Second-generation sulfonamide inhibitors of D-glutamic acid-adding enzyme: activity optimisation with conformationally rigid analogues of D-glutamic acid.

peer reviewedD-Glutamic acid-adding enzyme (MurD) catalyses the essential addition of d-glutamic acid to the cytoplasmic peptidoglycan precursor UDP-N-acetylmuramoyl-l-alanine, and as such it represents an important antibacterial drug-discovery target enzyme. Based on a series of naphthalene-N-sulfonyl-d-Glu derivatives synthesised recently, we synthesised two series of new, optimised sulfonamide inhibitors of MurD that incorporate rigidified mimetics of d-Glu. The compounds that contained either constrained d-Glu or related rigid d-Glu mimetics showed significantly better inhibitory activities than the parent compounds, thereby confirming the advantage of molecular rigidisation in the design of MurD inhibitors. The binding modes of the best inhibitors were examined with high-resolution NMR spectroscopy and X-ray crystallography. We have solved a new crystal structure of the complex of MurD with an inhibitor bearing a 4-aminocyclohexane-1,3-dicarboxyl moiety. These data provide an additional step towards the development of sulfonamide inhibitors with potential antibacterial activities

Rapid spread of complex change: a case study in inpatient palliative care

<p>Abstract</p> <p>Background</p> <p>Based on positive findings from a randomized controlled trial, Kaiser Permanente's national executive leadership group set an expectation that all Kaiser Permanente and partner hospitals would implement a consultative model of interdisciplinary, inpatient-based palliative care (IPC). Within one year, the number of IPC consultations program-wide increased almost tenfold from baseline, and the number of teams nearly doubled. We report here results from a qualitative evaluation of the IPC initiative after a year of implementation; our purpose was to understand factors supporting or impeding the rapid and consistent spread of a complex program.</p> <p>Methods</p> <p>Quality improvement study using a case study design and qualitative analysis of in-depth semi-structured interviews with 36 national, regional, and local leaders.</p> <p>Results</p> <p>Compelling evidence of impacts on patient satisfaction and quality of care generated 'pull' among adopters, expressed as a remarkably high degree of conviction about the value of the model. Broad leadership agreement gave rise to sponsorship and support that permeated the organization. A robust social network promoted knowledge exchange and built on an existing network with a strong interest in palliative care. Resource constraints, pre-existing programs of a different model, and ambiguous accountability for implementation impeded spread.</p> <p>Conclusions</p> <p>A complex, hospital-based, interdisciplinary intervention in a large health care organization spread rapidly due to a synergy between organizational 'push' strategies and grassroots-level pull. The combination of push and pull may be especially important when the organizational context or the practice to be spread is complex.</p

The impact of collagen fibril polarity on second harmonic generation microscopy

In this work, we report the implementation of interferometric second harmonic generation (SHG) microscopy with femtosecond pulses. As a proof of concept, we imaged the phase distribution of SHG signal from the complex collagen architecture of juvenile equine growth cartilage. The results are analyzed in respect to numerical simulations to extract the relative orientation of collagen fibrils within the tissue. Our results reveal large domains of constant phase together with regions of quasi-random phase, which are correlated to respectively high- and low-intensity regions in the standard SHG images. A comparison with polarization-resolved SHG highlights the crucial role of relative fibril polarity in determining the SHG signal intensity. Indeed, it appears that even a well-organized noncentrosymmetric structure emits low SHG signal intensity if it has no predominant local polarity. This work illustrates how the complex architecture of noncentrosymmetric scatterers at the nanoscale governs the coherent building of SHG signal within the focal volume and is a key advance toward a complete understanding of the structural origin of SHG signals from tissues

MONNET: Monitoring Pedestrians with a Network of Loosely-Coupled Cameras

MONNET is a visual surveillance system for tracking pedestrians over extended premises. The MONNET system is composed of intelligent nodes, which exchange information on the individually tracked pedestrians in an asynchronous manner. Each node in MONNET builds an appearance model for every observed pedestrian and compares it with models received from other nodes. The compact appearance models based on colour cues and face biometrics are stored locally on each node. The system is dynamically reconfigurable since its design allows for adding/removing nodes in a simple manner, comparable to the ‘plug and play ’ technology. MONNET also contains an optional ‘observer ’ node for interactive data visualization. This node displays a user interface which allows a human operator to observe and to interact in real-time with the distributed tracking process. MONNET was extensively tested with and without user input, and it is able to function correctly in both modes

Multimodality imaging in marantic endocarditis associated with cancer: a multicentric cohort study

International audienceAims We aimed to assess the role of multimodality imaging (MMI) in the diagnosis of marantic endocarditis (ME) associated with cancers and to describe clinical characteristics, management, and outcome of these patients. Methods and results In a retrospective multicentric study including four tertiary centers for treatment of endocarditis in France and Belgium, patients with a diagnosis of ME were included. Demographic, MMI (echocardiography, computed tomography (CT) and 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F -FDG PET/CT) and management data were collected. Long-term mortality was analyzed. Between November 2011 and August 2021, 47 patients with a diagnosis of ME were included. Mean age was 65 +/- 11 years. ME occurred in 43 cases (91%) on native valves. Vegetations were detected by echocardiography in all cases and in 12 cases (26%) by CT. No patient had an increased cardiac 18F -FDG valve uptake. The most common cardiac valve involved was aortic (34 cases, 73%). 22 patients (46%) had a known cancer before ME and 25 cases (54%) were diagnosed thanks to multimodality imaging. 18-FDG PET/CT was performed in 30 patients (64%) and allowed a new diagnosis of cancer in 14 patients (30%). Systemic embolism was frequent (40 patients, 85% of cases). 41 patients (87%) were treated medically with anticoagulation therapy. One year mortality was 55% (26 patients). Conclusions ME remains associated with high risk of complications and death

Modifications in dietary and alcohol intakes between before and after cancer diagnosis: Results from the prospective population-based NutriNet-Sante cohort

Postdiagnosis diet and alcohol consumption may be associated with cancer prognosis, recurrence and mortality. Our aim was to investigate food, nutrient and alcohol intake variations between before and after cancer diagnosis and their determinants in a prospective cohort. Subjects (n=696) were incident cancer cases diagnosed in the NutriNet-Sante cohort between 2009 and 2016. Food, nutrient and alcohol intakes were prospectively collected using repeated nonconsecutive 24-hr dietary records since subjects' inclusion (i.e. an average of 2 y before diagnosis). Mean number of dietary records per subject was 5.9 before and 8.1 after diagnosis. All dietary data before and after diagnosis were compared by mixed models. Factors associated with the main dietary changes observed were also investigated using multivariable logistic regressions. We observed a decrease in intakes of vegetables (mean decrease in intake in patients who decreased their intake=-102.479.8 g/d), dairy products (-93.982.8 g/d), meat/offal (-35.5 +/- 27.8/d), soy products (-85.8 +/- 104.1 g/d), sweetened soft drinks (-77.9 +/- 95.4 g/d), and alcoholic drinks (-92.9 +/- 119.9 g/d), and an increase in broths (42.1 +/- 34.9 g/d) and fats/sauces (18.0 +/- 13.4 g/d). We observed a decrease in energy intake (-377.2 +/- 243.5 kcal/d) and in intakes of alcohol (-7.6 +/- 9.4 g/d) proteins (-17.4 +/- 12.5 g/d), and several vitamins (p<0.05) and micronutrients (p<0.05). Conversely, lipid (19.4 +/- 14.6 g/d), SFA (9.3 +/- 7.0 g/d), MUFA (8.3 +/- 6.3 g/d) and vitamin E (3.9 +/- 3.3 mg/d) intakes increased after diagnosis. This large prospective study suggests that cancer diagnosis is a key period for nutritional changes. It highlights some healthy behaviors such as a decrease in alcohol and sweetened drink consumption, but also less favorable trends, such as a decrease in vegetable consumption and in many vitamin and mineral intakes. These results provide insights to identify and target recommendations to put forward for better nutritional care of cancer survivors. What's new? Postdiagnosis diet and alcohol consumption may be associated with cancer prognosis, recurrence and mortality. In this study, the authors analyzed the socio-demographic, economic, lifestyle and clinical factors associated with these dietary changes. They found that, while there was a decrease in alcohol consumption, there were a number of less favorable trends, such as decreased vegetable consumption and nutrient intake. These results offer insights to identify and target dietary recommendations to improve prognosis and quality of life for cancer patients

Evaluating the Recombinant T24H Enzyme-Linked Immunoelectrotransfer Blot Assay for the Diagnosis of Neurocysticercosis in a Panel of Samples from a Large Community-Based Randomized Control Trial in 60 Villages in Burkina Faso.

Current guidelines for the diagnosis of neurocysticercosis (NCC) recommend the use of the lentil lectin-bound glycoprotein enzyme-linked immunoelectrotransfer blot assay (LLGP-EITB) as the reference standard for serological testing. In response to the drawbacks involved with the use of the LLGP-EITB, a recombinant T24H antigen (rT24H) EITB assay was developed, with promising results. However, the test has yet to be evaluated among individuals from sub-Saharan Africa (SSA). The aim of the present study was to investigate the performance of the rT24H EITB assay for the detection of NCC cases in a panel of serum samples (N = 366, of which 173 patients presented with epileptic seizures and/or severe chronic headaches, and 193 matched manifestation-free participants) collected as part of a large community-based trial in Burkina Faso. A perfect agreement between the rT24H EITB and the native gp24 (and its homodimer, gp42) LLGP-EITB was found (kappa value of 1.0). Furthermore, among patients with the neurological manifestations of interest who underwent a computed tomography scan, the rT24H EITB and native antigen LLGP-EITB had a comparable ability to correctly identify NCC cases with multiple viable (rT24H: sensitivity: 80.0%), single viable (66.7%), and calcified/degenerating cysts only (25.0%), albeit for multiple viable and calcified cysts, the rT24H estimated sensitivity seemed lower, but more uncertain, than previously reported. The rT24H EITB specificity was high (98.2%) and in line with previous studies. This study confirms the value of the recombinant rT24H EITB as an alternative to the native antigen LLGP-EITB for the diagnosis of NCC in a SSA community setting

Infective endocarditis with neurological complications: Delaying cardiac surgery is associated with worse outcome

International audienc