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It is well recognized that chronic low-grade systemic inflammation and autoimmunity contribute to the pathogenesis of metabolic syndrome, its associated diseases (e.g. type 2 diabetes, non-alcoholic fatty liver disease) and type 1 diabetes, respectively. Consequently, anti-inflammatory agents might play a role in managing these immune associated metabolic diseases. Alpha-1 antitrypsin (AAT), an endogenous acute phase protein being used for treatment of AAT deficiency (a rare genetic disease), has multiple functions including anti-inflammatory, immunomodulatory, anti-apoptosis and cytoprotective effects. In this review, we summarized basic and clinical studies that reported potential therapeutic role of AAT in metabolic syndrome associated diseases and type 1 diabetes. Studies that demonstrated AAT had the possibility to be used as a novel biomarker to predict these immune associated metabolic diseases were also included.

Anterior cervical discectomy and fusion (ACDF) has been considered the standard treatment for degenerative cervical disc disease; however, recent trials have shown comparable outcomes with cervical disc arthroplasty (CDA). This study aimed to observe disparities in treatment paradigms of single-level cervical disc diseases and compare inpatient outcomes between procedures.A retrospective cohort of patients treated for single-level cervical disc herniation or degeneration without myelopathy was queried from the Nationwide Inpatient Sample spanning 2012-2015. Multivariate logistic regression was performed to assess the effects of demographics, temporality of admission, and hospital characteristics on odds of receiving CDA versus ACDF. Propensity-score matching was performed to compare cost, length of stay (LOS), non-home discharge, and inpatient complications.In total, 1028 CDAs and 44,374 ACDFs were performed for single-level cervical disc disease during 2012-2015. Matched comparison showed that while non-home discharges were not different between CDA and ACDF (P = 0.248), patients who received CDA had a 0.19-day shorter LOS (P0.001) and $4694 greater total cost (P0.001). There were no statistically significant differences in inpatient complication rates. Multivariate analysis showed that patients in the 26th-50th percentile, 51st-75th percentile, and 76th-100th percentile of median household income had greater odds of CDA compared with patients in the 0-25th percentile (odds ratio [OR] 1.35, P = 0.003; OR 1.31, P = 0.013; OR 1.34, P = 0.011, respectively). Patients with private insurance had greater odds of receiving CDA compared with patients on Medicare (OR 1.91, P0.001).CDA was associated with shorter LOS but greater costs compared with ACDF. Patients with greater median income and private insurance were more likely to receive CDA.

There is an urgent need to understand the functional effects of mutations in emerging variants of SARS-CoV-2. Variants of concern (alpha, beta, gamma and delta) acquired four patterns of spike glycoprotein mutations that enhance transmissibility and immune evasion: 1) mutations in the N-terminal domain (NTD), 2) mutations in the Receptor Binding Domain (RBD), 3) mutations at interchain contacts of the spike trimer, and 4) furin cleavage site mutations. Most distinguishing mutations among variants of concern are exhibited in the NTD, localized to sites of high structural flexibility. Emerging variants of interest such as mu, lambda and C.1.2 exhibit the same patterns of mutations as variants of concern. There is a strong likelihood that SARS-CoV-2 variants will continue to emerge with mutations in these defined patterns, thus providing a basis for the development of next line antiviral drugs and vaccine candidates.

There is an urgent need to identify therapies that prevent SARS-CoV-2 infection and improve the outcome of COVID-19 patients. Although repurposed drugs with favorable safety profiles could have significant benefit, widely available prevention or treatment options for COVID-19 have yet to be identified. Efforts to identify approved drugs with invitro activity against SARS-CoV-2 resulted in identification of antiviral sigma-1 receptor ligands, including antihistamines in the histamine-1 receptor binding class. We identified antihistamine candidates for repurposing by mining electronic health records of usage in population of more than 219,000 subjects tested for SARS-CoV-2. Usage of diphenhydramine, hydroxyzine and azelastine was associated with reduced incidence of SARS-CoV-2 positivity in subjects greater than age 61. We found diphenhydramine, hydroxyzine and azelastine to exhibit direct antiviral activity against SARS-CoV-2 invitro. Although mechanisms by which specific antihistamines exert antiviral effects is not clear, hydroxyzine, and possibly azelastine, bind Angiotensin Converting Enzyme-2 (ACE2) and the sigma-1 receptor as off-targets. Clinical studies are needed to measure the effectiveness of diphenhydramine, hydroxyzine and azelastine for disease prevention, for early intervention, or as adjuvant therapy for severe COVID-19.

The genetic code is the set of rules that define how information encoded in DNA is interpreted into amino acids to make proteins. With few naturally occurring exceptions, the vast majority of living organisms share the same genetic code. Recently, however, technological advances in DNA synthesis, sequencing and genome engineering are enabling the development of synthetic genomes with drastically altered genetic codes. Such comprehensive genome modifications endow these unnatural organisms with unique capabilities such as genetic isolation, virus resistance, and production of proteins with novel functionality. Here, we summarize recent efforts to develop alternative genetic codes, explore technical and biological challenges for alterations performed at whole chromosome scale, and discuss the impact of synthetic organisms for biological research and biotechnology.

This study aimed to identify small molecules that have the potential to treat alpha1-antitrypsin deficiency (AATD) by screening compounds available from a mixture-based scaffold library. 93 scaffold libraries (total diversity of >30 million compounds in mixture format) were screened using a cell model of AATD in order to identify samples that could either reduce intracellular aggregation of Z-form AAT protein, increase extracellular secretion of Z-AAT or both. Mixture libraries containing compounds with in vitro activity, for example library 1295, were screened further to identify individual active compounds. The mixture format of the scaffold library allowed for some preliminary structure-activity relationships to be developed and also enabled the rapid selection of a promising scaffold. Utilizing this scaffold, 1295, a collection of individual “control” compounds contained in the 1295 mixture sample were then screened. A sub-library of individual “control” compounds featuring structural diversity at position R1 (1295.R1), was screened and 7 compounds were found to reduce the intracellular accumulation of Z-AAT without affecting cell viability at a concentration of 25ug/ml (about 50 μM). Screening sub-libraries featuring structural diversity at R2 and R3 (1295.R2 and 1295.R3) identified an additional 15 active compounds. Titration experiments identified 3 compounds from the 1295.R2 library that retained activity at 5ug/ml (approx. 10uM). One compound (1295.263) from 1295.R2 decreased intracellular levels of Z-AAT without affecting cell viability and wild-type AAT levels at the concentration of 5ug/ml. Molecular docking of this compound to the Z-AAT crystal structure identified a potential binding site near the C-terminal domain, an identified polymerization site. Our results indicate that screening large mixture-based compound libraries can be used to identify small molecules that may have the potential to treat AATD and other disease.

All fifteen patients with HLA-A*32:01 restricted vancomycin-induced DRESS, showed negative ex vivo responses to dalbavancin however two showed cross-reactivity to teicoplanin and telavancin. Adjunctive diagnostic testing should be considered to detect potential cross-reactivity amongst glycopeptides.

Biofilm-forming Bacillus species are often involved in contamination of dairy products and therefore present a major microbiological challenge in the field of food quality and safety. In this study, we sequenced and analyzed the genomes of milk- and non-milk-derived Bacillus strains, and evaluated their biofilm-formation potential in milk. Unlike non-dairy Bacillus isolates, the dairy-associated Bacillus strains were characterized by formation of robust submerged and air-liquid interface biofilm (pellicle) during growth in milk. Moreover, genome comparison analysis revealed notable differences in putative biofilm-associated determinants between the dairy and non-dairy Bacillus isolates, which correlated with biofilm phenotype. These results suggest that biofilm formation by Bacillus species might represent a presumable adaptation strategy to the dairy environment.

Background Vancomycin is a prevalent cause of the severe hypersensitivity syndrome drug reaction with eosinophilia and systemic symptoms (DRESS), which leads to significant morbidity and mortality and commonly occurs in the setting of combination antibiotic therapy, affecting future treatment choices. Variations in HLA class I in particular have been associated with serious T cell–mediated adverse drug reactions, which has led to preventive screening strategies for some drugs. Objective We sought to determine whether variation in the HLA region is associated with vancomycin-induced DRESS. Methods Probable vancomycin-induced DRESS cases were matched 1:2 with tolerant control subjects based on sex, race, and age by using BioVU, Vanderbilt's deidentified electronic health record database. Associations between DRESS and carriage of HLA class I and II alleles were assessed by means of conditional logistic regression. An extended sample set from BioVU was used to conduct a time-to-event analysis of those exposed to vancomycin with and without the identified HLA risk allele. Results Twenty-three subjects met the inclusion criteria for vancomycin-associated DRESS. Nineteen (82.6%) of 23 cases carried HLA-A*32:01 compared with 0 (0%) of 46 of the matched vancomycin-tolerant control subjects (P = 1 × 10−8) and 6.3% of the BioVU population (n = 54,249, P = 2 × 10−16). Time-to-event analysis of DRESS development during vancomycin treatment among the HLA-A*32:01–positive group indicated that 19.2% had DRESS and did so within 4 weeks. Conclusions HLA-A*32:01 is strongly associated with vancomycin-induced DRESS in a population of predominantly European ancestry. HLA-A*32:01 testing could improve antibiotic safety, help implicate vancomycin as the causal drug, and preserve future treatment options with coadministered antibiotics.

We develop a dynamic programming methodology that seeks to maximize investor outcomes over multiple, potentially competing goals (such as upgrading a home, paying college tuition, or maintaining an income stream in retirement), even when financial resources are limited. Unlike Monte Carlo approaches currently in wide use in the wealth management industry, our approach uses investor preferences to dynamically make the optimal determination for fulfilling or not fulfilling each goal and for selecting the investor’s investment portfolio. This can be computed quickly, even for numerous investor goals spread over different or concurrent time periods, where each goal may be all-or-nothing or may allow for partial fulfillment. The probabilities of attaining each (full or partial) goal under the optimal scenario are also computed, so the investor can ensure the algorithm accurately reflects their preference for the relative importance of each of their goals. This approach vastly outperforms static portfolio strategies and target-date funds, widely used in the wealth management industry.

Background Sjogren's syndrome (SjS) is an autoimmune disease with a strong genetic association. To date, no vaccine or therapeutic agent exists to cure SjS, and patients must rely on lifelong therapies to treat symptoms. Human leukocyte antigens (HLA) are primary susceptibility loci that form the genetic basis for many autoimmune diseases, including SjS. In this study, we sought to determine whether blocking MHC class II I Ag7 antigen presentation in the NOD mouse would alleviate SjS by preventing the recognition of autoantigens by pathogenic T cells. Methods Mapping of the antigenic epitopes of Ro60 autoantigen to I Ag7 of the NOD mice was performed using structural modeling and in-vitro stimulation. Tetraazatricyclo-dodecane (TATD) and 8-Azaguanine (8-Aza) were previously identified as potential binders to I Ag7 of the NOD mice using in silico drug screening. Mice were treated with 20mgs/kg via IP every day five days/week for 23 weeks. Disease profiling was conducted. Findings Specific peptides of Ro60 autoantigen were identified to bind to I Ag7 and stimulated splenocytes of the NOD mice. Treating NOD mice with TATD or 8-Azaguanine alleviated SjS symptoms by improving salivary and lacrimal gland secretory function, decreasing the levels of autoantibodies, and reducing the severity of lymphocytic infiltration in the salivary and lacrimal glands. Interpretation This study presents a novel therapeutic approach for SjS by identifying small molecules capable of inhibiting T cell response via antigen-specific presentation. Funding CQN is supported financially in part by PHS grants AI130561, DE026450, and DE028544 from the National Institutes of Health.

To assess the effect of implementing an emergency surgery track for testicular torsion transfers. We hypothesized that transferring children from other facilities diagnosed with torsion straight to the operating room (STOR) would decrease ischemia time, lower costs, and reduce testicular loss.Demographics, arrival to incision time, hospital cost in dollars, and testicular outcome (determined by testicular ultrasound) at follow-up were retrospectively compared in all patients transferred to our tertiary care children's hospital with a diagnosis of testicular torsion from 2012 to 2016. Clinical data for STOR and non-STOR patients were compared by Wilcoxon rank-sum, 2-tailed t test, or Fisher exact test as appropriate.Sixty-eight patients met inclusion criteria: 35 STOR and 33 non-STOR. Children taken STOR had a shorter median arrival to incision time (STOR: 54 minutes vs non-STOR: 94 minutes, P .0001) and lower median total hospital costs (STOR: $3882 vs non-STOR: $4419, P .0001). However, only 46.8% of STOR patients and 48.4% of non-STOR patients achieved surgery within 6 hours of symptom onset. Testicular salvage rates in STOR and non-STOR patients were not significantly different (STOR: 68.4% vs non-STOR: 36.8%, P = .1), but follow-up was poor.STOR decreased arrival to incision time and hospital cost but did not affect testicular loss. The bulk of ischemia time in torsion transfers occurred before arrival at our tertiary care center. Further interventions addressing delays in diagnosis and transfer are needed to truly improve testicular salvage rates in these patients.

Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) is a life-threatening, immunologically-mediated and usually drug-induced disease with a high burden to individuals, their families and society with an annual incidence of 1–5/1,000,000. To effect significant reduction in short- and long-term morbidity and mortality, and advance clinical care and research, coordination of multiple medical, surgical, behavioral, and basic scientific disciplines is required. On March 2, 2017 an investigator-driven meeting was held immediately prior to the American Academy of Dermatology Annual meeting for the central purpose of assembling, for the first time in the United States, clinicians and scientists from multiple disciplines involved in SJS/TEN clinical care and basic science research. As a product of this meeting, this article summarizes the current state of knowledge and expert opinion related to SJS/TEN covering a broad spectrum of topics including epidemiology and pharmacogenomic networks; clinical management and complications; special populations such as pediatrics, the elderly, and pregnant women; regulatory issues and the electronic health record; new agents that cause SJS/TEN; pharmacogenomics and immunopathogenesis; and the patient perspective. Goals include the maintenance of a durable and productive multidisciplinary network that will significantly further scientific progress and translation into prevention, early diagnosis, and management of SJS/TEN. ©2017 American Academy of Allergy, Asthma & Immunology (J Allergy Clin Immunol Pract 2018;6:38–69)

We develop a dynamic programming methodology that seeks to maximize investor outcomes over multiple, potentially competing goals (such as upgrading a home, paying college tuition, or maintaining an income stream in retirement), even when financial resources are limited. Unlike Monte Carlo approaches currently in wide use in the wealth management industry, our approach uses investor preferences to dynamically make the optimal determination for fulfilling or not fulfilling each goal and for selecting the investor’s investment portfolio. This can be computed quickly, even for numerous investor goals spread over different or concurrent time periods, where each goal may allow for partial fulfillment or be all-or-nothing. The probabilities of attaining each (full or partial) goal under the optimal scenario are also computed, so the investor can ensure the algorithm accurately reflects their preference for the relative importance of each of their goals. These portfolio prescriptions are consistent with Prospect Theory.