It is estimated that over one billion persons worldwide have some form of disability. However, there is lack of knowledge and prioritisation of how to serve the needs and provide opportunities for people with disabilities. The community-based rehabilitation (CBR) guidelines, with sufficient and sustained support, can assist in providing access to rehabilitation services, especially in less resourced settings with low resources for rehabilitation. In line with strengthening the implementation of the health-related CBR guidelines, this study aimed to determine what workforce characteristics at the community level enable quality rehabilitation services, with a focus primarily on less resourced settings.This was a two-phase review study using (1) a relevant literature review informed by realist synthesis methodology and (2) Delphi survey of the opinions of relevant stakeholders regarding the findings of the review. It focused on individuals  providing services for persons with disabilities in less resourced settings.Thirty-three articles were included in this review. Three Delphi iterations with 19 participants were completed. Taken together, these produced 33 recommendations for developing health-related rehabilitation services. Several general principles for configuring the community rehabilitation workforce emerged: community-based initiatives can allow services to reach more vulnerable populations; the need for supportive and structured supervision at the facility level; core skills likely include case management, social protection, monitoring and record keeping, counselling skills and mechanisms for referral; community ownership; training in CBR matrix and advocacy; a tiered/teamwork system of service delivery; and training should take a rights-based approach, include practical components, and involve persons with disabilities in the delivery and planning.This research can contribute to implementing the WHO guidelines on the interaction between the health sector and CBR, particularly in the context of the Framework for Action for Strengthening Health Systems, in which human resources is one of six components. Realist syntheses can provide policy makers with detailed and practical information regarding complex health interventions, which may be valuable when planning and implementing programmes.The online version of this article (10.1186/s12960-017-0240-1) contains supplementary material, which is available to authorized users. It is estimated that over one billion persons worldwide have some form of disability, as defined by the United Nations Convention on the Rights of Persons with Disabilities (UNCRPD) as ‘those who have long-term physical, mental, intellectual, or sensory impairments which in interaction with various barriers may hinder their full and effective participation in society on an equal basis with others’ . HoweverWithin the domain of health, there is a global deficit of over four million trained health workers with low-income countries largely affected , 5; howeThe World Report on Disability notes ‘global information about the rehabilitation workforce is inadequate. In many countries, national planning and review of human resources for health do not refer to rehabilitation’ p. 108) . Where s . Where Rehabilitation work being undertaken by ‘lower level’ cadres has historically evolved from professions’ disciplinary domains, rather than being based on a set of tasks that need to be conducted in an integrated fashion. Scientific approaches to job specification, including evidence-based empirical approaches to articulating the core competencies to perform specific tasks, or a family of tasks, now exist. By specifying the core competencies required to do a job successfully and effectively, service systems are able to select, train, and appraise personnel more effectively .The paucity of research on the rehabilitation workforce is likely to constrain our ability to follow-through and deliver on the initiatives described above. Shortages of appropriately trained and deployed human resources for rehabilitation constitute a serious strategic bottleneck for the development of institution and community-based services, despite multiple proposals seeking to improve such services , 14–17. Examining the current literature on the CBR workforce to gain the most comprehensive picture, and supplementing with evidence from other community health workforce areas, could make an important contribution to developing this field. With this in mind, our study aimed to answer the question of ‘what are the human resource competencies required to implement the CBR guidelines in less resourced settings?’Focusing on human resources at the community level is advocated as a way of expanding and decentralising service delivery while increasing the supply of or access to human resources for rehabilitation . InvestiThis study utilised two methods: a review of the relevant literature informed by realist synthesis methodology, and a Delphi survey of the opinions of relevant stakeholders regarding the findings of the review. This approach was utilised to combine the rigour and explanatory mechanisms of a realist synthesis with additional stakeholder input for greater contextualised findings. Figure Realist synthesis methodology, pioneered by Pawson , aims toFor the purpose of this review, we refer to characteristics as a description of a person's or jobs’ attributes; skills as a set of learned abilities, often through training programmes; and competencies as a combination of skills and behaviours that are required to perform a job to a satisfactory degree.This research has been adapted from realist synthesis as described by Pawson and Tilley for two main reasons. First, and frankly, we recognise that we entered into this methodology with an incomplete understanding of its details. The research objectives and proposed questions and methodology were provided to the team. As our learnings on realist studies advanced, we had to adapt both our objectives and methods to find a balance between meeting the commissioned requests and needs, and attempting to maintain methodological rigour. Second, the research outputs required programmatic recommendations that were easily digestible to implementers, demanding that our study be framed within a very pragmatic lens, likely at the cost of more robust theoretical influence. Main adaptations were: (a) the initial theory was developed mainly through team consultation with minimal literature input to ensure consistency with research output requirements; (b) sub-questions were used to organise our data and were prepared prior to searching to best contribute to the research objective; and (c) the addition of the Delphi process, which aided in contextualising review findings while also translating these into implementation-focused recommendations.The initial review question sought to identify best practice for the development of the rehabilitation workforce for health-related rehabilitation for health systems strengthening. During the initial theory development and scoping process, this question was refined to better reflect the initial theory to: ‘what rehabilitation workforce characteristics enable quality rehabilitation services at the community level in less resourced settings and how, why and for whom do these work best?’The initial programme theory to be explored was developed through an on-going iterative process that involved consultations with research team members and the investigation of some relevant literature . The oveThe search consisted of extensive snowballing and a systematic style approach. Search terminology was developed in consultation with team members and a search librarian , abstract (BG and MML) and full-text (BG and HM). Discrepancies were mediated by a third reviewer until consensus was reached. All articles from snowballing were subject to full text review.Articles were deemed ‘suitable’ based on their potential ability to contribute to the theory revision. The selection, therefore, was not accompanied by discrete inclusion and exclusion criteria, but based on the articles’ content and researchers’ judgement relating to applicability. As such, the selection criteria were quite open, with the only restrictions relating to publication year (2003 and later); articles including a rehabilitation component with reference or implications to the workforce; and rehabilitation services that were specific and/or relatable to health rehabilitation.Using the data extraction table, information was collected on the intervention, the context and potential explanatory mechanisms in addition to article descriptions, which allowed reviewers to extract context-mechanism-outcome configurations (CMOCs) from each article. Two reviewers (BG and SC) independently reviewed all included articles and for each filled in as much of the data extraction sheet as possible, including CMOC development.The primary reviewer synthesised the findings from both reviewers’ CMOC extraction of articles and used a data analysis matrix, which was adapted from a previous realist synthesis  to incluThe CMOCs from both reviewers were populated into the six framework themes proposed at the beginning stages of the project Table , similarThe Delphi survey is a consensus finding tool commonly used in health and social science research , which mCM lead the Delphi study, with support from MML and BG. A panel of experts who could provide insight into the workforce for health-related rehabilitation was recruited through purposeful sampling via email, conforming to recommendations of 10 to 25 participants , 54. ParSearching was conducted between October 2013 and February 2014. A total of 1231 articles were identified from the database searches. An additional 54 articles were identified during the snowballing process. After a multi-researcher screening process, 33 articles were identified for inclusion in this study according to the document flow diagram in Fig. More than 30 countries were represented in the articles. Sub-Saharan Africa had the highest representation with 18 articles: Somalia ; EritreaThere were 17 articles that reported on the workforce in relation to physical rehabilitation , 83, 87.The reported workforce characteristics differed in regard to cadre description, job requirements, training, supervision and ratio of worker to client or household, a summary of which is provided in Table Context-mechanism-outcome configurations were developed from the included articles using the predesigned data extraction template and analysis matrix  and further enhanced by additional CBR literature presented previously, may be considered across different health systems in order to inform the rehabilitation workforce’s characteristics and competencies. First, community-based initiatives can promote decentralisation and cost-effectiveness, and allow services to reach more vulnerable populations. However, motivation and retention likely need to be carefully addressed in more decentralised systems, as with other community health worker programmes. Second, the workforce providing rehabilitation in communities likely needs supportive and structured supervision by rehabilitation professionals at the facility level. Third, while the specific rehabilitation skills required may vary, there were certain standards of a community worker implementing rehabilitation common across many included studies within this research. These include aspects such as case management, social protection, monitoring and record keeping, counselling skills and mechanisms for referral. Fourth, rehabilitation workforce and service requirements that take lead from communities and work to increase community ownership may better serve individuals and work to improve the rehabilitation health system via sustainability and quality. Fifth, the often transcending roles of rehabilitation workers in the community means that workers trained on the CBR Matrix, as well as skills on advocacy and empowerment, may more holistically benefit persons with disabilities. Sixth, tiered/teamwork systems of service delivery for rehabilitation are frequently implemented and have shown important influence, with more general skills in the community and mechanisms for referrals to more specialised skills in facilities. Lastly, training of community rehabilitation workers that takes a rights-based approach, incorporates practical components, and if possible involves persons with disabilities, may be more beneficial to clients and communities. A very prominent finding throughout this work was that it is difficult to consider ‘health-related CBR components’ in isolation. Understanding and supporting the workforce requires the integration of all CBR components: health, social, education, livelihoods and empowerment.The distinction between physical and mental health rehabilitation workers is also of interest. This may become even more relevant in the future with the predicted increase in community-based services for mental health problems . It is iOther less-resourced community-based health workforce literature has recognised the need for context-specific investigations using theory-driven methodologies , 90–92. The use of realist approaches to study the rehabilitation workforce has provided insight and evidence on this under-researched field that would not likely be possible with other empirical approaches. The combined use of the realist synthesis and Delphi study provided a unique approach to synthesis. Our approach drew on the strength of perspectives offered by different stakeholders by allowing them to comment on possible human resource implementation processes that had an established evidence base, while at the same time allowing stakeholders to make their own suggestions.The wide scope of the research topic required that we progressively narrow our overarching research question and our search of the literature, in order to provide a meaningful and focused analysis. However, several of the papers included in the review lacked detail on the rehabilitation workforce and this limited what could be learnt from the research studies. The Delphi method also has a number of specific limitations. For example, the panel of experts was chosen by the researchers and was dependent on their own networks and the willingness of people to participate. It also had an under-representation of persons with disabilities or service users. In particular, the realist informed review of our study has several limitations: its level of abstraction is at times very abstract due to its synthesis across differing programmes and therefore suffers from a lack of specific revised theory; time restrictions prohibited further rounds of literature searching beyond searching for clarification; we did not do a comprehensive pilot of our search; and CMOCs taken forward to the Delphi process were chosen mainly on frequency found across evidence sources, which may have excluded some valuable explanatory resources.This review highlighted that while there are indeed programmes for rehabilitation in communities, little evidence is provided on the workforces that implement these services. Researchers and programme managers should collect and disseminate more detailed evidence on the workforce so that this body of literature can be expanded and others can learn from their experiences. It also notes a dearth of evidence from the perspective of the rehabilitation workforce. As the longer-term effectiveness of programmes depends on the retention of their workers, such investigations should be given priority in order to highlight areas of concern and provide more recommendations on how to reduce attrition and provide quality and continuity of services for persons with disabilities in communities. Studies that investigate task shifting of rehabilitation services should be conducted to provide evidence on what types of workforce configurations work best in what contexts. Further theory-driven studies on individual CBR interventions, such as realist evaluation, could help to further refine CMOCs at more specific levels of abstraction, such as individual characteristics within specific cadres, as opposed to the more programmatic abstraction level offered within.To our knowledge, there have been no realist studies conducted on the rehabilitation workforce to date. While it is clear that no ‘one size fits all’, our synthesis suggests some common features that are likely facilitative to strengthening the role of community workers in implementing community rehabilitation. Such findings can be useful to support programme design to ensure contextually specific and holistically natured programmes that focus on overall rehabilitation health worker competencies and the systems in which they operate. Contextual variations within this study were mostly attributed to the configuration of the rehabilitation system and the characteristics of the rehabilitation worker. More specific recommendations for these varying contexts can be found within, such as the need for appropriate training, supervision and motivation considerations within a tiered system, and the need for advocacy and empowerment skills when task-shifting to communities, respectively.Our findings are consistent with other workforce studies in less resourced settings in their recognition that workforce characteristics and their management should be contextualised , 96. HowAdditional file 1:Finalised search terms. (DOCX 122 kb)Additional file 2:CBR Matrix and perceived training needs of CBR workers: a multi-country study. (DOCX 274 kb)


Sub-wavelength antireflection moth-eye structures were fabricated with Nickel mold using Roll-to-Plate (R2P) ultraviolet nanoimprint lithography (UV-NIL) on transparent polycarbonate (PC) substrates. Samples with well replicated patterns established an average reflection of 1.21% in the visible light range, 380 to 760 nm, at normal incidence. An excellent antireflection property of a wide range of incidence angles was shown with the average reflection below 4% at 50°. Compared with the unpatterned ultraviolet-curable resin coating, the resulting sub-wavelength moth-eye structure also exhibited increased hydrophobicity in addition to antireflection. This R2P method is especially suitable for large-area product preparation and the biomimetic moth-eye structure with multiple performances can be applied to optical devices such as display screens, solar cells, or light emitting diodes. As shown in Fig. 3. The effective refractive index between the air and the medium of the eye changes gradually due to these AR nanostructures that are smaller than the visible wavelengths (380 to 760 nm). In this way, the incident light will not experience a sudden variation in refractive index, which would cause proportional reflections4. Following this observation of AR nanostructures, the biomimetic sub-wavelength structures also showed such an excellent antireflective property, which was known as the “moth-eye effect”6. The rapid development of nanofabrication technology in recent years, had led to the biomimetic moth-eye structures being applied to optical devices such as display screens7, solar cells9, and light emitting diodes (LED)11.Research of sub-wavelength structures on the surface of moth eyes led to the original understanding of antireflective (AR) phenomenon in nature. Each ommatidium of the nocturnal moth is covered with AR nanostructures—an array of 200 to 300 nm sized pillars—which simultaneously reduce the reflection of light and enhance night vision capability. These features allow moths to see well in darkness with no reflection that could be visible to their predators12 and graded index coating14 were the two most commonly used approaches to fabricate an efficient AR coating. The former is based on physical vapor deposition to obtain ultrathin inorganic layers on different substrates. However, there are several limitations to this approach. The vapor deposition method is difficult to deal with large size surfaces. Precise thickness of each inorganic layer also should be accurately designed and repeatedly optimized to ensure high transmittance in wide ranges of incidence angles and wavelengths15. Furthermore, multilayer coating is known to have inherent problems like absorption and scattering loss, low durability, thermal deformation, etc16. Inspired by moth eyes, the latter approach utilizes graded index coating, to reduce reflection of incident light. This biomimetic coating, which is made up of highly ordered sub-wavelength structure arrays, has an advantage by obtaining ultralow reflectance in wide spectrums and field ranges17. To date, many surface treatment methods, such as plasma etching, electron-beam lithography, sol-gel method, and self-assembly method, have been developed and utilized to fabricate antireflection sub-wavelength structures on different kinds of substrates20. With benefits including its high precision, high efficiency, operation simplicity and low cost, the nanoimprint lithography (NIL) method22, which includes thermal nanoimprint lithography and ultraviolet nanoimprint lithography (UV-NIL), is also regarded as one of the most promising techniques for antireflection.Until now, multilayer coating23. This technique was firstly proposed by Chou et al.24 in 1995 for the preparation of sub-25 nm structures on polymer surfaces. Then in 1999, Grant Wilson and co-workers extended the NIL technique to nanostructure fabrication using UV-curable resins25. Therefore, thermal and UV imprinting are involved in the NIL technique, and both can be applied directly to polymer surfaces. In NIL process, a patterned mold  was covered with a layer of UV-curable resin or thermoplastic polymer and imprinted by applying appropriate imprinting force and temperature for a reasonable period.NIL is one of the most reliable and effective techniques for the fabrication of nanosized structures at a reasonably low costet al.26 transferred AR moth-eye structure onto the surface of glass substrates using UV-NIL method. The normal incident transmittances increased from ~91% for a bare glass substrate to ~93% and ~97% for single and double side patterned AR products over a 400 to 800 nm wavelength range. Kim and co-workers16 reported a similar research work based on thermal-NIL process on PC films with an average normal incident transmittance of ~92% (400 to 800 nm wavelength range). Abbott et al.27 reported a soft roller NIL technique for the preparation of subwavelength silicon moth-eye structures. Their products presented an average reflection of 3% in the spectral range of 400–1000 nm for 45° incident angle. Besides enhanced AR performances, advantageous hydrophobic behavior is a common by-product of the sub-wavelength moth-eye structure29. Normally, the water contact angles of AR structured samples prepared by NIL techniques on polymer or glass substrates can reach the range from ~100 to ~120° with different geometric structures26. For the AR structures formed by some chemical process (e.g. reactive ion etching) or special hierarchical structures, the AR products can present superhydrophobic performance with water contact angles higher than 150° (even higher than 170°)30.In the last decade, NIL technique had been intensively used in the fabrication of AR products. Jung 31, the sub-wavelength structures will behave as an effective medium when incident lights interact with the coating surface. For example, look at the case of UV-curable resin. The schematics of the refractive index variations are shown in Fig. air), UV-curable resin (nuv), and substrate (ns), respectively. However, a coating with columnar sub-wavelength structure arrays , which is controlled by the ratio between the structures and channels. While the effective refractive index (neff) of the conical subwavelength structure with triangular profile  UV-NIL method on the surface of transparent polycarbonate (PC) substrate. A GP756 UV-curable resin provided by Everwide Chemical Co., Ltd. was chosen for the preparation of AR coatings. The main component of GP756 was found to be Pentaerythritol Triacrylate (PETA) using infrared spectrum analysis  could be used as polymer adhesives, which meant GP756 had much stronger adhesive force with polymers than metals. All of these above made the AR structures formed from UV-curable resins tended to bind on the surface of PC substrate during demolding. Furthermore, the operation of demolding process should begin from one side slightly to avoid demolding defect caused by stress concentration.Besides, the demolding process would greatly influence the final shape of AR structures. In order to get well shaped AR structures, the following means were executed. Firstly, silanization treatment had been performed to the Ni mold to avoid pollution by UV-curable resin during imprinting. Secondly, optional Ar Plasma treatment to Ni mold and OA further comparison of the optical reflectance spectra at normal incidence is shown in Fig. The morphology and reflectance results of several representative AR sub-wavelength structured samples mentioned in section 3.2 and 3.3 are listed in Table Although the reflection performance of an AR sub-wavelength structure can be significantly affected by the variation of average height or replication rate, it was still lower than that of flat UV-curable resin coated PC substrate. This proved that the biomimetic moth-eye structure fabricated using UV-NIL process actually had a positive effect as an antireflection coating.Sample 4 in Table All the results listed above demonstrate that the light propagating on AR sub-wavelength structures produces a continuous variation in the refractive index between the air and the medium. As shown in Fig. 35. In our R2P UV-NIL process, the application of a PDMS flexible female mold was provided as an optional method to fabricate AR sub-wavelength structures on a polymer substrate. However, the PDMS flexible female mold itself also had the potential to be applied as soft AR products37.The AR samples mentioned in this study were coated with the UV-curable resin sub-wavelength structures on only one side (on the top). It should be pointed out that the optical reflectance can be further reduced with AR sub-wavelength structures on both sides (on the top and bottom) of the PC substrate39, which is very useful for outdoor applications. As a biomimetic moth-eye structured surface, the AR sub-wavelength structures fabricated using UV-NIL process can induce self-cleaning of small particles and dusts on sample surfaces40. The photographs of water contact angle on the surface of a bare PC substrate, a flat UV-curable resin coated PC substrate, and an AR sub-wavelength structured sample fabricated using UV-NIL process with an imprinting force of 350 N and a resin viscosity of 100 cps are shown in Fig. 42. Furthermore, once the AR product was applied as the cover layer of solar cells, the install inclination angle of solar cell panels (~40° in the middle and lower reaches of Yangtze River in China) would make it easier for the self-cleaning of dust deposition with the help of dew and rainwater.Nanostructure surfaces with large roughness can enhance the hydrophobic performanceIn the present work, Roll-to-Plate (R2P) ultraviolet nanoimprint lithography (UV-NIL) method was introduced for the fabrication of antireflection (AR) sub-wavelength structures. This technique was especially suitable for the continuous preparation of large-area AR products. The height of periodic sub-wavelength structures with parabola-shaped profile can be controlled by the variation of processing parameters, such as stage moving speed, imprinting force and resin viscosity, during UV-NIL process. It will also affect the change of optical reflection performance of obtained AR samples. In this study, the influence of imprinting force and resin viscosity were researched and discussed. An imprinting force of 350 N and a resin viscosity of 100 cps were found to be the best parameters, and the average reflectance of this AR sub-wavelength structured sample was only 1.21% in the visible light range at normal incidence. Furthermore, we found the biomimetic moth-eye structured samples also presented hydrophobicity and a water contact angle of 104.2° was obtained. The biomimetic moth-eye AR structured surfaces with dual functionality can be extended to future applications in the fields of display screens, solar cells, light emitting diodes, and related optical devices.2 were right under the roller. The effective imprint area of ERP-210 was 180 × 250 mm.A R2P UV Roller Press Scan imprinter of ERP-210  was used to fabricate AR sub-wavelength structures. As shown in Fig. The Ni mold with the AR sub-wavelength structure was provided by KYODO International Co., Ltd., Japan. The sub-wavelength structure was made by the method of two-beam laser interference photolithography, and the design of the mold was mainly focus on the mimic of moth-eye structures. Figure ® 184 (Dow Corning Corp.) was used for flexible female mold replication. Transparent PC substrates with a thickness of 0.25 mm were purchased from Dongguan Lingmei New Materials Co., Ltd., and its average transmittance was above 89%. UV-curable resin with a viscosity of 800 cps at 25 °C  was used for preparing the AR coatings. GP756 was a radical curing resin with high suitability and hardness, which was suitable for the fabrication of nanostructures with high aspect ratio. The GP756 resin coating on PC substrate had a shore hardness of D86, while the pencil hardness of the cured resin film was 4 H. Thus, the imprinted AR structure presented relatively high mechanical stability and durability. The AR performance of products still maintained after flushed with water and scrubbed with Kimwipe paper for more than 100 cycles. The result of infrared spectrum analysis of GP756 is shown in Fig. A kit (containing silicone elastomer base and curing agent) for a poly(dimethylsiloxane) (PDMS) prepolymer of SYLGARIn this paper, the influence of viscosity on the processing effect of an AR sub-wavelength structure was discussed. In order to get UV-curable resin with lower viscosity, Methoxy Polyethylene Glycol 400 Methacrylate (MPEG400MA) with a viscosity of 23 cps at 25 °C  was chosen as the diluting agent. With the help of MPEG400MA, UV-curable resin with different viscosities of 100 cps, 400 cps and 800 cps were prepared by mixing in the correct proportions.Figure 43 and an atomic force microscope . The reflectance of AR sub-wavelength structured surface at normal incidence was observed by a benchtop spectrophotometer . The instrument was equipped with a pulsed xenon arc lamp . The reflectance spectra at different angles  were observed using a variable angle multifunctional optical characteristic measuring system. A high-resolution optical fiber spectrometer  was used to transmit the spectral data to a computer, and the AvaSoft-Full software was further applied for data processing and recording. The water contact angles of bare PC substrate, flat UV-curable resin coated PC substrate and the AR sub-wavelength structured sample were measured a drop shape analyzer (KRUSS DSA100) to evaluate their hydrophobic performance.The morphology of AR sub-wavelength structured surfaces was characterized using a field emission scanning electron microscope


Despite aggressive treatment for localized cancer, prostate cancer (PC) remains a leading cause of cancer-related death for American men due to a subset of patients progressing to lethal and incurable metastatic castrate-resistant prostate cancer (CRPC). Organ-confined PC is treated by surgery or radiation with or without androgen deprivation therapy (ADT), while options for locally advanced and disseminated PC include radiation combined with ADT, or systemic treatments including chemotherapy. Progression to CRPC results from failure of ADT, which targets the androgen receptor (AR) signaling axis and inhibits AR-driven proliferation and survival pathways. The exact mechanisms underlying the transition from androgen-dependent PC to CRPC remain incompletely understood. Reactivation of AR has been shown to occur in CRPC despite depletion of circulating androgens by ADT. At the same time, the presence of AR-negative cell populations in CRPC has also been identified. While AR signaling has been proposed as the primary driver of CRPC, AR-independent signaling pathways may represent additional mechanisms underlying CRPC progression. Identification of new therapeutic strategies to target both AR-positive and AR-negative PC cell populations and, thereby, AR-driven as well as non-AR-driven PC cell growth and survival mechanisms would provide a two-pronged approach to eliminate CRPC cells with potential for synthetic lethality. In this review, we provide an overview of AR-dependent and AR-independent molecular mechanisms which drive CRPC, with special emphasis on the role of the Jak2-Stat5a/b signaling pathway in promoting castrate-resistant growth of PC through both AR-dependent and AR-independent mechanisms. Recent epidemiological data identifies prostate cancer (PC) as the most common non-cutaneous cancer and the second-leading cause of cancer-related death among males in the United States following lung cancer . AccordiPrior to 2010, the chemotherapeutic taxane docetaxel (Taxotere®) was the only drug demonstrated to improve survival of CRPC patients in comparison to palliative chemotherapy with mitoxantrone (Novantrone®), increasing median overall survival from 16.3 to 19.2 months , 6. In tThe therapeutic agents receiving FDA approval for treatment of advanced PC in the past five years include 1) abiraterone , 2) enzalutamide , 3) cabazitaxel , 4) sipuleucel-T  and 5) Alpharadin  (reviewed in ). AbiratSimilar to normal prostate, PC cells require androgens for continued growth . The reqADT by means of surgical or pharmacological castration, the latter in the form of luteinizing hormone-releasing hormone (LHRH) / Gonadotropin-releasing hormone (GnRH) agonists (e.g. leuprorelin (Lupron®); goserelin (Zoladex®)) reduces serum testosterone levels by 90-95%. This robust decrease in serum androgens is dampened by the fact that intraprostatic levels of DHT have been reported to decline by only about 50% . The stiPC is considered castrate resistant during ADT with castrate levels of serum testosterone (<50 ng/dL) if it fullfils one or more of the following criteria: 1) a rise of prostate-specific antigen (PSA) serum levels , 2) development of symptoms in the presence of pre-existing cancer  or 3) detection of new metastatic lesions on imaging (radiographic progression) , 52. CRPThe mechanisms driving progression from androgen-dependent PC to CRPC are still largely unclear. Continued AR signaling, despite depletion of circulating androgens and AR blockade, is thought to be central to the development of CRPC , 57. ReaOne mechanism of AR reactivation in CRPC is via increased expression of AR, which may be achieved through genomic amplification of the AR locus or upregulation of AR protein levels. Early work using patient-matched clinical specimens indicated that approximately 30% of CRPC tumors harbored high-level AR gene amplification as demonstrated by fluorescence in situ hybridization (FISH), in comparison to none of the androgen-dependent primary tumors , 59. IncSomatic AR mutations may occur selectively in response to androgen deprivation, although the exact frequency of AR mutations in PC remains unknown. A review of 27 clinical studies found that AR mutations in androgen-dependent tumors ranged from 2-25%, while the incidence in CRPC tumors was slightly higher at 10-40% . AdditioResistance to the second-generation antiandrogens enzalutamide (formerly MDV3100) and apalutamide (formerly ARN-509) was shown to be conferred by the novel AR LBD mutation F876L  in in vitro and in vivo models of PC –27. MoreAnalysis of plasma from patients with metastatic CRPC for circulating cell-free tumor DNA detected several AR LBD mutations associated with abiraterone resistance, including AR-T878A and AR-L702H , 72. In In the absence of circulating androgens produced by the testes, an alternative mechanism to activate AR signaling is through conversion of cholesterol and adrenal androgen precursors into testosterone and DHT in PC cells . ItConstitutively active AR splice variants (AR-Vs), generated through alternative gene splicing or rearrangement of the AR gene, have been increasingly studied as a contributor to castrate-resistant growth over the past several years. The expression of AR-Vs has now been well-documented in PC cell lines, xenograft tumors, and clinical PC samples –85. The Whether AR-Vs promote castrate-resistant growth of PC primarily by reactivating the normal AR transcriptome or generating an altered AR gene signature remains disputed. Although AR-Vs have been shown to be capable of activating canonical AR target genes such as KLK3 (encoding PSA), several studies have investigated whether AR-Vs can generate alternative gene signatures in CRPC cells –87. One The constitutive, ligand-independent activity of AR-Vs has substantial implications for treatment of CRPC. AR-V7 transcript and protein levels were found to be upregulated in clinical CRPC bone metastases and correlated with decreased survival rate after surgery . In a moA novel therapeutic strategy capable of inhibiting both full-length AR and AR-Vs relies on targeting of the AR N-terminus, which is conserved across all AR isoforms. EPI-001, a bisphenol A-derived small molecule antagonist, which covalently binds the AR N-terminal domain, was shown to block transcriptional activity of AR and several AR-Vs, including AR-V7 –96. BaseNumerous growth factors, cytokines, and hormones have been implicated in the activation of AR when androgens are absent or present at sub-physiological concentrations . Non-canPromotion of AR signaling in PC may also occur through loss of negative regulatory signals, which suppress AR function. This concept is supported by findings demonstrating that the cyclin D1b isoform of the widely studied cell cycle regulator does not possess AR inhibitory function attributed to the more common cyclin D1a isoform , and thaModulation of AR activity by receptor tyrosine kinases may contribute to progression of PC to castrate-resistant cancer. Overexpression of Her2/neu (ErbB2) has been shown to enhance AR transcriptional activity in both the presence and absence of androgens, stimulating proliferation of LNCaP cells under both settings , 109. MoWhile most research to date has focused on the continued importance of AR in CRPC, alternative signaling pathways supporting proliferation and survival of CRPC cells have been shown to be capable of completely bypassing AR –114. ConSeveral studies have investigated candidate genes which may support CRPC growth independently of AR. Whitworth and colleagues used an RNA interference (RNAi) phenotypic screen to profile 673 kinases and identify those which contributed most to castrate-resistant growth of LNCaP cells under androgen-depleted conditions . MoreoveA recent body of work supports the concept that the glucocorticoid receptor (GR) may be able to substitute for AR in binding to androgen response elements (AREs) and driving PC cell survival under certain circumstances , 121. ChThe cancer stem cell theory states that only a rare subpopulation of tumor cells possessing stem cell-like properties, most notably unlimited self-renewal capacity, and multilineage differentiation, can initiate tumor formation . The morSeveral putative populations of PC stem-like cells (PCSCs) have been reported in the literature, most commonly identified through fluorescence-activated cell sorting (FACS) of bulk tumor cell lines, xenograft tumors or clinical samples for stem-like cell surface markers. Reported marker profiles include CD44+/α2β1+/CD133+ , TRA-1-6Interspersed within prostate epithelium are neuroendocrine (NE) cells, which can be identified by morphology under electron microscopy or through positive staining for chromogranin A, synaptophysin, neuron-specific enolase or other markers of NE differentiation . These sNeuroendocrine prostate cancer (NEPC) describes a heterogeneous group of tumors, including prostate adenocarcinoma with NE differentiation, adenocarcinoma with Paneth cell NE differentiation, carcinoid tumors, pure small cell carcinomas, pure large cell NE cancer and adenocarcinomas with mixed histologies . ApproxiNEPC cells are negative for AR and PSA expression and highly proliferative . Recent The lack of AR expression in NEPC cells , 137 hasIn order to target AR-negative cell populations in CRPC and to impose an additional survival strain for AR-positive PC cells during ADT, identification of non-AR therapeutic targets may provide novel treatment strategies for CRPC. Stat5a/b are latent cytoplasmic proteins that function as both signaling molecules and nuclear transcription factors, which are critical for PC cell viability in vitro, in vivo and in patient-derived PCs ex vivo –174. TwoIn PC, Stat5a/b is predominantly activated by binding of prolactin (Prl) to the membrane-bound prolactin receptor (PrlR), which transmits signals through Jak2 kinase , 177. InSignaling through the Jak2-Stat5a/b pathway is initiated upon Prl binding to PrlR and subsequent receptor-associated Jak2 kinase activation by autophosphorylation. This leads to phosphorylation of cytoplasmic tyrosine residues of the cytokine receptor which serves as docking sites for Stat5a/b via binding of the Stat5a/b SH2 domain . Stat5a/Over the last decade, numerous reports have supported the role of Stat5a/b in clinical progression of PC. Stat5a/b is constitutively active in human PC, but not in normal prostate epithelium . ExaminaA substantial body of work supports the concept that Stat5a/b is highly critical for the viability of human PC cells in vitro and xenograft tumor growth in vivo. Inhibition of Stat5a/b by varied methods induced massive apoptotic death of PC cells in culture and suppressed the growth of xenograft tumors in nude mice , 199. AhThe first evidence of Stat5a/b promotion of metastatic behavior of PC cells in vitro and in vivo  was provStat5a/b has been shown to promote AR signaling in PC cells Figure . The firImportantly, Stat5a/b blockade, by either genetic or pharmacological knockdown, induces extensive apoptotic death of PC cells that do not express AR. Specifically, inhibition of Stat5a/b was found to induce rapid apoptotic death of DU145 PC cells, which are negative for AR expression, providing evidence that Stat5a/b sustains viability of PC cells independently of AR , 211. AtRecent studies demonstrate that enzalutamide provides a modest improvement in survival in patients with PC due to rapid development of resistance , 9. MorePharmacological inhibition of the Stat5a/b signaling pathway can be accomplished through blockade at various levels, with inhibitors directed against the cytokine/growth factor receptor, tyrosine kinase or Stat5a/b itself. Of note, highest specificity with least clinical side-effects is likely achieved through direct targeting of Stat5 instead of its upstream activators. Indeed, past work has shown that disruption of Stat5a/b dimerization, transactivation and/or DNA binding is possible by targeting of the appropriate domain(s). Initial approaches utilized a Stat5a/b dominant-negative mutant lacking the transactivation domain , 174 andCompounds which are currently in clinical use for a variety of oncologic and non-oncologic indications have been found to inhibit Stat5a/b in several preclinical studies Table . Nam andRecently, the Nevalainen group identified and validated a small molecule inhibitor which targets the Stat5a/b SH2 domain in both PC and CML, malignancies known to be driven by Stat5a/b signaling . In siliPC remains a leading cause of cancer-related death for American men, with a subset of patients progressing to metastatic CRPC despite receiving aggressive treatment for localized cancer. An improved understanding of the molecular biology driving cancer progression has allowed substantial expansion of the therapeutic landscape for CRPC. Over the past five years, a diverse array of novel agents has been approved by the FDA for use in CRPC, with many other experimental therapies now in late-stage clinical trials. Most notable in the newly expanded treatment options for CRPC are the androgen synthesis inhibitor abiraterone and second-generation antiandrogen enzalutamide, both of which have been widely adopted in clinical practice by medical oncologists. However, additional studies are required to optimally integrate these new and emerging therapies with existing standard-of-care treatment paradigms. In addition, drug sequencing strategies need to be designed to anticipate and overcome newly described resistance mechanisms. Despite the impressive progress to date, the lack of a curative therapy for CRPC underscores a remaining unmet need, which stems from the still incompletely understood transition from androgen-dependence to castrate-resistance.Identification of therapeutic targets which regulate non-AR-mediated proliferation and survival pathways represent an opportunity to improve treatment for advanced PC. Stat5a/b has been previously validated as a biomarker and therapeutic target in PC. Active Stat5a/b expression levels carry prognostic value by identifying patients at risk for cancer recurrence and poor clinical outcomes. Levels of active Stat5a/b carry predictive value as well, serving to predict treatment response to radical prostatectomy in patients with early stage PC. There is a strong rationale for pharmacological targeting of Stat5a/b based on its pleiotropic effects on sustaining PC growth and viability, enhancement of AR transcriptional activity and promotion of metastatic behavior. Stat5a/b serves not only as a critical survival factor for AR-positive but also AR-negative PC cells and xenograft tumors, providing a means for targeting PC outside of the AR signaling axis. The collective findings described in this review indicate that Stat5a/b acts through both AR-dependent and AR-independent molecular mechanisms, which are distinct but not mutually exclusive and therefore hold the potential for imposing synthetic lethal effects if blocked simultaneously. Pharmacological inhibition of Stat5a/b may thus represent a dual strategy to target growth of PC and delay onset of resistance to agents targeting AR in PC.


P < 0.05). The effects were marginal for CEA, anemia and CRC location (0.05 < P < 0.1). The multivariate analyses of preoperative factors suggested decreased age, CEA, CA19-9, neutrophils, proximal location, and increased platelets and diameter were significantly associated with increased probability of LNC ≥ 12 (P < 0.05). The nomogram achieved c-indexes of 0.75 and 0.73 before and after correction for overfitting. The AUC was 0.75  and the clinically valid threshold probabilities were between 10% and 60% for the nomogram to predict LNC < 12. Additionally, increased probability of adequate LNC before surgery was associated with increased LNC and negative lymph nodes rather than increased positive lymph nodes, lymph node ratio, pN stages or AJCC stages. Collectively, the results indicate the LNC is multifactorial and irrelevant to stage migration. The significant correlations with preoperative circulating markers may provide new explanations for LNC-related survival advantage which is reflected by the implication of regional and systemic antitumor immune responses.Increased lymph node count (LNC) has been associated with prolonged survival in colorectal cancer (CRC), but the underlying mechanisms are still poorly understood. The study aims to identify new predictors and develop a preoperative nomogram for predicting the probability of adequate LNC (≥ 12). 501 eligible patients were retrospectively selected to identify clinical-pathological factors associated with LNC ≥ 12 through univariate and multivariate logistic regression analyses. The nomogram was built according to multivariate analyses of preoperative factors. Model performance was assessed with concordance index (c-index) and area under the receiver operating characteristic curve (AUC), followed by internal validation and calibration using 1000-resample bootstrapping. Clinical validity of the nomogram and LNC impact on stage migration were also evaluated. Multivariate analyses showed patient age, CA19-9, circulating lymphocytes, neutrophils, platelets, tumor diameter, histology and deposit significantly correlated with LNC ( Lymph node count (LNC) is an important parameter of routine pathological report after resection of colorectal cancer (CRC) , 2. AdeqSeveral mechanisms have been proposed to explain LNC-related impact on survival. The most common mechanism is stage migration , 12, 13.Preoperative serum tumor markers and blood cell counts are routinely used to evaluate surgically-treated patients with CRC . The relMedical records of 690 consecutive patients with primary CRC, who received surgery with a curative intent at the department of gastrointestinal surgery of Shanghai East Hospital between August 2011 and June 2015, were retrospectively reviewed. Patients were considered for subsequent analysis based on the following exclusion criteria: (1) patient who underwent emergency surgeries (n = 6), (2) patients who received chemo-radiotherapy before blood tests and surgeries (n = 19), (3) pTis disease or multiple primaries (n = 13), (4) pathologically proven non-R0 resection (n = 8), and (5) patients with incomplete or inconsistent data to specify any used variables (n = 143).6/mL), neutrophil count , lymphocyte count , platelet count , hemoglobin concentration , serum carcinoembryonic antigen , CA19-9 , CA50 , CA72-4 , type of surgery (open surgery or laparoscopy), tumor location and maximum diameter indicated by preoperative computed tomography scan. Pathological parameters assessed were experience of pathologist (junior or senior title), tumor macroscopy, grade, histology, vascular invasion, perineural invasion, LNC and tumor deposit in addition to tumor-node-metastasis classification by the 7th edition AJCC cancer stating manual. Presence of anemia was defined as a Hb concentration ≤ 110 g/L for females or 120 g/L for males. The normal upper limit of PLT used was 320 × 106/mL for both sexes to define thrombocytosis. Laparoscopy was only implemented for patients who were appropriate and willing to receive it.Both preoperative and pathological variables were accessed for each patient. Preoperative variables included sex, age, white blood cell count  and the area under the ROC curve (AUC) with associated 95% confident interval (95% CI). Internal validation and calibration of the nomogram were conducted by 1000-resample bootstrapping. The ranges of threshold probability, between which the nomogram was clinically valid, were determined by decision curve analysis (DCA). After addressing model performance, each patient was given an aggregated point on the basis of the nomogram. The points of all patients were then divided into quartiles to investigate whether increased probability of adequate lymph node recovery had significant impact on diagnosis of nodal status as well as AJCC stages. Statistical significance of all tests was set as a two-sided P value < 0.05.Continuous variables were compared with parametric or nonparametric methods depending on the distribution of the data. Discontinuous variables were compared using Chi-squared test or Fisher exact test. Concentrations of blood markers were pre-categorized to predict LNC ≥ 12 according to their normal references  or optimal cut-off values determined by maximization of Yuden Index with receiver operating characteristic (ROC) curve analysis, based on clinical reasoning and significance. To identify correlative factors for LNC ≥ 12, significant variables in univariate logistic regression analysis were evaluated in multivariate logistic analysis with a stepwise forward elimination of insignificant variables using the PASW 18.0 program . To identify predictors for LNC ≥ 12 that would be used in the nomogram, similar univariate and multivariate logistic analyses were performed using preoperative variables to derive a final variable formula. Nomogram was built in R program (v 3.2.3) with the The study data were extracted and analyzed in January of 2016 under the condition of anonymity, during which the researchers did not have the access to patient-identifying information. The study adhered to the Declaration of Helsinki for medical research involving human subjects  and the A final set of 501 patients with CRC was selected. Related clinical-pathological characteristics were shown in P < 0.05). A marginal effect was seen with respect to CEA, anemia and location of CRC (P > 0.05 and P < 0.1). In the multivariate analysis (Model B in P < 0.05). These predictors were selected to establish the nomogram. Additionally, the effect of the presence of anemia remained marginal (P = 0.097).Results of univariate logistic regression analysis were shown in The nomogram to predict the probability of LNC ≥ 12 for CRC patients before surgery was shown in The c-index of the nomogram was 0.75 and 0.73 before and after correction for overfitting. The bootstrap calibration plot  indicateP < 0.001), and the odds ratios were less dominant for the 2nd  and the 3rd  quartiles.Four subgroups were classified by dividing the nomogram-derived total scores of all patients into quartiles. The probability of adequate lymph node recovery significantly corrected with score quartiles. Compared with the 1st quartile, the highest odds ratio (OR) to predict the probability was associated with the 4th quartile ; however it did not correlated with increased positive lymph node count (PLNC) or increased lymph node ratio (LNR) . Additional assessments with proportional stacked bar charts (P < 0.001). The increased probability also showed an association with deeper infiltration (P = 0.004) but did not lead to apparent migrations of the pN (P = 0.856) or AJCC stages (P = 0.089).Further comparisons using violin plots  revealedr charts  indicateIn the current study, we retrospectively identified a number of predictors for adequate lymph node recovery through univariate and multivariate logistic analyses. We also developed and internally validated a preoperative nomogram, which incorporated several operator-independent markers and achieved a moderate predictive accuracy. In addition, we demonstrated with the nomogram that increased probability of adequate lymph node recovery before surgery was associated with increased LNC and NLNC during pathological assessment but it did not lead to significant changes in PLNC, LNR, pN stages or AJCC stages.Previous researches have investigated and identified numerous clinical-pathological factors that significantly correlate with LNC. The spectrum of related variables in patients with CRC is generally wide, which includes patient-related, tumor-specific, technique-dependent and hospital-varying factors –14. In t+ tumor infiltrating lymphocytes are related to increased serum albumin and better outcomes in stage II and III CRC [First of all, the results of multivariate analysis agree with the consensus that the recovery of lymph node may be multifactorial. However, the significant correlation with circulating markers is inconsistent with the consideration of using LNC as an indicator for surgical or pathological quality. According to the latest NCCN guideline , adjuvan III CRC . This al III CRC . But due III CRC . This is III CRC . All of  III CRC , 41. As  III CRC . ObviousOur study has some limitations that allow us to interpret with caution. The research data were retrospectively collected and processed, during which the influence of selection bias might be underestimated. The cut-off values of circulating markers such as neutrophils and lymphocytes might be suboptimal due to a relatively small study population. Although the nomogram performed well in derivation cohort and remained stable during internal validation, it still needs independent external validation and attentions should be paid to the clinical validity of the nomogram during the external validation. Incorporation of new markers such as circulating tumor cells and cell-free DNAs may further promote the performance of the nomogram.In summary, the results of the study conclude some inexpensive and useful circulating markers that are capable of predicting the probability of adequate lymph node recovery before resection of CRC. The nomogram on the basis of the biomarkers exhibits promising performance that may allow for future validation and application in clinical practice. The identified predictors for LNC may also offer a number of new explanations of the association between increased LNC and prolonged survival. These explanations may involve the MSI phenotype, regional lymphocytic reaction, SIR, micrometastasis and host-tumor interactions under the background of cytokine imbalance. Moreover, it is likely that enhanced lymphocytic reactions are associated with improved survival by eliminating metastasis in lymph nodes and result in the increase of identifiable LNC and NLNC simultaneously. Although some studies have demonstrated that the prognostic value of LNR in CRC is superior to that of LNC, combination of LNC and LNR may achieve more prominent prognostic significance considering they are independent with each other. Next, the nomogram itself indicates that LNC is predictable. Under the context of homogeneous surgical procedures and pathological manipulations, the LNC retrieved from patients may mainly reflect patient-specific factors such as antitumor immunity and age at diagnosis rather than type of surgery or quality of pathologist. However, our study still supports a LNC ≥ 12 to be the benchmark for surgically-treated patients with CRC; because the benchmark remains evidence-based and is helpful for the standardization of surgical and pathological procedures. Eventually, the nomogram still needs external validation. Inclusion of circulating markers relating to SIR, antitumor immune response and tumor burdens may be directions of future studies.S1 Table(DOCX)Click here for additional data file.


Visual estimation of numerosity involves the discrimination of magnitude between two distributions or perceptual sets that vary in number of elements. How performance on such estimation depends on peripheral sensory stimulation is unclear, even in typically developing adults. Here, we varied the central and surround contrast of stimuli that comprised a visual estimation task in order to determine whether mechanisms involved with the removal of unessential visual input functionally contributes toward number acuity. The visual estimation judgments of typically developed adults were significantly impaired for high but not low contrast surround stimulus conditions. The center and surround contrasts of the stimuli also differentially affected the accuracy of numerosity estimation depending on whether fewer or more dots were presented. Remarkably, observers demonstrated the highest mean percentage accuracy across stimulus conditions in the discrimination of more elements when the surround contrast was low and the background luminance of the central region containing the elements was dark (black center). Conversely, accuracy was severely impaired during the discrimination of fewer elements when the surround contrast was high and the background luminance of the central region was mid level (gray center). These findings suggest that estimation ability is functionally related to the quality of low-order filtration of unessential visual information. These surround masking results may help understanding of the poor visual estimation ability commonly observed in developmental dyscalculia. The effect of peripheral visual stimulation, varying in contrast and or luminance, on the ability to make numerosity estimation judgments of centrally presented elements, has seldom been investigated in typically developing adults. The process of visual estimation involves the discrimination of magnitude between two distributions or perceptual sets that vary in number of elements. Peripheral visual stimulation at high sensory load deleteriously affects such discrimination. Examples of peripheral involvement include discrimination of texture regions , tilt ofThe The functional role of RF inhibition in V1 includes the attenuation of afferent input with high contrast gain ; the gatFrom the computational modeling, primate neurophysiology and psychophysical literature on visual suppressive phenomena, it has been suggested that the RF suppression of cells in LGN and V1 through surround-masking is likely to suppress sensory gain control resources, thereby reducing the signal to noise ratio (SNR) of sensory/afferent information. This, in turn, would generate perceptual ambiguity and representational noisiness . PrelimiAn earlier psychophysical study demonstrated that children with low mathematical skills show higher motion coherence discrimination thresholds than age-matched controls , suggestThe acquisition of visual number estimation skills for individuals with WS—a neurodevelopmental disorder strongly associated with DD—has been shown to be more variable and delayed over the course of developmental time compared to neurotypical age-matched controls . Over thSimilar to the individuals with WS , Piazza Thus, there is evidence to suggest that visual estimation ability in early childhood predicts later mathematical achievement during the course of cognitive development . But whaCould the scalar variability (noisiness) of visual estimation be influenced by the functional quality of inhibitory gain control mechanisms discussed earlier? We sought to answer this question directly via investigation of the effects of high contrast surround-masking on visual estimation performance in neurotypical observers. If high contrast surround-masking causes impairment of visual estimation accuracy of neurotypical observers, it shows cause to infer that the poor number acuity previously observed in DD cf.  may stemEighteen young adults with normal/corrected to normal vision  participated in this experiment. This sample mostly comprised undergraduate psychology students who were awarded course credit for their participation, and post-graduate students who participated voluntarily without compensation. The study was carried out in accordance with the Helsinki declaration and approved by the Swinburne University of Technology ethics committee. Written informed consent was obtained from all subjects. Upon inspection of the raw data, it was apparent that there were two individuals with psychophysical responses that were ±2 SDs from the mean, which were markedly deviant from the remaining 16 participants and hence were excluded from the analysis.www.vpixx.com), presented on a 1680 × 1050 pixel Mac Pro cinema display with a frame rate of 60 Hz, and viewed at a distance of 50 cm. The three main parametric variations of these experiments were background luminance of the central stimulus region ; visual estimation of number without an annular surround (gray background luminance or black background); and surround dot contrast (low 25% and high 95%). The CSR was a 6.5° × 6.5° aperture containing white dots , drifting randomly inside the CSR at 2.14°/s. Interleaved with the frames of the CSR and dots, was additive random dynamic binary noise (RDBN) of 0.2° granularity, giving the appearance of transparent noise. For the zero luminance CSR, the additive RDBN was at 90% contrast, and at 20% for uniform (gray). The mean luminances for black, gray, and white colors were 0.30, 40.1, and 168.3 cd/m2, respectively.The stimuli were generated using VPixx software  CSR was 8 and the maximum for estimating more dots was 104.When observers made their visual estimation judgments, the CSR was enveloped by either a high or low contrast annulus having an outer radius of 17.5° and inner radius of 3.4° and filled with RDBN—also of 0.2° granularity. There was no overlap between the CSR and surround. Because additive RDBN was interleaved with the dots, the mean luminance for CSR and surround were different. Therefore, separate mean luminance measurements were taken for the CSR and surround. This revealed that the mean luminance for the uniform/gray CSR was 44.0 cd/mFigure 1, there were six center/surround configurations making up the experiment. For each experimental run, there were 50 trials per condition . Hence, the entire experiment comprised a total of six separate runs using the method of constant stimuli, which was parametrically varied by CSR background luminance (uniform/zero); visual estimation with no surround, where the background luminance matched the CSR; and surround contrast (high/low). Participants took brief rests between experimental runs in order to minimize fatigue.As seen from Figure 2, the stimulus sequence within an experimental trial contained three CSR stimuli at different times. The first CSR to appear within the trial sequence contained the reference set of dots, which remained on the screen for 1000 ms (CSR1). The second CSR (CSR2) was replaced with RDBN that was matched to the contrast of the annular-surround that served as an inter-stimulus interval of 750 ms. The final CSR to appear in a trial—like CSR1, also contained a set of dots, however, this time, the CSR was embedded in a high or low contrast annulus (CSR3). The difference ratio of dots between CSR1 and CSR3 was held constant at 1:0.5 throughout all experimental conditions.As can be seen in Numerosity estimation is affected by many variables. Here, we investigated what effect contrast gain saturation had on the accuracy of numerosity estimation judgments via a series of 2 × 2 factorial designs that varied in central contrast, surround contrast, no surround, and numerosity. The objective of these experiments was to indicate by two alternate forced choice (2AFC) method whether CSR3 contained a fewer or more dots than CSR1. Observers were instructed to fixate upon the CSRs, and to indicate their responses after the onset of CSR3. Participants were instructed to respond as quickly and as accurately as possible. The experiments were performed in a darkened room without a chinrest, and each experimental run was counterbalanced across subjects in order to control for the effects of fatigue.For simplicity, only the mean PCR for visual estimation of more and less dots across experimental conditions were examined. The reaction time (RT) data was not included in this analysis given that there were no significant effects found for numerosity, center or surround contrast. This absence in significant RT data was likely attributed to the brief exposure time of the CSR3 stimuli (750 ms), where observers had to rapidly make estimation judgments before the trial lapsed.Post hoc comparisons of significant simple effects were performed via two-tailed paired t-tests. There were no Bonferroni corrections applied to the paired t-tests because multiple comparisons were not performed.Differences in PCR were compared through a two-way, within-subjects analysis of variance (ANOVA), with focus on the effect that surround contrast (high/low/none) had upon the PCR for visual estimation of more and less dots. Subsequent ANOVAs explored the combination of other factors thought to affect visual estimation ability, such as center contrast (gray center/black center), as a more detailed exploration into how various combinations in center-surround contrast influence the PCR, and to note any variables other than surround contrast which may have confounded the effects of reduced PCRs observed in this study. Table 1, with F ratio and significance values summarized in Table 2. A 2 (high/mid surround contrast) by 2 (fewer/more dots) within-subjects ANOVA of black center stimuli revealed a significant main effect for surround contrast , and no significant effect for set size of dots under black center conditions (blc) . The surround contrast by dot set interaction was nonetheless highly significant . Post hoc comparisons (paired t-tests) for this interaction revealed that the mean PCR for estimating less dots in the presence of the low contrast surround, was significantly lower than estimating more dots under the same surround contrast conditions . Under the high contrast surround condition the mean PCR for estimation of more dots was significantly lower than estimation of less dots .There were eight 2 by 2 within-subject ANOVAs performed, with the mean and SD of the PCR across each condition shown in Figure 3B), where under high contrast surround conditions, the PCR for more and less dots were at or below chance level . There was no significant effect for number, or significant surround contrast by dot set interaction (F < 1). Considered as a whole, these results suggest that for the black center background condition, the high contrast surround had the strongest impact upon the ability to discriminate whether there were more or less dots in CSR3 compared to CSR1.A 2 (high/mid surround contrast) by 2 (fewer/more dots) within-subjects ANOVA of gray center stimuli revealed marginally significant main effect for surround contrast with gray center (grc) during visual estimation of dots  by center contrast (grc/blc background) ANOVA for the PCR of less dots revealed a significant main effect for center contrast  but not surround contrast . In addition, the surround contrast by center contrast interaction observed in Figure 4A was highly significant , implying that the mean PCR for estimation of “less” under the gray center and high contrast surround condition, was substantially lower than the blc and high contrast surround condition. A paired t-test confirmed that these mean PCR differences were highly significant .A series of 2 (surround contrast) by 2 (center contrast) within-subjects ANOVAs were performed to examine whether the effects of visual estimation ability observed in Figure 4B) revealed a significant main effect for surround contrast  but not center contrast (F < 1), where visual estimation of more dots was impaired by the high contrast but not low contrast surround. This surround contrast by center contrast interaction was significant , indicating that the mean PCR for estimation of more dots under zero luminance center and high contrast surround conditions for more dots, was significantly lower than that of the PCR with a gray center and high contrast surround . It is also worth noting that the mean PCR for estimation of more dots under gray center and low contrast surround condition was significantly lower than the PCR with black center and low contrast surround .The surround contrast (high/low) by center contrast (grc/blc) ANOVA for the PCR of more dots  = 6.21, p = 0.025, partial η2 = 0.29] but not for background region (F < 1), where it was easier for observers to accurately discriminate more dots under gray center/gray background stimulus configuration . The background by dot set size interaction was also not significant (F < 1).A 2 (gray/black background) by 2 (less/more dots) within-subjects ANOVA was run to examine the differences in mean PCR when a surround did not envelop the CSR. There was a significant main effect for set size of dots  but not for surround (F < 1), meaning that estimation judgments of more dots were easier for observers under black center/low contrast surround conditions . The surround by dot set size interaction was not significant (F < 1).In order to examine in more detail whether the effects of surround contrast on visual estimation were distinguishable from those of background luminance (no surround), a 2 (high contrast surround/zero luminance background) by 2 (less dots/more dots) ANOVA for black center revealed that there were no significant main effects for neither surround (F < 1) or set of dots (F < 1). These findings suggest that the low contrast surround that enveloped the CSR3 with a gray center had the same effect as the gray background with no surround.The final set of within-subjects ANOVAs tested differences in mean PCR for surround (high and low contrast) and no surround of the gray center/gray background stimulus configuration. A 2 (low contrast surround/uniform luminance background) by 2 (less dots/more dots) ANOVA for gray center revealed that there were no significant main effects for surround  = 9.25, p = 0.008, partial η2 = 0.38] but not for surround (F < 1), meaning that irrespective of surround conditions (high contrast surround/gray background), it was once again easier for observers to make discrimination judgments of more dots . In particular, it was apparent that the mean PCR of fewer dots for high contrast surround and no surround was markedly lower than the PCR for more dots.A 2 (high contrast surround/no surround) by 2 (less dots/more dots) ANOVA for gray center revealed a highly significant main effect for dot set [Here we investigated the effect of peripheral visual stimulation varying in sensory load on the ability to make numerosity estimation judgments of centrally presented elements. The form of peripheral visual stimulation implemented here—surround-masking, has been consistently demonstrated in earlier psychophysical literature to impair the contrast discrimination of centrally embedded texture regions, making them appear dimmer to the observer than veridically so . The perTo the best of our knowledge, investigation into the relationship between RF inhibitory resource limits and the perception of non-symbolic number representation is novel. However, this investigation was initiated not only from the earlier psychophysical literature on surround-masking, but also from our preliminary electrophysiological and psychophysical evidence recorded in a population of young adults with self-reported difficulty in mathematics, that displayed greater contrast saturation levels of their VEPs during high contrast gain, compared to an age matched control group who reported no difficulty with mathematics . Also, tIt is worth pondering the relation between individual differences in visual estimation ability and the functional quality of RF suppressive mechanisms, and their influence upon the cognitive development of higher-order mathematical computations such as arithmetical or multiplicative operations. In relation to the observations of Figure 3A), it is conceivable that this center/surround configuration created the illusion that the dots in CSR3 were more “numerous” than the dots in CSR1, where an earlier psychophysical investigation into visual estimation revealed that the perceived numerosity was affected by luminance of dots (Figures 3B and 4A indicate either that the high contrast surround also created the illusion of more dots than veridically, or that it lowered the SNR of afferent input by swamping the available inhibitory RF resources, hence creating noisiness or scalar variability in the discriminability between CSR1 and CSR3 (It was found that center/surround contrast configuration influenced visual estimation of more and less dots differently—with more dots being easier to discriminate within a black center/low contrast surround, and less dots being more difficult to discriminate within a gray center/high contrast surround—suggestive of a center/surround contrast interaction with influence upon the perceived numerosity of elements within the stimulus display. For the estimation of more dots during black center/low contrast surround condition (see  of dots . Such efand CSR3 .Here we temporarily induced an impaired ability to make visual estimation judgments in neurotypical observers through high contrast surround-masking. The study has yielded novel evidence, establishing an initial link between the functional quality of inhibitory mechanisms, likely to reside in LGN/V1, and visual estimation ability. Our findings further suggest that the weak visual estimation skills observed in DD children  is unlikNJ wrote the manuscript, collected the data, developed the experiments, and analyzed the data. LH assisted with development of the psychophysical experiments, and proof read earlier drafts of the manuscript. SC and DC proof read each draft of the manuscript and assisted with figures.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.