography (CT) imaging; and other modern diagnostic methods, for this infection have been highlighted. However, due to the unavailability of adequate evidence, presently there are no officially approved drugs or vaccines available against SARS-CoV-2. Additionally, we have discussed various therapeutic strategies for COVID-19 under different categories, like the possible treatment plans with drug (antiviral drugs and anti-cytokines) therapy for disease prevention. Lastly, potentials candidates for the vaccines against SARS-CoV-2 infection have been described. Collectively, the review provides an overview of the SARS-CoV-2 infection outbreak along with the recent advancements and strategies for diagnosis and therapy of COVID-19.

The psychological adjustment of United States adopted adolescents and their nonadopted siblings.

Using data from a national sample of 715 United States adoptive families, comparisons were made between adopted adolescents and birth adolescents (children born to the adoptive parents) on the Youth Self-Report (Achenbach), 8 psychological and behavioral adjustment factor scales from the Attitudes and Behaviors survey (Benson), and an identity scale (Search Institute). Multivariate, followed by univariate, analyses of variance showed significant differences between the 2 groups on the psychological factor scales of Licit Drug Use and School Adjustment. A subsample of nonclinically referred adopted adolescents were also compared to norms on the Youth Self-Report. Nonreferred adopted boys showed higher levels of adjustment than the norm group on Withdrawn behaviors. Nonreferred adopted girls showed better adjustment than the norm group on Social Problems and Withdrawn behaviors and poorer adjustment on Delinquent Behavior and Externalizing behavior. (Standardized effect sizes were in the small to moderate range.) These same patterns were evidenced when controlling for ethnicity. These data are examined within Brodzinsky's stress and coping model of adoptee adjustment and support a body of adoption research that finds a pattern of small but significant differences between adopted and nonadopted persons. The differences showing poorer adoptee adjustment in comparison to nonadoptees should not be overstated as is sometimes the case in the adoption clinical literature, and areas in which adoptees evidence higher levels of psychological functioning should be further researched.

Descriptive epidemiology of intravenous heroin users--a new risk group for transmission of HIV in India.

India is considered to have a low incidence of HIV infection so far. Nevertheless, an epidemic of HIV infection has been reported recently among intra-venous drug users (IVDUs) in Manipur, a north-eastern state of India, bordering Myanmar (Burma). This report describes the epidemiology of intravenous drug abuse in the state of Manipur. Four hundred and fifty IVDUs were interviewed. Their age (median 24 years) and sex patterns (95% male) differ from those reported from western countries. It is estimated that there may be approximately 15,000 such addicts in a population of 1.8 million and 50% of them could be positive for HIV. Knowledge of AIDS and its transmission is significantly higher among the addicts than non-addict controls. Free availability of heroin was found to be the major factor responsible for the high rate of addiction. It is presumed that two other neighbouring States which are well-connected to Manipur and also have a common border with Myanmar (part of the 'Golden Triangle') may have a similar problem with HIV infection.