Changes in white matter microstructure predict lithium response in adolescents with bipolar disorder.

OBJECTIVES: To investigate whether response to lithium treatment in pediatric bipolar disorder can be predicted by changes in white matter microstructure in key cortico-limbic tracts involved in emotion regulation. METHODS: Eighteen clinically referred lithium-naive patients (mean age 15.5 years) were administered clinical rating scales and diffusion tensor imaging (DTI) examinations at baseline and following 4 weeks of lithium treatment. Clinical ratings were repeated following 8 weeks of treatment. Patients with Clinical Global Impressions (CGI) ratings of 1 ("very much improved") or 2 ("much improved") were classified as responders. Ten healthy volunteers received baseline and follow-up DTI examinations. Using the ENIGMA pipeline, we investigated the relationship between changes in fractional anisotropy (FA) in the cingulum hippocampus (CGH) and clinical response to lithium. RESULTS: Patients demonstrated significantly lower FA compared to healthy volunteers in the left and right CGH white matter at baseline. Following 4 weeks of lithium treatment, FA in the left CGH increased in patients, but no significant changes in FA were observed among the untreated healthy volunteers. Lithium responders had a significantly greater increase in FA compared to non-responders. Moreover, baseline (pre-treatment) FA in the left CGH white matter significantly predicted week 8 overall CGI severity score, with post hoc analyses indicating that these effects were evident for both severity of depression and mania. CONCLUSIONS: Our findings suggest that response to lithium treatment in pediatric bipolar disorder is associated with normalization of white matter microstructure in regions associated with emotion processing.

Variation in MSRA modifies risk of neonatal intestinal obstruction in cystic fibrosis.

Meconium ileus (MI), a life-threatening intestinal obstruction due to meconium with abnormal protein content, occurs in approximately 15 percent of neonates with cystic fibrosis (CF). Analysis of twins with CF demonstrates that MI is a highly heritable trait, indicating that genetic modifiers are largely responsible for this complication. Here, we performed regional family-based association analysis of a locus that had previously been linked to MI and found that SNP haplotypes 5' to and within the MSRA gene were associated with MI (P = 1.99 × 10(-5) to 1.08 × 10(-6); Bonferroni P = 0.057 to 3.1 × 10(-3)). The haplotype with the lowest P value showed association with MI in an independent sample of 1,335 unrelated CF patients (OR = 0.72, 95% CI [0.53-0.98], P = 0.04). Intestinal obstruction at the time of weaning was decreased in CF mice with Msra null alleles compared to those with wild-type Msra resulting in significant improvement in survival (P = 1.2 × 10(-4)). Similar levels of goblet cell hyperplasia were observed in the ilea of the Cftr(-/-) and Cftr(-/-)Msra(-/-) mice. Modulation of MSRA, an antioxidant shown to preserve the activity of enzymes, may influence proteolysis in the developing intestine of the CF fetus, thereby altering the incidence of obstruction in the newborn period. Identification of MSRA as a modifier of MI provides new insight into the biologic mechanism of neonatal intestinal obstruction caused by loss of CFTR function.

AHP DB: a reference database of proteins in the human aqueous humor.

The aqueous humor (AH) is a low-viscosity biofluid that continuously circulates from the posterior chamber to the anterior chamber of the eye. Recent advances in high-resolution mass-spectrometry workflows have facilitated the study of proteomic content in small-volume biofluids like AH, highlighting the potential clinical implications of the AH proteome. Nevertheless, in-depth investigations into the role of AH proteins in ocular diseases have encountered challenges due to limited accessibility to these workflows, difficulties in large-scale AH sample collection and the absence of a reference AH proteomic database. In response to these obstacles, and to promote further research on the involvement of AH proteins in ocular physiology and pathology, we have developed the web-based Aqueous Humor Proteomics Database (AHP DB). The current version of AHP DB contains proteomic data from 307 human AH samples, which were analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The database offers comprehensive information on 1683 proteins identified in the AH samples. Furthermore, relevant clinical data are provided for each analyzed sample. Researchers also have the option to download these datasets individually for offline use, rendering it a valuable resource for the scientific community. Database URL: https://ahp.augusta.edu/.

Diffusion tensor imaging atlas-based analyses in major depression after mild traumatic brain injury.

There are currently no known early neuroanatomical markers predictive of the development of major depression or depressive symptoms after mild traumatic brain injury (mTBI). The authors conducted a 1-year longitudinal pilot study to determine whether diffusion tensor imaging (DTI) measures collected within 1 month of mTBI could predict incident depression. Of the 14 subjects who met study inclusion criteria, 4 (28.6%) developed major depression over the follow-up period. Compared with the nondepressed group, those who developed depression had white-matter abnormalities in the fronto-temporal regions measured by DTI. These preliminary results highlight the need for additional studies, including studies using a larger sample and appropriate controls.

Changes in scientific characteristics of abstracts accepted to the Society for Academic Emergency Medicine Annual Meeting, 1990-2020.

OBJECTIVES: Since its founding in 1989, the Society for Academic Emergency Medicine (SAEM) has accepted thousands of abstracts for presentation at its annual meeting. We reviewed abstracts to characterize temporal changes in study design, abstract topics, quality scores, and proportion of abstracts published as manuscripts. METHODS: In this serial cross-sectional study, we compiled accepted SAEM abstracts at 5-year intervals (1990, 1995, 2000, 2005, 2010, 2015, 2020) and then randomly selected 100 abstracts from each year for review by two investigators. We documented each abstract's study design, sample size, and whether it was a single-center or multicenter study. We assigned each abstract to the most appropriate topic category. Applying SAEM's abstract scoring system from 2020, we calculated the mean overall quality score per year. Finally, we searched PubMed to determine if abstracts from 1990-2015 meetings were published as manuscripts. RESULTS: The number of accepted abstracts increased from 180 in 1990 to 879 in 2020 (+388%). The most common study design changed from laboratory study in 1990 (22%) to cohort study in 2020 (44%; p < 0.001). The median study sample size increased over time, from 105 (interquartile range [IQR] 25-389) in 1990 to 544 (IQR 102-2067) in 2020 (p < 0.001). Multicenter studies have become more common (19% in 1990 vs. 40% in 2020; p = 0.001). The most common topic categories also changed from cardiology/pulmonary/airway (40%) and orthopedic/trauma/burn (17%) in 1990 to health services research/health policy/operations (25%) and cardiology/pulmonary/airway (22%) in 2020. There was a 20% increase in overall quality scores (p < 0.001). Between 37% and 49% of the abstracts reviewed from each year were later published as manuscripts, with no significant change over time (p = 0.33). CONCLUSIONS: Over the past 30 years, there have been significant changes to the study designs, topics, and quality scores of SAEM meeting abstracts. However, conversion of abstracts to published manuscripts remains a challenge.

Effects of Race, Cardiac Mass, and Cardiac Load on Myocardial Function Trajectories from Childhood to Young Adulthood: The Augusta Heart Study.

Background The overall goal of this longitudinal study was to determine if the Black population has decreased myocardial function, which has the potential to lead to the early development of congestive heart failure, compared with the White population. Methods and Results A total of 673 subjects were evaluated over a period of 30 years including similar percentages of Black and White participants. Left ventricular systolic function was probed using the midwall fractional shortening (MFS). A longitudinal analysis of the MFS using a mixed effect growth curve model was performed. Black participants had greater body mass index, higher blood pressure readings, and greater left ventricular mass compared with White participants (all P<0.01). Black participants had a 0.54% decrease of MFS compared with White participants. As age increased by 1 year, MFS increased by 0.05%. As left ventricular mass increased by 1 g, MFS decreased by 0.01%. As circumferential end systolic stress increased by 1 unit, MFS decreased by 0.04%. The MFS trajectories for race differed from early age to young adulthood. Conclusions Changes in myocardial function mirror the race-dependent variations in blood pressure, afterload, and cardiac mass, suggesting that myocardial function depression occurs early in childhood in populations at high cardiovascular risk such as Black participants.

Rapid PCR-based diagnosis of septic arthritis by early Gram-type classification and pathogen identification.

Septic arthritis (SA) is a rheumatologic emergency associated with significant morbidity and mortality. Delayed or inadequate treatment of SA can lead to irreversible joint destruction and disability. Current methods of diagnosing SA rely on synovial fluid analysis and culture which are known to be imprecise and time-consuming. We report a novel adaptation of a probe-based real-time PCR assay targeting the 16S rRNA gene for early and accurate diagnosis of bacterial SA. The assay algorithm consists of initial broad-range eubacterial detection, followed by Gram typing and species characterization of the pathogen. The platform demonstrated a high analytical sensitivity with a limit of detection of 10(1) CFU/ml with a panel of SA-related organisms. Gram typing and pathogen-specific probes correctly identified their respective targets in a mock test panel of 36 common clinically relevant pathogens. One hundred twenty-one clinical synovial fluid samples from patients presenting with suspected acute SA were tested. The sensitivity and specificity of the assay were 95% and 97%, respectively, versus synovial fluid culture results. Gram-typing probes correctly identified 100% of eubacterial positive samples as to gram-positive or gram-negative status, and pathogen-specific probes correctly identified the etiologic agent in 16/20 eubacterial positive samples. The total assay time from sample collection to result is 3 h. We have demonstrated that a real-time broad-based PCR assay has high analytical and clinical performance with an improved time to detection versus culture for SA. This assay may be a useful diagnostic adjunct for clinicians, particularly those practicing in the acute care setting where rapid pathogen detection and identification would assist in disposition and treatment decisions.

StickySchedule: An Interactive Multi-user Application for Conference Scheduling on Large-scale Shared Displays.

Scheduling conferences is a common task in both research and industry, which requires relatively small groups to collaborate and negotiate in order to solve an often-large logistical problem with many nuances. For large conferences, the process can take days and it is traditionally a manual procedure performed using physical tools such as whiteboards and sticky notes. We present the design and implementation of StickySchedule, a multi-user application for use on interactive large-scale shared displays to better enable groups to organize large conference-scheduling data. To evaluate our tool, we present observations from novice users, and authentic use cases with expert feedback from organizers who are heavily involved in large conference scheduling. The main contributions of our work are documenting the collaborative and competitive aspects of conference scheduling, creating a tool that incorporates successful features and addresses identified issues with prior works, and verifying the usefulness of our tool by observing and discussing a variety of use cases, in both collocated and remote-distributed settings.

Genetic modifiers of nutritional status in cystic fibrosis.

BACKGROUND: Improved nutrition early in life is associated with better pulmonary function for patients with cystic fibrosis (CF). However, nutritional status is poorly correlated with the CFTR genotype. OBJECTIVE: We investigated the extent to which modifier genes influence nutrition in children with CF. DESIGN: BMI data were longitudinally collected from the CF Twin-Sibling Study and Cystic Fibrosis Foundation Patient Registry for twins and siblings from 2000 to 2010. A nutritional phenotype was derived for 1124 subjects by calculating the average BMI z score from 5-10 y of age (BMI-z(5to10)). The genetic contribution to the variation in BMI-z(5to10) (ie, heritability) was estimated by comparing the similarity of the phenotype in monozygous twins to that in dizygous twins and siblings. Linkage analysis identified potential modifier-gene loci. RESULTS: The median BMI-z(5to10) was -0.07 (range: -3.89 to 2.30), which corresponded to the 47th CDC percentile. BMI-z(5to10) was negatively correlated with pancreatic insufficiency, history of meconium ileus, and female sex but positively correlated with later birth cohorts and lung function. Monozygous twins showed greater concordance for BMI-z(5to10) than did dizygous twins and siblings; heritability estimates from same-sex twin-only analyses ranged from 0.54 to 0.82. For 1010 subjects with pancreatic insufficiency, genome-wide significant linkage was identified on chromosomes 1p36.1 [log of odds (LOD): 5.3] and 5q14 (LOD: 5.1). These loci explained ≥16% and ≥15%, respectively, of the BMI variance. CONCLUSIONS: The analysis of twins and siblings with CF indicates a prominent role for genes other than CFTR to BMI variation. Specifically, regions on chromosomes 1 and 5 appear to harbor genetic modifiers of substantial effect.

Multiple apical plasma membrane constituents are associated with susceptibility to meconium ileus in individuals with cystic fibrosis.

Variants associated with meconium ileus in cystic fibrosis were identified in 3,763 affected individuals by genome-wide association study (GWAS). Five SNPs at two loci near SLC6A14 at Xq23-24 (minimum P = 1.28 × 10(-12) at rs3788766) and SLC26A9 at 1q32.1 (minimum P = 9.88 × 10(-9) at rs4077468) accounted for ~5% of phenotypic variability and were replicated in an independent sample of affected individuals (n = 2,372; P = 0.001 and 0.0001, respectively). By incorporating the knowledge that disease-causing mutations in CFTR alter electrolyte and fluid flux across surface epithelium into a hypothesis-driven GWAS (GWAS-HD), we identified associations with the same SNPs in SLC6A14 and SLC26A9 and established evidence for the involvement of SNPs in a third solute carrier gene, SLC9A3. In addition, GWAS-HD provided evidence of association between meconium ileus and multiple genes encoding constituents of the apical plasma membrane where CFTR resides (P = 0.0002; testing of 155 apical membrane genes jointly and in replication, P = 0.022). These findings suggest that modulating activities of apical membrane constituents could complement current therapeutic paradigms for cystic fibrosis.

Genome-wide association and linkage identify modifier loci of lung disease severity in cystic fibrosis at 11p13 and 20q13.2.

A combined genome-wide association and linkage study was used to identify loci causing variation in cystic fibrosis lung disease severity. We identified a significant association (P = 3.34 × 10(-8)) near EHF and APIP (chr11p13) in p.Phe508del homozygotes (n = 1,978). The association replicated in p.Phe508del homozygotes (P = 0.006) from a separate family based study (n = 557), with P = 1.49 × 10(-9) for the three-study joint meta-analysis. Linkage analysis of 486 sibling pairs from the family based study identified a significant quantitative trait locus on chromosome 20q13.2 (log(10) odds = 5.03). Our findings provide insight into the causes of variation in lung disease severity in cystic fibrosis and suggest new therapeutic targets for this life-limiting disorder.

Rapid polymerase chain reaction-based screening assay for bacterial biothreat agents.

OBJECTIVES: To design and evaluate a rapid polymerase chain reaction (PCR)-based assay for detecting Eubacteria and performing early screening for selected Class A biothreat bacterial pathogens. METHODS: The authors designed a two-step PCR-based algorithm consisting of an initial broad-based universal detection step, followed by specific pathogen identification targeted for identification of the Class A bacterial biothreat agents. A region in the bacterial 16S rRNA gene containing a highly variable sequence flanked by clusters of conserved sequences was chosen as the target for the PCR assay design. A previously described highly conserved region located within the 16S rRNA amplicon was selected as the universal probe (UniProbe, Integrated DNA Technology, Coralville, IA). Pathogen-specific TaqMan probes were designed for Bacillus anthracis, Yersinia pestis, and Francisella tularensis. Performance of the assay was assessed using genomic DNA extracted from the aforementioned biothreat-related organisms (inactivated or surrogate) and other common bacteria. RESULTS: The UniProbe detected the presence of all tested Eubacteria (31/31) with high analytical sensitivity. The biothreat-specific probes accurately identified organisms down to the closely related species and genus level, but were unable to discriminate between very close surrogates, such as Yersinia philomiragia and Bacillus cereus. CONCLUSIONS: A simple, two-step PCR-based assay proved capable of both universal bacterial detection and identification of select Class A bacterial biothreat and biothreat-related pathogens. Although this assay requires confirmatory testing for definitive species identification, the method has great potential for use in ED-based settings for rapid diagnosis in cases of suspected Category A bacterial biothreat agents.