Structure-Activity Study of an All-d Antimicrobial Octapeptide D2D

The increasing emergence of multi-drug resistant bacteria is a serious threat to public health worldwide. Antimicrobial peptides have attracted attention as potential antibiotics since they are present in all multicellular organisms and act as a first line of defence against invading pathogens. We have previously identified a small all-d antimicrobial octapeptide amide kk(1-nal)fk(1-nal)k(nle)-NH2 (D2D) with promising antimicrobial activity. In this work, we have performed a structure-activity relationship study of D2D based on 36 analogues aimed at discovering which elements are important for antimicrobial activity and toxicity. These modifications include an alanine scan, probing variation of hydrophobicity at lys5 and lys7, manipulation of amphipathicity, N-and C-termini deletions and lys-arg substitutions. We found that the hydrophobic residues in position 3 (1-nal), 4 (phe), 6 (1-nal) and 8 (nle) are important for antimicrobial activity and to a lesser extent cationic lysine residues in position 1, 2, 5 and 7. Our best analogue 5, showed MICs of 4 µg/mL against A. baumannii, E. coli, P. aeruginosa and S. aureus with a hemolytic activity of 47% against red blood cells. Furthermore, compound 5 kills bacteria in a concentration-dependent manner as shown by time-kill kinetics. Circular dichroism (CD) spectra of D2D and compounds 1–8 showed that they likely fold into α-helical secondary structure. Small angle x-ray scattering (SAXS) experiments showed that a random unstructured polymer-like chains model could explain D2D and compounds 1, 3, 4, 6 and 8. Solution structure of compound 5 can be described with a nanotube structure model, compound 7 can be described with a filament-like structure model, while compound 2 can be described with both models. Lipid interaction probed by small angle X-ray scattering (SAXS) showed that a higher amount of compound 5 (~50–60%) inserts into the bilayer compared to D2D (~30–50%). D2D still remains the lead compound, however compound 5 is an interesting antimicrobial peptide for further investigations due to its nanotube structure and minor improvement to antimicrobial activity compared to D2D

Development of Risk Prediction Equations for Incident Chronic Kidney Disease

IMPORTANCE ‐ Early identification of individuals at elevated risk of developing chronic kidney disease  could improve clinical care through enhanced surveillance and better management of underlying health  conditions.  OBJECTIVE – To develop assessment tools to identify individuals at increased risk of chronic kidney  disease, defined by reduced estimated glomerular filtration rate (eGFR).  DESIGN, SETTING, AND PARTICIPANTS – Individual level data analysis of 34 multinational cohorts from  the CKD Prognosis Consortium including 5,222,711 individuals from 28 countries. Data were collected  from April, 1970 through January, 2017. A two‐stage analysis was performed, with each study first  analyzed individually and summarized overall using a weighted average. Since clinical variables were  often differentially available by diabetes status, models were developed separately within participants  with diabetes and without diabetes. Discrimination and calibration were also tested in 9 external  cohorts (N=2,253,540). EXPOSURE Demographic and clinical factors.  MAIN OUTCOMES AND MEASURES – Incident eGFR <60 ml/min/1.73 m2.  RESULTS – In 4,441,084 participants without diabetes (mean age, 54 years, 38% female), there were  660,856 incident cases of reduced eGFR during a mean follow‐up of 4.2 years. In 781,627 participants  with diabetes (mean age, 62 years, 13% female), there were 313,646 incident cases during a mean follow‐up of 3.9 years. Equations for the 5‐year risk of reduced eGFR included age, sex, ethnicity, eGFR, history of cardiovascular disease, ever smoker, hypertension, BMI, and albuminuria. For participants  with diabetes, the models also included diabetes medications, hemoglobin A1c, and the interaction  between the two. The risk equations had a median C statistic for the 5‐year predicted probability of  0.845 (25th – 75th percentile, 0.789‐0.890) in the cohorts without diabetes and 0.801 (25th – 75th percentile, 0.750‐0.819) in the cohorts with diabetes. Calibration analysis showed that 9 out of 13 (69%) study populations had a slope of observed to predicted risk between 0.80 and 1.25. Discrimination was  similar in 18 study populations in 9 external validation cohorts; calibration showed that 16 out of 18 (89%) had a slope of observed to predicted risk between 0.80 and 1.25. CONCLUSIONS AND RELEVANCE – Equations for predicting risk of incident chronic kidney disease developed in over 5 million people from 34 multinational cohorts demonstrated high discrimination and  variable calibration in diverse populations

Factors Associated with Revision Surgery after Internal Fixation of Hip Fractures

Background: Femoral neck fractures are associated with high rates of revision surgery after management with internal fixation. Using data from the Fixation using Alternative Implants for the Treatment of Hip fractures (FAITH) trial evaluating methods of internal fixation in patients with femoral neck fractures, we investigated associations between baseline and surgical factors and the need for revision surgery to promote healing, relieve pain, treat infection or improve function over 24 months postsurgery. Additionally, we investigated factors associated with (1) hardware removal and (2) implant exchange from cancellous screws (CS) or sliding hip screw (SHS) to total hip arthroplasty, hemiarthroplasty, or another internal fixation device. Methods: We identified 15 potential factors a priori that may be associated with revision surgery, 7 with hardware removal, and 14 with implant exchange. We used multivariable Cox proportional hazards analyses in our investigation. Results: Factors associated with increased risk of revision surgery included: female sex, [hazard ratio (HR) 1.79, 95% confidence interval (CI) 1.25-2.50; P = 0.001], higher body mass index (fo

Modelling human choices: MADeM and decision‑making

Research supported by FAPESP 2015/50122-0 and DFG-GRTK 1740/2. RP and AR are also part of the Research, Innovation and Dissemination Center for Neuromathematics FAPESP grant (2013/07699-0). RP is supported by a FAPESP scholarship (2013/25667-8). ACR is partially supported by a CNPq fellowship (grant 306251/2014-0)

The Lantibiotic NAI-107 Efficiently Rescues Drosophila melanogaster from Infection with Methicillin-Resistant Staphylococcus aureus USA300

We used the fruit fly Drosophila melanogaster as a cost-effective in vivo model to evaluate the efficacy of novel antibacterial peptides and peptoids for treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections. A panel of peptides with known antibacterial activity in vitro and/or in vivo was tested in Drosophila. Although most peptides and peptoids that were effective in vitro failed to rescue lethal effects of S. aureus infections in vivo, we found that two lantibiotics, nisin and NAI-107, rescued adult flies from fatal infections. Furthermore, NAI-107 rescued mortality of infection with the MRSA strain USA300 with an efficacy equivalent to that of vancomycin, a widely applied antibiotic for the treatment of serious MRSA infections. These results establish Drosophila as a useful model for in vivo drug evaluation of antibacterial peptides

Miljøgifter i norske kystområder 2018

Revised version of 7412-2019 / M-1515This programme examines the levels, trends and effects of contaminants in biota along the coast of Norway. The 2018-investigation included analyses of more than 133 different contaminants or biological effect parameters in five species (blue mussel, dogwhelk, common periwinkle, cod and the common eider). The contaminants include metals (Hg, Cd, Pb, Cu, Zn, Ag, As, Ni, Cr and Co), tributyltin (TBT), organochlorines (e.g. PCBs (PCB-7), DDT), PAHs, polybrominated diphenyl ethers (PBDEs), and perfluorinated alkylated substances (PFAS), as well as contaminants that have recently received much attention such as hexabromocyclododecane (HBCDs), chlorinated paraffins (SCCP, MCCP), bisphenol A (BPA), tetrabrombisphenol A (TBBPA), alkyphenols, siloxanes (D4, D5 and D6) and dechlorane plus. Biological effects parameters included VDSI, OH-pyrene metabolites, ALA-D and EROD. In the report, 30 representative substances or parameters were chosen for analyses of 713 time series (last 10 years). Of these there were statistically significant trends in 102 cases: 79 were downwards and 23 upwards. The upward trends were also associated with metals (78.3 %), primarily Hg (17.4 %).The dominance of downward trends indicated that contamination is decreasing for the measured substances. The downwards trends for TBT-concentrations and effect parameter (VDSI) confirmed that the legislation banning the use of TBT has been effective. Of the 2018-medians (last year) for all 713 time series, there were 323 cases that could be classified against EQS, of which 203 (62.8 %) were below the EQS and 120 (37.2 %) were above the EQS. Of the 2018-medians for the 713 time series, 641 cases could be classified using Norwegian provisional high reference contaminant concentrations (PROREF). Of these, 463 were below PROREF and 173 exceeded PROREF: 117 by a factor of less than two, 45 by a factor between two and five, eight by a factor between five and 10, four by a factor between 10 and 20, and four by a factor greater than 20. Some cases warrant special concern, such as high concentrations of several organic contaminants in cod liver from the Inner Oslofjord. High concentrations of DDE in mussels from the Sørfjord were related to earlier use of DDT as pesticide in orchards along the fjord. Concentrations of an expanded list of PFAS in cod liver from the Inner Oslofjord sampled since 1990 are presented. Results of analyses of stable isotopes of carbon and nitrogen are presented to investigate the role of food origin and trophic levels for observed contaminant concentrations.The Norwegian Environmental AgencypublishedVersio

Parent-Child Interaction Using a Mobile and Wireless System for Blood Glucose Monitoring

BACKGROUND: Children with type 1 diabetes and their parents face rigorous procedures for blood glucose monitoring and regulation. Mobile telecommunication systems show potential as an aid for families’ self-management of diabetes. OBJECTIVE: A prototype designed to automatically transfer readings from a child’s blood glucose monitor to their parent’s mobile phone was tested. In this formative stage of development, we sought insights into the appropriateness of the concept, feasibility of use, and ideas for further development and research. METHODS: During four months, a self-selected sample of 15 children (aged 9 to 15 years) with type 1 diabetes and their parents (n = 30) used the prototype approximately three times daily. Parent and child experiences were collected through questionnaires and through interviews with 9 of the parents. RESULTS: System use was easily integrated into everyday life, and parents valued the sense of reassurance offered by the system. Parents’ ongoing struggle to balance control of their children with allowing independence was evident. For children who measured regularly, use appeared to reduce parental intrusions. For those who measured irregularly, however, parental reminders (eg, “nagging”) appeared to increase. Although increased reminders could be considered a positive outcome, they can potentially increase parent-child conflict and thus also undermine proper metabolic control. Parents felt that system appropriateness tapered off with the onset of adolescence, partly due to a potential sense of surveillance from the child’s perspective that could fuel oppositional behavior. Parental suggestions for further developments included similar alerts of irregular insulin dosages and automatically generated dietary and insulin dosage advice. CONCLUSIONS: User enthusiasm suggests that such systems might find a consumer market regardless of whether or not they ultimately improve health outcomes. Thus, more rigorous studies are warranted to inform guidelines for appropriate use. Potentially fruitful approaches include integrating such systems with theory-based parenting interventions and approaches that can aid in interpreting and responding to experiences of surveillance, virtual presence, and balances of power in e-mediated relationships