Benefits of Aerosolized, Point-of-care, Autologous Skin Cell Suspension (ASCS) for the Closure of full Thickness Wounds from Thermal and Non-Thermal Causes: Learning Curves from the first 50 Consecutive cases at an Urban, Level 1 Trauma Center.

OBJECTIVE: To determine the utility of Autologous Skin Cell Suspension (ASCS) in closing full-thickness (FT) defects from injury and infection. SUMMARY BACKGROUND DATA: Although ASCS has documented success in closing partial-thickness burns, far less is known about the efficacy of ASCS in FT defects. METHODS: Fifty consecutive patients with FT defects (burn 17, necrotizing infection 13, crush 7, degloving 5, other 8) underwent closure with the bilayer technique of 3:1 widely-meshed, thin, split-thickness skin graft and 80:1 expanded ASCS. End points were limb salvage rate, donor site reduction, operative and hospital throughput, incidence of complications, and re-epithelialization by 4, 8, and 12 weeks. RESULTS: Definitive wound closure was achieved in 76%, 94%, and 98% of patients, at 4, 8, and 12 weeks, respectively. Limb salvage occurred in 42/43 patients (10 upper, 33 lower extremities). Mean area grafted was 435 cm2; donor site size was 212 cm2, representing a potential reduction of 50%. Mean surgical time was 71 minutes; total OR time was 124 minutes. Mean length-of-stay was 26.4 days; time from grafting to discharge was 11.2 days. 4/50 patients (8%) required 6 reoperations for bleeding (1), breakdown (4), and amputation (1). 4/50 patients (8%) developed hypertrophic scarring, which responded to silicone sheeting (2) and laser resurfacing (2). Mean follow-up was 92.7 days. CONCLUSION: When used for closure of FT wounds, point-of-care ASCS is effective and safe. Benefits include rapid re-epithelialization, high rate of limb salvage, reduction of donor site size and morbidity, and low incidence of hypertrophic scarring.

Incisional Release and Fat Grafting for the Surgical Management of Perioral Fibrosis in Scleroderma: A Technical Report and Institutional Review.

INTRODUCTION: Scleroderma (systemic sclerosis [SSc]) is a rare autoimmune, connective tissue disorder. Perioral fibrosis is a local cutaneous complication, negatively impacting functional capabilities and aesthetic satisfaction. Fat grafting has been postulated to aid in the management of SSc fibrosis thanks to stem cell enrichment. This technique's success has been demonstrated using different graft origin sites and different injection targets. We aim to demonstrate our SSc patients' success using abdominal fat and perioral target. METHODS: We queried our records for patients with preexisting SSc who underwent incisional release and fat grafting for perioral fibrosis from 2018 to 2021. For perioral release, a semisharp cannula was tunneled under the vermilion border into the vermilion and along the skin. For grafting, cannulas were used to infiltrate the fat with a retrograde filling technique in a radial-fanning manner. Their autoimmune diagnosis, anesthetic risk assessment, systemic disease complications, and degree of presenting symptoms were reviewed along with their postoperative outcomes. RESULTS: From 2018 to 2021, 16 patients diagnosed with SSc were treated with incisional release and fat grafting for the management of perioral fibrosis. Of the SSc patients, 8 presented with limited SSc, and 8 presented with diffuse SSc. The mean patient age was 54.31 years. All SSc patients presented with functional symptoms with the most common concern (n = 9) being "decreased mouth opening." Other common complaints were "difficulty eating" (n = 3) or "difficulty drinking" (n = 2). Some patients (n = 11) also presented with cosmetic concerns with "perioral rhytids" being the most common (n = 6). The mean number of systemic complications, at the time of presentation, was 3.06. The mean anesthetic risk assessment was 2.44. The average amount of fat grafted intraoperatively was 14.89 mL. Two patients with SSc required regrafting. For one patient, this was part of the original treatment plan and for the other due to fat resorption. Patients who followed up reported improved functionality and were pleased aesthetically. CONCLUSIONS: Patients with perioral fibrosis due to SSc can benefit from autologous fat grafting. Incisional release in combination with fat grafting can enhance procedure outcomes. This technique provides beneficial functional and aesthetic outcomes. Patients with both diffuse and limited disease are appropriate candidates for this procedure.

3D Mesh Releasing Method: A Retrospective Analysis of Fractional CO2 Treatment on Contracture Scars.

BACKGROUND AND OBJECTIVES: There has been reports on fractional CO2 laser successfully improving contracture scars that impair the function of a joint. It seems that certain contracture problems could be solved by laser instead of surgery. However, the clinical application could be difficult when the efficacy of the method remains unknown. The purpose of this study is to report the releasing capacity of the fractional CO2 laser on contracture scars based on a defined treatment method. STUDY DESIGN/MATERIALS AND METHODS: We conducted a retrospective study in patients with limited function in joints caused by contracture scars. Fractional CO2 laser and our "3D mesh releasing" protocol were applied. The primary outcome was the improvement measured in range of motion (ROM) of the relevant joint before all intervention and 6 months after the last treatment. RESULT: From November 2016 to January 2018, 11 joints of 10 cases were treated by the fractional CO2 laser. Patients went through 2.27 (standard deviation [SD] 1.42, 1-5) sessions. The average progress of ROM before and 6 months after all treatments was 19.13° (SD 10.25, P < 0.02). In six cases, we recorded that there was an 8.53° (SD 5.81, P < 0.02) of increase in ROM immediately after the laser session, and the average improvement reached up to 13.58° (SD 8.15, P < 0.02) after 2-3 months during the next follow-up. CONCLUSION: The fractional CO2 laser could achieve functional improvement in contracture scars and it maintained its effect for at least 6 months. The "3D Mesh Releasing" protocol would help to standardize the treatment procedure. This modality has minimal-invasiveness and potentially could become a supplement to the current treatment choices for mild contracture scars. Lasers Surg. Med. © 2020 Wiley Periodicals LLC.

Inappropriate Transfer of Burn Patients: A 5-Year Retrospective at a Single Center.

OBJECTIVE: Burn injuries have an annual incidence exceeding 40,000. The Burn Center Referral Criteria published by the American Burn Association (ABA) serve to guide health centers in determining appropriateness of patient transfer to a specialized center. With inappropriate transfer rates reaching up to 77%, reliance on the ABA criteria is critical as the decision to transfer a patient can impose significant costs to both the patient and healthcare system. The aim of this study is to evaluate the appropriateness of all burn patient transfers to a single burn center over a 5-year period and assess the potential role of telemedicine to optimize the assessment and care of this patient population. METHODS: A 5-year retrospective review was conducted to all burn patients transferred or consulted for transfer to our burn center between January 2013 and January 2017. After application of inclusion and exclusion criteria, 767 cases were analyzed, with 612 ultimately being transferred. Outcome measures included basic clinical and demographic information, as well as logistical burn and transfer data such as percent total body surface area and transfer distance. After data collection, 5-year descriptive trends were analyzed, and the ABA criteria were applied to each patient case to evaluate appropriateness of transfer. Patients transferred despite not meeting at least one of the ABA criteria were classified as inappropriately transferred. RESULTS: A total of 25 patients (3.2%) were found to be inappropriate transfers. Statistical analysis compared appropriately transferred patients (n = 587) with those inappropriately transferred. Overall, inappropriately transferred patients were more likely to have superficial partial thickness burns (76% vs 46%, P = 0.05), were less likely to need surgery (4% vs 22%, P < 0.05), and had a higher incidence of upper extremity burns (32% vs 4%, P < 0.01). CONCLUSIONS: Our study increases awareness of the most commonly seen presentation of inappropriately transferred burn patients over a 5-year period at our center. Given the advent of telemedicine, the ability of institutions to pinpoint a subset of patients most vulnerable to inappropriate transfer will allow for a streamlining of resources that will serve to benefit both patients and the health system.

Chronic Neuropathic Pain Following Hand Burns: Etiology, Treatment, and Long-Term Outcomes.

PURPOSE: Chronic neuropathic pain (CNP) after burn injury to the hand/upper extremity is relatively common, but not well described in the literature. This study characterizes patients with CNP after hand/upper extremity burns to help guide risk stratification and treatment strategies. We hypothesize that multiple risk factors contribute to the development of CNP and refractory responses to treatment. METHODS: Patients older than 15 years admitted to the burn center after hand/upper extremity burns, from January 1, 2014, through January 1, 2019, were included. Chronic neuropathic pain was defined as self-described pain for longer than 6 months after burn injury, not including pain due to preexisting illness/medications. Two analyses were undertaken: (1) determining risk factors for developing CNP among patients with hand/upper extremity burns, and (2) determining risk factors for developing refractory pain (ie, nonresponsive to treatment) among hand/upper extremity burn patients with CNP. RESULTS: Of the 914 patients who met the inclusion criteria, 55 (6%) developed CNP after hand/upper extremity burns. Twenty-nine of these patients (53%) had refractory CNP. Significant risk factors for developing CNP after hand/upper extremity burns included history of substance abuse and tobacco use. Among CNP patients, significant risk factors for developing refractory pain included symptoms of burning sensations. In all CNP patients, gabapentin and ascorbic acid were associated with significant decreases in pain scores on follow-up. CONCLUSIONS: Substance abuse and tobacco use may contribute to the development of CNP after hand/upper extremity burns. Those who developed refractory CNP were more likely to use the pain descriptor, burning sensations. Pharmacological pain management with gabapentin or pregabalin and ascorbic acid may provide the most relief of CNP symptoms. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

Diagnostic tests and treatment procedures performed prior to cardiovascular death in individuals with severe mental illness.

OBJECTIVE: To examine whether severe mental illnesses (i.e., schizophrenia or bipolar disorder) affected diagnostic testing and treatment for cardiovascular diseases in primary and specialized health care. METHODS: We performed a nationwide study of 72 385 individuals who died from cardiovascular disease, of whom 1487 had been diagnosed with severe mental illnesses. Log-binomial regression analysis was applied to study the impact of severe mental illnesses on the uptake of diagnostic tests (e.g., 24-h blood pressure, glucose/HbA1c measurements, electrocardiography, echocardiography, coronary angiography, and ultrasound of peripheral vessels) and invasive cardiovascular treatments (i.e., revascularization, arrhythmia treatment, and vascular surgery). RESULTS: Patients with and without severe mental illnesses had similar prevalences of cardiovascular diagnostic tests performed in primary care, but patients with schizophrenia had lower prevalences of specialized cardiovascular examinations (prevalence ratio (PR) 0.78; 95% CI 0.73-0.85). Subjects with severe mental illnesses had lower prevalences of invasive cardiovascular treatments (schizophrenia, PR 0.58; 95% CI 0.49-0.70, bipolar disorder, PR 0.78; 95% CI 0.66-0.92). The prevalence of invasive cardiovascular treatments was similar in patients with and without severe mental illnesses when cardiovascular disease was diagnosed before death. CONCLUSION: Better access to specialized cardiovascular examinations is important to ensure equal cardiovascular treatments among individuals with severe mental illnesses.

Comparison of arterial and venous implantable Doppler postoperative monitoring of free flaps: Systematic review and meta-analysis of diagnostic test accuracy.

BACKGROUND: Early detection of vascular compromise following free flap microsurgical reconstruction is essential. This can lead to timely reoperations and flap salvage. Both arteries and veins are monitored postoperatively with implantable ultrasound Dopplers based on surgeon preference with no consensus as to which method is best. This systematic review and meta-analysis compared arterial to venous implantable Dopplers for postoperative monitoring of microsurgical free flap reconstruction. METHODS: Five databases (MEDLINE via PubMed, EMBASE, Cochrane Library, Web of Science, and Scopus) were systematically and independently searched. PRISMA and Cochrane guidelines were strictly followed. Clinical characteristics, donor and recipient sites, specific arterial or venous vessels, diagnostic data, outcomes, and complications were recorded. RESULTS: The seven studies included in the meta-analysis were published from 1994 to 2018, with results from 38 of the possible 64 outcomes and complications queried. A total of 763 flaps with implantable Doppler probes on 527 arteries and 388 veins were included in the study. Compared to patients monitored with venous implantable Dopplers, arterial monitoring was associated with a risk of false-positives reduced by 74% (RR:0.26, 95% CI:0.12, 0.55, I2 = 40%, p = .0004) and risk of signal loss reduced by 63% (RR:0.37, 95% CI:0.24, 0.59, I2 = 26%, p < .0001). Patients being monitored with a venous implantable Doppler did not show significantly different sensitivities, specificities, true-positives, false-negatives, true-negatives, positive predictive values, negative predictive values, time to signal loss, take-backs, salvage rates, flap failures, flap failure rates, arterial, venous, vascular, and hematoma compromise compared to an arterial implantable Doppler. CONCLUSION: These findings suggest arteries may be the best vessels to monitor when using an implantable Doppler following free flap microsurgical reconstruction. Caution is advised when interpreting these findings for clinical significance due to no significant differences in take-backs, SR, flap failures, and FFR.

The protocadherin 17 gene affects cognition, personality, amygdala structure and function, synapse development and risk of major mood disorders.

Major mood disorders, which primarily include bipolar disorder and major depressive disorder, are the leading cause of disability worldwide and pose a major challenge in identifying robust risk genes. Here, we present data from independent large-scale clinical data sets (including 29 557 cases and 32 056 controls) revealing brain expressed protocadherin 17 (PCDH17) as a susceptibility gene for major mood disorders. Single-nucleotide polymorphisms (SNPs) spanning the PCDH17 region are significantly associated with major mood disorders; subjects carrying the risk allele showed impaired cognitive abilities, increased vulnerable personality features, decreased amygdala volume and altered amygdala function as compared with non-carriers. The risk allele predicted higher transcriptional levels of PCDH17 mRNA in postmortem brain samples, which is consistent with increased gene expression in patients with bipolar disorder compared with healthy subjects. Further, overexpression of PCDH17 in primary cortical neurons revealed significantly decreased spine density and abnormal dendritic morphology compared with control groups, which again is consistent with the clinical observations of reduced numbers of dendritic spines in the brains of patients with major mood disorders. Given that synaptic spines are dynamic structures which regulate neuronal plasticity and have crucial roles in myriad brain functions, this study reveals a potential underlying biological mechanism of a novel risk gene for major mood disorders involved in synaptic function and related intermediate phenotypes.

Undiagnosed cardiovascular disease prior to cardiovascular death in individuals with severe mental illness.

OBJECTIVE: To examine whether individuals with schizophrenia (SCZ) or bipolar disorder (BD) had equal likelihood of not being diagnosed with cardiovascular disease (CVD) prior to cardiovascular death, compared to individuals without SCZ or BD. METHODS: Multivariate logistic regression analysis including nationwide data of 72 451 cardiovascular deaths in the years 2011-2016. Of these, 814 had a SCZ diagnosis and 673 a BD diagnosis in primary or specialist health care. RESULTS: Individuals with SCZ were 66% more likely (OR: 1.66; 95% CI: 1.39-1.98), women with BD were 38% more likely (adjusted OR: 1.38; 95% CI: 1.04-1.82), and men with BD were equally likely (OR: 0.88, 95% CI: 0.63-1.24) not to be diagnosed with CVD prior to cardiovascular death, compared to individuals without SMI. Almost all (98%) individuals with SMI and undiagnosed CVD had visited primary or specialized somatic health care prior to death, compared to 88% among the other individuals who died of CVD. CONCLUSION: Individuals with SCZ and women with BD are more likely to die due to undiagnosed CVD, despite increased risk of CVD and many contacts with primary and specialized somatic care. Strengthened efforts to prevent, recognize, and treat CVD in individuals with SMI from young age are needed.

Genetic risk scores and family history as predictors of schizophrenia in Nordic registers.

BACKGROUND: Family history is a long-standing and readily obtainable risk factor for schizophrenia (SCZ). Low-cost genotyping technologies have enabled large genetic studies of SCZ, and the results suggest the utility of genetic risk scores (GRS, direct assessments of inherited common variant risk). Few studies have evaluated family history and GRS simultaneously to ask whether one can explain away the other. METHODS: We studied 5959 SCZ cases and 8717 controls from four Nordic countries. All subjects had family history data from national registers and genome-wide genotypes that were processed through the quality control procedures used by the Psychiatric Genomics Consortium. Using external training data, GRS were estimated for SCZ, bipolar disorder (BIP), major depression, autism, educational attainment, and body mass index. Multivariable modeling was used to estimate effect sizes. RESULTS: Using harmonized genomic and national register data from Denmark, Estonia, Norway, and Sweden, we confirmed that family history of SCZ and GRS for SCZ and BIP were risk factors for SCZ. In a joint model, the effects of GRS for SCZ and BIP were essentially unchanged, and the effect of family history was attenuated but remained significant. The predictive capacity of a model including GRS and family history neared the minimum for clinical utility. CONCLUSIONS: Combining national register data with measured genetic risk factors represents an important investigative approach for psychotic disorders. Our findings suggest the potential clinical utility of combining GRS and family history for early prediction and diagnostic improvements.

Genome-wide association study identifies SESTD1 as a novel risk gene for lithium-responsive bipolar disorder.

This corrects the article DOI: 10.1038/mp.2015.165.

LIBERTI: A SMART study in plastic surgery.

BACKGROUND/AIMS: Laser treatment of burns scars is considered by some providers to be standard of care. However, there is little evidence-based research as to the true benefit. A number of factors hinder evaluation of the benefit of laser treatment. These include significant heterogeneity in patient response and possible delayed effects from the laser treatment. Moreover, laser treatments are often provided sequentially using different types of equipment and settings, so there are effectively a large number of overall treatment options that need to be compared. We propose a trial capable of coping with these issues and that also attempts to take advantage of the heterogeneous response in order to estimate optimal treatment plans personalized to each individual patient. It will be the first large-scale randomized trial to compare the effectiveness of laser treatments for burns scars and, to our knowledge, the very first example of the utility of a Sequential Multiple Assignment Randomized Trial in plastic surgery. METHODS: We propose using a Sequential Multiple Assignment Randomized Trial design to investigate the effect of various permutations of laser treatment on hypertrophic burn scars. We will compare and test hypotheses regarding laser treatment effects at a general population level. Simultaneously, we hope to use the data generated to discover possible beneficial personalized treatment plans, tailored to individual patient characteristics. RESULTS: We show that the proposed trial has good power to detect laser treatment effect at the overall population level, despite comparing a large number of treatment combinations. The trial will simultaneously provide high-quality data appropriate for estimating precision-medicine treatment rules. We detail population-level comparisons of interest and corresponding sample size calculations. We provide simulations to suggest the power of the trial to detect laser effect and also the possible benefits of personalization of laser treatment to individual characteristics. CONCLUSION: We propose, to our knowledge, the first use of a Sequential Multiple Assignment Randomized Trial in surgery. The trial is rigorously designed so that it is reasonably straightforward to implement and powered to answer general overall questions of interest. The trial is also designed to provide data that are suitable for the estimation of beneficial precision-medicine treatment rules that depend both on individual patient characteristics and on-going real-time patient response to treatment.

Autism risk associated with parental age and with increasing difference in age between the parents.

Advancing paternal and maternal age have both been associated with risk for autism spectrum disorders (ASD). However, the shape of the association remains unclear, and results on the joint associations is lacking. This study tests if advancing paternal and maternal ages are independently associated with ASD risk and estimates the functional form of the associations. In a population-based cohort study from five countries (Denmark, Israel, Norway, Sweden and Western Australia) comprising 5 766 794 children born 1985-2004 and followed up to the end of 2004-2009, the relative risk (RR) of ASD was estimated by using logistic regression and splines. Our analyses included 30 902 cases of ASD. Advancing paternal and maternal age were each associated with increased RR of ASD after adjusting for confounding and the other parent's age (mothers 40-49 years vs 20-29 years, RR=1.15 (95% confidence interval (CI): 1.06-1.24), P-value<0.001; fathers⩾50 years vs 20-29 years, RR=1.66 (95% CI: 1.49-1.85), P-value<0.001). Younger maternal age was also associated with increased risk for ASD (mothers <20 years vs 20-29 years, RR=1.18 (95% CI: 1.08-1.29), P-value<0.001). There was a joint effect of maternal and paternal age with increasing risk of ASD for couples with increasing differences in parental ages. We did not find any support for a modifying effect by the sex of the offspring. In conclusion, as shown in multiple geographic regions, increases in ASD was not only limited to advancing paternal or maternal age alone but also to differences parental age including younger or older similarly aged parents as well as disparately aged parents.

A genome-wide association study of kynurenic acid in cerebrospinal fluid: implications for psychosis and cognitive impairment in bipolar disorder.

Elevated cerebrospinal fluid (CSF) levels of the glia-derived N-methyl-D-aspartic acid receptor antagonist kynurenic acid (KYNA) have consistently been implicated in schizophrenia and bipolar disorder. Here, we conducted a genome-wide association study based on CSF KYNA in bipolar disorder and found support for an association with a common variant within 1p21.3. After replication in an independent cohort, we linked this genetic variant-associated with reduced SNX7 expression-to positive psychotic symptoms and executive function deficits in bipolar disorder. A series of post-mortem brain tissue and in vitro experiments suggested SNX7 downregulation to result in a caspase-8-driven activation of interleukin-1ß and a subsequent induction of the brain kynurenine pathway. The current study demonstrates the potential of using biomarkers in genetic studies of psychiatric disorders, and may help to identify novel drug targets in bipolar disorder.

Genome-wide association study identifies SESTD1 as a novel risk gene for lithium-responsive bipolar disorder.

Lithium is the mainstay prophylactic treatment for bipolar disorder (BD), but treatment response varies considerably across individuals. Patients who respond well to lithium treatment might represent a relatively homogeneous subtype of this genetically and phenotypically diverse disorder. Here, we performed genome-wide association studies (GWAS) to identify (i) specific genetic variations influencing lithium response and (ii) genetic variants associated with risk for lithium-responsive BD. Patients with BD and controls were recruited from Sweden and the United Kingdom. GWAS were performed on 2698 patients with subjectively defined (self-reported) lithium response and 1176 patients with objectively defined (clinically documented) lithium response. We next conducted GWAS comparing lithium responders with healthy controls (1639 subjective responders and 8899 controls; 323 objective responders and 6684 controls). Meta-analyses of Swedish and UK results revealed no significant associations with lithium response within the bipolar subjects. However, when comparing lithium-responsive patients with controls, two imputed markers attained genome-wide significant associations, among which one was validated in confirmatory genotyping (rs116323614, P=2.74 × 10(-8)). It is an intronic single-nucleotide polymorphism (SNP) on chromosome 2q31.2 in the gene SEC14 and spectrin domains 1 (SESTD1), which encodes a protein involved in regulation of phospholipids. Phospholipids have been strongly implicated as lithium treatment targets. Furthermore, we estimated the proportion of variance for lithium-responsive BD explained by common variants ('SNP heritability') as 0.25 and 0.29 using two definitions of lithium response. Our results revealed a genetic variant in SESTD1 associated with risk for lithium-responsive BD, suggesting that the understanding of BD etiology could be furthered by focusing on this subtype of BD.

What Do Our Patients Truly Want? Conjoint Analysis of an Aesthetic Plastic Surgery Practice Using Internet Crowdsourcing.

BACKGROUND: What do patients want when looking for an aesthetic surgeon? When faced with attributes like reputation, years in practice, testimonials, photos, and pricing, which is more valuable? Moreover, are attributes procedure-specific? Currently, inadequate evidence exists on which attributes are most important to patients, and to our knowledge, none on procedure-specific preferences. OBJECTIVES: First, to determine the most important attributes to breast augmentation, combined breast/abdominal surgery, and facelift patients using conjoint analysis. Second, to test the conjoint using an internet crowdsourcing service (Amazon Mechanical Turk [MTurk]). METHODS: Anonymous university members were asked, via mass electronic survey, to pick a surgeon for facelift surgery based on five attributes. Attribute importance and preference was calculated. Once pre-tested, the facelift, breast augmentation and combined breast/abdominal surgery surveys were administered worldwide to MTurk. RESULTS: The university facelift cohort valued testimonials (33.9%) as the most important, followed by photos (31.6%), reputation (18.2%), pricing (14.4%), and practice years (1.9%). MTurk breast augmentation participants valued photos (35.3%), then testimonials (33.9%), reputation (15.7%), pricing (12.2%), and practice years (3%). MTurk combined breast/abdominal surgery and facelift participants valued testimonials (38.3% and 38.1%, respectively), then photos (27.9%, 29.4%), reputation (17.5%, 15.8%), pricing (13.9%, 13.9%), practice years (2.4%, 2.8%). CONCLUSIONS: Breast augmentation patients placed higher importance on photos; combined breast/abdominal surgery and facelift patients valued testimonials. Conjoint analysis has had limited application in plastic surgery. To our knowledge, internet crowdsourcing is a novel participant recruitment method in plastic surgery. Its unique benefits include broad, diverse and anonymous participant pools, low-cost, rapid data collection, and high completion rate.

Age at fatherhood: heritability and associations with psychiatric disorders.

BACKGROUND: Advancing paternal age has been linked to psychiatric disorders. These associations might be caused by the increased number of de novo mutations transmitted to offspring of older men. It has also been suggested that the associations are confounded by a genetic liability for psychiatric disorders in parents. The aim of this study was to indirectly test the confounding hypotheses by examining if there is a genetic component to advancing paternal age and if men with a genetic liability for psychiatric disorders have children at older ages. METHOD: We examined the genetic component to advancing paternal age by utilizing the twin model in a cohort of male twins (N = 14 679). We also studied ages at childbirth in men with or without schizophrenia, bipolar disorder and/or autism spectrum disorder. Ages were examined in: (1) healthy men, (2) affected men, (3) healthy men with an affected sibling, (4) men with healthy spouses, (5) men with affected spouses, and (6) men with healthy spouses with an affected sibling. RESULTS: The twin analyses showed that late fatherhood is under genetic influence (heritability = 0.33). However, affected men or men with affected spouses did not have children at older ages. The same was found for healthy individuals with affected siblings. Instead, these men were generally having children at younger ages. CONCLUSION: Although there is a genetic component influencing late fatherhood, our data suggest that the associations are not explained by psychiatric disorders or a genetic liability for psychiatric disorders in the parent.

Multidimensional assessment of impulsivity in schizophrenia, bipolar disorder, and major depressive disorder: testing for shared endophenotypes.

BACKGROUND: Impulsivity is associated with bipolar disorder as a clinical feature during and between manic episodes and is considered a potential endophenotype for the disorder. Schizophrenia and major depressive disorder share substantial genetic overlap with bipolar disorder, and these two disorders have also been associated with elevations in impulsivity. However, little is known about the degree of overlap among these disorders in discrete subfacets of impulsivity and whether any overlap is purely phenotypic or due to shared genetic diathesis. METHOD: We focused on five subfacets of impulsivity: self-reported attentional, motor, and non-planning impulsivity, self-reported sensation seeking, and a behavioral measure of motor inhibition (stop signal reaction time; SSRT). We examined these facets within and across disorder proband and co-twin groups, modeled heritability, and tested for endophenotypic patterning in a sample of twin pairs recruited from the Swedish Twin Registry (N = 420). RESULTS: We found evidence of moderate to high levels of heritability for all five subfacets. All three proband groups and their unaffected co-twins showed elevations on attentional, motor, and non-planning impulsivity. Schizophrenia probands (but not their co-twins) showed significantly lower sensation seeking, and schizophrenia and bipolar disorder probands (but not in their co-twins) had significantly longer SSRTs, compared with healthy controls and the other groups. CONCLUSIONS: Attentional, motor, and non-planning impulsivity emerged as potential shared endophenotypes for the three disorders, whereas sensation seeking and SSRT were associated with phenotypic affection but not genetic loading for these disorders.

Prevalence and predictors of anxiety and depression among esophageal cancer patients prior to surgery.

This study aims to establish the prevalence and predictors of anxiety and depression among esophageal cancer patients, post-diagnosis but prior to curatively intended surgery. This was a cross-sectional study using data from a hospital-based prospective cohort study, carried out at St Thomas' Hospital, London. Potential predictor variables were retrieved from medical charts and self-report questionnaires. Anxiety and depression were measured prior to esophageal cancer surgery, using the Hospital Anxiety and Depression Scale. Prevalence of anxiety and depression was calculated using the established cutoff (scores ≥8 on each subscale) indicating cases of 'possible-probable' anxiety or depression, and multivariable logistic regression analyses were performed to examine predictors of emotional distress. Among the 106 included patients, 36 (34%) scored above the cutoff (≥8) for anxiety and 24 (23%) for depression. Women were more likely to report anxiety than men (odds ratio 4.04, 95% confidence interval 1.45-11.16), and patients reporting limitations in their activity status had more than five times greater odds of reporting depression (odds ratio 6.07, 95% confidence interval 1.53-24.10). A substantial proportion of esophageal cancer patients report anxiety and/or depression prior to surgery, particularly women and those with limited activity status, which highlights a need for qualified emotional support.

Copy number variation in schizophrenia in Sweden.

Schizophrenia (SCZ) is a highly heritable neuropsychiatric disorder of complex genetic etiology. Previous genome-wide surveys have revealed a greater burden of large, rare copy number variations (CNVs) in SCZ cases and identified multiple rare recurrent CNVs that increase risk of SCZ although with incomplete penetrance and pleiotropic effects. Identification of additional recurrent CNVs and biological pathways enriched for SCZ CNVs requires greater sample sizes. We conducted a genome-wide survey for CNVs associated with SCZ using a Swedish national sample (4719 cases and 5917 controls). High-confidence CNV calls were generated using genotyping array intensity data, and their effect on risk of SCZ was measured. Our data confirm increased burden of large, rare CNVs in SCZ cases as well as significant associations for recurrent 16p11.2 duplications, 22q11.2 deletions and 3q29 deletions. We report a novel association for 17q12 duplications (odds ratio=4.16, P=0.018), previously associated with autism and mental retardation but not SCZ. Intriguingly, gene set association analyses implicate biological pathways previously associated with SCZ through common variation and exome sequencing (calcium channel signaling and binding partners of the fragile X mental retardation protein). We found significantly increased burden of the largest CNVs (>500 kb) in genes present in the postsynaptic density, in genomic regions implicated via SCZ genome-wide association studies and in gene products localized to mitochondria and cytoplasm. Our findings suggest that multiple lines of genomic inquiry--genome-wide screens for CNVs, common variation and exonic variation--are converging on similar sets of pathways and/or genes.