AI-MARRVEL - A Knowledge-Driven AI System for Diagnosing Mendelian Disorders.

BACKGROUND: Diagnosing genetic disorders requires extensive manual curation and interpretation of candidate variants, a labor-intensive task even for trained geneticists. Although artificial intelligence (AI) shows promise in aiding these diagnoses, existing AI tools have only achieved moderate success for primary diagnosis. METHODS: AI-MARRVEL (AIM) uses a random-forest machine-learning classifier trained on over 3.5 million variants from thousands of diagnosed cases. AIM additionally incorporates expert-engineered features into training to recapitulate the intricate decision-making processes in molecular diagnosis. The online version of AIM is available at https://ai.marrvel.org. To evaluate AIM, we benchmarked it with diagnosed patients from three independent cohorts. RESULTS: AIM improved the rate of accurate genetic diagnosis, doubling the number of solved cases as compared with benchmarked methods, across three distinct real-world cohorts. To better identify diagnosable cases from the unsolved pools accumulated over time, we designed a confidence metric on which AIM achieved a precision rate of 98% and identified 57% of diagnosable cases out of a collection of 871 cases. Furthermore, AIM's performance improved after being fine-tuned for targeted settings including recessive disorders and trio analysis. Finally, AIM demonstrated potential for novel disease gene discovery by correctly predicting two newly reported disease genes from the Undiagnosed Diseases Network. CONCLUSIONS: AIM achieved superior accuracy compared with existing methods for genetic diagnosis. We anticipate that this tool may aid in primary diagnosis, reanalysis of unsolved cases, and the discovery of novel disease genes. (Funded by the NIH Common Fund and others.).

Nesting Biology of Megachile (Chrysosarus) jenseni (Hymenoptera: Megachilidae) in Two Contrasting Pampean Agroecosystems: A Potential Pollinator for Alfalfa?

Several crops depend on both managed and wild bees to produce fruits and/or seeds, and the efficiency of numerous wild bees is higher than that of some managed species. Therefore, knowing and understanding the required resources for wild bees could enabled the establishment of management practices to increase their populations. Here, we provide information about the nesting biology of Megachile (Chrysosarus) jenseni, a Faboideae-specialist bee species. Based on observations from two populations occurring in contrasting agroecosystems, this bivoltine species showed common behavioral features shared with other species of subgenus Chrysosarus, such as the use of petal pieces and mud as nesting materials and the utilization of pre-existing cavities. Both studied populations showed a bivoltine life cycle with a rapid early-summer generation and a second generation, with most individuals overwintering. Main causes of mortality were unknown diseases (or other factors), causing the death of preimaginal stages. Moreover, this species was attacked by a cleptoparasite megachilid (Coelioxys remissa), a parasitic eulophid wasp (Melittobia sp.), and a bee fly (Anthrax oedipus). Finally, we discussed the potential use of this leaf-cutter bee species for alfalfa pollination.

Homopolymer switches mediate adaptive mutability in mismatch repair-deficient colorectal cancer.

Mismatch repair (MMR)-deficient cancer evolves through the stepwise erosion of coding homopolymers in target genes. Curiously, the MMR genes MutS homolog 6 (MSH6) and MutS homolog 3 (MSH3) also contain coding homopolymers, and these are frequent mutational targets in MMR-deficient cancers. The impact of incremental MMR mutations on MMR-deficient cancer evolution is unknown. Here we show that microsatellite instability modulates DNA repair by toggling hypermutable mononucleotide homopolymer runs in MSH6 and MSH3 through stochastic frameshift switching. Spontaneous mutation and reversion modulate subclonal mutation rate, mutation bias and HLA and neoantigen diversity. Patient-derived organoids corroborate these observations and show that MMR homopolymer sequences drift back into reading frame in the absence of immune selection, suggesting a fitness cost of elevated mutation rates. Combined experimental and simulation studies demonstrate that subclonal immune selection favors incremental MMR mutations. Overall, our data demonstrate that MMR-deficient colorectal cancers fuel intratumor heterogeneity by adapting subclonal mutation rate and diversity to immune selection.

Stepwise Transfer Learning for Expert-Level Pediatric Brain Tumor MRI Segmentation in a Limited Data Scenario.

"Just Accepted" papers have undergone full peer review and have been accepted for publication in Radiology: Artificial Intelligence. This article will undergo copyediting, layout, and proof review before it is published in its final version. Please note that during production of the final copyedited article, errors may be discovered which could affect the content. Purpose To develop, externally test, and evaluate clinical acceptability of a deep learning (DL) pediatric brain tumor segmentation model using stepwise transfer learning. Materials and Methods In this retrospective study, the authors leveraged two T2-weighted MRI datasets (May 2001-December 2015) from a national brain tumor consortium (n = 184; median age, 7 years (range: 1-23 years); 94 male) and a pediatric cancer center (n = 100; median age, 8 years (range: 1-19 years); 47 male) to develop and evaluate DL neural networks for pediatric low-grade glioma segmentation using a novel stepwise transfer learning approach to maximize performance in a limited data scenario. The best model was externally-tested on an independent test set and subjected to randomized, blinded evaluation by three clinicians, wherein they assessed clinical acceptability of expert- and artificial intelligence (AI)-generated segmentations via 10-point Likert scales and Turing tests. Results The best AI model used in-domain, stepwise transfer learning (median DSC: 0.88 [IQR 0.72-0.91] versus 0.812 [0.56-0.89] for baseline model; P = .049). On external testing, AI model yielded excellent accuracy using reference standards from three clinical experts (Expert-1: 0.83 [0.75-0.90]; Expert-2: 0.81 [0.70-0.89]; Expert-3: 0.81 [0.68-0.88]; mean accuracy: 0.82)). On clinical benchmarking (n = 100 scans), experts rated AI-based segmentations higher on average compared with other experts (median Likert score: median 9 [IQR 7-9]) versus 7 [IQR 7-9]) and rated more AI segmentations as clinically acceptable (80.2% versus 65.4%). Experts correctly predicted the origin of AI segmentations in an average of 26.0% of cases. Conclusion Stepwise transfer learning enabled expert-level, automated pediatric brain tumor auto-segmentation and volumetric measurement with a high level of clinical acceptability. ©RSNA, 2024.

Associations Between Stroke Type, Ischemic Stroke Subtypes, and Post-Stroke Cognitive Trajectories.

Background: It is unclear how post-stroke cognitive trajectories differ by stroke type and ischemic stroke subtype. We studied associations between stroke types (ischemic, hemorrhagic), ischemic stroke subtypes (cardioembolic, large artery atherosclerotic, lacunar/small vessel, cryptogenic/other determined etiology), and post-stroke cognitive decline. Methods: This pooled cohort analysis from four US cohort studies (1971-2019) identified 1,143 dementia-free individuals with acute stroke during follow-up: 1,061 (92.8%) ischemic, 82 (7.2%) hemorrhagic, 49.9% female, 30.8% Black. Median age at stroke was 74.1 (IQR, 68.6, 79.3) years. Outcomes were change in global cognition (primary) and changes in executive function and memory (secondary). Outcomes were standardized as T-scores (mean [SD], 50 [10]); a 1-point difference represents a 0.1-SD difference in cognition. Median follow-up for the primary outcome was 6.0 (IQR, 3.2, 9.2) years. Linear mixed-effects models estimated changes in cognition after stroke. Results: On average, the initial post-stroke global cognition score was 50.78 points (95% CI, 49.52, 52.03) in ischemic stroke survivors and did not differ in hemorrhagic stroke survivors (difference, -0.17 points [95% CI, -1.64, 1.30]; P=0.82) after adjusting for demographics and pre-stroke cognition. On average, ischemic stroke survivors showed declines in global cognition, executive function, and memory. Post-stroke declines in global cognition, executive function, and memory did not differ between hemorrhagic and ischemic stroke survivors. 955 ischemic strokes had subtypes: 200 (20.9%) cardioembolic, 77 (8.1%) large artery atherosclerotic, 207 (21.7%) lacunar/small vessel, 471 (49.3%) cryptogenic/other determined etiology. On average, small vessel stroke survivors showed declines in global cognition and memory, but not executive function. Initial post-stroke cognitive scores and cognitive declines did not differ between small vessel survivors and survivors of other ischemic stroke subtypes. Post-stroke vascular risk factor levels did not attenuate associations. Conclusion: Stroke survivors had cognitive decline in multiple domains. Declines did not differ by stroke type or ischemic stroke subtype.

Orchidinae-205: A new genome-wide custom bait set for studying the evolution, systematics, and trade of terrestrial orchids.

Terrestrial orchids are a group of genetically understudied, yet culturally and economically important plants. The Orchidinae tribe contains many species that produce edible tubers that are used for the production of traditional delicacies collectively called 'salep'. Overexploitation of wild orchids in the Eastern Mediterranean and Western Asia threatens to drive many of these species to extinction, but cost-effective tools for monitoring their trade are currently lacking. Here we present a custom bait kit for target enrichment and sequencing of 205 novel genetic markers that are tailored to phylogenomic applications in Orchidinae s.l. A subset of 31 markers capture genes putatively involved in the production of glucomannan, a water-soluble polysaccharide that gives salep its distinctive properties. We tested the kit on 73 taxa native to the area, demonstrating universally high locus recovery irrespective of species identity, that exceeds the total sequence length obtained with alternative kits currently available. Phylogenetic inference with concatenation and coalescent approaches was robust and showed high levels of support for most clades, including some which were previously unresolved. Resolution for hybridizing and recently radiated lineages remains difficult, but could be further improved by analysing multiple haplotypes and the non-exonic sequences captured by our kit, with the promise to shed new light on the evolution of enigmatic taxa with a complex speciation history. Offering a step-up from traditional barcoding and universal markers, the genome-wide custom loci targeted by Orchidinae-205 are a valuable new resource to study the evolution, systematics and trade of terrestrial orchids.

Forecasting the Burden of Cardiovascular Disease and Stroke in the United States Through 2050-Prevalence of Risk Factors and Disease: A Presidential Advisory From the American Heart Association.

BACKGROUND: Cardiovascular disease and stroke are common and costly, and their prevalence is rising. Forecasts on the prevalence of risk factors and clinical events are crucial. METHODS: Using the 2015 to March 2020 National Health and Nutrition Examination Survey and 2015 to 2019 Medical Expenditure Panel Survey, we estimated trends in prevalence for cardiovascular risk factors based on adverse levels of Life's Essential 8 and clinical cardiovascular disease and stroke. We projected through 2050, overall and by age and race and ethnicity, accounting for changes in disease prevalence and demographics. RESULTS: We estimate that among adults, prevalence of hypertension will increase from 51.2% in 2020 to 61.0% in 2050. Diabetes (16.3% to 26.8%) and obesity (43.1% to 60.6%) will increase, whereas hypercholesterolemia will decline (45.8% to 24.0%). The prevalences of poor diet, inadequate physical activity, and smoking are estimated to improve over time, whereas inadequate sleep will worsen. Prevalences of coronary disease (7.8% to 9.2%), heart failure (2.7% to 3.8%), stroke (3.9% to 6.4%), atrial fibrillation (1.7% to 2.4%), and total cardiovascular disease (11.3% to 15.0%) will rise. Clinical CVD will affect 45 million adults, and CVD including hypertension will affect more than 184 million adults by 2050 (>61%). Similar trends are projected in children. Most adverse trends are projected to be worse among people identifying as American Indian/Alaska Native or multiracial, Black, or Hispanic. CONCLUSIONS: The prevalence of many cardiovascular risk factors and most established diseases will increase over the next 30 years. Clinical and public health interventions are needed to effectively manage, stem, and even reverse these adverse trends.

The use of experimentally evolved coral photosymbionts for reef restoration.

The heat tolerance of corals is largely determined by their microbial photosymbionts (Symbiodiniaceae, colloquially known as zooxanthellae). Therefore, manipulating symbiont communities may enhance the ability of corals to survive summer heatwaves. Although heat-tolerant and -sensitive symbiont species occur in nature, even corals that harbour naturally tolerant symbionts have been observed to bleach during summer heatwaves. Experimental evolution (i.e., laboratory selection) of Symbiodiniaceae cultures under elevated temperatures has been successfully used to enhance their upper thermal tolerance, both in vitro and, in some instances, following their reintroduction into corals. In this review, we present the state of this intervention and its potential role within coral reef restoration, and discuss the next critical steps required to bridge the gap to implementation.

Alzheimer's disease risk allele of PICALM causes detrimental lipid droplets in microglia.

Despite genome-wide association studies of late-onset Alzheimer's disease (LOAD) having identified many genetic risk loci1-6, the underlying disease mechanisms remain largely unknown. Determining causal disease variants and their LOAD-relevant cellular phenotypes has been a challenge. Leveraging our approach for identifying functional GWAS risk variants showing allele-specific open chromatin (ASoC)7, we systematically identified putative causal LOAD risk variants in human induced pluripotent stem cells (iPSC)-derived neurons, astrocytes, and microglia (MG) and linked PICALM risk allele to a previously unappreciated MG-specific role of PICALM in lipid droplet (LD) accumulation. ASoC mapping uncovered functional risk variants for 26 LOAD risk loci, mostly MG-specific. At the MG-specific PICALM locus, the LOAD risk allele of rs10792832 reduced transcription factor (PU.1) binding and PICALM expression, impairing the uptake of amyloid beta (Aß) and myelin debris. Interestingly, MG with PICALM risk allele showed transcriptional enrichment of pathways for cholesterol synthesis and LD formation. Genetic and pharmacological perturbations of MG further established a causal link between the reduced PICALM expression, LD accumulation, and phagocytosis deficits. Our work elucidates the selective LOAD vulnerability in microglia for the PICALM locus through detrimental LD accumulation, providing a neurobiological basis that can be exploited for developing novel clinical interventions.

Dominant Missense Variants in SREBF2 are Associated with Complex Dermatological, Neurological, and Skeletal Abnormalities.

PURPOSE: We identified two individuals with de novo variants in SREBF2 that disrupt a conserved site 1 protease (S1P) cleavage motif required for processing SREBP2 into its mature transcription factor. These individuals exhibit complex phenotypic manifestations that partially overlap with SREBP pathway-related disease phenotypes, but SREBF2-related disease has not been previously reported. Thus, we set out to assess the effects of SREBF2 variants on SREBP pathway activation. METHODS: We undertook ultrastructure and gene expression analyses using fibroblasts from an affected individual and utilized a fly model of lipid droplet formation to investigate the consequences of SREBF2 variants on SREBP pathway function. RESULTS: We observed reduced lipid droplet (LD) formation, endoplasmic reticulum expansion, accumulation of aberrant lysosomes, and deficits in SREBP2 target gene expression in fibroblasts from an affected individual, indicating that the SREBF2 variant inhibits SREBP pathway activation. Using our fly model, we discovered that SREBF2 variants fail to induce LD production and act in a dominant-negative manner, which can be rescued by overexpression of S1P. CONCLUSION: Taken together, these data reveal a mechanism by which SREBF2 pathogenic variants that disrupt the S1P cleavage motif cause disease via dominant-negative antagonism of S1P, limiting the cleavage of S1P targets, including SREBP1 and SREBP2.

Bayesian modelling disentangles language versus executive control disruption in stroke.

Stroke is the leading cause of long-term disability worldwide. Incurred brain damage can disrupt cognition, often with persisting deficits in language and executive capacities. Yet, despite their clinical relevance, the commonalities and differences between language versus executive control impairments remain under-specified. To fill this gap, we tailored a Bayesian hierarchical modelling solution in a largest-of-its-kind cohort (1080 patients with stroke) to deconvolve language and executive control with respect to the stroke topology. Cognitive function was assessed with a rich neuropsychological test battery including global cognitive function (tested with the Mini-Mental State Exam), language (assessed with a picture naming task), executive speech function (tested with verbal fluency tasks), executive control functions (Trail Making Test and Digit Symbol Coding Task), visuospatial functioning (Rey Complex Figure), as well as verbal learning and memory function (Soul Verbal Learning). Bayesian modelling predicted interindividual differences in eight cognitive outcome scores three months after stroke based on specific tissue lesion topologies. A multivariate factor analysis extracted four distinct cognitive factors that distinguish left- and right-hemispheric contributions to ischaemic tissue lesions. These factors were labelled according to the neuropsychological tests that had the strongest factor loadings: One factor delineated language and general cognitive performance and was mainly associated with damage to left-hemispheric brain regions in the frontal and temporal cortex. A factor for executive control summarized mental flexibility, task switching and visual-constructional abilities. This factor was strongly related to right-hemispheric brain damage of posterior regions in the occipital cortex. The interplay of language and executive control was reflected in two distinct factors that were labelled as executive speech functions and verbal memory. Impairments on both factors were mainly linked to left-hemispheric lesions. These findings shed light onto the causal implications of hemispheric specialization for cognition; and make steps towards subgroup-specific treatment protocols after stroke.

Body Composition in Advanced Non-Small Cell Lung Cancer Treated With Immunotherapy.

Importance: The association between body composition (BC) and cancer outcomes is complex and incompletely understood. Previous research in non-small-cell lung cancer (NSCLC) has been limited to small, single-institution studies and yielded promising, albeit heterogeneous, results. Objectives: To evaluate the association of BC with oncologic outcomes in patients receiving immunotherapy for advanced or metastatic NSCLC. Design, Setting, and Participants: This comprehensive multicohort analysis included clinical data from cohorts receiving treatment at the Dana-Farber Brigham Cancer Center (DFBCC) who received immunotherapy given alone or in combination with chemotherapy and prospectively collected data from the phase 1/2 Study 1108 and the chemotherapy arm of the phase 3 MYSTIC trial. Baseline and follow-up computed tomography (CT) scans were collected and analyzed using deep neural networks for automatic L3 slice selection and body compartment segmentation (skeletal muscle [SM], subcutaneous adipose tissue [SAT], and visceral adipose tissue). Outcomes were compared based on baseline BC measures or their change at the first follow-up scan. The data were analyzed between July 2022 and April 2023. Main Outcomes and Measures: Hazard ratios (HRs) for the association of BC measurements with overall survival (OS) and progression-free survival (PFS). Results: A total of 1791 patients (878 women [49%]) with NSCLC were analyzed, of whom 487 (27.2%) received chemoimmunotherapy at DFBCC (DFBCC-CIO), 825 (46.1%) received ICI monotherapy at DFBCC (DFBCC-IO), 222 (12.4%) were treated with durvalumab monotherapy on Study 1108, and 257 (14.3%) were treated with chemotherapy on MYSTIC; median (IQR) ages were 65 (58-74), 66 (57-71), 65 (26-87), and 63 (30-84) years, respectively. A loss in SM mass, as indicated by a change in the L3 SM area, was associated with worse oncologic outcome across patient groups (HR, 0.59 [95% CI, 0.43-0.81] and 0.61 [95% CI, 0.47-0.79] for OS and PFS, respectively, in DFBCC-CIO; HR, 0.74 [95% CI, 0.60-0.91] for OS in DFBCC-IO; HR, 0.46 [95% CI, 0.33-0.64] and 0.47 [95% CI, 0.34-0.64] for OS and PFS, respectively, in Study 1108; HR, 0.76 [95% CI, 0.61-0.96] for PFS in the MYSTIC trial). This association was most prominent among male patients, with a nonsignificant association among female patients in the MYSTIC trial and DFBCC-CIO cohorts on Kaplan-Meier analysis. An increase of more than 5% in SAT density, as quantified by the average CT attenuation in Hounsfield units of the SAT compartment, was associated with poorer OS in 3 patient cohorts (HR, 0.61 [95% CI, 0.43-0.86] for DFBCC-CIO; HR, 0.62 [95% CI, 0.49-0.79] for DFBCC-IO; and HR, 0.56 [95% CI, 0.40-0.77] for Study 1108). The change in SAT density was also associated with PFS for DFBCC-CIO (HR, 0.73; 95% CI, 0.54-0.97). This was primarily observed in female patients on Kaplan-Meier analysis. Conclusions and Relevance: The results of this multicohort study suggest that loss in SM mass during systemic therapy for NSCLC is a marker of poor outcomes, especially in male patients. SAT density changes are also associated with prognosis, particularly in female patients. Automated CT-derived BC measurements should be considered in determining NSCLC prognosis.

DNA damage induces p53-independent apoptosis through ribosome stalling.

In response to excessive DNA damage, human cells can activate p53 to induce apoptosis. Cells lacking p53 can still undergo apoptosis upon DNA damage, yet the responsible pathways are unknown. We observed that p53-independent apoptosis in response to DNA damage coincided with translation inhibition, which was characterized by ribosome stalling on rare leucine-encoding UUA codons and globally curtailed translation initiation. A genetic screen identified the transfer RNAse SLFN11 and the kinase GCN2 as factors required for UUA stalling and global translation inhibition, respectively. Stalled ribosomes activated a ribotoxic stress signal conveyed by the ribosome sensor ZAKα to the apoptosis machinery. These results provide an explanation for the frequent inactivation of SLFN11 in chemotherapy-unresponsive tumors and highlight ribosome stalling as a signaling event affecting cell fate in response to DNA damage.

Does glial lipid dysregulation alter sleep in Alzheimer's and Parkinson's disease?

In this opinion article, we discuss potential connections between sleep disturbances observed in Alzheimer's disease (AD) and Parkinson's disease (PD) and the dysregulation of lipids in the brain. Research using Drosophila has highlighted the role of glial-mediated lipid metabolism in sleep and diurnal rhythms. Relevant to AD, the formation of lipid droplets in glia, which occurs in response to elevated neuronal reactive oxygen species (ROS), is required for sleep. In disease models, this process is disrupted, arguing a connection to sleep dysregulation. Relevant to PD, the degradation of neuronally synthesized glucosylceramides by glia requires glucocerebrosidase (GBA, a PD-associated risk factor) and this regulates sleep. Loss of GBA in glia causes an accumulation of glucosylceramides and neurodegeneration. Overall, research primarily using Drosophila has highlighted how dysregulation of glial lipid metabolism may underlie sleep disturbances in neurodegenerative diseases.

Changes in Oxidised Phospholipids in Response to Oxidative Stress in Microtubule-Associated Protein Tau (MAPT) Mutant Dopamine Neurons.

Microtubule-associated protein Tau (MAPT) is strongly associated with the development of neurodegenerative diseases. In addition to driving the formation of neurofibrillary tangles (NFT), mutations in the MAPT gene can also cause oxidative stress through hyperpolarisation of the mitochondria. This study explores the impact that MAPT mutation is having on phospholipid metabolism in iPSC-derived dopamine neurons, and to determine if these effects are exacerbated by mitochondrial and endoplasmic reticulum stress. Neurons that possessed a mutated copy of MAPT were shown to have significantly higher levels of oxo-phospholipids (Oxo-PL) than wild-type neurons. Oxidation of the hydrophobic fatty acid side chains changes the chemistry of the phospholipid leading to disruption of membrane function and potential cell lysis. In wild-type neurons, both mitochondrial and endoplasmic reticulum stress increased Oxo-PL abundance; however, in MAPT mutant neurons mitochondrial stress appeared to have a minimal effect. Endoplasmic reticulum stress, surprisingly, reduced the abundance of Oxo-PL in MAPT mutant dopamine neurons, and we postulate that this reduction could be modulated through hyperactivation of the unfolded protein response and X-box binding protein 1. Overall, the results of this study contribute to furthering our understanding of the regulation and impact of oxidative stress in Parkinson's disease pathology.

Influence of learned landmark correspondences on lung CT registration.

BACKGROUND: Disease or injury may cause a change in the biomechanical properties of the lungs, which can alter lung function. Image registration can be used to measure lung ventilation and quantify volume change, which can be a useful diagnostic aid. However, lung registration is a challenging problem because of the variation in deformation along the lungs, sliding motion of the lungs along the ribs, and change in density. PURPOSE: Landmark correspondences have been used to make deformable image registration robust to large displacements. METHODS: To tackle the challenging task of intra-patient lung computed tomography (CT) registration, we extend the landmark correspondence prediction model deep convolutional neural network-Match by introducing a soft mask loss term to encourage landmark correspondences in specific regions and avoid the use of a mask during inference. To produce realistic deformations to train the landmark correspondence model, we use data-driven synthetic transformations. We study the influence of these learned landmark correspondences on lung CT registration by integrating them into intensity-based registration as a distance-based penalty. RESULTS: Our results on the public thoracic CT dataset COPDgene show that using learned landmark correspondences as a soft constraint can reduce median registration error from approximately 5.46 to 4.08 mm compared to standard intensity-based registration, in the absence of lung masks. CONCLUSIONS: We show that using landmark correspondences results in minor improvements in local alignment, while significantly improving global alignment.

The relationship between object-based spatial ability and virtual navigation performance.

Spatial navigation is a multi-faceted behaviour drawing on many different aspects of cognition. Visuospatial abilities, such as mental rotation and visuospatial working memory, in particular, may be key factors. A range of tests have been developed to assess visuospatial processing and memory, but how such tests relate to navigation ability remains unclear. This understanding is important to advance tests of navigation for disease monitoring in various disorders (e.g., Alzheimer's disease) where spatial impairment is an early symptom. Here, we report the use of an established mobile gaming app, Sea Hero Quest (SHQ), as a measure of navigation ability in a sample of young, predominantly female university students (N = 78; 20; female = 74.3%; mean age = 20.33 years). We used three separate tests of navigation embedded in SHQ: wayfinding, path integration and spatial memory in a radial arm maze. In the same participants, we also collected measures of mental rotation (Mental Rotation Test), visuospatial processing (Design Organization Test) and visuospatial working memory (Digital Corsi). We found few strong correlations across our measures. Being good at wayfinding in a virtual navigation test does not mean an individual will also be good at path integration, have a superior memory in a radial arm maze, or rate themself as having a strong sense of direction. However, we observed that participants who were good in the wayfinding task of SHQ tended to perform well on the three visuospatial tasks examined here, and to also use a landmark strategy in the radial maze task. These findings help clarify the associations between different abilities involved in spatial navigation.

Acute Cholecystitis Due to Lactococcus lactis and Single-Center Experience With Infections Due to Lactococcus spp.

Background: Lactococcus species are used to ferment milk to yogurt, cheese, and other products. The gram-positive coccus causes diseases in amphibia and fish and is a rare human pathogen. Patients and Methods: A 51-year-old male underwent laparoscopic cholecystectomy for acute and chronic calculous cholecystitis. Lactococcus lactis was isolated from pus from his gallbladder empyema. Results: Our institutional database was searched for other cases of Lactococcus spp. infections and four patients (2 males, 2 females; aged 51, 64, 78, and 80 years) were identified during a four-year period. The three other patients had positive blood cultures associated with pneumonia, toxic megacolon, and severe gastroenteritis. All isolates were monocultures with Lactococcus lactis (2), Lactococcus garvieae (1) and Lactococcus raffinolactis (1). Two patients died related to their sepsis. We report the second case of cholecystitis involving Lactococcus. Conclusions: Lactococcus is a very rare pathogen mainly causing blood stream infections but needs to be considered to cause serious surgical infections in humans.

Association of Loneliness with Functional Connectivity MRI, Amyloid-ß PET, and Tau PET Neuroimaging Markers of Vulnerability for Alzheimer's Disease.

Background: Loneliness has been declared an "epidemic" associated with negative physical, mental, and cognitive health outcomes such as increased dementia risk. Less is known about the relationship between loneliness and advanced neuroimaging correlates of Alzheimer's disease (AD). Objective: To assess whether loneliness was associated with advanced neuroimaging markers of AD using neuroimaging data from Framingham Heart Study (FHS) participants without dementia. Methods: In this cross-sectional observational analysis, we used functional connectivity MRI (fcMRI), amyloid-ß (Aß) PET, and tau PET imaging data collected between 2016 and 2019 on eligible FHS cohort participants. Loneliness was defined as feeling lonely at least one day in the past week. The primary fcMRI marker was Default Mode Network intra-network connectivity. The primary PET imaging markers were Aß deposition in precuneal and FLR (frontal, lateral parietal and lateral temporal, retrosplenial) regions, and tau deposition in the amygdala, entorhinal, and rhinal regions. Results: Of 381 participants (mean age 58 [SD 10]) who met inclusion criteria for fcMRI analysis, 5% were classified as lonely (17/381). No association was observed between loneliness status and network changes. Of 424 participants (mean age 58 [SD = 10]) meeting inclusion criteria for PET analyses, 5% (21/424) were lonely; no associations were observed between loneliness and either Aß or tau deposition in primary regions of interest. Conclusions: In this cross-sectional study, there were no observable associations between loneliness and select fcMRI, Aß PET, and tau PET neuroimaging markers of AD risk. These findings merit further investigation in prospective studies of community-based cohorts.