Diagnostic validity of early-onset obsessive-compulsive disorder in the Danish Psychiatric Central Register:findings from a cohort sample

Employing national registers for research purposes depends on a high diagnostic validity. The aim of the present study was to examine the diagnostic validity of recorded diagnoses of early-onset obsessive-compulsive disorder (OCD) in the Danish Psychiatric Central Register (DPCR)

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Variants in GNAI1 cause a syndrome associated with variable features including developmental delay, seizures, and hypotonia

Purpose: Neurodevelopmental disorders (NDDs) encompass a spectrum of genetically heterogeneous disorders with features that commonly include developmental delay, intellectual disability, and autism spectrum disorders. We sought to delineate the molecular and phenotypic spectrum of a novel neurodevelopmental disorder caused by variants in the GNAI1 gene. Methods: Through large cohort trio-based exome sequencing and international data-sharing, we identified 24 unrelated individuals with NDD phenotypes and a variant in GNAI1, which encodes the inhibitory Gαi1 subunit of heterotrimeric G-proteins. We collected detailed genotype and phenotype information for each affected individual. Results: We identified 16 unique variants in GNAI1 in 24 affected individuals; 23 occurred de novo and 1 was inherited from a mosaic parent. Most affected individuals have a severe neurodevelopmental disorder. Core features include global developmental delay, intellectual disability, hypotonia, and epilepsy. Conclusion: This collaboration establishes GNAI1 variants as a cause of NDDs. GNAI1-related NDD is most often characterized by severe to profound delays, hypotonia, epilepsy that ranges from self-limiting to intractable, behavior problems, and variable mild dysmorphic features

Experience of decision-making for home breech birth: An interpretive description

Despite research and recommendations supporting shared decision-making and vaginal birth as a reasonable option for appropriately screened candidates with a term breech pregnancy, cesarean remains the only mode of birth available in most hospitals in the United States. Unable to find care for planned vaginal birth in a hospital setting, some individuals choose to pursue breech birth at home, potentially placing themselves and their infants at increased risk. Through this analysis of qualitative data gathered from a mixed methods study, we explored the experience of decision-making of 25 individuals who left the US hospital system to pursue a home breech birth. Data were gathered through open-ended survey responses (n = 25) and subsequent in-depth, semi-structured interviews (n = 23) and analyzed using an interpretive description approach informed by situational analysis. Five interwoven and dynamic themes were identified in this complex decision-making process: valuing and trusting in normal birth, being “backed into a corner,” asserting agency, making an informed choice, and drawing strength from the experience. This study provides a foundation for understanding the experience of decision-making and can inform future research and clinical practice to improve the provision of safe and respectful, person-centered care for breech pregnancy and birth

Assessing the Relationship between Performance on the University of California Performance Skills Assessment (UPSA) and Outcomes in Schizophrenia: A Systematic Review and Evidence Synthesis

Objective. To perform a systematic review of the published literature to evaluate how functional capacity, as measured by the University of California at San Diego (UCSD) Performance-based Skills Assessment (UPSA), relates to other functional measures and real-world outcomes among individuals with schizophrenia. Methods. The MEDLINE® and Embase® databases were searched to identify joint evaluations with UPSA and key functional outcomes (functional scale measures; generic or disease-specific, health-related quality of life [HRQoL]; or real-world outcomes [residential status; employment status]) in patients with schizophrenia. Pearson correlations were estimated between UPSA scores, HRQoL, other functional scale measures, and real-world outcomes, for outcomes described in at least six studies. Results. The synthesis included 76 studies that provided 73 unique data sets. Quantitative assessment between the Specific Level of Function (SLOF) (n=18) scores and UPSA scores demonstrated a moderate borderline-significant correlation (0.45, p=0.06). Quantitative analysis of the relationship between the Global Assessment of Functioning (GAF) (n=11) and the Multidimensional Scale of Independent Functioning (MSIF) (n=6) scales revealed moderate and small nonsignificant Pearson correlations of -0.34 (p=0.31) and 0.12 (p=0.83), respectively. There was a small borderline-significant correlation between UPSA score and residential status (n=36; 0.31; p=0.08), while no correlation was found between UPSA score and employment status (n=19; 0.04; p=0.88). Conclusion. The SLOF was the most often used functional measure and had the strongest observed correlation with the UPSA. Although knowledge gaps remain, evidence from this review indicates that there is a quantitative relationship between functional capacity and real-world outcomes in individuals with schizophrenia

Frequency and age at occurrence of clinical manifestations of disease in patients with hypophosphatasia: a systematic literature review

Abstract Background Hypophosphatasia (HPP) is a rare, inherited, metabolic disease caused by tissue-nonspecific alkaline phosphatase deficiency, characterized by bone mineralization defects and systemic complications. Understanding of the clinical course and burden of HPP is limited by its rarity. This systematic literature review and synthesis of case report data aimed to determine the frequency and timing of clinical HPP manifestations and events. Methods Case reports and series of patients with HPP who had been followed longitudinally for ≥1 year were identified. Demographics and clinical data of interest, identified through consultation with clinical experts in HPP, were extracted. Occurrences of clinical manifestations/events of interest were categorized, classified by age at first reported occurrence of HPP manifestations and visualized over time. Clinical manifestations/events considered to contribute to the clinical burden of HPP were identified. Kaplan–Meier curves were used to estimate the median (range) age at first occurrence of the most frequently reported manifestations/events. Results From the 283 studies that met the inclusion criteria, 265 patients with HPP with ≥1 year of longitudinal follow-up were identified (median [interquartile range] age 4 [0–34] years; 45% male). The types of clinical manifestations/events of interest experienced by individuals with ≥1 such manifestation/event (n = 261) often differed between older and younger patients. Most (94%) of the 265 patients experienced ≥1 manifestation/event deemed to contribute to the clinical burden of HPP; premature tooth loss (53.5%), fractures (35.8%), pain (33.6%), and gross motor/ambulation difficulties (30.9%) were most frequently reported. The median (range) age at first reported occurrence of respiratory symptoms, cranial abnormalities, and premature tooth loss ranged from 0.3 to 10 years, whereas the median age at first reported occurrence of fractures, pain, gross motor/ambulation difficulties, and surgery ranged from 33 to 70 years. Conclusions HPP is associated with a high clinical burden of disease, regardless of age at first reported occurrence of HPP manifestations. Over an individual’s lifetime, the types of manifestations/events experienced can change and multiple HPP-related clinical manifestations/events can accumulate. These observations may reflect evolution and progression of the disease