Bipolar disorder patients frequently present recurrent episodes and often experience subsyndromal symptoms, cognitive impairment and difficulties in functioning, with a low quality of life, illness relapses and recurrent hospitalization. Early diagnosis and appropriate intervention may play a role in preventing neuroprogression in this disorder. New technologies represent an opportunity to develop standardized psychological treatments using internet-based tools that overcome some of the limitations of face-to-face treatments, in that they are readily accessible and the timing of therapy can be tailored to user needs and availability. However, although many psychological programs are offered through the web and mobile devices for bipolar disorder, there is a lack of high quality evidence concerning their efficacy and effectiveness due to the great variability in measures and methodology used.This clinical trial is a simple-blind randomized trial within a European project to compare an internet-based intervention with treatment as usual. Bipolar disorder patients are to be included and randomly assigned to one of two groups: 1) the experimental group (tele-care support) and 2) the control group. Participants in both groups will be evaluated at baseline (pre-treatment) and post-treatment.This study describes the design of a clinical trial based on psychoeducation intervention that may have a significant impact on both prognosis and treatment in bipolar disorder. Specifically, bringing different services together (service aggregation), it is hoped that the approach proposed will significantly increase the impact of information and communication technologies on access and adherence to treatment, quality of the service, patient safety, patient and professional satisfaction, and quality of life of patients.NCT02924415. Retrospectively registered 27 September 2016The online version of this article (doi:10.1186/s12888-016-1159-0) contains supplementary material, which is available to authorized users. Bipolar disorder patients frequently present recurrent episodes and often experience subsyndromal symptoms, cognitive impairment and difficulties in functioning with a low quality of life –3, illneThe early stages of bipolar disorder is usually a critical period, and the time during which the disorder causes the most suffering in patients and their families, partly because of the impact the diagnosis and a lack of knowledge about the symptoms. Early educational interventions could increase knowledge and awareness of the illness and treatment adherence and thereby reduce relapses and hospitalizations . CognitiHowever there are several obstacles to the successful implementation of these types of psychological treatments. One of the major problems is the face-to-face nature of therapy that requires the patient and the therapist to be available at the same time. The level of commitment required for such treatments is difficult for many patients. Specifically, the therapy is administered over a long period of time  and the sessions take place on a fixed date and at a fixed time . These aspects of the treatment are associated with a high rate of dropout, especially in more functional patients. Moreover, to implement these intervention programs specialized therapists are needed and there is a gap between availability and demand , 18, andNew information and communication technologies represent an opportunity to develop standardized psychological treatments using internet-based tools that overcome some of the limitations of face-to-face treatments, in that they are readily accessible and the timing of therapy can be adjusted to the need and availability of each user. Moreover, such intervention programs offer the possibility of patients self-monitoring and continuously assessing their mood (depressive and manic symptoms) as well as other variables such as sleep or physical and social functioning, with two-way feedback between patients and healthcare providers , 20. ThiTo describe the design of an online psychoeducation treatment using new technologies and to compare its effectiveness with standard treatment in patients with bipolar disorder.To assess the effectiveness of a psychoeducation treatment based on telemedicine versus usual treatment in relation to outcomes in bipolar disorder To assess satisfaction with the treatment received and the contact with the health serviceThe online treatment of bipolar disorder will be effective for increasing awareness of the illness, improving depressive and manic symptoms and functionality of patients, and reducing relapses and hospitalizations.Patients receiving online treatment will be more satisfied with the treatment received and their contact with the health service than patients receiving the standard treatment.This is a clinical trial is a simple-blind randomized trial within a European project titled “The Future Internet Social and Technological Alignment Research” (FI-STAR), to compare an internet-based intervention with treatment as usual. This clinical trial fulfills with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT Checklist)  in the form of a platform developed to support telecare of bipolar disorder patients. The BPTM platform involves clinical professionals , patients and technicians connected using interfacing systems of the integrated multichannel service center, OSAREAN, which was already in place prior to this project. That is, the proposed solution for these patients has been developed with the internal legacy systems of Osakidetza, the largest important health service provider in the Basque Country.The platform designed provides advanced communication channels and interaction tools to treat, monitor, support and follow-up patients with bipolar disorder. The treatment consists of online psychoeducation which includes learning sessions (with associated assessment questionnaires) and related psychotherapy exercises. The participants will be able to access the psychoeducation functionalities, whenever and from wherever they choose, using whichever of the possible interfaces  they have and prefer. The psychiatric personnel defines the patient’s baseline parameters, assigns assessment questionnaires for patient monitoring, specifying how often they should be completed, and sets evaluation rules to generate alerts. Both psychiatric personnel and patients should be able to view follow-up data .Bipolar disorder patients who meet the inclusion criteria are to be included and randomly assigned to one of two treatment groups. To achieve a power of 80% to detect differences from the null hypothesis, H0: μ1 = μ2, using a bilateral Student’s t test for two independent samples, with a significance level of 5%, 25 patients will be included in the experimental group (tele-care support) and 25 patients in the control group, summing to a total of 50 patients for the study.Having a diagnosis of bipolar disorderBeing aged between 18 and 50 yearsBeing in remission (in a euthymic state)Being familiar with current information and communication technologies Being under treatment in the mental health network of the Basque Country (Osakidetza)Having hearing or literacy difficultiesHaving a diagnosis of mental retardationNot having access to a smartphone or other suitable deviceHaving manic or depressive symptomatology at the time of inclusion  and the intervention group will receive an online psychoeducation treatment, in addition to pharmacological treatment prescribed by the psychiatrist.Patients will be assessed after being informed of the objectives of the study and giving their informed consent to participate. Data will be collected following an assessment that will be implemented at baseline and post-treatment Fig. .Fig. 1StPatients are diagnosed according to the revised fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) criteria using the Structured Clinical Interview for DSM-IV-TR, Axis I Disorders . These iPatients are also assessed with the Mood Disorder Questionnaire , 41. ThiAll patients are to be assessed at baseline and post-treatment, in terms of depressive, manic and anxiety symptomatology, psychosocial functioning and lifestyle habits: diet, physical activity and sleep.Depressive symptoms are measured with the Beck Depression Inventory (BDI-II) , 40 and The BHS is a 20-item self-report inventory designed to measure three major aspects of hopelessness: feelings about the future, loss of motivation, and expectation , 45. ManAnxiety symptoms are measured with the State-Trait Anxiety Inventory (STAI) . The STAThe functioning of patients is measured using the Functioning Assessment Short Test . This isIn addition, all patients are monitored daily by collecting data on the following variables: mind state, number of hours slept, presence of stressful events, adherence and side effects and alcohol and drug use.The intervention program consists of nine sessions of online psychoeducation (once a week) focused on patient empowerment by providing specific telecare capabilities and multi-channel communication to enable interaction between the patients and the healthcare professionals .The psychoeducation comprises learning sessions (with associated assessment questionnaires) and related psychotherapy exercises using their preferred interface .The participants will be able to see the learning status of each assigned learning session and access the related multimedia content. It will be possible to download the associated PDF documents, if participants want, but the video content will only be available online. They will be able to annotate material for the learning sessions and store these notes for future consultation. Once participants have worked through the material for a given learning session, they will have to complete and submit, online, a specific questionnaire to assess their level of understanding.If the submission process fails, the system should provide appropriate feedback (process failure - subsequent delivery attempt) to the user. If the process succeeds, the system will evaluate the results of the assessment questionnaire, store them along with the usage parameters, provide feedback to the user on the success of the submission process and on the results of the questionnaire, and update the learning status of the learning session (depending on whether they answered the questions correctly). The data collected will be stored in the BPTM environment.The psychotherapy exercises are ongoing activities that require previous knowledge from the related learning sessions. There are a range of types of exercises on topics such as symptom detection and relapse prevention. Once the related learning session has been successfully completed, the patients will be able to access the related psychotherapy exercises and update them. As it is an ongoing process, the patients will be able to access the psychotherapy exercises over time. The new updates will be sent and stored and the user will get feedback on the status of the data submission process (successful or not). Like for the learning sessions, the data collected will be stored in the BPTM environment.If clarification is required in relation to learning sessions or psychotherapy exercises, the participants will be able to interact with the psychiatric personnel through asynchronous messages. The user will get feedback on the status of the submission process (successful or not) and the messages will be stored in the BPTM environment.The system will also be able to, automatically, identify potential alerts. Some examples of alert triggers are: a patient not having started the psychoeducation process after a certain period of time, and a patient “failing” the assessment questionnaire more than once. Patients should receive notifications based on their preferences . Alerts handled by the call center will be managed through the OSAREAN platform.What is bipolar disorder?Session 1. Information is provided to the patient about the nature of bipolar disorder .Symptoms of the disorderSession 2. The patient is taught to identify the characteristic symptoms of each phase of bipolar disorder.Course and prognosis of the disorderSession 3. Risk factors that may contribute to worsening the course of the disorder are explained, as are factors related to a good prognosis.Pharmacological treatment for the disorderSession 4. The mechanisms of action of medications are explained, as are potential side effects of the medication, in order to improve adherence and prevent the patient stopping the medication.Relapse prevention: risk and protective factorsSession 5. The patient is taught to recognize the symptoms that precede a relapse and risk factors that increase the likelihood of relapse, in order to improve the course of their illness.What can be done about a relapse?Session 6. It is explained to the patient that rapid identification of the prodromal symptoms and timely intervention can help to prevent relapse and bring him/her back to normal.Healthy lifestyleSession 7. Tips to maintain a healthy lifestyle are provided, seeking to improve the health, quality of life, satisfaction and happiness of the patient.Toxic habitsSession 8. The effect of toxic substances on the illness is explained, to motivate the patient to avoid their use, and thereby improve the prognosis of the illness.What can I do to improve my condition?Session 9. The patient is taught how to take an active role in their illness to improve their health and quality of life.The content of the nine online psychoeducation sessions is as follows:Outcomes in each of the groups of patients will be analyzed, to assess whether there has been clinical and/or functional improvement, comparing between baseline and post-treatment by T Student-test for differences in the means of related samples.The influence of the treatment will be analyzed comparing the clinical and functional improvement in each group through an analysis of covariance (ANCOVA) using the baseline and post-treatment scores.Finally, logistic regression models will be built to analyze variables potentially associated with relapses and hospitalizations such as sleep, lifestyle, medication adherence, side effects and adverse events.Telemedicine is potentially useful to complement usual treatment, helping patients to manage their illnesses, and helping health providers improve the care delivered, especially by giving clinicians feedback. Nevertheless, few randomized clinical trials have shown the effectiveness of this approach in bipolar disorder. The randomized clinical trial described in this paper concerns an internet-based psychoeducation program for bipolar disorder that could have a significant impact on both prognosis and treatment, and may be useful for identifying patients who need earlier and/or continuous therapeutic interventions.To help healthcare professionals care for as many patients as possible and save time  as well as to collect data for research, the BPTM platform will increase the availability of psychological treatment by providing tele-services (cheaply and with easy access), increase the therapist’s efficiency, reduce the need for face-to-face consultations, allow the involvement of the call center nurses to response promptly to alerts  and facilitate patient handover between doctors.To enhance the quality of care, improve the course of the illness, and reduce costs to the healthcare system, the BPTM platform will help clinicians to improve patient follow-up , support early identification of risk factors to respond better to patient needs  and provide an additional way to interact with both patients and caregivers .To supply online treatment suited to each patient’s needs, the BPTM platform will allow psychiatric personnel to tailor patient’s treatment .To provide patients with a way to enhance their knowledge about the management of their own illness and strategies to minimize its consequences  and to increase their treatment adherence, the BPTM platform will provide access to psychoeducation and psychotherapy in the form of learning sessions  and specific psychotherapy exercises which can be performed wherever and whenever the patient chooses .To enable patients to be actively involved in their treatment process, the BPTM platform will provide a way to monitor their status remotely by enabling the collection of data on physiological/biometric parameters  and psychological parameters and images , medication intake, and potential medication side effects as well as the course of the illness, by interacting with the system through their preferred available interface . Optionally biometric data could be gathered automatically through mobile devices by connecting to specific biometric sensors .To allow caregivers to become more involved, increase their knowledge about bipolar disorder and interact with clinicians to be able to better support the care recipients, the BPTM platform will enable their access to specific psychoeducation-related materials and will provide a channel of communication to interact with the psychiatric personnel. It is envisaged that the involvement of caregivers and/or relatives in the treatment will reduce the patient’s acute symptoms by stopping them developing and providing support for early detection. Patient adherence to treatment may also be improved by providing a better family environment and reducing patient anxiety caused by family disputes.To ensure safety, confidentially and privacy, the BPTM platform will comply with all local regulations and implement protocols to safeguard the confidentiality of medical data exchanged.To supply user-friendly interfaces and facilitate personalized interaction, the BPTM platform will allow participants (i.e. patients and caregivers) to use their preferred interface  and have a common user experience regardless of the choice of device, and allow them to select their preferred channels of communication for notifications. The platform will also support well-known interaction metaphors and usability criteria.The results of our study may have a significant impact on prognosis of bipolar disorder patients. Below, we set out what our study seeks to accomplish and how:The limitations of this study include difficulties in the management of the new technologies by patients, especially the older ones or those with more cognitive impairment. Likewise, the absence of face-to-face modality in these types of interventions may decrease adherence to the treatment due to a potential weakening of the therapeutic relationship with the therapist and loss of associated benefits. Nevertheless, combined approaches can be implemented, such as using the internet-based platform with additional support from the therapist for some patients.In conclusion, the platform we propose may help to improve functionality and quality of life in bipolar disorder, and what is most important, the act of bringing different services together (service aggregation) might significantly increase the impact of information and communication technologies on access and adherence to treatment, the quality of the service, patient safety, patient and professional satisfaction, and quality of life of the patients.


Minimally invasive surgery (MIS) continues to play an important role in general surgery as an alternative to traditional open surgery as well as traditional laparoscopic techniques. Since the 1980s, technological advancement and innovation have seen surgical techniques in MIS rapidly grow as it is viewed as more desirable. MIS, which includes natural orifice transluminal endoscopic surgery (NOTES) and single-incision laparoscopic surgery (SILS), is less invasive and has better cosmetic results. The technological growth and adoption of NOTES and SILS by clinicians in the last decade has however not been uniform. We look at the differences in new developments and advancement in the different techniques in the last 10 years. We also aim to explain these differences as well as the implications in general surgery for the future. Health care innovation, including ones in the field of minimally invasive surgery (MIS), can be defined as a dynamic and continuous process involving the introduction of a new technology or technique that initiates a change in practice.There are distinct patterns of growth, development, and innovations in MIS since the early 1980s represented by the number of patent applications and literature publications, with each of these patterns containing technologies with unique characteristics.The second growth phase noted is with regards to surgical robotics and image guidance. Their growth shows gradual and exponential patterns starting in the mid-1990s throughout 2000, and beyond.The latest and the third growth phase was noted in the late 2000s in relation to NOTES and SILS with its inception in the mid-2000s, peaking soon after that. Although the popularity of NOTES plateaued in late 2000, SILS has continued to receive interest. The reason for this plateau with NOTES is partly due to dwindling of innovation and interest in the technique, and partly due to the profound difference between innovators and adopters. Conversely, SILS may likely have a brighter future owing to easier access to technology and instrumentation, specialist to mainstream practice, and possibly with increasing popularity of robotics, which may complement SILS.One of the biggest advances in MIS in the last decade is in the field of robotic surgery. Robotics was introduced for surgery in civilian hospitals in the early 1990s, although it was initially used in the military environment performing surgeries in the 1970s.Robotic surgery has evolved immensely since the initial operating room version Zeus (Computer Motion). Newer models of surgical robots, Da Vinci , feature compact mobile platforms, multiple operating arms, and superior surgeon's console equipped with surgeon- piloted stereotactic 3D immersive and ergonomic handles intuitive to human hand movements providing improved dexterity. Other robotic platforms have been approved and are in various stages of development and introduction to the surgical market. They claimed to produce small robotic platforms with better maneuverability, more user-friendly in constricted spaces, provide force feedback and eye tracking capabilities. The eye tracking technology works with the aid of a camera mounted on an eyewear, which could track the surgeons' eye movements and move the scope inside the patient accordingly. Some of the examples are Amadeus Composer  from Canada and TELELAP Alf-X (TransEnterix) from Italy.The application of robotic surgery potentially is much wider than just restricted to operating theater where the robot is physically located. The current platform enables remote access enabling telesurgery, without the need for the surgeon to be present physically in the operating theater. One such event was a surgical operation performed in Strasbourg (France) by surgeons in New York (United States), which became a milestone in global telesurgery.The role of robotic surgery compared with laparoscopic surgery is debatable, mainly due to high cost and equivocal surgical outcome. In spite of that robotic surgery remained appealing to health care organizations and surgeons with a passion for cutting-edge technology. Astronomical cost while a disadvantage may change with improved platforms that are easier and quicker to set up, which improves further with experience, and lower cost with vanishing monopoly in the production of surgical robots.Robotic surgery in the peritoneal cavity has been investigated fairly extensively, and the technology has proven to be of benefit in selected operations. Robots have been used in colorectal surgery for over 10 years.In hepatobiliary surgery, robotic surgeries have not demonstrated a clear superiority compared with laparoscopic surgery.Another significant innovation in the last decade is NOTES, described by some as perhaps the most significant innovation in surgery since Phillipe Mouret of France performed the first laparoscopic cholecystectomy in 1987.There are several barriers to NOTES. Some of them include difficulty in the closure of enterotomy, anastomotic techniques, spatial orientation, long learning curve, lack of triangulation of instruments, control of hemorrhage, and prevention of the transluminal spread of infection. At the same time, there are advantages associated with NOTES. They include no scars, less external pain, lower cost, an alternative to the laparoscopic procedure in a patient not suitable for laparoscopy and it even could act as a complementary technology to laparoscopic surgery and avoid major resections.Unfortunately, over the last decade NOTES encountered more problems than solutions that the industries are still trying to correct. Therefore it has hit a plateau in its popularity, and usage.While the closure of an enterotomy remains a huge issue, access and triangulation are fundamental to the success of MIS. Some surgeons have endeavored to address these issues. Combining laparoscopy with NOTES has been suggested and trialed to improve insufflation, orientation, retraction, instrument navigation, and solid organ manipulation.Developments in VR, stereoscopic 3D cameras, and augmented reality (AR) camera are some of the areas worth following in the years to come. Conventional cameras are two-dimensional and lack depth perception. At present da Vinci robotic camera has 3D visualization capability but extending that technology to the laparoscopic camera has had its challenges. Although Olympus has introduced a video-assisted camera capable of 3D visualization, it lacks the resolution that robotic 3D camera provides. Some research groups have reported developing AR visualization for laparoscopic cameras.Another technology worth mentioning is a laparoscopic ultrasound (LUS), which is two-dimensional with the images displayed on a separate monitor that unfortunately forces the surgeons to take their eyes off the organ or laparoscopic screen. With the combination of LUS and AR technology in a stereoscopic 3D camera one can now view the organ that is subjected to ultrasound and its abnormalities in real-time directly on the organ itself and make surgical decisions for accurate dissection with precise movements, so that resection margins are kept to minimum but sufficient and safeguarding the surrounding structures that may not be visible in 2D view.Our future consists of exciting, new emerging technologies, which may make MIS even more efficient, exciting, and safe. The possibilities are limitless, and we await more innovations to enable more sensible applications of different surgical techniques and instruments.


While ADO is known to control inflammation and suppress immune responses, other aspects of ADO function are still obscure, mainly due to its short half-life in biological fluids. Human multiple myeloma (MM) grows in the closed system of the bone marrow (BM) niche representing an ideal setting for studying ectoenzymes and their products. Another source of information on ectoenzyme function may derive from in vivo results of anti-CD38 antibody therapy in MM. Current results, obtained from in vitro models and from preliminary in vivo findings, indicate that ectoenzymes produce ADO locally in the BM niche. Furthermore, MM cells release microvesicles (MV), which thanks to their molecular cargo and surface ectoenzymes may function as particulate communicators outside of the niche. During anti-CD38 antibody therapy, the MV carry therapeutic IgG, determining that the prevalent orientation of MV will be toward cells and tissues expressing receptors for the IgG Fc domain. The resulting picture is one where MM adopts an immune escape strategy based on reshaping the environmental niche. This adaptation is followed by actions of MV that are exerted in biological fluids and circulating immune cells. By coating FcRs+ cells, MV modify pericellular spaces, reproducing the metabolic halo generated by ectoenzymes within closed systems.Ectoenzymes are cell surface molecules, which represent functional bridges between the environment and the cytoplasm. One set of ectoenzymes—CD39, CD38, CD203a, and CD73—leads to the generation of adenosine (ADO) by metabolizing ATP and NAD Additional and somewhat unexpected evidence came to light with the introduction of innovative therapeutic drugs. The use of immunomodulators and monoclonal antibodies in cancer therapy revealed previously unknown facets of normal and tumor biology. For example, drug resistance was first observed when it became apparent that cancer cells could actively eliminate most of the toxic drugs used in therapy. Another important result was the identification of cell surface molecules able to drive the production of tolerogenic substances  and of establishing a tolerogenic environment .The present perspective aims to highlight the contribution of adenosinergic ectoenzymes to the metabolic pathways that contribute to tumor growth and active immune evasion. Part of the knowledge in this field has been inferred indirectly from recent findings obtained within the context of immune tolerance. Supporting evidence has also been from (i) +. It is known that evolutionary pressure led to the selection of ATP and Ca2+ as an inseparable tandem occurring as a leitmotif in the control of life, death, and cellular signaling. Schematically, the original function of ATP was to provide energy within the cell, while Ca2+ served as a key second messenger for extracellular signaling via purinergic P2 receptors  that are involved in the metabolism of ATP and NADeceptors .1 receptors , which metabolizes the substrate into AMP, subsequently taken up by CD73  and transformed into ADO. This nucleoside exerts modulatory effects on immune and cancer cells by binding Peceptors . The fun+) acceptor NAD+. The main acceptor of NAD+ in the extracellular space is CD38 and CD157 (BST1) both are ADP-ribosyl cyclases/cyclic ADP-ribose (ADPR) hydrolases, although with different catalytic characteristics , a Ca2+-mobilizing second messenger  and extracellular  biochemical pathways  and alsoSuch an extensive network of cytoplasmic enzymes, plasma membrane ectoenzymes and receptors, as well as extracellular or intracellular soluble products evolved in such a way as to make the system not operate in an all-or-nothing fashion. On the contrary, this intricate system is highly sensitive and capable of providing just the right biological effects required by a given tissue at a given time. The final results arise from a combination of the intrinsic functional characteristics of the enzymes, their affinity toward their substrates, and the promiscuity derived from a resulting sum of affinities, substrates, and actions. Adding further complexity is the notion that the majority of ectoenzymes are extremely susceptible to both the cytoplasmic and extracellular environment. As a consequence, ectoenzyme surface expression can range from nil to high, and similar variations in expression are also seen in the counterparts of receptors for the enzymatic products. The quantitative modifications are of physiological relevance, implementing negative or positive effects as a function of tissue distribution or functional status.Some steps of ADO functionality are still waiting to be defined, mainly as a consequence of its active metabolization in biological fluids, such as blood stream, considered as an open system. For these reasons, some hints were derived from diseases taken as models from which to infer conclusions valid in physiology.in vivo antibody therapy  has become a therapeutic target of  therapy .+ while yielding lactate and H+ as by-products.A few premises are necessary to understand how the BM niche and the cytoplasmic conditions of myeloma cells may influence the functions of ectoenzymes. Tumor growth demands energy; as a consequence, cells may become “addicted” to alternative metabolic pathways, including glucose metabolism for protein, lipid, and nucleotide synthesis Figure  12). Tu. Tu12). + in the tumor microenvironment is from the hydrolysis of ATP. Over time, lactate and H+ are exported from cancer cells into the interstitial space, where they accumulate because of defective blood perfusion. The result is further acidification of the extracellular tumor microenvironment. Acidosis can thus be considered as a tool selected by tumor cells to bypass in growth normal cells   .+ degradation. This was confirmed in the MM niche. Indeed, BM aspirates from MM patients indicated that the canonical adenosinergic CD39/CD73 pathway is flanked by another set of ectoenzymes, which in vivo leads to the production of ADO, this time using NAD+ as the starting substrate , but the metabolic halo around the cells forms a transmission chain of reaction products. A requisite is that the reactions take place in a closed microenvironment, where the tumor and host cells are intermingled located side by side. As a consequence, the metabolic activities in the BM niche promote the local accumulation of ADO, contributing to a local impairment of the immune status .in vivo.In conclusion, the different cellular components in the niche harbor at least two distinct pathways (CD203a/CD73 and CD38/CD203a/CD73), both potentially leading to the production of ADO. The niche provides the physical proximity necessary for the generation of intermediates and products, while the halo of enzymatic products surrounding juxtaposing cells mechanistically guarantees the functional effects of ADO, whose half-life is extremely short Multiple myeloma patients are characterized by a generalized impairment of the immune defenses. It therefore remains to be seen whether the observations seen in the niche may also hold true outside of a closed environment.+ to produce ADO. When derived from the cell membrane, MV can adhere and fuse with adjacent cells, which promote their egression from the MM niche and migration through tissues from where they eventually reach the blood circulation. Naturally occurring MV may adhere to cells, simply guided by their surface and adhesion molecules. This situation changes after treatment with therapeutic antibodies, when MV are coated with IgG. The consequence is that MV are driven as their preferred destination toward cells and tissues expressing FcRs with different affinities. MV adherence to and accumulation around cells delineates a pericellular space, one side formed by MV and their halo and the other by the membrane of the normal cells. The pericellular space reproduces what is seen in closed environment, with synthesis and use of short-lived products, as in this case with ADO  as part of a normal membrane dynamics . MV can with ADO .An even more challenging question is what happens when IgG-coated MV enters a cell. These MV have a cargo of proteins, lipids, nucleotides, and nucleic acids, whose functional effects are under scrutiny. Preliminary evidence indicates that the most up-modulated genes concern immune response, regulation of cell death and apoptosis, chemotaxis, and the inflammatory response.The identification of molecules that act as enzymes on the cell surface but whose final products are destined for use within the cytoplasm suggests that we urgently need to rethink our understanding of extracellular metabolism.It is generally accepted that cells surrounded by a halo of functional products can be sensed by adjacent cells, provided that the latter are equipped with the proper receptors. In the case of ADO, a marked functional difference is its limited half-life, making it act more like a neurotransmitter, in that it is operative only within a short distance from the production site. An improvement may come when ADO is produced in the context of a tissue or closed system, which facilitates the interaction among biological fluids and cells.in vivo therapy with therapeutic antibodies, when they target ectoenzymes   , 31. In ly CD73)  32)..in vivo AC and VQ contributed to the experimental part behind this perspective, and edited both text and graphical part. LA and DF revised the work in a critical and constructive way. AH and FM contributed to the conception and the design of the work. All the authors approved the final version of the manuscript and agreed to be accountable for all aspects of the work.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.


Sustainability is a key challenge for humanity in the 21st century. Ecosystem services—the benefits that people derive from nature and natural capital—is a concept often used to help explain human reliance on nature and frame the decisions we make in terms of the ongoing value of nature to human wellbeing. Yet ecosystem service science has not always lived up to the promise of its potential. Despite advances in the scientific literature, ecosystem service science has not yet answered some of the most critical questions posed by decision-makers in the realm of sustainability. Here, we explore the history of ecosystem service science, discuss advances in conceptualization and measurement, and point toward further work needed to improve the use of ecosystem service in decisions about sustainable development. At the same time, the use of ESs by people  is a necessary part of improving human wellbeing (HWB)3, and some of those uses are consumptive, impacting future provision of the service or the continued provision of other services. This ultimately leads to a situation in which society must determine how best to use ESs to improve HWB now while working to ensure that ESs will be provided equitably now and for future generations. This article examines the state of the science of ESs and considers what more we still need to learn to help ensure that ESs are being used sustainably.As human societies continue to transform the biosphere, sustainability—the ability for humans to continue to exist and even thrive on the planet—has emerged as a key challenge. Ecosystem services (ESs)—the benefits that people derive from nature and natural capital—is a concept often used to help explain human reliance on nature5. The ES concept also has the potential to bring together issues of sustainability and environment with those of international development, which has been discussed for quite some time in the environment and development literatures but has proven difficult to achieve7. ESs are also quantifiable, and differences in their provision thus can be related to biophysical or ecological aspects of landscapes, to land use and management decisions, or to changes in values, individual preferences, and social demand, making the concept ideal for those who aim to improve conservation while taking development into consideration.The concept of ESs has become hugely popular, in part because it frames the decisions we make affecting nature in terms of the value of nature to people  and makes those values more visible10. Indeed, despite considerable advancement in this field over the past few decades, ES science is still not answering some of the most critical questions posed by decision-makers in the realm of sustainability  to one that focused on threats to habitats (1970s and 1980s) to the emergence of ESs in the 1990s as a way to reveal the importance of nature to HWB and finally (currently) to a nuanced perspective that recognizes the complex, dynamic relationships between people and nature.Grappling with the human impact on the environment is not new; in some ways, the conversation about people, nature, and conservation is centuries old  of an activity that degrades an ecosystem for private benefit, it is difficult to incentivize  more sustainable behavior without an adequate accounting for the full cost of that degradation. The main challenge economists were beginning to grapple with in valuing nature by around the turn of the century was that the whole was greater than they could express through summing the parts; available methods for price setting and valuation focused on small  changes, while it was well understood that the life-support system provided by nature was priceless19. So the question for economists became the impact of intermediate change, especially when an intermediate amount of change can intersect an ecological threshold that pushes the system into a new state, resulting in fairly small ecological changes that can lead to significant impact on the long-term provision of ESs22.Early ecological literature on ESs continued to focus on the supporting services 1 were added to a conceptualization of services that was still very much oriented toward ecosystem functions, at least in the ecological literature . As the list of recognized ESs grew longer and more directly connected to HWB23, the relevance of the concept to policy and decision at a variety of levels became evident. Fundamentally, the concept of ESs grew out of a time when nature was ignored by many facets of human enterprise and scientists and conservationists desired a way to highlight the value of nature to society.The soaring popularity of ESs really emerged in the ecological literature by the late 1990s24. Ultimately, this became the Millennium Ecosystem Assessment (MA). The MA developed an ES framework that reflected the thinking of the time, showing a relationship between ESs  in place—the primary idea of even this new framework is that ecosystems alone ultimately provide services to people. That is, there is a general and primary flow from the left (ecosystems) to the right (people), and feedbacks are from the people to the ecosystem.In an update conceived by de Groott parts . Here, e26  is increasingly important in the Anthropocene and ought to be included in the way we understand and measure ESs.This rather linear conceptualization of ESs was given another significant update26 , includi28 and the (direct and indirect) contribution of ecosystems to HWB31. A major challenge in this has been in approaching the science of ESs as holistically as the concept implies, especially in terms of interactions between multiple services, spatial dynamics, and change over time.Beyond frameworks, the past decade has also brought considerable advances in measuring ESs and using these measurements as tools in decision-making. One of the most critical and basic advancements brought about by ES science is the focus on the ways that we use ecosystems (actively and passively) to ensure HWB32 or among multiple services and biodiversity  were quite rare, occupying just 3.3% of the landscape. These authors also found that trade-offs were not consistent across space. That is, whereas most locations had a trade-off between crop production and water quality, some locations had both high water quality and high crop production, suggesting that this trade-off is not inevitable or that it might be able to be ameliorated. This study not only provided specific data about ES provision in a particular place for decision-makers in that region but also developed some generalizable knowledge, such as that managing ESs over large areas is likely to improve our ability to manage for sustainable provision of services38.However, there are examples of ES studies that have focused on multiple services and sometimes on linking these to potential decisions or to HWB. For example, Batemanet al.39 identified five distinct types of ES bundles in Sweden: “forests and towns”, “remote forest”, “mosaic cropland-livestock”, “mosaic cropland-horse”, and “urban”. They found that the production of an ES or ES bundle was based on a combination of the social-ecological potential  of a landscape to produce it and the human demand for that same service. In this as in many studies on ES bundles, hot spots of provisioning service production are often cold spots for regulating services. Thus, it is increasingly apparent that both ecological and social gradients are needed to adequately predict patterns of ES provision across landscapes45.A recent development in ES sciences is the movement from studies of single services or pairs of services to studies that focus on bundles of ESs, associations of several ESs that appear together repeatedly in space or time. Queirozet al.46 suggest that there are three types of trade-off assessments. Supply-supply assessments are about how supply of one service affects supply of another; supply-demand assessments are about whether the ecosystem can meet demand; and demand-demand assessments are about stakeholders’ competing interests. The method the authors propose takes a step toward embracing social-ecological systems and complexity in considering both supply and demand as well as their interactions. The importance of understanding the difference between supply, demand, and ecosystem capacity to provide services was also highlighted by Villamagnaet al.47, who pointed out that it is the comparison of supply with demand in the current time that determines satisfaction with the services provided and that it is the comparison of capacity with supply that determines the potential for sustainability.In addition to understanding how social-ecological landscapes provide ES bundles, progress has been made in refining the idea of trade-offs among pairs of services. Mouchet49. Landscape complexity, measured in terms of the proportion or diversity of natural habitat or its arrangement in the areas surrounding agriculture or both, enhances the pollination of crops50 and pest control by natural predators51 in a variety of cropping systems and regions52. For these mobile organisms benefitting cropland, increasing interface between human and natural systems generally increases service provision, assuming an adequate ratio of natural to agricultural habitat. Other services may be reduced by this type of natural-agricultural mosaic; Chaplin-Krameret al.53 demonstrate that forest fragmentation reduces carbon sequestration by an average of 25% across the tropics. Whereas previous studies had estimated carbon sequestration on the basis of a benefits-transfer approach that assumes a direct relationship between forest area and carbon storage, the study by Chaplin-Krameret al. shows that the configuration of the land use, and especially the amount of forest edge created by deforestation, makes a difference to the amount of service provided. Studies of carbon storage in temperate forests also find important effects of both spatial structure and human management54. For water-related services, the aspect of landscape configuration that matters most is hydrologic connectivity to water courses55, which presents yet another type of spatial habitat pattern to consider in managing for multi-functional landscapes.Another advance in measuring and mapping ESs has been work to understand the role of landscape structure—the configuration of land use and land cover—in the provision of services. This is important for landscape management, especially over large areas, as suggested by Qiu and Turner, as the structure of the landscape is something that land use planners can influence with reasonable precision. Different spatial patterns of land use and cover may benefit different services, and trade-offs between services can be mitigated or exacerbated by fragmentation at different scales46. Recent studies have begun to examine how changes in landscapes over time have affected the provision of services. Renardet al.56 found that some individual service relationships varied through time, shifting from trade-offs or no relationship at the start of the study (1971) to synergies by the end (2006). In terms of bundles, in 1971, the landscape was diverse, but most municipalities across the landscape were all providing similar bundles; by 2006, the landscape remained fairly diverse, but each municipality tended to specialize in the provision of one or a few services.Although many ES studies have been snapshots of service provision at a single moment in time, it is widely acknowledged that ESs and their relationships with each other, and with the drivers that affect their supply, are unlikely to remain constant over time57. For example, work by Fisheret al.58 focused on understanding the various benefits of reducing deforestation in Tanzania.Finally, mapping and measuring ESs have been and will continue to be critical methods for understanding past trends and anticipating future trajectories and for evaluating the impact of policy interventions and whether goals are being met. However, many decisions require more information than can be gleaned from examining changes that have already occurred; policy-makers and other incentive setters wishing to promote the sustainable use of ESs have questions about where the most important places are to invest in conservation or restoration, what the impacts of allowing different types of development will be for different stakeholders, or how to most cost-effectively mitigate those impacts . In many60. Carpenteret al.9 suggest that part of the problem may be a discipline-bound focus of some of the science as well as failure to consider feedbacks over a range of biophysical and social systems. Reyerset al.26 propose that, in the rush to gather data, science has found itself with a plethora of measures that fall short of their intended purpose. That is, we have lots of measurements, but these use conflicting definitions or poor indicators, which makes use of ESs to assess targets like the Sustainable Development Goals difficult at best. Newer studies are advancing rapidly in developing multiple ES-based methods for assessing the effect of policy interventions on sustainability. For example, Hamannet al.61 developed and tested an approach to mapping social-ecological systems on the basis of characteristic bundles of ES use. The idea was that these bundles ultimately could be used as a tool to identify different social-ecological system types and target governance interventions more appropriately.These improvements in scientists’ ability to map, measure, and model individual ESs, pairs of ESs, and bundles of ESs have led to discussions about how ES science could be used to improve ecosystem management or to understand and assess progress toward policy targets such as the Sustainable Development Goals. However, actual use of ES science in decision-making has sometimes fallen short of expectations62. Cundill and Fabricius63 suggest that although there is a wealth of frameworks for understanding complex systems, relatively less attention has been given to co-design and other approaches that might facilitate learning as part of the monitoring process. Such co-design is important because it can help ensure that science is both interesting to the scientific community and useful to decision-makers64. This helps mainstream ESs as a part of decision-making. Similarly, researchers are now pointing out the need to include more nuanced, quantitative analyses of ESs and HWB65 and even developing indices to understand when and how wellbeing depends on provision of services66. Ultimately, if decision-makers are concerned with the wellbeing of constituents or stakeholders, research that goes only as far as the biophysical components of services may be less useful than work that quantifies HWB outcomes or seeks to understand relationships between services and wellbeing.One outcome of the focus on social-ecological systems has been increased interest in HWB and in co-design of research projects with stakeholders, research that actively involves decision-makers to improve uptake and use of information in decision-making68. Recognizing that enhancing ES resilience is crucial for meeting current and future societal needs, Biggset al.69 use the literature to suggest seven principles for enhancing the resilience of ESs in social-ecological systems: maintain diversity and redundancy, manage connectivity, manage slow variables and feedbacks, foster an understanding of social-ecological systems as complex adaptive systems, encourage learning and experimentation, broaden participation, and promote polycentric governance systems. Developing this definitive set of resilience-enhancing principles for ESs and a synthetic understanding of when and where they apply is important for those in the governance arena seeking to ensure a sustainable provision of services for the long term while avoiding large, non-linear changes in service provision, which can have catastrophic effects on HWB.Including social-ecological systems has also paved the way to merge concepts of resilience with ESs, a significant step forward in moving ES science to a place where it can improve ecosystem management for sustainability. Extensive anthropogenic changes, mostly to provide certain ESs such as food, have increased the likelihood of large, non-linear, and possibly irreversible changes in ecosystems72, which are an important step toward measuring and monitoring change in ESs on a large scale. Findings from such efforts are being translated to diverse contexts in many other countries through international collaborations such as the Intergovernmental Panel on Biodiversity and Ecosystem Services (IPBES) or the Group on Earth Observations–Biodiversity Observation Network (GEOBON). Experimental accounting methods—for example, promoted by the Wealth Accounting and Valuation of Ecosystem Services (WAVES) program—at institutions like the World Bank aim to transform national accounts to reflect ES values in countries’ financial ledgers. However, most of these examples are focused on assessing current baselines or past trends, and although this is an important first step to integrating ES into decisions, it does not provide action-ready and easily digestible information about the consequences of any particular land, ocean, or natural resource use decision. Although regional and national ecological and economic assessments are helpful, they do not typically help mainstream the type of decision support that is now needed across scales.Several countries, including the UK, China, and South Africa, have undertaken national ecosystem assessments73, and with some trial and error this may help to better articulate what form such standard approaches should take.Furthermore, although models exist for including ES in a cost-benefit analysis or return-on-investment calculation, too often models are not accessible enough at the time they are needed, or data are not available to complete them, with the result that ESs are often left out of environmental impact reports or development or zoning plans. Part of this is due to a failure on the part of the scientific community to standardize data and approaches in forms that could be used by agency staff or consulting groups they contract to make it standard practice. In a promising new development, the US has recently mandated all federal agencies to consider how ESs could be included in their planning74, and the field still faces multiple challenges: a fairly discipline-bound science9, limited involvement of stakeholders in the development of the questions that guide many scientific studies75, and confusion about the multiple potential indicators available for measuring ESs76. For these and perhaps other reasons, ES science has not been fully adopted by decision-makers and has not reached the full potential of socio-ecological integration it is intended to promote77.Additionally, despite advances, many gaps remain in our understanding of the ecology of ESs, some of which were already recognized more than a decade ago78. Although conceptually ESs seemed poised to make this happen, ES researchers have not yet been entirely successful. Many efforts remain bound by disciplinary boundaries. This may be, in part, because the types of questions that are interesting differ among disciplines in ways that present significant barriers to funding and publishing.One of the original agendas of ES researchers was to bring together natural science and economics, conservation, and development79. This may be because one benefit of co-designed science is the trust that is built between scientists and decision-makers80 or because it encourages scientists to work at the scale at which decisions are being made81.Involving stakeholders in question development, and sometimes in the scientific process of answering those questions, may also hold important keys for improving the use of ES science in decision-making. In fact, it is so important that some have found that stakeholder involvement in ES research is a better predictor of policy change than the nature of the findings themselveset al.76 surveyed the literature on pollination as an ES and found that, in 121 studies that self-identified as being about both ESs and pollination, 62 unique metrics were used to assess the amount of pollination. The authors showed how these inconsistent measurements complicate attempts at comparison or synthesis and can even lead to very different management decisions.There also remains considerable confusion in the use of terms, especially in the use of indicators. The difference between ecosystem process, function, and service remains muddled, and some scientists use these terms interchangeably whereas others make clear distinctions. Liss84. Moving from one ecosystem to another or, better yet, developing general principles4 has been difficult85. Some general principles emerging from this work are beginning to be included in broadly accessible, globally applicable tools for decision support and scenario analysis, such as Integrated Valuation of Ecosystem Services and Tradeoffs (InVEST)86, Artificial Intelligence for Ecosystem Services (ARIES)87, and others89 (seeUltimately, many are finding that, for a variety of reasons, ecology as it stands is limited in its predictive capacity to identify the sustainable use of any particular ES and to describe the trade-offs between uses of ESs92 or restoration opportunities93, understanding equity implications of development impacts94, and identifying where green infrastructure has the potential to support or enhance grey infrastructure95. Although many unanswered questions remain in defining and planning for truly sustainable development, we can learn from implementing policies based on the science we do have, tracking outcomes, and adaptively managing for improvement97.Despite such limitations, from a value-of-information perspective, the knowledge of ESs we are currently capable of representing is adequate for informing many types of decisions, including spatial targeting of best management practicesFor ESs to contribute to enhancing the sustainability of the human enterprise, ES science must move beyond conceptualizing and mapping and into addressing the difficult, complex questions that have dogged sustainability science for decades. Based on the review of the literature here, we propose a handful of critical future directions for ES science .The future directions we suggest include many that effectively expand the boundaries of ES research in several directions. We suggest that ES science consider longer time frames and include ongoing global change, non-linearities, and uncertainty in this analysis. ES science should also expand its disciplinary boundaries to include information about multiple forms of capital and the role of social systems in demand for, and provision of, services and include stakeholders in design and even implementation of some research plans. Expanding physical boundaries to include the role of trade in moving some types of services around the planet will also be a critical next step in understanding planetary ES provision and its implications for sustainability.ES science holds great promise to help society assess progress toward meeting planetary sustainability and development goals such as the Sustainable Development Goals. To fully achieve that potential and to answer the most important questions decision-makers are asking, the science must continue to develop beyond disciplinary boundaries to consider the long-term provision of ESs by social-ecological systems.ES, ecosystem service; HWB, human wellbeing; MA, Millennium Ecosystem Assessment.


Nigeria has about 3.8 million people living with HIV, the second largest globally. Stigma and discrimination are major barriers to testing, treatment uptake, and adherence. In this review, we synthesized information on research studies, policies, and programmes related to HIV-stigma in Nigeria. This was with a view to identify critical areas that research and programmes must address in order to accelerate the progress towards zero  target by year 2030. Existing studies were mostly devoted to stigma assessment using varieties of measures. Research, policies, and programmes in the past two decades have made very useful contributions to stigma reduction. We identified the need for a consistent, valid, and objective measure of stigma at different levels of the HIV response. Nigeria does not lack relevant policies; what needs to be strengthened are design, planning, implementation, monitoring, and evaluation of context-specific stigma reduction programmes. One of the successes recorded in the Millennium Development Goals was target 6A which aimed to halt HIV by 2015 and begin to reverse its spread. As of 2014, the number of new HIV infections and AIDS-related deaths has declined by 40% and 42%, respectively .3. With the largest population in SSA, only 26% of its people have ever done HIV testing [Meanwhile, recent statistics shows that 36.7 million persons were living with HIV as of the end of 2015 of which about 46% have access to treatment [According to UNAIDS 2015 guidelines on terminologies, stigma refers to beliefs and/or attitudes marking or staining a person or group of people as unworthy or discreditable , disclosIn congruence with the advancement in the global response, research and programmes on HIV-related stigma have witnessed improvement since the entrance of HIV into public health discourse. For instance, beyond the initial complexities associated with definition, measurement, impact assessment, and reduction of HIV-stigma , empiricNigeria as one of the countries with the largest number of PLHIV has strived to combat HIV-stigma and discrimination to curtail the epidemic. The early (1990s) and peak years (mid-2000s) of the epidemic in Nigeria were characterised by various forms of stigma and discrimination at different levels of human interaction . A revieIn March 2017, we searched electronic databases for articles on HIV-stigma in Nigeria between 1999 and 2016. The databases were PubMed, African Journal Online, and JSTOR. Search terms involved different combination of the following: HIV, AIDS, Stigma, Discrimination, and Nigeria. The word “attitude” was also used as a search term because many of the related articles used it to connote stigma or discrimination. Abstracts of each article in the search results were reviewed to determine whether they met criteria for inclusion in the review. For an article to be included in the review, it must address HIV/AIDS stigma or discrimination as a dependent or independent variable. Inclusion was not restricted to any study design; therefore, both quantitative and qualitative studies that addressed HIV-stigma and/or discrimination in Nigeria were selected. Full text of articles that met the inclusion criteria were retrieved and reviewed. For each reviewed article, information was extracted on authorship and year of publication; objective; research design; how stigma was measured (and whether as a dependent or independent variable); and the main findings. These details were summarised in a Compared to the previous review by Monjok et al. , we founMany population-based studies in Nigeria have attempted to measure HIV-related stigma using attitudinal questions as proxy. A tenuous challenge that emanates from many of these studies was that the attitudinal questions used to represent stigma were rarely the same across different studies. One of the earliest community-based research on HIV-stigma in Nigeria was a mixed-method study conducted in South West and South East Nigeria in the early 2000s  but publFertility desires among people living with HIV have attracted attention of researchers especially with improved quality of life offered by ART . To fillFew of the population-based studies of HIV-stigma in Nigeria have some semblance of interventions to assess the effectiveness of health educational intervention on stigma reduction. All the three studies in this category utilised a quasi-experimental design and showed that stigma reduction can be achieved using educational interventions. Although the interventions were conducted among market women , secondaVery few community-based qualitative studies of HIV-stigma were found in the course of the review. Incidentally, these were mostly based in Southern parts of Nigeria. Evidence from the south west revealed that social constructions of HIV-stigma are deeply rooted in cultural beliefs and perceptions about the lifestyle of those infected , 19. A cThe second group of studies on HIV-stigma found to be common in Nigeria were those conducted in health facilities. As expected, the study population were either healthcare providers or PLHIV who receive care and treatment from the facilities. An important observation about many of these studies was that they were domiciled mostly in facilities providing specialist or tertiary care and as such were in urban areas. Findings from the review of these studies are summarised according to the study population, healthcare workers and PLHIV.Majority of the studies among healthcare workers were conducted around early and mid-2000s. This was a time that could be referred to as the peak of the HIV epidemic in Nigeria. Virtually all of them were aimed at accessing attitudes towards care and treatment of PLHIV. The earliest among these studies was a quasi-experimental study in South South Nigeria by Ezedinachi et al. . They doThe second group of facility-based studies are those that documented stigmatization and discrimination experiences among PLHIV. Prevalence of stigmatizing experiences varied widely, ranging from 8% to 60%. This wide variation is due to the diverse indices/measures used for stigma. In fact, no two studies defined or measured HIV-stigma in the same manner. This posed limitations to study comparisons and generalisation from one study setting to another. As observed earlier, majority of the studies in this category were conducted at tertiary health facilities in Southern Nigeria except one at a Teaching Hospital in North Central region by Owolabi et al. . In the The burden of stigma among PLHIV may be higher than documented in quantitative studies as findings from FGD participants in Lagos, Nigeria, showed that almost 75% reported that life has become very traumatic due to stigmatization from friends, family members, healthcare workers, and workplace . StudiesQuite a few qualitative studies have also explored the experiences of stigma and discrimination among PLHIV. Results from focus group discussion in Southern parts of Benue State in North Central region of Nigeria highlighted the high level of rejection and discrimination of PLHIV in the late 1990s . IsolatiDrawing on Deacon's framework , a qualiWe found a study conducted among MSM in North Central Nigeria which investigated the impact of the law prohibiting such relationship in Nigeria . The autIn Nigeria, policies and programmes for the national HIV response are coordinated by the National AIDS Control Agency (NACA). Other key partners include the Federal Ministry of Health (FMoH) as well as the State AIDS Control Agency (SACA) and Ministries of Health in the 36 states of the Federation. Policies are usually formulated at the national level and domesticated by the states. Though the administrative structure in Nigeria stipulates that states are federating units with autonomy to develop their own policies and programmes on issues such as health and education, there is a lot of synergy and cooperation among the federal and state government agencies. In this review, only policies and programmes enacted by the national government are reviewed because they apply across the entire country. Also, in order not to lose sight of the aim of this paper, we focused on the policy and programme components related to HIV-stigma.The current HIV/AIDS policy in Nigeria was launched in 2009 . Prior tThis was the third in a series of plans to combat HIV epidemic in Nigeria. The first plan captioned HIV/AIDS Emergency Action Plan (HEAP) 2001–2003 was developed in early 2001 and targeted at public awareness about the epidemic. Its successor was the National Strategic Framework for Action 2005–2009 developed in 2004/2005. It served as blueprint on implementation for different stakeholders. The 2010–2015 NSP  which ha “eliminating discrimination and stigmatization in the workplace based on real or perceived HIV status including dealing with HIV testing, confidentiality, and disclosure.” The scope of the policy includes both public and private sectors including the uniformed services. Its guiding principles also conspicuously included “nondiscrimination” alongside nine others. To ensure that majority of Nigerians remain HIV-negative, the strategies itemised to achieve the objectives of the policy include prevention, HIV testing, treatment, care, and support, and promotion and protection of workers' rights. Responsibilities for the following stakeholders were also spelt out: Federal Ministry of Labour and Productivity, employers, workers, and their organisations, National Agency for Control of AIDS, State Agency for Control of AIDS, and National Steering Committee for HIV Workplace Issues. Curiously, implementation and action plans which were to be developed by different stakeholders are still being awaited.The Nigeria National Workplace Policy on HIV and AIDS was first developed in 2005 to address the workplace response to the epidemic. The latest review was adopted and published in 2013 . Such a First introduced to the National Legislature in 2005, the bill was passed and signed into law in April and November 2014, respectively. It serves a significant milestone in the national response to HIV/AIDS in Nigeria. This is because the nonpassage of the bill was a recurrent comment in the PLHIV stigma index and gender assessment report which are both reviewed in the next sections. The antidiscrimination act was very clear on rights of individuals ; their rIn response to the formidable threats posed by stigma and discrimination to the success of HIV prevention and treatment programmes, NACA in collaboration with other stakeholders developed the stigma reduction strategy for Nigeria . LauncheCountry annual report on the global response to HIV usually submitted to UNAIDS provides a comprehensive description of programmes implemented as part of the national response to HIV in Nigeria . The comwww.stigmaindex.org).The stigma index was designed to collect data on stigma, discrimination, and rights of people living with HIV. It was also aimed at serving as an advocacy tool and a way to operationalize the principle of Greater Involvement of People Living with HIV (GIPA). As of September 2013, it has been used in more than 50 countries including Nigeria. Further details on the development and processes involved in using the index are available on its dedicated website  in late 2009. Data was collected from 706 persons living with HIV selected from support groups in 12 states of the federation. The interviewers were also PLHIV. Report from the assessment documented several experiences of stigma and discrimination across three themes: exclusion, access to work, health, and educational services; internalised stigma; and fears . Nearly There has been a drive at international and regional levels to use laws as tools for HIV elimination. Particularly, to improve equity in access to services among key populations, law and regulatory environment must not be prohibitive. For instance, in Nigeria, HIV prevalence is higher among brothel-based female sex workers (19.4%), non-brothel-based female sex workers (8.6%), and men having sex with men (22.9%) . IncidenStigma and discrimination are a main driver of inadequate access to care and treatment among these key populations. This would constitute a weak link in the HIV prevention efforts if an enabling environment is not created to protect this group against marginalisation and stigma.The LEA in Nigeria was therefore designed to identify and review existing laws, regulations, and policies that could impact the national HIV response. Varieties of qualitative research methodologies  were employed for the exercise. Findings showed that the legal environment in Nigeria is weak for effective human rights based response to HIV/AIDS . Even thAlthough the measures used have not been consistent, there is evidence to show that the level of HIV-stigma in Nigeria has declined in the past two decades. This is demonstrated in results from analysis of attitudinal questions about people living with HIV in nationally representative surveys such as the NARHS 2003, 2005, 2007, and 2012 and NDHS 2013 , 29, 63.This review also revealed that the Government of Nigeria with support from development partners have done a lot to confront HIV-stigma. National policies and strategic plans have been revised about three times to align with international best practices as well as respond to the epidemiological and structural dynamics of the HIV epidemic in the country. A robust multisectoral approach with stakeholders involvement, political will, and policy advocacy at national and state levels have all contributed to general awareness about the urgent need to eliminate stigma and curtail HIV spread. To further improve on the successes recorded so far, some recommendations are made which could strengthen the stigma reduction programmes in the country.There is a need for reliable, validated empirical measures of HIV-stigma. Even though the Berger HIV-stigma scale was applied at a facility in SW Nigeria , its intAnother reason for new measures of stigma stems from the scale-up of ART services to secondary and primary healthcare facilities. It is expected that a deeper population penetration of ART would help correct the wrong belief that HIV is a death sentence. This misconception has been responsible for abandonment in the early 2000s. It also heightened the fear of casual transmission via mere physical contact. Now that treatment is closer to the grassroots, it ought to have indirectly mitigated some of the stigma. Operational research studies need to be undertaken to explore this proposition.Much of what is known about HIV-stigma in Nigeria have come largely from research studies in North Central, South East, South West, and South South regions. Considering the evidence about the dynamic sociocultural nature of stigma, there is need for complimentary evidence from the North East and North West regions. The case for the North East is even more sacrosanct because of the internal population displacement occasioned by the Boko Haram insurgency. There is anecdotal evidence of increased new HIV infections in internally displaced persons (IDP) camps. Although some of these internally displaced persons are being resettled in their communities, the level of HIV-stigma in IDP camps must have been enormous. The experiences of those affected and how they coped with the challenges would provide useful lessons for stigma reduction programmes in Nigeria.Another implication of the preponderance of HIV-stigma studies in Nigeria being domiciled in tertiary health facilities is that they also provide information about urban areas. Could stigma be higher in rural areas? Evidence from population-based surveys suggests that stigmatizing attitudes towards PLHIV was associated with lower education, poverty, and poor knowledge of HIV , 63. TheThe legislative environment in Nigeria is not favourable to key populations at risk of HIV such as MSM. This may also explain why investigation of HIV-stigma in this population is rare. The only study among this group showed that enactment of the law prohibiting same-sex partnership in Nigeria has contributed to higher level of fear , althougWithout prejudice to other strategies aimed at eliminating HIV by year 2030, stigma and discrimination reduction is a priority. Research, policies, and programmes in the past decade have made tremendous contributions to this drive. Newer approaches tailored to the epidemiological and social contexts of individual countries would continue to evolve. In this regard, this paper reviewed research studies, policies, and programmes related to HIV stigma in Nigeria, the country with the second largest number of people living with HIV in the world. This review identified the need for a consistent valid and objective measure of stigma at different levels of the HIV response. Empirical evidence on the awareness and effect of anti-HIV discrimination law and other interventions are urgently needed. Nigeria is not lacking in policies as this review shows that the country is nearly up to date in compliance with UNAIDS guidelines on several policy requirements. What need to be strengthened are programmes design, planning, monitoring, and evaluation. It is necessary to intensify advocacy, awareness, and enforcement of the anti-HIV discrimination law. It is also very important to develop systems for evaluating the impact of stigma and discrimination reduction programmes at national and subnational levels.


In addition to studies by Südhof's lab of signals that tell secretory vesicles when to release their cargo and the work of Schekman's lab describing a set of genes required for vesicle transport, the Rothman's lab determined the proteins termed SNAREs (soluble NSF-attachment protein receptors), that allow vesicles to fuse with their targets and thus transfer materials. Although the three interacting SNARE proteins  had previously been identified by several scientists, and were localized to the presynaptic region, their function was largely unknown. VAMP/synaptobrevin was found to reside on the vesicle, whereas SNAP-25 and syntaxin were found at the plasmalemma. This led to the SNARE hypothesis, which stipulated that target and vesicle SNAREs were critical for vesicle fusion through a set of sequential steps of synaptic docking, activation and fusion of vesicle with the plasmalemma. This interpretation was influenced by bulk biochemical studies, which revealed that the ternary SNARE complex is a thermally stable structure [In 2013, the Nobel prize was awarded for discoveries related to the regulation of the cellular transport system , however, it is much slower than in neurons . The paradigm of gliotransmission being present in vivo, critically depends on experiments in mice expressing the dnSNARE peptide. However, the mechanism of action of this peptide was only recently described [The last transition prior to full-fusion is inhibited by the dominant-negative domain of synaptobrevin 2 protein peptide (dnSNARE, Figure escribed . In contescribed . The dnSescribed , which i


Streptococcus intermedius in a healthy and immunocompetent patient secondary to mandibular implants. We describe how surgery combined with systemic application of antibiotics allowed conservation of the dental implants in the mandibular bone, discuss the probable source of contamination, and present the follow-up of the osteomyelitis.Dental implants are now broadly used to replace missing teeth, and the presence of infectious complications is rising. Dental implant therapy as a local risk factor for the onset of osteomyelitis and its management have not been widely explored. Here, we report an unusual case of mandibular suppurative osteomyelitis caused by Osteomyelitis is an infection of the bone that has a tendency to involve the adjacent cortex, periosteum and soft tissue. Osteomyelitis of the jaw is confined to the mandible in most cases, very likely due to the complex anatomy and the poor vasculature of this bone in contrast to the maxilla, which is characterized by rich vascularity and a thin cortical plate , 2.The inflammatory process includes necrosis of mineralized and marrow tissues, resorption, sclerosis, and hyperplasia; surgical debridement in addition to antibiotic therapy is necessary for cure. Osteomyelitis has exhibited a decline in prevalence, which has been attributed to the widespread use of antibiotics and better oral health. Nevertheless, this infection is known to occur in immunocompromised patients and is generally caused by inoculation of microorganisms into the jawbones as a result of trauma, a surgical procedure, dental infection, or chemotherapeutic drug use –6.Despite the increasing popularity of using implants to rehabilitate edentulous alveolar ridges and these implants' high long-term success rate, certain adverse complications  can occur. However, to the best of our knowledge, only a few case reports to date have linked infection leading to osteomyelitis of the jaws to dental implant therapy –10. DentA healthy female patient, aged 71 years and without medication, was referred to our Department of Oral Medicine with substantial pain and swelling in the submandibular area that had developed after the second stage of a dental treatment protocol.∗10 mm) with oral administration of amoxicillin (2 g/per day) for 6 days. The surgery was performed by experienced surgeons in a specific operating room with strict aseptic condition.The patient's past dental history revealed extractions of mandibular right first molar and both mandibular canines due to periapical lesions, with curettage of granulation tissue . Five moThe implants were submerged and left in place for a period of three months. Then, the second-stage surgery, which involved placement of prosthetic abutments, was performed without any problem by the same surgical team. Unlike implant surgery, the aseptic conditions were lower but in line with this type of intervention. One week later, the patient was referred to an emergency consultation for facial pain. Clinical examination revealed diffuse swelling of the submandibular region, which was firm and painful, with redness of the skin. The patient also reported labiomandibular paresthesia.On intraoral examination, there was gingival inflammation in the anterior part of the mandible. The swelling involved both the gingiva and the buccal vestibule.A panoramic radiograph revealed a radiolucent, diffuse osteolytic lesion with poorly defined borders in the symphysis area of the mandible . CBCT waOn the same day, the patient was transferred to the Department of Oral and Maxillofacial Pathology, and surgical intervention was performed under general anesthesia via an intravenous injection of amoxicillin/clavulanate (1 g/200 mg). Streptococcus intermedius bacteria.The affected mandibular region was opened, and a sequestrectomy of the mental region was performed. The area was thoroughly debrided and irrigated, and the two dental implants were left in place. A bone biopsy was sent for histopathology analyses, which confirmed the diagnosis of chronic osteomyelitis with diffuse neutrophil infiltration Figures . A microThe patient was hospitalized, and, five days after surgery, the symptoms and swelling disappeared. An oral course of antibiotics was prescribed for the following 2 months (amoxicillin 1 g two times per day). The follow-up consisted of one control consultation per week for one month and one control consultation per month for six months thereafter. Clinical and radiological analyses revealed healing in the mandibular region and no local complications. There was no evidence of local recurrence at 12 months Figures  after tr Streptococcus intermedius was the cause of the osteomyelitis in the patient described here; this bacterial strain belongs to the Streptococcus anginosus group. This group is recognized as consisting of commensal bacteria of the oral cavity and the gastrointestinal and urogenital tracts but is also known for abscess formation in various locations in the body and for infective endocarditis [Many species of bacteria have been implicated in osteomyelitis, but most described pathogens belong to the family of staphylococci . Streptocarditis . Streptococcus anginosus group bacteria, including 297 patients with osteomyelitis, and only eleven patients with Streptococcus anginosus organisms were identified. Among these, three cases of mandibular osteomyelitis were associated with tooth decay and bisphosphonate or radiation exposure [In the current case, the patient was immunocompetent and lacked medical risk factors, and the patient's osteomyelitis was caused by a bacterial species that is not known to have a tropism for bone. Griffin et al. published the largest series of patients with osteomyelitis due toexposure .In the current study, the infection was most likely related to contamination of dental implants. The first-stage surgery occurred in a clinical setting dedicated to implantology and was without complications. Three months afterward, the second-stage surgery was performed with placement of prosthetic abutments, and, one week later, the infection was diagnosed due to pain and swelling. We cannot rule out the possibility that periapical lesions of teeth were the source of bacterial contamination and infection before implant insertion, but the absence of early signs is remarkable, and the dental implants were placed several months afterward, allowing a long time for bone healing. During surgery, after curettages of nonvital bone, a conservative approach was selected, and the two implants were left in place. However, there is limited literature on the guidelines for removing or leaving implants in place if osteomyelitis is diagnosed. The fundamental principles of the treatment of osteomyelitis remain debridement and antibiotic therapy, but some new approach using vancomycin-impregnated calcium sulfate in the surgical debridement site seems to give good results . Indeed,Implant removal is recommended when apical lesions are involved and when mobility of the implants is confirmed .Given the popularity of an increase in dental implant treatments, it seems necessary to discuss the failure and complications of this treatment. Conventional protocols for endosseous implants  were shown to minimize the risk of implant failure and to establish osseointegration, with a high rate of success. Nevertheless, recently, Camps-Font et al. in a retrospective cohort study with 1273 implants included in 337 patients highlighted that 4 to 10% of patients receiving dental implants develop postoperative infections and that two-thirds of infected implants fail, most before prosthetic loading . To addrWe believe that this approach should be measured and used with caution especially in infected sites and those even in absence of clinical symptoms considering that it could induce potentially severe bone infections. It is challenging for clinicians to provide rapidly effective treatments with fewer complications to maintain the health of the alveolar bone , 20.Implant surgery has become widespread but remains an invasive bone surgery that can lead to serious infectious complications, including osteomyelitis. Strict aseptic operating conditions and a healthy oral environment are recommended. The causative organisms may be commensals in healthy individuals, as we have presented in this case. Physicians have to identify infectious implant complications and their etiology to make implant treatment even more predictable in the future.