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Abstract Genome-wide association studies have identified a protective mutation in the phospholipase C gamma 2 (PLCG2) gene which confers protection against Alzheimer’s disease (AD)-associated cognitive decline. Therefore, PLCG2, which is primarily expressed in immune cells, has become a target of interest for potential therapeutic intervention. The protective allele, known as P522R, has been shown to be hyper-morphic in microglia, increasing phagocytosis of amyloid-beta (Aβ), and increasing the release of inflammatory cytokines. However, the effect of this protective mutation on peripheral tissue-resident macrophages, and the extent to which sex modifies this effect, has yet to be assessed. Herein, we show that peripheral macrophages carrying the P522R mutation do indeed show functional differences compared to their wild-type (WT) counterparts, however, these alterations occur in a sex-dependent manner. In macrophages from females, the P522R mutation increases lysosomal protease activity, cytokine secretion, and gene expression associated with cytokine secretion and apoptosis. In contrast, in macrophages from males, the mutation causes decreased phagocytosis and lysosomal protease activity, modest increases in cytokine secretion, and induction of gene expression associated with negative regulation of the immune response. Taken together, these results suggest that the mutation may be conferring different effects dependent on sex and cell type, and highlight the importance of considering sex as a biological variable when assessing the effects of genetic variants and implications for potential immune system-targeted therapies.

A new genus, Nilssondytes gen. nov., is described for a unique new species, Nilssondytes diversus sp. nov., from Venezuela. This paper corrects an inadvertent mistake in a paper by the authors (Miller et al. 2024) in which the collection of deposition of the holotype of the species was not indicated making the new species unavailable which, therefore, made the new genus unavailable. A review of the relevant parts of the International Code of Zoological Nomenclature is included. Diagnostic features of the new genus and species are discussed and illustrated.

Jean Pierre Gafaranga,1,2 Leopold Bitunguhari,3,4 Charles Mudenge,1,5 Felix Manirakiza,6,7 Brian Kelly,8 Paul Gatabazi9– 11 1Department of Psychiatry and Behavioral Sciences, School of Medicine and Pharmacy, University of Rwanda, Kigali, Rwanda; 2Department of Mental Health, University Teaching Hospital of Kigali, Kigali, Rwanda; 3Department of Internal Medicine, University Teaching Hospital of Kigali, Kigali, Rwanda; 4Department of Internal Medicine, School of Medicine and Pharmacy, University of Rwanda, Kigali, Rwanda; 5Department of Psychiatry, Ndera Neuropsychiatric Teaching Hospital, Kigali, Rwanda; 6Department of Clinical Biology, School of Medicine and Pharmacy, University of Rwanda, Kigali, Rwanda; 7Department of Pathology, University Teaching Hospital of Kigali, Kigali, Rwanda; 8School of Medicine and Public Health, University of Newcastle, Callaghan, NSW, Australia; 9School of Economics and Business, College of Business and Economics, University of Johannesburg, Johannesburg, South Africa; 10Department of Mathematics and Applied Mathematics, University of Johannesburg, Johannesburg, South Africa; 11Department of Statistics, University of South Africa, Pretoria, South AfricaCorrespondence: Jean Pierre Gafaranga, Department of Psychiatry and Behavioral Sciences, School of Medicine and Pharmacy, University of Rwanda, Kigali, Rwanda, Tel +250788224864, Email j.p.gafaranga@ur.ac.rw; gafajepi@gmail.comBackground: Depression is a significant global public health concern, affecting individuals across different age groups and cultural backgrounds. However, screening for depression remains an essential but often neglected aspect of healthcare, particularly in outpatient settings. This study aimed to assess the prevalence of depression among outpatients visiting the internal medicine department of the University Teaching Hospital of Kigali in Rwanda and evaluate the feasibility of implementing a depression screening program in this setting.Methods: An institution-based cross-sectional study design was employed, involving 300 adult medical outpatients through convenience sampling, aged 18 years and above, who visited the internal medicine department between October 7 to November 6, 2019. The Patient Health Questionnaire-9 (PHQ-9) was used as the screening tool to assess depressive symptoms. Additionally, socio-demographic and clinical data were collected to explore potential risk factors associated with depression using a binary logistic regression model.Results: A high prevalence of depression was identified among internal medicine outpatients, with 45.7% of participants screened positive for depression, with moderate, moderately severe, and severe depression accounting for 21%, 17%, and 8%, respectively. The following factors were significantly associated with positive screening for depression: lack of formal education (OR=4.463, p=0.011, 95% CI= [1.410; 14.127]), secondary education (OR=3.402, p=0.003, 95% CI= [1.517; 7.630]), low-income (OR=2.392, p=0.049, 95% CI= [1.003; 5.706]) and headache as a chief complaint (OR=3.611, p=0.001, CI= [1.718; 7.591]).Conclusion: This study highlights the high prevalence of depression among medical outpatients. Due to the stigma associated with mental health, patients frequently seek help for physical symptoms such as headaches and other bodily complaints rather than mental health concerns. Introducing routine depression screening in medical departments could potentially facilitate early identification, and intervention, and lead to improved patient care. Future research should focus on evaluating such screening programs’ effectiveness and long-term outcomes in resource-limited settings like Rwanda.Keywords: depression, screening, medical outpatients, internal medicine department

Abstract Antibodies to programmed cell death protein 1 (anti‐PD‐1) have become a promising immunotherapy for triple negative breast cancer (TNBC), blocking PD‐L1 signaling from pro‐tumor cells through T cell PD‐1 receptor binding. Nevertheless, only 10%–20% of PD‐L1+ metastatic TNBC patients who meet criteria benefit from immune checkpoint blockade (ICB), and biomarkers to predict patient response have been elusive. We have previously developed an immunological niche, consisting of a microporous implant in the subcutaneous space, that supports tissue formation whose immune composition is consistent with that within vital organs. Herein, we investigated dynamic gene expression within this immunological niche to provide biomarkers of response to anti‐PD‐1. In a 4T1 model of metastatic TNBC, we observed sensitivity and resistance to anti‐PD‐1 based on primary tumor growth and survival. The niche was biopsied before, during, and after anti‐PD‐1 therapy, and analyzed for cell types and gene expression indicative of treatment refractivity. Myeloid cell‐to‐lymphocyte ratios were altered between ICB‐sensitivity and resistance. Longitudinal analysis of gene expression implicated dynamic myeloid cell function that stratified sensitivity from resistance. A niche‐derived gene signature predicted sensitivity or resistance prior to therapy. Analysis of the niche to monitor immunotherapy response presents a new opportunity to personalize care and investigate mechanisms underlying treatment resistance. Summary: A remote implant identified biomarkers that predict anti‐PD‐1 response before therapy, providing a unique tool to understand heterologous immunotherapy resistance in triple negative breast cancer.

IntroductionIntracranial 4D flow MRI enables quantitative assessment of hemodynamics in patients with intracranial atherosclerotic disease (ICAD). However, quantitative assessments are still challenging due to the time-consuming vessel segmentation, especially in the presence of stenoses, which can often result in user variability. To improve the reproducibility and robustness as well as to accelerate data analysis, we developed an accurate, fully automated segmentation for stenosed intracranial vessels using deep learning.Methods154 dual-VENC 4D flow MRI scans (68 ICAD patients with stenosis, 86 healthy controls) were retrospectively selected. Manual segmentations were used as ground truth for training. For automated segmentation, deep learning was performed using a 3D U-Net. 20 randomly selected cases (10 controls, 10 patients) were separated and solely used for testing. Cross-sectional areas and flow parameters were determined in the Circle of Willis (CoW) and the sinuses. Furthermore, the flow conservation error was calculated. For statistical comparisons, Dice scores (DS), Hausdorff distance (HD), average symmetrical surface distance (ASSD), Bland-Altman analyses, and interclass correlations were computed using the manual segmentations from two independent observers as reference. Finally, three stenosis cases were analyzed in more detail by comparing the 4D flow-based segmentations with segmentations from black blood vessel wall imaging (VWI).ResultsTraining of the network took approximately 10 h and the average automated segmentation time was 2.2 ± 1.0 s. No significant differences in segmentation performance relative to two independent observers were observed. For the controls, mean DS was 0.85 ± 0.03 for the CoW and 0.86 ± 0.06 for the sinuses. Mean HD was 7.2 ± 1.5 mm (CoW) and 6.6 ± 3.7 mm (sinuses). Mean ASSD was 0.15 ± 0.04 mm (CoW) and 0.22 ± 0.17 mm (sinuses). For the patients, the mean DS was 0.85 ± 0.04 (CoW) and 0.82 ± 0.07 (sinuses), the HD was 8.4 ± 3.1 mm (CoW) and 5.7 ± 1.9 mm (sinuses) and the mean ASSD was 0.22 ± 0.10 mm (CoW) and 0.22 ± 0.11 mm (sinuses). Small bias and limits of agreement were observed in both cohorts for the flow parameters. The assessment of the cross-sectional lumen areas in stenosed vessels revealed very good agreement (ICC: 0.93) with the VWI segmentation but a consistent overestimation (bias ± LOA: 28.1 ± 13.9%).DiscussionDeep learning was successfully applied for fully automated segmentation of stenosed intracranial vasculatures using 4D flow MRI data. The statistical analysis of segmentation and flow metrics demonstrated very good agreement between the CNN and manual segmentation and good performance in stenosed vessels. To further improve the performance and generalization, more ICAD segmentations as well as other intracranial vascular pathologies will be considered in the future.

Abstract Mounting data suggest an important role for the immune system in Parkinson’s disease (PD). Previous evidence of increased natural killer (NK) cell populations in PD suggests a potential role of NK cells in the pathogenesis of the disease. Previous studies have analyzed NK cell populations using aggregation by variable expression of CD56 and CD16. It remains unknown what differences may exist between NK cell subpopulations when stratified using more nuanced classification. Here, we profile NK cell subpopulations and elucidate the expressions of activating, NKG2D, inhibitory, NKG2A, and homing, CX3CR1, receptors on NK cell subpopulations in PD and healthy controls (HC). We analyzed cryopreserved PMBC samples using a 10-color flow cytometry panel to evaluate NK cell subpopulations in 31 individuals with sporadic PD and 27 HC participants. Here we identified significant differences in the CD56dim NK subset that changes with disease severity in PD. Furthermore, the expressions of NKG2D in all three NK cell subsets were significantly elevated in PD patients compared to HC. Notably, NKG2A expression in the CD56bright NK subset increased in PD patients with longer disease duration but there were no changes in CX3CR1. In summary, our data suggests that changes in NK cells may be influenced by the clinical severity and duration of PD.

The classification of the Neotropical Cybistrinae Sharp, 1880 (Coleoptera: Adephaga: Dytiscidae) is extensively revised based on a phylogenetic analysis of morphological features of the group. A new genus, Nilssondytes gen. nov. is described for a unique new species, Nilssondytes diversus sp. nov. from Venezuela. The New World genus, Megadytes Sharp, 1882, with several subgenera, was found to not be monophyletic. The type species of Megadytes, Dytiscus latus Fabricius, 1801 and the species Cybister parvus Trémouilles, 1984 were found to be monophyletic together, and phylogenetically more closely related to Cybister Curtis, 1827 than to other species assigned to Megadytes sensu stricto, which were found to also be monophyletic. The name Megadytes is here restricted to include only Megadytes latus and Megadytes parvus. These two species assigned to this newly restricted genus concept are reviewed and diagnosed. A new genus, Metaxydytes gen. nov., is erected to include all the other species currently assigned to Megadytes sensu stricto. The current subgenus names assigned to Megadytes, Bifurcitus Brinck, 1945, Paramegadytes Trémouilles & Bachmann, 1980, and Trifurcitus Brinck, 1945, are elevated to genus rank since they are variously paraphyletic. The two species assigned to Cybister (Neocybister) Miller, Bergsten & Whiting, 2007, Cybister (Neocybister) festae Griffini, 1895, and Cybister (Neocybister) puncticollis (Brullé, 1837) re reviewed and diagnosed with the former redescribed and its type specimens considered for the first time since its description. Another evidently new species and possible new genus, Megadytes species, IR57 (Ribera et al. 2008), from Peru, is also characterized, but not formally treated because of lack of important data for the single, partial specimen. Diagnostic features are illustrated for the entire group.

Purpose: To investigate the effects of thirst on later hydration status, total water intake (TWI-MA), and its potential sex differences. Methods: Twelve men (mean ± standard deviation; age: 21 ± 2 years; mass: 81.0 ± 15.9 kg) and twelve women (age: 22 ± 3 years; mass: 68.8 ± 15.2 kg) visited the laboratory in the morning (first thing in the morning) and afternoon (2:00–4:00 p.m.) for three consecutive days under a free-living condition. At each visit, urine osmolality (UOSM), urine specific gravity (USG), urine color (UCOL), body mass loss (BML), thirst, and plasma osmolality (POSM) were collected and analyzed. The participants recorded their food and fluid intake between the visits to determine TWI-MA. Linear regression was used to predict the effect of morning thirst on the afternoon hydration indices for all the participants, as well as for males and females separately. Results: Higher morning thirst predicted lower UOSM (r2 = 0.056, p = 0.045), USG (r2 = 0.096, p = 0.008), UCOL (r2 = 0.074, p = 0.021), and higher thirst (r2 = 0.074, p = 0.021) in the afternoon. However, morning thirst did not predict afternoon BML, POSM, or TWI-MA (p > 0.05). In males, higher morning thirst predicted lower afternoon UOSM (r2 = 0.130, p = 0.031) and USG (r2 = 0.153, p = 0.018). Additionally, higher morning thirst predicted higher TWI-MA (r2 = 0.154, p = 0.018) in females. Conclusions: Morning thirst had a negligible impact on later hydration status, specifically with afternoon urine indices. Furthermore, higher thirst sensation did not impact BML, POSM, or TWI-MA. However, thirst sensation minimally contributed to drinking behavior in females. Overall, individuals may not rely solely on thirst sensation to manipulate their drinking behavior to optimize their fluid balance during their daily lives due to the complexity of thirst mechanisms.

Microglia play a critical role in maintaining brain homeostasis but become dysregulated in neurodegenerative diseases. Regulator of G-protein Signaling 10 (RGS10), one of the most abundant homeostasis proteins in microglia, decreases with aging and functions as a negative regulator of microglia activation. RGS10-deficient mice exhibit impaired glucose tolerance, and high-fat diet induces insulin resistance in these mice. In this study, we investigated whether RGS10 modulates microglia activation in response to hyperglycemic conditions, complementing our previous findings of its role in inflammatory stimuli. In RGS10 knockdown (KD) BV2 cells, TNF production increased significantly in response to high glucose, particularly under proinflammatory conditions. Additionally, glucose uptake and GLUT1 mRNA levels were significantly elevated in RGS10 KD BV2 cells. These cells produced higher ROS and displayed reduced sensitivity to the antioxidant N-Acetyl Cysteine (NAC) when exposed to high glucose. Notably, both BV2 cells and primary microglia that lack RGS10 exhibited impaired uptake of alpha-synuclein aggregates. These findings suggest that RGS10 acts as a negative regulator of microglia activation not only in response to inflammation but also under hyperglycemic conditions.

Many Canadians use nicotine products such as cigarettes and e-cigarettes. A particular subpopulation of concern is post-secondary students given they have a higher prevalence of use. Many correlates of cigarette smoking and e-cigarette use have been identified. However, less focus has been on examining the correlates of cigarette smoking, e-cigarette use and dual use. This study explores the correlates of different nicotine modality use in post-secondary students. Using data from the Canadian Campus Wellbeing Survey (CCWS; n = 27,164), a multi-level nominal regression assessed the correlates of nicotine modality use. In comparison to individuals who were

Miradessus gen. nov. is described for two previously described species, Amarodytes pulchellus Guignot, 1955 from Colombia, with new records from Venezuela, and A. plaumanni Gschwendtner, 1935, from Brazil, and two previously unknown species, Miradessus beni sp. nov., from Bolivia and Peru, and Miradessus rikae sp. nov. from Ecuador. The genus is characterized by 1) occipital line absent; 2) basal pronotal striae present; 3) basal elytral stria absent; 4) sutural elytral stria absent; 5) transverse carina on elytral epipleuron at humeral angle absent; 6) distinct marginal bead on anterior clypeal margin absent; and 7) male median lobe deeply multilobed with a dorsal portion separate from a unilobed or bilobed ventral portion.

Iron physiology is regulated by a complex interplay of extracellular transport systems, coordinated transcriptional responses, and iron efflux mechanisms. Dysregulation of iron metabolism can result in defects in myelination, neurotransmitter synthesis, and neuronal maturation. In neonates, germinal matrix-intraventricular hemorrhage (GMH-IVH) causes iron overload as a result of blood breakdown in the ventricles and brain parenchyma which can lead to post-hemorrhagic hydrocephalus (PHH). However, the precise mechanisms by which GMH-IVH results in PHH remain elusive. Understanding the molecular determinants of iron homeostasis in the developing brain may lead to improved therapies. This manuscript reviews the various roles iron has in brain development, characterizes our understanding of iron transport in the developing brain, and describes potential mechanisms by which iron overload may cause PHH and brain injury. We also review novel preclinical treatments for IVH that specifically target iron. Understanding iron handling within the brain and central nervous system may provide a basis for preventative, targeted treatments for iron-mediated pathogenesis of GMH-IVH and PHH.

Abstract Accelerated progression of chronic obstructive pulmonary disease (COPD) is associated with increased risks of hospitalization and death. Prognostic insights into mechanisms and markers of progression could facilitate development of disease-modifying therapies. Although individual biomarkers exhibit some predictive value, performance is modest and their univariate nature limits network-level insights. To overcome these limitations and gain insights into early pathways associated with rapid progression, we measured 1305 peripheral blood and 48 bronchoalveolar lavage proteins in individuals with COPD [n = 45, mean initial forced expiratory volume in one second (FEV1) 75.6 ± 17.4% predicted]. We applied a data-driven analysis pipeline, which enabled identification of protein signatures that predicted individuals at-risk for accelerated lung function decline (FEV1 decline ≥ 70 mL/year) ~ 6 years later, with high accuracy. Progression signatures suggested that early dysregulation in elements of the complement cascade is associated with accelerated decline. Our results propose potential biomarkers and early aberrant signaling mechanisms driving rapid progression in COPD.

Abstract Background People with kidney failure often require surgery and experience worse postoperative outcomes compared to the general population, but existing risk prediction tools have excluded those with kidney failure during development or exhibit poor performance. Our objective was to derive, internally validate, and estimate the clinical utility of risk prediction models for people with kidney failure undergoing non-cardiac surgery. Design, setting, participants, and measures This study involved derivation and internal validation of prognostic risk prediction models using a retrospective, population-based cohort. We identified adults from Alberta, Canada with pre-existing kidney failure (estimated glomerular filtration rate [eGFR]

Declines and extirpations of American pika (Ochotona princeps) populations at historically occupied sites started being documented in the literature during the early 2000s. Commensurate with global climate change, many of these losses at peripheral and lower elevation sites have been associated with changes in ambient air temperature and precipitation regimes. Here, we report on a decline in available genetic resources for an iconic American pika metapopulation, located at the southwestern edge of the species distribution in the Bodie Hills of eastern California, USA. Composed of highly fragmented habitat created by hard rock mining, the ore dumps at this site were likely colonized by pikas around the end of the 19th century from nearby natural talus outcrops. Genetic data extracted from both contemporary samples and archived natural history collections allowed us to track population and patch-level genetic diversity for Bodie pikas across three distinct sampling points during the last half- century (1948–1949, 1988–1991, 2013–2015). Reductions in within-population allelic diversity and expected heterozygosity were observed across the full time period. More extensive sampling of extant patches during the 1988–1991 and 2013–2015 periods revealed an increase in population structure and a reduction in effective population size. Furthermore, census records from the last 51 years as well as archived museum samples collected in 1947 from a nearby pika population in the Wassuk range (Nevada, USA) provide further support of the increasing isolation and genetic coalescence occurring in this region. This study highlights the importance of museum samples and long-term monitoring in contextualizing our understanding of population viability.

Nineteen new species of Desmopachria Babington, 1841 are described from multiple species groups. Two new species groups are erected, the Desmopachria apicodente species group and the Desmopachria bifurcita species group. Desmopachria divergens sp. nov. (Venezuela), Desmopachria lineata sp. nov. (Venezuela), Desmopachria surinamensis sp. nov. (Suriname), and Desmopachria tenua sp. nov. (Guyana) are described in Desmopachria but are not assigned to a species group. Desmopachria apicodente sp. nov. (Guyana, Venezuela), Desmopachria lateralis sp. nov. (Venezuela), and Desmopachria tumida sp. nov. (Venezuela) are described in the new Desmopachria apicodente species group and are the only members of the group. Desmopachria bifurcita sp. nov. (Peru), and Desmopachria lata sp. nov. (Brazil) are described in the new Desmopachria bifurcita group. Other members of the Desmopachria bifurcita group are Desmopachria bifasciata Zimmermann, Desmopachria bolivari Miller, Desmopachria ovalis Sharp, and Desmopachria varians (each previously “ungrouped”). Desmopachria pseudocavia sp. nov. (Venezuela) is described in the Desmopachria convexa-signata species group. Desmopachria wolfei sp. nov. (Venezuela) is described in the Desmopachria nitida species group. Desmopachria angulata sp. nov. (Guyana, Suriname), Desmopachria emarginata sp. nov. (Guyana, Suriname, Venezuela), Desmopachria imparis sp. nov. (Guyana), Desmopachria impunctata sp. nov. (Suriname, Venezuela), and Desmopachria truncata sp. nov. (Guyana, Suriname) are described in the Desmopachria portmanni-aldessa species group. Desmopachria bisulcata sp. nov. (Suriname), and Desmopachria irregulara sp. nov. (Venezuela) are described in the Desmopachria portmanni-portmanni species group. Desmopachria robusta sp. nov. (Venezuela) is described in the Desmopachria striola species group. A key to the species groups is included. Male genitalia are figured for all new species and dorsal habitus images are provided for most new species.

The vaginal microbiome (VMB) is a complex microbial community that is closely tied to reproductive health. Optimal VMB communities have compositions that are commonly defined by the dominance of certain Lactobacillus spp. and can remain stable over time or transition to non-optimal states dominated by anaerobic bacteria and associated with bacterial vaginosis (BV). The ability to remain stable or undergo transitions suggests a system with either single (mono-stable) or multiple (multi-stable) equilibrium states, though factors that contribute to stability have been difficult to determine due to heterogeneity in microbial growth characteristics and inter-species interactions. Here, we use a computational model to determine whether differences in microbial growth and interaction parameters could alter equilibrium state accessibility and account for variability in community composition after menses and antibiotic therapies. Using a global uncertainty and sensitivity analysis that captures parameter sets sampled from a physiologically relevant range, model simulations predicted that 79.7% of microbial communities were mono-stable (gravitate to one composition type) and 20.3% were predicted to be multi-stable (can gravitate to more than one composition type, given external perturbations), which was not significantly different from observations in two clinical cohorts (HMP cohort, 75.2% and 24.8%; Gajer cohort, 78.1% and 21.9%, respectively). The model identified key microbial parameters that governed equilibrium state accessibility, such as the importance of non-optimal anaerobic bacteria interactions with Lactobacillus spp., which is largely understudied. Model predictions for composition changes after menses and antibiotics were not significantly different from those observed in clinical cohorts. Lastly, simulations were performed to illustrate how this quantitative framework can be used to gain insight into the development of new combinatorial therapies involving altered prebiotic and antibiotic dosing strategies. Altogether, dynamical models could guide development of more precise therapeutic strategies to manage BV.

BackgroundThe majority of high-throughput single-cell molecular profiling methods quantify RNA expression; however, recent multimodal profiling methods add simultaneous measurement of genomic, proteomic, epigenetic, and/or spatial information on the same cells. The development of new statistical and computational methods in Bioconductor for such data will be facilitated by easy availability of landmark datasets using standard data classes.ResultsWe collected, processed, and packaged publicly available landmark datasets from important single-cell multimodal protocols, including CITE-Seq, ECCITE-Seq, SCoPE2, scNMT, 10X Multiome, seqFISH, and G&T. We integrate data modalities via the MultiAssayExperiment Bioconductor class, document and re-distribute datasets as the SingleCellMultiModal package in Bioconductor's Cloud-based ExperimentHub. The result is single-command actualization of landmark datasets from seven single-cell multimodal data generation technologies, without need for further data processing or wrangling in order to analyze and develop methods within Bioconductor's ecosystem of hundreds of packages for single-cell and multimodal data.ConclusionsWe provide two examples of integrative analyses that are greatly simplified by SingleCellMultiModal. The package will facilitate development of bioinformatic and statistical methods in Bioconductor to meet the challenges of integrating molecular layers and analyzing phenotypic outputs including cell differentiation, activity, and disease.

Vaccine efficacy determined within the controlled environment of a clinical trial is usually substantially greater than real-world vaccine effectiveness. Typically, this results from reduced protection of immunologically vulnerable populations, such as children, elderly individuals and people with chronic comorbidities. Consequently, these high-risk groups are frequently recommended tailored immunisation schedules to boost responses. In addition, diverse groups of healthy adults may also be variably protected by the same vaccine regimen. Current population-based vaccination strategies that consider basic clinical parameters offer a glimpse into what may be achievable if more nuanced aspects of the immune response are considered in vaccine design. To date, vaccine development has been largely empirical. However, next-generation approaches require more rational strategies. We foresee a generation of precision vaccines that consider the mechanistic basis of vaccine response variations associated with both immunogenetic and baseline health differences. Recent efforts have highlighted the importance of balanced and diverse extra-neutralising antibody functions for vaccine-induced protection. However, in immunologically vulnerable populations, significant modulation of polyfunctional antibody responses that mediate both neutralisation and effector functions has been observed. Here, we review the current understanding of key genetic and inflammatory modulators of antibody polyfunctionality that affect vaccination outcomes and consider how this knowledge may be harnessed to tailor vaccine design for improved public health.

The influence of feeding Atlantic salmon for 90 days on diets that excluded fishmeal (FM) and fish oil (FO) was examined for influence on various quality traits. In addition, the effect of adding krill meal (KM; 0%, 2.5%, and 5%), as a putative feed palatant was also examined. Total replacement of FM/FO had a limited effect on production characteristics, affecting percentage yields of headed and gutted control fish and their standard length (p < 0.05). Variances between dietary groups were observed for pigmentation, and plant protein-based KM-free-fed fish returned deeper hues across their belly, NQC (Norwegian Quality Cut), and back portions (p < 0.03). No differences were measured for relative fin condition. δ13C and δ15N concentrations were lower and higher, respectively (p < 0.05) for fish fed the FM/FO-based diet. δ13C:δ15N likewise differed between treatments with FM/FO-fed salmon expressing higher ratios. Fillet mechanical characteristics varied with fish fed on animal protein-based diets, without KM expressing higher springiness and resilience (p < 0.05). Fish fed plant-based diets were generally preferred by younger taste testers. The results from this trial illustrate that FM/FO can be completely removed from salmon diets without problematic effects on quality and palatability attributes.

Abstract Background Dipteran parasitoids of Embioptera (webspinners) are few and extremely rare but known from all biogeographical regions except Australasia/Oceania. All belong to the fly family Tachinidae, a hyperdiverse and widespread clade of parasitoids attacking a variety of arthropod orders. Results The webspinner-parasitizing Diptera are reviewed based mostly on records from the collecting and rearing by Edward S. Ross. A new genus is erected to accommodate a new Afrotropical species, Embiophoneus rossi gen. et sp. nov. The genus Perumyia Arnaud is reviewed and a new species, Perumyia arnaudi sp. nov., is described from Central America while P. embiaphaga Arnaud is redescribed and new host records are given. A new species of Phytomyptera Rondani, P. woodi sp. nov., is described from Myanmar, representing the first report of a member of this genus obtained from webspinners. The genus Rossimyiops Mesnil is reviewed, R. longicornis (Kugler) is redescribed and R. aeratus sp. nov., R. fuscus sp. nov. and R. rutilans sp. nov. are newly described from the Oriental Region, and an updated key to species is given. Conclusions Webspinners were probably colonized independently at least four times by tachinids shifting from other hosts, most likely Lepidoptera.

We investigated epidemiologic and molecular characteristics of healthcare-associated (HA) and community-associated (CA) Clostridioides difficile infection (CDI) among adult patients in Canadian Nosocomial Infection Surveillance Program hospitals during 2015–2019. The study encompassed 18,455 CDI cases, 13,735 (74.4%) HA and 4,720 (25.6%) CA. During 2015–2019, HA CDI rates decreased by 23.8%, whereas CA decreased by 18.8%. HA CDI was significantly associated with increased 30-day all-cause mortality as compared with CA CDI (p

Mutations in the BRCA1 tumor suppressor gene, such as 5382insC (BRCA1insC), give carriers an increased risk for breast, ovarian, prostate, and pancreatic cancers. We have previously reported that, in mice, Brca1 deficiency in the hematopoietic system leads to pancytopenia and, as a result, early lethality. We explored the cellular consequences of Brca1-null and BRCA1insC alleles in combination with Trp53 deficiency in the murine hematopoietic system. We found that Brca1 and Trp53 codeficiency led to a highly penetrant erythroproliferative disorder that is characterized by hepatosplenomegaly and by expanded megakaryocyte erythroid progenitor (MEP) and immature erythroid blast populations. The expanded erythroid progenitor populations in both BM and spleen had the capacity to transmit the disease into secondary mouse recipients, suggesting that Brca1 and Trp53 codeficiency provides a murine model of hematopoietic neoplasia. This Brca1/Trp53 model replicated Poly (ADP-ribose) polymerase (PARP) inhibitor olaparib sensitivity seen in existing Brca1/Trp53 breast cancer models and had the benefits of monitoring disease progression and drug responses via peripheral blood analyses without sacrificing experimental animals. In addition, this erythroid neoplasia developed much faster than murine breast cancer, allowing for increased efficiency of future preclinical studies.

The immune response to SARS-CoV-2 infection is variable but has been linked to prognosis and the development of severe immunopathology. Here the authors assess a range of immune parameters in both peripheral blood and respiratory samples, providing a comparative assessment of the immune response between these compartments and their potential impact on immune-pathogenesis.

It remains unclear how rapid antibiotic switching affects the evolution of antibiotic resistance in individual patients. Here, Chung et al. combine short- and long-read sequencing and resistance phenotyping of 420 serial isolates of Pseudomonas aeruginosa collected from the onset of respiratory infection, and show that rare resistance mutations can increase by nearly 40-fold over 5–12 days in response to antibiotic changes, while mutations conferring resistance to antibiotics not administered diminish and even go to extinction.

The purpose of this study was to determine the influence of krill meal (KM) inclusion at various levels (0%, 2.5%, 5%) in plant-based and animal-based feeds, that were fishmeal (FM) and fish oil (FO) free, on Atlantic salmon growth. A FM/FO feed containing 0% KM was the control. Using a 2 × 3 factorial approach, diets were randomly assigned to one of 28 0.5 m3 flow-through tanks (n = 4 tanks per diet) initially stocked with 60 fish (148.4 ± 12.9 g; 23.6 ± 0.8 cm; condition factor (K) = 1.16 ± 0.08) each. Salmon were fed for 90 days using automatic feeders ad libitum. On day 45, stocking densities were reduced to 45 fish per tank by the random removal of 15 individuals to remove any potential of density affecting growth through the trial end. Water temperature, oxygen saturation, pH, and salinity throughout the trial were 11.8 °C, 103.5%, 7.38, and 32.0 g L−1, respectively. Fish fed plant-based feed without KM were lighter (p < 0.05) than all other groups at day 45 and 90, but those fed a plant-based feed with KM had comparable growth and feed intake compared to that of fish fed the control diet. Irrespective of the presence of KM, animal-based feeds achieved comparable weight growth (p > 0.05) to the control and 5% KM plant-based groups, with KM increasing feed intake (p < 0.05). Between day 45 and 90, feed conversion ratios increased in all groups except the control and 0% KM plant-based group, while specific growth rates (SGRs) decreased for all except the 0% KM plant-based diet. Between-group differences (p < 0.05) were also noted for the thermal growth coefficient. No differences were recorded in visceral or intestinal weight, and whole-body lipid levels were identical, proportional for all groups. Although differences (p < 0.05) were apparent in the concentrations of individual fillet fatty acids between groups, a 75 g serving size of any treatment would be sufficient to exceed daily intake recommendations for EPA + DHA. This trial determined that benefit, in terms of feed intake and growth performance, was gained when KM was added to plant-based feeds. However, no such advantage was observed when KM was used with animal-based feeds.

Abstract For range‐restricted species with disjunct populations, it is critical to characterize population genetic structure, gene flow, and factors that influence functional connectivity among populations in order to design effective conservation programs. In this study, we genotyped 314 individuals from 16 extant populations of Ivesia webberi, a United States federally threatened Great Basin Desert using six microsatellite loci. We assessed the effects of Euclidean distance, landscape features, and ecological dissimilarity on the pairwise genetic distance of the sampled populations, while also testing for a potential relationship between I. webberi genetic diversity and diversity in the vegetative communities. The results show low levels of genetic diversity overall (He = 0.200–0.441; Ho = 0.192–0.605) and high genetic differentiation among populations. Genetic diversity was structured along a geographic gradient, congruent with patterns of isolation by distance. Populations near the species’ range core have relatively high genetic diversity, supporting in part a central‐marginal pattern, while also showing some evidence for a metapopulation dynamic. Peripheral populations have lower genetic diversity, significantly higher genetic distances, and higher relatedness. Genotype cluster admixture results suggest a complex dispersal pattern among populations with dispersal direction and distance varying on the landscape. Pairwise genetic distance strongly correlates with elevation, actual evapotranspiration, and summer seasonal precipitation, indicating a role for isolation by environment, which the observed phenological mismatches among the populations also support. The significant correlation between pairwise genetic distance and floristic dissimilarity in the germinated soil seed bank suggests that annual regeneration in the plant communities contribute to the maintenance of genetic diversity in I. webberi.

Abstract Background People with kidney failure have a high incidence of major surgery, though the risk of perioperative outcomes at a population-level is unknown. Our objective was to estimate the proportion of people with kidney failure that experience acute myocardial infarction (AMI) or death within 30 days of major non-cardiac surgery, based on surgery type. Methods In this retrospective population-based cohort study, we used administrative health data to identify adults from Alberta, Canada with major surgery between April 12,005 and February 282,017 that had preoperative estimated glomerular filtration rates (eGFRs)

A new species of Callistege Hübner, [1823] (Lepidoptera, Erebidae, Erebinae, Euclidiini) is described from Cuatrociénegas Protected Area and Biosphere Preserve in Coahuila, Mexico. Adult male and female moths are illustrated, including genitalia. Callistege clara Homziak & Metzler, sp. nov. is one of 27 new species of insects discovered during an inventory survey of arthropods of White Sands National Monument, USA, and Cuatrociénegas Protected Area (Mexico), funded by the U.S. National Park Service. The Cuatrociénegas Basin is known for high endemism of aquatic and wetland biota within the Chihuahuan Desert. Callistege clara Homziak & Metzler, sp. nov. was found in a wetland environment.

This study's purpose was to examine the effects of the concrete-representational-abstract integrated (CRA-I) sequence on the performance of students who struggled with rational number concepts. Three students in southeastern U.S. fifth grade class participated in the study. The CRA-I intervention was grounded in the principles of explicit instruction and showed rational number concepts related to fractions and decimals using fraction blocks, number lines, base 10 blocks, and coins. Students learned about unit fractions, fraction magnitude, fraction equivalence, addition of fractions with unlike denominators, equivalent decimals, and notation of fractions as decimals. The researchers used a multiple probe across behaviors design and demonstrated a functional relation between CRA-I and three behaviors: decreased fraction estimation error, accuracy in adding fractions with unlike denominators, and accuracy writing fractions as decimals.

Antibody responses to SARS-CoV-2 are critical in the immune response to infection, but the potential cross-reactivity to other human corona viruses is poorly appreciated. Here the authors apply a systems based approach to characterise the antibody response in pre-pandemic cohorts and assess heterotypic reactivity to SARS-CoV-2.

Abstract Background Physiological homeostasis decline, immunosenescence, and increased risk for multiple diseases, including neurodegeneration, are all hallmarks of ageing. Importantly, it is known that the ageing process is sex-biased. For example, there are sex differences in predisposition for multiple age-related diseases, including neurodegenerative and autoimmune diseases. However, sex differences in age-associated immune phenotypes are not clearly understood. Results Here, we examined the effects of age on immune cell phenotypes in both sexes of C57BL/6J mice with a particular focus on NK cells. We found female-specific spleen weight increases with age and concordant reduction in the number of splenocytes per gram of spleen weight compared to young females. To evaluate sex- and age-associated changes in splenic immune cell composition, we performed flow cytometry analysis. In male mice, we observed an age-associated reduction in the frequencies of monocytes and NK cells; female mice displayed a reduction in B cells, NK cells, and CD8 + T cells and increased frequency of monocytes and neutrophils with age. We then performed a whole blood stimulation assay and multiplex analyses of plasma cytokines and observed age- and sex-specific differences in immune cell reactivity and basal circulating cytokine concentrations. As we have previously illustrated a potential role of NK cells in Parkinson’s disease, an age-related neurodegenerative disease, we further analyzed age-associated changes in NK cell phenotypes and function. There were distinct differences between the sexes in age-associated changes in the expression of NK cell receptors, IFN-γ production, and impairment of α-synuclein endocytosis. Conclusions This study demonstrates sex- and age-specific alterations in splenic lymphocyte composition, circulating cytokine/chemokine profiles, and NK cell phenotype and effector functions. Our data provide evidence that age-related physiological perturbations differ between the sexes which may help elucidate sex differences in age-related diseases, including neurodegenerative diseases, particularly Parkinson’s disease, where immune dysfunction is implicated in their etiology.

Abstract Background Distributional responses by alpine taxa to repeated, glacial-interglacial cycles throughout the last two million years have significantly influenced the spatial genetic structure of populations. These effects have been exacerbated for the American pika (Ochotona princeps), a small alpine lagomorph constrained by thermal sensitivity and a limited dispersal capacity. As a species of conservation concern, long-term lack of gene flow has important consequences for landscape genetic structure and levels of diversity within populations. Here, we use reduced representation sequencing (ddRADseq) to provide a genome-wide perspective on patterns of genetic variation across pika populations representing distinct subspecies. To investigate how landscape and environmental features shape genetic variation, we collected genetic samples from distinct geographic regions as well as across finer spatial scales in two geographically proximate mountain ranges of eastern Nevada. Results Our genome-wide analyses corroborate range-wide, mitochondrial subspecific designations and reveal pronounced fine-scale population structure between the Ruby Mountains and East Humboldt Range of eastern Nevada. Populations in Nevada were characterized by low genetic diversity (π = 0.0006–0.0009; θW = 0.0005–0.0007) relative to populations in California (π = 0.0014–0.0019; θW = 0.0011–0.0017) and the Rocky Mountains (π = 0.0025–0.0027; θW = 0.0021–0.0024), indicating substantial genetic drift in these isolated populations. Tajima’s D was positive for all sites (D = 0.240–0.811), consistent with recent contraction in population sizes range-wide. Conclusions Substantial influences of geography, elevation and climate variables on genetic differentiation were also detected and may interact with the regional effects of anthropogenic climate change to force the loss of unique genetic lineages through continued population extirpations in the Great Basin and Sierra Nevada.

We examined the use of “edge of flood” habitats by larval silver carp during the extensive flooding that occurred in Pool 26 of the Upper Mississippi River near Alton, IL, USA and St. Louis, MO, USA during the summer of 2015. We captured over 12,700 individual fishes including eight taxa, over 12,000 of which (> 95%) were larval silver carp between 5 and 21 mm standard length. Peak catch rates occurred near the confluence of the Illinois and Mississippi rivers. These findings suggest that larval silver carp have an affinity for edge of the flood habitat and further study is needed to better understand how this affects the dynamics of this invasive species in the Mississippi River. The high catch rates observed at the confluence of the Illinois and Mississippi rivers suggests that the Illinois River is an important source of larval silver carp to the Upper Mississippi River.

Bacterial vaginosis (BV) is typically caused by a shift in the vaginal microbiota from a Lactobacillus-dominant community to one colonised by strains of Gardenerella vaginalis and treatment with the antibiotic metronidazole (MNZ) often results in failure and recurrence. Here, the authors use modelling and in vitro assays to show that sequestration of MNZ by Lactobacillus is critical in reducing efficacy and women with a higher pre-treatment Lactobacillus/Gardnerella ratio are more likely to recur.

The use of assisted human reproduction (AHR) represents a meaningful and important life event for lesbians wishing to create biologically related families. Despite increasing numbers of lesbians utilizing AHR services, barriers to access persist. This qualitative study investigated the experiences of lesbians and their interactions with reproductive services in Ontario, Canada, where limited public funding is available for all AHR patients and where the lesbian, gay, bisexual, transgender, and queer (LGBTQ) community makes up to 30% of clientele. Eleven semi-structured interviews were conducted, and findings revealed a wide range of experiences. Lesbian patients expressed a desire for more support from their care providers in navigating a complex and costly medical journey through a system largely designed for the needs of heterosexual patients. Additionally, private fertility clinics, as the environment for accessing publicly funded services, were felt to contribute pressure to pay out-of-pocket for add-on medical procedures. To improve the quality of care, participants recommended providing more high-level information on the medical journey and taking an individual approach with lesbian patients, in particular, assuming a patient has sufficient fertility until proven otherwise.

Children with SARS-CoV-2 infection are more likely to have mild symptoms and may be asymptomatic, but underlying reasons remain unclear. Here, the authors show cellular, cytokine and antibody response to SARS-CoV-2 infection in three children who repeatedly tested negative for the virus by PCR, despite high exposure in the household.

Background: Patient satisfaction is a proxy for quality clinical care. Understanding the factors that drive patient satisfaction scores is important because they are publicly reported, may be used in determining hospital and physician compensation, and may allow patients to preselect physicians. Objective: This single-center survey study of adult patients at the Michigan Medicine outpatient dermatology clinics aimed to investigate how patients respond differently to theoretical dermatologic scenarios with varying dermatologist gender. Methods: Each questionnaire contained one of four clinical scenarios illustrating overall positive or negative encounters with a male or female dermatologist, followed by questions derived from the Press Ganey survey to assess patient satisfaction. Results: A total of 452 completed questionnaires were collected. There were statistically significant differences in overall patient satisfaction scores between positive versus negative female and positive versus negative male dermatologists, but there were no differences in scores between positive female and positive male dermatologists or between negative female and negative male dermatologists. There were also no differences in overall scores after controlling for patient demographic characteristics or patient–dermatologist gender concordance. Conclusion: Previous studies have suggested that male physicians receive better patient satisfaction scores compared to female physicians. However, our study found that, in response to hypothetical scenarios of positive and negative dermatology encounters, dermatologist gender did not affect any domain of patient satisfaction scores. Limitations include the use of hypothetical patient–dermatologist encounters and possible lack of generalizability because the study was conducted at one academic center in southeast Michigan with a predominantly Caucasian patient population.

We revise the Afrotropical Agabus raffrayi species group, motivated by the discovery of new diversity in Kenya and South Africa. Whilst Agabus is mainly a holarctic genus, the Agabus raffrayi group is restricted to high altitude regions of eastern Africa and temperate parts of South Africa, from where we describe the southernmost Agabus in the world. The following new species are introduced: Agabus anguluverpus sp. nov. from Mount Kenya in central Kenya, Agabus austellus sp. nov. a widespread species in South Africa, Agabus riberae sp. nov. from the Kamiesberg and northeastern Cederberg ranges in the Northern and Western Cape Provinces of South Africa and Agabus agulhas sp. nov. from the Agulhas Plain, Western Cape Province, South Africa. We provide a distribution map, a determination key for males, quantitative measurements of diagnostic characters, habitus photos and detailed photos of male genitalia for all described species in the group, as well as images of diagnostic characters and habitats. The presence or absence of an elongated section between the subapical broadening and the base of the apical and subapical teeth of the male aedeagus is a useful novel character, first revealed by our study. In contrast with the most recent revision of Afrotropical Agabus, we show that Agabus ruwenzoricus Guignot, 1936 is restricted to eastern Africa; South African records of this species having been based on misidentifications, no species of the group being common to southern and eastern Africa. We speculate that the raffrayi group may display phylogenetic niche conservatism, being restricted, as an originally temperate taxon, to higher elevations in tropical eastern Africa, but occurring at lower altitudes in temperate South Africa.

Introduction: Deep dyspareunia is a cardinal symptom of endometriosis, and as many as 40% of people with this condition experience comorbid superficial dyspareunia. Aim: To evaluate the relationship between sexual pain and infertility concerns among women with endometriosis. Methods: This is a cross-sectional study conducted at a university-based tertiary center for endometriosis. 300 reproductive-aged participants in the prospective Endometriosis Pelvic Pain Interdisciplinary Cohort (ClinicalTrials.gov Identifier: NCT02911090) with histologically confirmed endometriosis were included (2013–2017). Main Outcome Measure: The total score on the infertility concerns module of the Endometriosis Health Profile-30 categorized into 5 groups (0, 1–4, 5–8, 9–12, 13–16). Results: The odds of infertility concerns did not increase with severity of deep dyspareunia (odds ratio = 1.02, 95% CI: 0.95–1.09, P = .58). However, the odds of infertility concerns increased with severity of superficial dyspareunia (odds ratio = 1.09, 95% CI: 1.02–1.16, P = .011); this relationship persisted after adjusting for endometriosis-specific factors, infertility risk factors, reproductive history, and demographic characteristics (adjusted odds ratio [AOR] = 1.14, 95% CI: 1.06–1.24, P

Two new species are described in the Neotropical genus Agaporomorphus Guignot from Suriname: A. hamatocoles sp. nov. and A. tortus sp. nov. The species are included in a phylogenetic parsimony analysis of 13 morphological characters and all 12 known species. Two equally parsimonious arrangements are found with the only difference a rearrangement among the A. knischi clade. Agaporomorphus tortus belongs to the A. dolichodactylus group based on presence of an elongate, club-like lobe on the dorsal, basal surface of the male median lobe and long, subsinuate male mesotarsal claws and a small lobe at the apex of male mesotarsomere V. Agaporomorphus hamatocoles does not belong to a known species group and is phylogenetically isolated lacking synapomorphies characterizing the other groups, so the species is placed in its own species group. Male genitalia are illustrated for the new species and redrawn for all the species of the A. dolichodactylus group, and male mesotarsal claws are illustrated for A. tortus and redrawn for other members of the A. dolichodactylus group. New distribution records are reported for Suriname for the species A. colberti Miller and Wheeler and A. pereirai Guignot.

Two new species are described in the Desmopachria convexa species group in the Neotropical genus Desmopachria Babington: D. manco sp. nov. (Guyana), and D. mortimer sp. nov. (Costa Rica). Two subgroups, the D. convexa-convexa and the D. convexa-signata groups are defined. Desmopachria convexa-convexa species are from North and Central America and have a subapical articulable lobe on the male lateral lobe that is large and elongate and extends well beyond the slender, oblique apex of the lateral lobe. Desmopachria convexa-signata species are from South America and have a subapical articulable lobe on the male lateral lobe that is small and discrete and does not extend beyond the truncate apex of the lateral lobe. The male genitalia of all recognized species in the D. convexa group are redrawn from the literature. New species are illustrated from specimens and described species have morphological features redrawn from published illustrations.