Mitochondrial genome of the fluke pond snail, Austropeplea cf. brazieri (Gastropoda: Lymnaeidae).

BACKGROUND: Lymnaeid snails of the genus Austropeplea are an important vector of the liver fluke (Fasciola hepatica), contributing to livestock production losses in Australia and New Zealand. However, the species status within Austropeplea is ambiguous due to heavy reliance on morphological analysis and a relative lack of genetic data. This study aimed to characterise the mitochondrial genome of A. cf. brazieri, an intermediate host of liver fluke in eastern Victoria. METHODS: The mitochondrial genome was assembled and annotated from a combination of second- and third-generation sequencing data. For comparative purposes, we performed phylogenetic analyses of the concatenated nucleotide sequences of the mitochondrial protein-coding genes, cytochrome c oxidase subunit 1 and 16S genes. RESULTS: The assembled mt genome was 13,757 base pairs and comprised 37 genes, including 13 protein-coding genes, 22 transfer RNA genes and 2 ribosomal RNA genes. The mt genome length, gene order and nucleotide compositions were similar to related species of lymnaeids. Phylogenetic analyses of the mt nucleotide sequences placed A. cf. brazieri within the same clade as Orientogalba ollula with strong statistical supports. Phylogenies of the cox1 and 16S mt sequences were constructed due to the wide availability of these sequences representing the lymnaeid taxa. As expected in both these phylogenies, A. cf. brazieri clustered with other Austropeplea sequences, but the nodal supports were low. CONCLUSIONS: The representative mt genome of A. cf. brazieri should provide a useful resource for future molecular, epidemiology and parasitological studies of this socio-economically important lymnaeid species.

Synthesis and antibacterial action of 3',6'-disubstituted spectinomycins.

Spectinomycin is an aminocyclitol antibiotic with a unique ribosomal binding site. Prior synthetic modifications of spectinomycin have enhanced potency and antibacterial spectrum through addition at the 6'-position to produce trospectomycin and to the 3'-position to produce spectinamides and aminomethyl spectinomycins. This study focused on the design, synthesis, and evaluation of three 3',6'-disubstituted spectinomycin analogs: trospectinamide, N-benzyl linked aminomethyl, and N-ethylene linked aminomethyl trospectomycins. Computational experiments predicted that these disubstituted analogs would be capable of binding within the SPC ribosomal binding site. The new analogs were synthesized from trospectomycin, adapting the previously established routes for the spectinamide and aminomethyl spectinomycin series. In a cell-free translation assay, the disubstituted analogs showed ribosomal inhibition similar to spectinomycin or trospectomycin. These disubstituted analogs demonstrated inhibitory MIC activity against various bacterial species with the 3'-modification dictating spectrum of activity, leading to improved activity against mycobacterium species. Notably, N-ethylene linked aminomethyl trospectomycins exhibited increased potency against Mycobacterium abscessus and trospectinamide displayed robust activity against M. tuberculosis, aligning with the selective efficacy of spectinamides. The study also found that trospectomycin is susceptible to efflux in M. tuberculosis and M. abscessus. These findings contribute to the understanding of the structure-activity relationship of spectinomycin analogs and can guide the design and synthesis of more effective spectinomycin compounds.

Exosomes, and the potential for exosome-based interventions against COVID-19.

Since late 2019, the world has been devastated by the coronavirus disease 2019 (COVID-19) induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with more than 760 million people affected and ∼seven million deaths reported. Although effective treatments for COVID-19 are currently limited, there has been a strong focus on developing new therapeutic approaches to address the morbidity and mortality linked to this disease. An approach that is currently being investigated is the use of exosome-based therapies. Exosomes are small, extracellular vesicles that play a role in many clinical diseases, including viral infections, infected cells release exosomes that can transmit viral components, such as miRNAs and proteins, and can also include receptors for viruses that facilitate viral entry into recipient cells. SARS-CoV-2 has the ability to impact the formation, secretion, and release of exosomes, thereby potentially facilitating or intensifying the transmission of the virus among cells, tissues and individuals. Therefore, designing synthetic exosomes that carry immunomodulatory cargo and antiviral compounds are proposed to be a promising strategy for the treatment of COVID-19 and other viral diseases. Moreover, exosomes generated from mesenchymal stem cells (MSC) might be employed as cell-free therapeutic agents, as MSC-derived exosomes can diminish the cytokine storm and reverse the suppression of host anti-viral defences associated with COVID-19, and boost the repair of lung damage linked to mitochondrial activity. The present article discusses the significance and roles of exosomes in COVID-19, and explores potential future applications of exosomes in combating this disease. Despite the challenges posed by COVID-19, exosome-based therapies could represent a promising avenue for improving patient outcomes and reducing the impact of this disease.

Longitudinal prediction of psychosocial functioning outcomes: Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Section-II personality disorders versus alternative model personality dysfunction and traits.

We aimed to determine and compare the longitudinal predictive power of Diagnostic and Statistical Manual of Mental Disorders, fifth edition's (DSM-5) two models of personality disorder (PD) for multiple clinically relevant outcomes. A sample of 600 community-dwelling adults-half recruited by calling randomly selected phone numbers and screening-in for high-risk for personality pathology and half in treatment for mental health problems-completed an extensive battery of self-report and interview measures of personality pathology, clinical symptoms, and psychosocial functioning. Of these, 503 returned for retesting on the same measures an average of 8 months later. We used Time 1 interview data to assess DSM-5 personality pathology, both the Section-II PDs and the alternative (DSM-5) model of personality disorder's (AMPD) Criterion A (impairment) and Criterion B (adaptive-to-maladaptive-range trait domains and facets). We used these measures to predict 20 Time 2 functioning outcomes. Both PD models significantly predicted functioning-outcome variance, albeit modestly-averaging 12.6% and 17.9% (Section-II diagnoses and criterion counts, respectively) and 15.2% and 23.2% (AMPD domains and facets, respectively). Each model significantly augmented the other in hierarchical regressions, but the AMPD domains (6.30%) and facets (8.62%) predicted more incremental variance than the Section-II diagnoses (3.74%) and criterion counts (3.31%), respectively. Borderline PD accounted for just over half of Section II's predictive power, whereas the AMPD's predictive power was more evenly distributed across components. We note the predictive advantages of dimensional models and articulate the theoretical and clinical advantages of the AMPD's separation of personality functioning impairment from how this is manifested in personality traits. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Hypothesized life cycle of the snow algae Chlainomonas sp. (Chlamydomonadales, Chlorophyta) from the Cascade Mountains, USA.

Chlainomonas (Chlamydomonadales, Chlorophyta) is one of the four genera of snow algae known to produce annual pink or red blooms in alpine snow. No Chlainomonas species have been successfully cultured in the laboratory, but diverse cell types have been observed from many field-collected samples, from multiple species. The diversity of morphologies suggests these algae have complex life cycles with changes in ploidy. Over 7 years (2017-2023), we observed seasonal blooms dominated by a Chlainomonas species from late spring through the summer months on a snow-on-lake habitat in an alpine basin in the North Cascade Mountains of Washington, USA. The Bagley Lake Chlainomonas is distinct from previously reported species based on morphology and sequence data. We observed a similar collection of cell types observed in other Chlainomonas species, with the addition of swarming biflagellate cells that emerged from sporangia. We present a life cycle hypothesis for this species that links cell morphologies observed in the field to seasonally available habitat. The progression of cell types suggests cells are undergoing both meiosis and fertilization in the life cycle. Since the life cycle is the most fundamental biological feature of an organism, with direct consequences for evolutionary processes, it is critical to understand how snow algal life cycles will influence their responses to changes in their habitat driven by climate warming. For microbial taxa that live in extreme environments and are difficult to culture, temporal field studies, such as we report here, may be key to creating testable hypotheses for life cycles.

Early-onset Colorectal Cancer Patients Do Not Require Shorter Intervals for Post-surgical Surveillance Colonoscopy.

BACKGROUND & AIMS: Early-onset colorectal cancer (EO-CRC), diagnosed before age 50, is rising in incidence worldwide. Although post-surgical colonoscopy surveillance strategies exist, appropriate intervals in EO-CRC remain elusive, as long-term surveillance outcomes remain scant. We sought to compare findings of surveillance colonoscopies of EO-CRC with patients with average onset colorectal cancer (AO-CRC) to help define surveillance outcomes in these groups. METHODS: Single-institution retrospective chart review identified EO-CRC and AO-CRC patients with colonoscopy and no evidence of disease. Surveillance intervals and time to development of advanced neoplasia (CRC and advanced polyps [adenoma/sessile serrated]) were examined. For each group, 3 serial surveillance colonoscopies were evaluated. Statistical analyses were performed utilizing log-ranked Kaplan-Meier method and Cox proportional hazards. RESULTS: A total of 1259 patients with CRC were identified, with 612 and 647 patients in the EO-CRC and AO-CRC groups, respectively. Compared with patients with AO-CRC, patients with EO-CRC had a 29% decreased risk of developing advanced neoplasia from time of initial surgery to first surveillance colonoscopy (hazard ratio, 0.71; 95% confidence interval, 0.52-1.0). Average follow-up time from surgical resection to first surveillance colonoscopy was 12.6 months for both cohorts. Overall surveillance findings differed between cohorts (P = .003), and patients with EO-CRC were found to have less advanced neoplasia compared with their counterparts with AO-CRC (12.4% vs 16.0%, respectively). Subsequent colonoscopies found that, while patients with EO-CRC returned for follow-up surveillance colonoscopy earlier than patients with AO-CRC, the EO-CRC cohort did not have more advanced neoplasia nor non-advanced adenomas. CONCLUSIONS: Patients with EO-CRC do not have an increased risk of advanced neoplasia compared with patients with AO-CRC and therefore do not require more frequent colonoscopy surveillance than current guidelines recommend.

Phytochemical Profiling Studies of Alkaloids and Coumarins from the Australian Plant Geijera parviflora Lindl. (Rutaceae) and Their Anthelmintic and Antimicrobial Assessment.

Phytochemical profiling followed by antimicrobial and anthelmintic activity evaluation of the Australian plant Geijera parviflora, known for its customary use in Indigenous Australian ceremonies and bush medicine, was performed. In the present study, seven previously reported compounds were isolated including auraptene, 6'-dehydromarmin, geiparvarin, marmin acetonide, flindersine, and two flindersine derivatives from the bark and leaves, together with a new compound, chlorogeiparvarin, formed as an artefact during the isolation procedure and isolated as a mixture with geiparvarin. Chemical profiling allowed for a qualitative and quantitative comparison of the compounds in the leaves, bark, flowers, and fruit of this plant. Subsequently, a subset of these compounds as well as crude extracts from the plant were evaluated for their antimicrobial and anthelmintic activities. Anthelmintic activity assays showed that two of the isolated compounds, auraptene and flindersine, as well as the dichloromethane and methanol crude extracts of G. parviflora, displayed significant activity against a parasitic nematode (Haemonchus contortus). This is the first report of the anthelmintic activity associated with these compounds and indicates the importance of such fundamental explorations for the discovery of bioactive phytochemicals for therapeutic application(s).

Root Cause Analysis of Delayed Emergency Department Computed Tomography Scans.

Introduction: A solution for emergency department (ED) congestion remains elusive. As reliance on imaging grows, computed tomography (CT) turnaround time has been identified as a major bottleneck. In this study we sought to identify factors associated with significantly delayed CT in the ED. Methods: We performed a retrospective analysis of all CT imaging completed at an urban, tertiary care ED from May 1-July 31, 2021. During that period, 5,685 CTs were performed on 4,344 patients, with a median time from CT order to completion of 108 minutes (Quartile 1 [Q1]: 57 minutes, Quartile 3 [Q3]: 182 minutes, interquartile range [IQR]: 125 minutes). Outliers were defined as studies that took longer than 369 minutes to complete (Q3 + 1.5 × IQR). We systematically reviewed outlier charts to determine factors associated with delay and identified five factors: behaviorally non-compliant or medically unstable patients; intravenous (IV) line issues; contrast allergies; glomerular filtration rate (GFR) concerns; and delays related to imaging protocol (eg, need for IV contrast, request for oral and/or rectal contrast). We calculated confidence intervals (CI) using the modified Wald method. Inter-rater reliability was assessed with a kappa analysis. Results: We identified a total of 182 outliers (4.2% of total patients). Fifteen (8.2%) cases were excluded for CT time-stamp inconsistencies. Of the 167 outliers analyzed, 38 delays (22.8%, 95% confidence interval [CI] 17.0-29.7) were due to behaviorally non-compliant or medically unstable patients; 30 (18.0%, 95% CI 12.8-24.5) were due to IV issues; 24 (14.4%, 95% CI 9.8-20.6) were due to contrast allergies; 21 (12.6%, 95% CI 8.3-18.5) were due to GFR concerns; and 20 (12.0%, 95% CI 7.8-17.9) were related to imaging study protocols. The cause of the delay was unknown in 55 cases (32.9%, 95% CI 26.3-40.4). Conclusion: Our review identified both modifiable and non-modifiable factors associated with significantly delayed CT in the ED. Patient factors such as behavior, allergies, and medical acuity cannot be controlled. However, institutional policies regarding difficult IV access, contrast administration in low GFR settings, and study protocols may be modified, capturing up to 42.6% of outliers.

Complete Mitochondrial Genome for Lucilia cuprina dorsalis (Diptera: Calliphoridae) from the Northern Territory, Australia.

The Australian sheep blowfly, Lucilia cuprina dorsalis, is a major sheep ectoparasite causing subcutaneous myiasis (flystrike), which can lead to reduced livestock productivity and, in severe instances, death of the affected animals. It is also a primary colonizer of carrion, an efficient pollinator, and used in maggot debridement therapy and forensic investigations. In this study, we report the complete mitochondrial (mt) genome of L. c. dorsalis from the Northern Territory (NT), Australia, where sheep are prohibited animals, unlike the rest of Australia. The mt genome is 15,943 bp in length, comprising 13 protein-coding genes (PCGs), two ribosomal RNAs (rRNAs), 22 transfer RNAs (tRNAs), and a non-coding control region. The gene order of the current mt genome is consistent with the previously published L. cuprina mt genomes. Nucleotide composition revealed an AT bias, accounting for 77.5% of total mt genome nucleotides. Phylogenetic analyses of 56 species/taxa of dipterans indicated that L. c. dorsalis and L. sericata are the closest among all sibling species of the genus Lucilia, which helps to explain species evolution within the family Luciliinae. This study provides the first complete mt genome sequence for L. c. dorsalis derived from the NT, Australia to facilitate species identification and the examination of the evolutionary history of these blowflies.

New records of Hepatozoon and Oswaldofilaria from saltwater crocodiles (Crocodylus porosus) in Australia.

Diseases affecting wild Australian saltwater crocodiles (Crocodylus porosus) are rarely reported due to the difficulty in capturing animals and obtaining samples. In this investigation, we identified two haemoparasites (Hepatozoon and a filarial nematode) in saltwater crocodiles in Darwin, Australia. Light microscopic examination identified Hepatozoon in 7/7 (100%) wild crocodiles and in 2/20 (10%) of captive ones. When genomic DNAs from these same samples were further investigated using polymerase chain reaction (PCR)-based sequencing, we detected Hepatozoon in all 27 blood samples. Using both microscopy and PCR-based sequencing, we detected a filarial worm (proposed to be Oswaldofilaria) in one of 20 captive crocodiles. The sequence data were compared with sequence data available in public databases, and phylogenetic analyses indicated that the operational taxonomic units of Hepatozoon and Oswaldofilaria discovered here in these crocodiles are likely new species. This study is the first to use molecular tools to explore haemoparasites in Australian saltwater crocodiles and highlights the importance of health investigations in poorly studied vertebrate hosts.

Prenatal and Postnatal Disparities in Very-Preterm Infants in a Study of Infections between 2018-2023 in Southeastern US.

BACKGROUND: The birthrate of Black preterm (BPT) infants is 65% higher than White preterm (WPT) infants with a BPT mortality that is 2.3 times higher. The incidence of culture-positive late-onset sepsis is as high as 41% in very-preterm infants. The main purpose of this study was to examine thermal gradients and the heart rate in relation to the onset of infection. This report presents disparities in very-preterm infection incidence, bacteria, and mortality data amongst BPT and WPT infants. METHODS: 367 preterms born at <32 weeks gestational age (GA) between 2019-2023 in five neonatal intensive care units (NICUs) were enrolled to study the onset of infections and dispositions; REDCap data were analyzed for descriptive statistics. RESULTS: The 362 infants for analyses included 227 BPTs (63.7%) and 107 WPTs (29.6%), with 28 infants of other races/ethnicities (Hispanic, Asian, and other), 50.6% female, mean GA of 27.66 weeks, and 985.24 g birthweight. BPT infants averaged 968.56 g at birth (SD 257.50), and 27.68 (SD 2.07) weeks GA, compared to WPT infants with a mean birthweight of 1006.25 g (SD 257.77, p = 0.2313) and 27.67 (SD 2.00, p = 0.982) weeks GA. Of the 426 episodes of suspected infections evaluated across all the enrolled infants, the incidence of early-onset sepsis (EOS) was 1.9%, with BPT infants having 2.50 times higher odds of EOS than WPT infants (p = 0.4130, OR (odds ratio) = 2.50, p_or = 0.408). The overall incidence of late-onset sepsis (LOS) was 10.8%, with LOS in 11.9% of BPT infants versus 9.3% (p = 0.489, OR = 1.21, p_or = 0.637) of WPT infants. BPT infants made up 69.2% of the 39 infants with Gram-positive infections vs. 25.6% for WPT infants; 16 infants had Gram-negative culture-positive infections, with 81.2% being BPT infants versus 18.8% being WPT infants. Of the 27 urinary tract infections, 78% were in BPTs. The necrotizing enterocolitis incidence was 6.9%; the incidence in BPT infants was 7.5% vs. 6.5% in WPT infants. The overall mortality was 8.3%, with BPTs at 8.4% vs. WPT infants at 9.3%, (p = 0.6715). CONCLUSIONS: BPTs had a higher rate of positive cultures, double the Gram-negative infections, a much higher rate of urinary tract infections, and a higher rate of mortality than their WPT counterparts. This study emphasizes the higher risk of morbidity and mortality for BPTs.

MINocyclinE to Reduce inflammation and blood-brain barrier leakage in small Vessel diseAse (MINERVA): A phase II, randomized, double-blind, placebo-controlled experimental medicine trial.

INTRODUCTION: Cerebral small vessel disease (SVD) is a common cause of stroke/vascular dementia with few effective treatments. Neuroinflammation and increased blood-brain barrier (BBB) permeability may influence pathogenesis. In rodent models, minocycline reduced inflammation/BBB permeability. We determined whether minocycline had a similar effect in patients with SVD. METHODS: MINERVA was a single-center, phase II, randomized, double-blind, placebo-controlled trial. Forty-four participants with moderate-to-severe SVD took minocycline or placebo for 3 months. Co-primary outcomes were microglial signal (determined using 11C-PK11195 positron emission tomography) and BBB permeability (using dynamic contrast-enhanced MRI). RESULTS: Forty-four participants were recruited between September 2019 and June 2022. Minocycline had no effect on 11C-PK11195 binding (relative risk [RR] 1.01, 95% confidence interval [CI] 0.98-1.04), or BBB permeability (RR 0.97, 95% CI 0.91-1.03). Serum inflammatory markers were not affected. DISCUSSION: 11C-PK11195 binding and increased BBB permeability are present in SVD; minocycline did not reduce either process. Whether these pathophysiological mechanisms are disease-causing remains unclear. INTERNATIONAL CLINICAL TRIALS REGISTRY PORTAL IDENTIFIER: ISRCTN15483452 HIGHLIGHTS: We found focal areas of increased microglial signal and increased blood-brain barrier permeability in patients with small vessel disease. Minocycline treatment was not associated with a change in these processes measured using advanced neuroimaging. Blood-brain barrier permeability was dynamic but MRI-derived measurements correlated well with CSF/serum albumin ratio. Advanced neuroimaging is a feasible outcome measure for mechanistic clinical trials.

Understanding Symptom Self-Monitoring Needs Among Postpartum Black Patients: Qualitative Interview Study.

BACKGROUND: Pregnancy-related death is on the rise in the United States, and there are significant disparities in outcomes for Black patients. Most solutions that address pregnancy-related death are hospital based, which rely on patients recognizing symptoms and seeking care from a health system, an area where many Black patients have reported experiencing bias. There is a need for patient-centered solutions that support and encourage postpartum people to seek care for severe symptoms. OBJECTIVE: We aimed to determine the design needs for a mobile health (mHealth) patient-reported outcomes and decision-support system to assist Black patients in assessing when to seek medical care for severe postpartum symptoms. These findings may also support different perinatal populations and minoritized groups in other clinical settings. METHODS: We conducted semistructured interviews with 36 participants-15 (42%) obstetric health professionals, 10 (28%) mental health professionals, and 11 (31%) postpartum Black patients. The interview questions included the following: current practices for symptom monitoring, barriers to and facilitators of effective monitoring, and design requirements for an mHealth system that supports monitoring for severe symptoms. Interviews were audio recorded and transcribed. We analyzed transcripts using directed content analysis and the constant comparative process. We adopted a thematic analysis approach, eliciting themes deductively using conceptual frameworks from health behavior and human information processing, while also allowing new themes to inductively arise from the data. Our team involved multiple coders to promote reliability through a consensus process. RESULTS: Our findings revealed considerations related to relevant symptom inputs for postpartum support, the drivers that may affect symptom processing, and the design needs for symptom self-monitoring and patient decision-support interventions. First, participants viewed both somatic and psychological symptom inputs as important to capture. Second, self-perception; previous experience; sociocultural, financial, environmental, and health systems-level factors were all perceived to impact how patients processed, made decisions about, and acted upon their symptoms. Third, participants provided recommendations for system design that involved allowing for user control and freedom. They also stressed the importance of careful wording of decision-support messages, such that messages that recommend them to seek care convey urgency but do not provoke anxiety. Alternatively, messages that recommend they may not need care should make the patient feel heard and reassured. CONCLUSIONS: Future solutions for postpartum symptom monitoring should include both somatic and psychological symptoms, which may require combining existing measures to elicit symptoms in a nuanced manner. Solutions should allow for varied, safe interactions to suit individual needs. While mHealth or other apps may not be able to address all the social or financial needs of a person, they may at least provide information, so that patients can easily access other supportive resources.

Analysis of Haemonchus embryos at single cell resolution identifies two eukaryotic elongation factors as intervention target candidates.

Advances in single cell technologies are allowing investigations of a wide range of biological processes and pathways in animals, such as the multicellular model organism Caenorhabditis elegans - a free-living nematode. However, there has been limited application of such technology to related parasitic nematodes which cause major diseases of humans and animals worldwide. With no vaccines against the vast majority of parasitic nematodes and treatment failures due to drug resistance or inefficacy, new intervention targets are urgently needed, preferably informed by a deep understanding of these nematodes' cellular and molecular biology - which is presently lacking for most worms. Here, we created the first single cell atlas for an early developmental stage of Haemonchus contortus - a highly pathogenic, C. elegans-related parasitic nematode. We obtained and curated RNA sequence (snRNA-seq) data from single nuclei from embryonating eggs of H. contortus (150,000 droplets), and selected high-quality transcriptomic data for > 14,000 single nuclei for analysis, and identified 19 distinct clusters of cells. Guided by comparative analyses with C. elegans, we were able to reproducibly assign seven cell clusters to body wall muscle, hypodermis, neuronal, intestinal or seam cells, and identified eight genes that were transcribed in all cell clusters/types, three of which were inferred to be essential in H. contortus. Two of these genes (i.e. Hc-eef-1A and Hc-eef1G), coding for eukaryotic elongation factors (called Hc-eEF1A and Hc-eEF1G), were also demonstrated to be transcribed and expressed in all key developmental stages of H. contortus. Together with these findings, sequence- and structure-based comparative analyses indicated the potential of Hc-eEF1A and/or Hc-eEF1G as intervention targets within the protein biosynthesis machinery of H. contortus. Future work will focus on single cell studies of all key developmental stages and tissues of H. contortus, and on evaluating the suitability of the two elongation factor proteins as drug targets in H. contortus and related nematodes, with a view to finding new nematocidal drug candidates.

The Role of Screening and Early Detection in Upper Gastrointestinal Cancers.

Upper gastrointestinal cancers are among the leading causes of cancer deaths worldwide with exceptionally poor prognosis, which is largely attributable to frequently delayed diagnosis. Although effective screening is critical for early detection, the highly variable incidence of upper gastrointestinal cancers presents challenges, rendering universal screening programs suboptimal in most populations globally. Optimal strategies in regions of modest incidence, such as the United States, require a targeted approach, focused on high-risk individuals based on demographic, familial, and clinicopathologic risk factors. Assessment of underlying precancerous lesions has key implications for risk stratification and informing clinical decisions to improve patient outcomes.

Are central and systemic inflammation associated with fatigue in cerebral small vessel disease?

BACKGROUND: Fatigue is a common symptom in cerebral small vessel disease (SVD), but its pathogenesis is poorly understood. It has been suggested that inflammation may play a role. We determined whether central (neuro) inflammation and peripheral inflammation were associated with fatigue in SVD. METHODS: Notably, 36 patients with moderate-to-severe SVD underwent neuropsychometric testing, combined positron emission tomography and magnetic resonance imaging (PET-MRI) scan, and blood draw for the analysis of inflammatory blood biomarkers. Microglial signal was taken as a proxy for neuroinflammation, assessed with radioligand 11C-PK11195. Of these, 30 subjects had full PET datasets for analysis. We assessed global 11C-PK11195 binding and hotspots of 11C-PK11195 binding in the normal-appearing white matter, lesioned tissue, and combined total white matter. Peripheral inflammation was assessed with serum C-reactive protein (CRP) and using the Olink cardiovascular III proteomic panel comprising 92 biomarkers of cardiovascular inflammation and endothelial activation. Fatigue was assessed using the fatigue severity scale (FSS), the visual analog fatigue scale, and a subscale of the Geriatric Depression Scale. RESULTS: Mean (SD) age was 68.7 (11.2) years, and 63.9% were male. Of these, 55.6% showed fatigue on the FSS. Fatigued participants had higher disability scores (p = 0.02), higher total GDS scores (p = 0.02), and more commonly reported a history of depression (p = 0.04). 11C-PK11195 ligand binding in the white matter was not associated with any measure of fatigue. Serum CRP was significantly associated with average fatigue score on FSS (ρ = 0.48, p = 0.004); this association persisted when controlling for age, sex, disability score, and depression (ß = 0.49, 95% CI (0.17, 2.26), p = 0.03). Blood biomarkers from the Olink panel showed no association with fatigue. CONCLUSION: In symptomatic SVD patients, neuroinflammation, assessed with microglial marker 11C-PK11195, was not associated with fatigue. We found some evidence for a role of systematic inflammation, evidenced by an association between fatigue severity and raised CRP, but further studies are required to understand this relationship and inform whether it could be therapeutically modified to reduce fatigue severity. DATA ACCESS STATEMENT: Data for this study are available from the corresponding author upon reasonable request.

Comparative structure activity and target exploration of 1,2-diphenylethynes in Haemonchus contortus and Caenorhabditis elegans.

Infections and diseases caused by parasitic nematodes have a major adverse impact on the health and productivity of animals and humans worldwide. The control of these parasites often relies heavily on the treatment with commercially available chemical compounds (anthelmintics). However, the excessive or uncontrolled use of these compounds in livestock animals has led to major challenges linked to drug resistance in nematodes. Therefore, there is a need to develop new anthelmintics with novel mechanism(s) of action. Recently, we identified a small molecule, designated UMW-9729, with nematocidal activity against the free-living model organism Caenorhabditis elegans. Here, we evaluated UMW-9729's potential as an anthelmintic in a structure-activity relationship (SAR) study in C. elegans and the highly pathogenic, blood-feeding Haemonchus contortus (barber's pole worm), and explored the compound-target relationship using thermal proteome profiling (TPP). First, we synthesised and tested 25 analogues of UMW-9729 for their nematocidal activity in both H. contortus (larvae and adults) and C. elegans (young adults), establishing a preliminary nematocidal pharmacophore for both species. We identified several compounds with marked activity against either H. contortus or C. elegans which had greater efficacy than UMW-9729, and found a significant divergence in compound bioactivity between these two nematode species. We also identified a UMW-9729 analogue, designated 25, that moderately inhibited the motility of adult female H. contortus in vitro. Subsequently, we inferred three H. contortus proteins (HCON_00134350, HCON_00021470 and HCON_00099760) and five C. elegans proteins (F30A10.9, F15B9.8, B0361.6, DNC-4 and UNC-11) that interacted directly with UMW-9729; however, no conserved protein target was shared between the two nematode species. Future work aims to extend the SAR investigation in these and other parasitic nematode species, and validate individual proteins identified here as possible targets of UMW-9729. Overall, the present study evaluates this anthelmintic candidate and highlights some challenges associated with early anthelmintic investigation.

Ocular Dirofilariasis in Migrant from Sri Lanka, Australia.

We describe a case of imported ocular dirofilariasis in Australia, linked to the Hong Kong genotype of Dirofilaria sp., in a migrant from Sri Lanka. Surgical extraction and mitochondrial sequences analyses confirmed this filarioid nematode as the causative agent and a Dirofilaria sp. not previously reported in Australia.

A phenotypic screen of the Global Health Priority Box identifies an insecticide with anthelmintic activity.

BACKGROUND: Infection with parasitic nematodes (helminths), particularly those of the order Strongylida (such as Haemonchus contortus), can cause significant and burdensome diseases in humans and animals. Widespread drug (anthelmintic) resistance in livestock parasites, the absence of vaccines against most of these nematodes, and a lack of new and effective chemical entities on the commercial market demands the discovery of new anthelmintics. In the present study, we searched the Global Health Priority Box (Medicines for Malaria Venture) for new candidates for anthelmintic development. METHODS: We employed a whole-organism, motility-based phenotypic screening assay to identify compounds from the Global Health Priority Box with activity against larvae of the model parasite H. contortus, and the free-living comparator nematode Caenorhabditis elegans. Hit compounds were further validated via dose-response assays, with lead candidates then assessed for nematocidal activity against H. contortus adult worms, and additionally, for cytotoxic and mitotoxic effects on human hepatoma (HepG2) cells. RESULTS: The primary screen against H. contortus and C. elegans revealed or reidentified 16 hit compounds; further validation established MMV1794206, otherwise known as 'flufenerim', as a significant inhibitor of H. contortus larval motility (half-maximal inhibitory concentration [IC50] = 18 µM) and development (IC50 = 1.2 µM), H. contortus adult female motility (100% after 12 h of incubation) and C. elegans larval motility (IC50 = 0.22 µM). Further testing on a mammalian cell line (human hepatoma HepG2 cells), however, identified flufenerim to be both cytotoxic (half-maximal cytotoxic concentration [CC50] < 0.7 µM) and mitotoxic (half-maximal mitotoxic concentration [MC50] < 0.7 µM). CONCLUSIONS: The in vitro efficacy of MMV1794206 against the most pathogenic stages of H. contortus, as well as the free-living C. elegans, suggests the potential for development as a broad-spectrum anthelmintic compound; however, the high toxicity towards mammalian cells presents a significant hindrance. Further work should seek to establish the protein-drug interactions of MMV1794206 in a nematode model, to unravel the mechanism of action, in addition to an advanced structure-activity relationship investigation to optimise anthelmintic activity and eliminate mammalian cell toxicity.