Search Results (13)

Background/Objective: SeptiCyte RAPID is a transcriptional host response assay that discriminates between sepsis and non-infectious systemic inflammation (SIRS) with a one-hour turnaround time. The overall performance of this test in a cohort of 419 patients has recently been described [Balk et al., J Clin Med 2024, 13, 1194]. In this study, we present the results from a detailed stratification analysis in which SeptiCyte RAPID performance was evaluated in the same cohort across patient groups and subgroups encompassing different demographics, comorbidities and disease, sources and types of pathogens, interventional treatments, and clinically defined phenotypes. The aims were to identify variables that might affect the ability of SeptiCyte RAPID to discriminate between sepsis and SIRS and to determine if any patient subgroups appeared to present a diagnostic challenge for the test. Methods: (1) Subgroup analysis, with subgroups defined by individual demographic or clinical variables, using conventional statistical comparison tests. (2) Principal component analysis and k-means clustering analysis to investigate phenotypic subgroups defined by unique combinations of demographic and clinical variables. Results: No significant differences in SeptiCyte RAPID performance were observed between most groups and subgroups. One notable exception involved an enhanced SeptiCyte RAPID performance for a phenotypic subgroup defined by a combination of clinical variables suggesting a septic shock response. Conclusions: We conclude that for this patient cohort, SeptiCyte RAPID performance was largely unaffected by key variables associated with heterogeneity in patients suspected of sepsis. Full article

(1) Background: SeptiCyte RAPID is a molecular test for discriminating sepsis from non-infectious systemic inflammation, and for estimating sepsis probabilities. The objective of this study was the clinical validation of SeptiCyte RAPID, based on testing retrospectively banked and prospectively collected patient samples. (2) Methods: The cartridge-based SeptiCyte RAPID test accepts a PAXgene blood RNA sample and provides sample-to-answer processing in ~1 h. The test output (SeptiScore, range 0–15) falls into four interpretation bands, with higher scores indicating higher probabilities of sepsis. Retrospective (N = 356) and prospective (N = 63) samples were tested from adult patients in ICU who either had the systemic inflammatory response syndrome (SIRS), or were suspected of having/diagnosed with sepsis. Patients were clinically evaluated by a panel of three expert physicians blinded to the SeptiCyte test results. Results were interpreted under either the Sepsis-2 or Sepsis-3 framework. (3) Results: Under the Sepsis-2 framework, SeptiCyte RAPID performance for the combined retrospective and prospective cohorts had Areas Under the ROC Curve (AUCs) ranging from 0.82 to 0.85, a negative predictive value of 0.91 (sensitivity 0.94) for SeptiScore Band 1 (score range 0.1–5.0; lowest risk of sepsis), and a positive predictive value of 0.81 (specificity 0.90) for SeptiScore Band 4 (score range 7.4–15; highest risk of sepsis). Performance estimates for the prospective cohort ranged from AUC 0.86–0.95. For physician-adjudicated sepsis cases that were blood culture (+) or blood, urine culture (+)(+), 43/48 (90%) of SeptiCyte scores fell in Bands 3 or 4. In multivariable analysis with up to 14 additional clinical variables, SeptiScore was the most important variable for sepsis diagnosis. A comparable performance was obtained for the majority of patients reanalyzed under the Sepsis-3 definition, although a subgroup of 16 patients was identified that was called septic under Sepsis-2 but not under Sepsis-3. (4) Conclusions: This study validates SeptiCyte RAPID for estimating sepsis probability, under both the Sepsis-2 and Sepsis-3 frameworks, for hospitalized patients on their first day of ICU admission. Full article

Early stage chemical development presents numerous challenges, and achieving a functional balance is a major hurdle, with many early compounds not meeting the clinical requirements for advancement benchmarks due to issues like poor oral bioavailability. There is a need to develop strategies for achieving the desired systemic concentration for these compounds. This will enable further evaluation of the biological response upon a compound–target interaction, providing deeper insight into the postulated biological pathways. Our study elucidates alternative drug delivery paradigms by comparing formulation strategies across oral (PO), intraperitoneal (IP), subcutaneous (SC), and intravenous (IV) routes. While each modality boasts its own set of merits and constraints, it is the drug’s formulation that crucially influences its pharmacokinetic (PK) trajectory and the maintenance of its therapeutic levels. Our examination of model compounds G7883 and G6893 highlighted their distinct physio-chemical attributes. By harnessing varied formulation methods, we sought to fine-tune their PK profiles. PK studies showcased G7883′s extended half-life using an SC oil formulation, resulting in a 4.5-fold and 2.5-fold enhancement compared with the IP and PO routes, respectively. In contrast, with G6893, we achieved a prolonged systemic coverage time above the desired target concentration through a different approach using an IV infusion pump. These outcomes underscore the need for tailored formulation strategies, which are dictated by the compound’s innate properties, to reach the optimal in vivo systemic concentrations. Prioritizing formulation and delivery optimization early on is pivotal for effective systemic uptake, thereby facilitating a deeper understanding of biological pathways and expediting the overall clinical drug development timeline. Full article

Sexual manipulation in the giant freshwater prawn Macrobrachium rosenbergii has proven successful in generating monosex (both all-male and all-female) populations for aquaculture using a crustacean-specific endocrine gland, the androgenic gland (AG), which serves as a key masculinizing factor by producing and secreting an insulin-like AG hormone (IAG). Here, we provide a summary of the advancements from the discovery of the AG and IAG in decapods through to the development of monosex populations in M. rosenbergii. We discuss the broader sexual development pathway, which is highly divergent across decapods, and provide our future perspective on the utility of novel genetic and genomic tools in promoting refined approaches towards monosex biotechnology. Finally, the future potential benefits of deploying monosex prawn populations for environmental management are discussed. Full article

Background: The investigation of sexual fantasies is a delicate issue within sex research. Most studies have focused on the content of these fantasies, rather than on use, experiences, attitudes, and sharing issues, which are fundamental aspects within sexual therapy. The main aim of the present study was to develop and validate the “Sexual Desire and Erotic Fantasies questionnaire-Part 2. Use of Erotic Fantasies (SDEF2)”. Methods: The SDEF2 was completed by 1773 Italian participants (1105 women, 645 men, and 23 other genders). Results: The final 21-item version presented a five-factor structure (fantasies frequency, fantasies normality, fantasies importance, negative emotions, and sharing and experiencing). The SDEF2 showed good psychometric properties, internal reliability, construct, and discriminant validity, appearing to be able to differentiate between sexually clinical and functional women and men (based on the FSFI and IIEF cut-off scores). Conclusions: The possibility of assessing fantasies frequency, attitudes, and emotions may be extremely useful both for research and clinical purposes. The current study seems to validate that the SDEF2 is a useful measure of assessing the different aspects related to a fantasizing activity, which was shown to be associated with sexual functioning and satisfaction. Full article

Human neuronal loss occurs through different cellular mechanisms, mainly studied in vitro. Here, we characterized neuronal death in B. schlosseri, a marine colonial tunicate that shares substantial genomic homology with mammals and has a life history in which controlled neurodegeneration happens simultaneously in the brains of adult zooids during a cyclical phase named takeover. Using an ultrastructural and transcriptomic approach, we described neuronal death forms in adult zooids before and during the takeover phase while comparing adult zooids in takeover with their buds where brains are refining their structure. At takeover, we found in neurons clear morphologic signs of apoptosis (i.e., chromatin condensation, lobed nuclei), necrosis (swollen cytoplasm) and autophagy (autophagosomes, autolysosomes and degradative multilamellar bodies). These results were confirmed by transcriptomic analyses that highlighted the specific genes involved in these cell death pathways. Moreover, the presence of tubulovesicular structures in the brain medulla alongside the over-expression of prion disease genes in late cycle suggested a cell-to-cell, prion-like propagation recalling the conformational disorders typical of some human neurodegenerative diseases. We suggest that improved understanding of how neuronal alterations are regulated in the repeated degeneration–regeneration program of B. schlosseri may yield mechanistic insights relevant to the study of human neurodegenerative diseases. Full article

Although genetics affects early childhood caries (ECC) risk, few studies have focused on finding its specific genetic determinants. Here, we performed genome-wide association studies (GWAS) in five cohorts of children (aged up to 5 years, total N = 2974, cohorts: Center for Oral Health Research in Appalachia cohorts one and two [COHRA1, COHRA2], Iowa Fluoride Study, Iowa Head Start, Avon Longitudinal Study of Parents and Children [ALSPAC]) aiming to identify genes with potential roles in ECC biology. We meta-analyzed the GWASs testing ~3.9 million genetic variants and found suggestive evidence for association at genetic regions previously associated with caries in primary and permanent dentition, including the β-defensin anti-microbial proteins. We then integrated the meta-analysis results with gene expression data in a transcriptome-wide association study (TWAS). This approach identified four genes whose genetically predicted expression was associated with ECC (p-values < 3.09 × 10⁻⁶; CDH17, TAS2R43, SMIM10L1, TAS2R14). Some of the strongest associations were with genes encoding members of the bitter taste receptor family (TAS2R); other members of this family have previously been associated with caries. Of note, we identified the receptor encoded by TAS2R14, which stimulates innate immunity and anti-microbial defense in response to molecules released by the cariogenic bacteria, Streptococcus mutans and Staphylococcus aureus. These findings provide insight into ECC genetic architecture, underscore the importance of host-microbial interaction in caries risk, and identify novel risk genes. Full article

(1) Background: Autism spectrum disorder (ASD) is a neurodevelopmental disorder that is highly associated with various somatic conditions that can be masked by the core symptoms of ASD and thus complicate the diagnosis. Identifying co-occurring somatic disorders is critical for providing effective healthcare and social services for ASD populations and influences their long-term outcomes. A systematic assessment of co-occurring somatic conditions is essential during this ASD diagnostic process. Therefore, this study aimed to identify the organization and content of the initial somatic assessment (ISA). (2) Methods: We conducted a systematic review of the clinical practice guidelines (CPG) for the ASD diagnostic process published between January 2005 and December 2019 in English and French and performed an appraisal following the Appraisal of Guidelines Research and Evaluation, second edition (AGREE-II). (3) Results: We selected 14 CPGs that were heterogeneous in quality, with methodological scores between 32.3 and 91.9. Clinical examinations are the first step in the ISA, and the participation of pediatric, neuropediatric, and genetic specialists was highly recommended by the majority of the CPGs. The recommendations included hearing screening tests (10/14), visual examinations (8/14), and systematic genetic investigations (4/14). The CPGs also described additional investigations that should be conducted based on numerous warning signs. (4) Conclusions: Screening for consensual international warning signs is necessary to perform a comprehensive and systematic ISA during the ASD diagnostic process. A “referral form” could be used to guide clinicians and improve the coordination process. This tool may reinforce epidemiological data on co-occurring somatic disorders in patients with ASD. Full article

HIV-1 patients place an economic burden on the health system. The objectives of this study were to estimate the direct HIV-1 costs and cost-related factors of HIV-1 patients in Israel and identify cost predictors. We conducted a retrospective study of randomly selected HIV-1 patients aged ≥18 who visited a large outpatient clinic in 2015 and/or 2019. Yearly costs of physician and nurse visits, antiretroviral therapy (ART) and laboratory tests were calculated in USD using the 2020 purchasing power parities. Associations between disease characteristics and costs were analyzed using univariate and multivariable analysis. The median (IQR) total direct costs per patient per year were USD 12,387 (9813–14,124) and USD 12,835 (11,651–13,970) in 2015 (n = 284) and 2019 (n = 290), respectively. ART accounted for approximately 77% of all direct costs, followed by laboratory tests (20%) and medical visits (3%) in both studied years. Being female (USD +710), first yearly viral load <50 c/mL (+$1984) and ≥20 years with HIV-1 (USD +1056) were independently associated with higher costs. In conclusion, HIV-1 cost was stable in the studied period. Viral load and time since diagnosis were the major determinants associated with HIV-1 costs. ART and laboratory tests accounted for 97% of the costs. Therefore, these factors should be considered when planning future expenditures. Full article

Understanding the mechanisms that sustain immunological nonreactivity is essential for maintaining tissue in syngeneic and allogeneic settings, such as transplantation and pregnancy tolerance. While most transplantation rejections occur due to the adaptive immune response, the proinflammatory response of innate immunity is necessary for the activation of adaptive immunity. Botryllus schlosseri, a colonial tunicate, which is the nearest invertebrate group to the vertebrates, is devoid of T- and B-cell-based adaptive immunity. It has unique characteristics that make it a valuable model system for studying innate immunity mechanisms: (i) a natural allogeneic transplantation phenomenon that results in either fusion or rejection; (ii) whole animal regeneration and noninflammatory resorption on a weekly basis; (iii) allogeneic resorption which is comparable to human chronic rejection. Recent studies in B. schlosseri have led to the recognition of a molecular and cellular framework underlying the innate immunity loss of tolerance to allogeneic tissues. Additionally, B. schlosseri was developed as a model for studying hematopoietic stem cell (HSC) transplantation, and it provides further insights into the similarities between the HSC niches of human and B. schlosseri. In this review, we discuss why studying the molecular and cellular pathways that direct successful innate immune tolerance in B. schlosseri can provide novel insights into and potential modulations of these immune processes in humans. Full article

There is growing interest in uncovering the viral diversity present in wild animal species. The remote Antarctic region is home to a wealth of uncovered microbial diversity, some of which is associated with its megafauna, including penguin species, the dominant avian biota. Penguins interface with a number of other biota in their roles as marine mesopredators and several species overlap in their ranges and habitats. To characterize the circular single-stranded viruses related to those in the phylum Cressdnaviricota from these environmental sentinel species, cloacal swabs (n = 95) were obtained from King Penguins in South Georgia, and congeneric Adélie Penguins, Chinstrap Penguins, and Gentoo Penguins across the South Shetland Islands and Antarctic Peninsula. Using a combination of high-throughput sequencing, abutting primers-based PCR recovery of circular genomic elements, cloning, and Sanger sequencing, we detected 97 novel sequences comprising 40 ssDNA viral genomes and 57 viral-like circular molecules from 45 individual penguins. We present their detection patterns, with Chinstrap Penguins harboring the highest number of new sequences. The novel Antarctic viruses identified appear to be host-specific, while one circular molecule was shared between sympatric Chinstrap and Gentoo Penguins. We also report viral genotype sharing between three adult-chick pairs, one in each Pygoscelid species. Sequence similarity network approaches coupled with Maximum likelihood phylogenies of the clusters indicate the 40 novel viral genomes do not fall within any known viral families and likely fall within the recently established phylum Cressdnaviricota based on their replication-associated protein sequences. Similarly, 83 capsid protein sequences encoded by the viruses or viral-like circular molecules identified in this study do not cluster with any of those encoded by classified viral groups. Further research is warranted to expand knowledge of the Antarctic virome and would help elucidate the importance of viral-like molecules in vertebrate host evolution. Full article

Circoviruses infect a variety of animal species and have small (~1.8–2.2 kb) circular single-stranded DNA genomes. Recently a penguin circovirus (PenCV) was identified associated with an Adélie Penguin (Pygoscelis adeliae) with feather disorder and in the cloacal swabs of three asymptomatic Adélie Penguins at Cape Crozier, Antarctica. A total of 75 cloacal swab samples obtained from adults and chicks of three species of penguin (genus: Pygoscelis) from seven Antarctic breeding colonies (South Shetland Islands and Western Antarctic Peninsula) in the 2015−2016 breeding season were screened for PenCV. We identified new variants of PenCV in one Adélie Penguin and one Chinstrap Penguin (Pygoscelis antarcticus) from Port Charcot, Booth Island, Western Antarctic Peninsula, a site home to all three species of Pygoscelid penguins. These two PenCV genomes (length of 1986 nucleotides) share > 99% genome-wide nucleotide identity with each other and share ~87% genome-wide nucleotide identity with the PenCV sequences described from Adélie Penguins at Cape Crozier ~4400 km away in East Antarctica. We did not find any evidence of recombination among PenCV sequences. This is the first report of PenCV in Chinstrap Penguins and the first detection outside of Ross Island, East Antarctica. Given the limited knowledge on Antarctic animal viral diversity, future samples from Antarctic wildlife should be screened for these and other viruses to determine the prevalence and potential impact of viral infections. Full article

Tuberculosis (TB), the leading single infectious diseases killer globally, is driven by poverty. Conversely, having TB worsens impoverishment. During TB illness, lost income and out-of-pocket costs can become “catastrophic”, leading patients to abandon treatment, develop drug-resistance, and die. WHO’s 2015 End TB Strategy recommends eliminating catastrophic costs and providing socioeconomic support for TB-affected people. However, there is negligible evidence to guide the design and implementation of such socioeconomic support, especially in low-income, TB-endemic countries. A national, multi-sectoral workshop was held in Kathmandu, Nepal, on the 11th and 12th September 2019, to develop a shortlist of feasible, locally appropriate socioeconomic support interventions for TB-affected households in Nepal, a low-income country with significant TB burden. The workshop brought together key stakeholders in Nepal including from the Ministry of Health and Population, Department of Health Services, Provincial Health Directorate, Health Offices, National TB Program (NTP); and TB/Leprosy Officers, healthcare workers, community health volunteers, TB-affected people, and external development partners (EDP). During the workshop, participants reviewed current Nepal NTP data and strategy, discussed the preliminary results of a mixed-methods study of the socioeconomic determinants and consequences of TB in Nepal, described existing and potential socioeconomic interventions for TB-affected households in Nepal, and selected the most promising interventions for future randomized controlled trial evaluations in Nepal. This report describes the activities, outcomes, and recommendations from the workshop. Full article