A Formative Evaluation of the Family Strengthening Program in the Treasure Valley

Family Advocates, a nonprofit organization serving families in the Treasure Valley in Idaho, offers the Family Strengthening Program. This is a 20-week program providing weekly meetings for families who need to develop strong family cohesion, resilience, and parenting skills to maintain healthy families. The program uses the Strengthening Families’ approach with an emphasis on the protective factors framework and provides incentives to participants for participation. A third-party evaluation team from a local university conducted a formative evaluation of the program to help improve its quality. The evaluation team used both goal-based and goal-free, needs-based evaluation approaches, and analyzed quantitative and qualitative data. This included survey data from past weekly sessions, Facebook alumni group communications, and group interviews and surveys with participants, graduates, volunteers, and staff. The triangulated data indicated that program participants were highly satisfied with the program and felt the program helped improve their protective factors. The data also revealed the parents’ perceptions regarding program incentives as well as their preference for learning in socialized contexts. Based on the formative evaluation results and considering the participants’ perceptions and experiences, the program amended their curriculum and incentive plans to better accommodate the participants’ needs

Comprehensive behavioral testing in the R6/2 mouse model of Huntington's disease shows no benefit from CoQ10 or minocycline

Previous studies of the effects of coenzyme Q10 and minocycline on mouse models of Huntington’s disease have produced conflicting results regarding their efficacy in behavioral tests. Using our recently published best practices for husbandry and testing for mouse models of Huntington’s disease, we report that neither coenzyme Q10 nor minocycline had significant beneficial effects on measures of motor function, general health (open field, rotarod, grip strength, rearing-climbing, body weight and survival) in the R6/2 mouse model. The higher doses of minocycline, on the contrary, reduced survival. We were thus unable to confirm the previously reported benefits for these two drugs, and we discuss potential reasons for these discrepancies, such as the effects of husbandry and nutrition

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

Subinhibitory Concentrations of LFF571 Reduce Toxin Production by Clostridium difficile

LFF571 is a novel semisynthetic thiopeptide antibacterial that is undergoing investigation for safety and efficacy in patients with moderate Clostridium difficile infections. LFF571 inhibits bacterial protein synthesis by interacting with elongation factor Tu (EF-Tu) and interrupting complex formation between EF-Tu and aminoacyl-tRNA. Given this mechanism of action, we hypothesized that concentrations of LFF571 below those necessary to inhibit bacterial growth would reduce steady-state toxin levels in C. difficile cultures. We investigated C. difficile growth and toxin A and B levels in the presence of LFF571, fidaxomicin, vancomycin, and metronidazole. LFF571 led to strain-dependent effects on toxin production, including decreased toxin levels after treatment with subinhibitory concentrations, and more rapid declines in toxin production than in inhibition of colony formation. Fidaxomicin, which is an RNA synthesis inhibitor, conferred a similar pattern to LFF571 with respect to toxin levels versus viable cell counts. The incubation of two toxigenic C. difficile strains with subinhibitory concentrations of vancomycin, a cell wall synthesis inhibitor, increased toxin levels in the supernatant over those of untreated cultures. A similar phenomenon was observed with one metronidazole-treated strain of C. difficile. These studies indicate that LFF571 and fidaxomicin generally result in decreased C. difficile toxin levels in culture supernatants, whereas treatment of some strains with vancomycin or metronidazole had the potential to increase toxin levels. Although the relevance of these findings remains to be studied in patients, reducing toxin levels with sub-growth-inhibitory concentrations of an antibiotic is hypothesized to be beneficial in alleviating symptoms

Peptide deformylase as an antibacterial target: a critical assessment.

Peptide deformylase (PDF) is among the few antibacterial targets against which novel synthetic inhibitors derived from rationally designed, mechanism-based libraries have progressed into clinical trials. Nearly two decades of investigation led to this milestone; however, increased understanding of resistance to these compounds and recent evidence of catalytically active human mitochondrial PDF impact the perception of PDF as an antibacterial target. There are also many unanswered questions concerning the mechanism of action of PDF inhibitors and the necessity of the formylation/deformylation cycle in bacteria. Nevertheless, the experience gained from research on PDF serves as perhaps the best current illustration of the risks and possibilities associated with novel target-based antibiotic discovery

DegS and YaeL participate sequentially in the cleavage of RseA to activate the σ(E)-dependent extracytoplasmic stress response

All cells have stress response pathways that maintain homeostasis in each cellular compartment. In the Gram-negative bacterium Escherichia coli, the σ(E) pathway responds to protein misfolding in the envelope. The stress signal is transduced across the inner membrane to the cytoplasm via the inner membrane protein RseA, the anti-sigma factor that inhibits the transcriptional activity of σ(E). Stress-induced activation of the pathway requires the regulated proteolysis of RseA. In this report we show that RseA is degraded by sequential proteolytic events controlled by the inner membrane-anchored protease DegS and the membrane-embedded metalloprotease YaeL, an ortholog of mammalian Site-2 protease (S2P). This is consistent with the mechanism of activation of ATF6, the mammalian unfolded protein response transcription factor by Site-1 protease and S2P. Thus, mammalian and bacterial cells employ a conserved proteolytic mechanism to activate membrane-associated transcription factors that initiate intercompartmental cellular stress responses

Antimicrobial activity of a novel peptide deformylase inhibitor, LBM415, tested against respiratory tract and cutaneous infection pathogens: a global surveillance report (2003-2004).

To evaluate the spectrum of activity and potency of LBM415, the first of the peptide deformylase inhibitor (PDFI) class to be developed for treatment of community-acquired respiratory tract infections and uncomplicated skin and soft tissue infections (uSSTI), against a large, contemporary international collection of targeted pathogens collected during 2003-2004

Subcellular Chemical Imaging of Antibiotics in Single Bacteria Using C₆₀-Secondary Ion Mass Spectrometry

The inherent difficulty of discovering new and effective antibacterials and the rapid development of resistance particularly in Gram-negative bacteria, illustrates the urgent need for new methods that enable rational drug design. Here we report the development of 3D imaging cluster Time-of-Flight secondary ion mass spectrometry (ToF-SIMS) as a label-free approach to chemically map small molecules in aggregated and single Escherichia coli cells, with ∼300 nm spatial resolution and high chemical sensitivity. The feasibility of quantitative analysis was explored, and a nonlinear relationship between treatment dose and signal for tetracycline and ampicillin, two clinically used antibacterials, was observed. The methodology was further validated by the observation of reduction in tetracycline accumulation in an E. coli strain expressing the tetracycline-specific efflux pump (TetA) compared to the isogenic control. This study serves as a proof-of-concept for a new strategy for chemical imaging at the nanoscale and has the potential to aid discovery of new antibacterials

Genetic Selection for and Molecular Dynamic Modeling of a Protein Transmembrane Domain Multimerization Motif from a Random Escherichia coli Genomic Library

Introduction Integral membrane proteins play essential roles in numerous cellular functions, including cell division, intra and inter-cellular signaling, and transport of macromolecules. 14 Mutations affecting structure and assembly of membrane proteins often lead to cell toxicity in microbes and pathologies such as cystic brosis and Alzheimer's disease in humans. 5,6 With the advent of modern genomics, integral membrane proteins have gained much attention. For example, they are often identi ed from genome-wide viability screens for new drug targets. Yet compared to soluble proteins, sufcient tools generally do not exist to map the interactions that are required for tertiary structure and oligomeric assembly of integral membrane proteins. In depth structural studies of several model integral membrane proteins such as the human erythrocyte protein glycophorin A (GpA) and phospholamban have dened some basic rules of membrane protein structure and assembly. Integral membrane protei