The impact of cumulative obstetric complications and childhood trauma on brain volume in young people with psychotic experiences.

Psychotic experiences (PEs) occur in 5-10% of the general population and are associated with exposure to childhood trauma and obstetric complications. However, the neurobiological mechanisms underlying these associations are unclear. Using the Avon Longitudinal Study of Parents and Children (ALSPAC), we studied 138 young people aged 20 with PEs (n = 49 suspected, n = 53 definite, n = 36 psychotic disorder) and 275 controls. Voxel-based morphometry assessed whether MRI measures of grey matter volume were associated with (i) PEs, (ii) cumulative childhood psychological trauma (weighted summary score of 6 trauma types), (iii) cumulative pre/peri-natal risk factors for psychosis (weighted summary score of 16 risk factors), and (iv) the interaction between PEs and cumulative trauma or pre/peri-natal risk. PEs were associated with smaller left posterior cingulate (pFWE < 0.001, Z = 4.19) and thalamus volumes (pFWE = 0.006, Z = 3.91). Cumulative pre/perinatal risk was associated with smaller left subgenual cingulate volume (pFWE < 0.001, Z = 4.54). A significant interaction between PEs and cumulative pre/perinatal risk found larger striatum (pFWE = 0.04, Z = 3.89) and smaller right insula volume extending into the supramarginal gyrus and superior temporal gyrus (pFWE = 0.002, Z = 4.79), specifically in those with definite PEs and psychotic disorder. Cumulative childhood trauma was associated with larger left dorsal striatum (pFWE = 0.002, Z = 3.65), right prefrontal cortex (pFWE < 0.001, Z = 4.63) and smaller left insula volume in all participants (pFWE = 0.03, Z = 3.60), and there was no interaction with PEs group. In summary, pre/peri-natal risk factors and childhood psychological trauma impact similar brain pathways, namely smaller insula and larger striatum volumes. The effect of pre/perinatal risk was greatest in those with more severe PEs, whereas effects of trauma were seen in all participants. In conclusion, environmental risk factors affect brain networks implicated in schizophrenia, which may increase an individual's propensity to develop later psychotic disorders.

Intraincisional Pin Placement is Safe for Robotic-Assisted Total Knee Arthroplasty.

BACKGROUND: While robotic-arm assisted total knee arthroplasty (RA-TKA) has seen a major increase in its utilization, it requires bone array pins to be fixed into the femur and tibia, which intrinsically carries a risk. As it is currently off-label with some robotic platforms to place pins intraincisional, we aimed to evaluate the safety of intraincisional pin placement during RA-TKAs. METHODS: A prospective cohort of 2,343 patients who underwent RA-TKA at a North American Healthcare System between January 2018 and March 2022 was included. Primary outcomes included periprosthetic fracture or infection (eg, superficial or deep). Secondary outcomes included 1-year reoperation rate due to any cause. Cases were retrospectively reviewed to determine whether complications could be attributed to metaphyseal intraincisional pin placement (4.0 mm pins; two tibial and two femoral). The 90-day follow-up was 100% and the 1-year follow-up rate was 70.6% (n = 1,655). RESULTS: The pin-site related periprosthetic fracture incidence at 90 days was 0.09% (2 out of 2,343). The 90-day infection incidence was 1.4% (superficial: 22; deep: 13). The 1-year reoperation rate was 1.8% (29 out of 1,655). The most common causes of reoperation at 1-year were deep infection (n = 14; 0.83%), superficial infection (n = 3; 0.18%), periprosthetic fracture, mechanical symptoms, instability, and hematoma (n = 2; 0.12% for each). CONCLUSIONS: One in 1,172 patients may experience a pin-related periprosthetic fracture after RA-TKA with intraincisional bone array pin placement. There was a low 90-day infection incidence and reoperations within 1-year after RA-TKA were rare.

Anhedonia, Apathy, Pleasure, and Effort-Based Decision-Making in Adult and Adolescent Cannabis Users and Controls.

BACKGROUND: Cannabis use may be linked with anhedonia and apathy. However, previous studies have shown mixed results, and few have examined the association between cannabis use and specific reward sub-processes. Adolescents may be more vulnerable than adults to harmful effects of cannabis. This study investigated (1) the association between non-acute cannabis use and apathy, anhedonia, pleasure, and effort-based decision-making for reward; and (2) whether these relationships were moderated by age group. METHODS: We used data from the "CannTeen" study. Participants were 274 adult (26-29 years) and adolescent (16-17 years) cannabis users (1-7 d/wk use in the past 3 months) and gender- and age-matched controls. Anhedonia was measured with the Snaith-Hamilton Pleasure Scale (n = 274), and apathy was measured with the Apathy Evaluation Scale (n = 215). Effort-based decision-making for reward was measured with the Physical Effort task (n = 139), and subjective wanting and liking of rewards was measured with the novel Real Reward Pleasure task (n = 137). RESULTS: Controls had higher levels of anhedonia than cannabis users (F1,258 = 5.35, P = .02, η p2 = .02). There were no other significant effects of user-group and no significant user-group*age-group interactions. Null findings were supported by post hoc Bayesian analyses. CONCLUSION: Our results suggest that cannabis use at a frequency of 3 to 4 d/wk is not associated with apathy, effort-based decision-making for reward, reward wanting, or reward liking in adults or adolescents. Cannabis users had lower anhedonia than controls, albeit at a small effect size. These findings are not consistent with the hypothesis that non-acute cannabis use is associated with amotivation.

Hallucinations as a risk marker for suicidal behaviour in individuals with a history of sexual assault: a general population study with instant replication.

BACKGROUND: Research has shown a strong relationship between hallucinations and suicidal behaviour in general population samples. Whether hallucinations also index suicidal behaviour risk in groups at elevated risk of suicidal behaviour, namely in individuals with a sexual assault history, remains to be seen. AIMS: We assessed whether hallucinations were markers of risk for suicidal behaviour among individuals with a sexual assault history. METHODS: Using the cross-sectional 2007 (N = 7403) and 2014 (N = 7546) Adult Psychiatric Morbidity Surveys, we assessed for an interaction between sexual assault and hallucinations in terms of the odds of suicide attempt, as well as directly comparing the prevalence of suicide attempt in individuals with a sexual assault history with v. without hallucinations. RESULTS: Individuals with a sexual assault history had increased odds of hallucinations and suicide attempt compared to individuals without a sexual assault history in both samples. There was a significant interaction between sexual assault and hallucinations in terms of the odds of suicide attempt. In total, 14-19% of individuals with a sexual assault history who did not report hallucinations had one or more suicide attempt. This increased to 33-52% of individuals with a sexual assault history who did report hallucinations (2007, aOR = 2.85, 1.71-4.75; 2014, aOR = 4.52, 2.78-7.35). CONCLUSIONS: Hallucinations are a risk marker for suicide attempt even among individuals with an elevated risk of suicidal behaviour, specifically individuals with a sexual assault history. This finding highlights the clinical significance of hallucinations with regard to suicidal behaviour risk, even among high-risk populations.

Hosting the Tobacco Industry Supply Chain and Political Interference.

INTRODUCTION: We found no comprehensive studies on the location of transnational tobacco and leaf company (TTLC) subsidiaries (business entities they control) or the consequences of their presence on health policy. AIMS AND METHODS: Here we assess (1) the global reach of TTLCs by mapping their tobacco growing and manufacturing subsidiaries and (2) the relationship between in-country presence of the tobacco industry and their power and interference. Data on subsidiaries were collated through systematic searching for countries' supply chain activities in documents and web pages. Cross-sectional multiple regression analysis was used to assess the association between the number of agricultural and manufacturing TTLCs and the Tobacco Industry Interference score, and the degree to which these were mediated by tobacco control, good governance, and economic importance of tobacco. RESULTS: TTLC supply chain activity had global reach. As the number of TTLCs with tobacco growing and manufacturing activities rose, interference increased significantly. Interference was associated with poorer tobacco control. The association with more TTLCs undertaking final product manufacturing was related to higher-value tobacco exports but was not related to tobacco making a bigger contribution to the economy. CONCLUSIONS: TTLCs continue to control the global tobacco supply chain through their globe-spanning subsidiaries. The presence of TTLCs in a country is associated with political interference. Countries should consider their participation in the tobacco supply chain alongside the understanding that they are likely to cede political power to TTLCs, potentially undermining the health of their populations. IMPLICATIONS: Tobacco control research has traditionally concentrated on the demand side of tobacco. Our results lend support to calls for more research on the supply of tobacco. Governments should require tobacco companies to provide detailed, up-to-date information in an easily accessible format on in-country supply chain activities. Policymakers should take the likelihood of political interference in health and environmental policy into account when making decisions about foreign direct investment offered by the tobacco industry.

Cooling vest improves surgeons' thermal comfort without affecting cognitive performance: a randomised cross-over trial.

OBJECTIVES: Surgeons become uncomfortable while performing surgery because heat transfer and evaporative cooling are restricted by insulating surgical gowns. Consequently, perceptions of thermal discomfort during surgery may impair cognitive performance. We, therefore, aimed to evaluate surgeons' thermal comfort, cognitive performance, core and mean skin temperatures, perceptions of sweat-soaked clothing, fatigue and exertion with and without a CoolSource cooling vest (Cardinal Health, Dublin, Ohio, USA). METHODS: Thirty orthopaedic surgeons participated in a randomised cross-over trial, each performing four total-joint arthroplasties with randomisation to one of four treatment sequences. The effects of cooling versus no cooling were measured using a repeated-measures linear model accounting for within-subject correlations. RESULTS: The cooling vest improved thermal comfort by a mean (95% CI) of -2.1 (-2.7 to -1.6) points on a 0-10 scale, p<0.001, with no evidence of treatment-by-period interaction (p=0.94). In contrast, cooling had no perceptible effect on cognition, with an estimated mean difference (95% CI) in Cleveland Clinic Cognitive Battery (C3B) Processing Speed Test score of 0.03 (95% CI -2.44 to 2.51), p=0.98, or in C3B Visual Memory Test score with difference of 0.88 (95% CI -2.25 to 4.01), p=0.57. Core temperature was not lower with the cooling vest, with mean difference (95% CI) of -0.13 (-0.33°C to 0.07°C), p=0.19, while mean skin temperature was lower, with mean difference of -0.23 (95% CI -0.40°C to -0.06°C) lower, p=0.011. The cooling vest significantly reduced surgeons' perceptions of sweat-soaked clothing, fatigue and exertion. CONCLUSIONS: A cooling vest worn during surgery lowered core and skin temperatures, improved thermal comfort, and decreased perceptions of sweating and fatigue, but did not improve cognition. Thermal discomfort during major orthopaedic surgery is thus largely preventable, but cooling does not affect cognition. TRIAL REGISTRATION NUMBER: NCT04511208.

Are Patients Being Appropriately Selected for Same-Day Discharge Total Knee Arthroplasty?

BACKGROUND: Decreased cost associated with same-day discharge (SDD) total knee arthroplasty (TKA) has led to an increased interest in this topic. The purpose of this study is to investigate whether there is a population of TKA patients in which SDD has similar rates of 30-day complications compared to patients discharged on postoperative day 1 or 2. METHODS: Using the American College of Surgeons National Surgical Quality Improvement Program database from 2012 to 2018, 6,327 TKA patients who had a SDD (length of stay [LOS] = 0) were matched to TKA patients who had an LOS of 1 or 2 days. All SDD patients were successfully matched 1:1 using the morbidity probability variable (a composite variable of demographics, comorbidities, and laboratory values). Patients were divided into quartiles based on their morbidity probability. Bivariate logistic regressions were then used to compare any complication and major complication rates in the SDD quartiles to the corresponding quartiles with an LOS of 1 or 2 days. RESULTS: When comparing the 1st quartiles (healthiest), there was no difference between the cohorts in any complication (odds ratio [OR] = 0.960, 95% CI 0.552-1.670, P = .866) and major complications (OR = 0.999, 95% CI = 0.448-2.231, P = .999). The same was observed in quartile 2 (any complications: OR = 1.161, 95% CI = 0.720-1.874, P = .540). Comparing the third quartiles, there was an increase in all complications with SDD (OR = 1.784, 95% CI = 1.125-2.829, P = .014), but no difference in major complications (OR = 1.635, 95% CI = 0.874-3.061, P = .124). Comparing the fourth quartiles (least healthy), there was an increase in all complications (OR = 1.384, 95% CI = 1.013-1.892, P = .042) and major complications (OR = 1.711, 95% CI = 1.048-2.793, P = .032) with SDD. CONCLUSION: The unhealthiest 50% of patients in this study who underwent SDD TKA were at an increased risk of having any complication, calling into question the current state of patient selection for SDD TKA. LEVEL OF EVIDENCE: III.

Blood management in total hip arthroplasty: a nationwide trend analysis from 2011 to 2018.

PURPOSE: With the advent of practice changes surrounding preoperative patient optimization and postoperative protocols, a marked reduction has been reported in blood transfusion rates following total hip arthroplasty (THA). Thus, the purpose of this study was to examine differences in the prevalence of preoperative anemia, thrombocytopenia, elevated international normalized ratio (INR), bleeding disorders, and pre- and postoperative blood transfusions over the last decade. METHODS: From 2011 to 2018, the American College of Surgeons National Quality Improvement Program database was queried for all primary THA procedures (n = 208,796). The following continuous variables were examined using analysis of variance: preoperative hematocrit (HCT), platelet count, and INR. The following categorical variables were analyzed by chi-squared tests: anemia (HCT < 35.5% for females and < 38.5% for males), thrombocytopenia (platelet count < 150,000/µL), INR > 2.0, bleeding disorders, preoperative transfusions, and postoperative transfusions. RESULTS: There were decreases in preoperative anemia (2011: 16.2%; 2018: 11.4%, p < 0.001) and postoperative transfusions (2011: high = 22.2%; 2018: low = 1.3%, p < 0.001). Statistically significant but clinically irrelevant changes were observed in preoperative HCT (2011: low = 40.3, 2018: high = 41.1, p < 0.001), platelet count (2011: low = 248,700; 2018: high = 250,100, p < 0.001), thrombocytopenia (2011: high = 4.9%; 2018: low = 4.3%, p = 0.036), INR > 2.0 (2011: high = 1.1%; 2018: low = 0.7%, p = 0.001), bleeding disorders (2011: high = 2.9%; 2018: low = 2.0%, p < 0.001), and preoperative transfusions (2011: high = 0.2%; 2018: low = 0.1%, p = 0.007). CONCLUSION: Large decreases in the number of patients with preoperative anemia and those receiving postoperative blood transfusion were observed during the study period. Future investigation is needed to ascertain whether this is due to patient optimization, practice changes, "cherry-picking" of healthy patients, or a combination of these factors. LEVEL OF EVIDENCE: III.

The effects of Δ9-tetrahydrocannabinol on the dopamine system.

The effects of Δ9-tetrahydrocannabinol (THC), the main psychoactive ingredient in cannabis, are a pressing concern for global mental health. Patterns of cannabis use are changing drastically owing to legalization, the availability of synthetic analogues (commonly termed spice), cannavaping and an emphasis on the purported therapeutic effects of cannabis. Many of the reinforcing effects of THC are mediated by the dopamine system. Owing to the complexity of the cannabinoid-dopamine interactions that take place, there is conflicting evidence from human and animal studies concerning the effects of THC on the dopamine system. Acute THC administration causes increased dopamine release and neuron activity, whereas long-term use is associated with blunting of the dopamine system. Future research must examine the long-term and developmental dopaminergic effects of THC.

The Lebanese Regie state-owned tobacco monopoly: lessons to inform monopoly-focused endgame strategies.

BACKGROUND: Many countries have started pursuing tobacco 'endgame' goals of creating a 'tobacco-free' country by a certain date. Researchers have presented models to attain this goal, including shifting the supply of tobacco to a monopoly-oriented endgame model (MOEM), wherein a state-owned entity controls the supply and distribution of tobacco products. Although not designed to end tobacco use, the Regie in Lebanon exhibits some of the key features identified in MOEM and hence can serve as a practical example from which to draw lessons. METHODS: We comprehensively review previous literature exploring tobacco endgame proposals featuring a MOEM. We distil these propositions into core themes shared between them to guide a deductive analysis of the operations and actions of the Regie to investigate how it aligns (or does not) with the features of the MOEM. RESULTS: Analysing the endgame proposals featuring MOEM, we generated two main themes: the governance of the organisation; and its operational remit. In line with these themes, the investigation of the Regie led to several reflections on the endgame literature itself, including that it: (i) does not seem to fully appreciate the extent to which the MOEM could end up acting like Transnational Tobacco Companies (TTC); (ii) has only vaguely addressed the implications of political context; and (iii) does not address tobacco growing despite it being an important element of the supply chain. CONCLUSION: The implementation of tobacco endgame strategies of any type is now closer than ever. Using the Regie as a practical example allows us to effectively revisit both the potential and the pitfalls of endgame strategies aiming to introduce some form of monopoly and requires a focus on: (i) establishing appropriate governance structures for the organisation; and (ii) adjusting the financial incentives to supress any motivation for the organisation to expand its tobacco market.

Effectiveness of psychosocial interventions in mitigating adverse mental health outcomes among disaster-exposed health care workers: A systematic review.

Health care workers worldwide are at an increased risk of a range of adverse mental health outcomes, including posttraumatic stress disorder (PTSD), following the unprecedented demand placed upon them during the COVID-19 pandemic. Psychosocial interventions offered to mitigate these risks should be based on the best available evidence; however, limited information regarding the comparative effectiveness of interventions is available. We undertook a systematic review of psychosocial interventions delivered to health care workers before, during, and after disasters. Eight databases were searched, including the Cochrane Central Register of Controlled Trials, PubMed/MEDLINE, EMBASE, and PsycINFO. Our primary outcomes were changes in symptoms of PTSD, anxiety, depression, and sleep. We calculated effect sizes, where unreported, and reliable change indices to appraise intervention effectiveness. The study was registered with PROSPERO (CRD42020182774). In total, 12,198 papers were screened, 14 of which were included in the present review. Interventions based on evidence-based protocols, including individual and group-based cognitive behavioral therapy (CBT) for PTSD, anxiety, and depression were found to lead to reliable changes in PTSD and anxiety symptoms. Single-session debriefing and psychological first aid workshops showed limited efficacy. There is limited evidence on psychosocial interventions for health care workers faced with disasters, with the strongest evidence base for CBT-based approaches. Future research should include controlled evaluations of interventions and aim to target identified risk factors.

Acute effects of cannabis on speech illusions and psychotic-like symptoms: two studies testing the moderating effects of cannabidiol and adolescence.

BACKGROUND: Acute cannabis administration can produce transient psychotic-like effects in healthy individuals. However, the mechanisms through which this occurs and which factors predict vulnerability remain unclear. We investigate whether cannabis inhalation leads to psychotic-like symptoms and speech illusion; and whether cannabidiol (CBD) blunts such effects (study 1) and adolescence heightens such effects (study 2). METHODS: Two double-blind placebo-controlled studies, assessing speech illusion in a white noise task, and psychotic-like symptoms on the Psychotomimetic States Inventory (PSI). Study 1 compared effects of Cann-CBD (cannabis containing Δ-9-tetrahydrocannabinol (THC) and negligible levels of CBD) with Cann+CBD (cannabis containing THC and CBD) in 17 adults. Study 2 compared effects of Cann-CBD in 20 adolescents and 20 adults. All participants were healthy individuals who currently used cannabis. RESULTS: In study 1, relative to placebo, both Cann-CBD and Cann+CBD increased PSI scores but not speech illusion. No differences between Cann-CBD and Cann+CBD emerged. In study 2, relative to placebo, Cann-CBD increased PSI scores and incidence of speech illusion, with the odds of experiencing speech illusion 3.1 (95% CIs 1.3-7.2) times higher after Cann-CBD. No age group differences were found for speech illusion, but adults showed heightened effects on the PSI. CONCLUSIONS: Inhalation of cannabis reliably increases psychotic-like symptoms in healthy cannabis users and may increase the incidence of speech illusion. CBD did not influence psychotic-like effects of cannabis. Adolescents may be less vulnerable to acute psychotic-like effects of cannabis than adults.

Experiences of frontline healthcare workers and their views about support during COVID-19 and previous pandemics: a systematic review and qualitative meta-synthesis.

BACKGROUND: Healthcare workers across the world have risen to the demands of treating COVID-19 patients, potentially at significant cost to their own health and wellbeing. There has been increasing recognition of the potential mental health impact of COVID-19 on frontline workers and calls to provide psychosocial support for them. However, little attention has so far been paid to understanding the impact of working on a pandemic from healthcare workers' own perspectives or what their views are about support. METHODS: We searched key healthcare databases (Medline, PsychINFO and PubMed) from inception to September 28, 2020. We also reviewed relevant grey literature, screened pre-print servers and hand searched reference lists of key texts for all published accounts of healthcare workers' experiences of working on the frontline and views about support during COVID-19 and previous pandemics/epidemics. We conducted a meta-synthesis of all qualitative results to synthesise findings and develop an overarching set of themes and sub-themes which captured the experiences and views of frontline healthcare workers across the studies. RESULTS: This review identified 46 qualitative studies which explored healthcare workers' experiences and views from pandemics or epidemics including and prior to COVID-19. Meta-synthesis derived eight key themes which largely transcended temporal and geographical boundaries. Participants across all the studies were deeply concerned about their own and/or others' physical safety. This was greatest in the early phases of pandemics and exacerbated by inadequate Personal Protective Equipment (PPE), insufficient resources, and inconsistent information. Workers struggled with high workloads and long shifts and desired adequate rest and recovery. Many experienced stigma. Healthcare workers' relationships with families, colleagues, organisations, media and the wider public were complicated and could be experienced concomitantly as sources of support but also sources of stress. CONCLUSIONS: The experiences of healthcare workers during the COVID-19 pandemic are not unprecedented; the themes that arose from previous pandemics and epidemics were remarkably resonant with what we are hearing about the impact of COVID-19 globally today. We have an opportunity to learn from the lessons of previous crises, mitigate the negative mental health impact of COVID-19 and support the longer-term wellbeing of the healthcare workforce worldwide.

The Potential Effects of Imposing a Body Mass Index Threshold on Patient-Reported Outcomes After Total Knee Arthroplasty.

BACKGROUND: Operative eligibility thresholds based on body mass index (BMI) alone may risk restricting access to improved pain control, function, and quality of life. This study evaluated the use of BMI-cutoffs to offering TKA in avoiding: 1) 90-day readmission, 2) one-year mortality, and 3) failure to achieve clinically important one-year PROMS improvement (MCID). METHODS: A total of 4126 primary elective unilateral TKA patients from 2015 to 2018 were prospectively collected. For specific BMI(kg/m2) cutoffs: 30, 35, 40, 45, and 50, the positive predictive value (PPV) for 90-day readmission, one-year mortality, and failure to achieve one-year MCID were calculated. The number of patients denied complication-free postoperative courses per averted adverse outcome/failed improvement was estimated. RESULTS: Rates of 90-day readmission and one-year mortality were similar across BMI categories (P > .05, each). PPVs for preventing 90-day readmission and one-year mortality were low across all models of BMI cutoffs. The highest PPV for 90-day readmission and one-year mortality was detected at cutoffs of 45 (6.4%) and 40 (0.87%), respectively. BMI cutoff of 40 would deny 18 patients 90-day readmission-free, and 194 patients one-year mortality-free postoperative courses for each averted 90-day readmission/one-year mortality. Such cutoff would also deny 11 patients an MCID per avoided failure. Implementing BMI thresholds alone did not influence the rate of improvements in KOOS-PS, KRQOL, or VR-12. CONCLUSION: Utilizing BMI cutoffs as the sole determinants of TKA ineligibility may deny patients complication-free postoperative courses and clinically important improvements. Shared decision-making supported by predictive tools may aid in balancing the potential benefit TKA offers to obese patients with the potentially increased complication risk and cost of care provision.

Perioperative Management of Chronic Antithrombotic Agents in Elective Hip and Knee Arthroplasty.

Total hip and knee arthroplasty are common major orthopedic operations being performed on an increasing number of patients. Many patients undergoing total joint arthroplasty (TJA) are on chronic antithrombotic agents due to other medical conditions, such as atrial fibrillation or acute coronary syndrome. Given the risk of bleeding associated with TJAs, as well as the risk of thromboembolic events in the post-operative period, the management of chronic antithrombotic agents perioperatively is critical to achieving successful outcomes in arthroplasty. In this review, we provide a concise overview of society guidelines regarding the perioperative management of chronic antithrombotic agents in the setting of elective TJAs and summarize the recent literature that may inform future guidelines. Ultimately, antithrombotic regimen management should be patient-specific, in consultation with cardiology, internal medicine, hematology, and other physicians who play an essential role in perioperative care.

The effect of the DISC1 Ser704Cys polymorphism on striatal dopamine synthesis capacity: an [18F]-DOPA PET study.

Whilst the role of the Disrupted-in-Schizophrenia 1 (DISC1) gene in the aetiology of major mental illnesses is debated, the characterization of its function lends it credibility as a candidate. A key aspect of this functional characterization is the determination of the role of common non-synonymous polymorphisms on normal variation within these functions. The common allele (A) of the DISC1 single-nucleotide polymorphism (SNP) rs821616 encodes a serine (ser) at the Ser704Cys polymorphism, and has been shown to increase the phosphorylation of extracellular signal-regulated protein Kinases 1 and 2 (ERK1/2) that stimulate the phosphorylation of tyrosine hydroxylase, the rate-limiting enzyme for dopamine biosynthesis. We therefore set out to test the hypothesis that human ser (A) homozygotes would show elevated dopamine synthesis capacity compared with cysteine (cys) homozygotes and heterozygotes (TT and AT) for rs821616. [18F]-DOPA positron emission tomography (PET) was used to index striatal dopamine synthesis capacity as the influx rate constant Kicer in healthy volunteers DISC1 rs821616 ser homozygotes (N = 46) and healthy volunteers DISC1 rs821616 cys homozygotes and heterozygotes (N = 56), matched for age, gender, ethnicity and using three scanners. We found DISC1 rs821616 ser homozygotes exhibited a significantly higher striatal Kicer compared with cys homozygotes and heterozygotes (P = 0.012) explaining 6.4% of the variance (partial η2 = 0.064). Our finding is consistent with its previous association with heightened activation of ERK1/2, which stimulates tyrosine hydroxylase activity for dopamine synthesis. This could be a potential mechanism mediating risk for psychosis, lending further credibility to the fact that DISC1 is of functional interest in the aetiology of major mental illness.

Acute effects of cannabinoids on addiction endophenotypes are moderated by genes encoding the CB1 receptor and FAAH enzyme.

Understanding genetic factors that contribute to cannabis use disorder (CUD) is important, but to date, findings have been equivocal. Single-nucleotide polymorphisms (SNPs) in the cannabinoid receptor 1 gene (CNR1; rs1049353 and rs806378) and fatty acid amide hydrolase (FAAH) gene (rs324420) have been implicated in CUD. Their relationship to addiction endophenotypes such as cannabis-related state satiety, the salience of appetitive cues, and craving after acute cannabinoid administration has not been investigated. Forty-eight cannabis users participated in a double-blind, placebo-controlled, four-way crossover experiment where they were administered treatments in a randomized order via vaporization: placebo, Δ9 -tetrahydrocannabinol (THC) (8 mg), THC + cannabidiol (THC + CBD) (8 + 16 mg), and CBD (16 mg). Cannabis-related state satiety, appetitive cue salience (cannabis and food), and cannabis craving were assessed each day. Participants were genotyped for rs1049353, rs806378, and rs324420. Results indicated that CNR1 rs1049353 GG carriers showed increased state satiety after THC/THC + CBD administration in comparison with placebo and reduced the salience of appetitive cues after THC in comparison with CBD administration; A carriers did not vary on either of these measures indicative of a vulnerability to CUD. CNR1 rs806378 CC carriers showed greater salience to appetitive cues in comparison with T carriers, but there was no evidence for changes in state satiety. FAAH rs324420 A carriers showed greater bias to appetitive cues after THC, in comparison with CC carriers. FAAH CC carriers showed reduced bias after THC in comparison with CBD. No SNPs modulated craving. These findings identify candidate neurocognitive mechanisms through which endocannabinoid system genetics may influence vulnerability to CUD.

Residues in Transmembrane Segments of the P2X4 Receptor Contribute to Channel Function and Ethanol Sensitivity.

Mouse models of alcohol use disorder (AUD) revealed purinergic P2X4 receptors (P2X4Rs) as a promising target for AUD drug development. We have previously demonstrated that residues at the transmembrane (TM)-ectodomain interface and within the TM1 segment contribute to the formation of an ethanol action pocket in P2X4Rs. In the present study, we tested the hypothesis that there are more residues in TM1 and TM2 segments that are important for the ethanol sensitivity of P2X4Rs. Using site-directed mutagenesis and two electrode voltage-clamp electrophysiology in Xenopus oocytes, we found that arginine at position 33 (R33) in the TM1 segment plays a role in the ethanol sensitivity of P2X4Rs. Molecular models in both closed and open states provided evidence for interactions between R33 and aspartic acid at position 354 (D354) of the neighboring TM2 segment. The loss of ethanol sensitivity in mixtures of wild-type (WT) and reciprocal single mutants, R33D:WT and D354R:WT, versus the WT-like response in R33D-D354R:WT double mutant provided further support for this interaction. Additional findings indicated that valine at TM1 position 49 plays a role in P2X4R function by providing flexibility/stability during channel opening. Collectively, these findings identified new activity sites and suggest the importance of TM1-TM2 interaction for the function and ethanol sensitivity of P2X4Rs.

Artificial Intelligence and Arthroplasty at a Single Institution: Real-World Applications of Machine Learning to Big Data, Value-Based Care, Mobile Health, and Remote Patient Monitoring.

BACKGROUND: Driven by the recent ubiquity of big data and computing power, we established the Machine Learning Arthroplasty Laboratory (MLAL) to examine and apply artificial intelligence (AI) to musculoskeletal medicine. METHODS: In this review, we discuss the 2 core objectives of the MLAL as they relate to the practice and progress of orthopedic surgery: (1) patient-specific, value-based care and (2) human movement. RESULTS: We developed and validated several machine learning-based models for primary lower extremity arthroplasty that preoperatively predict patient-specific, risk-adjusted value metrics, including cost, length of stay, and discharge disposition, to provide improved expectation management, preoperative planning, and potential financial arbitration. Additionally, we leveraged passive, ubiquitous mobile technologies to build a small data registry of human movement surrounding TKA that permits remote patient monitoring to evaluate therapy compliance, outcomes, opioid intake, mobility, and joint range of motion. CONCLUSION: The rapid rate with which we in arthroplasty are acquiring and storing continuous data, whether passively or actively, demands an advanced processing approach: AI. By carefully studying AI techniques with the MLAL, we have applied this evolving technique as a first step that may directly improve patient outcomes and practice of orthopedics.