catena-Poly[[[bis­(N,N-dimethyl­formamide)iron(II)]-{μ-2,2′-bis­(diphenyl­phosphino­yl)-N,N′-[(1R,2R)-cyclo­hexane-1,2-di­yl]dibenzamide}] bis­(perchlorate) N,N-dimethyl­formamide disolvate]

The title extended solid coordination compound, {[Fe(C44H40N2O4P2)(C3H7NO)2](ClO4)2·2C3H7NO}n, was crystallized un­ex­pectedly from the reaction mixture containing the Trost ligand (1R,2R)-(+)-1,2-diamino­cyclo­hexane-N,N′-bis­(2′-di­phenyl­phosphinobenzo­yl) and Fe(ClO4)2·6H2O in a 1:1 ratio in dimethyl­formamide (DMF) under reflux conditions. The polymeric complex is characterized by FeII metal centers that are coordinated by two oxidized Trost ligands, each coordinated in a bidentate fashion in a square plane, along with two DMF mol­ecules above and below the plane [average Fe—ODMF = 2.086 (4) Å], forming an overall pseudo-octa­hedral geometry. The Trost ligand binds adjacent FeII centers, each FeII being bound through the O atom of one of the phosphine oxides [average Fe—OPPh2 = 2.115 (4) Å] and the carbonyl O atom of the adjacent amide [average Fe—Oamide = 2.192 (3) Å]. Disorder is observed in the co-solvated solvent: there are two DMF mol­ecules per FeII centre, which were modeled as one DMF mol­ecule with complete occupancy and the other being modeled in two positions with equal occupancy. Disorder was also observed with one of the perchlorate anions, which was modeled in two positions with 0.75:0.25 occupancy

Carbon­yl[tris­(3,5-diphenyl­pyrazol-1-yl-κN 2)methane]copper(I) hexa­fluorido­phosphate–dichloro­methane–diethyl ether (4/3/1)

In the title compound, [Cu(C46H34N6)(CO)]PF6·0.75CH2Cl2·0.25C4H10O, the CuI atom is coordinated by three N atoms from the tridentate chelating tris­(3,5-diphenyl­pyrazol-1-yl)methane ligand (average Cu—N distance = 2.055 Å) and the C atom from a carbon monoxide ligand in a distorted tetra­hedral coordination geometry. The average N—Cu—N angle between adjacent pyrazole-ring-coordinated N atoms is 88.6°, while the average N—Cu—C angle between the pyrazole-bound N atom and the C atom of carbon monoxide is 126.3°. One of the 3-phenyl rings of the tris­(pyrazol­yl)methane ligand is disordered over two sites each with an occupancy factor of 0.50. The structure also exhibits disorder of the monosolvate that has been modeled with 0.75 CH2Cl2 and 0.25 Et2O occupancy

Protocol evaluating the effectiveness of a school-based group programme for parents of children at risk of ADHD: The 'PArents, Teachers and CHildren WORKing together (PATCHWORK)' cluster RCT protocol

Introduction Early intervention for childhood behavioural problems may help improve health and educational outcomes in affected children and reduce the likelihood of developing additional difficulties. The National Institute for Health and Clinical Excellence guidelines for attention deficit/hyperactivity disorder (ADHD), a common childhood behavioural disorder, recommend a stepped care approach for the identification and management of these problems. Parents of children with high levels of hyperactivity and inattention may benefit from intervention programmes involving behavioural management and educational approaches. Such interventions may be further enhanced by providing training and feedback to teachers about the strategies discussed with parents. In relation to children with high levels of hyperactivity, impulsiveness and inattention, we aim to test the feasibility and effectiveness of a parenting programme (with and without an accompanying teacher session) in primary schools. Methods and analysis This clustered (at the level of school) randomised controlled trial (RCT) focuses on children in their first four school years (ages 4–8 years) in the East Midlands area of England. Parents will complete a screening measure, the Strengths and Difficulties Questionnaire, to identify children with high levels of hyperactivity/inattention. Three approaches to reducing hyperactivity and attention problems will be compared: a group programme for parents (parent-only intervention); group programme for parents combined with feedback to teachers (combined intervention); and waiting list control (no intervention). Differences between arms on the short version of Conners’ Parent and Teacher Rating Scales Revised will be compared and also used to inform the sample size required for a future definitive cluster RCT. A preliminary cost-effectiveness analysis will also be conducted. Ethics and dissemination The outcomes of this study will inform policy makers about the feasibility, acceptability and effectiveness of delivering targeted behavioural interventions within a school setting. The study has received ethical approval from the University of Nottingham Medical School Ethics Committee

The Dynamics of Pyrethroid Nesistance in Anopheles Arabiensis from Zanzibar and an Assessment of the Underlying Genetic Basis.

The emergence of pyrethroid resistance in the malaria vector, Anopheles arabiensis, threatens to undermine the considerable gains made towards eliminating malaria on Zanzibar. Previously, resistance was restricted to the island of Pemba while mosquitoes from Unguja, the larger of the two islands of Zanzibar, were susceptible. Here, we characterised the mechanism(s) responsible for resistance on Zanzibar using a combination of gene expression and target-site mutation assays. WHO resistance bioassays were conducted using 1-5d old adult Anopheles gambiae s.l. collected between 2011 and 2013 across the archipelago. Synergist assays with the P450 inhibitor piperonyl-butoxide were performed in 2013. Members of the An. gambiae complex were PCR-identified and screened for target-site mutations (kdr and Ace-1). Gene expression in pyrethroid resistant An. arabiensis from Pemba was analysed using whole-genome microarrays. Pyrethroid resistance is now present across the entire Zanzibar archipelago. Survival to the pyrethroid lambda-cyhalothrin in bioassays conducted in 2013 was 23.5-54.3% on Unguja and 32.9-81.7% on Pemba. We present evidence that resistance is mediated, in part at least, by elevated P450 monoxygenases. Whole-genome microarray scans showed that the most enriched gene terms in resistant An. arabiensis from Pemba were associated with P450 activity and synergist assays with PBO completely restored susceptibility to pyrethroids in both islands. CYP4G16 was the most consistently over-expressed gene in resistant mosquitoes compared with two susceptible strains from Unguja and Dar es Salaam. Expression of this P450 is enriched in the abdomen and it is thought to play a role in hydrocarbon synthesis. Microarray and qPCR detected several additional genes putatively involved in this pathway enriched in the Pemba pyrethroid resistant population and we hypothesise that resistance may be, in part, related to alterations in the structure of the mosquito cuticle. None of the kdr target-site mutations, associated with pyrethroid/DDT resistance in An. gambiae elsewhere in Africa, were found on the islands. The consequences of this resistance phenotype are discussed in relation to future vector control strategies on Zanzibar to support the ongoing malaria elimination efforts on the islands

Modelling frontal discontinuities in wind fields

A Bayesian procedure for the retrieval of wind vectors over the ocean using satellite borne scatterometers requires realistic prior near-surface wind field models over the oceans. We have implemented carefully chosen vector Gaussian Process models; however in some cases these models are too smooth to reproduce real atmospheric features, such as fronts. At the scale of the scatterometer observations, fronts appear as discontinuities in wind direction. Due to the nature of the retrieval problem a simple discontinuity model is not feasible, and hence we have developed a constrained discontinuity vector Gaussian Process model which ensures realistic fronts. We describe the generative model and show how to compute the data likelihood given the model. We show the results of inference using the model with Markov Chain Monte Carlo methods on both synthetic and real data

High Annual Risk of Tuberculosis Infection among Nursing Students in South India: A Cohort Study

Background: Nurses in developing countries are frequently exposed to infectious tuberculosis (TB) patients, and have a high prevalence of TB infection. To estimate the incidence of new TB infection, we recruited a cohort of young nursing trainees at the Christian Medical College in Southern India. Annual tuberculin skin testing (TST) was conducted to assess the annual risk of TB infection (ARTI) in this cohort. Methodology/Principal Findings: 436 nursing students completed baseline two-step TST testing in 2007 and 217 were TST-negative and therefore eligible for repeat testing in 2008. 181 subjects completed a detailed questionnaire on exposure to tuberculosis from workplace and social contacts. A physician verified the questionnaire and clinical log book and screened the subjects for symptoms of active TB. The majority of nursing students (96.7%) were females, almost 84% were under 22 years of age, and 80% had BCG scars. Among those students who underwent repeat testing in 2008, 14 had TST conversions using the ATS/CDC/IDSA conversion definition of 10 mm or greater increase over baseline. The ARTI was therefore estimated as 7.8% (95%CI: 4.3-12.8%). This was significantly higher than the national average ARTI of 1.5%. Sputum collection and caring for pulmonary TB patients were both high risk activities that were associated with TST conversions in this young nursing cohort. Conclusions: Our study showed a high ARTI among young nursing trainees, substantially higher than that seen in the general Indian population. Indian healthcare providers and the Indian Revised National TB Control Programme will need to implement internationally recommended TB infection control interventions to protect its health care workforce

PIP5KIβ Selectively Modulates Apical Endocytosis in Polarized Renal Epithelial Cells

Localized synthesis of phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2] at clathrin coated pits (CCPs) is crucial for the recruitment of adaptors and other components of the internalization machinery, as well as for regulating actin dynamics during endocytosis. PtdIns(4,5)P2 is synthesized from phosphatidylinositol 4-phosphate by any of three phosphatidylinositol 5-kinase type I (PIP5KI) isoforms (α, β or γ). PIP5KIβ localizes almost exclusively to the apical surface in polarized mouse cortical collecting duct cells, whereas the other isoforms have a less polarized membrane distribution. We therefore investigated the role of PIP5KI isoforms in endocytosis at the apical and basolateral domains. Endocytosis at the apical surface is known to occur more slowly than at the basolateral surface. Apical endocytosis was selectively stimulated by overexpression of PIP5KIβ whereas the other isoforms had no effect on either apical or basolateral internalization. We found no difference in the affinity for PtdIns(4,5)P2-containing liposomes of the PtdIns(4,5)P2 binding domains of epsin and Dab2, consistent with a generic effect of elevated PtdIns(4,5)P2 on apical endocytosis. Additionally, using apical total internal reflection fluorescence imaging and electron microscopy we found that cells overexpressing PIP5KIβ have fewer apical CCPs but more internalized coated structures than control cells, consistent with enhanced maturation of apical CCPs. Together, our results suggest that synthesis of PtdIns(4,5)P2 mediated by PIP5KIβ is rate limiting for apical but not basolateral endocytosis in polarized kidney cells. PtdIns(4,5)P2 may be required to overcome specific structural constraints that limit the efficiency of apical endocytosis. © 2013 Szalinski et al

Design, Construction, and Test of Compact, Distributed-Charge, X-Band Accelerator Systems that Enable Image-Guided, VHEE FLASH Radiotherapy.

The design and optimization of laser-Compton x-ray systems based on compact distributed charge accelerator structures can enable micron-scale imaging of disease and the concomitant production of beams of Very High Energy Electrons (VHEEs) capable of producing FLASH-relevant dose rates. The physics of laser-Compton x-ray scattering ensures that the scattered x-rays follow exactly the trajectory of the incident electrons, thus providing a route to image-guided, VHEE FLASH radiotherapy. The keys to a compact architecture capable of producing both laser-Compton x-rays and VHEEs are the use of X-band RF accelerator structures which have been demonstrated to operate with over 100 MeV/m acceleration gradients. The operation of these structures in a distributed charge mode in which each radiofrequency (RF) cycle of the drive RF pulse is filled with a low-charge, high-brightness electron bunch is enabled by the illumination of a high-brightness photogun with a train of UV laser pulses synchronized to the frequency of the underlying accelerator system. The UV pulse trains are created by a patented pulse synthesis approach which utilizes the RF clock of the accelerator to phase and amplitude modulate a narrow band continuous wave (CW) seed laser. In this way it is possible to produce up to 10 μA of average beam current from the accelerator. Such high current from a compact accelerator enables production of sufficient x-rays via laser-Compton scattering for clinical imaging and does so from a machine of "clinical" footprint. At the same time, the production of 1000 or greater individual micro-bunches per RF pulse enables > 10 nC of charge to be produced in a macrobunch of < 100 ns. The design, construction, and test of the 100-MeV class prototype system in Irvine, CA is also presented

B Cells Regulate Neutrophilia during Mycobacterium tuberculosis Infection and BCG Vaccination by Modulating the Interleukin-17 Response

We have previously demonstrated that B cells can shape the immune response to Mycobacterium tuberculosis, including the level of neutrophil infiltration and granulomatous inflammation at the site of infection. The present study examined the mechanisms by which B cells regulate the host neutrophilic response upon exposure to mycobacteria and how neutrophilia may influence vaccine efficacy. To address these questions, a murine aerosol infection tuberculosis (TB) model and an intradermal (ID) ear BCG immunization mouse model, involving both the μMT strain and B cell-depleted C57BL/6 mice, were used. IL (interleukin)-17 neutralization and neutrophil depletion experiments using these systems provide evidence that B cells can regulate neutrophilia by modulating the IL-17 response during M. tuberculosis infection and BCG immunization. Exuberant neutrophilia at the site of immunization in B cell-deficient mice adversely affects dendritic cell (DC) migration to the draining lymph nodes and attenuates the development of the vaccine-induced Th1 response. The results suggest that B cells are required for the development of optimal protective anti-TB immunity upon BCG vaccination by regulating the IL-17/neutrophilic response. Administration of sera derived from M. tuberculosis-infected C57BL/6 wild-type mice reverses the lung neutrophilia phenotype in tuberculous μMT mice. Together, these observations provide insight into the mechanisms by which B cells and humoral immunity modulate vaccine-induced Th1 response and regulate neutrophila during M. tuberculosis infection and BCG immunization. © 2013 Kozakiewicz et al

Early efficacy of CABG care delivery in a low procedure-volume community hospital: operative and midterm results

BACKGROUND: The Leapfrog Group recommended that coronary artery bypass grafting (CABG) surgery should be done at high volume hospitals (>450 per year) without corresponding surgeon-volume criteria. The latter confounds procedure-volume effects substantially, and it is suggested that high surgeon-volume (>125 per year) rather than hospital-volume may be a more appropriate indicator of CABG quality. METHODS: We assessed 3-year isolated CABG morbidity and mortality outcomes at a low-volume hospital (LVH: 504 cases) and compared them to the corresponding Society of Thoracic Surgeons (STS) national data over the same period (2001–2003). All CABGs were performed by 5 high-volume surgeons (161–285 per year). "Best practice" care at LVH – including effective practice guidelines, protocols, data acquisition capabilities, case review process, dedicated facilities and support personnel – were closely modeled after a high-volume hospital served by the same surgeon-team. RESULTS: Operative mortality was similar for LVH and STS (OM: 2.38% vs. 2.53%), and the corresponding LVH observed-to-expected mortality (O/E = 0.81) indicated good quality relative to the STS risk model (O/E<1). Also, these results were consistent irrespective of risk category: O/E was 0, 0.9 and 1.03 for very-low risk (<1%), low risk (1–3%) and moderate-to-high risk category (>3%), respectively. Postoperative leg wound infections, ventilator hours, renal dysfunction (no dialysis), and atrial fibrillation were higher for LVH, but hospital stay was not. The unadjusted Kaplan-Meier survival for the LVH cohort was 96%, 94%, and 92% at one, two, and three years, respectively. CONCLUSION: Our results demonstrated that high quality CABG care can be achieved at LVH programs if 1) served by high volume surgeons and 2) patient care procedures similar to those of large programs are implemented. This approach may prove a useful paradigm to ensure high quality CABG care and early efficacy at low volume institutions that wish to comply with the Leapfrog standards