Psychosis brain subtypes validated in first-episode cohorts and related to illness remission: results from the PHENOM consortium.

Using machine learning, we recently decomposed the neuroanatomical heterogeneity of established schizophrenia to discover two volumetric subgroups-a 'lower brain volume' subgroup (SG1) and an 'higher striatal volume' subgroup (SG2) with otherwise normal brain structure. In this study, we investigated whether the MRI signatures of these subgroups were also already present at the time of the first-episode of psychosis (FEP) and whether they were related to clinical presentation and clinical remission over 1-, 3-, and 5-years. We included 572 FEP and 424 healthy controls (HC) from 4 sites (Sao Paulo, Santander, London, Melbourne) of the PHENOM consortium. Our prior MRI subgrouping models (671 participants; USA, Germany, and China) were applied to both FEP and HC. Participants were assigned into 1 of 4 categories: subgroup 1 (SG1), subgroup 2 (SG2), no subgroup membership ('None'), and mixed SG1 + SG2 subgroups ('Mixed'). Voxel-wise analyses characterized SG1 and SG2 subgroups. Supervised machine learning analyses characterized baseline and remission signatures related to SG1 and SG2 membership. The two dominant patterns of 'lower brain volume' in SG1 and 'higher striatal volume' (with otherwise normal neuromorphology) in SG2 were identified already at the first episode of psychosis. SG1 had a significantly higher proportion of FEP (32%) vs. HC (19%) than SG2 (FEP, 21%; HC, 23%). Clinical multivariate signatures separated the SG1 and SG2 subgroups (balanced accuracy = 64%; p < 0.0001), with SG2 showing higher education but also greater positive psychosis symptoms at first presentation, and an association with symptom remission at 1-year, 5-year, and when timepoints were combined. Neuromorphological subtypes of schizophrenia are already evident at illness onset, separated by distinct clinical presentations, and differentially associated with subsequent remission. These results suggest that the subgroups may be underlying risk phenotypes that could be targeted in future treatment trials and are critical to consider when interpreting neuroimaging literature.

Deconfounded Dimension Reduction via Partial Embeddings.

Dimension reduction tools preserving similarity and graph structure such as t-SNE and UMAP can capture complex biological patterns in high-dimensional data. However, these tools typically are not designed to separate effects of interest from unwanted effects due to confounders. We introduce the partial embedding (PARE) framework, which enables removal of confounders from any distance-based dimension reduction method. We then develop partial t-SNE and partial UMAP and apply these methods to genomic and neuroimaging data. Our results show that the PARE framework can remove batch effects in single-cell sequencing data as well as separate clinical and technical variability in neuroimaging measures. We demonstrate that the PARE framework extends dimension reduction methods to highlight biological patterns of interest while effectively removing confounding effects.

Croup during the Coronavirus Disease 2019 Omicron Variant Surge.

We conducted a retrospective review of medical records of patients with croup seen during the coronavirus disease 2019 pandemic. Approximately 50% underwent testing for severe acute respiratory syndrome coronavirus 2. During the Delta wave, 2.8% of those tested were positive for severe acute respiratory syndrome coronavirus 2; this increased to 48.2% during the Omicron wave, demonstrating a strong correlation between the Omicron variant and croup.

Pharmacokinetic Profile of Spectrum Reduced Nicotine Cigarettes.

INTRODUCTION: Spectrum research cigarettes have been developed with varying nicotine content for use in studies evaluating the effects of a regulatory policy reducing the permissible nicotine content in cigarettes. This study aimed to characterize the nicotine pharmacokinetic profile of Spectrum cigarettes. METHODS: Twelve daily smokers attended four sessions and had blood nicotine, exhaled carbon monoxide, and subjective effects measured before and after smoking either a single cigarette of their preferred brand or high (10.9 mg/cigarette), medium (3.2 mg/cigarette), or low (0.2 mg/cigarette) nicotine content Spectrum research cigarettes, in a double-blind design with order counterbalanced. RESULTS: The boost in blood nicotine concentration was dose-dependent, with a boost of 0.3, 3.9, and 17.3 ng/mL for low-, medium-, and high-nicotine content Spectrum cigarettes. The high dose Spectrum had a similar nicotine boost to the "preferred brand" cigarettes (19 ng/mL). Subjects took longer puffs on the low nicotine cigarettes, but smoked these cigarettes faster than other cigarette types. High nicotine Spectrum cigarettes reduced the urge to smoke more than other cigarette types. CONCLUSIONS: This study shows that Spectrum research cigarettes produce blood nicotine absorption in a dose-dependent manner, and therefore, are appropriate for use in studies of nicotine reduction in cigarettes. IMPLICATIONS: This is the first study to determine the pharmacokinetic profile of Spectrum reduced nicotine content research cigarettes following an overnight abstinence. These data could provide evidence to regulatory agencies about the effects of reduced nicotine cigarettes when considering regulations on tobacco reduction.

Evaluation of prophylactic antibiotic regimens on recurrence and mortality in spontaneous bacterial peritonitis.

INTRODUCTION AND OBJECTIVES: Limited data describe current SBP epidemiology and specific secondary SBP prophylactic regimens, leading to variable prescribing practices. This work aims to compare 90-day and one-year SBP recurrence and mortality based on secondary SBP antibiotic prophylaxis regimens. MATERIALS AND METHODS: We performed a retrospective cohort of patients >18 years with an SBP diagnosis from 2010 to 2015 at two academic institutions. Eligible patients had ascitic PMN counts ≥250cells/mm3 or a positive ascitic culture. Patients were compared based on secondary SBP prophylaxis regimens (i.e., daily, intermittent, or no prophylaxis). RESULTS: Of 791 patients with ascitic fluid samples, 86 patients were included. Antibiotic prophylaxis included daily (n=34), intermittent (n=36), or no prophylaxis (n=16). Nearly half of SBP episodes had a positive ascitic fluid culture; 50% were gram-negative pathogens, and 50% were gram-positive pathogens. Daily and intermittent regimens had similar rates of recurrence at 90-days (19.4% vs. 14.7%, p=0.60) and one-year (33.3% vs. 26.5%, p=0.53). Similarly, mortality did not differ among daily and intermittent regimens at 90-days (32.4% vs. 30.6%, p=0.87) or one-year (67.6% vs. 63.9%, p=0.74). When comparing any prophylaxis vs. no prophylaxis, there were no differences in 90-day or one-year recurrence or mortality. CONCLUSIONS: In patients with a history of SBP, our data indicate similar outcomes with daily, intermittent, or no secondary antibiotic prophylaxis. With available data, including ours, demonstrating a changing epidemiology for SBP pathogens, further data is required to determine if traditional approaches to secondary SBP prophylaxis remain appropriate.

Neuroimaging Findings in US Government Personnel With Possible Exposure to Directional Phenomena in Havana, Cuba.

IMPORTANCE: United States government personnel experienced potential exposures to uncharacterized directional phenomena while serving in Havana, Cuba, from late 2016 through May 2018. The underlying neuroanatomical findings have not been described. OBJECTIVE: To examine potential differences in brain tissue volume, microstructure, and functional connectivity in government personnel compared with individuals not exposed to directional phenomena. DESIGN, SETTING, AND PARTICIPANTS: Forty government personnel (patients) who were potentially exposed and experienced neurological symptoms underwent evaluation at a US academic medical center from August 21, 2017, to June 8, 2018, including advanced structural and functional magnetic resonance imaging analytics. Findings were compared with imaging findings of 48 demographically similar healthy controls. EXPOSURES: Potential exposure to uncharacterized directional phenomena of unknown etiology, manifesting as pressure, vibration, or sound. MAIN OUTCOMES AND MEASURES: Potential imaging-based differences between patients and controls with regard to (1) white matter and gray matter total and regional brain volumes, (2) cerebellar tissue microstructure metrics (eg, mean diffusivity), and (3) functional connectivity in the visuospatial, auditory, and executive control subnetworks. RESULTS: Imaging studies were completed for 40 patients (mean age, 40.4 years; 23 [57.5%] men; imaging performed a median of 188 [range, 4-403] days after initial exposure) and 48 controls (mean age, 37.6 years; 33 [68.8%] men). Mean whole brain white matter volume was significantly smaller in patients compared with controls (patients: 542.22 cm3; controls: 569.61 cm3; difference, -27.39 [95% CI, -37.93 to -16.84] cm3; P < .001), with no significant difference in the whole brain gray matter volume (patients: 698.55 cm3; controls: 691.83 cm3; difference, 6.72 [95% CI, -4.83 to 18.27] cm3; P = .25). Among patients compared with controls, there were significantly greater ventral diencephalon and cerebellar gray matter volumes and significantly smaller frontal, occipital, and parietal lobe white matter volumes; significantly lower mean diffusivity in the inferior vermis of the cerebellum (patients: 7.71 × 10-4 mm2/s; controls: 8.98 × 10-4 mm2/s; difference, -1.27 × 10-4 [95% CI, -1.93 × 10-4 to -6.17 × 10-5] mm2/s; P < .001); and significantly lower mean functional connectivity in the auditory subnetwork (patients: 0.45; controls: 0.61; difference, -0.16 [95% CI, -0.26 to -0.05]; P = .003) and visuospatial subnetwork (patients: 0.30; controls: 0.40; difference, -0.10 [95% CI, -0.16 to -0.04]; P = .002) but not in the executive control subnetwork (patients: 0.24; controls: 0.25; difference: -0.016 [95% CI, -0.04 to 0.01]; P = .23). CONCLUSIONS AND RELEVANCE: Among US government personnel in Havana, Cuba, with potential exposure to directional phenomena, compared with healthy controls, advanced brain magnetic resonance imaging revealed significant differences in whole brain white matter volume, regional gray and white matter volumes, cerebellar tissue microstructural integrity, and functional connectivity in the auditory and visuospatial subnetworks but not in the executive control subnetwork. The clinical importance of these differences is uncertain and may require further study.

A surface-in gradient of thalamic damage evolves in pediatric multiple sclerosis.

OBJECTIVE: Central nervous system pathology in multiple sclerosis includes both focal inflammatory perivascular injury and injury to superficial structures, including the subpial region of the cortex, which reportedly exhibits a gradient of damage from the surface inward. We assessed how early in the multiple sclerosis course a "surface-in" process of injury suggesting progressive biology may begin. METHODS: We focused on the thalamus, which notably has both a cerebrospinal fluid (CSF) interface and a white matter interface. Thalamic volume trajectories were assessed in a prospectively followed cohort of children from initial presentation with either multiple sclerosis or monophasic acquired demyelination, and healthy controls. Voxelwise volume changes were calculated using deformation-based morphometry, and analyzed in relation to distance from the CSF interface by mixed effects modeling and semiparametric smoothing methods. RESULTS: Twenty-seven children with multiple sclerosis and 73 children with monophasic demyelination were prospectively followed with yearly brain scans (mean follow-up = 4.6 years, standard deviation = 1.9). A total of 282 healthy children with serial scans were included as controls. Relative to healthy controls, children with multiple sclerosis and children with monophasic demyelination demonstrated volume loss in thalamic regions adjacent to the white matter. However, only children with multiple sclerosis exhibited an additional surface-in gradient of thalamic injury on the ventricular side, which was already notable in the first year of clinical disease (asymptote estimate = 3.01, 95% confidence interval [CI] = 1.44-4.58, p = 0.0002) and worsened over time (asymptote:time estimate = 0.33, 95% CI = 0.12-0.54, p = 0.0021). INTERPRETATION: Our results suggest that a multiple sclerosis disease-specific surface-in process of damage can manifest at the earliest stages of the disease. ANN NEUROL 2019;85:340-351.

MIMoSA: An Automated Method for Intermodal Segmentation Analysis of Multiple Sclerosis Brain Lesions.

BACKGROUND AND PURPOSE: Magnetic resonance imaging (MRI) is crucial for in vivo detection and characterization of white matter lesions (WMLs) in multiple sclerosis. While WMLs have been studied for over two decades using MRI, automated segmentation remains challenging. Although the majority of statistical techniques for the automated segmentation of WMLs are based on single imaging modalities, recent advances have used multimodal techniques for identifying WMLs. Complementary modalities emphasize different tissue properties, which help identify interrelated features of lesions. METHODS: Method for Inter-Modal Segmentation Analysis (MIMoSA), a fully automatic lesion segmentation algorithm that utilizes novel covariance features from intermodal coupling regression in addition to mean structure to model the probability lesion is contained in each voxel, is proposed. MIMoSA was validated by comparison with both expert manual and other automated segmentation methods in two datasets. The first included 98 subjects imaged at Johns Hopkins Hospital in which bootstrap cross-validation was used to compare the performance of MIMoSA against OASIS and LesionTOADS, two popular automatic segmentation approaches. For a secondary validation, a publicly available data from a segmentation challenge were used for performance benchmarking. RESULTS: In the Johns Hopkins study, MIMoSA yielded average Sørensen-Dice coefficient (DSC) of .57 and partial AUC of .68 calculated with false positive rates up to 1%. This was superior to performance using OASIS and LesionTOADS. The proposed method also performed competitively in the segmentation challenge dataset. CONCLUSION: MIMoSA resulted in statistically significant improvements in lesion segmentation performance compared with LesionTOADS and OASIS, and performed competitively in an additional validation study.

Biodiversity of Actinomycetes associated with Caribbean sponges and their potential for natural product discovery.

Marine actinomycetes provide a rich source of structurally unique and bioactive secondary metabolites. Numerous genera of marine actinomycetes have been isolated from marine sediments as well as several sponge species. In this study, 16 different species of Caribbean sponges were collected from four different locations in the coastal waters off Puerto Rico in order to examine diversity and bioactive metabolite production of marine actinomycetes in Caribbean sponges. Sediments were also collected from each location, in order to compare actinomycete communities between these two types of samples. A total of 180 actinomycetes were isolated and identified based on 16S rRNA gene analysis. Phylogenetic analysis revealed the presence of at least 14 new phylotypes belonging to the genera Micromonospora, Verruscosispora, Streptomyces, Salinospora, Solwaraspora, Microbacterium and Cellulosimicrobium. Seventy-eight of the isolates (19 from sediments and 59 from sponges) shared 100 % sequence identity with Micromonospora sp. R1. Despite having identical 16S rRNA sequences, the bioactivity of extracts and subsequent fractions generated from the fermentation of both sponge- and sediment-derived isolates identical to Micromonospora sp. R1 varied greatly, with a marked increase in antibiotic metabolite production in those isolates derived from sponges. These results indicate that the chemical profiles of isolates with high 16S rRNA sequence homology to known strains can be diverse and dependent on the source of isolation. In addition, seven previously reported dihydroquinones produced by five different Streptomyces strains have been purified and characterized from one Streptomyces sp. strain isolated in this study from the Caribbean sponge Agelas sceptrum.

Novel linear megaplasmid from Brevibacterium sp. isolated from extreme environment.

Brevibacterium sp. Ap13, isolated from flamingo's feces in Laguna Aparejos, a high-altitude lake located at approximately 4,200 m in the northwest of Argentina was previously found to be resistant to multiple antibiotics, and was therefore screened for plasmids that may be implicated in antibiotic resistance. Brevibacterium sp. Ap13 was found to contain two plasmids of approximately 87 and 436 kb, designated pAP13 and pAP13c, respectively. Only pAP13 was stably maintained and was extensively characterized by pulsed-field gel electrophoresis to reveal that this plasmid is linear and likely has covalently linked terminal proteins associated with its 5' ends. This is the first report of a linear plasmid in the genus Brevibacterium and may provide a new tool for genetic manipulation of this commercially important genus.

First report of linear megaplasmids in the genus Micrococcus.

High-altitude wetlands (above 4200m) in the northwest of Argentina are considered pristine and extreme environments. Micrococcus sp. A1, H5, and V7, isolated from such environments, were shown to contain linear megaplasmids, designated pLMA1, pLMH5, and pLMV7, respectively. As known from linear plasmids of other actinomycetes, all three plasmids were resistant to lambda exonuclease treatment, which is consistent with having terminal proteins covalently attached to their 5' DNA ends. Electrophoretic mobility, Southern analysis, and restriction endonuclease patterns revealed pLMA1 and pLMH5 being indistinguishable plasmids, even though they were found in different strains isolated from two distant wetlands - Laguna Azul and Laguna Huaca Huasi. Analysis of 16S rDNA sequences of Micrococcus sp. A1, H5, and V7 suggested a close relationship to Micrococcus luteus. Typing of isolates was performed using fingerprint patterns generated by BOX-PCR. Plasmid-deficient strains, generated from Micrococcus sp. A1, showed a significantly decreased resistance level for erythromycin.

Eccentric Training and Static Stretching Improve Hamstring Flexibility of High School Males.

OBJECTIVE: To determine if the flexibility of high-school-aged males would improve after a 6-week eccentric exercise program. In addition, the changes in hamstring flexibility that occurred after the eccentric program were compared with a 6-week program of static stretching and with a control group (no stretching). DESIGN AND SETTING: We used a test-retest control group design in a laboratory setting. Subjects were assigned randomly to 1 of 3 groups: eccentric training, static stretching, or control. SUBJECTS: A total of 69 subjects, with a mean age of 16.45 +/- 0.96 years and with limited hamstring flexibility (defined as 20 degrees loss of knee extension measured with the thigh held at 90 degrees of hip flexion) were recruited for this study. MEASUREMENTS: Hamstring flexibility was measured using the passive 90/90 test before and after the 6-week program. RESULTS: Differences were significant for test and for the test-by-group interaction. Follow-up analysis indicated significant differences between the control group (gain = 1.67 degrees ) and both the eccentric-training (gain = 12.79 degrees ) and static-stretching (gain = 12.05 degrees ) groups. No difference was found between the eccentric and static-stretching groups. CONCLUSIONS: The gains achieved in range of motion of knee extension (indicating improvement in hamstring flexibility) with eccentric training were equal to those made by statically stretching the hamstring muscles.

Screening of heavy metal-tolerant actinomycetes isolated from the Salí River.

Fifty-three strains of actinomycetes resistant to heavy metals were isolated from the Salí River in northwest Argentina. Screening procedures that involve solid and liquid synthetic media containing Cd(2+), Cu(2+), or Hg(2+) allowed the selection of six strains. These strains showed a quantitative sorption of Cd(2+) and Cu(2+) by more than 98% of the initial metal concentrations (0.1, 0.5, and 1.0 mM) tested.