Alpha-Gal Bound Aptamer and Vancomycin Synergistically Reduce Staphylococcus aureus Infection In Vivo.

Methicillin-resistant Staphylococcus aureus (MRSA) is a pervasive and persistent threat that requires the development of novel therapies or adjuvants for existing ones. Aptamers, small single-stranded oligonucleotides that form 3D structures and can bind to target molecules, provide one possible therapeutic route, especially when presented in combination with current antibiotic applications. BALB/c α-1, 3-galactosyltransferase (-/-) knockout (GTKO) mice were infected with MRSA via tail vein IV and subsequently treated with the αSA31 aptamer (n = 4), vancomycin (n = 12), or αSA31 plus vancomycin (n = 12), with split doses in the morning and evening. The heart, lungs, liver, spleen, and kidneys were harvested upon necropsy for histological and qPCR analysis. All mice treated with αSA31 alone died, whereas 5/12 mice treated with vancomycin alone and 7/12 mice treated with vancomycin plus αSA31 survived the course of the experiment. The treatment of MRSA-infected mice with Vancomycin and an adjuvant aptamer αSA31 reduced disease persistence and dispersion as compared to treatment with either vancomycin SA31 alone, indicating the combination of antibiotic and specifically targeted αSA31 aptamer could be a novel way to control MRSA infection. The data further indicate that aptamers may serve as a potential therapeutic option for other emerging antibiotic resistant pathogens.

NPP-669, a Novel Broad-Spectrum Antiviral Therapeutic with Excellent Cellular Uptake, Antiviral Potency, Oral Bioavailability, Preclinical Efficacy, and a Promising Safety Margin.

DNA viruses are responsible for many diseases in humans. Current treatments are often limited by toxicity, as in the case of cidofovir (CDV, Vistide), a compound used against cytomegalovirus (CMV) and adenovirus (AdV) infections. CDV is a polar molecule with poor bioavailability, and its overall clinical utility is limited by the high occurrence of acute nephrotoxicity. To circumvent these disadvantages, we designed nine CDV prodrug analogues. The prodrugs modulate the polarity of CDV with a long sulfonyl alkyl chain attached to one of the phosphono oxygens. We added capping groups to the end of the alkyl chain to minimize ß-oxidation and focus the metabolism on the phosphoester hydrolysis, thereby tuning the rate of this reaction by altering the alkyl chain length. With these modifications, the prodrugs have excellent aqueous solubility, optimized metabolic stability, increased cellular permeability, and rapid intracellular conversion to the pharmacologically active diphosphate form (CDV-PP). The prodrugs exhibited significantly enhanced antiviral potency against a wide range of DNA viruses in infected human foreskin fibroblasts. Single-dose intravenous and oral pharmacokinetic experiments showed that the compounds maintained plasma and target tissue levels of CDV well above the EC50 for 24 h. These experiments identified a novel lead candidate, NPP-669. NPP-669 demonstrated efficacy against CMV infections in mice and AdV infections in hamsters following oral (p.o.) dosing at a dose of 1 mg/kg BID and 0.1 mg/kg QD, respectively. We further showed that NPP-669 at 30 mg/kg QD did not exhibit histological signs of toxicity in mice or hamsters. These data suggest that NPP-669 is a promising lead candidate for a broad-spectrum antiviral compound.

Experiences and perceptions of family members of emergency first responders with post-traumatic stress disorder: a qualitative systematic review.

OBJECTIVE: The objective of this review was to examine the perceptions and experiences of family members of emergency first responders (EFRs) with post-traumatic stress disorder (PTSD). INTRODUCTION: Research indicates that rates of PTSD in EFRs are approximately double civilian rates; however, little is known about the resultant effects on their family members. This review identifies the qualitative literature and data examining the perceptions and experiences of families with a current or former EFR family member with diagnosed or undiagnosed PTSD. INCLUSION CRITERIA: This review included all relevant articles, books, reports, and doctoral theses in English, globally, with no time limits, examining the experiences of family members of current or former EFRs family with diagnosed or undiagnosed PTSD. All possible familial configurations and family members were considered, including nuclear, separated, and blended families, of an EFR. There were no age restrictions on EFRs or their family members, or limitations on recency of service. EFRs included police, ambulance/paramedics, firefighters, and rescue personnel. METHODS: The databases searched included MEDLINE (PubMed), PsycINFO (Ovid), Embase, CINAHL (EBSCOhost), and Scopus. Hand-searching of relevant journals was conducted across Australian Paramedic , Australasian Journal of Paramedicine , British Paramedic Journal , International Paramedic Practice , Irish Journal of Paramedicine , Journal of Paramedic Practice , Prehospital and Disaster Medicine , and Prehospital Emergency Care . Sources of unpublished studies and gray literature, such as dissertations, were searched via PTSDpubs (ProQuest) and OpenGrey (DANS EASY Data Archive). The search was updated in October 2021. Titles, abstracts, and full texts were screened by 2 independent reviewers against the inclusion criteria, and any conflicting views were resolved by discussion. Results were critically appraised for methodological quality. Post-data extraction results were synthesized and evaluated for credibility and dependability in accordance with the a priori protocol. RESULTS: The search yielded 1264 records and 48 were deemed eligible for full-text review. Seven studies were critically appraised, and 5 studies were agreed upon for inclusion in the synthesis. From these 5 studies, 53 findings were extracted with associated illustrations and synthesized into 9 categories. Following meta-aggregation, 4 broad synthesized findings were developed: i) Changed family member roles, spousal relationships difficulties, and family functioning when living with an EFR with PTSD; ii) Spouses of an EFR with PTSD may experience vicarious trauma, secondary trauma, and/or overburden as a consequence of protecting the family unit; iii) Children of an EFR parent with PTSD may experience secondary trauma, vicarious trauma, and/or separation anxiety; and iv) Spouses' help-seeking and support needs for their EFR partners with PTSD, their children, and themselves. The first 3 findings received a low ConQual score due to low dependability and moderate credibility. The final finding received a moderate ConQual score due to low dependability and high credibility. CONCLUSIONS: The findings of the 5 qualitative studies included in the review showed significant mental health and functional impacts for family members of EFR with PTSD. Most studies focused on spouses, with some limited data on children. Two of the 5 studies focused on the 9/11 World Trade Center terrorist attacks in the United States. The findings also indicate the need for targeted psychological and social services for EFR family members. Recommendations derived from the synthesized findings of this review include the need for further qualitative research, not only to deepen the understanding about the impacts and needs of EFR with PTSD on family members, but also to inform the design and provision of support services. SYSTEMATIC REVIEW REGISTRATION NUMBER: PROSPERO CRD42020196605.

Experiences and perceptions of family members of emergency first responders with post-traumatic stress disorder: a qualitative systematic review protocol.

OBJECTIVE: The objective of this review is to understand the perceptions and experiences of family members of emergency first responders with post-traumatic stress disorder. INTRODUCTION: Research indicates that rates of post-traumatic stress disorder in emergency first responders are approximately double civilian rates; however, little is known about the effects of post-traumatic stress disorder on family members. This review seeks to identify qualitative research on families' experiences and perceptions. INCLUSION CRITERIA: This review will consider all studies of family members of current or former emergency first responders with diagnosed or undiagnosed post-traumatic stress disorder of any level of severity. All possible familial configurations and family members will be considered, including nuclear, separated, and blended families, of a current or former emergency first responder. There will be no age restrictions on emergency first responders or their family members, or limitations on recency of service. Emergency first responders may include police, ambulance workers, paramedics, firefighters, or rescue personnel, with no restriction on geographic location. METHODS: The databases to be searched will include PubMed, PsycINFO, Embase, CINAHL, PTSDpubs, and Scopus, as well as handsearching of relevant journals. Unpublished studies and gray literature will be searched via PTSDpubs and OpenGrey. The search will aim to find English-language publications with no time limits. Titles and abstracts will be reviewed and then full texts, all screened by two independent reviewers against the inclusion criteria. Any conflicting views will be resolved by discussion or a third reviewer. Results will be critically appraised for methodological quality. Data extraction results will be synthesized and evaluated for credibility and dependability. SYSTEMATIC REVIEW REGISTRATION NUMBER: PROSPERO CRD42020196605.

Solvothermal synthesis of graphene oxide and its composites with poly(ε-caprolactone).

Graphene oxide (GO) was prepared by a solvothermal synthesis method using sodium and ethanol. A sequence of pyrolysis, washing and purification steps was developed for the total removal of all by-products. The first pyrolysis step is essential to obtain graphitic forms of carbon while a washing and a second pyrolysis step further improved the graphenic structures obtained via the reduction of OH/COOH and C-O groups and the attendant increase in C[double bond, length as m-dash]C bonding (sp2 hybridization). Two purification processes were employed to remove sodium carbonate (by-product), i.e. vacuum filtration and centrifugation, but the latter produced a more stable GO product, typically with a few-layer (ca. 3 nm) stack and relatively long platelets (up to ca. 1.3 µm). The functionality of this GO was demonstrated by preparing composites of it with poly(ε-caprolactone) (PCL). Some of the GO was arranged in flower-like domains dispersed in the PCL matrix. The crystalline content of PCL decreased on addition of GO, though the dynamic modulus of PCL increased and an electrical percolation at 0.5 vol% GO was obtained, manifest by a ∼104 increase in electrical conductivity (in an overall increase of ∼105 achieved at >1 vol%), more than sufficient for anti-static applications.

Prescription of opioids to post-operative orthopaedic patients at time of discharge from hospital: a prospective observational study.

BACKGROUND AND AIMS: Excessive opioid prescribing can lead to adverse consequences including stockpiling, misuse, dependency, diversion and mortality. Increased prescriptions to post-operative inpatients as part of their discharge planning may be a significant contributor. Primary aims included comparing the amount of opioids prescribed, consumed, left unused and their relationship with pain and functionality. METHODS: A total of 132 consecutive patients who underwent elective orthopaedic surgery were prospectively audited. Daily oral morphine equivalent (DME) of opioids prescribed was compared with opioids consumed and amount left unused 7-10 days after discharge. For analysis, patients were split into three groups: total knee replacement (TKR), hand surgery (Hands), and miscellaneous (Misc). RESULTS: The mean dose of opioid prescribed per patient was 108.5 mg DME. TKR consumed 33-35% more opioids than Misc (p=0.0283) and Hands (p=0.0975). Age was a significant independent factor for opioid consumption in the 50th and 75th percentiles of Hands (p≤0.05). An average of 36 mg DME per patient was left unused with Hands having the highest median DME (37 mg) unused. In the total cohort, 26% of patients were discharged with more DME than their last 24 h as an inpatient and had at least 50% of their tablets left unused at follow-up. CONCLUSIONS: Over-prescription of opioids occurs at discharge which can increase the risk of harm. New intervention is needed to optimise prescribing practises. IMPLICATIONS: Changes to prescribing habits and workplace culture are required to minimise unnecessary opioid prescribing but will be challenging to implement. A multi-layered approach of electronic prescribing, opioid stewardship and targeted educational awareness programmes is recommended.

Fecal Microbiota Signatures Are Associated with Response to Ustekinumab Therapy among Crohn's Disease Patients.

The fecal microbiota is a rich source of biomarkers that have previously been shown to be predictive of numerous disease states. Less well studied is the effect of immunomodulatory therapy on the microbiota and its role in response to therapy. This study explored associations between the fecal microbiota and therapeutic response of Crohn's disease (CD) patients treated with ustekinumab (UST; Stelara) in the phase 2 CERTIFI study. Using stool samples collected over the course of 22 weeks, the composition of these subjects' fecal bacterial communities was characterized by sequencing the 16S rRNA gene. Subjects in remission could be distinguished from those with active disease 6 weeks after treatment using random forest models trained on subjects' baseline microbiota and clinical data (area under the curve [AUC] of 0.844, specificity of 0.831, sensitivity of 0.774). The most predictive operational taxonomic units (OTUs) that were ubiquitous among subjects were affiliated with Faecalibacterium and Escherichia or Shigella The median baseline community diversity in subjects in remission 6 weeks after treatment was 1.7 times higher than that in treated subjects with active disease (P = 0.020). Their baseline community structures were also significantly different (P = 0.017). Two OTUs affiliated with Faecalibacterium (P = 0.003) and Bacteroides (P = 0.022) were significantly more abundant at baseline in subjects who were in remission 6 weeks after treatment than those with active CD. The microbiota diversity of UST-treated clinical responders increased over the 22 weeks of the study, in contrast to nonresponsive subjects (P = 0.012). The observed baseline differences in fecal microbiota and changes due to therapeutic response support the potential for the microbiota as a response biomarker.IMPORTANCE CD is a global health concern, with increasing incidence and prevalence, causing large economic and health care impacts. Finding prognostic biomarkers that give clinicians the ability to identify patients more likely to respond to CD treatment at diagnosis will reduce the time subjects receive drugs that are unlikely to be beneficial. OTUs associated with remission after treatment induction, especially Faecalibacterium, could be biomarkers for successful UST treatment of anti-tumor necrosis factor alpha (anti-TNF-α) refractory CD patients. More broadly, these results suggest that the fecal microbiota could be a useful noninvasive biomarker for directing or monitoring the treatment of gastrointestinal diseases.

From protective intelligence to threat assessment: Strategies critical to preventing targeted violence and the active shooter.

Acts of targeted violence - including active shooter incidents - are typically over within 15 minutes, often before the first law enforcement personnel can respond to the scene. More than a third of active shooter incidents in the USA, for example, last less than five minutes. While this stark fact is often used, with unimpeachable validity, as the cornerstone of employee security awareness training and the need for each employee to make a quick decision on whether to run, hide or fight, it also underscores the importance of another critical priority: prevention. This paper focuses on several of the most effective strategies and tactics - increasingly used across the USA, but applicable all over the world - in preventing an act of targeted violence or active shooter event. It starts with a brief discussion of the common roadblocks to prevention within enterprises today as well as the warning signs that can reveal an individual's path toward an act of violence. Next, it defines targeted violence and summarises patterns that research has helped uncover with respect to attackers' backgrounds, motives and target selection. This paper also outlines the crucial role played by protective intelligence and threat assessment protocols and provides several case studies to illustrate key concepts in real-world applications. Finally, this discussion points to several emerging trends in the USA and Europe, among other regions - such as radicalisation within the workforce - that are likely to continue to mature in 2016 and the years ahead.

The value of prevention: managing the risks associated with targeted violence and active shooters.

Every time we turn on the news, or open our Internet browsers, a story about an active shooter--at a school, house of worship, public place and even in our workplace--spills onto the page, the author reports. In this article he focuses on how we can prevent these incidents from occurring. What exactly is "targeted violence"--and why is what experts call "behavioral threat assessment" one of the single most effective ways to prevent the next active shooter incident in any organization?

Detection of low-concentration contaminants in solution by exploiting chemical derivatization in surface-enhanced Raman spectroscopy.

A simple derivatization methodology is shown to extend the application of surface-enhanced Raman spectroscopy (SERS) to the detection of trace concentration of contaminants in liquid form. Normally in SERS the target analyte species is already present in the molecular form in which it is to be detected and is extracted from solution to occupy sites of enhanced electromagnetic field on the substrate by means of chemisorption or drop-casting and subsequent evaporation of the solvent. However, these methods are very ineffective for the detection of low concentrations of contaminant in liquid form because the target (ionic) species (a) exhibits extremely low occupancy of enhancing surface sites in the bulk liquid environment and (b) coevaporates with the solvent. In this study, the target analyte species (acid) is detected via its solid derivative (salt) offering very significant enhancement of the SERS signal because of preferential deposition of the salt at the enhancing surface but without loss of chemical discrimination. The detection of nitric acid and sulfuric acid is demonstrated down to 100 ppb via reaction with ammonium hydroxide to produce the corresponding ammonium salt. This yields an improvement of ~4 orders of magnitude in the low-concentration detection limit compared with liquid phase detection.

Architectural arrangement of the small nuclear RNA (snRNA)-activating protein complex 190 subunit (SNAP190) on U1 snRNA gene promoter DNA.

Myb repeats ∼52 amino acid residues in length were first characterized in the oncogenic Myb transcription factor, which contains three tandem Myb repeats in its DNA-binding domain. Proteins of this family normally contain either one, two, or three tandem Myb repeats that are involved in protein-DNA interactions. The small nuclear RNA (snRNA)-activating protein complex (SNAPc) is a heterotrimeric transcription factor that is required for expression of small nuclear RNA genes. This complex binds to an essential promoter element, the proximal sequence element, centered ∼50 base pairs upstream of the transcription start site of snRNA genes. SNAP190, the largest subunit of SNAPc, uncharacteristically contains 4.5 tandem Myb repeats. Little is known about the arrangement of the Myb repeats in the SNAPc-DNA complex, and it has not been clear whether all 4.5 Myb repeats contact the DNA. By using a site-specific protein-DNA photo-cross-linking assay, we have now mapped specific nucleotides where each of the Myb repeats of Drosophila melanogaster SNAP190 interacts with a U1 snRNA gene proximal sequence element. The results reveal the topological arrangement of the 4.5 SNAP190 Myb repeats relative to the DNA and to each other when SNAP190 is bound to a U1 promoter as a subunit of SNAPc.

Conrad: gene prediction using conditional random fields.

We present Conrad, the first comparative gene predictor based on semi-Markov conditional random fields (SMCRFs). Unlike the best standalone gene predictors, which are based on generalized hidden Markov models (GHMMs) and trained by maximum likelihood, Conrad is discriminatively trained to maximize annotation accuracy. In addition, unlike the best annotation pipelines, which rely on heuristic and ad hoc decision rules to combine standalone gene predictors with additional information such as ESTs and protein homology, Conrad encodes all sources of information as features and treats all features equally in the training and inference algorithms. Conrad outperforms the best standalone gene predictors in cross-validation and whole chromosome testing on two fungi with vastly different gene structures. The performance improvement arises from the SMCRF's discriminative training methods and their ability to easily incorporate diverse types of information by encoding them as feature functions. On Cryptococcus neoformans, configuring Conrad to reproduce the predictions of a two-species phylo-GHMM closely matches the performance of Twinscan. Enabling discriminative training increases performance, and adding new feature functions further increases performance, achieving a level of accuracy that is unprecedented for this organism. Similar results are obtained on Aspergillus nidulans comparing Conrad versus Fgenesh. SMCRFs are a promising framework for gene prediction because of their highly modular nature, simplifying the process of designing and testing potential indicators of gene structure. Conrad's implementation of SMCRFs advances the state of the art in gene prediction in fungi and provides a robust platform for both current application and future research.