The relationship between subjective sleep disturbance and attenuated psychotic symptoms after accounting for anxiety and depressive symptoms.

BACKGROUND AND HYPOTHESES: Sleep disturbances are increasingly recognized as cooccurring with psychotic symptoms. The potential importance of this relationship is complicated when considering the effects of anxiety and depressive symptoms which commonly present in early-stage illness states. This study aimed to investigate the relationship between self-reported sleep disturbance on the development of attenuated psychotic symptoms (APS) cross-sectionally and longitudinally while adjusting for roles of anxiety and depressive symptoms. DESIGN: Eight-hundred and two help-seeking young people aged 12 to 25 years who engaged with our Australian early intervention services were included in the study (the "Transitions" cohort). Cross sectional mediation and cross-lagged longitudinal (12-month) mediation models were developed with outcomes being different APS domains. RESULTS: Only baseline excessive daytime sleepiness predicted later APS when accounting for previous APS, anxiety and depressive symptomatology. Cross sectionally, self-reported sleep disturbance showed both direct and indirect predictive relationships with all APS domains. Partial mediation through anxiety and depression was shown for unusual thought content, perceptual abnormalities, and disorganised speech, while full mediation through depression was shown for non-bizarre ideas. CONCLUSIONS: The specificity of the relationship between self-reported sleep disturbance on APS highlights the potential for different roles in mechanistic models of psychotic symptom expression. This further indicates the need for further experimental research to illuminate potential causal pathways. Future research should continue to use continuous, symptom level approaches across a range of timeframes to more accurately model the complex dynamics present in the sleep-psychosis relationship.

Has improved treatment contributed to the declining rate of transition to psychosis in ultra-high-risk cohorts?

BACKGROUND: The factors contributing to declining psychotic disorder transition rates in ultra-high-risk populations remain unclear. We examined the contribution of longitudinal changes in standard clinical treatment ('treatment as usual') to this decline. METHOD: An audit was conducted on 105 clinical files of patients who received standard care at a specialised ultra-high-risk service. The session notes of these files were quantified, allowing examination of treatment quantity, targets, psychotherapy, and medication. Differences in these aspects across patients' year of clinic entry were assessed. Variables with significant differences across years were examined using cox regression to assess their contribution to psychosis transition rates. RESULTS: Findings were that, as a function of patients' year of clinic entry, there were increases in: patients' number of sessions, cognitive behavioural therapy (CBT), problem and solving therapy. There was a relationship between baseline year cohort and psychosis transition rate, with lower rates observed in more recent cohorts. When changes in treatment between cohorts were adjusted for, the relationship between baseline year cohort and transition rate disappeared. The relationship between baseline year and transition rate was attenuated most by increases in CBT. CONCLUSION: Changes in standard treatment, particularly increases in CBT, may have contributed to the decline in psychosis risk observed in recent ultra-high-risk cohorts, although these variables do not fully explain this trend. Implications for clinical practice, prediction and intervention research are discussed. Future ultra-high-risk research should investigate the impact of other treatment factors, such as therapeutic alliance.

Toxoplasma gondii, Herpesviridae and long-term risk of transition to first-episode psychosis in an ultra high-risk sample.

BACKGROUND: Ultra high-risk (UHR) criteria were introduced to identify people at imminent risk of developing psychosis. To improve prognostic accuracy, additional clinical and biological risk factors have been researched. Associations between psychotic disorders and infections with Toxoplasma gondii and Herpesviridae have been found. It is unknown if exposure to those pathogens increases the risk of transition to psychosis in UHR cohorts. METHODS: We conducted a long-term follow-up of 96 people meeting UHR criteria, previously seen at the Personal Assessment and Crisis Evaluation (PACE) clinic, a specialized service in Melbourne, Australia. Transition to psychosis was assessed using the Comprehensive Assessment of the At-Risk Mental State (CAARMS) and state public mental health records. The relationship between IgG antibodies to Herpesviridae (HSV-1, HSV-2, CMV, EBV, VZV) and Toxoplasma gondii and risk for transition was examined with Cox regression models. RESULTS: Mean follow-up duration was 6.46 (±3.65) years. Participants who transitioned to psychosis (n = 14) had significantly higher antibody titers for Toxoplasma gondii compared to those who did not develop psychosis (p = 0.03). After adjusting for age, gender and year of baseline assessment, seropositivity for Toxoplasma gondii was associated with a 3.6-fold increase in transition hazard in multivariate Cox regression models (HR = 3.6; p = 0.036). No significant association was found between serostatus for Herpesviridae and risk of transition. CONCLUSIONS: Exposure to Toxoplasma gondii may contribute to the manifestation of positive psychotic symptoms and increase the risk of transitioning to psychosis in UHR individuals.

Safety and efficacy of magnetic seed localisation of non-palpable breast lesions: pilot study in a Chinese population.

INTRODUCTION: A magnetic seed marker system (Magseed, Endomagnetics, Cambridge, United Kingdom) is used as a localisation method for non-palpable breast lesions in the United States, Europe, and Hong Kong. It overcomes many limitations of conventional techniques and allows scheduling flexibility. We sought to evaluate its efficacy and safety in the Chinese population. METHODS: We retrospectively reviewed all Chinese women who underwent magnetic seed marker-guided breast lesion excision from June 2019 to February 2020 at a single institution. Placement success (final target-to-seed distance <10 mm) was evaluated by imaging on the day of surgery. Specimen radiographs and pathology reports were reviewed for magnetic seed markers and target removal. Margin clearance and re-excision rates were analysed. RESULTS: Twenty two magnetic seed markers were placed in 21 patients under sonographic or stereotactic guidance to localise 21 target lesions. One target lesion required two magnetic seed markers for bracketing. There was no migration of nine markers placed 6 to 56 days before the day of surgery. Placement success was achieved in 20 (90.9%) cases. Mean final target-to-seed distance was 3.1 mm. Two out of 21 (9.5%) lesions required alternative localisation due to marker migration ≥10 mm, while 19 (90.5%) lesions underwent successful magnetic seed marker-guided excision. Three of these 19 lesions (15.8%) were excised with therapeutic intent, one of which (33%) required re-excision due to a close margin. All 22 magnetic seed markers were successfully removed. No complications were reported. CONCLUSION: Magnetic seed markers demonstrated safety and efficacy in Chinese women for breast lesion localisation and excision.

Update to the Hong Kong Epilepsy Guideline: evidence-based recommendations for clinical management of women with epilepsy throughout the reproductive cycle.

Since the publication of the Hong Kong Epilepsy Guideline in 2009, there has been significant progress in antiepileptic drug development. New AEDs have emerged, and data about their uses have been published. Women require special attention in epilepsy care. Drug teratogenicity, pregnancy, breastfeeding, contraception, reproduction technology, menopause, and catamenial epilepsy are major topics. Antiepileptic drugs should be chosen individually for patients who are pregnant or may become pregnant with consideration of their teratogenicity and seizure control properties. Folate is commonly prescribed for women of childbearing age who are taking antiepileptic drugs. Spontaneous vaginal delivery and breastfeeding are not contra-indicated in most cases but need to be considered individually based on the patient's medical condition and wishes. Serum drug level monitoring of certain antiepileptic drugs during pregnancy and puerperium can guide dosage adjustment. For catamenial epilepsy, intermittent benzodiazepines such as clobazam during the susceptible phase of the menstrual cycle could be a treatment option.

Depth-dependent changes in cartilage T2 under compressive strain: a 7T MRI study on human knee cartilage.

OBJECTIVE: To assess the potential of using ΔT2 as an indirect index of cartilage strain by quantifying the relationship between local in situ compressive strain and ΔT2 through the full depth of human tibial and femoral articular cartilage. DESIGN: Osteochondral samples (n = 4) of human tibial and femoral cartilage were harvested from cadavers and imaged in a Bruker 7T research MRI scanner under increasing displacement-controlled compressive strains. T2 was calculated for 3D double echo steady state (DESS) image volumes at each strain level. A decaying exponential model estimated local, depth-dependent strains. Strained image volumes were non-linearly warped back to their unloaded configurations and ΔT2 was calculated by image subtraction. Linear modeling assessed local relationships between strain and ΔT2. RESULTS: Bulk average tibial T2 was 13.2 ms for unstrained cartilage and ranged from 13.0 to 13.1 ms under strain; femoral T2 was 14.0 ms for unstrained cartilage and ranged from 13.5 to 14.8 ms under strain. Local ΔT2 in strained cartilage varied with depth. Linear modeling revealed significant correlations between in situ strain and ΔT2 for both tibial and femoral cartilage; correlation coefficients were higher for tibial cartilage. CONCLUSIONS: Changes in bulk average T2 are unsuitable as a quantitative surrogate measure of cartilage strain because bulk averaging masks important local variations. High-resolution measures of local ΔT2 have potential value as a surrogate for strain; however, their value is limited until we fully understand the influence of factors like age, joint surface and degeneration on the strain vs T2 relationship.

Basic symptoms in young people at ultra-high risk of psychosis: Association with clinical characteristics and outcomes.

There has been limited research into the predictive value of basic symptoms and their relationship with other psychopathology in patients identified using the 'ultra high risk' (UHR) for psychosis approach. The current study investigated whether basic symptoms, specifically cognitive disturbances (COGDIS), were associated with a greater risk of transition to psychotic disorder and persistent attenuated psychotic symptoms (APS) at medium term follow-up (mean = 3.4 years) in UHR patients, as well as with general psychopathology at baseline. The sample included 304 UHR participants (mean age = 19.12 years) involved in an international multicenter trial of omega-3 fatty acids. UHR individuals who also met the COGDIS criteria (basic symptoms risk criteria) did not have a greater risk of transition than those who met the UHR criteria alone. However, meeting COGDIS risk criteria was associated with a greater likelihood of meeting the UHR attenuated psychotic symptoms risk group (i.e., having persistent attenuated psychotic symptoms) at 12-month follow-up (odds ratio = 1.85; 95% CI = 1.03, 3.32). Greater severity of cognitive basic symptoms was also independently associated with more severe general psychopathology at study entry. The findings do not support the notion that combined risk identification approaches (UHR and basic symptoms) aid in the identification of individuals at greatest risk of psychosis, although this interpretation is limited by the modest transition to psychosis rate (13%) and the time of follow up. However, the findings indicate that basic symptoms may be a clinically useful marker of more severe general psychopathology in UHR groups and risk for persistent attenuated psychotic symptoms.

The prognostic significance of attenuated psychotic symptoms in help-seeking youth.

BACKGROUND: Recent findings suggest that attenuated psychotic symptoms (APS) might serve as a risk factor for general mental health impairment in help-seeking youth. The current study was designed to test this possibility by examining the prognostic significance of APS in a large cohort of help-seeking youth not selected for psychosis risk. METHOD: 465 youth aged 12-25 referred to general youth mental health services were grouped as either APS + or APS- based on whether or not they met 'ultra high risk' for psychosis APS risk criteria as assessed using the Comprehensive Assessment of At Risk Mental States (CAARMS). They completed clinical assessments at baseline and at 12-month follow-up, measuring a range of psychopathology (depression, anxiety, eating disorders, general psychological distress, substance abuse) and psychosocial functioning. RESULTS: APS + had significantly poorer outcomes at 12-months on a range of clinical variables, even after adjusting for baseline scores and amount of treatment received. However, the APS + group showed greater improvement in functioning at follow-up compared to APS-. CONCLUSION: Attenuated psychotic symptoms are a prognostic indicator of persistent transdiagnostic mental health problems and reduced response to treatment in help-seeking youth over the short term. Hence, it is critical to screen and assess attenuated psychotic symptoms at the primary and secondary mental health services level, especially given that these subclinical symptoms are rarely voluntarily reported.

Dynamic prediction of transition to psychosis using joint modelling.

Considerable research has been conducted seeking risk factors and constructing prediction models for transition to psychosis in individuals at ultra-high risk (UHR). Nearly all such research has only employed baseline predictors, i.e. data collected at the baseline time point, even though longitudinal data on relevant measures such as psychopathology have often been collected at various time points. Dynamic prediction, which is the updating of prediction at a post-baseline assessment using baseline and longitudinal data accumulated up to that assessment, has not been utilized in the UHR context. This study explored the use of dynamic prediction and determined if it could enhance the prediction of frank psychosis onset in UHR individuals. An emerging statistical methodology called joint modelling was used to implement the dynamic prediction. Data from the NEURAPRO study (n = 304 UHR individuals), an intervention study with transition to psychosis study as the primary outcome, were used to investigate dynamic predictors. Compared with the conventional approach of using only baseline predictors, dynamic prediction using joint modelling showed significantly better sensitivity, specificity and likelihood ratios. As dynamic prediction can provide an up-to-date prediction for each individual at each new assessment post entry, it can be a useful tool to help clinicians adjust their prognostic judgements based on the unfolding clinical symptomatology of the patients. This study has shown that a dynamic approach to psychosis prediction using joint modelling has the potential to aid clinicians in making decisions about the provision of timely and personalized treatment to patients concerned.

Exploring the impact of adverse childhood experiences on symptomatic and functional outcomes in adulthood: advances, limitations and considerations.

Exposure to traumatic experiences in childhood is a risk (and potentially causal) factor for the development of a range of adverse physical and mental health conditions. In addition to the onset of clinical disorders, there is emerging evidence that childhood trauma may also be associated with other long-term outcomes, such as the persistence and severity of an individual's symptoms, as well as their long-term social and occupational functioning. However, the reasons for this remain poorly understood. A greater understanding both of the mediators that drive these associations, and those variables that enhance resilience against such damaging experiences may help to inform effective therapeutic interventions. In addition to biological and cognitive measures, there is a need to consider social and environmental factors, such as parental bonding and attachment, when investigating these complex relationships.

Enhancing social functioning in young people at Ultra High Risk (UHR) for psychosis: A pilot study of a novel strengths and mindfulness-based online social therapy.

BACKGROUND: Psychological and pharmacological treatments have been shown to reduce rates of transition to psychosis in Ultra High Risk (UHR) young people. However, social functioning deficits have been unresponsive to current treatments. AIMS: The study aims were to: i) describe the theoretical basis and therapeutic targets of a novel intervention targeting social functioning in UHR young people; and ii) examine its acceptability, safety and preliminary effect on social functioning. METHODS: An international, multidisciplinary team developed a new intervention (MOMENTUM) to improve social functioning in UHR young people. MOMENTUM blends two novel approaches to social recovery: strengths and mindfulness-based intervention embedded within a social media environment, and application of the self-determination theory of motivation. The acceptability and safety of MOMENTUM were tested through a 2-month pilot study with 14 UHR participants. RESULTS: System usage was high, with over 70% of users being actively engaged over the trial. All participants reported a positive experience using MOMENTUM, considered it safe and would recommend it to others. 93% reported it to be helpful. There were large, reliable improvements in social functioning (d = 1.83, p < 0.001) and subjective wellbeing (d = 0.75, p = 0.03) at follow-up. There were significant increases in the mechanisms targeted by the intervention including strengths usage (d = 0.70, p = 0.03), mindfulness skills (d = 0.66, p = 0.04) and components of social support. Social functioning improvement was significantly correlated with indicators of system usage. CONCLUSION: MOMENTUM is engaging and safe. MOMENTUM appeared to engage the hypothesized mechanisms and showed promise as a new avenue to improve social functioning in UHR young people.

NEURAPRO: a multi-centre RCT of omega-3 polyunsaturated fatty acids versus placebo in young people at ultra-high risk of psychotic disorders-medium-term follow-up and clinical course.

This study reports a medium-term follow-up of a randomised, double-blind, placebo-controlled trial of omega-3 polyunsaturated fatty acids (PUFA) in ultra-high risk for psychosis (UHR) patients. Primary outcomes of interest were transition to psychosis and symptomatic and functional outcome. A secondary aim was to investigate clinical predictors of medium-term outcome. Three hundred four UHR participants were recruited across 10 specialised early psychosis services in Australia, Asia, and Europe. The intervention consisted of 1.4 g/daily of omega-3 PUFA or placebo, plus up to 20 sessions of cognitive-behavioural case management (CBCM), over the 6-month study period, with participants receiving further CBCM sessions on basis of need between months 6-12. Mean time to follow-up was 3.4 (median = 3.3; SD = 0.9) years. There was a modest increase in transitions between 12-month and medium-term follow-up (11-13%) and substantial improvement in symptoms and functioning between baseline and follow-up, with no differences between the treatment groups. Most improvement had been achieved by end of the intervention. 55% of the sample received mental health treatment between end of intervention and follow-up. Omega-3 PUFA did not provide additional benefits to good quality psychosocial intervention over the medium term. Although most improvement had been achieved by end of intervention the substantial rates of post-intervention mental health service use indicate longer-term clinical need in UHR patients. The post-intervention phase treatment or the longer-term effect of CBCM, or a combination of the two, may have contributed to maintaining the gains achieved during the intervention phase and prevented significant deterioration after this time.

The Ultra-High-Risk for psychosis groups: Evidence to maintain the status quo.

Individuals are considered Ultra-High-Risk (UHR) for psychosis if they meet a set of standardised criteria including presumed genetic vulnerability (Trait), or a recent history of Attenuated Psychotic Symptoms (APS) or Brief Limited Intermittent Psychotic Symptoms (BLIPS). Recent calls to revise these criteria have arisen from evidence that Trait, APS and BLIPS groups may transition to psychosis at different rates. Concurrently, it has become clear that the UHR status confers clinical risk beyond transition to psychosis. Specifically, most UHR individuals will not develop psychosis, but will experience high rates of non-psychotic disorders, persistent APS and poor long-term functional outcomes. Rather than focus on transition, the present study investigated whether UHR groups differ in their broader clinical risk profile by examining baseline clinical characteristics and long-term outcomes other than transition to psychosis. Four UHR groups were defined: Trait-only, APS-only, Trait+APS, and any BLIPS. Participants (N=702) were recruited upon entry to early intervention services and followed-up over a period of up to 13years (mean=4.53, SD=3.84). The groups evidenced similar symptom severity (SANS for negative symptoms, BPRS for positive and depression/anxiety symptoms) and psychosocial functioning (SOFAS, GAF, QLS) at baseline and follow-up as well as similar prevalence of non-psychotic disorders at follow-up. Our findings demonstrate that UHR groups evidence a similar clinical risk profile when we expand this beyond transition to psychosis, and consequently support maintaining the existing UHR criteria.

Implementing an innovative intervention to increase research capacity for enhancing early psychosis care in Indonesia.

WHAT IS KNOWN ON THE TOPIC?: In low- and middle-income settings (LMICs) such as Indonesia, the burden from psychotic illness is significant due to large gaps in treatment provision Mental health workers and community nurses are a growing workforce requiring new evidence to support practice and enhanced roles and advanced competencies among UK mental health nurses also requires greater research capacity Research capacity building projects can strengthen research institutions, enhance trial capacity, improve quality standards and improve attitudes towards the importance of health research. WHAT THIS PAPER ADDS?: Delivering innovative, cross-cultural workshops to enhance research capacity to multidisciplinary, early career researchers in Indonesia and the UK are rated highly by attendees Supporting people in this way helps them to gain competitive grant funding to complete their own research which can improve the health of the population To our knowledge, there are no other studies reporting the attainment of grant income as a successful outcome of international research partnerships for mental health nursing so our finding is novel. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: This method could be implemented to improve networking and collaboration between UK academics and early career researchers in other lower- and middle-income settings This strategy can also strengthen existing partnerships among early career researchers in the UK to meet the demands for greater research mentorship and leadership among mental health nurses and enhance nurses capabilities to contribute to evidence for practice. ABSTRACT: Aim To strengthen research capacity for nurses and early career researchers in Indonesia and the UK to develop a local evidence base in Indonesia to inform policy and improve the nation's health. These strategies can strengthen research institutions, enhance trial capacity, improve quality standards and improve attitudes towards the importance of health research. Methods Four days of workshops were held in Jakarta, Indonesia developing collaborative groups of academic nurses and early career researchers from the UK and Indonesia (30 people including mentors) to produce competitive grant bids to evaluate aspects of early psychosis care. Qualitative and quantitative evaluations were conducted. Results Participants evaluated the workshops positively finding benefit in the structure, content and delivery. Research impact was shown by attaining several successful small and large grants and developing offshoot collaborative relationships. Discussion These novel findings demonstrate that collaborative workshops can strengthen research capacity by developing partnerships and instigating new collaborations and networks. No other studies of international research partnerships among mental health nurses have reported this outcome to our knowledge. Implications for Practice This method could be implemented to improve networking and collaboration between UK academics and early career researchers and also with external colleagues in other LMICs.

Outcome of Treatment of Osteoarthritis with Arthroscopic Debridement and Autologous Conditioned Plasma.

INTRODUCTION: Worldwide estimates are that 9.6% of men and 18.0% of women aged over 60 years have symptomatic osteoarthritis. The current treatment options vary from conservative to joint replacement. Recently, debridement of the joint has become an option for symptomatic relief. We evaluated the outcome of arthroscopic debridement with autologous conditioned plasma. The latter helps to promote cellular repair. We have evaluated our results over a two year period. MATERIALS AND METHODS: We retrospectively analyzed a cohort of 52 patients who underwent arthroscopic knee debridement with autologous conditioned plasma in 2011. The patients were followed up in clinic till discharge. The case notes were reviewed and baseline demographic data obtained. This included age, medical history, occupation, range of movement, BMI measurements, duration of operation and radiographic scores. We analyzed the outcomes against those factors. RESULTS: Of the 52 patients in our study, 16 were female and 36 were male. The mean follow-up period in the clinic was 6.5 months. The Kellgren-Lawrence score was 21.2% Grade 1, 13.5% Grade 2, 51.9% Grade 3 and 13.5% Grade 4. Improvement in range of movement was seen in 32.7% of patients. CONCLUSIONS: This study shows that arthroscopic debridement with autologous conditioned plasma (ACP) has a role to play in the treatment of osteoarthritis. In view of these findings, we recommend that surgeons should consider arthroscopic debridement with autologous conditioned plasma as part of their treatment armamentarium.

Cannabis use and symptom severity in individuals at ultra high risk for psychosis: a meta-analysis.

OBJECTIVE: We aimed to assess whether individuals at ultra high risk (UHR) for psychosis have higher rates of cannabis use and cannabis use disorders (CUDs) than non-UHR individuals and determine whether UHR cannabis users have more severe psychotic experiences than non-users. METHOD: We conducted a meta-analysis of studies reporting cannabis use in the UHR group and/or positive or negative symptoms among UHR cannabis users and non-users. Logit event rates were calculated for cannabis use, in addition to odds ratios to assess the difference between UHR and controls. Severity of clinical symptoms in UHR cannabis users and non-users was compared using Hedges' g. RESULTS: Thirty unique studies were included (UHR n = 4205, controls n = 667) containing data from cross-sectional and longitudinal studies, and randomised control trials. UHR individuals have high rates of current (26.7%) and lifetime (52.8%) cannabis use, and CUDs (12.8%). Lifetime use and CUDs were significantly higher than controls (lifetime OR: 2.09; CUD OR: 5.49). UHR cannabis users had higher rates of unusual thought content and suspiciousness than non-users. CONCLUSION: Ultra high risk individuals have high rates of cannabis use and CUDs, and cannabis users had more severe positive symptoms. Targeting substance use during the UHR phase may have significant benefits to an individual's long-term outcome.

The effects of vitamin and mineral supplementation on symptoms of schizophrenia: a systematic review and meta-analysis.

BACKGROUND: When used as an adjunctive with antipsychotics, certain vitamins and minerals may be effective for improving symptomatic outcomes of schizophrenia, by restoring nutritional deficits, reducing oxidative stress, or modulating neurological pathways. METHOD: We conducted a systematic review of all randomized controlled trials (RCTs) reporting effects of vitamin and/or mineral supplements on psychiatric symptoms in people with schizophrenia. Random-effects meta-analyses were used to calculate the standardized mean difference between nutrient and placebo treatments. RESULTS: An electronic database search in July 2016 identified 18 eligible RCTs, with outcome data for 832 patients. Pooled effects showed that vitamin B supplementation (including B6, B8 and B12) reduced psychiatric symptoms significantly more than control conditions [g = 0.508, 95% confidence interval (CI) 0.01-1.01, p = 0.047, I 2 = 72.3%]. Similar effects were observed among vitamin B RCTs which used intention-to-treat analyses (g = 0.734, 95% CI 0.00-1.49, p = 0.051). However, no effects of B vitamins were observed in individual domains of positive and negative symptoms (both p > 0.1). Meta-regression analyses showed that shorter illness duration was associated with greater vitamin B effectiveness (p = 0.001). There were no overall effects from antioxidant vitamins, inositol or dietary minerals on psychiatric symptoms. CONCLUSIONS: There is preliminary evidence that certain vitamin and mineral supplements may reduce psychiatric symptoms in some people with schizophrenia. Further research is needed to examine how the benefits of supplementation relate to nutrient deficits and the impact upon underlying neurobiological pathways, in order to establish optimal nutrient formulations for improving clinical outcomes in this population. Future studies should also explore the effects of combining beneficial nutrients within multi-nutrient formulas.