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Brain abscesses (BA) are focal parenchymal infections that remain life-threatening conditions. Polymicrobial BAs (PBAs) are complex coinfections of bacteria or bacterial and nonbacterial pathogens such as fungi or parasites, with diagnostic and therapeutic challenges. In this article, we comprehensively review the prevalence, pathogenesis, clinical manifestations, and microbiological, histopathological, and radiological features of PBAs, as well as treatment and prognosis. While PBAs and monomicrobial BAs have some similarities such as nonspecific clinical presentations, PBAs are more complex in their pathogenesis, pathological, and imaging presentations. The diagnostic challenges of PBAs include nonspecific imaging features at early stages and difficulties in identification of some pathogens by routine techniques without the use of molecular analysis. Imaging of late-stage PBAs demonstrates increased heterogeneity within lesions, which corresponds to variable histopathological features depending on the dominant pathogen-induced changes in different areas. This heterogeneity is particularly marked in cases of coinfections with nonbacterial pathogens such as Toxoplasma gondii. Therapeutic challenges in the management of PBAs include initial medical therapy for possibly underrecognized coinfections prior to identification of multiple pathogens and subsequent broad-spectrum antimicrobial therapy to eradicate identified pathogens. PBAs deserve more awareness to facilitate prompt and appropriate treatment.

Toxoplasma gondii (TG) affects one-third of the global human population and commonly involves the central nervous system (CNS)/brain more frequently in immunocompromised patients.1 Subclinical or asymptomatic cerebral toxoplasmosis is relatively common in immunocompetent individuals and occasionally seen in immunocompromised patients. The immunocompromised status can result from immunosuppressant and/or immunomodulatory treatment in patients after organ transplantation, and other immunosuppressive conditions such as human immunodeficiency virus infection.1–5 Focal CNS infectious lesions or brain abscesses are known complications of transplantation, and have been documented in 0.36–1% of organ transplant recipients.2 CNS toxoplasmosis occurs variably in transplant recipients with the highest incidence (13–53%) in cardiac transplantation and the lowest incidence in liver transplantation (rarely reported). Subsequent brain magnetic resonance imaging (MRI) disclosed multiple T2/FLAIR hyperintense, and T1 post-contrast nodular or ring enhancing lesions in the brain parenchyma including the left frontal region (largest, 22.5 × 10.1 mm, with brain edema and mass effect causing a left-to-right midline shift), as well as left temporal, right frontal, and parietal regions (Figure 1). A systematic review of TG infection after liver transplantation revealed that IgM anti-Toxoplasma antibodies were found in 30% of the recipients, and Toxoplasma DNA or tachyzoites were reported in 67% of the seronegative recipients,10 while the pretransplant TG serology was usually negative.5 TG infection may be reactivated in the recipients due to their immunosuppressive treatment or other events that further suppress the immune system.

Habitat ranges of ground-dwelling spiders were studied by pitfall trapping in and around a freshwater pond during the spring and summer of 1998 in central Alberta, Canada. Sixty species from 14 families were collected, and catches of several species suggested distinct habitat affinities along transects between the pond and adjacent terrestrial habitats. Variation in the catches of Pirata piraticus (Clerck 1757), Pardosa moesta Banks 1892, Pardosa fuscula (Thorell 1875), and immature Pirata species were partially explained by soil moisture at trap locations extending from the shore. We devised a “floating” pitfall trap that captured several species, including mature and immature Dolomedes triton (Walckenaer 1837), Pirata piraticus, and other immature Lycosidae, directly on the water surface. A DCA ordination revealed distinct spider assemblages were associated with three habitat types: 1) the water surface; 2) the moist habitats closely associated with the water's edge; and 3) the drier, terrestrial grassland habitats located >2 m from the shore. A new, more inclusive definition of semi-aquatic spiders was developed, based on knowledge about both male and female activity near the shore, and affinities towards soil moisture. Thus, Pirata piraticus, Dolomedes triton, and Pardosa fuscula were defined as semi-aquatic spiders.

Cardiometabolic diseases are a major cause of morbidity and mortality in kidney transplant recipients (KTR) due to clustering of traditional and non-traditional risk factors including poor physical fitness and physical inactivity. Exercise may mitigate the risk of these diseases in this population but evidence is limited, and physical activity levels are low. The ECSERT randomised controlled trial assessed the feasibility of delivering a structured, home-based exercise intervention in KTR at increased cardiometabolic risk. Fifty KTR (>1-year post-transplant) were randomised 1:1 to: intervention (INT: a 12-week home-based combined aerobic and resistance exercise programme) or control (CTR: guideline-directed care). The a-priori thresholds for feasibility were: recruitment of 20% of eligible participants (≥2 participants per month); adherence (an average of ≥ 3 exercise sessions per week); and attrition (≤30%). One hundred and seventy-one patients were screened and 94 (55%) were eligible and invited to take part in the study. Fifty of those invited (53%) were recruited across 22 months of recruitment. Consented participant characteristics were: age 50 ± 14 years (INT 49 ± 13; CTR 51 ± 15), 23 male (INT 10; CTR 13), eGFR 59 ± 19 ml/min/1.73m2 (INT 60 ± 20; CTR 61 ± 21), 35 White British (WB), 13 South Asian (SA), 1 Caribbean, and 1 Mixed ethnicity (INT 17 WB, 7 SA, 1 Mixed; CTR 18 WB, 6 SA, 1 Caribbean). Intervention participants (n = 22 completed) recorded an average of 4.4 ± 1.4 exercise sessions per week (aerobic 2.8 ± 1.1; strength 1.6 ± 0.5). Three participants withdrew from the intervention group (1 COVID-19 infection, 1 recurrent urine infections unrelated to the trial, 1 time/family circumstances) and one from the control group (lost to follow-up; 8% attrition). There were no serious adverse events reported. Despite previous evidence showing physical fitness and activity levels are low in KTR, the present results support that a structured, home-based exercise programme is feasible in this population. Specifically, a-priory recruitment, adherence, and retention thresholds were all exceeded. The groups were well matched and there was encouraging representation of female participants and participants from a non-white background. Thus, this study supports further development and testing of home-based programmes of exercise and activity for KTR. ClinicalTrials.gov NCT04123951.

A method of overcoming barriers associated with implementing lifestyle interventions in CKD may be through the use of eHealth technologies. The aim of this review was to provide an up-to-date overview of the literature on this topic. Four bibliographical databases, two trial registers, and one database for conference proceedings were searched from inception to August 2023. Studies were eligible if they reported a lifestyle intervention using eHealth technologies. A narrative synthesis of the findings from the included studies structured around the type of eHealth intervention was presented. Where a sufficient number of studies overlapped in terms of the type of intervention and outcome measure these were brought together in a direction of effect plot. There were 54 included articles, of which 23 were randomised controlled trials (RCTs). The main component of the intervention for the included studies was mobile applications ( n = 23), with the majority being in the dialysis population ( n = 22). The majority of eHealth interventions were reported to be feasible and acceptable to participants. However, there was limited evidence that they were efficacious in improving clinical outcomes with the exception of blood pressure, intradialytic weight gain, potassium, and sodium. Although eHealth interventions appear acceptable and feasible to participants, there is insufficient evidence to make recommendations for specific interventions to be implemented into clinical care. Properly powered RCTs which not only demonstrate efficacy, but also address barriers to implementation are needed to enhance widespread adoption.

Expansion of a single repetitive DNA sequence, termed a tandem repeat (TR), is known to cause more than 50 diseases 1 , 2 . However, repeat expansions are often not explored beyond neurological and neurodegenerative disorders. In some cancers, mutations accumulate in short tracts of TRs, a phenomenon termed microsatellite instability; however, larger repeat expansions have not been systematically analysed in cancer 3 – 8 . Here we identified TR expansions in 2,622 cancer genomes spanning 29 cancer types. In seven cancer types, we found 160 recurrent repeat expansions (rREs), most of which (155/160) were subtype specific. We found that rREs were non-uniformly distributed in the genome with enrichment near candidate cis -regulatory elements, suggesting a potential role in gene regulation. One rRE, a GAAA-repeat expansion, located near a regulatory element in the first intron of UGT2B7 was detected in 34% of renal cell carcinoma samples and was validated by long-read DNA sequencing. Moreover, in preliminary experiments, treating cells that harbour this rRE with a GAAA-targeting molecule led to a dose-dependent decrease in cell proliferation. Overall, our results suggest that rREs may be an important but unexplored source of genetic variation in human cancer, and we provide a comprehensive catalogue for further study. An atlas explores the landscape of recurrent repeat expansions in human cancer genomes.

We developed My Kidneys & Me (MK&M), a digital health intervention (DHI) that delivers specialist health and lifestyle education, to improve self-management in people with chronic kidney disease (CKD). We aimed to explore the uptake and usability of MK&M alongside patient experiences of using MK&M. Adult patients with CKD stages 3-4 were recruited from 26 hospital kidney services in England. Overall, 420 participants were randomized 2:1 to the intervention (MK&M) or control (usual care) group. Uptake and usage data were collected from the MK&M program. Perceived usefulness of the MK&M sessions and features were collected via web-based surveys (scores were rated out of 10, where 0=\"not useful at all\" and 10=\"very useful\"). Qualitative (semistructured and think-aloud) interviews were used to explore participants' experiences of using and engaging with MK&M. Usage metrics were assessed using descriptive and frequency analyses. Qualitative data were analyzed using thematic analysis. Overall, 280 participants were randomized to receive the MK&M intervention (age: mean 60.8, SD 12.8 y; n=161, 57.5% male; eGFR: mean 38.9, SD 18.5 mL/min/1.73 m ). Of those, 225 (80.3%) participants activated and used their MK&M account. The median number of log-ins per person was 10.0 (IQR 4.0-28.0). The median time per log-in was 12 (IQR 7-25) minutes. \"The kidneys\" was the most accessed session (152/225, 67.6%). The educational sessions were the most valued and engaging content, while health and symptom trackers were the least used features. All sessions received scores ≥7 out of 10 for perceived usefulness, with \"Kidney disease and general health\" considered most useful (score=8.7/10). Goal setting for health behaviors was considered the most useful tracker (score=8.5/10) and symptoms the least (score=6.7/10). Overall, 33 participants were interviewed (n=6, 18% think-aloud; n=27, 81% semistructured). Themes relating to use, usability, and engagement with MK&M were identified. MK&M was well-received, with participants reporting that the user interface was easy to use, with clear and logical navigation and appropriate presentation of information. Learning sessions were more widely accessed and used than the action (\"How to...\") sessions, with participants highlighting not having enough time to engage with all the MK&M content during the study period. MK&M users had positive experiences of using the program; however, there was ambivalence regarding content and features, which could be explained by personal preference rather than usability issues. Participants had a desire for continued learning and perceived the relevance of MK&M to be greater with time and disease progression. The MK&M DHI was well-received and used by the participants. Our findings show that a wide range of people with CKD, including older adults, are capable and willing to use DHIs for kidney health. Identification of real-life use and usability issues will help refine MK&M to improve the content and delivery for clinical implementation.

Magnetic resonance imaging (MRI) has transformed our understanding of the human brain through well-replicated mapping of abilities to specific structures (for example, lesion studies) and functions 1 – 3 (for example, task functional MRI (fMRI)). Mental health research and care have yet to realize similar advances from MRI. A primary challenge has been replicating associations between inter-individual differences in brain structure or function and complex cognitive or mental health phenotypes (brain-wide association studies (BWAS)). Such BWAS have typically relied on sample sizes appropriate for classical brain mapping 4 (the median neuroimaging study sample size is about 25), but potentially too small for capturing reproducible brain–behavioural phenotype associations 5 , 6 . Here we used three of the largest neuroimaging datasets currently available—with a total sample size of around 50,000 individuals—to quantify BWAS effect sizes and reproducibility as a function of sample size. BWAS associations were smaller than previously thought, resulting in statistically underpowered studies, inflated effect sizes and replication failures at typical sample sizes. As sample sizes grew into the thousands, replication rates began to improve and effect size inflation decreased. More robust BWAS effects were detected for functional MRI (versus structural), cognitive tests (versus mental health questionnaires) and multivariate methods (versus univariate). Smaller than expected brain–phenotype associations and variability across population subsamples can explain widespread BWAS replication failures. In contrast to non-BWAS approaches with larger effects (for example, lesions, interventions and within-person), BWAS reproducibility requires samples with thousands of individuals. Combined data from three large studies, with a total sample size of around 50,000 individuals, indicate that many previous studies linking the brain to complex phenotypes have been statistically underpowered, producing inflated and irreproducible effects.

The authors use tiled CRISPR activation for functional enhancer discovery across two autoimmunity risk loci, CD69 and IL2RA , and identify elements with features of stimulus-responsive enhancers, including an IL2RA enhancer that harbours a fine-mapped autoimmunity risk variant. CRISPRa mapping of enhancer functions Enhancers are gene regulatory elements that shape cell-type-specific transcriptional programs and responses to specific extracellular cues. Mapping enhancer function is challenging because of our limited understanding of the cellular context in which each enhancer contributes to gene regulation. Here, Alexander Marson and colleagues use a tiled CRISPR activation (CRISPRa) approach for functional enhancer discovery across two autoimmunity risk loci: CD69 and IL2RA. They identify several elements with features of stimulus-responsive enhancers, including an IL2RA enhancer that contains an autoimmunity risk variant. This approach should be useful for discovering functional enhancers without prior knowledge of their specific biological context. The majority of genetic variants associated with common human diseases map to enhancers, non-coding elements that shape cell-type-specific transcriptional programs and responses to extracellular cues 1 , 2 , 3 . Systematic mapping of functional enhancers and their biological contexts is required to understand the mechanisms by which variation in non-coding genetic sequences contributes to disease. Functional enhancers can be mapped by genomic sequence disruption 4 , 5 , 6 , but this approach is limited to the subset of enhancers that are necessary in the particular cellular context being studied. We hypothesized that recruitment of a strong transcriptional activator to an enhancer would be sufficient to drive target gene expression, even if that enhancer was not currently active in the assayed cells. Here we describe a discovery platform that can identify stimulus-responsive enhancers for a target gene independent of stimulus exposure. We used tiled CRISPR activation (CRISPRa) 7 to synthetically recruit a transcriptional activator to sites across large genomic regions (more than 100 kilobases) surrounding two key autoimmunity risk loci, CD69 and IL2RA . We identified several CRISPRa-responsive elements with chromatin features of stimulus-responsive enhancers, including an IL2RA enhancer that harbours an autoimmunity risk variant. Using engineered mouse models, we found that sequence perturbation of the disease-associated Il2ra enhancer did not entirely block Il2ra expression, but rather delayed the timing of gene activation in response to specific extracellular signals. Enhancer deletion skewed polarization of naive T cells towards a pro-inflammatory T helper (T H 17) cell state and away from a regulatory T cell state. This integrated approach identifies functional enhancers and reveals how non-coding variation associated with human immune dysfunction alters context-specific gene programs.