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ABSTRACT The type VIIb secretion system (T7SSb) is a multisubunit protein export machine found in Gram-positive Bacillota which plays a key role in interbacterial competition. The T7SSb secretes a variety of toxic effector proteins targeting closely related strains; however, the mechanism of secretion and the roles of numerous conserved genes within T7SSb gene clusters remain unknown. EsaD is a nuclease toxin secreted by the Staphylococcus aureus T7SSb, which forms a pre-secretion complex with its cognate immunity protein, EsaG, and chaperone EsaE. Encoded upstream of EsaD are three small secreted proteins of unknown function: EsxB, EsxC, and EsxD. Here, we show that these three proteins bind to EsaD and function as EsaD export factors and we report preliminary structural information for a complete T7SSb substrate pre-secretion complex. Cryo-electron microscopy of the EsaDEG trimer and the EsaDEG-EsxBCD hexamer shows that incorporation of EsxBCD confers an elongated conformation comprising a flexible globular cargo domain attached to a long narrow shaft that is likely to be crucial for efficient toxin export. IMPORTANCE Staphylococcus aureus is an opportunistic human pathogen associated with severe infections and antimicrobial resistance. S. aureus strains utilize a type VII secretion system to secrete toxins targeting competitor bacteria, likely facilitating colonization. EsaD is a nuclease toxin secreted by the type VII secretion system in many strains of S. aureus as well as other related bacterial species. Here, we identify three small proteins of previously unknown function as export factors, required for efficient secretion of EsaD. We show that these proteins bind to the transport domain of EsaD, forming a complex with a striking cane-like conformation.

Bacterial type III protein secretion systems inject effector proteins into eukaryotic host cells in order to promote survival and colonization of Gram-negative pathogens and symbionts. Secretion across the bacterial cell envelope and injection into host cells is facilitated by a so-called injectisome. Its small hydrophobic export apparatus components SpaP and SpaR were shown to nucleate assembly of the needle complex and to form the central "cup" substructure of a Salmonella Typhimurium secretion system. However, the in vivo placement of these components in the needle complex and their function during the secretion process remained poorly defined. Here we present evidence that a SpaP pentamer forms a 15 Å wide pore and provide a detailed map of SpaP interactions with the export apparatus components SpaQ, SpaR, and SpaS. We further refine the current view of export apparatus assembly, consolidate transmembrane topology models for SpaP and SpaR, and present intimate interactions of the periplasmic domains of SpaP and SpaR with the inner rod protein PrgJ, indicating how export apparatus and needle filament are connected to create a continuous conduit for substrate translocation.

Background: Existing research identified substantial gaps between NHS mental health services and the criminal justice system for individuals with enduring moderate to severe mental health needs (EMHN). A pilot study in Cornwall echoed these findings, identifying deficiencies in provision at the interface of police and mental health services. Aim: To explore the interagency management of individuals with EMHN as they come into contact with the police. Design: A mixed-methods approach within a community psychology framework to enhance the implementation of findings. Stage 1: policy review and clinical audit to identify a sample of mental health service users who were in contact with the police. Stage 2: case-linkage study of 80 service user journeys through services at the time of three types of police contact (Section 136 detention; arrest for criminal offence and contact that did not result in detention); and a health economics component including analysis of the actual cost of 55 service user journeys and enhanced service scenarios. Stage 3: local stakeholder consultation to validate and contextualise case-linkage findings, including a national event. Setting: The research site was the county of Cornwall within the organisational contexts of Cornwall Partnership NHS Foundation Trust and Devon & Cornwall Police. Sample: Proportionate stratified random sampling identified a sample of 80 cases examined in the case-linkage study from the 538 linked cases identified by the clinical audit. Data sources: Case-linkage and health economics data involved individuals’ police and mental health records; stakeholder consultation data involved focus groups and interviews. Results: Of the sample of 80 cases examined, 23 individuals had been detained under Section 136 of the Mental Health Act (1983: Great Britain. Mental Health Act 1983. Chapter 20. London: The Stationery Office; 1983) (accounting for 32 detentions), 52 had been detained in custody on suspicion of an offence (accounting for 126 arrests) and 15 had non-detention contact with the police. Findings showed that where police were aware of mental health needs and individuals were on caseload of a Mental Health Team, there was increased interaction and enhanced outcomes for service users and organisations. The health economics scenario modelling suggests that enhancing services has minimal effects on individual level costs compared with current practice. Conclusions: The research revealed discrepancy in police and mental health professionals’ assessment of risk and interpretation of protocol and highlighted the need for joint interagency protocols and training to improve information sharing between agencies to enhance the management of individuals with enduring moderate to severe mental health needs. Funding: The National Institute for Health Research Health Services and Delivery Research programme.

Abstract Background Health profession students develop practical skills whilst integrating theory with practice in a real world environment as an important component of their training. Research in the area of practice placements has identified challenges and barriers to the delivery of effective placement learning. However, there has been little research in podiatry and the question of which factors impact upon clinical educators' capacity to engage with the role remains an under‐researched area. This paper presents the second phase of an action research project designed to determine the factors that impact upon clinical educators' capacity to engage with the mentorship role. Methods An online survey was developed and podiatry clinical educators recruited through National Health Service (NHS) Trusts. The survey included socio‐demographic items, and questions relating to the factors identified as possible variables influencing clinical educator capacity; the latter was assessed using the ‘Clinical Educator Capacity to Engage’ scale (CECE). Descriptive statistics were used to explore demographic data whilst the relationship between the CECE and socio‐demographic factors were examined using inferential statistics in relation to academic profile, career profile and organisation of the placement. Results The survey response rate was 42 % (n = 66). Multiple linear regression identified four independent variables which explain a significant proportion of the variability of the dependent variable, ‘capacity to engage with clinical education’, with an adjusted R2 of 0.428. The four variables were: protected mentorship time, clinical educator relationship with university, sign‐off responsibility, and volunteer status. Conclusion The identification of factors that impact upon clinical educators' capacity to engage in mentoring of students has relevance for strategic planning and policy‐making with the emphasis upon capacity‐building at an individual level, so that the key attitudes and characteristics that are linked with good clinical supervision are preserved.

The motility and invasion of Plasmodium parasites is believed to require a cytoplasmic actin-myosin motor associated with a cell surface ligand belonging to the TRAP (thrombospondin-related anonymous protein) family. Current models of invasion usually invoke the existence of specific receptors for the TRAP-family ligands on the surface of the host cell; however, the identities of these receptors remain largely unknown. Here, we identify the GPI-linked protein Semaphorin-7A (CD108) as an erythrocyte receptor for the P. falciparum merozoite-specific TRAP homolog (MTRAP) by using a systematic screening approach designed to detect extracellular protein interactions. The specificity of the interaction was demonstrated by showing that binding was saturable and by quantifying the equilibrium and kinetic biophysical binding parameters using surface plasmon resonance. We found that two MTRAP monomers interact via their tandem TSR domains with the Sema domains of a Semaphorin-7A homodimer. Known naturally-occurring polymorphisms in Semaphorin-7A did not quantitatively affect MTRAP binding nor did the presence of glycans on the receptor. Attempts to block the interaction during in vitro erythrocyte invasion assays using recombinant proteins and antibodies showed no significant inhibitory effect, suggesting the inaccessibility of the complex to proteinaceous blocking agents. These findings now provide important experimental evidence to support the model that parasite TRAP-family ligands interact with specific host receptors during cellular invasion.

In a 500-household pilot, we tested an innovative approach to water demand management, implemented in collaboration with a water utility in a large city in the Middle East and North Africa (MENA) region. We provided a novel intervention, called a Water Savings Credit (WSC), which granted participants volumetric rebates on their water bills for their reductions in water consumption. WSCs were effective at encouraging conservation in our pilot in Marrakech. Our approach has the benefits of a price incentive, without the political risk of a tariff increase. For urban water utilities that provide highly subsidized services, this approach could ultimately pay for itself, or potentially result in net financial savings. Our approach may be especially effective in the countries of the MENA region, as the region has a high rate of subsidization for water services, and because it is facing increasing water scarcity from economic growth, urbanization, and climate change. HIGHLIGHTS A Water Savings Credit (WSC) is a novel intervention that provides a volumetric reward for reduced consumption.; WSCs were effective at encouraging conservation in our pilot in Marrakech.; WSCs have the potential to be more politically acceptable than rate increases and can protect equitable access while encouraging conservation.;

Extreme precipitation poses a major challenge for local governments, including the City and County of San Francisco, California, as flooding can damage and destroy infrastructure and property. As the climate continues to warm, reliable future precipitation projections are needed to provide the best possible information to decision makers. However, future changes in the magnitude of extreme precipitation are uncertain, as current state-of-the-art global climate models are typically run at relatively coarse horizontal resolutions that require the use of convective parameterization and have difficulty simulating observed extreme rainfall rates. Here, we performed ensembles of convection-permitting regional climate model simulations to investigate how five historically impactful extreme precipitation events over the San Francisco Bay Area could change if similar events occurred in future climates. We found that changes in storm-total precipitation depend strongly on storm type. Precipitation associated with an atmospheric river (AR) accompanied by an extratropical cyclone (ETC) is projected to increase at a rate exceeding (by up to 1.5 times) the theoretical Clausius Clapeyron scaling of 6–7% per °C warming. On the other hand, future precipitation changes are weak or negative for events characterized by an AR only, despite increases in precipitable water and integrated vapor transport that are similar to those of the co-occurring AR and ETC events. The differences in the sign of future precipitation change between AR-only events and co-occurring AR and ETC events is instead linked with changes in mid-tropospheric vertical velocity. Given that the majority of observed ARs are associated with an ETC, this research has important implications for future precipitation impacts over the Bay Area, as it indicates that storm-total precipitation associated with the most common type of storm event may increase by up to 26–37% in 2100 relative to historical.

Background: Health profession students develop practical skills whilst integrating theory with practice in a real world environment as an important component of their training. Research in the area of practice placements has identified challenges and barriers to the delivery of effective placement learning. However, there has been little research in podiatry and the question of which factors impact upon clinical educators' capacity to engage with the role remains an under-researched area. This paper presents the second phase of an action research project designed to determine the factors that impact upon clinical educators' capacity to engage with the mentorship role. Methods: An online survey was developed and podiatry clinical educators recruited through National Health Service (NHS) Trusts. The survey included socio-demographic items, and questions relating to the factors identified as possible variables influencing clinical educator capacity; the latter was assessed using the 'Clinical Educator Capacity to Engage' scale (CECE). Descriptive statistics were used to explore demographic data whilst the relationship between the CECE and socio-demographic factors were examined using inferential statistics in relation to academic profile, career profile and organisation of the placement. Results: The survey response rate was 42% (n = 66). Multiple linear regression identified four independent variables which explain a significant proportion of the variability of the dependent variable, 'capacity to engage with clinical education', with an adjusted R2 of 0.428. The four variables were: protected mentorship time, clinical educator relationship with university, sign-off responsibility, and volunteer status. Conclusion: The identification of factors that impact upon clinical educators' capacity to engage in mentoring of students has relevance for strategic planning and policy-making with the emphasis upon capacity-building at an individual level, so that the key attitudes and characteristics that are linked with good clinical supervision are preserved. [ABSTRACT FROM AUTHOR]

Information about several papers discussed at a "Implementing the Human Right to Water in the West Conference" held February 3-5, 2011 sponsored by the Willamette University in Salem, Oregon on Human Rights to Water is presented. Topics include the human rights to water and sanitation, western water law and conservation of water. The conference featured several officials including Jon Clyde, Terrence Green and Josh Weber.

Abstract Background Strains of the Beijing genotype of Mycobacterium tuberculosis (MTB) are reportedly associated with the virulence of tuberculosis (TB) infection, unfavorable outcomes of anti-TB treatment, and the global TB pandemic. Rv0679c, a hypothetical membrane protein related to host cell invasion, has a Beijing genotype-specific mutation at residue 142 (Asn142Lys). Antigenicity differences between Rv0679c-Asn142 (N-type) and Rv0679c-Lys142 (K-type) have been previously observed in mice antigen-antibody responses. However, the immune response to Rv0679c in humans remains unknown. Therefore, we aimed to investigate the anti-Rv0679c immune response in TB patients from the endemic and non-endemic regions of the Beijing MTB genotype. Methods We analyzed the Rv0679c-specific antibody responses in 84 subjects from the endemic region of the Beijing genotype MTB in China, including 45 pulmonary TB patients (C-PTB) and 39 healthy controls (C-HC), and 81 subjects from the Philippines (the endemic region of the non-Beijing genotype), including 51 pulmonary TB patients (P-PTB) and 30 healthy controls (P-HC). Anti-tuberculous-glycolipid (TBGL) antigen was used as the control antibody. Results TBGL IgG titers were higher in both C-PTB and P-PTB than those in their corresponding HC (C-PTB median 4.2, P-PTB median 11.2; C-PTB vs. P-PTB, p > 0.05), suggesting immune response comparability in PTB from two different countries. C-PTB showed a higher response compared to C-HC for anti-K-type IgG (53.3%) than anti-N-type IgG (6.67%); this response was not observed in P-PTB (both N-type and K-type 9.80%). Conclusion Dimorphic antigen Rv0679c was found to be associated with distinct immune response patterns, indicating the role of Beijing/non-Beijing genotype of MTB in stimulating specific responses in TB patients from the endemic region of Beijing MTB. Meanwhile, reactions to Rv0679c in patients and HC from non-endemic regions of the Beijing MTB may be caused by the response to the common epitope of Rv0679c N/K-type.

Background: The incidence of tuberculosis (TB) in the Philippines is 288/100,000 populations (2014), wherein 2% of new cases and 21% of retreatment cases are multidrug-resistant TB (MDR-TB). In addition, the rate of human immunodeficiency virus (HIV) infection has been alarmingly over the past 7 years in the subpopulation of men who have sex with men in the Philippines. In June 2016, there were 841 new HIV-seropositive individuals reported to the HIV/AIDS and Antiretroviral Therapy Registry of the Philippines. In the present study, we aimed to investigate the prevalence of HIV among MDR-TB patients in a Manila hospital from 2011 to 2015. Methods: TB patients who referred to the programmatic management of drug-resistant TB (2012 to 2015) were tested for MDR-TB (using Xpert MTB/RIF assay) and HIV infection. In addition, the available data that belong to patients before the introduction of the Xpert MTB/RIF assay were included. Results: A total of 4515 presumptive drug-resistant TB patients were screened (2012–2015) to determine the percentage of MDR-TB cases: 16% (2012), 14% (2013), and 11% (2014 and 2015). Among the MDR-TB patients, the percentage of HIV-positive cases increased yearly: 0.5% (2011), 3% (2012), 5% (2013), 9% (2014), and 15% (2015). The high mortality rate ranged from 42% to 66%. The cure rate among the enrolled MDR-TB cases was 47% in 2012, which increased from 27% in 2011, but it did not improve thereafter (46% in 2013 and 51% in 2014). Conclusion: A remarkable increase in the prevalence of HIV among MDR-TB patients was found. The raises are alarming and need urgent attention on different risk factors and/or living style of patients.

Tuberculosis (TB) is the second most common cause of death from infectious diseases and results in high socioeconomic losses to many countries. Proper diagnosis is the first step in TB eradication. To develop a rapid, simple, and accurate diagnostic TB test and to characterize the prevalence of Mycobacterium tuberculosis (MTB) genotypes and immune profiles of TB patients, a total of 37 TB patients and 30 healthy control (HC) from Metro Manila were enrolled. Loop-mediated isothermal amplification (LAMP) reliably detected MTB infection. Manila genotype was identified by spoligotyping method in all TB patients. Osteopontin (OPN), interferon-γ-induced protein 10 kDa (IP-10), and neutrophil counts were found to reflect the acute stage of MTB infection. The sensitivity and specificity were 94.6% and 93.3%, respectively, for both OPN and IP-10, and they were 83.8% and 78.6%, respectively, for neutrophils. The combination of OPN, IP-10, neutrophil count, IL-6, IL-8, TNF-α, MCP-1, platelets, galectin-9, and leukocyte count correctly identifies all the HC and 96.3% of TB patients. LAMP method may serve as a rapid, supportive method in addition to time-consuming culture methods. OPN, IP-10, and neutrophil counts are useful in detecting MTB infection and may have utility in monitoring the course of the disease.

Background: Substantial policy, communication and operational gaps exist between mental health services and the police for individuals with enduring mental health needs., Aims: To map and cost pathways through mental health and police services, and to model the cost impact of implementing key policy recommendations., Method: Within a case-linkage study, we estimated 1-year individual-level healthcare and policing costs. Using decision modelling, we then estimated the potential impact on costs of three recommended service enhancements: street triage, Mental Health Act assessments for all Section 136 detainees and outreach custody link workers., Results: Under current care, average 1-year mental health and police costs were £10 812 and £4552 per individual respectively (n = 55). The cost per police incident was £522. Models suggested that each service enhancement would alter per incident costs by between -8% and +6%., Conclusions: Recommended enhancements to care pathways only marginally increase individual-level costs., Competing Interests: Declaration of interest None., (© The Royal College of Psychiatrists 2017.)