Buteo regalis) across Wyoming, USA, 2011–2013. We also tested correlations of territory re-occupancy with oil and gas infrastructure—a leading cause of habitat modification throughout the range of this species of conservation concern. Probability of re-occupancy was not related to any covariates we investigated in 2011, had a strong negative relationship with cover of sagebrush (Artemisia spp.) in 2012, was slightly higher for territories with artificial platforms than other nest substrates in 2013, and had a positive relationship with abundance of ground squirrels (Urocitellus spp.) that was strong in 2012 and weak in 2013. Associations with roads were weak and varied by year, road-type, and scale: in 2012, re-occupancy probability had a weak positive correlation with density of roads not associated with oil and gas fields at the territory-scale; however, in 2013 re-occupancy had a very weak negative correlation with density of oil and gas field roads near nest sites (≤500 m). Although our results indicate re-occupancy of breeding territories by ferruginous hawks was compatible with densities of anthropogenic infrastructure in our study area, the lack of relationships between oil and gas well density and territory re-occupancy may have occurred because pre-treatment data were unavailable. We used probabilistic sampling at a broad spatial extent, methods to account for imperfect detection, and conducted extensive prey sampling; nonetheless, future research using before-after-control-impact designs is needed to fully assess impacts of oil and gas development on ferruginous hawks.Grassland and shrubland birds are declining globally due in part to anthropogenic habitat modification. Because population performance of these species is also influenced by non-anthropogenic factors, it is important to incorporate all relevant ecological drivers into demographic models. We used design-based sampling and occupancy models to test relationships of environmental factors that influence raptor demographics with re-occupancy of breeding territories by ferruginous hawks ( Habitat heterogeneity can regulate animal populations through effects on individual fitness, survival, and reproduction . Qualityth century )e (AICc) . At eachr Arnold , to haveionships .We located 67 ferruginous hawk territories during nest surveys in 2010, which we monitored for re-occupancy during 2011. Nest surveys in 2011 resulted in the addition of 38 territories, for a total sample of 105 territories monitored for re-occupancy during 2012 and 2013.squirrel = 0.71, 95% CI = 0.27–1.16), a strong negative relationship to percent cover of sagebrush , and a weak positive relationship to length of improved roads not associated with oil and gas developments at the territory-extent , and was higher for artificial nest structures  suggest this relationship was not important , but strong overlap of coefficient 95% CI with zero suggest this relationship was not important. We did not consider covariate relationships in other competitive models , and weak in 2012  and 2013 . We did not test this explicitly, but the relationship of detection to nest height in 2011 appeared non-linear: detection probability increased from 0.14 to 0.98 as nest height increased from 0 m to 6 m, but detection stabilized at >0.99 for nests with heights from 6 m to 15 m  and pocket gophers (Thomomys spp.). Although management to reduce sagebrush cover has occurred in our study area, we are not aware of any affected ferruginous hawk territories in our sample. We therefore interpret this result to reflect higher probability of re-occupancy for ferruginous hawks in areas in which sagebrush naturally occurs at lower density, including badlands, playas, salt desert shrublands, and prairies.Ferruginous hawks are associated with low vegetative cover throughout their range  and our We found some evidence to support previous research suggesting re-occupancy rates of ferruginous hawks were higher on artificial nest platforms than other substrates , 61. AvaOur results affirm the importance of accounting for influences of year and site characteristics on detection of raptors. Though generally high, detection rates were <1, influenced by nest height, and varied between years. Height of ferruginous hawk nests was strongly correlated with detection probability during the first year of re-occupancy surveys when observers were naïve to nest site locations, and less strongly correlated in subsequent years. Lack of correlation between detection and substrate groups of Ayers and Anderson  may alsoThe lack of relationships between re-occupancy probability and covariates during the first year of our study (2011) was likely the result of smaller sample sizes and less time for territories to transition from their initial occupied state. Longer-term studies using multi-season occupancy models, larger sample sizes, and year-specific covariates could, thus, help clarify the relative importance of the different environmental factors that we found were related to re-occupancy between years. Future research could also benefit from longer data sets because disturbance may take years or generations to affect patterns of occupancy for long-lived organisms, like raptors, that exhibit high degrees of site-fidelity and natal philopatry . In the n = 12) with occupied nest sites ≤500 m from active well pads—the extent at which we predicted disturbance would be greatest. Because our study was conducted post-construction and monitored recently occupied territories, it is possible that negative impacts that might have been incurred when pairs initially selected territories were not captured. In addition, it is possible that occupied sites in close proximity to infrastructure had combinations of characteristics that maximized benefits and minimized costs for raptors occupying developed areas, or were occupied by individuals tolerant of disturbance. We therefore suggest before-after control-impact [Despite stratification by density of oil and gas wells, our sample contained few territories . While our results indicate re-occupancy of territories by ferruginous hawks was compatible with densities of oil and gas infrastructure observed during this study, we emphasize that our findings do not imply territory re-occupancy is unaffected by higher densities of infrastructure, or that other aspects of ferruginous hawk behavior and ecology are not affected by oil and gas development.Our results suggest efforts to conserve ferruginous hawk nest sites and habitat should be focused on areas with abundant ground squirrels and low natural sagebrush cover, and provide additional support for continued use of artificial nest platforms for habitat enhancement and to mitigate loss of natural nest substrates . Our stuWe emphasize the importance and feasibility of using probabilistic sampling and methods that account for imperfect detection to monitor species of conservation concern at broad spatial extents. We suggest our monitoring approach and sample of territories will increase in value as longer time-series permit use of more complex, multi-season and multi-state models that can be useful for monitoring ferruginous hawks relative to multiple factors, including accelerating development of energy resources.S1 Appendix(DOCX)Click here for additional data file.S2 Appendix(DOCX)Click here for additional data file.


Lipochitooligosaccharides (LCOs) produced by rhizobia act as return signals to the host plant and are recognized by specific lysine motif receptor like kinases, which triggers a signal cascade leading to nodulation of legume roots. LCOs also enhance plant growth, particularly when plants are stressed. Chitooligosaccharides activate plant immune responses, providing enhanced resistance against diseases. Co-inoculation of rhizobia with other plant growth promoting rhizobacteria (PGPR) can improve nodulation and crop growth. PGPR also alleviate plant stress by secreting signal compounds including phytohormones and antibiotics. Thuricin 17, a small bacteriocin produced by a phytomicrobiome member promotes plant growth. Lumichrome synthesized by soil rhizobacteria function as stress-sensing cues. Inter-organismal signaling can be used to manage/engineer the phytomicrobiome to enhance crop productivity, particularly in the face of stress. Stressful conditions are likely to become more frequent and more severe because of climate change.The organisms of the phytomicrobiome use signal compounds to regulate aspects of each other’s behavior. Legumes use signals (flavonoids) to regulate rhizobial  The perspectives provided in this theme volume illustrate that members of the phytomicrobiome utilize inter-organismal signal compounds to affect the behavior of the plants they associate with, and signal compounds from the plants regulate the behavior of the phytomicrobiome. Presumably, one organism alters the behavior of another for its own benefit, but often to the benefit of the other organism as well, leading to mutualistic symbiosis. An example of this is improved stress tolerance in a plant by a signal compound from an associated microbe, where the resulting enhanced plant growth means expanded niche space and more reduced carbon for the specific phytomicrobiome member.Nod genes involved in synthesis of nodulation factors  necessitates a filtering system in the plants, disallowing unsuitable microorganisms, perhaps pathogens that could harm their tissues. On the other side, a microbe entering a disadvantageous plant would risk being recognized as unacceptable and killed. Signal/recognition compounds facilitate communication between mutually beneficial organisms and ensure continuum of their relationship until senescence. Flavonoids  in the rhizosphere are constituents of root exudates and well studied for their function as legume-to-rhizobia signal compounds . Their stors NF; . Alteredtors NF; . Flavonotors NF; . Flavonotors NF; . Thus, tNod genes in some rhizobia .A range of very diverse non-flavonoid compounds present in the root exudates also induces rhizobia : betainerhizobia , aldonicrhizobia . The jasNod-genes secrete signals (Nod factors) back to the plant: lipochitooligosaccharides (LCOs) and exopolysaccharides (EPS). LCOs are conserved at the core but are diverse due to degree of saturation and the substitutions (glycosylation or sulfation) in the N-Acetyl chain at both reducing ends and vary widely between different rhizobial species, which are essential for host plant specificity (NSP1 and NSP2) and encodes GRAS domain transcription factors involved in nodulation specific functions. They are associated with promoters of Nodulation inception genes (NIN) and early nodulation genes (ENOD) and ensure that nodulation is stimulated under appropriate circumstances  application of correct Nod factors (LCOs isolated from B. elkanii) trigger formation of complete and anatomically precise, albeit, empty nodules  is known to supress plant immunity  have been shown to facilitate colonization of rhizobia in roots, prevent MAPK signaling, supress the plant immune system, affect formation of nitrogen-fixing nodules, timing of nodule establishment and final number of nodules formed (Effector proteins secreted by pathogens trigger effector mediated immunity (ETI) in plants due to activation of resistance (R) genes encoding nucleotide-binding site—leucine rich repeat proteins . Leucines formed . Interess formed .Bacteroid differentiation inside the nodule is regulated by antimicrobial peptides (nodule cysteine rich peptides), which functions similar to plant defensins . The bacBacillus species. Inoculation of Rhizobium with Bacillus strains improved root structure and nodule formation in bean, pigeon pea and soybean  secrete phytohormones, such as cytokinins, gibberellins, auxin, and ACC deaminase and influence plant growth and functions  changes the hormone levels of Arabidopsis and soybean (increased IAA and SA) and causes profound alterations in the proteome  involved in synthesis of spermidine, a plant growth stimulating polyamine , leading to greater production of biomass in many plants , related to enhanced starch and ethylene metabolism. Adversely, 10-fold greater concentrations can retard plant growth and development  accelerates leaf production, onset of stem elongation, and leaf area development (at a concentration of 5 × 10elopment . Similarelopment . Lumichrelopment .Azospirillum in wheat) and function in as biocontrol , the length of the lipid side chain dictates characteristics of the signal compound’s activity  in the laboratory can be overcome by culture independent techniques such as metagenomics, metaproteomics, and metabolomics and usage of next generation sequencing tools to understand the complexity of the phytomicrobiome . Our abiIt is clear that members of the phytomicrobiome exchange signal compounds that are effective at hormonal concentrations, so that inter-organismal, indeed, inter-kingdom exohormones are now understood to play a crucial role in controlling the growth, composition and development of plants, including the crop plants that we depend on as food sources. The commercial deployment of LCOs in non-legume crop plants  indicateThe DS conducts research in collaboration with Inocucor Technologies, which manufactures and sells microbial consortia for inoculation on plants, where the research is funded through a Canadian Federal Government program (Mitacs) which levers industrial funding. The other authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Dengue, a global health threat, is a leading cause of morbidity and mortality in most tropical and subtropical countries. Dengue can range from asymptomatic, relatively mild dengue fever to severe and life-threatening dengue hemorrhagic fever. Disease severity and outcome is largely associated with the host immune response. Several candidate vaccines in clinical trials appear promising as effective measures for dengue disease control. Vaccine development has been hampered by safety and efficacy issues, driven by a lack of understanding of the host immune response. This review focuses on recent research findings on the dengue host immune response, particularly in humans, and the relevance of these findings to challenges in vaccine development. Aedes aegypti and Aedes albopictus, due to urbanization and climate change, and increase in population. A. aegypti, a mosquito prevalent in the tropics, is closely associated with large dengue epidemics due to its ability to efficiently transmit DENV. In contrast, the habitat range of A. albopictus is not limited to the tropics but includes the temperate subtropical regions of Europe, North America, and East Asia. Because of the widespread distribution of A. albopictus, there is a potential threat of dengue spreading to wider geographical areas.Dengue virus (DENV) annually infects up to 390 million people living in tropical and subtropical areas . It is eFlaviviridae, a group comprised of antigenically closely related viruses that cause disease in humans, including the Japanese encephalitis virus (JEV), yellow fever virus (YFV), and West Nile virus (WNV). The genome of DENV is a single, plus-stranded RNA which encodes three structural proteins  and seven nonstructural proteins . Infection with any of the four DENV serotypes that are antigenically and genetically related causes symptoms ranging from acute febrile illness to severe manifestations that include bleeding and organ failure. Without appropriate treatment, the mortality rate of dengue hemorrhagic fever (DHF) is approximately 25 %. Currently, there is no specific treatment or vaccine for dengue.DENV belongs to the genus DENV causes a wide range of clinical symptoms, ranging from asymptomatic infection and dengue fever (DF) to the severe forms of illness, DHF, and dengue shock syndrome (DSS). Symptoms typically appear 4–7 days after an incubation period following a bite from an infected mosquito. DF is a self-limited febrile illness characterized by a sudden onset of fever accompanied by a generalized morbilliform rash, headache, myalgias, and retro-orbital pain during the acute phase. The febrile phase generally lasts for a week. Symptoms are also accompanied by thrombocytopenia and leukopenia. A small proportion of dengue patients develop severe dengue (DHF or DSS). In severe dengue, life-threatening symptoms of plasma leakage, severe thrombocytopenia, hemorrhagic manifestations, and coagulation disorders may lead to shock and multiple organ failure during the critical phase of the disease. After the critical phase, most patients recover without any sequelae, although some develop fatigue and depression that lasts for several weeks after the acute phase. In severe dengue, an estimated 500,000 require hospitalization, and the mortality rate is 2.5 %, particularly in infants and young children .Humoral and cellular immune responses may play important roles in both disease pathogenesis and protection –12. The Epidemiological studies have found that primary dengue patients, after a short cross-protective period, are at higher risk of developing severe dengue during a consecutive infection with another DENV serotype , 13. TheUpon secondary infection with a heterogeneic serotype during this period of waning immunity, homotypic serotype-specific memory T and B cells are activated. This early serotype-specific immunity is directed against infection by the prior DENV serotype, but not to the current infecting serotype , 10. DurAs the disease progresses to the convalescent phase, serotype cross-reactive immunity with high avidity to all four DENV serotypes develops. These broadly reactive antibodies confer protection to all four DENV serotypes. A third or fourth infection may occur in hyperendemic areas, although a majority of these infections are hypothesized to be asymptomatic or mild .Epidemiological evidence has demonstrated that two groups of individuals are at higher risk of developing severe dengue: (1) adults with waning homotypic immunity and (2) infants born to dengue-immune mothers –15. SeruSerum samples from convalescent DENV patients typically demonstrate ADE activity at higher dilutions and neutralizing activity at lower dilutions, indicating that antibodies induced after infection possess two contrasting activities . In patiNeutralizing antibodies are considered central in protection against DENV infection. Antibodies targeting DENV possess two competing activities related to pathogenicity: virus neutralization and infection enhancement. At higher avidity, antibodies neutralize DENV, whereas lower levels of antibodies enhance DENV infection and hamper virus neutralization . The conAfter acute infection, a high proportion of the antibodies is directed against the E protein, and some target the prM and NS1 proteins. The virion envelope is a lipid bilayer, which consists of the E and M proteins. A majority of the induced antibodies target the E protein; therefore, virus neutralization may involve neutralization of the E protein epitopes. The antibodies induced consistently react with the E protein, but there is variability in the reactivity to domains I, II, and III; the considerable variability in reactivity in each of the domains isolated from individual patients indicates that virus neutralization may involve several epitopes , 29.In DENV hyperendemic regions, co-circulation of several serotypes demonstrates an epidemiological pattern in which outbreaks arise from a dominant serotype, in a 2–4-year cycle , 31. TheAs neutralizing activity of an antibody is considered central in providing protection against dengue, levels of neutralizing antibody have been used as a proxy for disease protection. Determination of levels of neutralizing antibody is also important to analyze the immune response after vaccination. Neutralizing antibody to dengue is determined by using the plaque reduction neutralization test (PRNT). The PRNT is regarded as the gold standard for determination of neutralizing antibodies . High tiAlthough assays to determine neutralization antibody titers have been developed, the correlate of protection for dengue has yet to be defined. For JEV, a titer of ≥1:10 at PRNT50 has been suggested as a threshold that demonstrates protection , 40. ForAlthough the PRNT is the most reliable test to determine neutralizing antibodies, it is laborious and requires skilled personnel. Considering the magnitude of the dengue problem, standardized high-throughput assays are needed for both research and industrial settings. Early studies using flow cytometry, peroxidase-antiperoxidase (PAP) and an enzyme-linked immunosorbent assay (ELISA) that employs FcγR-expressing cells have proved useful in the determination of neutralizing activity of DENV antibodies –38. ToolCurrently, there are no licensed dengue vaccine which are used clinically. Dengue vaccine research has been carried out for the past 70 years, beginning with the first isolation of the virus during epidemics in Hawaii and Japan. Within a few decades, live-attenuated virus, inactivated vaccine, chimeric flavivirus, DNA, and subunit vaccines have been developed Table . HoweverThe observation of the development of severe dengue during heterotypic secondary infection implies the need for a vaccine that possesses the ability to simultaneously induce long-term protective immunity to all four serotypes. Multiple vaccine formulations are currently under development, and several candidates are currently in preclinical and clinical stages. Currently, the live-attenuated tetravalent chimeric YFV/DENV vaccine (CYD-TDV) is in the most advanced clinical trial stage (phase III) . The phaRecent DENV vaccine clinical trials and patient cohort studies have found that despite the presence of seroconversion PRNT50 >1:20) in vaccines, protection against DENV-2 was minimal . Althoug:20 in vaAlternatively, it is hypothesized that neutralizing activity of an antibody displays differential activity against DENV genotypes. In vitro and animal studies have demonstrated that differential neutralizing activity when Asian and American DENV-2 strains are induced after exposure to DENV-1 , 48. AltIn addition to protective efficacy issues, hypothetical safety concerns include (1) possible enhancement of clinical response to live-attenuated vaccine in individuals with a flavivirus-immune background, (2) non-protective or waning immunity in vaccinated individuals that could potentially increase the risk of severe dengue, and (3) insufficient attenuation of vaccine strains. The CYD-TDV candidate vaccine trial has demonstrated that the vaccine is safe, and efficacy has been demonstrated through lesser number of virologically confirmed cases within the 2-year study period . HoweverWith half of the world population at risk of DENV infection, an effective dengue vaccine that confers long-term protective immunity to all four dengue serotypes would contribute significantly to disease control. Other considerations in dengue disease control would include suitability of the vaccination program, cost constraints, and identification of disease burden. The CYD-TDV (Dengvaxia) vaccine has been approved as the first registered dengue vaccine in Mexico in December 2015. The CYD-TDV vaccine is also currently under review for clinical introduction in other endemic regions and is anticipated to reduce dengue burden. Follow-up observations on the CYD-TDV vaccine efficacy would however be needed, particularly on breakthrough infections and severe dengue in vaccine recipients. Other promising vaccine candidates in clinical and preclinical trials include virus-vectored and VLP-based vaccines. These next-generation vaccine candidates may offer improved approaches to disease control as they have been demonstrated to be safe due to the non-infectious nature of the vaccine, highly immunogenic, and could be modified rapidly to match recent epidemic strains. With dengue disease burden being the highest in developing countries, a cost-effective, safe vaccine that confers protection with a single dose would be ideal in disease control programs.Dengue epidemics continue to be a serious public health problem in many areas of the world. Disease control remains a challenge in the absence of a vaccine and specific therapies. Development of tools and robust animal models to advance understanding of the host immune response will facilitate a better understanding of vaccine efficacy and safety issues and contribute to the development of dengue vaccine and treatment programs.


The window of opportunity is a concept critical to rheumatoid arthritis treatment. Early treatment changes the outcome of rheumatoid arthritis treatment, in that response rates are higher with earlier disease-modifying anti-rheumatic drug treatment and damage is substantially reduced. Axial spondyloarthritis is an inflammatory axial disease encompassing both nonradiographic axial spondyloarthritis and established ankylosing spondylitis. In axial spondyloarthritis, studies of magnetic resonance imaging as well as tumor necrosis factor inhibitor treatment and withdrawal studies all suggest that early effective suppression of inflammation has the potential to reduce radiographic damage. This potential would suggest that the concept of a window of opportunity is relevant not only to rheumatoid arthritis but also to axial spondyloarthritis. The challenge now remains to identify high-risk patients early and to commence treatment without delay. Developments in risk stratification include new classification criteria, identification of clinical risk factors, biomarkers, genetic associations, potential antibody associations and an ankylosing spondylitis-specific microbiome signature. Further research needs to focus on the evidence for early intervention and the early identification of high-risk individuals. Axial spondyloarthritis (axSpA) is an inflammatory disease of the axial skeleton and pelvis. Regardless of whether it progresses onto ankylosing spondylitis (AS), axSpA has an appreciable disease burden. axSpA is also associated with co-morbidities such as uveitis, psoriasis, inflammatory bowel disease, cardiovascular disease, osteoporosis and significant loss of work productivity. There is emerging evidence that early treatment may change the outcome in axSpA.The window of opportunity is a concept of critical importance in rheumatoid arthritis (RA). Early treatment results in reductions of disease activity, joint erosions, and better treatment responses the earlier disease-modifying anti-rheumatic drugs are commenced. It also results in a greater proportion of patients in drug-free remission after treatment withdrawal. These findings have led to changes in RA treatment pdigms, with increasing emphasis on early diagnosis and treatment.So how is this concept relevant to axSpA? A number of studies have demonstrated early treatment that suppresses inflammation may change the outcome of axSpA.Whilst initial studies suggested that radiographic progression of AS is not slowed by treatment with tumor necrosis factor inhibitor (TNFi) medications, two observational studies have now shown a reduction in radiographic progression with these agents ,2. One oIntriguingly there is also new evidence that the age of the inflammatory lesion may influence progression to ankylosis, suggesting that a longer duration of inflammation is associated with more syndesmophyte formation. Maksymowych and colleagues have shown that early, acute type A lesions, without fatty metaplasia, infiltration or erosion, are less likely to progress to syndesmophytes as compared with type B lesions characterized by loss of signal at the vertebral corner . This loTaken together, these observations provide strong circumstantial evidence that treatment, especially early effective treatment, may influence radiographic outcome.Trials of TNFi therapy in early axSpA have yielded encouraging results, with greater treatment responses than in disease of longer duration. In Barkham and colleagues’ study of very early axSpA (mean symptom duration 15.3 months), infliximab achieved an Assessment of SpondyloArthritis international Society (ASAS) partial remission rate of 56% -10. In tWithdrawal studies of TNFi agents in early axSpA and AS also suggest that the frequency of drug-free remission is higher the earlier a patient is treated. In established AS patients treated with a TNFi agent and monitored for 6 months or more after discontinuation, 91 to 100% of patients flare -14. In tThe major challenge now remains to accurately identify patients who have poor prognosis. The ASAS axSpA criteria have gone some way to enabling earlier identification of early axSpA but do have some limitations including the ability to capture self-limiting disease ,18. ClinEmerging work examining the gut microbiome of axSpA patients may provide information not only about etiology, but also about prognosis. A distinct microbial signature has been associated with AS . In very recent work Van Praet and colleagues have also found an association between the degree of bowel inflammation, and MRI-demonstrated bone marrow edema of the sacroiliac joints .Finally, clinical prediction from genetic analysis - whilst essentially dominated by HLA-B27 until recently - has progressed significantly, and there are now many independent AS genetic associations . This anThere may therefore be a time when genetic analysis, probably combined with other biomarkers or clinical features, enables accurate prognostication of disease onset, features and severity. Early, or even potentially prophylactic, treatment could then be applied to stop or attenuate disease.We should also acknowledge that the data currently available are not conclusive and that a number of studies are required before the evidence becomes compelling. Randomized controlled trials of TNFi therapy withdrawal in very early disease are needed, and some are underway. Longitudinal studies of cohorts of nonradiographic axSpA are required to better understand the natural history of early disease, including remission and progression rates. Further work is required for the development of better biomarkers of early disease and case-identification strategies, which will be required to implement an early intervention strategy.In conclusion, there is mounting evidence that early effective treatment of inflammation in axSpA can change disease outcome. Identification of high-risk individuals and prompt institution of therapy is going to have increasing importance in clinical practice. We should therefore encourage industry and independent investigators to design and conduct studies in axSpA to confirm the importance of the window of opportunity as well as the accurate identification of high-risk individuals. Early treatment combined with another concept borrowed from RA, treat to target, will hopefully enable patients to enjoy the huge therapeutic progress seen in RA to be translated into axSpA.AS: Ankylosing spondylitis; ASAS: Assessment of SpondyloArthritis international Society; ASAS40: 40% improvement from baseline using the ASAS criteria; axSpA: Axial spondyloarthritis; MRI: Magnetic resonance imaging; RA: Rheumatoid arthritis; TNFi: Tumor necrosis factor inhibitor.PCR has received travel support, speaking fees, and research grants, has undertaken clinical trials and has participated in advisory boards for Abbvie, Pfizer, UCB and/or Janssen. MAB has participated in advisory boards for Janssen, Pfizer, Abbvie and UCB, has participated in a speakers’ bureau for Abbvie, and has received research grants and travel support from Abbvie.


PLGA has excellent biodegradability and biocompatibility and is generally recognized as safe by international regulatory agencies including the United States Food and Drug Administration and the European Medicines Agency. The physicochemical properties of PLGA may be varied systematically by changing the ratio of lactic acid to glycolic acid. This in turn alters the release rate of microencapsulated therapeutic molecules from PLGA microparticle formulations. The obstacles hindering more widespread use of PLGA for producing sustained-release formulations for clinical use include low drug loading, particularly of hydrophilic small molecules, high initial burst release and/or poor formulation stability. In this review, we address strategies aimed at overcoming these challenges. These include use of low-temperature double-emulsion methods to increase drug-loading by producing PLGA particles with a small volume for the inner water phase and a suitable pH of the external phase. Newer strategies for producing PLGA particles with high drug loading and the desired sustained-release profiles include fabrication of multi-layered microparticles, nanoparticles-in-microparticles, use of hydrogel templates, as well as coaxial electrospray, microfluidics, and supercritical carbon dioxide methods. Another recent strategy with promise for producing particles with well-controlled and reproducible sustained-release profiles involves complexation of PLGA with additives such as polyethylene glycol, poly(ortho esters), chitosan, alginate, caffeic acid, hyaluronic acid, and silicon dioxide.Poly(lactic- Drug delivery systems with high efficiency and tuneable release characteristics continue to be sought. This is despite recent advances in the field of nanobiotechnology that have produced a range of new materials for improving control over drug delivery rates  (PLGA), is a widely used biodegradable material use for encapsulation of a broad range of therapeutic agents including hydrophilic and hydrophobic small molecule drugs, DNA, proteins, and the like Zheng, , due to However, factors limiting more widespread use of PLGA in pharmaceutical products include relatively low drug loading efficiency, difficulties in controlling encapsulated drug release rates and/or formulation instability , hydrophilic molecules in polymeric particles is more difficult than for hydrophobic small molecules, despite the large number of micro-encapsulation methods described in peer-reviewed publications and patents  but little mass loss whereas in the second phase, the opposite occurs. This indicates that PLGA particle degradation involves heterogeneous mechanisms and that drug release is underpinned primarily by diffusion rather than polymer degradation  functionality] that influence microparticle morphology  and high incorporation efficiencies ~100%) to be achieved and are amenable to small molecules and biologics  produces double-layered microparticles using an electric field applied to both the outer (PLGA carrier) and the inner (drug loaded) solutions sprayed simultaneously through two separate feeding channels of a coaxial needle into the one nozzle  provides a “green” alternative to traditional microparticle formulation techniques as it avoids use of toxic organic solvents or elevated temperatures  from natural compounds or to form polymers , undergo spontaneous rearrangement of the polymer chains to produce healing (repair)  low drug loading, (ii) particle instability, and (iii) adequate control of drug release profiles for PLGA-based microparticle drug delivery systems. Strategies for increasing drug loading in PLGA-microspheres include modification of the classical solvent evaporation methods, preparation of multi-layered microparticles, and development of novel methods for microparticle fabrication including hydrogel templates, coaxial electrospray, microfluidics, and scCOAll authors listed, have made substantial, direct and intellectual contribution to the work, and approved it for publication.FH is supported by a postdoctoral fellowship funded by a National Health and Medical Research Council (NHMRC) grant, APP1107723.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


CsA’s immunosuppressive effects are mediated by a calcium-regulated phosphatase, calcineurin. Treatment of neurospheres with an inhibitor of calcineurin had no effect on NPC survival, whereas a non-immunosuppressive analogue of CsA (NIM811) is able to mimic the pro-survival effect of the drug. NIM811 can also promote functional recovery in a mouse model of stroke. These data provide molecular evidence that CsA enhances NPC survival without triggering immunosuppressive pathways, supporting the repurposing of this drug in novel regenerative therapies for CNS disease or injury. 953Page Injury and diseases of the central nervous system can have a devastating effect on quality of life. Given recent progress in regenerative medicine, there is increasing interest in the development of therapies that regenerate or repair damaged nerve tissue to enable functional recovery. Strategies that aim to harness the regenerative potential of resident neural precursor cells (NPCs) are particularly promising. Recently, it has been shown that an FDA-approved immunosuppressive drug, cyclosporin A (CsA), can potentiate NPC survival. Interestingly, it has direct effects on NPCs and the pro-survival effects are not mediated by immunosuppression. Here, Cindi Morshead and co-authors use an elegant


Recently, there has been increasing interest in the use of non invasive ventilation (NIV) to increase exercise capacity. In individuals with COPD, NIV during exercise reduces dyspnoea and increases exercise tolerance.Different modalities of mechanical ventilation have been used non-invasively as a tool to increase exercise tolerance in COPD, heart failure and lung and thoracic restrictive diseases. Inspiratory support provides symptomatic benefit by unloading the ventilatory muscles, whereas Continuous Positive Airway Pressure (CPAP) counterbalances the intrinsic positive end-expiratory pressure in COPD patients.Severe stable COPD patients undergoing home nocturnal NIV and daytime exercise training showed some benefits. Furthermore, it has been reported that in chronic hypercapnic COPD under long-term ventilatory support, NIV can also be administered during walking.Despite these results, the role of NIV as a routine component of pulmonary rehabilitation is still to be defined. During exercise in people with chronic obstructive pulmonary disease (COPD), expiratory flow limitation and increased respiratory frequency may reduce the expiratory time, resulting in increase in end-expiratory lung volume, a condition also known as dynamic hyperinflation (DH). In such condition, tidal breathing takes place at lung volumes closer to total lung capacity . An unavPulmonary rehabilitation is a recognised core component of the comprehensive management of COPD patients, mainly based on exercise training . In patiRecently, there has been an increasing interest in the use of non invasive ventilation (NIV) to improve exercise capacity -8, basedIn a study on healthy trained cyclists it was shown that the WOB required to sustain high-intensity exercise significantly inversely correlated with leg blood flow ,10. In oAnother aspect may be important. Systemic inflammation has been related to the development of comorbidities in COPD. The level of systemic inflammatory mediators is increased in response to exercise in these patients . Non invTable Different modalities of mechanical ventilation have been delivered non-invasively by nasal, facial Masks or mouthpiece during exercise .Theoretically, CPAP should reduce the inspiratory threshold load on the inspiratory muscles of hyperinflated COPD patients and optimise neuromuscular coupling, thus improving dyspnoea and exercise tolerance -20. CPAPIt has been suggested that the level of CPAP should be titrated on an individual basis to optimise benefit and comfort. Nevertheless, this implies the measurement of PEEPi, which is difficult if not impossible to perform on a routine basis . CPAP seInspiratory Pressure Support (IPS) is a pressure-targeted mode in which each breath is triggered and supported by the patient . This moProportional Assist Ventilation (PAV) is a mode of partial ventilatory assistance endowed with characteristics of proportionality and adaptability to the intensity and timing of spontaneous ventilatory pattern by providing inspiratory flow and pressure in proportion to patient’s effort . PAV wasIn a comparison study  submaximAssist-control ventilation is a combination mode of ventilation in which the ventilator delivers a positive pressure breath at a preset tidal volume in response to a patient’s inspiratory effort. The ventilator also delivers breaths at a preset rate if no patient effort occurs within the preselected time period . This moThe message of these physiologic studies can be summarised as follows: acute NIV, either as CPAP, IPS, or PAV, during exercise reduces WOB and dyspnoea increasing exercise tolerance in COPD patients and with less level of evidence in restrictive disease patients . The nexOne randomised controlled study  found noIn another study COPD patients were randomised into three groups for an intervention of 12 weeks: exercise training alone, NIV alone and combined treatment. All exercise capacity parameters improved after training and the combined treatment. In addition, peripheral muscle strength and six-minute walk distance (6MWD) increased after NIV. Levels of interleukin 8 and tumour necrosis factor α decreased after ventilation, and interleukin 8, C-reactive protein and surfactant protein D decreased after training, while all four of these inflammatory markers fell after the combined treatment .Other investigators have confirmed benefits of performing NIV during exercise training as a part of PRP -57.Interface. During high-intensity exercise, some patients may breathe through their mouth rather than (or together with) their nose, therefore they may require a full-face mask or a mouthpiece. Full-face masks may be more uncomfortable than nasal masks, potentially reducing the patient’s compliance to the procedure.Comorbidities. Most of COPD patients have significant comorbidities, including a high prevalence of ischaemic cardiac disease [ disease . The rel disease  might alPracticalities. In the study [he study , there whe study ,6,59.There are some potential problems with the use of NIV in PRP:Severe stable COPD patients undergoing home nocturnal NIV and daytime exercise training showed a significant improvement in exercise capacity and health related quality of life compared with patients undergoing exercise training alone -62.Furthermore, it has been reported that, in chronic hypercapnic COPD under long-term ventilatory support, NIV can also be administered during walking, resulting in improved oxygenation, decreased dyspnoea and increased walking distance. Therefore, NIV during walking could prevent hypoxia-induced complications ,64.Non invasive ventilation improves exercise tolerance in patients with acute exacerbations of chronic respiratory diseases, but the applicability of this approach in routine clinical practice may be limited ,66. In pTwo recent meta-analyses concluded that, given the small number of available studies, the small sample sizes, and the complete absence of power calculation, there is the need of randomised clinical trials with larger sample sizes based on statistical power calculations and designed to investigate the effect of training duration and intensity on rehabilitation ,71.Who is the ideal candidate ? Differences in results of different studies may be explained on the basis of different case mix, and apparently no study has directly addressed the topic of the best indication. Further studies are needed to identify the pathology , the patient type, .Which are the most effective protocols? .Which are the most appropriate outcome indices to evaluate results? .As application of NIV in rehabilitation programs is a demanding tool in terms of heath resources, there is the need to identify the best indications. Several questions remain open:Despite promising results, for the above reasons and until the above questions are not answered, the authors of this review believe that the use of NIV during exercise training programs is unlikely to have a role in routine pulmonary rehabilitation settings. The use of NIV during exercise training as a component of PRP should be reserved to individual cases.


The key structural and signaling roles of collagen in the extracellular matrix (ECM) make it an attractive biomaterial for tissue engineering, but there are limitations in the standardization and purity of natural collagen sources currently available for such applications , a post-translationally modified amino acid known to be critical to the thermal stability of mammalian collagens. Initial interest in bacterial collagen-like proteins focused on their roles in pathogenesis. However, recent work has focused on one specific bacterial collagen protein, designated Scl2, to demonstrate the utility of recombinant bacterial collagen as a tool for defining collagen sequence/structure/function relationships and for establishing a class of novel collagen-based biomaterials.Over the past 10 years, collagen-like proteins have been identified from numerous bacterial genomes database based on the signature (Gly-Xaa-Yaa)Streptococcus pyogenes contains two collagen-like proteins, Scl1 and Scl2, which have been well characterized in terms of structure and functional properties  even though there is no Pro hydroxylation. In animal collagens, Pro residues in the Y positions of the repeating Gly-X-Y sequence are hydroxylated to Hyp, and this hydroxylation is required to stabilize the triple-helix: Tm of hydroxylated collagen = 37°C, while Tm of unhydroxylated collagen = 26°C  (Kadler, in vitro binding, cleavage, and cell culture assays. The Scl2 sequence will apparently fold the short human collagen insert into a triple helix, while the correctly folded human collagen sequence imparts the corresponding biological function to the chimeric protein. The introduction of the integrin and fibronectin binding sites promoted the growth of different types of mammalian cells in vitro, while Scl2 molecules with MMP cleavage sites show enzyme cleavage at the native position. More collagen bioactive sites are being identified each year primarily through synthetic collagen mimetic Toolkit peptides (Farndale et al., In addition to production advantages, the ability to express the collagen-like protein in  Kadler, . Examina Kadler, . Various Kadler, , fibrone Kadler, , heparin Kadler, , and MMP Kadler, . The insWith recombinant DNA technologies, it has been possible to manipulate the Scl2 protein, studying individual fragments of the triple-helix (Yu et al., E. coli system usually has an upper threshold for the size of the recombinant protein it can produce, but it may be possible to transfer the Scl2 expression system into yeast or insect cells to further increase its chain length. Crystal structures on small collagen model peptides and studies on recombinant tobacco type I collagen suggest Hyp may be essential for collagen fibril formation (Kramer et al., While facile manipulation of the Scl2 protein can optimize molecular and biological properties, successful biomaterial applications will require optimization of material properties as well. The most abundant animal collagens self-associate into characteristic periodic cross-linked fibrils, which provide the mechanical properties for tissues and biomaterials. Thus far, Scl2 exhibits limited ability to form fibrillar structures (Yoshizumi et al., E. coli is a mature industrial process with excellent scalability. This has already been demonstrated for Scl2 production (Peng et al., Animal extracted collagens are produced in large quantity and are generally inexpensive. However, difficulties in developing standardized preparations of these collagens and in producing minor types of collagens that are free of collagen I and biological contaminants are major limitations. Potential infectious and allergic risks of animal collagen products are also a concern. The recombinant bacterial collagens have attached tags, such as His-tag and Strep II tags to simplify standardized chromatographic purification. A high-throughput batch purification methodology for Scl2 has also been developed (Peng et al., Pichia and Nicotiana, have been formulated into hydrogels and explored for their potential as artificial cornea (Merrett et al., in vivo is needed to evaluate its suitability as medical implants.Translational science remains a less explored area for recombinant collagens. Recombinant human collagens obtained from systems with high scalability, such as Figure S pyogenes, bacterial collagens represent a biosynthetic ground up approach, where a triple-helical non-animal collagen molecule with no specific bioactivity can be designed to include desired interactions and regulated degradation. Although research has focused on Scl2, the approach could be extended to other collagen-like proteins from bacteria and viruses, which may bring new properties and variations useful for biomaterials. Fundamental studies on Scl2 and other bacterial collagens will continue to elucidate basic features of collagen, with a focus on chemistry, sequence, biological activity, and self-assembly. The success of the bacterial collagen approach toward biomaterial applications will depend on developing the capacity to generate biomaterials with desirable biomechanical properties useful for in vivo applications.Extracted bovine collagen is likely to remain a staple for biomaterial construction due to its low cost and useful material properties, but challenges in standardization and concerns for bioburdens, as well as a desire to modify collagen sequence and function, will lead to continued interest in research and applications with recombinant collagens. As described here for the specific Scl2 protein from The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Harmful gender norms and inequalities, including gender-based violence, are important structural barriers to effective HIV programming. We assess current evidence on what forms of gender-responsive intervention may enhance the effectiveness of basic HIV programmes and be cost-effective.Effective intervention models were identified from an existing evidence review (“what works for women”). Based on this, we conducted a systematic review of published and grey literature on the costs and cost-effectiveness of each intervention identified. Where possible, we compared incremental costs and effects.Our effectiveness search identified 36 publications, reporting on the effectiveness of 22 HIV interventions with a gender focus. Of these, 11 types of interventions had a corresponding/comparable costing or cost-effectiveness study. The findings suggest that couple counselling for the prevention of vertical transmission; gender empowerment, community mobilization, and female condom promotion for female sex workers; expanded female condom distribution for the general population; and post-exposure HIV prophylaxis for rape survivors are cost-effective HIV interventions. Cash transfers for schoolgirls and school support for orphan girls may also be cost-effective in generalized epidemic settings.There has been limited research to assess the cost-effectiveness of interventions that seek to address women's needs and transform harmful gender norms. Our review identified several promising, cost-effective interventions that merit consideration as critical enablers in HIV investment approaches, as well as highlight that broader gender and development interventions can have positive HIV impacts. By no means an exhaustive package, these represent a first set of interventions to be included in the investment framework. Three decades into the epidemic, HIV incidence remains persistently high in some regions, and HIV/AIDS is still a leading global cause of morbidity and mortality . Gender In the context of limited resources and the political commitment to the HIV response, UNAIDS and partners have proposed an investment approach to ensure that resources are invested in the most cost-effective interventions, including for populations most at risk . This “iThe investment framework has played an important role in framing budget estimates and national-level planning and grant negotiations . EstimatAlthough recognized as important, there has been a lack of clarity regarding how or what gender-responsive interventions should be included in HIV investment approaches . Gender All programmatic interventions can be classified along a “gender continuum” according to the level of change they seek to achieve ,22. We cOur approach consisted of three main steps. We first synthesized existing evidence on effective gender-responsive HIV interventions from low- and middle-income countries, drawing on the findings from an existing review on what HIV interventions work for women . For thewww.whatworksforwomen.org) to identify effective interventions. For each intervention identified, we reviewed the primary source article, and retained studies that met the following inclusion criteria:Effectiveness evidence rated as I to III on an adjusted Grey scale  ,31.Contained data from a low- or middle-income country.Presented quantitative intervention impact data on either reported HIV-related behaviours or biologically confirmed outcomes .Existing evidence on the effectiveness of gender-responsive HIV interventions was extracted from an extensive review conducted with support from the US President's Emergency Plan for AIDS Relief's Gender Technical Working Group and the Open Society Foundations . We usedWhen compiling the evidence on effectiveness, we chose to group the interventions identified into three types. The first are gender-responsive activities that can be added to basic HIV programmes to enhance their effectiveness and efficiency by addressing gender-related barriers to behaviour change, service uptake and retention (HIV+). The second comprises HIV-specific interventions that could be added onto gender-responsive development programmes, to achieve a synergistic HIV effect (Gender+). The last type (Gender) consists of gender-responsive development interventions that do not explicitly include programmatic HIV components, but may nevertheless have secondary HIV benefits because of their impact on gender inequalities and/or violence.To identify all published costing and economic evaluation studies of gender-responsive HIV interventions, we searched PubMed, EconLit, Eldis and HIV, and gender websites, following PRISMA guidance . The terArticles identified were included if they had been published in English, French or Spanish between 1 January 1990 and 30 June 2014; presented cost or economic evaluation data; and assessed gender-responsive interventions. Additional bibliography searches from review articles were conducted and recommendations from the UNAIDS expert reference group considered . Additional articles analyzing intervention effectiveness that were identified through this search were included under the effectiveness category if they met the inclusion criteria mentioned above.The only exception to the review was data on the integration of sexual and reproductive health and HIV services. Integration is a gender-responsive intervention, as it restructures services to better meet women's needs. However, as a recent systematic review has extracted this cost-effectiveness data , we usedAfter the first title-based screening, citations were downloaded into reference management software (Endnote X3) for a second round of title/abstract screening, conducted by another researcher. Full texts were then read to ensure correct inclusion. Any uncertainty was resolved through discussion among at least two authors.A data extraction spreadsheet was developed, capturing intervention and study characteristics. Outcomes related to HIV/STI  incidence or prevalence, disability or quality-adjusted life years (DALYs/QALYs), proxies of unprotected sex , sexual behaviour, HIV service uptake and risk factors (e.g. experiencing violence) were extracted. For the costing studies, we also extracted detailed information on methods and cost estimates. Costs were adjusted to 2011 United States' Dollars (US$).British Medical Journal's checklist for economic evaluations [The quality of the costing and economic evaluation studies was assessed using an adapted version of the luations    were conWhere the intervention was clearly an incremental investment on a basic HIV programme or an HIV component of a gender-responsive health or development programme, the cost markup was estimated using internally consistent data from the same study, where possible. Otherwise, approximate cost markups were estimated by comparing the unit cost of the gender-responsive component to the country-specific cost used in the investment framework for the specific basic HIV programme or development synergy .The effectiveness search identified 36 publications describing 22 gender-responsive interventions found to be effective for HIV . Most ofGender-responsive activities for programmes to prevent vertical transmission included promoting male involvement through couple counselling–46and tIn terms of key population programmes, effective gender-responsive components were identified for female sex workers (FSWs) and people who inject drugs (PWID). The former included community mobilization to prevent violence and promote gender empowerment through collectivization and stakeholder engagement–53; eduIn terms of condom promotion, modelling suggests that expanded female condom promotion and distribution to increase availability could increase consistent condom use among the general population . AnotherTraditional HIV behaviour change interventions were proven to be enhanced by more gender-responsive approaches, some of which worked with women only, men only or both. Two studies assessed women-focussed HIV risk reduction interventions in South Africa and India that were based on the theory of gender and power, and aimed to build skills in relationship communication and control. Both interventions reduced the rate of reported unprotected sex ,66, but There was evidence of the effectiveness of gender-responsive approaches that promoted a participatory process of critical reflection and debate about gender norms and expectations in relationships. A randomized controlled trial of a participatory gender training with young women and men in South Africa (“stepping stones”) showed a significant incremental impact on HSV-2 incidence, male reported problem-drinking, male soliciting transactional sex and male reported perpetration of violence, although no impact on female reported experience of violence was found . Quasi-eIn addition to approaches targeting enrolled individuals, a community mobilization intervention in Uganda (“SASA!”) seeking to promote community-level change in social norms to prevent violence against women and reduce HIV risk through a community diffusion approach delivered by community activists, led to a significant reduction in sexual concurrency reported by men in non-polygamous relationships and social acceptance of IPV by women .There was also evidence that a multimedia “edutainment” model that integrated the prevention of GBV and HIV messages into a popular soap opera, both increased reported condom use and HIV testing, as well as reduced the acceptance of violence ,72.In terms of broader development programmes, a cluster randomized controlled trial (the IMAGE intervention) showed that the addition of participatory gender/HIV training onto an existing microfinance scheme for women in rural South Africa had a significant impact on levels of physical and/or sexual partner violence over two years, and also increased HIV testing and reduced unprotected sex among younger beneficiaries ,74. TherThree effective education-related development programmes were rigorously evaluated in randomized trials. A one-off school-based information session on relative HIV risk profiles by age and sex in Kenya  significantly reduced teenage pregnancies . Cash trAnother potentially synergistic intervention for GBV prevention among female apprentices and hawkers in Nigeria suggested the potential to reduce violence in the context of HIV through stakeholder mobilization . FinallyOur cost and cost-effectiveness search identified 14 publications, including 1 in submission  Table 2Table 2. The studies were of mixed quality, as described in more detail in the Supplementary appendix. Nonetheless, all but two ,63 contaSeven studies provided CERs in terms of costs per HIV infection averted, HIV DALY averted or HIV QALY gained ,63,80,84In the absence of relevant CERs in some studies, Overall, these examples suggest that investment in strengthening the gendered components of projects – though adding costs over and above basic programme costs – could generate significant additional HIV benefits. Some may even be cost-saving, especially if averted treatment costs are considered. Such interventions include gender-responsive community mobilization for FSWs, female condom promotion for FSWs and PEP for rape survivors. It also appears that although female condom promotion (including for FSWs) and PEP may be highly cost-effective, they may be considerably under-budgeted in global resource needs estimates.Unfortunately there was insufficient data to determine whether the remaining gender-responsive interventions, though effective, are good value for money. For example, although the unit costs of interventions working with young men to transform gender norms seem reasonable (US$106–158 per participant in Brazil), it was not possible to assess their HIV-related incremental effects or cost-effectiveness.This is the first study to systematically review the costs and cost-effectiveness of gender-responsive interventions for HIV. We identified a range of interventions with demonstrated impacts either on HIV or its proximate determinants. Most appear to function as the investment framework's critical enablers of basic HIV programmes, although several examples of development synergy type interventions were also identified . The strWhere cost data were available, among the interventions found to be cost-effective, enrolling couples in programmes to prevent vertical transmission seems to help reduce the inefficiencies associated with high loss to follow-up along the service cascade ,87. BecaSimilarly, to be a more attractive investment, female condom promotion may require intensified demand creation through woman-focussed, transformative programmes and/or subsidised distribution. Although it is already considered a basic HIV programme and modelled studies found that it was cost-effective ,63, it iEvidence from India suggests that gender-responsive community mobilization activities aiming to promote collectivization are highly cost-effective critical enablers to basic FSW programmes . AdditioEvidence from South Africa suggests that PEP for rape survivors is cost-effective  and an iThe evidence from the IMAGE study of the impact of combined economic empowerment and gender/HIV training illustrates the potential to add HIV-specific components onto livelihood programmes for women, leveraging the development synergy, at low incremental cost.Certain GBV prevention interventions could function as both critical enablers as well as development synergies. For example, gender-transformative activities focussing on young men could either be classified as critical enablers, where the gender norms component is integrated in standard group HIV behaviour change programmes; or as development synergies, where an HIV component is added to a broader gender transformation programme. This would have implications for their cost-effectiveness, as it would determine what such additional investments are incremental to. Similarly, mass media campaigns are already considered critical enablers of HIV behaviour change; hence, the more explicit inclusion of GBV prevention messaging could be considered a gender-responsive critical enabler. However, where such a multimedia campaign exists with a focus on GBV and gender transformation, this again represents an opportunity to leverage related development resources.There is evidence that other gender-responsive development programmes can also influence HIV-related outcomes through structural pathways and still be cost-effective for HIV. The provision of cash transfers to keep girls in school ,90, for Although we did not review evidence on the impact and costs of the integration of sexual and reproductive health and HIV services, this area does merit consideration as a gender-responsive enabling approach, as it restructures services to better meet women's needs. A systematic review reported consistent and multiple HIV-related benefits from a range of integration models, including reduced HIV incidence . AnotherIt is worth noting that the review did not identify any (cost-) effectiveness studies of gender-responsive components linked to ART, male circumcision or programmes for men who have sex with men and their female partners. Yet, gender inequalities in these areas underscore the need to ensure their gender-responsive delivery, particularly given the important share of HIV budgets that they claim with about 50% of HIV spending going to treatment and care across low- and middle-income countries ,94.This review has several limitations. Fundamentally, there is limited evidence on the costs and cost-effectiveness of gender-responsive interventions; and even fewer analyses of how gender-specific components may serve to increase the impact of basic programmes, or the potential impacts of HIV-relevant components in gender-specific development programmes. These are important areas for further investigation. We have included effectiveness studies even where cost/cost-effectiveness data was lacking in an attempt to highlight these gaps and recommend them as key opportunities for additional economic research.We decided to include self-reported behavioural outcomes when considering intervention effectiveness, despite the known challenges of these indicators as proxies of behaviour change and programme effectiveness. The lack of availability of intervention evaluations with biological outcomes is not unique to this field, and the resulting conclusions need to be interpreted with caution. However, we felt that it was preferable to include such evidence as a starting point for programming, rather than have a potentially overly narrow focus of intervention evidence.Although we were interested in incremental investments over and above basic programmes, not all retained studies actually measured this incremental cost/effect. For example, the GBV and HIV messaging in the Soul City multimedia campaign were fully integrated and it was not possible to isolate the GBV component's effect . In suchAnother important limitation is the extent to which single or a small number of studies per intervention have external validity. Moreover, the quality of the cost and effectiveness data was mixed, with particularly little consistency in outcomes measured and costing methods. This hampered any interpretation of the cost-effectiveness of gender-responsive training sessions with young men, for example.Publication bias could also imply that we are overestimating effectiveness and by only considering interventions with quantifiable evidence of effect, we may have excluded important qualitative evidence, as well as complex interventions that are not amenable to experimental designsDespite the critical role of gender inequality and GBV in fuelling the HIV epidemic and impeding service effectiveness ,11, therGiven the many data gaps, these interventions are by no means an exhaustive package, but rather the first set of promising interventions in a neglected field. Countries may want to consider these interventions for gender-responsive HIV programming. Indeed, the absence of cost-effectiveness data should not be interpreted as evidence that these investments are not good value-for-HIV-money. More research is needed to establish the return on these investments, in terms of increased utilization of and adherence to HIV services, and ultimately infections and deaths averted, especially for interventions known to be effective.The findings of this study have important financing implications. Although cost data are limited and the type of interventions too heterogeneous to determine a standard cost benchmark, the compiled evidence appears to justify an additional allocation of at least 5%, over and above the current 10% markup for critical enablers, to accommodate activities that address gender equality and GBV. This could initially require an overall increase in resource needs for the global HIV response, but it is likely that this investment could reduce future treatment costs and increase programme efficiency. Reallocating current spending may also be considered. That being said, there is increasing commitment from donors to make high-impact gender-responsive investments. For example, the Global Fund's new funding model requirements include a strong focus on gender-responsive programming and also encourage the use of grants to fill gaps relating to the cost of priority interventions that address gender inequality .Interventions that tackle the structural drivers of HIV, such as inequalities in access to education, poor livelihoods and harmful gender norms commonly have multiple societal benefits, including for HIV. As such, the HIV sector should co-finance these interventions with other sectors, to ensure that all benefits are generated ,103 and Click here for additional data file.


Background. Silicoanthracosis is a pneumoconiosis due to occupational inhalation of silica and carbon dusts. Clinically, it can be associated with vasculitis or rheumatoid arthritis. In association with these diseases, silicoanthracosis can present within the lung with multiple pulmonary nodules which, as a differential diagnosis, can mimic metastatic disease or multiple abscesses. Case Presentation. We present the case of a 62-year old former pit worker with pulmonary nodules, chondrocalcinosis due to calcium pyrophosphate deposition (CPPD), and a history of renal cancer. Within a short period of time, pulmonary nodules grew rapidly. Thoracoscopically, the resected lung specimen revealed silicoanthracosis associated with small-to-medium-size vasculitis in the presence of antineutrophil cytoplasmatic autoantibodies (c-ANCA). Conclusion. Pulmonary silicoanthracotic lesions on the base of ANCA-associated vasculitis and CPPD arthritis can rapidly grow. A mutual correlation between silicoanthracosis, ANCA-associated vasculitis, and CPPD seems possible. Apart from this, consideration of metastatic disease should be obligatory in patients with a history of cancer at the same time being immunosuppressed. Silicoanthracosis (SA) is a pneumoconiosis derived from accumulation of carbon and silica in the lungs from inhaled coal dust; the silica content can produce fibrous nodules throughout the body . HistoloThis case describes a patient with the unusual course of ANCA-positive vasculitis associated with silicosis and preexisting calcium pyrophosphate deposition disease (CPPD). Particularly the sudden outbreak of clinical symptoms with the development of multiple new lung nodules additionally underlines the significance of important differential diagnoses of multiple pulmonary nodules in the context of arthritis and with a history of cancer.A 62-year-old male patient presented in January 2011 with cough and hemoptysis, microhematuria, polyarthritis of both ankles, knees, and left wrist, bilateral lymphadenopathy, and pulmonary nodules revealed by a CT-scan . This noA follow-up thoracic CT scan (January 2014) revealed new bilateral multiple round lesions . HistoloGrowing evidence suggests that silica exposure may induce autoimmune diseases by T-cell activation such as RA, Sjögren's syndrome, sarcoidosis, systemic sclerosis, or ANCA-associated vasculitis . The herTwo lessons can be learned from this case. First, a rapid progression of pulmonary nodules can be due to the ANCA-positive vasculitis itself but might be caused by other diseases. Since the patient's presentation was unusual due to the fast appearance of symptoms and rapid growth of pulmonary nodules within a few months compared to the slow and mild course before, a malignant cause such as metastases was considered in first instance, particularly considering the positive history of cancer and being under immunosuppressive therapy. Another important aspect why pulmonary nodules rapidly increased in size and morphology is the intake of methotrexate, which is thought to exacerbate rheumatoid nodule formation in selected patients with RA despite the suppression of synovial inflammation . This acThe second lesson from this case is the complex differential diagnosis of patients with SA and the occurrence of polyarthritis. Therefore, Caplan syndrome (CS) was initially suspected. The possible diagnosis could have matched the symptoms and radiological presentation . HoweverThis case presentation reflects how heterogeneous the cause of rapidly growing, symptomatic multiple lung nodules in a complex clinical scenario can be. On the one hand, there seems to be a causative relationship if not a mutual correlation between silicosis and ANCA-associated vasculitis and possibly CPPD disease. On the other hand, given the immunosuppressive state of this patient and a positive history of cancer, lung metastases strongly need to be taken into consideration as an important differential diagnosis.


Chronic recurrent multifocal osteomyelitis (CRMO) is a term, referred to a group of several autoinflammatory disorders (some of unknown genetic background) of children and young adults that is characterized by non-infectious osteomyelitis with or without high inflammatory activity and occasionally involvement of other organs. Patients typically present with bone pain secondary to multifocal osseous lesions, the disease has a remitting course. To specialists who care for patients with autoinflammatory disorders the clinical presentation of CRMO is very recognizable. Yet in the settings of multi-specialty clinic, a newly referred patient with bone lesions poses a certain diagnostic challenge and thorough differential diagnosis is required.We conducted a study analyzing diagnosis and outcomes of children referred to tertiary center with bone lesions in 2014. Children with bacterial osteomyelitis were not included in the study.Laboratory, radiological tests, bone lesion biopsies were performed in all cases, other types of tests - as were required by clinical situation.Most of the patients were diagnosed with various oncological/ oncohematological disease: Ewing's sarcoma was found in 22% of cases, osteosarcoma - 29%, histiocytosis X - 9%, bone metastases - 9%. In 24% of cases the disease was not associated with bone tissue: chondroblastoma, bone cyst, synovial sarcoma, osteochondroma etc. Only 5% of patients we were able to confidently diagnose chronic multifocal osteomyelitisIn conclusion, newly diagnosed bone lesions in children require joint diagnostic efforts of various specialist. Our study showed, that in most cases swift and correct diagnosis and pathogenic treatment was only possible upon biopsy.


Juvenile dermatomyositis (JDM) is a rare but severe autoimmune inflammatory myositis of childhood. International collaboration is essential in order to undertake clinical trials, understand the disease and improve long-term outcome. The aim of this study was to propose from existing collaborative initiatives a preliminary minimal dataset for JDM. This will form the basis of the future development of an international consensus-approved minimum core dataset to be used both in clinical care and inform research, allowing integration of data between centres.A working group of internationally-representative JDM experts was formed to develop a provisional minimal dataset. Clinical and laboratory variables contained within current national and international collaborative databases of patients with idiopathic inflammatory myopathies were scrutinised. Judgements were informed by published literature and a more detailed analysis of the Juvenile Dermatomyositis Cohort Biomarker Study and Repository, UK and Ireland.A provisional minimal JDM dataset has been produced, with an associated glossary of definitions. The provisional minimal dataset will request information at time of patient diagnosis and during on-going prospective follow up. At time of patient diagnosis, information will be requested on patient demographics, diagnostic criteria and treatments given prior to diagnosis. During on-going prospective follow-up, variables will include the presence of active muscle or skin disease, major organ involvement or constitutional symptoms, investigations, treatment, physician global assessments and patient reported outcome measures.An internationally agreed minimal dataset has the potential to significantly enhance collaboration, allow effective communication between groups, provide a minimal standard of care and enable analysis of the largest possible number of JDM patients to provide a greater understanding of this disease. This preliminary dataset can now be developed into a consensus-approved minimum core dataset and tested in a wider setting with the aim of achieving international agreement. Juvenile dermatomyositis (JDM) is a severe, autoimmune, inflammatory myositis that can cause death and major long-term health problems -3. ThereTo date, two parallel processes have led to the development of two ‘core sets’ for JDM in America  -12 and iDisease specific registries, particularly when linked to a biobank of biological specimens, can be powerful tools enabling epidemiological research, identification of risk factors to develop disease (such as gene-environment interaction) and identification of patients for clinical trials . They caThe concept underpinning disease-specific registries is a user-friendly, accessible database that can be useful in clinical practice and encourages data-entry for research purposes. In order to achieve this, databases need to collect important information that helps to define disease outcome and if possible inform treatment, but not be so extensive that it is too time-consuming. Ideally, it should be linked to the patient record to avoid duplication  and yet Currently, existing databases within JDCBS, CARRA and Euromyositis have dataset parameters that are partially overlapping but use different data items. Analysis of information held within these individual data collections has led to a greater understanding of the disease, resulting in numerous publications on JDM ,20. HoweA group of five JDM experts from the UK, Italy and Canada  representative of the major groups studying JDM and maintaining databases  formed a working group which aimed to produce a provisional minimal dataset for JDM .A literature search, carried out by one author (LM), aimed to identify any variables potentially missing from current database collections but used within validated research tools. The search  identified 272 publications. Articles containing variables used within published ‘core sets’ for research purposes (PRINTO/IMACS) and variables used within articles describing disease classification, diagnostic criteria, clinical characteristics, disease monitoring, outcome assessment/response to treatment or definition of inactive disease were listed for initial consideration and presented to the group.http://www.juveniledermatomyositis.org.uk), CARRA (http://www.carragroup.org), and Euromyositis (http://www.euromyositis.eu), as well as those used in a Paediatric Rheumatology INternational Trials Organisation (PRINTO) coordinated retrospective study analyzing 490 JDM patients [A detailed analysis of variables from three existing large registries of patients with Idiopathic Inflammatory Myopathies (IIM), namely JDCBS  showed that 19 variables were common to all four datasets, 16 were common to three datasets, and 24 were common to two datasets  and muscle biopsy evidence of myositis. There were some differences in how these data were documented, particularly when comparing adult and paediatric registries. All databases asked about the presence of skin ulceration, calcinosis, arthritis and cardiac/respiratory involvement although there were differences in how the questions were asked and data presented. All databases asked for medication history.Two databases asked about neurological involvement. Capture of systemic symptoms  varied between databases. There were differences in how disease activity over time was monitored, although the majority of databases included patient/parent Visual Analogue Scale (VAS), a Health Assessment Questionnaire (CHAQ/HAQ), physician global VAS, and a measure of muscle strength; either the Childhood Myositis Assessment Scale (CMAS) and/or Manual Muscle Testing (MMT) . The PRIThe presence of Raynaud’s phenomenon was retained due to the potential significance of progression of childhood onset myositis into scleroderma or myositis/scleroderma overlap in adult life . The preScrutiny of the UK JDCBS database, which included routine collection of 54 out of a total of 61 possible variables in the provisional minimal database, showed that at baseline, 8/54 (15%) variables were completed in <50% of patients. Specific concerns were noted with completion of family history, Childhood Health Assessment Questionnaire, Child Health Questionnaire, parental visual analogue scale of disease activity, pain visual analogue score, as well as nail-fold capillary changes, lipodystrophy and Raynaud’s phenomenon. Analysis of completion rates for two of these variables (nail-fold changes and Raynaud’s) could have been confounded by the fact that they were not included in the original data collection forms, but added at a later date. With prospective collection, parameters performing poorly (completed in <50% patients) were MRI, muscle biopsy, antibody and pulmonary function test results. Discussion within the expert group confirmed the importance of these parameters but led to rephrasing of questions to support future enhanced data completion. For example, the question ‘pulmonary involvement due to myositis’ was favoured as opposed to asking clinicians to document the results of pulmonary function tests.A provisional minimal dataset was therefore established from the existing collaborative datasets for use in clinics and inform clinical trials and research studies. This provisional dataset was then configured into user-friendly forms Figures , 4 and 5http://www.euromyositis.eu).Our working group includes a member of the Euromyositis Steering Committee and in collaboration with the Euromyositis Research Group, we have used the provisional dataset as a platform to create a paediatric-specific webpage for the Euromyositis database, ensuring compatibility with the web-based system used to collect data on adult-onset idiopathic inflammatory  and allow analysis to be undertaken on the largest possible number of JDM patients. This has the potential to improve understanding of disease phenotype and outcome in a way that will define research questions and underpin prioritisation of future clinical trials. Analysis of a large number of JDM patients with international collaboration has the potential to help answer fundamental questions including characteristics of patients who develop JDM, how patients develop the disease, time to diagnosis (and raise awareness leading to quicker diagnosis), which tests are most useful for diagnosis and which features predict a more severe disease course. Increasingly, distinct clinical subtypes are recognised within IIM, associated with myositis specific antibodies, but differences are seen in adults and children . Our undA large international collection has the potential to allow detailed evaluation of ‘real world’ treatment interventions used in clinical practice – based on clinician’s intention to treat, to see if one treatment is better than another. The CARRA database includes the option of clinicians choosing which of a predefined number of treatment strategies to use within the context of a consensus treatment plan . If othehttp://www.euromyositis.eu). This web-page complements current data collection on adult myositis and will allow comparison between the two groups. New variables that are proposed as part of this international minimal dataset could be incorporated into the Euromyositis data collection. An important part of this collaboration is to ensure that children entered into adult networks have paediatric-specific outcomes (such as growth) recorded. Collaborative efforts in JDM have led to data-driven approaches such as recently published PRINTO-driven criteria for defining clinically inactive disease in JDM [International collaboration has the potential to enable comparative studies of differences between adult and juvenile dermatomyositis. Our group has collaborated with Euromyositis to produce a paediatric specific web page for data entry for patients with JDM  for JDM as well as other paediatric rheumatological conditions .A provisional minimal dataset has been defined by consensus between a group of experts in JDM, representative of the major national and international JDM collaborative efforts. This now needs to be refined and tested for its usefulness and acceptability in a wider international setting. In order to achieve this, a formal consensus-driven methodology is required of all stakeholders. This will include a Delphi process to gain widespread opinion via the established JDM networks that will help to inform a more detailed face-to-face nominal group consensus process by internationally representative JDM experts.JDM is a rare but serious inflammatory condition with an appreciable risk of long-term morbidity. There are many unanswered questions around epidemiology, pathogenesis, treatment and outcome of the disease. The provisional dataset developed to date will be used as a template to aid a formal multi-stage consensus process, involving large groups of clinicians caring for children with JDM, with the aim of developing a feasible, internationally agreed minimal dataset for clinical use that can inform research.JDM: Juvenile dermatomyositis; IIM: Idiopathic Inflammatory Myopathy; JDRG: Juvenile Dermatomyositis Research Group (UK and Ireland); JDCBS: Juvenile Dermatomyositis Cohort Biomarker Study and Repository, UK and Ireland; CARRA: Childhood Arthritis and Rheumatology Research Alliance; PRINTO: Paediatric Rheumatology INternational Trials Organisation; IMACS: International Myositis and Clinical Studies group; OMERACT: Outcome Measures in Rheumatology; EMG: Electromyogram; MRI: Magnetic Resonance Imaging; CHAQ: Childhood Health Assessment Questionnaire; VAS: Visual Analogue Scale; CMAS: Childhood Myositis Assessment Scale (CMAS); MMT: Manual Muscle Testing (MMT); DAS: Disease Activity Score (DAS); MITAX: Myositis Intention to Treat Activity Index (MITAX); MYOACT: Myositis Disease Activity Assessment Visual Analogue Scales.The authors declare that they have no competing interests.LM, CP, LW, AH, AR involved in all stages of the development of minimal dataset. LB was involved in scrutinising the UK JDCBS (carrying out data queries) and administrative tasks. KA was involved in scrutinising the UK JDCBS database, carrying out administrative tasks and developing the database format / clinical forms. LM, CP, MB, LW involved in intellectual content and obtaining funding to take this work forward. All authors read and approved the final manuscript.Form A: provisional definitions, Form B: provisional definitions (to be refined further as part of on-going work)[ing work)-37Click here for file


Proper function of the nervous system critically relies on sophisticated neuronal networks interconnected in a highly specific pattern. The architecture of these connections arises from sequential developmental steps such as axonal growth and guidance, dendrite development, target determination, synapse formation and plasticity. Leucine-rich repeat (LRR) transmembrane proteins have been involved in cell-type specific signaling pathways that underlie these developmental processes. The members of this superfamily of proteins execute their functions acting as trans-synaptic cell adhesion molecules involved in target specificity and synapse formation or working in cis as cell-intrinsic modulators of neurotrophic factor receptor trafficking and signaling. In this review, we will focus on novel physiological mechanisms through which LRR proteins regulate neurotrophic factor receptor signaling, highlighting the importance of these modulatory events for proper axonal extension and guidance, tissue innervation and dendrite morphogenesis. Additionally, we discuss few examples linking this set of LRR proteins to neurodevelopmental and psychiatric disorders. The establishment of a functional nervous system requires connecting neurons into complex neuronal networks with exquisite precision. To achieve this, growing dendrites and axons must navigate toward their target regions, recognize their appropriate target cells and establish specific synaptic contacts with these cells. Along this pathway, dendrites and axons are guided by a group of short- and long-range signals that help them sense and navigate the environment and establish appropriate contacts with specific target cells.Neurotrophic factors are a group of secreted and diffusible molecules that play a crucial role in the development, survival and maintenance of the peripheral and central nervous system. The two major families of neurotrophic factors are: the neurotrophins and the glial cell line-derived neurotrophic factor (GDNF) family of ligands , Artemin (ARTN), and Persephin (PSPN). GDNF was originally discovered by its ability to induce the survival of ventral midbrain dopaminergic neurons. Later work showed that GFLs control growth and survival of specific subpopulations of motor neurons and many peripheral neurons, including sympathetic and sensory neurons. GFLs promote these trophic effects acting through two types of receptor subunits, one specialized in ligand binding, represented by the glycosyl-phosphatidylinositol (GPI)-anchored co-receptor, GFRα and another involved in transmembrane signaling, represented by the RTK, Ret or the neural cell adhesion molecule  receptor cannot be activated by their cognate vertebrate GDNF ligands because they are not expressed in flies. However, a recent work has shown novel functions for dRet as a regulator of sensory neuron dendrite growth and patterning, through a mechanism that requires signaling crosstalk with integrins, but does not involve GDNF binding  send axons to the periphery to innervate the skin and muscles, and project central axons to the second-order neurons in the spinal cord. Evidence from different subtypes of somatosensory neurons has revealed a common requirement of target-derived neurotrophins during projection of sensory axons toward their respective central and peripheral targets. Thus, TrkA expressed in cutaneous nociceptive sensory neurons is required for nociceptor innervation of the skin and for the generation of proper axonal projections in the spinal cord  acts via TrkA to support axonal extension, but not retrograde survival, whereas NGF produced from final targets  supports not only axonal growth but also survival and gene expression through retrograde signaling. Interestingly, these studies illustrate a model in which a hierarchical neurotrophin signaling cascade coordinates the specificity of sympathetic neuronal innervation  have been identified  is a LRR transmembrane protein that was identified as a TrkA and Ret signaling component  is another protein that was described as a neurotrophic factor receptor interactor. This molecule belongs to the Lrig family of single-pass transmembrane proteins, which modulate a variety of signaling pathways across evolution. In vertebrates, there are three family members, , which are defined by closely related extracellular domains with a similar arrangement of 15 LRRs and three Ig-like domains and a cytoplasmic region with no apparent homology to other proteins. Lrig1 is the best functionally-characterized member of the family, which controls the activity of different growth factor RTKs, such as EGFR, ErbB 2–4 and Met, by promoting receptor ubiquitination and degradation , an autosomal-recessive disease characterized by congenital urinary bladder dysfunction associated with a significant risk of kidney failure and abnormal facial expression. Although the mechanism underlying this effect is still unknown, the evidence indicates that Lrig2 is required for normal autonomic innervation of the urinary tract  that contain extracellular LRR domains homologous to the axon guidance molecule Slit and intracellular C-terminal tyrosine residues with sequences homologous to the Trk molecules. In particular, Slitrk6 promotes the survival and innervation of sensory neurons in the inner ear, at least in part by modulating neurotrophin–Trk receptor signaling. Interestinlgy, NTR and other partnering with Trk neurotrophin receptors  complex mediating axonal growth cone collapse , represents a novel and alternative p75Dendrite size and morphology are key determinants of the functional properties of neurons, and many neurodevelopmental and psychiatric disorders are due primarily to structural abnormalities of dendrites and their connections  located in the presynaptic side, Slitrk5 has emerged as a TrkB receptor component that facilitates BDNF-induced TrkB signaling required to dendrite morphogenesis of striatal GABAergic neurons. Upon BDNF stimulation, Slitrk5 forms a physical complex with TrkB through their LRR domains and directs TrkB receptor to Rab11-positive recycling endosomes promoting neurotrophin signaling. In this context, Slitrk5-null mice exhibit reduced striatal volume, decreased dendrite complexity and affected basal ganglia circuitry and function, similar to the phenotype reported in the striatum of mice with genetic deficiencies in BDNF and TrkB signaling , epilepsy, essential tremor (ET), Alzheimer’s (AD) and Parkinson’s disease  death. Both Lingo1 and NgR were found to be upregulated in RGCs in an ocular hypertension paradigm in rats (Fu et al., Recently, Fernandez-Enright et al.  have proFinally, altered BDNF/TrkB signaling has been implicated in the pathophysiology of neurodegenerative and psychiatric disorders including, AD, PD, HD, bipolar disease and epilepsy (Chen et al., Finally, genetic evidence also links some LRR proteins with congenital disorders of the nervous system. Thus, Lrig2 has been associated with congenital urinary bladder dysfunction, a disease characterized by abnormal innervation of the urinary tract (Stuart et al., Thus, the modulation of neurotrophic factor receptor signaling represents a powerful therapeutic approach for reversing neuronal dysfunctions associated with neurodegenerative, neurodevelopmental and psychiatric disorders.More than 20 years after the discovery of neurotrophic factor receptors, recent findings continue providing novel receptor modulators/components capable to execute complex regulatory mechanisms of receptor signaling that diversify neurotrophic function. These studies establish that engagement of neurotrophic receptors with specific LRR proteins represents a general mechanism that explains how neurons within a particular region of the nervous system expand the repertoire of neurotrophic factor signaling outputs during circuit development. We are now beginning at understanding the mechanistic details through which LRR proteins regulate guidance/neurotrophic factor receptor signaling. The evidence obtained so far indicate that these proteins can modulate receptor activity in opposite ways, inhibiting or promoting receptor activation through different mechanisms such as ligand binding, receptor ubiquitination, shedding, and trafficking (Ledda et al., Many LRR proteins have multiple binding partners across the synapses, in trans, and as neurotrophin receptor interactors functioning in cis. Despite these advances, several key questions remain unanswered. For instance, it will be important to fully characterize these protein interaction networks, identify the molecular domains that govern these interactions, and determine the physiological contribution of these proteins for nervous system development and function.Although several questions remain to be addressed, an increased understanding of the roles of LRR proteins promises to give insights into the many neurodevelopmental and psychiatric disorders typified by alterations in neural circuitry, and may aid to achieve effective therapies to cure these neurological diseases.Neurotrophic factors have emerged as promising disease-modifying molecules for neurological disorders and regeneration of damaged axons, and some of them are currently being used in clinical trials. However, they had limited success in the treatment of neurodegenerative diseases due to pharmacokinetic and delivery issues. It appears likely that many of these LRR proteins represent new potential therapeutic targets for these disorders. Thus, targeting endogenous regulators/components of neurotrophic factor receptor signaling, such as Lrig1, Slitrk5, Lingo1 and Amigo3, might be of clinical interest, maximizing the therapeutic power of neurotrophic factors on injured neurons in a region-specific manner.FL and GP wrote the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.