Advanced paternal age has been suggested as a risk factor for autism, but empirical evidence is mixed. This study examines whether the association between paternal age and autism in the offspring (1) ...persists controlling for documented autism risk factors, including family psychiatric history, perinatal conditions, infant characteristics and demographic variables; (2) may be explained by familial traits associated with the autism phenotype, or confounding by parity; and (3) is consistent across epidemiological studies. Multiple study methods were adopted. First, a Swedish 10-year birth cohort (N=1 075 588) was established. Linkage to the National Patient Register ascertained all autism cases (N=883). Second, 660 families identified within the birth cohort had siblings discordant for autism. Finally, meta-analysis included population-based epidemiological studies. In the birth cohort, autism risk increased monotonically with increasing paternal age. Offspring of men aged ≥50 years were 2.2 times (95% confidence interval: 1.26-3.88: P=0.006) more likely to have autism than offspring of men aged ≤29 years, after controlling for maternal age and documented risk factors for autism. Within-family analysis of discordant siblings showed that affected siblings had older paternal age, adjusting for maternal age and parity (P<0.0001). Meta-analysis demonstrated advancing paternal age association with increased risk of autism across studies. These findings provide the strongest evidence to date that advanced paternal age is a risk factor for autism in the offspring. Possible biological mechanisms include de novo aberration and mutations or epigenetic alterations associated with aging.
Preconception, prenatal and postnatal maternal stress is associated with increased offspring psychopathology, but findings are inconsistent and need replication. We estimated associations between ...maternal bereavement stress and offspring autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), bipolar disorder, schizophrenia, suicide attempt and completed suicide.
Using Swedish registers, we conducted the largest population-based study to date examining associations between stress exposure in 738,144 offspring born 1992-2000 for childhood outcomes and 2,155,221 offspring born 1973-1997 for adult outcomes with follow-up to 2009. Maternal stress was defined as death of a first-degree relative during (a) the 6 months before conception, (b) pregnancy or (c) the first two postnatal years. Cox proportional survival analyses were used to obtain hazard ratios (HRs) in unadjusted and adjusted analyses.
Marginal increased risk of bipolar disorder and schizophrenia following preconception bereavement stress was not significant. Third-trimester prenatal stress increased the risk of ASD adjusted HR (aHR) 1.58, 95% confidence interval (CI) 1.15-2.17 and ADHD (aHR 1.31, 95% CI 1.04-1.66). First postnatal year stress increased the risk of offspring suicide attempt (aHR 1.13, 95% CI 1.02-1.25) and completed suicide (aHR 1.51, 95% CI 1.08-2.11). Bereavement stress during the second postnatal year increased the risk of ASD (aHR 1.30, 95% CI 1.09-1.55).
Further research is needed regarding associations between preconception stress and psychopathological outcomes. Prenatal bereavement stress increases the risk of offspring ASD and ADHD. Postnatal bereavement stress moderately increases the risk of offspring suicide attempt, completed suicide and ASD. Smaller previous studies may have overestimated associations between early stress and psychopathological outcomes.
Schizophrenia is a highly heritable disorder with a polygenic pattern of inheritance and a population prevalence of ~1%. Previous studies have implicated synaptic dysfunction in schizophrenia. We ...tested the accumulated association of genetic variants in expert-curated synaptic gene groups with schizophrenia in 4673 cases and 4965 healthy controls, using functional gene group analysis. Identifying groups of genes with similar cellular function rather than genes in isolation may have clinical implications for finding additional drug targets. We found that a group of 1026 synaptic genes was significantly associated with the risk of schizophrenia (P=7.6 × 10(-11)) and more strongly associated than 100 randomly drawn, matched control groups of genetic variants (P<0.01). Subsequent analysis of synaptic subgroups suggested that the strongest association signals are derived from three synaptic gene groups: intracellular signal transduction (P=2.0 × 10(-4)), excitability (P=9.0 × 10(-4)) and cell adhesion and trans-synaptic signaling (P=2.4 × 10(-3)). These results are consistent with a role of synaptic dysfunction in schizophrenia and imply that impaired intracellular signal transduction in synapses, synaptic excitability and cell adhesion and trans-synaptic signaling play a role in the pathology of schizophrenia.
Sellgren C, Landén M, Lichtenstein P, Hultman CM, Långström N. Validity of bipolar disorder hospital discharge diagnoses: file review and multiple register linkage in Sweden.
Objective: Hospital ...discharge registers (HDRs) are frequently used in epidemiological research. However, the validity of several important psychiatric diagnostic entities, including bipolar disorder, remains uncertain. Hence, we aimed to develop an optimal algorithm for register‐based identification of DSM‐IV‐TR bipolar disorder.
Method: We identified potential cases in the Swedish national HDR using two separate discharge diagnoses of bipolar disorder according to ICD versions 8–10 during January 1, 1973 to December 31, 2004. In a randomly selected subsample of 135 cases from the county of Sörmland, two senior psychiatrists reassessed the diagnostic status based on patients’ medical records. We scrutinized false‐positive cases and modified the initial algorithm to improve positive predictive value while minimizing false negatives. Finally, we externally validated resulting caseness algorithms by linking HDR diagnostic data with best‐estimate clinical diagnoses from the National Quality Assurance Register for Bipolar Disorder (BipoläR), dispensed lithium prescriptions from the National Prescribed Drug Register, and the ICD‐10 diagnoses from the National Outpatient Register respectively.
Results: The algorithm with two discharge diagnoses of bipolar disorder yielded a positive predictive value of 0.81. Modification by excluding individuals diagnosed with ICD‐8 296.20 (manic‐depressive psychosis, depressed type), and/or ICD‐9 296.B (unipolar affective psychosis, melancholic form), gave a positive positive predictive value of 0.92. The modified algorithm also had statistically superior external validity compared with the original algorithm.
Conclusion: Our findings suggest that DSM‐IV‐TR bipolar disorder caseness based on two inpatient episodes with a bipolar disorder diagnosis is sufficiently sensitive and specific to be used in further epidemiological study of bipolar disorder.
OBJECTIVES:Hypertrophic burn scars produce significant morbidity, including itching, pain, stiffness, and contracture, but best management practices remain unclear. We present the largest study to ...date that examines long-term impact of laser therapies, a potentially transformative technology, on scar remodeling.
METHODS:We conducted a prospective, before-after cohort study in burn patients with hypertrophic scars. Pulsed-dye laser was used for pruritus and erythema; fractional CO2 laser was used for stiffness and abnormal texture. Outcomes included (1) Vancouver Scar Scale (VSS), which documents pigmentation, erythema, pliability, and height, and (2) University of North Carolina “4P” Scar Scale (UNC4P), which rates pain, pruritus, paresthesias, and pliability.
RESULTS:A total of 147 burn patients (mean age, 26.9 years; total body surface area, 16.1%) received 415 laser sessions (2.8 sessions/patient), 16 months (median) after injury, including pulsed dye laser (n = 327) and CO2 (n = 139). Laser treatments produced rapid, significant, and lasting improvements in hypertrophic scar. Provider-rated VSS dropped from 10.43 standard deviation (SD) 2.37 to 5.16 (SD 1.92), by the end of treatments, and subsequently decreased to 3.29 (SD 1.24), at a follow-up of 25 months. Patient-reported UNC4P fell from 5.40 (SD 2.54) to 2.05 (SD 1.67), after the first year, and further decreased to 1.74 (SD 1.72), by the end of the study period.
CONCLUSIONS:For the first time, ever, in a large prospective study, laser therapies have been shown to dramatically improve both the signs and symptoms of hypertrophic burn scars, as measured by objective and subjective instruments. Laser treatment of burn scars represents a disruptive innovation that can yield results not previously possible and may displace traditional methods of operative intervention.
Schizophrenia (SCZ) and bipolar disorder (BD) are highly heritable psychiatric disorders with overlapping susceptibility loci and symptomatology. We conducted a genome-wide association study (GWAS) ...of these disorders in a large Swedish sample. We report a new and independent case-control analysis of 1507 SCZ cases, 836 BD cases and 2093 controls. No single-nucleotide polymorphisms (SNPs) achieved significance in these new samples; however, combining new and previously reported SCZ samples (2111 SCZ and 2535 controls) revealed a genome-wide significant association in the major histocompatibility complex (MHC) region (rs886424, P=4.54 × 10(-8)). Imputation using multiple reference panels and meta-analysis with the Psychiatric Genomics Consortium SCZ results underscored the broad, significant association in the MHC region in the full SCZ sample. We evaluated the role of copy number variants (CNVs) in these subjects. As in prior reports, deletions were enriched in SCZ, but not BD cases compared with controls. Singleton deletions were more frequent in both case groups compared with controls (SCZ: P=0.003, BD: P=0.013), whereas the largest CNVs (>500 kb) were significantly enriched only in SCZ cases (P=0.0035). Two CNVs with previously reported SCZ associations were also overrepresented in this SCZ sample: 16p11.2 duplications (P=0.0035) and 22q11 deletions (P=0.03). These results reinforce prior reports of significant MHC and CNV associations in SCZ, but not BD.
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.
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.
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.
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.
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.
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-1β 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.
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