A mutagenesis study of autoantigen optimization for potential T1D vaccine design.

A previously reported autoreactive antigen, termed the X-idiotype, isolated from a unique cell population in Type 1 diabetes (T1D) patients, was found to stimulate their CD4+ T cells. This antigen was previously determined to bind more favorably than insulin and its mimic (insulin superagonist) to HLA-DQ8, supporting its strong role in CD4+ T cell activation. In this work, we probed HLA-X-idiotype-TCR binding and designed enhanced-reactive pHLA-TCR antigens using an in silico mutagenesis approach which we functionally validated by cell proliferation assays and flow cytometry. From a combination of single, double, and swap mutations, we identified antigen-binding sites p4 and p6 as potential mutation sites for HLA binding affinity enhancement. Site p6 is revealed to favor smaller but more hydrophobic residues than the native tyrosine, such as valine (Y6V) and isoleucine (Y6I), indicating a steric mechanism in binding affinity improvement. Meanwhile, site p4 methionine mutation to hydrophobic residues isoleucine (M4I) or leucine (M4L) modestly increases HLA binding affinity. Select p6 mutations to cysteine (Y6C) or isoleucine (Y6I) exhibit favorable TCR binding affinities, while a swap p5-p6 tyrosine-valine double mutant (V5Y_Y6V) and a p6-p7 glutamine-glutamine double mutant (Y6Q_Y7Q) exhibit enhanced HLA binding affinity but weakened TCR affinity. This work holds relevance to potential T1D antigen-based vaccine design and optimization.

Genotypic distribution of human papillomavirus and phylogenetic analysis of E6 and E7 gene of HR-HPV variants isolated from Pakistani population.

High-risk-human papillomavirus (HR-HPV)-induced cervical cancer is the second most common cause of death among females worldwide. HPV16 is the most prevalent HR-HPV infection worldwide. This study found the genotypic distribution of HR-HPV in the local population and investigated the sequence variations among the E6 and E7 oncogenes of the local HPV16 genotype to the E6 and E7 oncogenes of the foreign HPV16 genotypes and constructed a phylogenetic relationship based on nucleotide sequence comparison among the variants identified in our study along with previously reported isolates that were obtained from different regions of the world. The samples were collected from patients with cervical cancer. Genomic DNA was extracted, and HR-HPV genotypes were determined using real-time PCR. The HPV16 E6 and E7 genes were amplified and sequenced. A HPV16 phylogenetic tree was constructed using the maximum likelihood method with MEGA 7. HPV16 was the most prevalent human papillomavirus (HPV) type identified in the present study. HPV16 isolates belonged to the A1 sublineage of the European branch. Twenty-one nucleotide sequences were included in this analysis. The first, second, and third codon positions are also included. The final dataset included 776 positions.

Association of Cardiovascular Disease Risk Factors with Exclusive Smokeless Tobacco Use among US Males: Cross-Sectional Analysis of NHANES Data 2003-2018.

PURPOSE: To evaluate cardiovascular disease (CVD) risk factors among smokeless tobacco (ST) users. Exclusive ST users were compared to exclusive cigarette smokers and non-tobacco users. DESIGN: Cross-sectional study. SAMPLE: Data were used from 16,336 adult males who participated in one of the National Health and Nutrition Examination Surveys (NHANES) from 2003 to 2018. MEASURES: Biochemically verified tobacco use, CVD risk factors (hypertension, cholesterol levels, BMI categories), physical activity, cotinine concentration, and sociodemographic variables. ANALYSIS: Weighted analysis of the aggregate data was performed. ST users were compared with cigarette smokers and nontobacco users for their association with CVD risk factors. Associations were examined using univariate and multiple logistic regression with odds ratios (OR) and 95% confidence intervals (CI) reported. RESULTS: Prevalence of exclusive ST use was 4.4% whereas, exclusive smoking was 22.2%. Among ST users, 36.2% were hypertensive, 24.5% had high cholesterol levels, and most of them were overweight (31.1%) or obese (52.6%). ST users were more likely to have hypertension compared to smokers (aOR = 1.48, 95%CI: 1.12, 1.95) and nontobacco users (aOR = 1.41, 95%CI: 1.09, 1.83) adjusted for other covariates. ST users were twice more likely to be obese than nontobacco users (aOR = 2.18, 95%CI: 1.52, 3.11). ST users had significantly higher cotinine concentration than smokers. CONCLUSION: Study findings indicate substantial association of ST use among males with hypertension and obesity which are independent risk factors of CVD.

Measurement of malignant spiculated mass lesions on mammogram: Do we include the length of the spicules?

AIM: The aim of this study is to determine if the core size or size with spicules has a better correlation with the final histologic size of spiculated mass lesions. METHODS: A retrospective study of 48-month duration from January 2014 to December 2017 of biopsy-proven invasive ductal carcinoma presenting as spiculated mass lesions on mammogram was conducted. RESULTS: There were 195 patients in the study. The mean of the core size was 16.6 mm; when spicules were included the mean size was 27.4mm and final histologic size 21.1 mm. Using unpaired Student 't' test difference in the means was statistically significant (p<0.0001). Pearson number (R) core size versus final histologic size was 0.535 (P < 0.001) and for size with spicules versus final histologic size was 0.495 (P < 0.001). CONCLUSION: Our study demonstrated that the core size has a stronger positive correlation to final histologic size and should be used preoperatively in decision-making about surgery.

Skeletal Fluorosis: A Case of Inhalant Abuse Leading to a Diagnosis of Colon Cancer.

Skeletal fluorosis is a long-term bone disease that develops when prolonged fluoride toxicity leads to osteosclerosis and bone deformities that result in crippling pain and debility. The disease is endemic to many countries due to environmental or industrial exposures. However, rare cases in the United States have been reported from various causes including heavy toothpaste ingestion, excessive tea consumption, voriconazole use, and inhalant abuse. Here, we present a case of a 41-year-old man who presented for weight loss and severe joint pains due to bony sclerotic lesions found on X-rays. Social history revealed that he had been recreationally inhaling compressed air dusters used for cleaning electronics. Owing to concern for malignancy, he underwent an extensive work-up which led to a diagnosis of colon cancer, but positron emission tomography/computed tomography (PET/CT) and bone biopsy were unexpectedly negative for metastatic bone disease. Further characterization of his lesions by skeletal survey led to a diagnosis of skeletal fluorosis secondary to inhalant abuse. As in this patient, the disease can be difficult for clinicians to recognize as it can be mistaken for various boney diseases such as metastatic cancer. However, once there is clinical suspicion for skeletal fluorosis, various tests to help confirm the diagnosis can include serum and urine fluoride levels, skeletal survey, and bone ash fluoride concentration. Treatment of skeletal fluorosis primarily involves cessation of fluoride exposure, and recovery can take years. Ultimately, further study is required to develop recommendations and guidelines for diagnosis, management, and prognosis of the disease in the United States.

Male Triple-Negative Breast Cancer.

Male breast cancer is a rarely encountered disease, when compared with female breast cancer, often detected in more advanced stage at the time of diagnosis, and associated with more lymph node metastasis rates, more estrogen receptors positivity, and less human epidermal growth factor receptor-2 expression (HER-2) rates. Surgical management also shows some difference, where the most common operative technique of male breast cancer patients is mastectomy and/or axillary surgery. Triple-negative breast cancer is less frequent than other subtypes and is associated with poorer prognosis. This is because of its association with higher histopathological grade than that in other types of breast cancer. Only fewer treatment options are available compared to hormone-positive, HER-2 positive breast cancer. We are present a case of 71-year-old gentleman with triple-negative breast cancer.

Surface modified multifaceted nanocarriers for oral non-conventional cancer therapy; synthesis and evaluation.

Inflammatory cells orchestrate tumor niche for the proliferating neoplastic cells, leading to neoangiogenesis, lymphangiogenesis, tumor growth and metastasis. Emergence of severe side effects, multiple drug resistance and associated high cost has rendered conventional chemotherapy less effectual. The aim was to develop a multipurpose, less toxic, more potent and cheaper, oral non-conventional anticancer therapeutic. Cyclooxygenase associated with tumor niche inflammation and proliferative neoplastic cells were targeted synergistically, through anti-inflammatory and anti-proliferative effects of model drug, diclofenac sodium and fluorescent silver nanoparticles (AgNPs), respectively. Drug entrapped AgNPs were surface modified with PVA (for controlling particle size, preferred cellular uptake, evading opsonization and improved dispersion). XRD, FTIR, DSC, TGA, LIBS, particle size and surface plasmon resonance analysis confirmed the efficient drug encapsulation and PVA coating with 62% loading efficiency. In-vitro, the formulation exhibited 1st order release kinetics with sustained and maximal release at slightly acidic conditions (pH 4.5) enabling the potential for passive tumor targeting. Also, nanoparticles showed efficient protein denaturation inhibition potential, hemo-compatibility (<0.8%) and potent anti-cancer activity (P < 0.05) against breast cancer cell line (MCF-7). In-vivo, developed nanoparticles improved pharmacokinetics (2.8 fold increased AUC, 6.9 h t1/2, Cmax = 1.6 ±â€¯0.03 µg/ml, Kel = 0.1) and pharmacodynamics manifested by potent anti-inflammatory, analgesic and anti-pyretic effects (P < 0.05) at 20 fold lower doses. LD50 determination revealed a wide therapeutic window. The study showed promise of synthesized nanomaterials as cheaper, less toxic, hemo-compatible, oral and more potent anti-inflammatory and non-conventional fluorescent anti-cancer agents, vanquishing tumor niche inflammation and repressing proliferation of malignant cells.

Removal of Radioactive Iodine Using Silver/Iron Oxide Composite Nanoadsorbents.

Efficient and cost-effective removal of radioactive iodine (radioiodine) from radioactive contaminated water has become a crucial task, following nuclear power plant disasters. Several materials for removing radioiodine have been reported in the literature. However, most of these materials exhibit some limitations, such as high production cost, slow adsorption kinetics, and poor adsorption capacity. Herein, we present silver/iron oxide nanocomposites (Ag/Fe3O4) for the efficient and specific removal of iodine anions from contaminated water. The Ag/Fe3O4 were synthesized using a modified method and characterized via scanning electron microscopy, transmission electron microscopy, and X-ray diffraction analyses. This adsorbent showed a high adsorption capacity for iodine anions (847 mg/g of the adsorbent) in pure water. Next, Ag/Fe3O4 was applied to the removal of radioiodine, and high removal efficiencies were observed in water. In addition, its desalination capacity was retained in the presence of competitive ions and varied pH. After the adsorption process, Ag/Fe3O4 was easily removed from the water by applying an external magnetic field. Moreover, the same operation can be repeated several times without a significant decrease in the performance of Ag/Fe3O4. Therefore, it is expected that the findings presented in this study will offer a new method for desalinating radioiodine in various aqueous media.

The Association Between Preoperative Opioid Exposure and Prolonged Postoperative Use.

OBJECTIVE: To determine the effect of nonchronic, periodic preoperative opioid use on prolonged opioid fills after surgery. BACKGROUND: Nonchronic, periodic opioid use is common, but its effect on prolonged postoperative opioid fills is not well understood. We hypothesize greater periodic opioid use before surgery is correlated with persistent postoperative use. METHODS: We used a national private insurance claims database, Optum's de-identifed Clinformatics Data Mart Database, to identify adults undergoing general, gynecologic, and urologic surgical procedures between 2008 and 2015 (N = 191,043). We described patterns of opioid fills based on dose, recency, duration, and continuity to categorize preoperative opioid exposure. Patients with chronic use were excluded. Our primary outcome was persistent postoperative use, defined as filling an opioid prescription between 91- and 180-days post-discharge. The association between preoperative opioid use and persistent use was determined using multivariable logistic regression, controlling for clinical covariates. RESULTS: In the year before surgery, 41% of patients had nonchronic, periodic opioid fills. Compared with other risk factors, patterns of preoperative fills were most strongly correlated with persistent postoperative opioid use. Patients with recent intermittent use were significantly more likely to have prolonged fills after surgery compared with opioid-naïve patients [minimal use: odds ratio (OR): 2.0, 95% confidence interval (CI) 1.89-2.03; remote intermittent: OR 4.7, 95% CI 4.46-4.93; recent intermittent: OR 12.2, 95% CI 11.49-12.90]. CONCLUSIONS: Patients with nonchronic, periodic opioid use before surgery are vulnerable to persistent postoperative opioid use. Identifying opioid use before surgery is a critical opportunity to optimize care after surgery.

The electron affinity of astatine.

One of the most important properties influencing the chemical behavior of an element is the electron affinity (EA). Among the remaining elements with unknown EA is astatine, where one of its isotopes, 211At, is remarkably well suited for targeted radionuclide therapy of cancer. With the At- anion being involved in many aspects of current astatine labeling protocols, the knowledge of the electron affinity of this element is of prime importance. Here we report the measured value of the EA of astatine to be 2.41578(7) eV. This result is compared to state-of-the-art relativistic quantum mechanical calculations that incorporate both the Breit and the quantum electrodynamics (QED) corrections and the electron-electron correlation effects on the highest level that can be currently achieved for many-electron systems. The developed technique of laser-photodetachment spectroscopy of radioisotopes opens the path for future EA measurements of other radioelements such as polonium, and eventually super-heavy elements.

Phytochemical screening and enzymatic and antioxidant activities of Erythrina suberosa (Roxb) bark.

BACKGROUND: This study aimed to evaluate the phytochemicals screening of Erythrina suberosa (Roxb) bark and to analyze the enzymatic activities of its various organic fractions. MATERIALS AND METHODS: Crude methanolic fraction of E. suberosa (Roxb) bark and its respective fractions were screened for the presence of different phytochemicals with different reagents. On the basis of increasing order of polarity, different organic solvents were used to obtain different fractions. Enzymatic studies were performed on crude methanolic extract of the plant. All the assays were performed under standard in vitro conditions. RESULTS: The phytochemical analysis shows the presence of alkaloids, phenols, triterpenoids, phytosterols, and flavonoids. Phenolic compounds and flavonoids are the major constituents of the plant. In anticholinesterase assay, the percent inhibition of standard drug (eserine) was 91.27 ± 1.17 and the half maximal inhibitory concentration (IC50) was 0.04 ± 0.0001. For α-glucosidase inhibition, the IC50 value for Dichloromethane fraction was 8.45 ± 0.13, for Methanol fraction it was 64.24 ± 0.15, and for aqueous fraction it was 42.62 ± 0.17 as compared with standard IC50 that is 37.42 (acarbose). Furthermore, results show that all fractions have potential against anti-urease enzyme, but DCM fraction of crude aqueous extract has significant IC50 value (45.26 ± 0.13) than other fractions. CONCLUSION: Keeping in view all the results, it is evident that the plant can be used in future for formulating effective drugs against many ailments. Secondary metabolites and their derivatives possess different biological activities, for example, .g. flavonoids in cancer, asthma, and Alzheimer. Furthermore, the extracts of this plant can be used in their crude form, which is an addition to the complementary and alternative treatment strategies.

A Public BCR Present in a Unique Dual-Receptor-Expressing Lymphocyte from Type 1 Diabetes Patients Encodes a Potent T Cell Autoantigen.

T and B cells are the two known lineages of adaptive immune cells. Here, we describe a previously unknown lymphocyte that is a dual expresser (DE) of TCR and BCR and key lineage markers of both B and T cells. In type 1 diabetes (T1D), DEs are predominated by one clonotype that encodes a potent CD4 T cell autoantigen in its antigen binding site. Molecular dynamics simulations revealed that this peptide has an optimal binding register for diabetogenic HLA-DQ8. In concordance, a synthetic version of the peptide forms stable DQ8 complexes and potently stimulates autoreactive CD4 T cells from T1D patients, but not healthy controls. Moreover, mAbs bearing this clonotype are autoreactive against CD4 T cells and inhibit insulin tetramer binding to CD4 T cells. Thus, compartmentalization of adaptive immune cells into T and B cells is not absolute, and violators of this paradigm are likely key drivers of autoimmune diseases.

Complicated coarctation repair: The importance of three-dimensional cross-sectional imaging in late postoperative assessment.

Coarctation of the aorta (CoA) represents 5%-8% of congenital heart disease patients and is one of the most common causes of neonatal surgical intervention. These patients require close lifelong follow-up due to frequent long-term complications. Although transthoracic echocardiography is the first-line technique for its diagnosis and follow-up, cross-sectional imaging with cardiovascular magnetic resonance (CMR) gives excellent anatomical and functional information, especially in complex CoA. We present the case of a 17-year-old patient who underwent complicated neonatal CoA repair and demonstrate how CMR and thorough operative records helped to define the exact anatomy of repair many years after surgery. Furthermore, we conclude that keeping surgical drawings in the patient records can be of great importance, especially in complicated cases.

Use of Gabapentin in the Treatment of Substance Use and Psychiatric Disorders: A Systematic Review.

Objective: Gabapentin (GBP) is an anticonvulsant medication that is also used to treat restless legs syndrome (RLS) and posttherapeutic neuralgia. GBP is commonly prescribed off-label for psychiatric disorders despite the lack of strong evidence. However, there is growing evidence that GBP may be effective and clinically beneficial in both psychiatric disorders and substance use disorders. This review aimed to perform a systematic analysis of peer-reviewed published literature on the efficacy of GBP in the treatment of psychiatric disorders and substance use disorders. Methods: This review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The PubMed and Ovid MEDLINE literature databases were screened and filtered by using specific search terms and inclusion/exclusion criteria. The full texts of selected studies were subsequently retrieved and reviewed. The search terms generated 2,604 results from the databases. After excluding all duplicates, 1,088 citations were left. Thereafter, we applied inclusion and exclusion criteria; a total of 54 papers were retained for detailed review. Results: This literature review concludes that GBP appears to be effective in the treatment of various forms of anxiety disorders. It shows some effectiveness in bipolar disorder as an adjunctive therapeutic agent, while the evidence for monotherapy is inconclusive. In substance use disorders, GBP is effective for acute alcohol withdrawal syndrome (AWS) with mild to moderate severity; it reduces cravings, improves the rate of abstinence, and delays return to heavy drinking. GBP may have some therapeutic potential in the treatment of opioid addiction and cannabis dependence, but there is limited evidence to support its use. No significant benefit of GBP has been conclusively observed in the treatment of OCD, PTSD, depression, or cocaine and amphetamine abuse. Conclusion: GBP appears to be effective in some forms of anxiety disorders such as preoperative anxiety, anxiety in breast cancer survivors, and social phobia. GBP has shown to be safe and effective in the treatment of alcohol dependence. However, the literature suggests that GBP is effective as an adjunctive medication rather than a monotherapy. More clinical trials with larger patient populations are needed to support gabapentin's off-label use in psychiatric disorders and substance use disorders. It is worth noting that numerous clinical studies that are discussed in this review are open-label trials, which are inherently less rigorously analyzed. Therefore, more extensive investigations are required to examine not only the efficacy of GBP, but also its safety and tolerance.

Efficacy and Safety of Varenicline for Smoking Cessation in Schizophrenia: A Meta-Analysis.

Objective: Smoking represents a major public health problem among patients with schizophrenia. To this end, some studies have investigated the efficacy of varenicline for facilitating smoking cessation in schizophrenia patients. The present review seeks to synthesize the results of these studies as well as document the reported side effects of using this medication. Methods: An electronic search was performed using five major databases: PubMed, Scopus, EMBASE, Web of Science, and Cochrane Library. Included in the current analysis were randomized clinical trials (RCTs) that have investigated the effect of varenicline in promoting smoking cessation in patients with schizophrenia. Risk of bias among included RCTs was assessed using the Cochrane Collaboration's quality assessment tool. Results: Among the 828 screened articles, only four RCTs, which involved 239 participants, were eligible for meta-analysis. In patients with schizophrenia, varenicline treatment when compared to placebo significantly reduced the number of cigarettes consumed per day [SMD (95% CI) = 0.89(0.57-1.22)] and expired carbon monoxide levels [SMD (95% CI) = 0.50 (0.06-0.94)] respectively. Conclusion: Despite a limited number of studies included in the meta-analysis, our results suggest that varenicline is an effective and safe drug to assist smoking cessation in patients with schizophrenia. Future large-scale well-designed RCTs are required to validate these findings.

The Accuracy of Conflict-of-Interest Disclosures Reported by Plastic Surgeons and Industry.

BACKGROUND: The purpose of this study was to analyze the frequency and nature of self-reported conflict-of-interest disclosures in the plastic surgery literature and to compare these findings to the Physician Payments Sunshine Act database. METHODS: All articles published from August of 2013 through December of 2013 in four major plastic surgery journals were analyzed. For every publication, the conflict-of-interest disclosure statement for each investigator was reviewed. These statements were then compared to transactions of value for each investigator as reported by biomedical companies in the Sunshine Act database. An analysis was performed to identify and characterize specific factors associated with conflict-of-interest disclosures. RESULTS: A total of 1002 independent investigators/authors were identified. Of these, 90 investigators (9 percent) self-reported a conflict of interest. In contrast, a total of 428 authors (42.7 percent) were found to have received transactions of value from a biomedical company according to the Sunshine Act database. Conversely, a total of 22 authors (2.2 percent) self-reported a conflict of interest but were not found to have received transactions of value in the Sunshine Act database. Our analysis found that (1) academic investigators, (2) transactions of value in excess of $500, and (3) publishing articles related to the sponsoring biomedical company were all statistically associated with reporting conflicts of interest (p < 0.0001). CONCLUSIONS: Discordance exists between investigator/authors self-reporting in scientific journals and the government-mandated reporting of conflicts of interest by industry. Factors associated with conflict-of-interest disclosure include academic status, transaction amount, and article content related to the sponsoring biomedical company.

The Dawn of Transparency: Insights from the Physician Payment Sunshine Act in Plastic Surgery.

BACKGROUND: The Physician Payments Sunshine Act (PSSA) is a government initiative that requires all biomedical companies to publicly disclose payments to physicians through the Open Payments Program (OPP). The goal of this study was to use the OPP database and evaluate all nonresearch-related financial transactions between plastic surgeons and biomedical companies. METHODS: Using the first wave of OPP data published on September 30, 2014, we studied the national distribution of industry payments made to plastic surgeons during a 5-month period. We explored whether a plastic surgeon's scientific productivity (as determined by their h-index), practice setting (private versus academic), geographic location, and subspecialty were associated with payment amount. RESULTS: Plastic surgeons (N = 4195) received a total of US $5,278,613. The median (IQR) payment to a plastic surgeon was US $115 (US $35-298); mean, US $158. The largest payment to an individual was US $341,384. The largest payment category was non-CEP speaker fees (US $1,709,930) followed by consulting fees (US $1,403,770). Plastic surgeons in private practice received higher payments per surgeon compared with surgeons in academic practice (median [IQR], US $165 [US $81-$441] vs median [IQR], US $112 [US $33-$291], rank-sum P < 0.001). Among academic plastic surgeons, a higher h-index was associated with 77% greater chance of receiving at least US $1000 in total payments (RR/10 unit h-index increase = 1.47 1.772.11, P < 0.001). This association was not seen among plastic surgeons in private practice (RR = 0.89 1.091.32, P < 0.4). CONCLUSIONS: Plastic surgeons in private practice receive higher payments from industry. Among academic plastic surgeons, higher payments were associated with higher h-indices.