An Atypical Parvovirus Drives Chronic Tubulointerstitial Nephropathy and Kidney Fibrosis.

The occurrence of a spontaneous nephropathy with intranuclear inclusions in laboratory mice has puzzled pathologists for over 4 decades, because its etiology remains elusive. The condition is more severe in immunodeficient animals, suggesting an infectious cause. Using metagenomics, we identify the causative agent as an atypical virus, termed "mouse kidney parvovirus" (MKPV), belonging to a divergent genus of Parvoviridae. MKPV was identified in animal facilities in Australia and North America, is transmitted via a fecal-oral or urinary-oral route, and is controlled by the adaptive immune system. Detailed analysis of the clinical course and histopathological features demonstrated a stepwise progression of pathology ranging from sporadic tubular inclusions to tubular degeneration and interstitial fibrosis and culminating in renal failure. In summary, we identify a widely distributed pathogen in laboratory mice and establish MKPV-induced nephropathy as a new tool for elucidating mechanisms of tubulointerstitial fibrosis that shares molecular features with chronic kidney disease in humans.

Orthogonal SARS-CoV-2 Serological Assays Enable Surveillance of Low-Prevalence Communities and Reveal Durable Humoral Immunity.

We conducted a serological study to define correlates of immunity against SARS-CoV-2. Compared to those with mild coronavirus disease 2019 (COVID-19) cases, individuals with severe disease exhibited elevated virus-neutralizing titers and antibodies against the nucleocapsid (N) and the receptor binding domain (RBD) of the spike protein. Age and sex played lesser roles. All cases, including asymptomatic individuals, seroconverted by 2 weeks after PCR confirmation. Spike RBD and S2 and neutralizing antibodies remained detectable through 5-7 months after onset, whereas α-N titers diminished. Testing 5,882 members of the local community revealed only 1 sample with seroreactivity to both RBD and S2 that lacked neutralizing antibodies. This fidelity could not be achieved with either RBD or S2 alone. Thus, inclusion of multiple independent assays improved the accuracy of antibody tests in low-seroprevalence communities and revealed differences in antibody kinetics depending on the antigen. We conclude that neutralizing antibodies are stably produced for at least 5-7 months after SARS-CoV-2 infection.

BamA forms a translocation channel for polypeptide export across the bacterial outer membrane.

The ß-barrel assembly machine (BAM) integrates ß-barrel proteins into the outer membrane (OM) of Gram-negative bacteria. An essential BAM subunit (BamA) catalyzes integration by promoting the formation of a hybrid-barrel intermediate state between its own ß-barrel domain and that of its client proteins. Here we show that in addition to catalyzing the integration of ß-barrel proteins, BamA functions as a polypeptide export channel. In vivo structural mapping via intermolecular disulfide crosslinking showed that the extracellular "passenger" domain of a member of the "autotransporter" superfamily of virulence factors traverses the OM through the BamA ß-barrel lumen. Furthermore, we demonstrate that a highly conserved residue within autotransporter ß-barrels is required to position the passenger inside BamA to initiate translocation and that during translocation, the passenger stabilizes the hybrid-barrel state. Our results not only establish a new function for BamA but also unify the divergent functions of BamA and other "Omp85" superfamily transporters.

Sequencing chromosomal abnormalities reveals neurodevelopmental loci that confer risk across diagnostic boundaries.

Balanced chromosomal abnormalities (BCAs) represent a relatively untapped reservoir of single-gene disruptions in neurodevelopmental disorders (NDDs). We sequenced BCAs in patients with autism or related NDDs, revealing disruption of 33 loci in four general categories: (1) genes previously associated with abnormal neurodevelopment (e.g., AUTS2, FOXP1, and CDKL5), (2) single-gene contributors to microdeletion syndromes (MBD5, SATB2, EHMT1, and SNURF-SNRPN), (3) novel risk loci (e.g., CHD8, KIRREL3, and ZNF507), and (4) genes associated with later-onset psychiatric disorders (e.g., TCF4, ZNF804A, PDE10A, GRIN2B, and ANK3). We also discovered among neurodevelopmental cases a profoundly increased burden of copy-number variants from these 33 loci and a significant enrichment of polygenic risk alleles from genome-wide association studies of autism and schizophrenia. Our findings suggest a polygenic risk model of autism and reveal that some neurodevelopmental genes are sensitive to perturbation by multiple mutational mechanisms, leading to variable phenotypic outcomes that manifest at different life stages.

N-glycosylation is a potent regulator of prion protein neurotoxicity.

The C-terminal domain of the cellular prion protein (PrPC) contains two N-linked glycosylation sites, the occupancy of which impacts disease pathology. In this study, we demonstrate that glycans at these sites are required to maintain an intramolecular interaction with the N-terminal domain, mediated through a previously identified copper-histidine tether, which suppresses the neurotoxic activity of PrPC. NMR and electron paramagnetic resonance spectroscopy demonstrate that the glycans refine the structure of the protein's interdomain interaction. Using whole-cell patch-clamp electrophysiology, we further show that cultured cells expressing PrP molecules with mutated glycosylation sites display large, spontaneous inward currents, a correlate of PrP-induced neurotoxicity. Our findings establish a structural basis for the role of N-linked glycans in maintaining a nontoxic, physiological fold of PrPC.

The influence of postural threat-induced anxiety on locomotor learning and updating.

The ability to adapt our locomotion in a feedforward (i.e., "predictive") manner is crucial for safe and efficient walking behavior. Equally important is the ability to quickly deadapt and update behavior that is no longer appropriate for the given context. It has been suggested that anxiety induced via postural threat may play a fundamental role in disrupting such deadaptation. We tested this hypothesis, using the "broken escalator" phenomenon: Fifty-six healthy young adults walked onto a stationary walkway ("BEFORE" condition, 5 trials), then onto a moving walkway akin to an airport travelator ("MOVING" condition, 10 trials), and then again onto the stationary walkway ("AFTER" condition, 5 trials). Participants completed all trials while wearing a virtual reality headset, which was used to induce postural threat-related anxiety (raised clifflike drop at the end of the walkway) during different phases of the paradigm. We found that performing the locomotor adaptation phase in a state of increased threat disrupted subsequent deadaptation during AFTER trials: These participants displayed anticipatory muscular activity as if expecting the platform to move and exhibited inappropriate anticipatory forward trunk movement that persisted during multiple AFTER trials. In contrast, postural threat induced during AFTER trials did not affect behavioral or neurophysiological outcomes. These findings highlight that actions learned in the presence of postural threat-induced anxiety are strengthened, leading to difficulties in deadapting these behaviors when no longer appropriate. Given the associations between anxiety and persistent maladaptive gait behaviors (e.g., "overly cautious" gait, functional gait disorders), the findings have implications for the understanding of such conditions.NEW & NOTEWORTHY Safe and efficient locomotion frequently requires movements to be adapted in a feedforward (i.e., "predictive") manner. These adaptations are not always correct, and thus inappropriate behavior must be quickly updated. Here we showed that increased threat disrupts this process. We found that locomotor actions learned in the presence of postural threat-induced anxiety are strengthened, subsequently impairing one's ability to update (or "deadapt") these actions when they are no longer appropriate for the current context.

Butyrate and tributyrin reduce LPS-induced inflammatory cytokine production from human visceral fat.

INTRODUCTION: The current obesity crisis has resulted in many people with excess adipose tissue suffering from chronic inflammation. This inflammation is largely due to the release of cytokines and chemokines from visceral fat. The aim of this study was to identify potential anti-inflammatory agents that might alleviate obesity-induced chronic inflammation. METHODS: To identify agents that might alleviate this obesity-induced chronic inflammation we have developed a simple protocol for incubating intact pieces of human visceral adipose tissue in 35 mm tissue culture plates, in the presence of low-dose lipopolysaccharide (LPS) and co-incubating these samples with potential anti-inflammatory agents. RNA-Seq analysis was performed to identify enriched gene expression signatures among the most significantly differentially expressed genes. RESULTS: From this screen, we have identified the short-chain fatty acid (SCFA) sodium butyrate and its triacylglyceride form, tributyrin, as effective agents, significantly reducing the production of LPS-induced inflammatory cytokines and chemokines from all adipose tissue samples tested. As well, these agents appear to be non-toxic at the concentrations tested. RNA-Seq analysis has revealed that IL36γ is one of the most upregulated genes in response to LPS and one of the most downregulated when sodium butyrate is added to human fat samples stimulated with LPS. IL-36γ ELISAs confirmed this holds true at the protein level as well. CONCLUSIONS: These studies suggest that the short-chain fatty acid, sodium butyrate, and its triacylglyceride form, tributyrin, might alleviate the chronic inflammation that is associated with many individuals with obesity.

Multicenter, multivendor validation of liver quantitative susceptibility mapping in patients with iron overload at 1.5 T and 3 T.

PURPOSE: To evaluate the repeatability and reproducibility of QSM of the liver via single breath-hold chemical shift-encoded MRI at both 1.5 T and 3 T in a multicenter, multivendor study in subjects with iron overload. METHODS: This prospective study included four academic medical centers with three different MRI vendors at 1.5 T and 3 T. Subjects with known or suspected liver iron overload underwent multi-echo spoiled gradient-recalled-echo scans at each field strength. A subset received repeatability testing at either 1.5 T or 3 T. Susceptibility and R 2 * $$ {\mathrm{R}}_2^{\ast } $$ maps were reconstructed from the multi-echo images and analyzed at a single center. QSM-measured susceptibility was compared with R 2 * $$ {\mathrm{R}}_2^{\ast } $$ and a commercial R2-based liver iron concentration method across centers and field strengths using linear regression and F-tests on the intercept and slope. Field-strength reproducibility and test/retest repeatability were evaluated using Bland-Altman analysis. RESULTS: A total of 155/80 data sets (test/retest) were available at 1.5 T, and 159/70 data sets (test/retest) were available at 3 T. Calibrations across sites were reproducible, with some variability (e.g., susceptibility slope with liver iron concentration ranged from 0.102 to 0.123 g/[mg · $$ \cdotp $$ ppm] across centers at 1.5 T). Field strength reproducibility was good (concordance correlation coefficient = 0.862), and test/retest repeatability was excellent (intraclass correlation coefficient = 0.951). CONCLUSION: QSM as an imaging biomarker of liver iron overload is feasible and repeatable across centers and MR vendors. It may be complementary with R 2 * $$ {\mathrm{R}}_2^{\ast } $$ as they are obtained from the same acquisition. Although good reproducibility was observed, liver QSM may benefit from standardization of acquisition parameters. Overall, QSM is a promising method for liver iron quantification.

Acute calcium pyrophosphate crystal arthritis is associated with an increased rate of hip and knee joint surgery.

OBJECTIVE: Acute calcium pyrophosphate (CPP) crystal arthritis is a distinct manifestation of calcium pyrophosphate crystal deposition (CPPD). No studies have specifically examined whether acute CPP crystal arthritis is associated with progressive structural joint damage. The objective of this retrospective cohort study was to evaluate the relative rate of hip and knee joint arthroplasties as an estimate of structural joint damage accrual, in a population of patients with acute CPP crystal arthritis. METHODS: Data were collected from Waikato District Health Board (WDHB) to identify an acute CPP crystal arthritis cohort with clinical episodes highly characteristic of acute CPP crystal arthritis. Data on hip and knee joint arthroplasties were collected from the New Zealand Orthopaedic Association's Joint Registry. The rate of arthroplasties in the cohort was compared with the age-ethnicity-matched New Zealand population. Additional analysis was performed for age, obesity (BMI) and ethnicity. RESULTS: The acute CPP crystal arthritis cohort included 99 patients; 63 were male and the median age was 77 years (interquartile range, 71-82). The obesity rate was 36% with a median BMI of 28.4 kg/m2 (interquartile range, 25.8-32.2), comparable to the New Zealand population. The standardized surgical rate ratio in the cohort vs the age-ethnicity-matched New Zealand population was 2.54 (95% CI: 1.39, 4.27). CONCLUSION: Our study identified a considerable increase in the rate of hip and knee joint arthroplasties in patients with episodes of acute CPP crystal arthritis. This suggests CPP crystal arthritis may be a chronic condition, leading to progressive joint damage.

Practical Application of Multivendor MRI-Based R2* Mapping for Liver Iron Quantification at 1.5 T and 3.0 T.

BACKGROUND: Recent multicenter, multivendor MRI-based R2* vs. liver iron concentration (LIC) calibrations (i.e., MCMV calibrations) may facilitate broad clinical dissemination of R2*-based LIC quantification. However, these calibrations are based on a centralized offline R2* reconstruction, and their applicability with vendor-provided R2* maps is unclear. PURPOSE: To determine R2* ranges of agreement between the centralized and three MRI vendors' R2* reconstructions. STUDY TYPE: Prospective. SUBJECTS: Two hundred and seven subjects (mean age 37.6 ± 19.6 years; 117 male) with known or suspected iron overload from four academic medical centers. FIELD STRENGTH/SEQUENCE: Standardized multiecho spoiled gradient echo sequence at 1.5 T and 3.0 T for R2* mapping and a multiple spin-echo sequence at 1.5 T for LIC quantification. MRI vendors: GE Healthcare, Philips Healthcare, and Siemens Healthineers. ASSESSMENT: R2* maps were generated using both the centralized and vendor reconstructions, and ranges of agreement were determined. R2*-LIC linear calibrations were determined for each site, field strength, and reconstruction and compared with the MCMV calibrations. STATISTICAL TESTS: Bland-Altman analysis to determine ranges of agreement. Linear regression, analysis of covariance F tests, and Tukey's multiple comparison testing to assess reproducibility of calibrations across sites and vendors. A P value <0.05 was considered significant. RESULTS: The upper limits of R2* ranges of agreement were approximately 500, 375, and 330 s-1 for GE, Philips, and Siemens reconstructions, respectively, at 1.5 T and approximately 700 and 800 s-1 for GE and Philips, respectively, at 3.0 T. Within the R2* ranges of agreement, vendor R2*-LIC calibrations demonstrated high reproducibility (no significant differences between slopes or intercepts; P ≥ 0.06) and agreed with the MCMV calibrations (overlapping 95% confidence intervals). DATA CONCLUSION: Based on the determined upper limits, R2* measurements obtained from vendor-provided R2* maps may be reliably and practically used to quantify LIC less than approximately 8-13 mg/g using the MCMV calibrations and similar acquisition parameters as this study. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 3.

The Significance of Intracellular versus Extracellular Calcium Pyrophosphate Crystals in Diagnosing Calcium Pyrophosphate Crystal Arthritis.

OBJECTIVE: Acute and chronic calcium pyrophosphate (CPP) crystal arthritis is characterised by the presence of synovial CPP crystals within a clinically inflamed joint. CPP crystals may be situated intracellularly or extracellularly, however the clinical significance of their location remains under studied. The objective of this retrospective cohort study was to assess the relevance of the CPP crystal location in diagnosing acute/chronic CPP crystal arthritis. METHODS: Data was collected from Waikato District Health Board to identify a study population with synovial fluid samples positive for CPP crystals. The cohort was stratified into two groups based on crystal location: intracellular and extracellular. The proportion of acute/chronic CPP crystal arthritis cases were compared between these groups. Acute/chronic CPP crystal arthritis was diagnosed when synovial CPP crystals were present, with objective evidence of joint inflammation and no other alternative diagnosis. Further analysis was made with respect to demographics, other laboratory results and cartilage calcification. RESULTS: This study included 134 patients, 108 with intracellular CPP crystals and 26 with extracellular CPP crystals. Acute/chronic CPP crystal arthritis was diagnosed in 85% of the intracellular and 50% of the extracellular group (p<0.001). Following exclusion of the septic arthritis cases, acute/chronic CPP crystal arthritis was diagnosed in 97% of the intracellular and 62% of the extracellular group (p<0.001). CONCLUSION: The presence of intracellular CPP crystals is more strongly associated with acute/chronic CPP crystal arthritis, whereas an extracellular CPP crystal location appears less specific.

Testing predictive coding theories of autism spectrum disorder using models of active inference.

Several competing neuro-computational theories of autism have emerged from predictive coding models of the brain. To disentangle their subtly different predictions about the nature of atypicalities in autistic perception, we performed computational modelling of two sensorimotor tasks: the predictive use of manual gripping forces during object lifting and anticipatory eye movements during a naturalistic interception task. In contrast to some accounts, we found no evidence of chronic atypicalities in the use of priors or weighting of sensory information during object lifting. Differences in prior beliefs, rates of belief updating, and the precision weighting of prediction errors were, however, observed for anticipatory eye movements. Most notably, we observed autism-related difficulties in flexibly adapting learning rates in response to environmental change (i.e., volatility). These findings suggest that atypical encoding of precision and context-sensitive adjustments provide a better explanation of autistic perception than generic attenuation of priors or persistently high precision prediction errors. Our results did not, however, support previous suggestions that autistic people perceive their environment to be persistently volatile.

Directed assembly of small binary clusters of magnetizable ellipsoids.

We report the effect of shape anisotropy and material properties on the directed assembly of binary suspensions composed of magnetizable ellipsoids. In a Monte Carlo simulation, we implement the ellipsoid-dipole model to calculate the pairwise dipolar interaction energy as a function of position and orientation. The analysis explores dilute suspensions of paramagnetic and diamagnetic ellipsoids with different aspect ratios in a superparamagnetic medium. We analyze the local order of binary structures as a function of particle aspect ratio, medium permeability, and dipolar interaction strength. Our results show that local order and symmetry are tunable under the influence of a uniform magnetic field when one component of the structure is dilute with respect to the other. The simulation results match previously reported experiments on the directed assembly of binary suspension of spheres. Additionally, we report the conditions on particle aspect ratios and medium properties for various structures with rotational symmetries, as well as open and enclosed structures under the influence of a uniform magnetic field.

STAT3 Activates the Pentraxin 3 Gene in Chronic Lymphocytic Leukemia Cells.

Pentraxin-related protein 3 (PTX3), commonly produced by myeloid and endothelial cells, is a humoral pattern recognition protein of the innate immune system. Because PTX3 plasma levels of patients with chronic lymphocytic leukemia (CLL) are high and most circulating cells in patients with CLL are CLL cells, we reasoned that CLL cells produce PTX3. Western immunoblotting revealed that low-density cells from seven of seven patients with CLL produce high levels of PTX3, flow cytometry analysis revealed that the PTX3-producing cells are B lymphocytes coexpressing CD19 and CD5, and confocal microscopy showed that PTX3 is present in the cytoplasm of CLL cells. Because STAT3 is constitutively activated in CLL cells, and because we identified putative STAT3 binding sites within the PTX3 gene promoter, we postulated that phosphorylated STAT3 triggers transcriptional activation of PTX3. Immunoprecipitation analysis of CLL cells' chromatin fragments showed that STAT3 Abs precipitated PTX3 DNA. STAT3 knockdown induced a marked reduction in PTX3 expression, indicating a STAT3-induced transcriptional activation of the PTX3 gene in CLL cells. Using an EMSA, we established and used a dual-reporter luciferase assay to confirm that STAT3 binds the PTX3 gene promoter. Downregulation of PTX3 enhanced apoptosis of CLL cells, suggesting that inhibition of PTX3 might benefit patients with CLL.

Resistance of African tropical forests to an extreme climate anomaly.

The responses of tropical forests to environmental change are critical uncertainties in predicting the future impacts of climate change. The positive phase of the 2015-2016 El Niño Southern Oscillation resulted in unprecedented heat and low precipitation in the tropics with substantial impacts on the global carbon cycle. The role of African tropical forests is uncertain as their responses to short-term drought and temperature anomalies have yet to be determined using on-the-ground measurements. African tropical forests may be particularly sensitive because they exist in relatively dry conditions compared with Amazonian or Asian forests, or they may be more resistant because of an abundance of drought-adapted species. Here, we report responses of structurally intact old-growth lowland tropical forests inventoried within the African Tropical Rainforest Observatory Network (AfriTRON). We use 100 long-term inventory plots from six countries each measured at least twice prior to and once following the 2015-2016 El Niño event. These plots experienced the highest temperatures and driest conditions on record. The record temperature did not significantly reduce carbon gains from tree growth or significantly increase carbon losses from tree mortality, but the record drought did significantly decrease net carbon uptake. Overall, the long-term biomass increase of these forests was reduced due to the El Niño event, but these plots remained a live biomass carbon sink (0.51 ± 0.40 Mg C ha-1 y-1) despite extreme environmental conditions. Our analyses, while limited to African tropical forests, suggest they may be more resistant to climatic extremes than Amazonian and Asian forests.

Evaluating the impact of virtual reality game training on upper limb motor performance in children and adolescents with developmental coordination disorder: a scoping review using the ICF framework.

OBJECTIVE: This scoping review aims to explore published literature testing Virtual Reality (VR) interventions for improving upper limb motor performance in children and adolescents with Developmental Coordination Disorder (DCD). Our primary focus was on the types of VR systems used and the measurement tools employed within the International Classification of Functioning, Disability and Health Children and Youth Version (ICF-CY) domains in these studies. METHODS: A comprehensive search of six electronic databases up to 11th January 2024 was conducted using predefined terms. Inclusion and exclusion criteria were applied to determine study eligibility, with two authors independently assessing titles, abstracts, and full-text articles. RESULTS: Out of 788 potential studies, 14 met the eligibility criteria. Studies predominantly utilized non-immersive VR (nVR) systems, for example, commercial platforms such as Nintendo Wii. Most interventions targeted general motor coordination or balance, with only four studies specifically focusing on upper limb motor performance. The Movement Assessment Battery for Children-2 was the predominant assessment tool. However, the use of game scores and trial durations raised concerns about the accuracy of assessments. The majority of studies reported no significant improvement in upper limb motor performance following VR interventions, though some noted improvements in specific tasks or overall outcomes. CONCLUSION: The findings suggest that, while nVR interventions are being explored for paediatric motor rehabilitation, their impact on enhancing upper limb motor performance in children with DCD is unclear. The variability in intervention designs, outcome measures, and the predominant focus on general motor skills rather than specific upper limb improvements highlight the need for more targeted research in this area. IMPACT: This review underscores the importance of developing precise and clinically relevant measurement tools in a broader range of VR technologies to optimize the use of VR in therapy for children with DCD. Future research should aim for more rigorous study designs and emerging immersive technologies to maximize therapeutic benefits.

Using a boundary crossing lens to understand basic science educator and clinical educator collaboration in instructional design.

PURPOSE: Collaborations between basic science educators (BE) and clinical educators (CE) in medical education are common and necessary to create integrated learning materials. However, few studies describe experiences of or processes used by educators engaged in interdisciplinary teamwork. We use the lens of boundary crossing to explore processes described by BE and CE that support the co-creation of integrated learning materials, and the impact that this work has on them. MATERIALS AND METHODS: We conducted qualitative content analysis on program evaluation data from 27 BE and CE who worked on 12 teams as part of a multi-institutional instructional design project. RESULTS: BE and CE productively engaged in collaboration using boundary crossing mechanisms. These included respecting diverse perspectives and expertise and finding efficient processes for completing shared work that allow BE and CE to build on each other's contributions. BE and CE developed confidence in connecting clinical concepts with causal explanations, and willingness to engage in and support such collaborations at their own institutions. CONCLUSIONS: BE and CE report the use of boundary crossing mechanisms that support collaboration in instructional design. Such practices could be harnessed in future collaborations between BE and CE.

The role of prediction and visual tracking strategies during manual interception: An exploration of individual differences.

The interception (or avoidance) of moving objects is a common component of various daily living tasks; however, it remains unclear whether precise alignment of foveal vision with a target is important for motor performance. Furthermore, there has also been little examination of individual differences in visual tracking strategy and the use of anticipatory gaze adjustments. We examined the importance of in-flight tracking and predictive visual behaviors using a virtual reality environment that required participants (n = 41) to intercept tennis balls projected from one of two possible locations. Here, we explored whether different tracking strategies spontaneously arose during the task, and which were most effective. Although indices of closer in-flight tracking (pursuit gain, tracking coherence, tracking lag, and saccades) were predictive of better interception performance, these relationships were rather weak. Anticipatory gaze shifts toward the correct release location of the ball provided no benefit for subsequent interception. Nonetheless, two interceptive strategies were evident: 1) early anticipation of the ball's onset location followed by attempts to closely track the ball in flight (i.e., predictive strategy); or 2) positioning gaze between possible onset locations and then using peripheral vision to locate the moving ball (i.e., a visual pivot strategy). Despite showing much poorer in-flight foveal tracking of the ball, participants adopting a visual pivot strategy performed slightly better in the task. Overall, these results indicate that precise alignment of the fovea with the target may not be critical for interception tasks, but that observers can adopt quite varied visual guidance approaches.

Bringing back the core concepts of physiology in an advanced medical school senior elective.

Integrating physiology core concepts into the clinical years of medical education has been challenging despite efforts. This article describes a fourth-year medical school elective, Advanced Physiology in Critical Care Medicine, that focused on integrating physiology core concepts in a case-based learning approach. The elective used interdisciplinary faculty in a virtual forum. Senior students were asked to generate mechanism of disease (MOD) maps, highlight the physiology core concepts associated with paper cases of critically ill patients, and discuss with faculty the relevance of the underlying basic science. The weekly footprint consisted of a student-led session presenting MOD maps for three cases, which examined aspects of core physiology concepts, and, later in the same week, student presentation of order sets for the management of the cases. Students ended the 4-wk elective with a mini-grand rounds presentation on a topic of their choice incorporating the core concept paradigm. Student perception data and faculty reflections of the elective course are included. Student data and faculty observations suggest that students appreciate and can apply physiological core concepts to patient care. Faculty experience in the course suggests that this senior elective helped them better approach all preclinical teaching with the Core Concepts framework in mind.NEW & NOTEWORTHY This article presents an innovative approach to integration of physiology core concepts with clinical management using cases of critically ill patients in an online senior elective for medical students. It uses a multidisciplinary faculty conducting a course primarily using case-based learning led by student presentations and discussions of concept maps and order sets.

Obesity: a perfect storm for carcinogenesis.

Obesity-related cancers account for 40% of the cancer cases observed in the USA and obesity is overtaking smoking as the most widespread modifiable risk factor for carcinogenesis. Here, we use the hallmarks of cancer framework to delineate how obesity might influence the carcinogenic hallmarks in somatic cells. We discuss the effects of obesity on (a) sustaining proliferative signaling; (b) evading growth suppressors; (c) resisting cell death; (d) enabling replicative immortality; (e) inducing angiogenesis; (f) activating invasion and metastasis; (g) reprogramming energy metabolism; and (h) avoiding immune destruction, together with its effects on genome instability and tumour-promoting inflammation. We present the current understanding and controversies in this evolving field, and highlight some areas in need of further cross-disciplinary focus. For instance, the relative importance of the many potentially causative obesity-related factors is unclear for each type of malignancy. Even within a single tumour type, it is currently unknown whether one obesity-related factor consistently plays a predominant role, or if this varies between patients or, even in a single patient with time. Clarifying how the hallmarks are affected by obesity may lead to novel prevention and treatment strategies for the increasingly obese population.