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Courts in seven U.S. states have removed children with “obesity” from parental custody until children could maintain “healthy weights.” These rulings—alongside qualitative reports from parents of children with high weight (PoCHs)—suggest that PoCHs are judged as bad parents. Yet little work has tested whether people genuinely stigmatize PoCHs or what drives this phenomenon. In three experiments with U.S. online community participants ( N = 1,011; two preregistered), we tested an attribution theory model: Social perceivers attribute children’s weights to parents and thus stigmatize those parents. Experiments 1 and 2 support this model (across parent and child gender). Experiment 3 manipulated attributions of parental responsibility for child weight, revealing attenuated stigma with low attributions of responsibility. Findings are among the first to describe and explain stigma toward a large demographic (parents of children with obesity)—with real-world implications (e.g., for family separation, health care)—and may additionally illuminate the psychology underlying stigma toward parents of children with other potentially stigma-evoking identities.

The goal of the project is to test and develop an herbal face pack that contains natural herbal compounds that act as antioxidants, antiseptics, and skin brighteners. Natural herbal components including coffee, multani mitti, arjuna powder, rice flour, gram flour, orange peel powder, nutmeg, milk powder, saffron, aloe vera gel. All natural components were sieved through #120 mesh, carefully weighed, and geometrically blended for a homogeneous formulation, and then tested for phytochemical, morphological, physical, stability, and irritancy, microbial as well as physicochemical properties. Herbal face masks or packs are used to revitalize muscles and improve blood circulation while maintaining healthy skin and eliminating pollutants from pores. All face pack formulations were determined to be good in physical criteria and clear of skin irritations, indicating that the face packs have good qualities, according to this report's results. To identify the practical aids of face packs for human consumption as cosmetic items, more optimization research are needed on this study.

The research aimed to produce an herbal facial scrub. The majority of times, the skin on the face is in regular contact with dirt, pollution, and other contaminants. The scrub comprises various natural components that are safe to use, have fewer adverse effects, and have antibacterial, anti-infective, antioxidant, anti-aging, and moisturizing characteristics. The primary ingredient in this scrub is coffee. Coffee contains a lot of antioxidant properties. In addition, coffee grounds have a different aroma and a coarse grain and can be used to remove dirt skin cells that have died. The scrub was made with a simple mixing procedure and a variety of materials, including coffee beans, nutmeg, masoor dal, corn starch, and coconut oil mixed in melted beeswax. Other ingredients such as glycerine, light liquid paraffin, stearic acid, tween 80, and a perfuming agent was added to this formulation with effective results.

Supplementary Figure 1 from Estimating CDKN2A Carrier Probability and Personalizing Cancer Risk Assessments in Hereditary Melanoma Using MelaPRO

Supplementary Table 1 from Estimating CDKN2A Carrier Probability and Personalizing Cancer Risk Assessments in Hereditary Melanoma Using MelaPRO

Ketamine was discovered in 1964 by merging a ketone with an amine. Patients described feeling disconnected like they were floating in outer. Thus, it was characterized as a dissociative anesthetic. It is a unique drug that expresses hypnotic, analgesic, and amnesic effects. No other drug used in clinical practice produces these three important effects at the same time. Its newly found neuroprotective, anti-inflammatory, antitumor effects and low dose applications have helped to widen the clinical profile of ketamine. Ketamine as an analgesic adjunct in chronic pain patients is currently being researched. Combined use of ketamine and an opiate analgesic has been found to provide good perioperative pain control with reduction in symptoms such as nausea and vomiting, sedation, and respiratory insufficiency.

Individuals with osteoporosis, i.e., low bone mass, are at enhanced risk for fracture, disability, and death. Hospitalizations for osteoporotic fractures exceed those for heart attack, stroke, and breast cancer. Osteoporosis rates are predicted to increase due to an aging global population yet there are limited pharmacological treatment options for osteoporosis, particularly for long-term management of this chronic condition. Moreover, the drug development pipeline is relatively bereft of new strategies and drug candidates, creating an urgent need for developing new therapeutic strategies for treating osteoporosis. In this mini-review, we speculate about the potential for non-invasive soft tissue manipulation (STM) to exert anabolic effects on the skeleton that may provide therapeutic benefit for individuals with low bone mass. Our rationale is premised on work by us and others showing that STM leads to decreased levels of chemokines and pro-inflammatory cytokines (such as Interleukin (IL)-3, IL-6, and IL-8) known to restrict the differentiation and/or activity of bone-forming osteoblasts. However, there are no published studies examining whether STM impacts bone mass, potentially limiting the widespread use of this non-invasive and non-pharmacological intervention in the worldwide treatment of patients with osteoporosis, individuals with low bone mass due to being bed-ridden or otherwise mobility-limited, and persons subjected to spaceflight-related bone loss.

Because regulation of gene expression is heritable and context-dependent, we investigated AD-related gene expression patterns in cell types in blood and brain. Cis-expression quantitative trait locus (eQTL) mapping was performed genome-wide in blood from 5257 Framingham Heart Study (FHS) participants and in brain donated by 475 Religious Orders Study/Memory & Aging Project (ROSMAP) participants. The association of gene expression with genotypes for all cis SNPs within 1 Mb of genes was evaluated using linear regression models for unrelated subjects and linear-mixed models for related subjects. Cell-type-specific eQTL (ct-eQTL) models included an interaction term for the expression of “proxy” genes that discriminate particular cell type. Ct-eQTL analysis identified 11,649 and 2533 additional significant gene-SNP eQTL pairs in brain and blood, respectively, that were not detected in generic eQTL analysis. Of note, 386 unique target eGenes of significant eQTLs shared between blood and brain were enriched in apoptosis and Wnt signaling pathways. Five of these shared genes are established AD loci. The potential importance and relevance to AD of significant results in myeloid cell types is supported by the observation that a large portion of GWS ct-eQTLs map within 1 Mb of established AD loci and 58% (23/40) of the most significant eGenes in these eQTLs have previously been implicated in AD. This study identified cell-type-specific expression patterns for established and potentially novel AD genes, found additional evidence for the role of myeloid cells in AD risk, and discovered potential novel blood and brain AD biomarkers that highlight the importance of cell-type-specific analysis.

Vitamin D supplementation has been linked to improved outcomes from respiratory virus infection, and the COVID19 pandemic has renewed interest in understanding the potential role of vitamin D in protecting the lung from viral infections. Therefore, we evaluated the role of Vitamin D using animal models of pandemic H1N1 influenza and SARS-CoV-2 infection. In mice, dietary induced vitamin D deficiency resulted in lung inflammation that was present prior to infection. Vitamin D sufficient (D+) and deficient (D-) wildtype (WT) and D+ and D-Cyp27B1 (Cyp) knockout (KO, cannot produce 1,25(OH)2D) mice were infected with pandemic H1N1. D- WT, D+ Cyp KO, and D- Cyp KO mice all exhibited significantly reduced survival compared to D+ WT mice. Importantly, survival was not the result of reduced viral replication as influenza M gene expression in the lungs was similar for all animals. Based on these findings, additional experiments were performed using the mouse and hamster models of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. In these studies, high dose vitamin D supplementation reduced lung inflammation in mice but not hamsters. A trend to faster weight recovery was observed in 1,25(OH)2D treated mice that survived SARS-CoV-2 infection. There was no effect of vitamin D on SARS-CoV-2 N gene expression in the lung of either mice or hamsters. Therefore, vitamin D deficiency enhanced disease severity, while vitamin D sufficient/supplementation reduced inflammation following infections with H1N1 influenza and SARS-CoV-2.

In this study, for the first time, we have used Citrus macroptera juice to synthesize dihydropyrimidine (DHPM) derivatives via the Biginelli reaction, which showed better yield, shorter reaction time, and did not require an organic solvent for the reaction. A series of DHPM derivatives were synthesized, and characterized, and structural analysis was achieved through SCXRD & Hirshfeld surface analysis. We observed that these synthesized dihydropyrimidine (DHPM) derivatives showed C–H⋯π, C–H⋯O, C–H⋯N, C–H⋯C, lone pair⋯π, π⋯π, etc. interactions. We also performed in silico studies for their inhibitory activities against human kinesin Eg5 enzyme, and the cytotoxic activity of the synthesized compounds was carried out against A549 lung adenocarcinoma cells. In silico analysis demonstrated that compounds with a chloro-group at the 3- or 4-position in the substituted ring of DHPM showed higher binding affinity for the human kinesin Eg5 enzyme (−7.9 kcal mol−1) than the standard drug monastrol (−7.8 kcal mol−1). Furthermore, in vitro cellular studies revealed that compounds with a chloro-group at the 3- or 4-position in the substituted ring of DHPM induced significant cell death in human A549 lung adenocarcinoma cells. This result indicates that a deactivating group (chlorine) at the 3- or 4-position in the substituted ring of DHPM might be a promising anticancer drug candidate for treating different types of cancers, particularly cancer of the lung.

Worldwide, cancer is one of the leading causes of mortality and cancer rates are set to increase at alarming rate globally. There are various types of cancer in which the leading type is the lung cancer. In recent years lipid-based carriers, such as liposomes, have successfully encapsulated chemotherapeutic agents ameliorating some toxicity issues, while enhancing the overall therapeutic activity in cancer patients. In addition to this, nanomaterials can help to improved half-life in the body, morphology, for increased drug loading and many other ways. The survey discussed in this review will lead the anticancer therapy and cancer management which will provide the platform to the next generation. Therefore, this critical review includes the therapeutic interventions, liposomes target delivery, active and passive drug loading. Finally, we attempt to summarize the current challenges in nanotherapeutics and provide an outlook on the future of this important field. Keywords: Drug Delivery, Liposomes target Delivery, Nanostructures, Drug loading

Courts in seven U.S. states have removed children with “obesity” from parental custody until children could maintain “healthy weights.” These rulings—alongside qualitative reports from parents of children with higher-weight (PoCH)—suggest parents of PoCH are stigmatized. Yet little work tests whether social perceivers genuinely stigmatize PoCH, or what drives this. In three experiments (two pre-registered), we test an attribution theory model: Social perceivers attribute children’s (excess) weights to parents, and thus stigmatize those parents. Experiments 1 and 2 support this model (across parent and child gender). Experiment 3 manipulates the extent to which parents are attributed responsibility for child weight, revealing attenuated stigma with lesser attributions of responsibility. Findings are among the first to describe and explain stigma toward a growing demographic (parents of children with “obesity”), may illuminate the psychology underlying stigma toward parents of children with other stigma-evoking identities, and have real-world implications (e.g., for family separation).

Meningitis creates a life-threatening clinical crisis. Moreover, the administered antibiotics result into multi-drug resistance, thereby necessitating development of alternative therapeutic strategies. This study aimed at identifying novel-drug targets in Neisseria meningitidis and therapeutic molecules which can be exploited for the treatment of meningitis. Novel targets were identified by applying a pathogenomic approach involving protein data-set mining, subtractive channel analysis and subsequent qualitative analysis comprising of in silico pharmacokinetics, molecular docking and pharmacophore generation. Pathogenomic studies revealed Neisserial Surface Protein A (NSP-A) and Iron-III-Substrate Binding Protein (Fe-IIISBP) as potential targets. Two pharmacophore models comprising of 2-(biaryl) carbapenems, efavirenz, praziquantel and pyrimethamine for NSP-A and 2-(biaryl) carbapenems, trimipramine and pyrimethamine for Fe-IIISBP, showed successful docking, followed drug-likeness criteria and generated pharmacophore model with a score of 8.08 and 8.818, respectively, which had further been docked to the target stably. Thus, our study identifies NSP-A and Fe-IIISBP as novel targets in Neisseria meningitidis for which 2-(biaryl) carbapenems, efavirenz, praziquantel, trimipramine and pyrimethamine may be employed for effective treatment of meningitis.

Colorectal cancer is the third most commonly diagnosed cancer in the world characterized by neoplasia in the colon, rectum, or vermiform appendix. Current treatment approaches include chemotherapy, radiotherapy and surgery however non-specific bio-distribution of anti-cancer drug, lack of effective and safe drug delivery career, drug resistance and relapse are major limiting factors of current therapy. Gene therapy is a technique for correcting defective genes responsible for disease development. The future of gene therapy depends on achieving successful delivery of wild type gene to replace a faulty gene. Recently, there has been an increasing interest in delivery of drugs and gene via the gastrointestinal tract. Gene therapy via this route has many advantages, including non-invasive access and the versatility to treat local diseases, such as inflammatory bowel disease, colorectal cancer, as well as systemic diseases, such as haemophilia. However, the intestine presents several distinct barriers and, therefore, the design of robust non-viral delivery systems is key to future success. The review covers obstacles in the path of successful gene therapy using oral route to treat colorectal cancer as well as strategies to overcome. Keywords: Colorectal cancer, Oral gene delivery, Targeted delivery

BACKGROUND Introduction: On 11 March 2020, World Health Organization (WHO) announce that COVID-19 as a pandemic health problem [1,2]. According to report on 25 January 2021, worldwide cases reached to 100 million [3]. The first confirmed case of COVID-19 in India was reported on 30, January 2020 in Kerala and affected individual had come from Wuhan, china [4]. Corona virus is spread over 220 countries across the world [2]. In order to prevent corona virus all the countries are taken initiative to prepare effective vaccine against corona virus. There is not any effective treatment is available for corona so far vaccine is the key preventive aspect against corona virus. There are presently above 125 vaccines go through pre-clinical investigation for covid-19[5]. India has develop two types of vaccine (Covaxin and covidshield) in primary phase and from 01 January 2021, Indian government started vaccination namely Covidshield to health workers (front line workers) [6]. So in primary stage target set to cover 30 million health workers followed by policeman and old age peoples to be vaccinated against corona [6]. During primary phase of corona vaccine we don’t have appropriate research and literature, about side effects and how far vaccine is reliable that why due so some miner side effect and negative media publicity peoples are very scared to take vaccine. So few peoples were started denial get vaccinated OBJECTIVE 1. To assess the existing level of perception toward COVID 19 vaccine among students and faculties of Nursing colleges at Anand and Kheda Districts. 2. To assess the behavior towards COVID 19 vaccine among students and faculties of Nursing colleges at Anand and Kheda Districts. METHODS Design and Setting Descriptive cross sectional survey research design was used and non-probability (snowball) sampling method was used to drawn samples through online Google form [7]. Due to Covid-19 pandemic situation research has adopted online snowball sampling method, where after tool validation from various subject experts, all questions were plots on Google form and inform consent form also has been conducted online prior to data collection from the samples[8]. Prior to data collection written setting permission obtain from nursing colleges principals, for the data collection researcher were selected total 03 nursing institutes which were namely Dinsha Patel College of Nursing, Vinayaka College of Nursing, Nadiad, Vinayaka College of Nursing, Anand, and Zydus College of nursing, Anand. The total sample size was 254 nursing college students and faculties. The tool consist of following Section-01 Demographic variables, section-02 Nursing students and faculties information related to covid-19 vaccination during 1st and 2nd dose and Section-3 Questions related to perception and behaviour towards COVID 19 vaccine. Statistical Analysis used Descriptive statistics applied where, data were analyzed by using SPSS software, and Frequency, percentage, tables etc. were used to represent the statistical data in the tables and graph and figure. Chi-square test was used to assess the significant association between the demographic and level of perception to test the hypothesis. RESULTS Results Out of 254, 245(96.45%) were belong age 17-25 years, 219(86.22%) were females, 53(20.87%) were study Diploma course and 178(70.08%) were study degree course, 223(87.79%) belong to Hindu, religion, 227(89.37%) were Unmarried, 134(52.75%) were from urban area, and rest 120 (47.24%) belongs to Rural area. Sources of information about COVID 19 vaccine 109(42.92%) got from online media, 44(17.32%) from television, 243(95.67%) received free of cost corona vaccine, 199(78.35%) mindset was not influenced by negative media publicity about vaccine, 248(97.63%) do not have any co-morbidities. 219(86.22%) taken Covid-19 vaccine empty stomach. 221(87%) of samples were taken willingly vaccine, 205(80.71%) of samples were received covidshield vaccine and others 49(19.29%) were taken Covaxin, 109(42.91%) samples noticed mild fever, 53(20.87%) samples noticed moderate fever, 18(7.08%) noticed severe fever and rest 74(29.13%) didn’t noticed fever. CONCLUSIONS Conclusions Regarding perception and behaviour towards COVID 19 vaccine, the majority of samples has good perception and behaviour, 74.00% has good perception and only 23.00 had moderate to poor perception, majority of participant were willingly taken vaccine and agree to recommend to others, not evidence any serious side effect due to vaccination. CLINICALTRIAL NOT REGISTERED BEACUSE IT NOT REQUIRED THIS IS AN SURVEY STUDY

IntroductionOn 11 March 2020, World Health Organization (WHO) announce that COVID-19 as a pandemic health problem [1,2]. According to report on 25 January 2021, worldwide cases reached to 100 million [3]. The first confirmed case of COVID-19 in India was reported on 30, January 2020 in Kerala and affected individual had come from Wuhan, china [4]. Corona virus is spread over 220 countries across the world [2]. In order to prevent corona virus all the countries are taken initiative to prepare effective vaccine against corona virus. There is not any effective treatment is available for corona so far vaccine is the key preventive aspect against corona virus. There are presently above 125 vaccines go through pre-clinical investigation for covid-19[5].India has develop two types of vaccine (Covaxin and covidshield) in primary phase and from 01 January 2021, Indian government started vaccination namely Covidshield to health workers (front line workers) [6]. So in primary stage target set to cover 30 million health workers followed by policeman and old age peoples to be vaccinated against corona [6]. During primary phase of corona vaccine we don’t have appropriate research and literature, about side effects and how far vaccine is reliable that why due so some miner side effect and negative media publicity peoples are very scared to take vaccine. So few peoples were started denial get vaccinated.AimsThe current study is aimed to assess the perception and behavior towards Covid-19 vaccine among students and faculties of nursing colleges those who have taken vaccine against corona. The researcher wan to explore the positivity through the research result to reduce the negative mindset of the peoples toward corona vaccine, Because in India few peoples has fear to take vaccine against corona due to negative media publicity and scared of side effect.ObjectiveTo assess the existing level of perception toward COVID 19 vaccine among students and faculties of Nursing colleges at Anand and Kheda Districts.To assess the behavior towards COVID 19 vaccine among students and faculties of Nursing colleges at Anand and Kheda Districts.To find out the association between selected socio-demographic variables and perceptions towards COVID 19 vaccine.MethodologyDesign and SettingDescriptive cross sectional survey research design was used and non-probability (snowball) sampling method was used to drawn samples through online Google form [7]. Due to Covid-19 pandemic situation research has adopted online snowball sampling method, where after tool validation from various subject experts, all questions were plots on Google form and inform consent form also has been conducted online prior to data collection from the samples[8].Prior to data collection written setting permission obtain from nursing colleges principals, for the data collection researcher were selected total 03 nursing institutes which were namely Dinsha Patel College of Nursing, Vinayaka College of Nursing, Nadiad, Vinayaka College of Nursing, Anand, and Zydus College of nursing, Anand. The total sample size was 254 nursing college students and faculties.The tool consist of following Section-01 Demographic variables, section-02 Nursing students and faculties information related to covid-19 vaccination during 1st and 2nd dose and Section-3 Questions related to perception and behaviour towards COVID 19 vaccine.Statistical Analysis usedDescriptive statistics applied where, data were analyzed by using SPSS software, and Frequency, percentage, tables etc. were used to represent the statistical data in the tables and graph and figure. Chi-square test was used to assess the significant association between the demographic and level of perception to test the hypothesis.ResultsOut of 254, 245(96.45%) were belong age 17-25 years, 219(86.22%) were females, 53(20.87%) were study Diploma course and 178(70.08%) were study degree course, 223(87.79%) belong to Hindu, religion, 227(89.37%) were Unmarried, 134(52.75%) were from urban area, and rest 120 (47.24%) belongs to Rural area. Sources of information about COVID 19 vaccine 109(42.92%) got from online media, 44(17.32%) from television, 243(95.67%) received free of cost corona vaccine, 199(78.35%) mindset was not influenced by negative media publicity about vaccine, 248(97.63%) do not have any co-morbidities. 219(86.22%) taken Covid-19 vaccine empty stomach.221(87%) of samples were taken willingly vaccine, 205(80.71%) of samples were received covidshield vaccine and others 49(19.29%) were taken Covaxin, 109(42.91%) samples noticed mild fever, 53(20.87%) samples noticed moderate fever, 18(7.08%) noticed severe fever and rest 74(29.13%) didn’t noticed fever.ConclusionsRegarding perception and behaviour towards COVID 19 vaccine, the majority of samples has good perception and behaviour, 74.00% has good perception and only 23.00 had moderate to poor perception, majority of participant were willingly taken vaccine and agree to recommend to others, not evidence any serious side effect due to vaccination.

Because studies of rare variant effects on gene expression have limited power, we investigated set-based methods to identify rare expression quantitative trait loci (eQTL) related to Alzheimer disease (AD). Gene-level and pathway-level cis rare-eQTL mapping was performed genome-wide using gene expression data derived from blood donated by 713 Alzheimer’s Disease Neuroimaging Initiative participants and from brain tissues donated by 475 Religious Orders Study/Memory and Aging Project participants. The association of gene or pathway expression with a set of all cis potentially regulatory low-frequency and rare variants within 1 Mb of genes was evaluated using SKAT-O. A total of 65 genes expressed in the brain were significant targets for rare expression single nucleotide polymorphisms (eSNPs) among which 17% (11/65) included established AD genes HLA-DRB1 and HLA-DRB5. In the blood, 307 genes were significant targets for rare eSNPs. In the blood and the brain, GNMT, LDHC, RBPMS2, DUS2, and HP were targets for significant eSNPs. Pathway enrichment analysis revealed significant pathways in the brain (n = 9) and blood (n = 16). Pathways for apoptosis signaling, cholecystokinin receptor (CCKR) signaling, and inflammation mediated by chemokine and cytokine signaling were common to both tissues. Significant rare eQTLs in inflammation pathways included five genes in the blood (ALOX5AP, CXCR2, FPR2, GRB2, IFNAR1) that were previously linked to AD. This study identified several significant gene- and pathway-level rare eQTLs, which further confirmed the importance of the immune system and inflammation in AD and highlighted the advantages of using a set-based eQTL approach for evaluating the effect of low-frequency and rare variants on gene expression.

Because regulation of gene expression is heritable and context-dependent, we investigated AD-related gene expression patterns in cell-types in blood and brain. Cis-expression quantitative trait locus (eQTL) mapping was performed genome-wide in blood from 5,257 Framingham Heart Study (FHS) participants and in brain donated by 475 Religious Orders Study/Memory & Aging Project (ROSMAP) participants. The association of gene expression with genotypes for all cis SNPs within 1Mb of genes was evaluated using linear regression models for unrelated subjects and linear mixed models for related subjects. Cell type-specific eQTL (ct-eQTL) models included an interaction term for expression of “proxy” genes that discriminate particular cell type. Ct-eQTL analysis identified 11,649 and 2,533 additional significant gene-SNP eQTL pairs in brain and blood, respectively, that were not detected in generic eQTL analysis. Of note, 386 unique target eGenes of significant eQTLs shared between blood and brain were enriched in apoptosis and Wnt signaling pathways. Five of these shared genes are established AD loci. The potential importance and relevance to AD of significant results in myeloid cell-types is supported by the observation that a large portion of GWS ct-eQTLs map within 1Mb of established AD loci and 58% (23/40) of the most significant eGenes in these eQTLs have previously been implicated in AD. This study identified cell-type specific expression patterns for established and potentially novel AD genes, found additional evidence for the role of myeloid cells in AD risk, and discovered potential novel blood and brain AD biomarkers that highlight the importance of cell-type specific analysis.

Clinical documentation is an important extension of a genetic counseling encounter. The traditional types of clinical documentation include the clinical visit note (including follow-up visit note), letter to the referring physician, letter to the patient, and result summary to the patient and referring physician. Increasing patient volumes, new genetic counseling service delivery models, transition to electronic medical records (EMR), new specialty clinics in genetics, and advances in genetic testing technologies challenge the practice of writing multiple types of clinical documents. This practice resource (PR) seeks to provide best practices for U.S.-based genetic counselors to write efficient and comprehensive clinical documentation using a hybrid clinical document designed to facilitate communication between individual providers, providers, and patients/families, and providers and payers. The content of the hybrid clinical documentation will vary by genetic specialty but may include a summary of genetic services evaluation, genetic testing options and eligibility information, genetic test results, potential risks for genetic conditions, implications for family members, and medical management recommendations. An outline of a general hybrid document along with examples of hybrid clinic notes for three types of genetic counseling specialties is included in this document.

In this study, a series of five non-aromatic dihydropyridones were synthesized, crystallized, and single-crystal X-ray diffraction was used to obtain their molecular geometries. The supramolecular assembly of the molecules through non-covalent interactions was then studied and demonstrated. The weak intermolecular interactions in the molecular packing of compounds were further validated through Hirshfeld surface analysis. The synthesized compounds were screened in vitro using lung adenocarcinoma (A549) cells to assess their cytotoxic effects. A molecular docking study has also been employed to gain insight into the binding mode of the synthesized compounds in the allosteric binding pocket of the Eg5 motor domain and survivin protein. The results showed that the title compounds have mild to moderate cytotoxic effects in these cells. Ethyl-5-cyano-4-(2,5-dimethoxyphenyl)-2-methyl-6-oxo-1,4,5,6-tetrahydropyridine-3-carb-oxylate has shown more significant cytotoxicity among all the synthesized compounds. This study has further demonstrated the importance of non-covalent intermolecular interactions of dihydropyridones for exhibiting diverse supramolecular architectures as well as for having a significant binding affinity towards the receptor.

The Alzheimer’s Disease Sequencing Project (ADSP) undertook whole exome sequencing in 5,740 late-onset Alzheimer disease (AD) cases and 5,096 cognitively normal controls primarily of European ancestry (EA), among whom 218 cases and 177 controls were Caribbean Hispanic (CH). An age-, sex- and APOE based risk score and family history were used to select cases most likely to harbor novel AD risk variants and controls least likely to develop AD by age 85 years. We tested ~1.5 million single nucleotide variants (SNVs) and 50,000 insertion-deletion polymorphisms (indels) for association to AD, using multiple models considering individual variants as well as gene-based tests aggregating rare, predicted functional, and loss of function variants. Sixteen single variants and 19 genes that met criteria for significant or suggestive associations after multiple-testing correction were evaluated for replication in four independent samples; three with whole exome sequencing (2,778 cases, 7,262 controls) and one with genome-wide genotyping imputed to the Haplotype Reference Consortium panel (9,343 cases, 11,527 controls). The top findings in the discovery sample were also followed-up in the ADSP whole-genome sequenced family-based dataset (197 members of 42 EA families and 501 members of 157 CH families). We identified novel and predicted functional genetic variants in genes previously associated with AD. We also detected associations in three novel genes: IGHG3 (p = 9.8 × 10−7), an immunoglobulin gene whose antibodies interact with β-amyloid, a long non-coding RNA AC099552.4 (p = 1.2 × 10−7), and a zinc-finger protein ZNF655 (gene-based p = 5.0 × 10−6). The latter two suggest an important role for transcriptional regulation in AD pathogenesis.

Background: India is projected to be the most populous country according to United Nations’ report; therefore, the knowledge and awareness of contraceptive methods is of utmost important for small family norms and to increase inter-pregnancy interval, so that we can achieve optimum maternal and child outcomes. This study was conducted to assess knowledge, awareness, and acceptance of contraceptive methods among reproductive-age women during Corona pandemic.Methods: A prospective observational questionnaire-based study involving 513 women belonging to the 15-49 years of age group were interviewed with consent. This was a knowledge, attitude and practice (KAP) study regarding socio-demographic profile, knowledge, awareness, and acceptance of the contraceptive method.Results: Statistical analysis of data was done by using chi-square and percentage. Out of 513 participants, 63 participants were not using any method of contraception. Barrier method is the most commonly preferred method of contraception. There was significant association of education of women and husband, occupation with usage of contraception (p

Contact with environmental microbes are arguably the most common species interaction in which any animal participates. Studies have noted diverse relationships between hosts and resident microbes, which can have strong consequences for host development, physiology, and behavior. Many of these studies focus specifically on pathogens or beneficial microbes, while the benign microbes, of which the majority of bacteria could be described, are often ignored. Here, we explore the nature of the relationships between the grass spider Agelenopsis pennsylvanica and bacteria collected from their cuticles in situ. First, using culture-based methods, we identified a portion of the cuticular bacterial communities that are naturally associated with these spiders. Then, we topically exposed spiders to a subset of these bacterial monocultures to estimate how bacterial exposure may alter 3 host behavioral traits: boldness, aggressiveness, and activity level. We conducted these behavioral assays 3 times before and 3 times after topical application, and compared the changes observed in each trait with spiders that were exposed to a sterile control treatment. We identified 9 species of bacteria from the cuticles of 36 spiders and exposed groups of 20 spiders to 1 of 4 species of cuticular bacteria. We found that exposure to Dermacoccus nishinomiyaensis and Staphylococcus saprophyticus was associated with a 10-fold decrease in the foraging aggressiveness of spiders toward prey in their web. Since bacterial exposure did not have survival consequences for hosts, these data suggest that interactions with cuticular bacteria, even non-pathogenic bacteria, could alter host behavior.

Epilepsy is one of the most common neurological disorders with about 500 genes thought to be involved across the phenotypic spectrum (Busch et al. 2014; Ran et al. 2014), which includes monogenic, multigenic, epistatic and pleiotropic phenotype manifestations (Busch et al. 2014; Thomas et al. 2014), driving the need for a comprehensive diagnostic test. Next-generation sequencing (NGS) allows for the simultaneous investigation of a large number of genes, making it a very attractive option for a condition as diverse as epilepsy at a low cost compared to traditional Sanger sequencing (Lemke et al. 2012; Németh et al. 2013). Our 377 gene epilepsy NGS test was developed to include genes known to cause or have published association with epilepsy and seizure-related disorders. Given the scale of information that is generated, the efficacy of an NGS panel depends on a number of factors, including the genes present on the panel, prebioinformatic and postbioinformatic analysis protocols, as well as reporting criteria, prompting the current study, a retrospective analysis of 305 cases tested for the epilepsy panel.

Clinical inertia is a widespread reason for suboptimal control of patients with diabetes (DM). One approach to addressing clinical inertia is to include non-physician providers in DM management. Evidence suggests that intervention by pharmacists improves glycemic control more than usual care. There is little data, however, on the effect of pharmacist care delivered by phone as an adjunct to DM care provided by an Endocrinologist. We conducted a retrospective analysis to assess the effect of phone-based DM management by a Doctor of Pharmacy (PharmD) on glycemic control among patients seen by an Endocrinologist. Between 02/2018-12/2018, 65 adult DM patients were referred by their Endocrinologists to a PharmD for phone intervention at an urban academic medical center. The intervention included medication reconciliation, education on medication self-administration, coordination with pharmacies to dispense medications, and adjustment of DM medications. A total of 41 patients (INT) received 1+ intervention phone call (median [iQR] 3 [2-5] calls), and 24 patients (NoINT) were referred but could not be contacted (n=20) or required no intervention (n=4). At baseline, all INT patients and 96% of NoINT patients were on insulin, 41% and 21% were on a GLP-1RA, and 56% and 46% were on oral medication(s). In the INT group, mean A1C decreased significantly 1.9 ± 2.2% from 10.2 ± 2.4% before the first call to 8.3 ± 1.7% (p Phone-based DM management of Endocrinology patients by a PharmD may lead to better glycemic control than management by an Endocrinologist alone. These data should encourage the conduct of an RCT to test this promising strategy for addressing clinical inertia in DM patients. Disclosure D.J. Rubin: Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc. J. Wu: None. D. Patel: None. U. Hajari: None. M. Barros: None.

Hereditary diffuse gastric cancer (HDGC) syndrome results from a germline CDH1 mutation, and microscopic foci of signet-ring carcinoma cells (SRCC) are present in nearly all gastrectomy specimens.1 The lifetime risk of invasive gastric cancer (GC) has been thought to be 70%,2 but recent data have suggested a lower risk of 37%.3 Prophylactic total gastrectomy is considered the standard of care, but many patients choose surveillance endoscopy instead. We sought to define the outcomes in CDH1-positive individuals who pursued endoscopic surveillance.

Background The study of DNA methylation quantitative trait loci (meQTLs) helps dissect regulatory mechanisms underlying genetic associations of human diseases. In this study, we conducted the first genome-wide examination of genetic drivers of methylation variation in response to a triglyceride-lowering treatment with fenofibrate (response-meQTL) by using an efficient analytic approach. Methods Subjects (n = 429) from the GAW20 real data set with genotype and both pre- (visit 2) and post- (visit 4) fenofibrate treatment methylation measurements were included. Following the quality control steps of removing certain cytosine-phosphate-guanine (CpG) probes, the post−/premethylation changes (post/pre) were log transformed and the association was performed on 208,449 CpG sites. An additive linear mixed-effects model was used to test the association between each CpG probe and single nucleotide polymorphisms (SNPs) around ±1 Mb region, with age, sex, smoke, batch effect, and principal components included as covariates. Bonferroni correction was applied to define the significance threshold (p 0.8) with rs7443270, which was previously reported to be associated with fenofibrate response (p = 5.00 × 10− 6). Conclusions By using a novel analytic approach, we efficiently identified thousands of cis re-meQTLs that provide a unique resource for further characterizing functional roles and gene targets of the SNPs that are most responsive to fenofibrate treatment. Our efficient analytic approach can be extended to large response quantitative trait locus studies with large sample sizes and multiple time points data.

The current practice of cancer genetic counseling is undergoing widespread change and scrutiny. While there are clinical resources for genetic counselors (GCs) regarding the delivery of cancer genetic services, there is limited literature regarding effective management of a genetic counseling clinical program. We have developed administrative tools to manage a large team of GCs at a single academic medical center over a period of increasing demand for genetics services, with the initial aim of decreasing wait time for urgent genetic counseling visits. Here, we describe the three main elements of the clinical operations: Balancing patient volume between GCs, scheduling tracks for both routine and urgent appointments, and a team of triaging GCs to ensure appropriate patient referrals. For each of these elements, we describe how they have been modified over time and present data to support the utility of these strategies. The preliminary evidence offered here suggests that these tools allow for an equitable distribution of patient volume between team members, as well as the timely and accurate scheduling of urgent patients. As a result of the experiences presented here, other genetic counseling programs grappling with similar issues should be aware that it is possible to shift clinical operations to serve certain patient populations in a more timely fashion while keeping both providers and GC staff satisfied.

Key Points Question Can rare genetic variants for Alzheimer disease be identified using nonstatistical approaches? Findings In this genetic association study, variants with high functional effect were observed in participants with Alzheimer disease but not in controls in NOTCH3, a gene previously associated with cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), and TREM2 (Q33X) that in homozygous form causes Nasu-Hakola disease. Meaning Different mutations in the same gene or variable dose of a particular mutation may be associated with dissimilar types of dementia., Importance Some of the unexplained heritability of Alzheimer disease (AD) may be due to rare variants whose effects are not captured in genome-wide association studies because very large samples are needed to observe statistically significant associations. Objective To identify genetic variants associated with AD risk using a nonstatistical approach. Design, Setting, and Participants Genetic association study in which rare variants were identified by whole-exome sequencing in unrelated individuals of European ancestry from the Alzheimer’s Disease Sequencing Project (ADSP). Data were analyzed between March 2017 and September 2018. Main Outcomes and Measures Minor alleles genome-wide and in 95 genes previously associated with AD, AD-related traits, or other dementias were tabulated and filtered for predicted functional impact and occurrence in participants with AD but not controls. Support for several findings was sought in a whole-exome sequencing data set comprising 19 affected relative pairs from Utah high-risk pedigrees and whole-genome sequencing data sets from the ADSP and Alzheimer’s Disease Neuroimaging Initiative. Results Among 5617 participants with AD (3202 [57.0%] women; mean [SD] age, 76.4 [9.3] years) and 4594 controls (2719 [59.0%] women; mean [SD] age, 86.5 [4.5] years), a total of 24 variants with moderate or high functional impact from 19 genes were observed in 10 or more participants with AD but not in controls. These variants included a missense mutation (rs149307620 [p.A284T], n = 10) in NOTCH3, a gene in which coding mutations are associated with cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), that was also identified in 1 participant with AD and 1 participant with mild cognitive impairment in the whole genome sequencing data sets. Four participants with AD carried the TREM2 rs104894002 (p.Q33X) high-impact mutation that, in homozygous form, causes Nasu-Hakola disease, a rare disorder characterized by early-onset dementia and multifocal bone cysts, suggesting an intermediate inheritance model for the mutation. Compared with controls, participants with AD had a significantly higher burden of deleterious rare coding variants in dementia-associated genes (2314 vs 3354 cumulative variants, respectively; P = .006). Conclusions and Relevance Different mutations in the same gene or variable dose of a mutation may be associated with result in distinct dementias. These findings suggest that minor differences in the structure or amount of protein may be associated with in different clinical outcomes. Understanding these genotype-phenotype associations may provide further insight into the pathogenic nature of the mutations, as well as offer clues for developing new therapeutic targets., This genetic association study uses whole-exome sequencing to identify genetic variants associated with the risk of Alzheimer disease in Alzheimer’s Disease Sequencing Project participants of European ancestry.

The management of hereditary diffuse-type gastric cancer revolves around surveillance biopsies and the timing of prophylactic gastrectomy. In the absence of a validated surveillance biopsy protocol, we modeled bioptic diagnostic yield on the basis of the topographic distribution of cancer foci in a series of 10 gastrectomies in CDH1-mutation carriers. Complete histologic examination was performed in all cases, and 1817 slides were evaluated for the presence of in situ, intramucosal, or submucosal diffuse-type carcinoma. Detailed maps determined the density of cancer foci. On the basis of the number of sampled glands per biopsy in routine surveillance preoperative endoscopy, we estimated the theoretical number of biopsies necessary for a 90% rate of detection of neoplastic foci, and we evaluated this number, taking into account the regional distribution of these foci. A total of 96 m of gastric mucosa with ≈ 1,193,453 gastric glands yielded 302 cancer foci [in situ (n=89), intramucosal (n=209), and submucosal (n=4)] spanning the width of a total of 1820 glands (8 to 1205 per case; average 182 ± 115). On the basis of the number of glands per stomach and the average number of glands sampled during surveillance biopsy (28.7 ± 1.7; range, 0 to 79; n=112), the theoretical number of biopsies necessary to capture at least 1 cancer focus was estimated to be 1768 (range, 50 to 5832) to assure a 90% detection rate. Mapping of cancer foci showed the highest density in the anterior proximal fundus (37%) and cardia/proximal fundus (27%). Our results argue for the incorporation of cancer focus distribution into any biopsy protocol, although detection is likely to remain extremely low, and they call into question the validity of endoscopic surveillance.

Deleterious mutations in BRCA1 and BRCA2 include those identified by sequencing technology as well as large genomic rearrangements (LGR). The main testing laboratory in the United States, Myriad Genetics Laboratory (MGL), has defined criteria for inclusion of LGR testing (i.e., BRACAnalysis Rearrangement Test, or BART™) when BRCA1 and BRCA2 testing is ordered. We were interested in determining how many of our patients with LGR mutations in BRCA1 and BRCA2 fulfilled these MGL criteria. A retrospective chart review was performed on all individuals who underwent genetic testing at our institution since August 2006. Individuals who underwent LGR testing were classified as either having or not having a LGR in BRCA1 or BRCA2. Each individual's history was classified as meeting MGL defined LGR criteria, meeting criteria using third-degree relatives, or not meeting criteria. A total of 257 BART tests were ordered at our institution from August 2006 to August 2009. Five individuals (1.9%) had an LGR mutation. Two LGR were identified in patients who met MGL defined LGR criteria. One LGR was identified in a patient that met MGL defined LGR criteria only when using third-degree relatives. Two LGR were identified in individuals who did not meet MGL defined criteria. LGR are present in individuals who do not have a high pretest probability of carrying a mutation in BRCA1 or BRCA2. These data suggest that when BRCA1 and BRCA2 genetic testing is performed, testing should always include LGR testing so that the results are the most comprehensive and reliable.

Background Germline mutation of the CDH1 gene, which encodes for the E-cadherin adhesion protein, is rare but confers an estimated lifetime risk of hereditary diffuse gastric cancer of 87%. Fewer than 100 prophylactic total gastrectomies have been reported for this condition. Methods Patients with germline CDH1 mutation who underwent multidisciplinary counseling followed by prophylactic total gastrectomy were reviewed. Results Ten patients (6 male, 4 female) with a median age of 42 years (range, 26–51) underwent prophylactic total gastrectomy between 2006 and 2009. Of the 6 families represented, there were 4 missense, 1 frameshift, and 1 splice site mutation. Median time from genetic testing to surgery was 3 months (range, 1–7). All patients had an upper endoscopy before surgery, identifying only 1 patient with a focus of diffuse gastric cancer. After prophylactic total gastrectomy, extensive pathologic analysis demonstrated that 9 patients had up to 77 foci of noninvasive cancer, and 2 of these patients had 4–12 foci of T1 invasive cancer. Median operative time was 213 minutes; there were no anastomotic leaks, and the length of stay was 7–8 days. One patient had a complication within 30 days (pulmonary embolism), and 3 patients had late complications (2 small bowel obstructions and 1 anastomotic stricture). Median weight loss at 6 months was 19%. Conclusion The majority of patients with germline CDH1 mutation have foci of noninvasive or invasive gastric cancer by middle age. Serial upper endoscopies provide inadequate screening. Prophylactic total gastrectomy is the procedure of choice for definitive treatment.

In the genetic counseling setting, the health care provider can be challenged by opposing duties to members of the same family: protecting the privacy of the patient identified with a gene mutation and the ethical obligation to warn at-risk relatives. In a situation of nondisclosure between members of a family with a known disease-predisposing mutation, this type of dilemma can present in acute form for the provider who cares for different members of the family. This can hinder effective medical decision making. To minimize this effect, we recommend detailed pretest genetic counseling steps to empower the patient to communicate with their at-risk relatives their intent to pursue testing and willingness to share information. In addition, post-test counseling should reiterate the implications of a positive result for at-risk relatives and conclude with a written summary that patients can share with their family.

A 38-year-old woman came to the Gastrointestinal Cancer Genetics Clinic of this hospital because of a family history of breast and gastric cancer. Her mother had died of gastric cancer, and her maternal aunt had bilateral breast cancer and died of gastric cancer. Screening upper gastrointestinal endoscopy had been negative in the patient. A diagnostic procedure was performed.

Families that have several relatives with melanoma, multiple primary melanomas in one individual, younger than average ages of melanoma onset, and/or the presence of both pancreatic cancer and melanoma may be suggestive of a hereditary melanoma syndrome and are candidates for genetic counseling and risk assessment. Genetic counseling for hereditary melanoma presents many complexities. Only a minority of hereditary melanoma cases have been attributed to a single genetic factor, CDKN2A. Both the frequency and the penetrance of CDKN2A mutations has been shown to be dependent on multiple factors. The clinical utility of genetic testing for hereditary melanoma families is debatable because CDKN2A status may not impact medical management in patients with melanoma. No standard medical management guidelines exist for families with CDKN2A mutations; however, family history of melanoma and pancreatic cancer may warrant further discussion. Clinicians should discuss the clinical and psychological implications before genetic testing. Genetic counseling and pretest education regarding melanoma risk factors provides an opportunity to increase knowledge and understanding of melanoma risk, while addressing psychological risks and concerns.

Although only 5–10% of all cases of cancer are attributable to a highly penetrant cancer predisposition gene, the identification of individuals at inherited risk for cancer has become an integral part of the practice of predictive and preventative medicine. Identifying those individuals with a significantly higher risk of developing specific cancers allows health-care providers to intervene with appropriate counseling and education, increased cancer surveillance, and sometimes even cancer prevention. This chapter focuses on the identification of patients at high risk for cancer and the importance of referral to genetic counselors and other genetics professionals. The chapter also discusses the intricacies surrounding genetic testing, including the ethical, legal, and social implications of identifying those at increased risk for cancer.

Personalized cancer risk assessment remains an essential imperative in postgenomic cancer medicine. In hereditary melanoma, germline CDKN2A mutations have been reproducibly identified in melanoma-prone kindreds worldwide. However, genetic risk counseling for hereditary melanoma remains clinically challenging. To address this challenge, we developed and validated MelaPRO, an algorithm that provides germline CDKN2A mutation probabilities and melanoma risk to individuals from melanoma-prone families. MelaPRO builds on comprehensive genetic information, and uses Mendelian modeling to provide fine resolution and high accuracy. In an independent validation of 195 individuals from 167 families, MelaPRO exhibited good discrimination with a concordance index (C) of 0.86 [95% confidence intervals (95% CI), 0.75–0.97] and good calibration, with no significant difference between observed and predicted carriers (26; 95% CI, 20–35, as compared with 22 observed). In cross-validation, MelaPRO outperformed the existing predictive model MELPREDICT (C, 0.82; 95% CI, 0.61–0.93), with a difference of 0.05 (95% CI, 0.007–0.17). MelaPRO is a clinically accessible tool that can effectively provide personalized risk counseling for all members of hereditary melanoma families. Cancer Res; 70(2); 552–9