Pediatric cardiac surgery is associated with significant perioperative blood loss needing blood product transfusion. Transfusion carries serious risks and implications on clinical outcomes in this vulnerable population. The need for transfusion is higher in children and is attributed to several factors including immaturity of the hemostatic system, hemodilution from the CPB circuit, excessive activation of the hemostatic system, and preoperative anticoagulant drugs. Other patient characteristics such as smaller relative size of the patient, higher metabolic and oxygen requirements make successful blood transfusion management extremely challenging in this population and require meticulous planning and multidisciplinary teamwork. In this narrative review we aim to summarize risks and complications associated with blood transfusion in pediatric cardiac surgery and also to summarize perioperative coagulation management and blood conservation strategies. Pediatric cardiac surgery on cardiopulmonary bypass (CPB) is associated with significant bleeding and blood transfusion requirements. Bleeding after pediatric cardiac surgery is generally related to a combination of several factors and include immaturity of the hemostatic system, hemodilution from the CPB circuit, excessive activation of the hemostatic system, and potentially preoperative anticoagulant drugs. The number of children undergoing cardiac surgery has significantly increased in the past few decades and blood transfusion management has become an integral aspect of intra-operative patient care and is vital to successful outcomes. However, there is an increasing concern regarding the risks and complications associated with homologous blood transfusion in the pediatric cardiac surgical population. Hence there is an effort to develop various perioperative strategies both to avoid and restrict blood transfusions in this population.transfusion risk, pediatric cardiac surgery, blood conservation, postoperative bleeding, blood products, cardiopulmonary bypass were used. References cited in the retrieved literature were also examined for relevance.This narrative review is based on a targeted search of the literature databases including PubMed, Embase, Medline and the Cochrane Database of Systematic Reviews. Search terms combining In the United states the cost of health care is anticipated to grow at a rapid pace causing tremendous burden on the healthcare system, patients and the government. The Center for Medicare and Medicaid Services estimates that the national health spending is projected to grow at an average rate of 5.5 percent per year for 2018–27 and to reach $6.0 trillion by 2027. Health spending is projected to grow 0.8 percentage point faster than Gross Domestic Product (GDP) per year over the 2018–27 period; as a result, the health share of GDP is expected to rise from 17.9 percent in 2017 to 19.4 percent by 2027.According to the National Blood Collection and Utilization Survey Report, 14.9 million RBC units were transfused in the United States in 2009 .It is estimated that between 10 and 20% of the total erythrocytes transfused in the United States annually are given to cardiac surgical patients and within this group the need for transfusion in pediatric cardiac surgery is even higher , 5. ApprWorld health organization's recognition of blood and blood products as essential medicine emphasizes their crucial importance in any national healthcare system . Blood tMany factors determine the need for blood transfusion in pediatric cardiac surgery. Hemoglobin levels, lactates, arteriovenous oxygen differences and clinical picture are some of the factors that drive the decision to transfuse. Apart from direct risks associated with transfusion, it has a significant impact on clinical outcomes.A retrospective single-center cohort study by Kneyber et al. showed that RBC transfusion was independently associated with increased mortality, prolonged duration of mechanical ventilation, increased need for infusion of vasoactive agents, and increased duration of pediatric intensive care unit stay. It also showed higher mortality rates among patients with multiple transfusions . LacroixA study looking into perioperative risk factors for surgical site infections (SSI) in pediatric cardiac surgery showed that receipt of three or more units of red blood cells was independently associated with subsequent development of organ space SSI . This isTable 2). The non-infective causes account for majority (>80%) of the complications commonly encountered in pediatric cardiac surgery.Risks associated with transfusion can be classified into infective and non-infective causes. The non-infective causes can be further divided into immune and non-immune mediated complications  and transmission of hepatitis C virus (HCV). However, with better screening and testing methods there has been remarkable successes in reducing transmission of known viral agents and rapid responses to emerging infectious diseases that are documented to be transmitted by blood transfusion. Prior to current viral testing procedures, viruses presented the greatest risk for transfusion-transmitted infection . HoweverThe non-infectious causes account for most of the transfusion associated mortality and serious morbidity. Transfusion related acute lung injury (TRALI), transfusion associated circulatory overload (TACO) and hemolytic transfusion reactions (HTRs) account for majority of them. Although rare, transfusion related immunomodulation (TRIM) and transfusion associated graft vs. host disease (TAGVHD) are serious risks .Transfusion related acute lung injury is defined as new acute lung injury (ALI) occurring during or within 6 h after a transfusion . The patTACO is an underreported complication of transfusion and is often avoidable. It is caused by an excessive quantity of transfused blood components or an increased rate of transfusion. The National Healthcare Safety Network definition requires- new onset, or acute exacerbation of three or more of the following, within 6 h of transfusion: respiratory distress, raised brain natriuretic peptide (BNP or NT-pro-BNP), increased central venous pressure, left heart failure, positive fluid balance, or pulmonary edema . AlthougHTRs occur when there is immunologic incompatibility between a transfusion recipient and the red blood cells (RBCs) from the blood donor. Hemolysis is the rupture of red blood cells and can occur intravascularly (circulation) or extravascularly . Based on the timing of the reaction they are classified as acute HTR that happen within 24 h of transfusion and delayed HTRs that happen after 24 h. Delayed HTRs usually manifest 1–2 weeks after transfusion, often tends to mild and goes undiagnosed. ABO incompatibility is the most common cause of acute HTRs and is commonly the result of clerical or procedural error. Clinically the classic triad consisting of fever, flank pain, and red or brown urine is not often seen. HTRs can range in severity from mild, clinically inapparent hemolysis weeks after the transfusion to rapid instantaneous, massive, intravascular hemolysis that may cause disseminated intravascular coagulation, shock, renal failure and even death. The prevalence of acute HTRs has been estimated at ~1 in 70,000 per blood product transfused .The pediatric surgical population is a challenging group due to many of its unique characteristics such as smaller relative size of the patient with respect to the CPB circuit, immature blood vessels and coagulation systems, higher metabolic needs which means higher oxygen requirements and longer duration on CPB and surgery. These characteristics not only increase the incidence of the resulting complications, but also their severity when they occur. These unique characteristics also make successful blood transfusion management extremely challenging in this population. Hence blood conservation techniques require meticulous planning and multidisciplinary teamwork throughout the various stages of the perioperative continuum. Many institutions over have developed protocols and guidelines for efficient conduct of these strategies and is summarized in The JW population present significant challenges in transfusion management in pediatric cardiac surgery. Patients of JW faith refuse allogeneic blood products, viewing blood transfusion a direct violation of god's will and their faith. JW refuse the four main components of blood including red blood cells, white blood cells, plasma, and platelets and also autologous blood that has been removed from the body. The acceptance of other products such as factor concentrates, albumin or erythropoietin is subjective and needs to be discussed during preoperative planning . Some JWIt is key to identify patients who are at a higher risk of bleeding and plan accordingly. Patients with cyanotic CHD, coagulations disorders, those on anticoagulation medications and neonates have a higher bleeding risk.Secondary polycythemia is common in patients with cyanotic CHD, this can cause thrombocytopenia, platelet function abnormalities, disseminated intravascular coagulation, decreased production of coagulation factors, impaired liver function, vitamin K deficiency and primary fibrinolysis .Opinion and recommendation of a hematologist should be sought for coagulation management of patient with primary coagulation disorders.Neonates by the virtue of their immature coagulation system need a planned and strategic approach to postoperative hemostasis.Children on antithrombotic medications undergoing cardiac surgery have a higher risk of perioperative bleeding due to the nature of the surgery, duration and the indication for anticoagulation . With imPlanning cessation of antithrombotic treatment for elective cardiac surgery and reversal for emergency surgery should be done meticulously and guidelines for this is summarized in Preoperative autologous donation (PAD) has been studied extensively in the pediatric cardiac surgical population. Matsuda et al. looked at PAD in children <20 kgs between the ages 3 and 9 years undergoing open heart surgery. PAD was done up to 6+/-2 times preoperatively removing 5–10 ml/kg on each occasion. Results showed that the study group did not receive any allogeneic blood, compared with 80% of controls . DespitePreoperative erythropoietin and iron supplements have been extensively studied and shown to be effective in increasing hemoglobin levels and to decrease the use of blood and blood products preoperatively. A large meta-analysis and systematic review involving 32 trials (9 cardiac surgery studies) looking at preoperative erythropoietin and iron supplementation showed a significant reduction in homologous blood transfusion without risk of thromboembolic complications . MajoritANH is a process wherein blood is removed from the patient, anticoagulated with a citrate solution, and stored. This blood is then transfused back to the patient following separation from CPB and heparin reversal with protamine. The primary objective of ANH is to protect platelets and coagulation factors from the untoward effects of cardiopulmonary bypass and offers an important autologous blood product that improves hemostasis at the conclusion of surgery. Traditionally during ANH, blood is replaced with crystalloid or colloid in a 3:1 ratio. This may not be applicable in children as it may result in results in both excessive hemodilution and unacceptably low hematocrit on CPB. ANH may have to be modified by avoiding fluid replacement, using monitors to watch hemodynamic including cerebral oximetry and using small doses of pressors or inotropes as needed to support the hemodynamics . The amoTarget hematocrit on CPB =Starting HCT [circulating blood volume (CBV)] −Volume of ANH removed)/ (CBV + Prime volume for CPB) .A large meta-analysis looking at ANH in adult world showed a clear reduction in the use of allogenic blood transfusion . In neonSuperior surgical skills, meticulous technique, short CPB and hypothermia time and shorter duration of procedure all play a key role in minimizing perioperative bleeding. The ability of the surgeon to adequately manage bleeding in the OR cannot be understated. Electrocautery and ultrasonic devices are commonly used to help toward achieving this goal and this along with use of passive and active topical hemostatic agents are extremely valuable. Topical agents achieve hemostasis by activating the coagulation pathway either directly or indirectly and include bovine collagen, cellulose, porcine gelatin and thrombin.Surgery for congenital heart defects in pediatric patients undergoing cardiopulmonary bypass (CPB) has induced up to a 300% hemodilutional effect due to circuit prime volumes . CondensThis consists of replacing the CPB pump circuit volume with patients' blood. Prior to initiation of CPB the arterial and venous lines are drained into the CPB circuit and the bloodless prime is drained into a reservoir. This is a well-established and beneficial strategy in adult cardiac surgery to reduce autologous blood transfusion , 40. TheThe fundamental objectives of ultrafiltration during pediatric cardiac surgery are to increase the concentration of red blood cells and coagulation factors, remove excess fluid and inflammatory mediators during or immediately following conclusion of CPB. There are different modalities of ultrafiltration and include conventional ultrafiltration (CUF), zero balance ultrafiltration (ZBUF) and modified ultrafiltration (MUF). CUF is used in all pediatric cardiac surgery needing CPB and involves removal of excess fluid by a hemofilter and concentrated blood returned to the venous reservoir. This is usually done intermittently to avoid excessive volume depletion. Unlike CUF, ZBUF replaces the volume of ultrafiltrate removed with crystalloid without running into circuit volume contraction, thus potentially improving or increasing the amount of inflammatory mediator removal , 42. MUFIntraoperative cell salvage is a blood conservation technique to reduce allogeneic transfusion requirements related to excessive blood loss. This technique recovers blood lost in the operative field and is then anticoagulated, washed and centrifuged in a cell-saver machine and given back to the patient. The washing is said to remove debris from shed blood thus reducing the risk of cerebral thromboembolism and improving neurological outcomes. Washing also removes platelets, coagulation factors and other plasma proteins and hence its use is controversial. The ability of the newer machines to salvage even smaller volumes of blood has enabled its use in children. Cell salvage is widely used in pediatric cardiac surgery and has shown to be safe and effective in reducing postoperative allogenic blood and blood product transfusions , 46.Despite all the measures outlined so far, clinicians should be prepared to deal with blood loss and coagulation abnormalities that are produced by multiple factors in pediatric heart surgery. This will include judicious and timely use of blood products and hemostatic agents guided by clinical observations, laboratory and point of care testing where available.Peri-operative and post-operative blood tests and their frequency should be selected for value in providing information crucial to the essential care of the patient, while limiting the total volume of blood sampled for this information. Using smallest sampling tubes and volumes that maintain accuracy of testing can be helpful . There is conflicting evidence whether preoperative or intraoperative testing can predict which patients are at risk for excessive bleeding due to coagulopathy post cardiac surgery. Routine coagulation testing preop is not indicated but should be performed on a case-by-case basis .A complete Blood count (CBC) and cross matching for appropriate amount of blood products is accepted practice in the majority of centers. Clinical examination, preoperative history and hospital course and family history may indicate more elaborate preoperative testing. For example, further PREOPERATIVE testing may be indicated if abnormalities are observed in routine tests, or if anemia management mandates it . Other indications may include known or suspected abnormal liver function, preoperative anticoagulation, history of thromboembolic phenomenon and congenital coagulopathy.During the intraoperative pre-CPB arterial blood gas, baseline Activated Clotting Time (ACT) and heparin level are obtained. A predicted heparin response is obtained via the heparin assay.Adequate anticoagulation is essential to prevent thrombosis in the extracorporeal circuit, a devastating complication, but it also helps blood conservation by preventing unbridled activation of the coagulation cascade, thrombin generation and consumption of coagulation factors and platelets which causes more bleeding post-CPB.Unfractionated heparin is the preferred anticoagulant during CPB with a long history of clinical use and overall safety. It has a short half-life, reliably reversed by protamine sulfate, and unaffected by renal function. It potentiates the inhibition of antithrombin III (AT III) on thrombin and factor Xa, as well as tissue factor pathway inhibitor. Heparin-induced anticoagulation during CPB is monitored by ACT, which measures the coagulation status of whole blood. Recommended dose of 400 IU per kg is administered by central venous access and ACT is used to confirm a satisfactory response based on institutional protocols .However, the ACT is influenced by hypothermia, platelet dysfunction and hemodilution on CPB and the gold standard is laboratory assay of plasma heparin concentration by estimating anti-Xa activity. Traditional weight-based dosing derived from adults may lead to lower than adequate heparin levels in infants because of higher hemodilution, metabolic rates and blood volume to weight ratios. This may be inadequate to prevent thrombin generation, leading to more platelet dysfunction and more postoperative bleeding. Ideally the heparin dosing and protamine reversal should be individualized for optimum anticoagulation. A useful alternative for infants is an automatic protamine-titration device for whole blood heparin concentration in the OR . This often predicts higher heparin dosing in infants than weight-based dosing, which theoretically prevents hemostatic activation on CPB and better preservation of hemostatic functions post-CPB. A protocol based on the HMS adjusted for infants reduced bleeding in a neonatal trial . The accNeonates and small infants are observed to have lower Antithrombin III (ATIII) level producing heparin resistance and an inadequate ACT response, placing them at higher risk for thrombin generation. This may necessitate administration of Fresh Frozen Plasma (FFP) to restore AT III levels. The Network for the Advancement of Patient Blood Management, Hemostasis and Thrombosis (NATA) recommends considering FFP in pump prime in neonates. Antithrombin III concentrates are also available.An alternative to heparin is the direct thrombin inhibitor (DTI) Bivalirudin, which does not require AT III, has a short onset and elimination half-life (25 min) and is administered by continuous infusion. Besides direct inhibition of circulating and clot bound thrombin, it also reduces thrombin induced platelet activation. There is no specific reversal of Bivalirudin, but it is short acting and clinical effect wears off within 30–60 min of ceasing infusion. Approved for percutaneous coronary interventions, it has a role in cardiac surgery with previous adverse reactions to Heparin and Heparin Induced Thrombocytopenia (HIT) as well as anticoagulation for extracorporeal support and ventricular assisted devices. Monitoring of effect is usually by activated Partial Thromboplastin Time (aPTT) or ACT, but non-linear relationship in these tests has resulted in emergence of alternative assays like dilute thrombin time (dTT), chromogenic anti-IIa assays, and the ecarin clotting time (ECT). DTIs may cause a concentration dependent elevation in the international normalized ratio (INR) .This should be given as a slow bolus while watching for adverse reactions. Side effects include several types of protamine reactions which can vary from mild to catastrophic (severe systemic hypotension and pulmonary hypertension necessitating returning to CPB support). Using a 1:1 reversal dosing may give rise to excessive protamine dosing, which can actually impede coagulation. A heparin assay like Hepcon HMS can be used to determine the appropriate reversal dose. Managing heparin dosing and reversal with protamine using measurement of heparin level is perhaps a better approach than ACT guided and weight-based dosing. In practice we use both simultaneously at our institution.Post-CPB management includes timely restoration of the coagulation system guided by clinical parameters as well as coagulation tests. Viscoelastic testing (VET) has become a useful tool in monitoring and restoration of coagulation in addition to the gold standard of coagulation tests [Prothrombin time (PT)/aPTT/INR/ Fibrinogen levels].Both Thromboelastography  and rotational thromboelastometry  have been extensively studied in adult cardiac surgery, though pediatric literature is not as robust. In their latest iterations  they offer a point of care (POC) solution to provide a holistic status of the coagulation process in real time following a brief lag. In many centers the parameters of TEG or ROTEM can be visualized in the operating room continuously. These tests are based on the measuring the viscoelastic properties of the developing clot and subsequent clot lysis. Each technology has established unique normal parameters and ranges that point to the contribution of platelets, fibrinogen and other factors to clot strength as well as fibrinolytic activity. Abnormalities in these can guide specific targeted product replacement. Transfusion algorithms guided by VET and other POC tests have shown to reduce bleeding and transfusions in some pediatric studies . In a paA recent technology addition is the Quantra QPlus System  and the newest thromboelastographic monitor from Haemonetics, the TEG 6S, that use an ultrasound-based technology, called sonic estimation of elasticity via resonance (SEER) sonorheometry which interrogates the developing clot with ultrasonic waves to obtain proprietary parameters based on resonance, defining platelet, fibrinogen and factor contribution to clot strength. These may have the advantage of ease of use based on cartridge technology and a shorter lag time before results but has undergone limited evaluation. Overall VET seems to reproduce coagulation process, suffer from some false positives but have good negative predictive values and results are not mutually interchangeable. No technology seems to be vastly superior to others . Whichevin vivo remain a subject of debate with TXA, although its efficacy is fairly well-established. Inhibition of glycine mediated inhibitory pathways by TXA, and inhibition of GABA receptors is a proposed mechanism for seizures in high doses, though it is rarely reported in pediatrics. Thromboembolic complications are a potential concern. Great variability exists in the dosing regimens across institutions as the ideal plasma concentration that blocks fibrinolysis in vivo is not established. Based on review of existing literature NATA guidelines propose a dosing regimen as below . Excessive fibrinolysis can contribute significantly to ongoing blood loss despite restoration of coagulation pathway components. Antifibrinolytic agents such as Lysine analogs, Tranexamic Acid (TXA) and Epsilon Aminocaproic acid (EACA), have been shown to reduce blood loss and transfusions in multiple surgical scenarios. Dosing regimens for pediatric patients and optimal plasma levels as below :Children <1 year of age—TXA loading dose of 30 mg/kg followed by a continuous infusion of 10 mg/kg/hChildren >1 year of age—TXA loading dose of 10 mg/kg followed by a continuous infusion of 10 mg/kg/h can be used until the end of surgery.Additional labs to assess oxygen delivery  and general metabolic and physiological homeostasis  should be monitored to support transfusion algorithms to ensure the hematocrit and cardiac output is adequate for tissue oxygenation.The cell-based model of hemostasis  is of thConcentrated pooled product of plasma is high in fibrinogen (Factor II) content as well as Factor VIII. After protamine administration, ongoing bleeding with a low fibrinogen level (<150 mg/dl) or VET indications of hypofibrinogenemia should indicate Cryoprecipitate transfusion of 1 unit per 5 kg (fibrinogen 250–700 mg per unit) An alternative is to give Fibrinogen concentrate if available.As a concentrated product which has undergone pasteurization, theoretically FC offer a safe lower volume alternative to Cryoprecipitate for Hypofibrinogenemia and can be considered.Rich in Vit K dependent factors, FFP can restore both volume and probably help hemostasis in factor deficiency but is due to larger volumes required is implicated in the development of post op TRALI and is a poor source of fibrinogen. It may, however, be useful as part of the pump prime in neonates .These are available in 4-factor (4F)  and 3-factor (3F)  preparations. They have several theoretical advantages over FFP in reversing coagulopathy due to deficient Vitamin K dependent factors, low volume required, less infection risk and rapid reversal and have been used anecdotally in children with excessive bleeding or in small series, but concerns remain about thrombotic risk. A recent observational study of 50 children (0–6 years) early use of fibrinogen, platelets and PCCs based on clinical bleeding score and VET reduced bleeding and improved hemostasis with no complications . The EurFIEBA is another PCC containing FII, FIX, FX, and activated VIIa. It is approved for hemophilia A and B patients with high inhibitor levels and has been used anecdotally in pediatric cardiac surgery for excessive bleeding. For example in a single center review, recombinant Factor VIIa and FEIBA use resulted in reduction in post cardiac surgery bleeding in children and adults, but was associated with thrombotic phenomena . SimilarRecombinant activated factor VIIa  is indicated for the treatment of bleeding in Hemophilia with inhibitors and aids in thrombin generation.There are multiple case reports and small series of successful use of these hemostatic agents in pediatric heart surgeries. This is balanced by ongoing concerns about thromboembolic complications, appropriate dosing and clear indications .It is expected that PCCs, FEIBA and Factor VIIa will continue to be used in an off-label fashion in the face of excessive ongoing bleeding when usual measures are exhausted. These patients should be carefully monitored for thrombotic phenomena.An intriguing option is to use autologous umbilical cord blood  for autotransfusion in neonatal heart surgery. Although anecdotal cases exist of the plausibility, issues of collection, storage, timing of surgery (amongst others) need clarification as evidence is gathered to establish its future role .www.nataonline.com) has come up with evidence-based recommendations after an expert review of the available evidence (While often necessary due to the nature and complexity of cardiac surgery, there is increasing evidence that transfusion of blood components is not benign and may lead to adverse outcomes in both adults and children following heart surgery. Guidelines are available for patient blood management in adult cardiac surgery but their widespread adoption in practice is uncertain . There ievidence . The strBoth Authors share a lot of interest in the topic and has contributed throughout.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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Astronauts experience post-flight disturbances in postural and locomotor control due to sensorimotor adaptations during spaceflight. These alterations may have adverse consequences if a rapid egress is required after landing. Although current exercise protocols can effectively mitigate cardiovascular and muscular deconditioning, the benefits to post-flight sensorimotor dysfunction are limited. Furthermore, some exercise capabilities like treadmill running are currently not feasible on exploration spaceflight vehicles. Thus, new in-flight operational countermeasures are needed to mitigate postural and locomotor control deficits after exploration missions. Data from spaceflight and from analog studies collectively suggest that body unloading decreases the utilization of proprioceptive input, and this adaptation strongly contributes to balance dysfunction after spaceflight. For example, on return to Earth, an astronaut’s vestibular input may be compromised by adaptation to microgravity, but their proprioceptive input is compromised by body unloading. Since proprioceptive and tactile input are important for maintaining postural control, keeping these systems tuned to respond to upright balance challenges during flight may improve functional task performance after flight through dynamic reweighting of sensory input. Novel approaches are needed to compensate for the challenges of balance training in microgravity and must be tested in a body unloading environment such as head down bed rest. Here, we review insights from the literature and provide observations from our laboratory that could inform the development of an in-flight proprioceptive countermeasure. Crew health and safety are NASA’s top priorities for future exploration missions to the Moon and Mars . For exaCountermeasures for exploration missions must also be accomplished under new constraints. For example, exploration vehicles will impose greater restrictions on exercise capabilities than the ISS. These restrictions include less habitable volume and greater need for vibration isolation and stabilization . Thus, cThe overall purpose of this review is to support the conception and development of countermeasures that address the issue of balance impairments after long-duration spaceflight and are compatible with exploration spaceflight conditions. Rather than describe in detail each of the potential countermeasures that have been proposed, here we elucidate the recent findings that drive current directions. We aim to (a) compare postural and locomotor dysfunction after spaceflight and after spaceflight analogs and describe the effectiveness of exercise for mitigating these dysfunctions; (b) justify the need for and challenges of developing a proprioceptive countermeasure for use in the microgravity environment; and (c) recommend promising modalities for inclusion in an in-flight/in-bed proprioceptive countermeasure.Central nervous system (CNS) adaptations to spaceflight manifest as a reinterpretation of vestibular and somatosensory inputs . On retuThese recently recorded decrements in post-flight performance were present despite the astronauts performing vigorous exercise as a primary countermeasure while in orbit . SpecifiA significant barrier to countermeasure development is the limited opportunity to perform randomized controlled trials in space. Long-duration head down bed rest (HDBR) and dry immersion (DI) are well-accepted analogs of the effects of fluid shifts and axial body-unloading that occur during spaceflight  study compared a 70 days HDBR control group to a corresponding HDBR exercise group that performed a high-intensity integrated aerobic and resistance exercise training prescription using horizontal exercise devices with similar exercise capabilities as those available to ISS astronauts . On BR +Current balance training interventions on Earth may provide clues for designing in-flight countermeasures. There are two main classes of balance training: reactive and proactive. Reactive balance training protocols involve repeated exposure to instability that mimics balance disturbances. During traditional reactive balance training, subjects attempt to stand or to perform dynamic activities on an unstable surface and use internal feedback to achieve the stability goal . ExampleIn contrast, proactive balance training protocols involve voluntary initiation of movement with known support surface interactions. During traditional proactive balance training, the balance system is activated (consciously or unconsciously) in anticipation of predicted perturbations . ExampleBoth reactive and proactive balance training approaches appear to be useful for both rehabilitation and prevention. However, methodologic limitations and high variability in assessment methods and training parameters preclude making strong statements on the efficacy of these protocols . In addiWe recognize from the history of in-flight exercise hardware that simply adapting Earth-based concepts to a microgravity environment is not always optimal or even feasible . For exaOur recent observations during parabolic flight further suggest that unstable conditions on Earth are not necessarily unstable in microgravity. During the weightless phases of parabolic flight, subjects were loaded axially onto a platform and instructed to balance on various wobble boards. A similar platform system has been used in parabolic flight previously . The wobThese observations during bouts of weightlessness lasting 20–25 s suggest that current harness loading attachments do not create unstable postures for subjects during simulated standing. On Earth, humans are accustomed to using reliable visual, vestibular, and somatosensory input to control complex balance processes . For somMicrogravity alters proprioceptive function, and this appears to affect the feedback control of movement during spaceflight . For exaMicrogravity also alters tactile function essential for maintaining the postural and locomotor control systems. For example, the absence of tactile input from the feet in microgravity alters preparatory activations of the lower limbs that normally precede arm raises on Earth . The addMicrogravity also induces vestibular adaptations that lead to unreliable vestibular inputs during the early post-flight period . The antCountermeasures are intended to maintain sufficient physiological function in all crewmembers, allowing them to perform mission-specific tasks, both nominal and off-nominal, including those immediately after landing, without approaching the limits of their physical capacity . It is eSince the balance system as a whole cannot be trained in microgravity, the approach presented here involves targeting the proprioceptive and tactile systems that are required for successful balance outcomes. Proprioceptive training is defined as an intervention that targets the improvement of proprioceptive function, focusing on the use of somatosensory signals such as proprioceptive or tactile afferents . For botAt the mechanistic level, an in-flight proprioceptive countermeasure may keep the proprioceptive system tuned to respond to upright balance challenges in gravitational environments. This approach takes advantage of the convergence of multisensory cues to aid improvement in performance during periods of sensory discordance due to gravitational transitions . By keepVarious potential countermeasures have been proposed. Unlike candidates for systemic benefits to neuromuscular function and neuronal health, like nutraceuticals  or enhanBody load sensing is important for controlling dynamic balance function because it modulates motor control . Even acCountermeasures should aim to provide axial loading up to one full-body weight to stimulate load afferents. Various methods of loading have been used. A wearable garment called the Penguin Suit has been used in-flight to provide chronic axial loading throughout the day and during treadmill running . AlthougEarlier we described how greater resistance training loads provided by the ARED attenuates post-flight decrements in agility and postural stability compared to its predecessor . HoweverProprioception is closely linked to movement. Given this and the training principle of specificity , it is eAnother method of providing proprioceptive challenges involves shifting the control point from the body to an external environment with inherent instability. For example, the lower extremity dexterity task uses a spring-loaded support surface to test the capability to regulate dynamic interactions between the foot and support . PerformIt has been hypothesized that the loss of support afferentation experienced during spaceflight induces neuromuscular dysfunction leading to loss of tonic muscle activation and subsequent post-flight postural and locomotor instability . To restThere are various other ways to provide tactile input to the feet in microgravity. A simple way to add tactile stimulation is through textured shoe insoles for use during in-flight aerobic and resistance exercise. This may help improve active joint position sense at the ankle during loading like has been demonstrated on Earth , 2003. WProprioceptive training can be enhanced by real-time, non-proprioceptive feedback . Adding Vibrotactile feedback may also improve sensorimotor performance and training by providing an intuitive orientation reference without distracting users from natural visual cues . This apCurrent trends in neurorehabilitation involving muscle and brain stimulation techniques may someday lead to solutions that get integrated in a sensorimotor countermeasure suite. Electrical muscle stimulation (EMS) has well-established positive effects on muscle size and function, especially during disuse and aging . In addiBrain stimulation offers a promising strategy for restoring the functional state of the sensorimotor system; however, based on recent evidence, the underlying concepts need to be further clarified, and approaches need to be further developed. Most of the positive evidence for brain stimulation involves small enhancements of upper extremity function in clinical populations . An imprAnother key consideration for proprioceptive countermeasures is the incorporation of assessment capabilities. In-flight assessments are critical to provide objective quantifications of performance, as it relates to the proprioceptive countermeasure system, to track changes over time and thus monitor training effectiveness . The repNASA’s Human Research Program is in the early stages of development for an in-flight operational countermeasure that supplements aerobic and resistance exercise for the mitigation of post-flight decrements in postural and locomotor control. One approach involves keeping the proprioceptive and tactile systems reliable enough to overcome transient vestibular deficiencies for functional task performance upon return to a gravitational environment. The four promising modalities identified for inclusion in the countermeasure include axial body loading, postural/proprioceptive challenges, tactile input, and sensory feedback. Integrating these modalities with other countermeasures (such as LBNP) may increase the efficiency of risk mitigation strategies and have additional indirect benefits. In terms of training schedule, some data suggest that undulated training approaches utilizing variable postural challenges and conditions of feedback may enhance the benefits for adapting to novel sensorimotor environments . HoweverTM, BP, and JB conceived of the presented idea. TM took the lead in writing the manuscript. BP, SW, and JB contributed to the comprehensive examination of the literature. GC and LO provided critical feedback that helped shape the balance training and proprioception countermeasure sections. All authors discussed and contributed to the final manuscript.TM, BP, and GC were employed by KBR and LO was employed by RxFunction. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Early CNS transplantation studies used foetal derived cell products to provide a foundation of evidence for functional recovery in preclinical studies and early clinical trials. However, it was soon recognised that the practical limitations of foetal tissue make it unsuitable for widespread clinical use. Considerable effort has since been directed towards producing target cell phenotypes from pluripotent stem cells (PSCs) instead, and there now exist several publications detailing the differentiation and characterisation of PSC-derived products relevant for transplantation in Huntington’s disease (HD). In light of this progress, we ask if foetal tissue transplantation continues to be justified in HD research. We argue that (i) the extent to which accurately differentiated target cells can presently be produced from PSCs is still unclear, currently making them undesirable for studying wider CNS transplantation issues; (ii) foetal derived cells remain a valuable tool in preclinical research for advancing our understanding of which products produce functional striatal grafts and as a reference to further improve PSC-derived products; and (iii) until PSC-derived products are ready for human trials, it is important to continue using foetal cells to gather clinical evidence that transplantation is a viable option in HD and to use this opportunity to optimise practical parameters  to pave the way for future PSC-derived products. The underpinning concept of cell therapies in regenerative medicine is restoration of structure and function. This can be achieved through several approaches, including implantation of cells to provide support for vulnerable host cells  or implantation of cells which will integrate and adopt the function of cells lost to the disease process . Here, wHTT) gene is associated with 100% penetrance. The earliest and most profound pathological change in HD is the dysfunction and degeneration of striatal medium spiny neurons (MSNs), starting years before clinical disease onset [HD is a devastating neurodegenerative disease which most commonly manifests in mid-life and results in progressive deterioration of movement, cognition and mental health . No disese onset ,5. This se onset .CNS transplantation has a history going back several decades, with Parkinson’s disease (PD) and HD as the most frequently studied target conditions. Early studies demonstrated the need to transplant immature cells, rather than fully differentiated cells which survive the transplantation process poorly . SelectiConsidering these advancements, is it still justified to continue pursuing transplants of foetal derived cell products? To determine this, we must consider whether these PSC-derived products are currently a viable alternative to foetal derived cells, particularly with regard to their use in cell replacement therapy. Additionally, we need to consider whether further understanding of the complex developmental course of MSNs is warranted to optimise the novel PSC-derived cell therapy products. For HD, it is currently understood that transplanted cell products will need to reconnect the degenerated neural circuits of the striatum by forming appropriate synaptic connections and performing the function of normal adult MSNs . Therefobona fide MSNs . Specifically, we have shown that ESC and iPSC derived MSN-like cells have a vastly different epigenome compared with foetal WGE. (i.e. authentic MSN progenitors) [There are a number of published protocols for differentiating PSCs towards an MSN-like phenotype, by first inducing a neuroectodermal fate and then guiding regional specificity by manipulating Shh and Wnt pathways ,23,25,26enitors) , furtherDespite this, there is some evidence that PSC-derived MSNs may be able to elicit some functional recovery in animal models ,16,25,26Furthermore, there has been a tendency to focus on single target phenotypes (such as MSNs) and ignore the other neural phenotypes present in foetal donor cell populations (such as glia and interneurons), but the success of foetal transplants may be at least in part due to these additional populations. Indeed, there is now some evidence that transplantation of astrocytes can also offer some functional recovery in models of HD ,31. UndeGiven that PSC-derived donor cells are progressing towards, but not currently ready for, clinical trials in HD, we propose that it is important to continue gathering clinical evidence that transplantation is a viable therapeutic option for HD. A number of studies over an extended number of years have provided preliminary data suggesting that the safety of foetal cell transplants is acceptable (reviewed in ). There There remain many challenges to undertaking transplantation studies, irrespective of the donor cell source. One in particular is that of the effective and safe delivery of viable cells. The impermeable nature of the intact blood–brain barrier means that many therapeutics intended to reach the brain cannot be delivered systemically attempts are ongoing to identify viable alternative routes of administration . This isThe value of exploring cell therapy in HD goes beyond treating individuals with HD; understanding and optimising cell therapy strategies in HD will provide key information for other neurodegenerative conditions. There are several reasons for regarding HD as a model neurodegenerative condition to test cell therapies: it features the major pathophysiological hallmarks of the most prevalent multigenic and/or multifactorial neurodegenerative diseases, including progressive and selective neuronal death, transcriptional dysregulation, mitochondrial dysfunction, and protein aggregation ; the ranIn summary, we argue that foetal cells remain an essential research tool, offering a precise and detailed understanding of the characteristics of authentic human striatal cells and as a standard against which to test PSC-derived MSNs. We also maintain that human studies of foetal cell transplantation remain important, both for testing the value of cell therapy in HD and for future validation of PSC-derived products in people.


PDOs are organ specific 3D tumour cultures that can accurately represent the histology and genomics of their native tumour, as well as offer the possibility as models for pharmaceutical drug testing platforms, offering timing advantages and potential use as prospective personalised models to guide clinical decision-making. Such applications could maximise the benefit of drug treatments to patients on an individual level whilst minimising use of less effective, yet toxic, therapies. PDOs are likely to play a greater role in both academic research and drug development in the future and have the potential to revolutionise future patient treatment and clinical trial pathways. Similarly, ex vivo tumour slices or explants have also shown recent renewed promise in their ability to provide a fast, specific, platform for drug testing that accurately represents in vivo tumour response. Tumour explants retain tissue architecture, and thus incorporate the majority of tumour microenvironment making them an attractive method to re-capitulate in vivo conditions, again with significant timing and personalisation of treatment advantages for patients. This review will discuss the current treatment landscape and research models for EOC, their development and new advances towards the discovery of novel biomarkers or combinational therapeutic strategies to increase treatment options for women with ovarian cancer.Epithelial ovarian cancer (EOC) is a heterogenous disease associated with variations in presentation, pathology and prognosis. Advanced EOC is typified by frequent relapse and a historical 5-year survival of less than 30% despite improvements in surgical and systemic treatment. The advent of next generation sequencing has led to notable advances in the field of personalised medicine for many cancer types. Success in achieving cure in advanced EOC has however been limited, although significant prolongation of survival has been demonstrated. Development of novel research platforms is therefore necessary to address the rapidly advancing field of early diagnostics and therapeutics, whilst also acknowledging the significant tumour heterogeneity associated with EOC. Within available tumour models, patient-derived organoids (PDO) and explant tumour slices have demonstrated particular promise as novel  Ovarian cancer is a spectrum of different clinical and pathological entities with variable presentations and behaviour. Epithelial Ovarian Cancer (EOC), of which the most common subtype is serous, comprises approximately 90% of cases . Other eHGSOC is a genomically diverse cancer, displaying significant genomic instability and intra-tumoural heterogeneity. TP53 mutations are almost ubiquitous 96%), BRCA1/2 germline and somatic mutations are observed in 22% of tumours and approximately half of cases display deficiencies in homologous recombination %, BRCA1/, which hHigh grade serous ovarian cancer typically presents in postmenopausal women with non-specific symptoms such as bloating, abdominal pain, distension, gastrointestinal disturbance or systemic symptoms such as sweats or weight loss. It can also manifest as an incidental finding. Cancer antigen-125 (CA-125) is frequently elevated, and the use of ultrasonography and multimodal cross-sectional imaging  is crucial to establish accurate radiological staging prior to treatment decision making.In conjunction with systemic approaches, maximal effort surgery is one of the cornerstones of ovarian cancer treatment. Even in the advanced forms of the disease , there is substantial evidence demonstrating that surgical tumour debulking is significantly associated with prolonged remission and survival, including in those situations of high tumour burden , 15. ValDebulking surgery can occur in the primary upfront or interval setting following neoadjuvant chemotherapy depending on the presentation, pathology and pattern of the disease, but also patient related factors such as performance status, fragility scores and patient wishes. Large prospective randomised trials with translational aspect are awaited to clarify the question of timing of surgery in operable patients within a specialised setting , 18. RegGiven the high proportion of homologous recombination (HR) deficiencies in HGSOC, treatment development has focused on targeting DNA repair to exploit these defects therapeutically . The stavia a different mechanism and at a different stage of the cell cycle than platinum compounds. Paclitaxel inhibits cell division through promoting stable microtubule assembly during cell division which prevents depolymerisation and disassembly with subsequent G2/M cell cycle arrest  plays a key role in angiogenesis, a vital component of tumour growth and metastasis , 41. WitVEGF inhibitors, notably bevacizumab, have been extensively trialled within EOC in an attempt to therapeutically exploit this commonly overexpressed pathway. Bevacizumab  was the first targeted therapy approved for EOC . However, its benefit has not been as clear as that seen with carboplatin and paclitaxel in the first-line setting, with retrospective subgroup analyses identifying only those patients with poor prognosis disease as those who benefit significantly from anti-VEGF treatment –46. HoweMore recently ovarian cancer treatment has been revolutionised by the discovery of Poly (ADP-Ribose) Polymerase inhibitors (PARPi). PARPi exert their action through binding to the catalytic site of PARP1, preventing its release from DNA and thereby trapping it in the PARP/DNA nucleoprotein complex –50. The BRCA proteins are vital to achieve successful HR, and thus PARP inhibition can exploit synthetic lethality in patients with homozygous BRCA mutations. PARPi are also involved in the protection of stalled replication forks and are likely to have further reaching effects given the roles of PARP1 and PARP2 in transcription, apoptosis and immune function . In addiSeveral PARPi have now been licensed following success in advanced EOC in both first line , 55 and However, not all patients will respond to treatment [up to 25% of patients have platinum refractory disease at presentation ], and idin vivo tumour treatment response are needed for further exploration of the possible indicators of resistance as well as evaluation of future treatment options and biomarkers of response.Whilst our understanding of potential resistance mechanisms has improved, the significant genetic diversity of this disease and the variability in treatment responses means that reliable methods are required to identify which patients are likely to benefit from particular treatments. In addition, models that accurately mimic the 2D cell monolayers comprise primary tumour cell cultures and immortalised cell lines. Primary cell cultures are formed from the mechanical dissociation of tumour cells, or from isolation and culture from ascites . They moin vivo. It is important to recognise also that any secondary cell line that has arisen in ex vivo culture may not represent a true clonal outgrowth that could have arisen in vivo, rather a sub-clone that has adapted particularly well to cell culture conditions.However, generation of cell lines, whether primary or immortalised, can be time consuming and difficult to establish - for example, only 1 primary culture out of 156 ovarian tumour cultures spontaneously immortalised in one study , or multin vitro phenotype with genetic drift and new genetic variations not observed in the original tumour arising  that can influence cell metabolism, which can have a knock-on effect on cellular responses to drug treatments . Therefoll death , 87.Spheroids were initially described in 1971 following culture of cancer cell lines in non-adherent conditions . They arUse of spheroids as a culture model in EOC is inherently attractive as they are commonly found in ascites , and theSpheroids have also been developed from EOC tumours , 92 and PDOs are organ specific 3D structures derived from primary tumour cells or human stem cells, that have now been established for EOC , 96–101.ex vivo selection than that seen in cell lines or PDX models. They are relatively easy to manipulate and generate functional assays on which to test drug treatments. A summary of the advantages and disadvantages of different EOC models is presented in PDO technology lies in the use of a combination of growth factors and small molecules used in combination with a basement membrane mimic   in an atImprovements on the original organoid methodology have also been attempted e.g. use of a mini ring method in comparison to traditional drop seeding, to quickly generate organoids from a small number of cells to use for a rapid turnaround for high throughput drug screening , though PDX models have been established in a variety of different cancer types including EOC . PDX modPDX models more accurately represent the three-dimensional TME than cell line xenografts by better retaining tumour architecture and containing components of the original tumour stroma, vasculature and immune cells . They hain vivo similarity with the tumour-TME interface as well as differences in pharmacodynamics and pharmacokinetics between human and mouse  through their measurement of their activity in the conditioned media –122.Historically however there have been issues with the short duration of cell viability [likely as a consequence of absent functional vasculature ] and thein vivo tumour response. Explants have also demonstrated the ability to evaluate underlying treatment resistance mechanisms (Ex-Vivo Organ Culture (EVOC)] is due to open soon (NCT04599608), with a view to progression to a subsequent phase II trial of EVOC predicted therapy versus physician choice if successful. If this accurately reflects in vivo tumour dynamics, this could further progress the next generation of personalised medicine.However new advances in the field of explant technology are being developed, some of which have shown promising results with good clinical correlation, such as the CANscript and Curesponse™ platforms , 125. Thchanisms . Both mochanisms , 125. A Other techniques have utilised dynamic, agitation-based culture systems to improve explant perfusion and thus viability , enablinin vivo to further understanding of cancer adhesion and invasion, as well as provide models for high throughput drug screening  which has dissected the role platelets play in HGSOC metastases, and is also likely to permit further evaluation of this metastatic niche . Other ain vivo tumour genomics and applicability for drug testing  have been shown to have high morphological, molecular and genetic homology with the original tumour  with success rates of 80% . TargetePredictive biomarkers of treatment response are very valuable to assess clinical benefit in patients from treatments and remains an unmet need in ovarian cancer.® CDx, Myriad Genetics)] ] , 143. Monetics)] , 145. Thnetics)] , highlignetics)] , 98 and netics)] . Howeversiveness  indicatiin vivo tumour is anticipated to further development in this field.Whilst a number of different prognostic and predictive biomarkers for ovarian cancer have been explored , sensitiex vivo in a way that accurately depicts the in vivo environment is a key focus in drug development.The heterogeneity in ovarian cancer genotypes and phenotypes, as well as differential patient responses to treatment means the ability to reliably test different drugs in vivo response (EOC PDOs have undergone drug sensitivity and resistance testing (DSRT) in a number of different studies. Short-term PDOs have been tested against different compounds including olaparib, carboplatin, gemcitabine, paclitaxel, doxorubicin, the CHK1 inhibitor prexasertib and ATR inhibitor VE-822, with correlations observed between PDO resistance/sensitivity and response . Additioresponse . This stin vivo comparison  as well as retained CD4 and CD8 T cell populations . Similarin vivo stroma, vasculature and immune cells, which play an important role in tumour growth and dissemination. The tumour microenvironment is an important facilitator in tumour growth and treatment response. Additionally, the availability of resources such as nutrients and oxygen contribute to intra-tumoural heterogeneity  may only require small amounts of tissue  and reagents  have also recently been investigated as a 3D model for cancer, following their use in tissue engineering and tissue regeneration . Decelluin vitro immune interaction with organoids. Jenkins et al. showed that the PD-1/PDL-1 interaction could be simulated in spheroid models of different solid tumours . However, these studies were predominantly demonstrated in tumour types with a high mutational burden and thus it may not be feasible to perform in cancers like OC which typically is associated with a low mutational burden. Whilst it may not have a high mutational burden, EOC is viewed as potentially immunoreactive given the association seen between clinical outcome and the presence of tumour infiltrating lymphocytes . StrategAnother study focused on functional and single-cell RNA sequencing profiling on HGSOC organoid-immune cell co-cultures and identified 3 immune therapy targets in HGSOC through use of a novel bi-specific antibody . This lein vitro epithelial-mesenchymal transition  and other tumour explant trials that are soon to open . This is likely to be where the majority of early phase trials are heading, with benefits for patients, clinicians, researchers and pharmaceutical companies alike. Whether PDOs could be used in combination with explants to give the most representative ex vivo simulation of in vivo response remains to be evaluated.In addition to the clinical perspective, there is also a research and economic perspective in that the extensive cost involved in early phase drug testing could be significantly mitigated with more accurate and clinically relevant ex vivo models in recent years which is likely to significantly improve research into novel biomarkers and therapeutics. They also have the potential to change the way both academic research and drug development are conducted, whilst also revolutionising patient treatment pathways to incorporate a new level of personalisation into the clinic to optimise patient outcomes.Overall, there has been significant progress in the development of new in vivo therapeutic efficacy. Whilst tumour explants provide a better representation of the TME ex vivo, their use also has its limitations, notably their short duration of ex vivo viability and the absence of self-renewing capability.PDOs have been an exciting development that are likely to play an increasing role in biomarker and therapy development. The absence of accurate representation of the TME at present hinders evaluation of an important part of the tumour-treatment response and there remains a need to improve models to reliably represent However, with both commercial and clinical interest focused on refinement of 3D models, this is likely to be the forefront of the next generation of individualised treatment assays as well as contributing to drug development to improve prognoses and treatment options for this devastating disease.JC and PC were involved in the initial review design and composition. JC, PC, CF, and JK contributed to manuscript content and format. All authors contributed to the article and approved the submitted version.JC is supported by the Dangoor Fellowship. PC and CF acknowledge support from the Ovarian Fund, Imperial Health Charity.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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Moreover, molecules traditionally considered to elicit effector functions are now being directly linked to the regulation of leukocyte migration. Here, myeloperoxidase (MPO) has been reported to negatively regulate neutrophil infiltration during inflammation and its absence significantly enhanced the migration capacity of neutrophils .The ability of leukocytes to exit the vasculature  and enter tissue  is critical for the health and wellbeing of an organism. These processes form a tightly regulated cascade of sequential steps, each of which educates the migrating leukocyte. Whilst some believe that our knowledge of the leukocyte adhesion/migration cascade is complete, advances in imaging technologies and genetically modified animals and cell-lines, amongst others, are still revealing new insights to the original cascade described in 1995. For instance, unbiased omics approaches coupled with interactome mapping are expanding our appreciation of the cytoskeletal proteins, signalling events, and phosphorylation patterns coupled to integrin-mediated migration and effector function in leukocytes. Our current understanding of downstream inside-out and outside-in signalling through βLightfoot, et al.). Although there is still much to learn about galectins, such differences are likely to have a big impact on leukocyte-BEC interactions and thus leukocyte entry into inflamed tissues. Focusing on tissue egress Tadayon et al., have describe a dual role for Clever-1: (i) acting as a key adhesion molecule to support dendritic cell (DC) migration across LEC; whilst also (ii) negatively regulating the inflammatory phenotype of LEC . Consequently, LEC Clever-1 educates migrating DC, imparting an immunosuppressive signal that regulates the magnitude of immune response created in the draining lymph nodes.Vascular endothelial cells are key gatekeepers of the tissue: with blood endothelial cells (BEC) facilitating leukocyte ingress and lymphatic endothelial cells (LEC) supporting their tissue egress. Renewed interest in glycan-binding proteins has revealed that specific expression patterns of galectin family members on BEC from different tissues or in response to different stimuli . MKL1 deficiency is characterised by severe defects in neutrophil adhesion and migration, as well as the potential for myeloid cells to spread and form filipodia to sense chemotactic and haptotactic gradients . Additionally, changes in adhesion molecule expression can provide novel insights into microbial responses, for example SARS-CoV-2 infection significantly reduced the expression of the gut-homing integrin, α4β7, on circulating blood lymphocytes, indicative of priming in the GALT and potentially the preferential recruitment of these cells from blood into peripheral tissues .Leukocyte migration is unequivocally linked to their ability to mediate their effector functions – whether this is acting as first responders to invading pathogens and/or tissue injury in peripheral tissues; mounting highly specific antigen driven detection systems in lymphoid tissues; or regulating the degree and duration of such responses. Deficiencies in genes responsible for actin regulation, which is crucial for cellular movement, are associated with primary immunodeficiencies, including megakaryoblastic leukaemia (MKL1) ; chronic obstructive pulmonary disease ; and inflammatory bowel disease . RNAseq analysis has revealed that rheumatoid synovial fluid fundamentally alters the migratory potential of healthy neutrophils, contributing to their accumulation, retention and the maintenance of an activated phenotype in the rheumatoid joint . Similarly, dyslipidaemia associated with atherosclerosis, in particular low levels of ApoA1, were correlated with elevated expression of integrin and chemokine receptors on circulating monocytes , thus supporting aberrant monocyte extravasation and potentially driving plaque progression.Conversely, the inappropriate accumulation and activation of leukocytes underpins pathology and tissue damage in numerous immune-mediated inflammatory diseases, such as rheumatoid arthritis , the elderly  or in cancer . Additionally, one could envisage clinically taking advantage of the diurnal rhythmicity of leukocyte trafficking to maximise these responses . Alternatively, treatment options might include limiting the trafficking of pathogenic effector leukocytes at sites of chronic inflammation, combined with agents that promote the migration of regulatory leukocytes to trigger resolution of inflammation and tissue repair. These concepts are elegantly highlighted by Bonilha et al., where antagonising junctional adhesion molecule- A (JAM-A) may control leukocyte trafficking in preclinical models of IMIDs, whilst the same treatment appears to enhance immune responses against cancerous cells in tumors .Our ability to target leukocyte migration offers the opportunity to influence leukocyte trafficking profiles based on the underlying defect. For example, promoting recruitment in individuals where responses have diminished, e.g., in the primary immunodeficiencies . Opportunistic infection and poor vaccine responses are common side-effects to many of the biologics in development or that have been developed, which is not surprising when considering the clinical attributes of primary immunodeficiencies. Moreover, attempts to target leukocyte accumulation by modulating their recruitment with chemokine receptor inhibitors has been unsuccessful in a number of contexts, including COPD , due to promiscuity and redundancy within this family. Further directions should focus on interactions that are unique to “disease” settings to minimise off-target effects, but also attempt to identify shared pathways hijacked across multiple conditions that might benefit from early, preclinical interventions.Caution is required when designing any therapy that targets leukocyte adhesion and migration: Many of the molecules involved in these processes are ubiquitously expressed and utilised by all leukocyte’s subtypes in their movement around the body. One of the major therapeutic success stories is vedolizumab, the anti-αTargeting Leukocyte Trafficking: Insights and Future Directions” includes a combination of reviews and original papers highlighting advances in our fundamental understanding of the molecular processes regulating leukocyte trafficking in health, during a day or over a lifespan, and in response to infection and disease. Each article further explores how this knowledge has and is being translated into novel pharmacological tools, providing current and future perspectives in this arena. The editorial team would like to thank all those who contributed to this collection.The Frontiers Research Topic “All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Pharmacists across Canada have varying degrees of ability to prescribe medications depending on their jurisdiction of licensure. The purpose of this study was to the evaluate attitudes, beliefs, and perceptions of independent pharmacist prescribing among health authority- and community-based pharmacists. This prospective, cross-sectional online survey assessed the perceptions of independent pharmacist prescribing of health authority and community pharmacists practising in northern British Columbia (BC), which was defined as within the geographical boundaries of Northern Health. Responses were analysed using descriptive statistics and a regression analysis. There were 45 respondents to the survey: 22 community pharmacists and 23 health authority pharmacists. Both community and health authority pharmacists held positive perceptions of independent pharmacist prescribing and did not identify any barriers to incorporating independent pharmacist prescribing into their practice. Respondents were highly likely to apply for independent pharmacist prescribing authority, if available. Pharmacists in BC are currently not able to independently prescribe schedule I medications. The provincial regulatory body has proposed a framework for a Certified Pharmacist Prescriber designation, which if approved would allow pharmacists to prescribe in collaborative practice settings. This study provides some insight into the perception of pharmacists in northern BC in pursuing this designation, which may be valuable for planning purposes in case of adoption of the framework. These results are also likely applicable to other non-urban practice settings in Canada. Pharmacists in northern BC perceived independent pharmacist prescribing positively and a high proportion were likely to apply for this authority if it were permitted via legislation. It is well recognised that pharmacists have the skills and knowledge to benefit patients beyond the dispensation of medications ,18,19,20Evidence has demonstrated that independent pharmacist prescribing in the United States results in improved outcomes for patients with certain medical conditions , which has been associated with reduced costs ,5. SincePatients in non-urban areas of Canada have less access to health care providers than patients in urban areas . This maPharmacists in the province of British Columbia, Canada are currently not able to independently prescribe schedule I medications. Recently, the provincial regulatory body  proposed a framework for a Certified Pharmacist Prescriber designation . If apprThe objective of this study was to determine the perceptions of, attitudes toward, and beliefs about independent pharmacist prescribing among health authority —and community-based  pharmacists in northern British Columbia, as well as to identify potential barriers and enablers to the implementation of independent pharmacist prescribing and assess respondents’ intention to apply for prescribing authority if it were to become available.2. The survey was anonymous, and questions were designed to limit the risk of respondents being identified based on their responses, as some communities within Northern Health have a limited number of pharmacists.This prospective, observational, online survey study assessed the perceptions of pharmacists in northern British Columbia, Canada about independent pharmacist prescribing. The survey questions were modified from previous similar surveys and are available from the corresponding author on request ,25,26. AThe online survey link was distributed to participants via an e-mail distribution list for 67 Northern Health pharmacists and via facsimile to community pharmacies. The denominator for community pharmacists was estimated based on the number of pharmacists in the northern British Columbia communities, as per the provincial regulatory body  database of workplace location. Informed consent was obtained from participants prior to responding to the survey. The survey was open for four weeks (23 January to 20 February 2020) and participants were sent one reminder after two weeks.Data was analysed with Microsoft Excel  using descriptive statistics. A regression analysis was performed using SPSS  to identify potential demographic characteristics that may have been associated with the likelihood to apply for prescribing authority.A total of 45 pharmacists responded to the survey. Twenty-two of the respondents were community pharmacists (estimated to be a response rate of 11%) and 23 were health authority pharmacists (response rate of 34%). Respondent demographic characteristics are included in Survey respondents identified no perceived barriers to incorporating independent pharmacist prescribing into their respective practices . Health When assessing the intentions of northern British Columbia pharmacists to apply for prescribing authority, it was found that 89% of respondents overall would be likely to apply for prescribing authority if made available. The regression analysis did not demonstrate any statistically significant associations between respondent characteristics’ and likelihood of applying for independent pharmacist prescribing. Eighty-seven percent of respondents were likely to apply for independent pharmacist prescribing authority if additional training was required, and there were no statistically significant differences between responses of health authority- and community-based pharmacists. Most pharmacists were willing to pay at least $1000 CAD to obtain prescribing authority, with health authority pharmacists willing to pay a higher mean amount than community pharmacists.The online survey of pharmacists’ perceptions of independent pharmacist prescribing had an estimated response rate of 17% among pharmacists in northern British Columbia. A higher response rate among health authority-based pharmacists (34%) versus community-based pharmacists (estimated at 11%) was expected, as this group may have had more interest in collaborative prescribing. Health authority-based pharmacists may also have been more likely to participate due to receiving the invitation via e-mail versus facsimile due to the convenience of accessing an online survey. With the exception of education level, there were no statistically significant differences between health authority- and community-based pharmacists with respect to demographic characteristics. Even though hospital pharmacists had a higher level of pharmacy education, the overall results were similar between groups. As such, the desire to expand scope of practice does not seem to be dependent on level of education. Despite the differences in practice settings, respondents were highly likely overall to report working in a collaborative environment with other prescribers. Therefore, many community pharmacists perceived themselves to practice in a collaborative practice setting despite likely not being located in the same physical location as the other prescribers.A study by Prasad and colleagues was the first study to assess health authority pharmacists’ perceptions of independent pharmacist prescribing in British Columbia. The study was conducted across mostly urban settings in the Lower Mainland of British Columbia, and it found that pharmacists held mostly positive perceptions of independent pharmacist prescribing and would be likely to apply for the authority, if available. However, it did not include pharmacists practicing in community-based settings.Community-based pharmacists were more likely to somewhat or moderately agree with positive statements about independent pharmacist prescribing, whereas health authority-based pharmacists were more likely to strongly agree with these statements. This may be because the framework for pharmacist prescribing developed by the College of Pharmacists of British Columbia is potentially more relevant to hospital-based practice. Pharmacists in this study did not identify any barriers to incorporating independent pharmacist prescribing into their practices. However, health authority-based pharmacists were more likely to identify factors as enablers, whereas community-based pharmacists were more likely to identify factors as being neutral. Similar to the findings regarding beliefs about independent pharmacist prescribing, this may be because collaborative prescribing is more relatable to hospital practice.Pharmacists in northern British Columbia were more likely to identify independent pharmacist prescribing to be helpful for practice-based activities, or that they already had the authority to prescribe in these circumstances. These results suggest that respondents generally have positive perceptions about the impact of independent pharmacist prescribing on their practice environments. When compared to the survey of urban pharmacists from Vancouver, British Columbia and the surrounding area, pharmacists in northern British Columbia were more likely to identify as already having authority for prescribing activities . This maA majority of respondents intend to apply for independent pharmacist prescribing if it were to be granted through legislation, which was similar among both health authority- and community-based pharmacists. Overall, this was higher among pharmacists in northern British Columbia, as compared to pharmacists in Vancouver  . Again, With respect to limitations, this survey had a relatively small sample size and therefore is at risk of sampling and response bias. In addition, as the survey was conducted prior to the implementation of independent pharmacist prescribing, it should be noted that respondents’ perceptions, attitudes, and beliefs might differ once this authority is actually granted. Therefore, future studies are warranted to assess pharmacists’ beliefs regarding independent prescribing once it is implemented in practice.Pharmacists in northern British Columbia demonstrated generally positive perceptions of independent pharmacist prescribing. Despite differences between health authority- and community-based pharmacists with respect to attitudes towards and beliefs about independent pharmacist prescribing, a high proportion of respondents in both groups would be likely to apply for this authority if it were to be granted.


Social cognition is an important area of mental functioning relevant to psychiatric disorders and social functioning, that may be affected by psychiatric drug treatments. The aim of this review was to investigate the effects of medications with sedative properties, on social cognition.This systematic review included experimental and neuroimaging studies investigating drug effects on social cognition. Data quality was assessed using a modified Downs and Black checklist . The review used narrative synthesis to analyse the data.40 papers were identified for inclusion, 11 papers investigating benzodiazepine effects, and 29 investigating antipsychotic effects, on social cognition.Narrative synthesis showed that diazepam impairs healthy volunteer’s emotion recognition, with supporting neuroimaging studies showing benzodiazepines attenuate amygdala activity. Studies of antipsychotic effects on social cognition gave variable results. However, many of these studies were in patients already taking medication, and potential practice effects were identified due to short-term follow-ups.Healthy volunteer studies suggest that diazepam reduces emotional processing ability. The effects of benzodiazepines on other aspects of social cognition, as well as the effects of antipsychotics, remain unclear. Interpretations of the papers in this review were limited by variability in measures, small sample sizes, and lack of randomisation. More robust studies are necessary to evaluate the impact of these medications on social cognition.The online version contains supplementary material available at 10.1186/s12888-021-03545-z. Social cognition is defined as the mental processes which underlie the ability to understand and act on the thoughts, intentions, and behaviours of others . Deficit; emotion processing - the ability to perceive emotions and interpret them appropriately [; social perception - the ability to process social cues and context to decipher social situations [Social cognition can be separated into individual testable domains. However, many of these domains overlap, and there is no consistent agreement between cognitive scientists as to which are the most important. In psychiatry research the domains most frequently studied tend to reflect those identified by the National Institute of Mental Health (NIMH) at their meeting to define social cognition in schizophrenia in 2006 . These dpriately ; social tuations ; attributuations ; and soctuations . AdditioSocial functioning deficits are a core feature of most psychiatric diagnoses and considered an integral treatment target for many conditions, in order to promote recovery , 14. SocThe existing studies showing social cognition deficits in psychiatric disorders often involve people who are currently taking psychiatric medication . HoweverAlong with sedative effects, psychiatric medications affect emotion and motivation. Antipsychotics, for example, reduce motivation and suppress emotions in volunteers , effectsTherefore, there is good reason to believe that psychiatric medications may influence social cognition, especially those with sedative actions that are known to impair neurocognitive functioning in volunteers. Clarifying these effects is important in order to understand the nature of social cognitive deficits in psychiatric disorders, and to evaluate the effects of treatment on social cognition and associated outcomes, such as social functioning. A previous review highlighted the paucity of evidence on the effects of antipsychotic treatment, but it did not explore the use of other medications or effects in volunteers . VolunteThe realisation that social disability may be linked to cognitive dysfunction has led to the employment of neuroimaging techniques to study this phenomenon in psychiatric populations, including the use of electroencephalography (EEG) and functional magnetic resonance imaging (fMRI). EEG can identify temporal changes in brain activity in response to specific tasks via event-related potentials (ERP), and fMRI is used to detect the location of changes in brain activity via variations in blood-oxygen-level-dependence (BOLD) , 33. ERPDespite evidence of effects on neurocognitive functioning, there has been little consideration of how psychiatric medications affect social cognition. We hypothesised that psychiatric medications that produce sedative effects might affect social cognition, and we conducted a systematic review of the literature in this area. We included research on healthy volunteers as well as research conducted with patients with diagnosed psychiatric disorders.An additional aim of this review was to explore any temporal or spatial brain differences between healthy volunteers and clinical populations with psychiatric diagnoses conducting social cognition tasks after administration of psychiatric medication using neuroimaging technology. Notable differences in brain activity may reflect the effects of medication on social cognitive processing.The review will help to clarify the nature of any underlying deficits in social cognition in people diagnosed with psychiatric disorders, and this will help in the development of targeted treatments for social cognition, which may also improve social functioning and general outcomes .This review follows the PRISMA guidelines for reporting systematic reviews . The revThe scope of our narrative synthesis was to examine the effects of sedative medications on social cognition. Following guidance from Popay et al.  we used greylit.org and opengrey.eu. Database-specific search terms included the keywords ‘social cognition’, ‘mental disorder’, ‘neuroleptic agents’, ‘sedatives’, and ‘tranquilisers’ with intervention-specific terms , diagnosis-specific terms, outcome-specific subtypes and synonyms . An attempt to find additional studies was made through a backward reference search and contacting experts in the field.We searched the following major databases: MEDLINE (OViD), Embase, Psychinfo, Web of Science, Lilacs, and Scopus as well as grey literature through Citations were imported to Mendeley and all duplicates were removed. ZH independently screened all citation titles for their applicability . Titles Study quality was evaluated using the Downs and Black checklist  as it alThe search identified 2931 papers fitting the eligibility criteria, with 2681 remaining after de-duplication. The abstracts and titles of those records were then screened and 2511 were excluded due to not meeting the inclusion criteria. This resulted in 170 papers for full-paper screening. A further 130 papers were excluded during this stage, for reasons shown in Fig. Data quality was rated by ZH on all 40 full-text papers and AJW on 20% randomly selected papers. An interrater reliability score Cohens Kappa Coefficient of 0.85 was calculated , indicatFour benzodiazepine studies conducted in healthy volunteers showed significant impairments in emotion recognition social cognition tasks following diazepam administration , 44, 81,One study was conducted in patients with schizophrenia, which looked at the effects of benzodiazepine withdrawal. Patients who were in the process of withdrawing from benzodiazepines were significantly impaired in recognising negative emotions compared to healthy volunteers, in contrast to patients who had already withdrawn, who were not. However, all patients were likely to have been on other medications .All neuroimaging studies compared social cognition before and immediately after administration of the experimental drug. Del-Ben et al.  showed t.A study investigating benzodiazepine effects on patients with ‘catatonic’ schizophrenia and patients with bipolar disorder found that lorazepam induced BOLD signal decreases in the occipital cortex and medial prefrontal cortex (MPFC) in patients with schizophrenia when undertaking a negative emotion recognition task. This resulted in BOLD patterns resembling those of healthy volunteers taking a placebo drug during the same emotion recognition tasks . HoweverN = 14) found that recognition of angry facial expressions was reduced in participants taking sulpiride, but recognition of other expressions was not affected. In addition, a larger randomised parallel group trial of quetiapine versus placebo by Rock et al. [N = 27) found no effect of the medication on facial expression recognition, though dropout rates were high (25%) in the quetiapine arm, which may have obscured an effect.Only two studies tested the effects of antipsychotics on social cognition in healthy volunteers. A small crossover study by Lawrence et al.  (N = 14)k et al.  (N = 27)All studies comparing patients with schizophrenia and healthy volunteers found patients performed less well on social cognition tasks whether or not they were taking antipsychotics at baseline , 63, 68.When studies were classified by the prior medication status of participants, two longitudinal studies involved patients who were previously drug naïve. One of these studies detected improvements on an emotional processing task at follow-up , the othn = 11) or drug free (n = 12)) showed significant improvements in emotion recognition at 6 months compared to healthy volunteers.One study tested healthy volunteers at baseline and follow-up to control for practice effects . It founOne longitudinal study involving 29 people with schizophrenia and 28 with bipolar disorder explored dose-response relationships . FindingStudies comparing different antipsychotics produced inconsistent results. Some found that patients treated with second-generation drugs did better than those taking first-generation antipsychotics , 69, 70,One study involving participants with Huntingdon’s disease showed poorer performance on facial recognition tests in those taking antipsychotics compared to those who were not, after controlling for the stage of the disease .In this review, several studies were conducted by authors who received funding from pharmaceutical companies for research purposes or consulting. One study had a pharmaceutical company provide the medication for the research . StudiesA study by Sumiyoshi et al.  investigA study investigating the effect of sultopride on emotion processing in healthy volunteers found decreased BOLD responses in the amygdala when viewing negatively valenced stimuli compared to before sultopride administration . There wClarifying the effects of prescribed medication on social cognitive ability is important since social cognition appears to be impaired in people across psychiatric diagnoses, and this impairment may be related to deficits in social functioning that represent a significant disability. Hypothetically, psychiatric drugs may impair social cognition due to their sedative effects, or may, through improving psychiatric symptoms, benefit social cognition.The findings suggest that psychiatric drugs with sedative properties, such as benzodiazepines, can impair emotion recognition in healthy volunteers , 44, 81.Results of studies with patient populations found that antipsychotic treatment improves or has no effect on social cognition in patients with schizophrenia. The studies suffered from several important methodological limitations, however. First, practice effects in cognitive tasks are common , and as In contrast to studies showing improvement in social cognition with antipsychotics, one study on emotion processing identified a negative effect with a dose-response relationship, such that higher doses of antipsychotics related to higher levels of social cognitive impairment in patients with schizophrenia, but this was only found in people diagnosed with schizophrenia and not with bipolar disorder. The study with patients with Huntingdon’s disease also found worse facial recognition performance associated with antipsychotic use, even after adjusting for disease severity . This isPatients who experience psychiatric disorders are likely to experience neurocognitive deficits such as poor attention and decision-making skills due to the nature of their symptoms , which mNeuroimaging findings suggest that medication may be affecting brain processes that have been found to be associated with social cognitive ability. Sumiyoshi et al.  found anOne of the most important strengths of this review was establishing the current literature on the effects of sedative psychiatric medications on social cognition using a rigorous search strategy of published and unpublished work.We included all psychiatric populations, and healthy volunteer studies in our search. However, in our review we found the research was largely limited to studies of benzodiazepine effects in healthy volunteers, and studies of antipsychotics in patients with schizophrenia with one study of patients with the neuropsychiatric disorder, Huntingdon’s disease . ResearcWe made efforts to also include all prescribed psychiatric medications with sedative effects in our search, but we may have omitted some medications that are not commonly used. We also excluded drugs that are prescribed for mental disorders but are predominantly used for non-psychiatric indications, such as gabapentin or beta-blockers. We also did not include drugs with sedative effects that are routinely used for physical disorders, such as opiate anaesthetics, for example, and we also did not include recreational sedatives such as alcohol or heroin in our search. The review focused on prescribed psychiatric medication in order to clarify the effects of these medications in people with diagnoses of mental disorders, but recreational drugs are commonly used amongst patients with a mental health diagnosis , and theAn integral strength of our search for this review was the inclusion of all known terminology for social cognitive domains and measures. However, this was difficult due to the use of interchangeable terms for similar items, exposing a feature of the social cognition field that needs to be addressed.A limitation of the current review was the poor quality of available studies. Our data quality analysis tool allowed us to identify several deficiencies with current papers available in the field, such as small sample sizes, non-randomised designs, and few adherence to medication measures. Only four of the studies found conducted power analysis to qualify their sample size. This resulted in many of the included studies having small numbers of recruits, undermining the internal and external validity of the research findings. During quality analysis, researchers also found only three of the longitudinal studies included were recording medication adherence. In addition to this, very few studies considered the influence of practice effects, which have an important influence on the results of longitudinal studies of cognitive performance, and there were few randomised placebo-controlled studies that would allow conclusions about whether changes in patients taking antipsychotics were attributable to specific medication effects, or whether they were the result of unrelated symptom improvement or of practice effects. Additionally, only one study of antipsychotics, and no benzodiazepine studies, looked at dose-dependent effects. This variability in studies also restricted analysis of the papers included, making a meaningful meta-analysis impossible to conduct.One other major limitation of this review was that 80% of the included studies explored emotion processing tasks, leaving the other domains of social cognition largely ignored in the literature. Resultingly, our review is more of an insight into the effects of sedative medications on emotion processing, rather than the broader area of social cognition as a whole.Finally, benzodiazepines have reasonably consistent effects, but antipsychotics vary widely in their receptor targets, pharmacological actions and sedative profiles , 48. TheWe suggest that further research of higher quality is needed to clarify the effects of sedative medications on social cognition in healthy volunteers and patients with psychiatric diagnoses.Further studies conducted with neuroimaging techniques will allow better insight into structural or functional brain changes resulting from administration of psychiatric medication with sedative effects. Conducting these studies with a behavioural performance element will also allow researchers to identify if brain changes are consistent with changes in social cognitive ability.Further studies also need to control for practice effects, and studies involving patients should include placebo or no treatment control groups in order to distinguish the effects of medication from the natural evolution of psychiatric symptoms. Studies should be conducted across a range of social cognition domains, to ensure we are getting an accurate picture of complete social cognitive ability. Additionally, studies should be conducted across a range of psychiatric medications with sedative properties, to ensure we are able to identify any significant differences between drugs, and in different psychiatric diagnoses to clarify the effects of medication across conditions.Notably, recent research in the field of social cognition and psychiatry has focused on the potential benefits of non- pharmacological interventions, such as social cognition and interaction training (SCIT), metacognitive reflection and insight therapy (MRIT), and metacognitive training. A review in 2009 by Choi and colleagues  found thDeficits in social cognition have been identified in people with psychiatric diagnoses, and are associated with impaired social functioning, yet we remain uncertain to what extent these are attributable to the effects of the disorder or the effects of its treatment. A number of healthy volunteer studies suggest that diazepam and lorazepam can impair emotion processing abilities. Studies on antipsychotics were inconclusive and suffered from methodological limitations. There were no studies on any other drugs with recognised sedative properties, and studies focused mainly on the emotion processing domain of social cognition. Better data on the ability of drugs to affect social cognition will help to improve our understanding of the nature of social cognitive deficits in mental disorders, and the effects of treatment. Optimising the treatment of social cognition could potentially lead to better social functioning outcomes.Additional file 1: Appendix A. Literature Search Strategy.