An empowered, clinically viable hematopoietic stem cell gene therapy for the treatment of multisystemic mucopolysaccharidosis type II.

Mucopolysaccharidosis type II (MPS II), or Hunter syndrome, is a rare X-linked recessive lysosomal storage disorder due to a mutation in the lysosomal enzyme iduronate-2-sulfatase (IDS) gene. IDS deficiency leads to a progressive, multisystem accumulation of glycosaminoglycans (GAGs) and results in central nervous system (CNS) manifestations in the severe form. We developed up to clinical readiness a new hematopoietic stem cell (HSC) gene therapy approach for MPS II that benefits from a novel highly effective transduction protocol. We first provided proof of concept of efficacy of our approach aimed at enhanced IDS enzyme delivery to the CNS in a murine study of immediate translational value, employing a lentiviral vector (LV) encoding a codon-optimized human IDS cDNA. Then the therapeutic LV was tested for its ability to efficiently and safely transduce bona fide human HSCs in clinically relevant conditions according to a standard vs. a novel protocol that demonstrated superior ability to transduce bona fide long-term repopulating HSCs. Overall, these results provide strong proof of concept for the clinical translation of this approach for the treatment of Hunter syndrome.

Enteral Nutrition Therapy: Historical Perspective, Utilization, and Complications.

PURPOSE OF REVIEW: Enteral nutrition (EN) therapy can provide vital nutrition support for patients with various medical conditions as long as it is indicated and supported by ethical reasoning. This review seeks to offer a detailed account of the history of EN development, highlighting key milestones and recent advances in the field. Additionally, it covers common complications associated with EN and their management. RECENT FINDINGS: After years of research and development, we have reached newer generations of enteral feeding formulations, more options for enteral tubes and connectors, and a better understanding of EN therapy challenges. Given the availability of many different formulas, selecting a feeding formula with the best evidence for specific indications for enteral feeding is recommended. Initiation of enteral feeding with standard polymeric formula remains the standard of care. Transition to small-bore connectors remains suboptimal. Evidence-based practices should be followed to recognize and reduce possible enteral feeding complications early.

Evaluation of Antifungal Activity of Endophytic Bacillus spp. and Identification of Secondary Metabolites Produced Against the Phytopathogenic Fungi.

Endophytic bacteria serve as a rich source of diverse antimicrobial compounds. Recently, there has been a growing interest in utilizing endophytic Bacillus spp. as biological agents against phytogenic fungi, owing to their potential to produce a wide range of antimicrobial substances. The objective of this research was to investigate the protective abilities of 15 endophytic Bacillus spp. isolated from previous study from wheat plant, against the phytopathogenic fungi, Fusarium graminearum and Macrophomina phaseolina. A dual culture plate assay was conducted as a preliminary analysis, revealing that 7 out of 15 endophytic Bacillus spp. demonstrated inhibition against one or both of the phytopathogenic fungi used in this study. All seven endophytes were further assessed for the presence of diffusible antifungal metabolites. The cultures were grown in potato dextrose broth for 120 h, and the cell-free supernatant was extracted and analyzed using the cup plate method. The methanolic extract yielded similar results to the dual culture plate analysis, except for WL2-15. Additionally, deformities in the mycelial structure were examined under the light microscope upon exposure to methanolic extract. Furthermore, the analysis and identification of metabolites were carried out via gas chromatography-mass spectrometry of methanolic extract from selected seven endophytic Bacillus spp. The chromatogram revealed the presence of some major peaks such as tridecanoic acid, methyl ester, hydroperoxide, 1-methylbutyl, 9-octadecenamide, (z)-, hexane-1,3,4-triol, 3,5-dimethyl- tetradecanoic acid. To the best of our knowledge, this is the first report of these biocontrol agents in endophytic Bacillus spp. Interestingly, volatile organic compound production was also seen in all the isolates against the phytopathogenic fungi.

Perioperative pain optimization in the age of the opioid epidemic.

PURPOSE OF REVIEW: The opioid epidemic remains a constant and increasing threat to our society with overdoses and overdose deaths rising significantly during the COVID-19 pandemic. Growing evidence suggests a link between perioperative opioid use, postoperative opioid prescribing, and the development of opioid use disorder (OUD). As a result, strategies to better optimize pain management during the perioperative period are urgently needed. The purpose of this review is to summarize the most recent multimodal analgesia (MMA) recommendations, summarize evidence for efficacy surrounding the increased utilization of Enhanced Recovery After Surgery (ERAS) protocols, and discuss the implications for rising use of buprenorphine for OUD patients who present for surgery. In addition, this review will explore opportunities to expand our treatment of complex patients via transitional pain services. RECENT FINDINGS: There is ample evidence to support the benefits of MMA. However, optimal drug combinations remain understudied, presenting a target area for future research. ERAS protocols provide a more systematic and targeted approach for implementing MMA. ERAS protocols also allow for a more comprehensive approach to perioperative pain management by necessitating the involvement of surgical specialists. Increasingly, OUD patients taking buprenorphine are presenting for surgery. Recent guidance from a multisociety OUD working group recommends that buprenorphine not be routinely discontinued or tapered perioperatively. Lastly, there is emerging evidence to justify the use of transitional pain services for more comprehensive treatment of complex patients, like those with chronic pain, preoperative opioid tolerance, or substance use disorder. SUMMARY: Perioperative physicians must be aware of the impact of the opioid epidemic and explore methods like MMA techniques, ERAS protocols, and transitional pain services to improve the perioperative pain experience and decrease the risks of opioid-related harm.

Efficacy of Liposomal Bupivacaine for Sternotomy Pain After Cardiac Surgery: A Retrospective Analysis.

BACKGROUND: Multimodal analgesia is a cornerstone of postoperative pain management. Different formulations of local anesthetics are available. Data to support these treatment options are limited. OBJECTIVE: To determine the efficacy of liposomal bupivacaine compared with bupivacaine or ropivacaine in patients undergoing sternotomy for coronary artery bypass graft (CABG) and/or valve surgery. METHODS: Single-center, retrospective, observational study at a community teaching hospital. Patients included were 18 years of age or older undergoing CABG and/or valve surgery via median sternotomy and received either liposomal bupivacaine or an active comparator. The primary outcome was opioid utilization in morphine milligram equivalent (MME) from 0 to 72 hours. RESULTS: A total of 376 patients were included, 223 in the liposomal bupivacaine arm and 153 in the active comparator arm. There was no difference in the MME use from 0 to 72 hours among patients in the liposomal bupivacaine group compared with the comparator group (114.2 mg [75.55] vs 107.6 mg [68.4], P = 0.38). After Bonferroni correction, there was no difference in pain scores at individual time points. At 24- and 48-hour post-op, pain scores were higher with liposomal bupivacaine at 4.4 (2.7) vs 3.5 (2.8) (P = 0.01) and 3.1 (2.9) vs 2.4 (2.6) (P = 0.02). CONCLUSION AND RELEVANCE: Based on these findings and previous studies, liposomal bupivacaine should not be routinely used for CABG and/or valve surgery through a median sternotomy given lack of superiority. This helps inform surgical practice to the role of anesthetics as part of the multimodal analgesia regimen.

Effects of Hallux Valgus Surgery on Balance and Gait in Middle Aged and Older Adults.

Hallux valgus is associated with balance deficits, and has been implicated as an independent risk factor for falls in older adults. However, it is unknown what effect hallux valgus surgery has on static and dynamic (i.e., while walking) balance in older adults. We enrolled 13 middle-aged and older aged adults (mean age 54.3 ± 12.7 years, range 47 to 70) who underwent isolated hallux valgus surgery and followed them for 12 months. Preoperative and postoperative gait and balance performance was assessed using non-invasive body worn sensors with standardized and validated testing protocols. Visual analog scale (VAS) for pain and radiographic angles were also assessed. All subjects reported improvements in pain (VAS mean change -38.3 ± 10.3 mm), and all subjects demonstrated improvements in their hallux valgus angles and first/second intermetatarsal angles (mean change 16.3 ± 8.8°, and 5.5 ± 3.0°, respectively). While standing in full tandem, center of mass (COM) sway was improved upon by 59% at 1 year postoperative (p < .05, paired t-test). While most gait parameters demonstrated little change postoperatively, patients tended to spend less time in double support (p = .08, paired t-test), while gait variability increased by 55% (p = .03, paired t-test) and medial-lateral sway while walking increased by 43% (p = .08, paired t-test) 12 months postoperatively. Balance improved after hallux valgus surgery in our population, particularly when subjects were forced to rely on their operative foot for support (e.g., full tandem). Patients also seemed to walk with greater variability in stride velocity and with greater medial-lateral sway postoperatively, suggesting perhaps increased ambulatory confidence after successful hallux valgus surgery.

Enterococcus durans Cardiac Implantable Electronic Device Lead Infection and Review of Enterococcus durans Endocarditis Cases.

Introduction: Cardiac implantable electronic device (CIED) infections present a growing problem in medicine due to a significant increase in the number of implanted devices and the age of the recipient population. Enterococcus spp. are Gram-positive, facultative anaerobic, lactic acid bacteria; they are relatively common pathogens in humans, but uncommon as the cause of CIED lead infections. Only eight cases of Enterococcus durans endocarditis have been reported in the literature thus far; however, there are no reported cases of Enterococcus durans CIED lead infection. Case presentation: A 58-year-old gentleman with a previously implanted St. Jude Medical single-chamber implantable cardioverter-defibrillator (ICD) due to tachy/brady arrhythmias presented with nonspecific constitutional symptoms (i.e., low-grade fevers, chills, fatigue), and was found to have innumerable bilateral pulmonary nodules via computed tomography angiography of the chest. Many of these pulmonary nodules were cavitated and highly concerning for septic pulmonary emboli and infarcts. Within 24 h from presentation, blood cultures in all four culture bottles grew ampicillin- and vancomycin-susceptible Enterococcus durans. Transthoracic echocardiogram confirmed vegetations on the ICD lead in the right ventricle. The patient underwent laser extraction of the ICD lead with generator removal and recovered completely after a 6-week intravenous antibiotic course. Conclusion: To our knowledge, this is the first report of CIED lead infection caused by Enterococcus durans. In this case, management with antibiotics along with ICD lead extraction led to complete recovery. Clinicians should be aware of this rare but potentially devastating infection in patients with native and artificial valves, but also in those with CIEDs.

Comparative biological study between quinazolinyl-triazinyl semicarbazide and thiosemicarbazide hybrid derivatives.

Practical synthesis and biological activities of quinazolinyl-triazinyl semicarbazides (10a-j) and quinazolinyl-triazinyl thiosemicarbazides (11a-j) have been described. The novel semicarbazides and thiosemicarbazides were prepared by condensation of different nucleophiles like isocyanate and isothiocyanate by the displacement of chlorine atoms on the basis of functionality concept on varying conditions. The synthesized quinazolinyl-triazinyl semicarbazide and thiosemicarbazide derivatives were evaluated for their expected antimicrobial activity. All the final synthesized derivatives were characterized by their melting point, mass spectra, 1H NMR and 13C NMR as well as elemental microanalysis. The final analogues were then analyzed for their in vitro antimicrobial activity against bacteria (Gram positive and negative) and fungus using the agar streak dilution method as well as in vitro anti-HIV activity against two types of viral strains, viz. HIV type I (IIIB) and type II (ROD) by using MTT assay method. SAR and HOMO-LUMO studies were also carried out for proving the structural biological activity. Among them, compounds 10e, 10f, 11h and 11j gave best results as their energy gap is very low which makes their activity higher.

Wheat Growth Dependent Succession of Culturable Endophytic Bacteria and Their Plant Growth Promoting Traits.

Endophytic bacteria present ubiquitously in all plant parts. Their community structure may vary depending on plant tissue and growth condition. This work mainly focused on exploring the diversity of culturable nitrogen-fixing endophytic bacteria in above-ground plant parts of wheat by harvesting it during various growth points (Seed stage, 1st, 2nd, and 3rd month old plants, respectively). Distinct endophytic bacterial colonies were selected on Jensen's agar plate. Based on the 16S rRNA sequencing, 43 putative nitrogen-fixing endophytic bacteria were identified. Most of the isolates were found unique to the plant growth phase except for Pseudomonas sp., Bacillus sp., Paenibacillus sp., Microbacterium sp., Exiguobacterium sp. Further, endophytic bacteria were scrutinized for their plant growth promoting traits. They were found positive for IAA production (100%), P-solubilization (21%), Zn-solubilization (63%), ammonia production (93%), and nifH gene (33%). Extracellular enzyme production was found positive for cellulase (98%), pectinase (98%), and protease (100%). Their endophytic colonization ability was assessed using reactive oxygen species (ROS) induction assay, upon their entry inside the host plant.

Protective and Non-Protective Factors of Mental Health Distress in the United States during the COVID-19 Pandemic: A Systematic Review.

Background and objectives: Health care organizations continue to respond to the COVID-19 global pandemic and an ongoing array of related mental health concerns. These pandemic-related challenges continue to be experienced by both the U.S. population and those abroad. Materials and methods: This systematic review queried three research databases to identify applicable studies related to protective and non-protective factors of mental health distress experienced during the pandemic within the United States. Results: Three primary factors were identified as protective factors, potentially helping to moderate the incidence of mental distress during the pandemic: demographics, personal support/self-care resources, and income/financial concerns. Researchers also identified these same three constructs of non-protective factors of mental health distress, as well as two additional variables: health/social status and general knowledge/government mistrust. Conclusions: This systematic review has identified protective and non-protective factors of mental health distress experienced in the United States during the COVID-19 pandemic (to date) that can further assist medical providers in the U.S. and beyond as the pandemic and related mental health concerns continue at a global level.

Pyrene-Based Noncovalent Immobilization of Nitrogenase on Carbon Surfaces.

Early work with viologen-mediated nitrogenase bio-electrochemistry focused on bio-electrocatalysis with the enzyme in solution, but biocatalyst immobilization at electrode surfaces is favorable as it provides a high effective concentration of biocatalyst at the electrode surface. We have used a pyrene-peptide linker as a method for immobilizing nitrogenase on carbon electrode surfaces for nitrogenase bio-electrocatalysis.

Intimate Partnerships, Suicidal Ideation and Suicide-Related Hospitalization Among Young Kenyan Men.

The first study focused on a three-month chart review containing information on suicide attempts (n = 34) admitted to a local mission hospital in Meru County, Kenya. The second study utilized a cross-sectional survey administered to men 18-34 years old (n = 532) residing in rural Kenya. Data posit intimate partnership discord as salient to suicide ideation and behavior. Men who reported their partner status was "divorced" had four-times the odds of reporting suicide ideation than other partnership states, an association significantly mediated by loneliness. Violent conflict tactics predicted suicidal ideation, mediated by loneliness and decreased marital satisfaction.

Do Aspirin and Flavonoids Prevent Cancer through a Common Mechanism Involving Hydroxybenzoic Acids?-The Metabolite Hypothesis.

Despite decades of research to elucidate the cancer preventive mechanisms of aspirin and flavonoids, a consensus has not been reached on their specific modes of action. This inability to accurately pinpoint the mechanism involved is due to the failure to differentiate the primary targets from its associated downstream responses. This review is written in the context of the recent findings on the potential pathways involved in the prevention of colorectal cancers (CRC) by aspirin and flavonoids. Recent reports have demonstrated that the aspirin metabolites 2,3-dihydroxybenzoic acid (2,3-DHBA), 2,5-dihydroxybenzoic acid (2,5-DHBA) and the flavonoid metabolites 2,4,6-trihydroxybenzoic acid (2,4,6-THBA), 3,4-dihydroxybenzoic acid (3,4-DHBA) and 3,4,5-trihydroxybenzoic acid (3,4,5-THBA) were effective in inhibiting cancer cell growth in vitro. Limited in vivo studies also provide evidence that some of these hydroxybenzoic acids (HBAs) inhibit tumor growth in animal models. This raises the possibility that a common pathway involving HBAs may be responsible for the observed cancer preventive actions of aspirin and flavonoids. Since substantial amounts of aspirin and flavonoids are left unabsorbed in the intestinal lumen upon oral consumption, they may be subjected to degradation by the host and bacterial enzymes, generating simpler phenolic acids contributing to the prevention of CRC. Interestingly, these HBAs are also abundantly present in fruits and vegetables. Therefore, we suggest that the HBAs produced through microbial degradation of aspirin and flavonoids or those consumed through the diet may be common mediators of CRC prevention.

Upgraded Bioelectrocatalytic N2 Fixation: From N2 to Chiral Amine Intermediates.

Enantiomerically pure chiral amines are of increasing value in the preparation of bioactive compounds, pharmaceuticals, and agrochemicals. ω-Transaminase (ω-TA) is an ideal catalyst for asymmetric amination because of its excellent enantioselectivity and wide substrate scope. To shift the equilibrium of reactions catalyzed by ω-TA to the side of the amine product, an upgraded N2 fixation system based on bioelectrocatalysis was developed to realize the conversion from N2 to chiral amine intermediates. The produced NH3 was in situ reacted with l-alanine dehydrogenase to generate alanine with NADH as a coenzyme. ω-TA transferred the amino group from alanine to ketone substrates and finally produced the desired chiral amine intermediates. The cathode of the upgraded N2 fixation system supplied enough reducing power to synchronously realize the regeneration of reduced methyl viologen (MV•+) and NADH for the nitrogenase and l-alanine dehydrogenase. The coproduct, pyruvate, was consumed by l-alanine dehydrogenase to regenerate alanine and push the equilibrium to the side of amine. After 10 h of reaction, the concentration of 1-methyl-3-phenylpropylamine achieved 0.54 mM with the 27.6% highest faradaic efficiency and >99% enantiomeric excess (eep). Because of the wide substrate scope and excellent enantioselectivity of ω-TA, the upgraded N2 fixation system has great potential to produce a variety of chiral amine intermediates for pharmaceuticals and other applications.

Electroenzymatic C-C Bond Formation from CO2.

Over the past decade, there has been significant research in electrochemical reduction of CO2, but it has been difficult to develop catalysts capable of C-C bond formation. Here, we report bioelectrocatalysis of vanadium nitrogenase from Azotobacter vinelandii, where cobaltocenium derivatives transfer electrons to the catalytic VFe protein, independent of ATP-hydrolysis. In this bioelectrochemical system, CO2 is reduced to ethylene (C2H4) and propene (C3H6), by a single metalloenzyme.

Increased risk of mortality by fibrosis stage in nonalcoholic fatty liver disease: Systematic review and meta-analysis.

Liver fibrosis is the most important predictor of mortality in nonalcoholic fatty liver disease (NAFLD). Quantitative risk of mortality by fibrosis stage has not been systematically evaluated. We aimed to quantify the fibrosis stage-specific risk of all-cause and liver-related mortality in NAFLD. Through a systematic review and meta-analysis, we identified five adult NAFLD cohort studies reporting fibrosis stage-specific mortality (0-4). Using fibrosis stage 0 as a reference population, fibrosis stage-specific mortality rate ratios (MRRs) with 95% confidence intervals (CIs) for all-cause and liver-related mortality were estimated. The study is reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Included were 1,495 NAFLD patients with 17,452 patient years of follow-up. Compared to NAFLD patients with no fibrosis (stage 0), NAFLD patients with fibrosis were at an increased risk for all-cause mortality, and this risk increased with increases in the stage of fibrosis: stage 1, MRR = 1.58 (95% CI 1.19-2.11); stage 2, MRR = 2.52 (95% CI 1.85-3.42); stage 3, MRR = 3.48 (95% CI 2.51-4.83); and stage 4, MRR = 6.40 (95% CI 4.11-9.95). The results were more pronounced as the risk of liver-related mortality increased exponentially with each increase in the stage of fibrosis: stage 1, MRR = 1.41 (95% CI 0.17-11.95); stage 2, MRR = 9.57 (95% CI 1.67-54.93); stage 3, MRR = 16.69 (95% CI 2.92-95.36); and stage 4, MRR = 42.30 (95% CI 3.51-510.34). Limitations of the study include an inability to adjust for comorbid conditions or demographics known to impact fibrosis progression in NAFLD and the inclusion of patients with simple steatosis and nonalcoholic steatohepatitis without fibrosis in the reference comparison group. CONCLUSION: The risk of liver-related mortality increases exponentially with increase in fibrosis stage; these data have important implications in assessing the utility of each stage and benefits of regression of fibrosis from one stage to another. (Hepatology 2017;65:1557-1565).

School nurse asthma program reduces healthcare utilization in children with persistent asthma.

OBJECTIVE: We examined the impact of a novel, school nurse-supervised asthma therapy program on healthcare utilization. METHODS: We retrospectively reviewed charts of 84 children enrolled in this program in central Massachusetts between 2012 and 2015. Physicians identified children with persistent asthma and poor medication adherence. These children were enrolled in the program to receive daily-inhaled corticosteroid at school, supervised by their school nurse, with ongoing communication between physician's office and school nurse through the school year. This program relied on established family, provider and school resources rather than research staff. The primary outcome was change in the number of emergency department (ED) visits in the year before and after enrollment. Secondary outcomes were hospital admissions, school absences, and rescue medication use. RESULTS: The study population was on average 10.5 years old, 63% male, 67% Hispanic, 19% black, 14% white with 95% using Medicaid insurance. Asthma-related ED visits over a 1-year period decreased 37.5%, from a pre-intervention mean of 0.8 visits to a post-intervention mean of 0.3 visits (p < 0.001). Asthma-related hospital admissions decreased from a pre-intervention mean of 0.3 admissions to post-intervention mean of 0 admissions (p < 0.001). Asthma rescue medication refills decreased by 46.3% from the pre- to post-intervention period (p = <.001). There were also non-significant declines in school absences and oral steroid use for children enrolled. CONCLUSIONS: We demonstrate a significant reduction in healthcare utilization for children enrolled in this unique school nurse-supervised asthma program, which utilizes a clinical-school partnership to deliver preventative asthma medication to school-aged children under sustainable conditions.

Palladium-catalyzed acid-free Fujiwara-Moritani alkenylation of 4-thiazolidinones.

Herein, we report a facile method for the alkenylation of a 4-thiazolidinone motif without using external acid and high-pressure gas, which are required in conventional Fujiwara-Moritani reactions. Mild reaction conditions, one-pot synthesis, and utilization of an oxidant made this process more feasible in comparison with previously reported methods. Functionalization of the slightly more acidic [Formula: see text] C-H bond with the less acidic [Formula: see text] C-H bond yielded the alkenylated motif. This pathway opens new possibilities for organic synthesis.

A preference test for sweet taste that uses edible strips.

A novel delivery method is described for the rapid determination of taste preferences for sweet taste in humans. This forced-choice paired comparison approach incorporates the non-caloric sweetener sucralose into a set of one-inch square edible strips for the rapid determination of sweet taste preferences. When compared to aqueous sucrose solutions, significantly lower amounts of sucralose were required to identify the preference for sweet taste. The validity of this approach was determined by comparing sweet taste preferences obtained with five different sucralose-containing edible strips to a set of five intensity-matched sucrose solutions. When compared to the solution test, edible strips required approximately the same number of steps to identify the preferred amount of sweet taste stimulus. Both approaches yielded similar distribution patterns for the preferred amount of sweet taste stimulus. In addition, taste intensity values for the preferred amount of sucralose in strips were similar to that of sucrose in solution. The hedonic values for the preferred amount of sucralose were lower than for sucrose, but the taste quality of the preferred sucralose strip was described as sweet. When taste intensity values between sucralose strips and sucralose solutions containing identical amounts of taste stimulus were compared, sucralose strips produced a greater taste intensity and more positive hedonic response. A preference test that uses edible strips for stimulus delivery should be useful for identifying preferences for sweet taste in young children, and in clinical populations. This test should also be useful for identifying sweet taste preferences outside of the lab or clinic. Finally, edible strips should be useful for developing preference tests for other primary taste stimuli and for taste mixtures.