Estimating Potential Infection Transmission Routes in Hospital Wards Using Wearable Proximity Sensors

Contacts between patients, patients and health care workers (HCWs) and among HCWs represent one of the important routes of transmission of hospital-acquired infections (HAI). A detailed description and quantification of contacts in hospitals provides key information for HAIs epidemiology and for the design and validation of control measures. We used wearable sensors to detect close-range interactions ("contacts") between individuals in the geriatric unit of a university hospital. Contact events were measured with a spatial resolution of about 1.5 meters and a temporal resolution of 20 seconds. The study included 46 HCWs and 29 patients and lasted for 4 days and 4 nights. 14037 contacts were recorded. The number and duration of contacts varied between mornings, afternoons and nights, and contact matrices describing the mixing patterns between HCW and patients were built for each time period. Contact patterns were qualitatively similar from one day to the next. 38% of the contacts occurred between pairs of HCWs and 6 HCWs accounted for 42% of all the contacts including at least one patient, suggesting a population of individuals who could potentially act as super-spreaders. Wearable sensors represent a novel tool for the measurement of contact patterns in hospitals. The collected data provides information on important aspects that impact the spreading patterns of infectious diseases, such as the strong heterogeneity of contact numbers and durations across individuals, the variability in the number of contacts during a day, and the fraction of repeated contacts across days. This variability is associated with a marked statistical stability of contact and mixing patterns across days. Our results highlight the need for such measurement efforts in order to correctly inform mathematical models of HAIs and use them to inform the design and evaluation of prevention strategies

Trends of antimicrobial resistance and combination susceptibility testing of cystic fibrosis multidrug-resistant Pseudomonas aeruginosa : A ten-year update

Acknowledgements The authors would like to thank the laboratories and clinicians who use the Cystic Fibrosis Antibiotics Susceptibility testing service (CFASS) for their support in sending samples. CFASS is an adult patient testing facility funded by the National Services Division of the Common Services Agency. IMG serves as a consultant to and/ speaker to Pfizer and MSD. All other authors declare no competing interests.Peer reviewedPostprin

Longitudinal Surveillance and Combination Antimicrobial Susceptibility Testing of Multidrug-Resistant Achromobacter Species from Cystic Fibrosis Patients

Acknowledgements: The authors would like to thank the laboratories and clinicians who use the Cystic Fibrosis Antibiotics Susceptibility testing service (CFASS) for their support in sending samples. CFASS is an adult patient testing facility funded by the National Services Division of the Common Services Agency of the Scottish Executive. Achromobacter spp. identification was supported by grants from the University of Aberdeen and the NHS Grampian Clinical Microbiology Fund (NHS Grampian Endowment Funds Registered Charity Number SC017296). IMG serves as a consultant to and/ speaker to Pfizer and MSD. All other authors declare no competing interestPeer reviewedPostprin

Antimicrobial Synergy Testing : Comparing the Tobramycin and Ceftazidime Gradient Diffusion Methodology Used in Assessing Synergy in Cystic Fibrosis-Derived

Funding: This research was funded by the NHS Grampian Endowment fund, grant number EA9431, and the NHS Grampian Clinical Microbiology Fund (NHS Grampian Endowment Funds, Registered Charity Number SC017296). Acknowledgments: The authors would like to thank the laboratories and clinicians who use the Cystic Fibrosis Susceptibility Testing Service. CFASS is an adult patient-testing facility, funded by the National Services Division of the Common Services Agency of the Scottish Executive.Peer reviewedPublisher PD

Risk of Mild Behavioral Impairment: the role of gender and APOE allele carrier status

Background Gender differences in dementia and dementia‐related neuropsychiatric symptoms are well described. Similarly, the Apolipoprotein E (APOE) ε4 allele is a well‐known predictor of Alzheimer’s disease. However, their impact on the clinical manifestation of Mild Behavioral Impairment (MBI) remains unclear. Using data from the Australian population‐based PATH Through Life Study we explored the associations between gender and APOE ε4 carrier status with MBI. We hypothesized that MBI likelihood would be greater in males and ε4 carriers. Method 1316 dementia‐free participants (48% female; aged 72‐79) were included. Gender was self‐reported (female/male). Participants were classified as APOE ε4+ if they carried at least one ε4 allele (APOE ε4/ε4, ε2/ε4, ε3/ε4). MBI was approximated using a previously published transformation algorithm, which utilizes items from the Neuropsychiatric Inventory assessed at a single study visit. Binomial logistic regression was used to examine the role of gender and APOE ε4 carrier status, and their interaction, on predicting MBI status, while controlling for self‐reported years of education. Result Of the 1316 participants, 339 (25.8%) were APOE ε4+ and 445 (34%) had MBI symptoms. A higher proportion of APOE ε4+ carriers (χ2 (1) = 5.99, p = .014) and men (χ2 (1) = 4.59, p = .032) were in the MBI group compared to the non‐MBI group. Binomial logistic regression showed APOE ε4 carrier status (OR = 1.58, 95% CI: 1.063‐2.344) and male gender (OR = 1.45, 95% CI: 1.093‐1.925) were associated with a greater likelihood of MBI. Male gender was also associated with a 2‐fold greater likelihood of having symptoms of the Decreased Motivation (OR = 2.08, 95% CI: 1.13‐3.86) and Impulse Dyscontrol (OR = 2.16, 95% CI: 1.54‐3.03) domains. No interaction effects were found between gender and APOE ε4 carrier status for MBI or any of its domains. Conclusion The current study found that in dementia‐free older adults both male gender and APOE ε4+ status increased the risk of having MBI. However, no cumulative/interaction effect between gender and APOE ε4 carrier status was found, suggesting that being both male and APOE ε4+ does not further increase the risk of MBI. These results provide novel and valuable insight into the connection between gender, APOE ε4 carrier status and MBI

Les lipodystrophies secondaires aux traitements antirétroviraux de l’infection par le VIH

Les traitements antirétroviraux de l’infection par le VIH sont responsables d’effets secondaires parfois sévères qui touchent en priorité le tissu adipeux, modifiant sa localisation (lipodystrophie avec lipoatrophie périphérique et hypertrophie centrale) et les paramètres du métabolisme glucido-lipidique (dyslipidémie, diabète). Les deux principales classes thérapeutiques, inhibiteurs de protéase et analogues nucléosidiques, sont délétères sur ces paramètres par des mécanismes différents mais qui convergent sur le tissu adipeux. Certaines des molécules de ces deux classes modifient profondément sa différenciation, son métabolisme, sa fonction mitochondriale et l’équilibre des hormones (leptine, adiponectine) et cytokines (TNFα, IL-6) qu’il sécrète. Ce syndrome de lipodystrophie induit un risque cardiovasculaire et de stéatohépatite grevant le pronostic vital. Le traitement reste difficile chez les patients atteints et privilégie le remplacement des molécules les plus délétères par des molécules antirétrovirales plus récentes et moins agressives sur le tissu adipeux.HIV infection requires the continuous administration of antiretroviral molecules. Individual molecules belonging to the two main classes, protease inhibitors (PIs) and nucleoside analogues inhibitors of the viral reverse transcriptase (NRTIs) have been shown to be involved in deleterious side effects collectively called the lipodystrophy syndrome. This syndrome associates altered body fat repartition (peripheral lipoatrophy and visceral fat hypertrophy) and metabolic alterations (dyslipidemia, insulin resistance and diabetes). The pathophysiology of these alterations is complex but different studies argue for adipose tissue being a target of some PIs and NRTIs acting through different mechanisms. NRTIs are able to induce mitochondrial dysfonction and to modify adipocyte phenotype and adipose tissue pattern of secretion of cytokines (TNFα, IL-6) and other adipokines (adiponectin, leptin) probably through the production of reactive oxygen species. Some PIs also act on adipocyte, alter its differentiation and insulin sensitivity and also the pattern of secretion of adipokines by adipose tissue. These hypotheses could explain the loss of adipose tissue, while the mechanisms of visceral fat hypertrophy remain speculative. Since some adipokines and the free fatty acids released by adipocytes play a major role in the control of liver and muscles insulin sensitivity, these alterations are probably involved in the metabolic alterations seen in the patients. In addition, lipodystrophic adipose tissue could be involved in the increased lesions of atherogenesis and steatohepatitis presented by these patients. The treatment of lipodystrophy remains difficult and, at present, privileges the switch of the more deleterious drugs towards new molecules less aggressive for adipose tissue

Pharmacological and Toxicological Properties of the Potent Oral γ-Secretase Modulator BPN-15606.

Alzheimer's disease (AD) is characterized neuropathologically by an abundance of 1) neuritic plaques, which are primarily composed of a fibrillar 42-amino-acid amyloid-β peptide (Aβ), as well as 2) neurofibrillary tangles composed of aggregates of hyperphosporylated tau. Elevations in the concentrations of the Aβ42 peptide in the brain, as a result of either increased production or decreased clearance, are postulated to initiate and drive the AD pathologic process. We initially introduced a novel class of bridged aromatics referred tγ-secretase modulatoro as γ-secretase modulators that inhibited the production of the Aβ42 peptide and to a lesser degree the Aβ40 peptide while concomitantly increasing the production of the carboxyl-truncated Aβ38 and Aβ37 peptides. These modulators potently lower Aβ42 levels without inhibiting the γ-secretase-mediated proteolysis of Notch or causing accumulation of carboxyl-terminal fragments of APP. In this study, we report a large number of pharmacological studies and early assessment of toxicology characterizing a highly potent γ-secretase modulator (GSM), (S)-N-(1-(4-fluorophenyl)ethyl)-6-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl)-4-methylpyridazin-3-amine (BPN-15606). BPN-15606 displayed the ability to significantly lower Aβ42 levels in the central nervous system of rats and mice at doses as low as 5-10 mg/kg, significantly reduce Aβ neuritic plaque load in an AD transgenic mouse model, and significantly reduce levels of insoluble Aβ42 and pThr181 tau in a three-dimensional human neural cell culture model. Results from repeat-dose toxicity studies in rats and dose escalation/repeat-dose toxicity studies in nonhuman primates have designated this GSM for 28-day Investigational New Drug-enabling good laboratory practice studies and positioned it as a candidate for human clinical trials

Constitutively active Notch4 receptor elicits brain arteriovenous malformations through enlargement of capillary-like vessels

Arteriovenous (AV) malformation (AVM) is a devastating condition characterized by focal lesions of enlarged, tangled vessels that shunt blood from arteries directly to veins. AVMs can form anywhere in the body and can cause debilitating ischemia and life-threatening hemorrhagic stroke. The mechanisms that underlie AVM formation remain poorly understood. Here, we examined the cellular and hemodynamic changes at the earliest stages of brain AVM formation by time-lapse two-photon imaging through cranial windows of mice expressing constitutively active Notch4 (Notch4*). AVMs arose from enlargement of preexisting microvessels with capillary diameter and blood flow and no smooth muscle cell coverage. AV shunting began promptly after Notch4* expression in endothelial cells (ECs), accompanied by increased individual EC areas, rather than increased EC number or proliferation. Alterations in Notch signaling in ECs of all vessels, but not arteries alone, affected AVM formation, suggesting that Notch functions in the microvasculature and/or veins to induce AVM. Increased Notch signaling interfered with the normal biological control of hemodynamics, permitting a positive feedback loop of increasing blood flow and vessel diameter and driving focal AVM growth from AV connections with higher blood velocity at the expense of adjacent AV connections with lower velocity. Endothelial expression of constitutively active Notch1 also led to brain AVMs in mice. Our data shed light on cellular and hemodynamic mechanisms underlying AVM pathogenesis elicited by increased Notch signaling in the endothelium.American Heart Association (Grant 0715062Y)Tobacco-Related Disease Research Program (Predoctoral Fellowship 18DT-0009

Resolving the contributions of the membrane-bound and periplasmic nitrate reductase systems to nitric oxide and nitrous oxide production in Salmonella enterica serovar Typhimurium

The production of cytotoxic nitric oxide (NO) and conversion into the neuropharmacological agent and potent greenhouse gas nitrous oxide (N2O) is linked with anoxic nitrate catabolism by Salmonella enterica serovar Typhimurium. Salmonella can synthesize two types of nitrate reductase: a membrane-bound form (Nar) and a periplasmic form (Nap). Nitrate catabolism was studied under nitrate-rich and nitrate-limited conditions in chemostat cultures following transition from oxic to anoxic conditions. Intracellular NO production was reported qualitatively by assessing transcription of the NO-regulated genes encoding flavohaemoglobin (Hmp), flavorubredoxin (NorV) and hybrid cluster protein (Hcp). A more quantitative analysis of the extent of NO formation was gained by measuring production of N2O, the end-product of anoxic NO-detoxification. Under nitrate-rich conditions, the nar, nap, hmp, norV and hcp genes were all induced following transition from the oxic to anoxic state, and 20% of nitrate consumed in steady-state was released as N2O when nitrite had accumulated to millimolar levels. The kinetics of nitrate consumption, nitrite accumulation and N2O production were similar to those of wild-type in nitrate-sufficient cultures of a nap mutant. In contrast, in a narG mutant, the steady-state rate of N2O production was ~30-fold lower than that of the wild-type. Under nitrate-limited conditions, nap, but not nar, was up-regulated following transition from oxic to anoxic metabolism and very little N2O production was observed. Thus a combination of nitrate-sufficiency, nitrite accumulation and an active Nar-type nitrate reductase leads to NO and thence N2O production, and this can account for up to 20% of the nitrate catabolized