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Abstract The maintenance of intestinal homeostasis is a fundamental process critical for organismal integrity. Sitting at the interface of the gut microbiome and mucosal immunity, adaptive and innate lymphoid populations regulate the balance between commensal micro-organisms and pathogens. Checkpoint inhibitors, particularly those targeting the CTLA-4 pathway, disrupt this fine balance and can lead to inflammatory bowel disease and immune checkpoint colitis. Here, we show that CTLA-4 is expressed by innate lymphoid cells and that its expression is regulated by ILC subset-specific cytokine cues in a microbiota-dependent manner. Genetic deletion or antibody blockade of CTLA-4 in multiple in vivo models of colitis demonstrates that this pathway plays a key role in intestinal homeostasis. Lastly, we have found that this observation is conserved in human IBD. We propose that this population of CTLA-4-positive ILC may serve as an important target for the treatment of idiopathic and iatrogenic intestinal inflammation.

Abstract Normal respiratory rates (RR) for children under five in the tropics are well-documented, but data for older children are limited. This study tracked RR changes with age and examined associations with nutritional status and environmental factors. We monitored rural Gambian children aged 6 months to 14 years, recording RR during home visits twice weekly over two rainy seasons. Using a generalized additive model, we constructed RR reference curves, and a linear mixed-effect model identified factors influencing RR. A total of 830 children provided 67,512 RR measurements. Their median age was 6.07 years (interquartile range 4.21–8.55) and 400 (48.2%) were female. Age, stunting, ambient temperature, and time of RR measurement were independent predictors of respiratory rate. Strikingly, children showing signs of illness had greater variability in repeat RR measurements. We constructed a RR reference chart for children aged one to 13 years and proposed a cutoff of > 26 breaths/min for raised RR among children aged > 5 years bridging an important gap in this age group. Although the time of data collection, nutritional status, and ambient temperature were predictors of RR, their effect size is not clinically significant enough to warrant a change in the current WHO guidelines owing to the prevailing uncertainty in the measurement of RR. The finding that RRs between repeat measurements were more variable among children with signs of illness suggests that a single RR measurement may be inadequate to reliably assess the status of sick children—a population in which accurate diagnosis is essential to enable targeted interventions with lifesaving treatment.

Introduction High-dose glucocorticoid (GC)-based dual immunosuppressive treatment regimens are still frequently used in active lupus nephritis (LN) despite their known association with dose-dependent toxicities and incomplete efficacy. We hypothesised that the addition of voclosporin to low-dose GCs and mycophenolate mofetil (MMF) would reduce exposure to the toxicities of high-dose GC-based dual immunosuppressive therapy regimens, resulting in an improved safety profile without compromising efficacy.Methods Propensity score matching generated two groups of matched participants from the voclosporin arms (in combination with MMF (2 g/day) and low-dose GCs) of the Phase 2 AURA-LV and Phase 3 AURORA 1 studies and the MMF (3 g/day) and intravenous cyclophosphamide (IVC) arms (both in combination with high-dose GCs) of the Aspreva Lupus Management Study (ALMS) induction study. Safety and efficacy outcomes were assessed over 6 months.Results There were 179 matched participants identified between the AURA-LV/AURORA 1 studies and ALMS. The overall incidence of adverse events (AEs) was higher in IVC- and MMF-treated participants of ALMS; more voclosporin-treated participants reported AEs by preferred term of glomerular filtration rate decreased, hypertension and anaemia. The incidence of serious AEs was similar across treatments. There were four (2.2%) deaths in IVC- and MMF-treated participants of ALMS compared with seven (3.9%) deaths in voclosporin-treated participants. Significantly more voclosporin-treated participants achieved a ≥25% reduction in urine protein creatinine ratio (UPCR) from baseline at 3 months and ≥50% reduction in UPCR from baseline at 6 months.Conclusions Compared with the high-dose GC-based regimens used in ALMS, voclosporin-based triple immunosuppressive therapy resulted in fewer AEs overall and greater and earlier reductions in proteinuria over the first 6 months of treatment. These data reinforce the feasibility of using low doses of GCs and MMF to treat LN when combined with voclosporin as a third agent.

# Background Medical oxygen is frequently used in healthcare settings. Challenges with oxygen disruption, such as oxygen tanks running out due to communication issues between staff or tanks not being set up properly, have been noted in the limited existing literature. Challenges and patient safety issues associated with oxygen disruption persist. Utilizing a human factors approach, our study aims to understand the contributing factors and context of oxygen disruption--related patient safety event reports in the inpatient setting and provide person-based and system-based solutions. # Methods Through keyword matching, we identified and then qualitatively analyzed 298 patient safety event reports to understand the factors contributing to oxygen disruption, patient location when the oxygen disruptions occurred, hand-off breakdowns by healthcare team member role, and whether high supplemental oxygen was being administered. # Results The most frequent contributing factor to oxygen disruption was the patient not being transferred to another source of oxygen (n=135 of 298, 45.3%), followed by tank found empty (n=107, 35.9%), patient connected to a functioning oxygen source, no oxygen flowing (n=25, 8.4%), oxygen delivery device malfunction (n=22, 7.4%), and no oxygen available (n=9, 3.0%). Over one-third of all oxygen disruption events occurred on the unit where the patient was admitted (n=109 of 298, 36.6%). Roughly 40% of reports involved a hand-off breakdown (n=123 of 298, 41.3%) and the most frequent breakdowns occurred between a nurse and a patient transporter (n=47 of 123, 38.2%). Almost one quarter of reports involved a patient with high supplemental oxygen requirements (n=74 of 298, 24.8%). # Conclusion Oxygen disruption events can have serious patient safety implications. Many of the oxygen disruption events we reviewed occurred due to lack of situational awareness and hand-off breakdowns. Combining person-based solutions, such as paper-based tools and checklists, with system-based solutions involving central monitoring and supervisory systems may help reduce the risk of oxygen disruption events.

Abstract Visual illusions and mental imagery are non-physical sensory experiences that involve cortical feedback processing in the primary visual cortex. Using laminar functional magnetic resonance imaging (fMRI) in two studies, we investigate if information about these internal experiences is visible in the activation patterns of different layers of primary visual cortex (V1). We find that imagery content is decodable mainly from deep layers of V1, whereas seemingly ‘real’ illusory content is decodable mainly from superficial layers. Furthermore, illusory content shares information with perceptual content, whilst imagery content does not generalise to illusory or perceptual information. Together, our results suggest that illusions and imagery, which differ immensely in their subjective experiences, also involve partially distinct early visual microcircuits. However, overlapping microcircuit recruitment might emerge based on the nuanced nature of subjective conscious experience.

Caregivers' goals influence their interactions with their children. In this preregistered study, we examined whether directing parents to "teach" their baby versus "learn" from their baby influenced the extent to which they engaged in intrusive (e.g., controlling, adult-centered rather than child-centered), sensitive, warm, or cognitively stimulating caregiving behaviors. Mothers and their 6-month-old infants (N = 66; 32 female infants) from the San Francisco Bay Area participated in a 10-min "free-play" interaction, coded in 2-min epochs for degree of parental intrusiveness. Prior to the final epoch, mothers were randomly assigned to receive instructions to focus on (a) "teaching" something to their infant or (b) "learning" something from their infant. A control group of mothers received no instructions. Analyses of within-person changes in intrusive behavior from before to after receiving these instructions indicated that mothers assigned to teach their infant increased in intrusiveness whereas mothers assigned to learn from their infant and mothers in the control group did not significantly change in intrusiveness. The study provides experimental evidence that caregivers' explicit goals to teach infants result, on average, in more controlling and adult-centered caregiving behavior.

Circulating follicular helper T cells (cTfh) can show phenotypic alterations in disease settings, including in the context of tissue-damaging autoimmune or anti-viral responses. Using severe COVID-19 as a paradigm of immune dysregulation, we have explored how cTfh phenotype relates to the titre and quality of antibody responses. Severe disease was associated with higher titres of neutralising S1 IgG and evidence of increased T cell activation. ICOS, CD38 and HLA-DR expressing cTfh correlated with serum S1 IgG titres and neutralising strength, and interestingly expression of TIGIT by cTfh showed a negative correlation. TIGIT+cTfh expressed increased IFNγ and decreased IL-17 compared to their TIGIT-cTfh counterparts, and showed reduced capacity to help B cells in vitro. Additionally, TIGIT+cTfh expressed lower levels of CD40L than TIGIT-cTfh, providing a potential explanation for their poor B-helper function. These data identify phenotypic changes in polyclonal cTfh that correlate with specific antibody responses and reveal TIGIT as a marker of cTfh with altered function.

ObjectiveThe effect of physical activity on the risk of developing knee osteoarthritis (OA) is unclear. We undertook this study to examine the relationship between recreational physical activity and incident knee OA outcomes using comparable physical activity and OA definitions.MethodsData were acquired from 6 global, community-based cohorts of participants with and those without knee OA. Eligible participants had no evidence of knee OA or rheumatoid arthritis at baseline. Participants were followed up for 5-12 years for incident outcomes including the following: 1) radiographic knee OA (Kellgren-Lawrence [K/L] grade ≥2), 2) painful radiographic knee OA (radiographic OA with knee pain), and 3) OA-related knee pain. Self-reported recreational physical activity included sports and walking/cycling activities and was quantified at baseline as metabolic equivalents of task (METs) in days per week. Risk ratios (RRs) were calculated and pooled using individual participant data meta-analysis. Secondary analysis assessed the association between physical activity, defined as time (hours per week) spent in recreational physical activity and incident knee OA outcomes.ResultsBased on a total of 5,065 participants, pooled RR estimates for the association of MET days per week with painful radiographic OA (RR 1.02 [95% confidence interval (95% CI) 0.93-1.12]), radiographic OA (RR 1.00 [95% CI 0.94-1.07]), and OA-related knee pain (RR 1.00 [95% CI 0.96-1.04]) were not significant. Similarly, the analysis of hours per week spent in physical activity also showed no significant associations with all outcomes.ConclusionOur findings suggest that whole-body, physiologic energy expenditure during recreational activities and time spent in physical activity were not associated with incident knee OA outcomes.

BackgroundIn 2015, herpes simplex virus 1 (HSV-1)-derived talimogene laherparepvec (T-VEC) was the first oncolytic virus approved by the US Food and Drug Administration as a therapeutic agent for cancer treatment. However, its antitumor application is limited to local treatment of melanoma, and there is a lack of understanding of the mechanisms underlying the regulation of HSV-1 replication in cancer cells and the associated antitumor immunity. We hypothesized that increasing the replication capacity of HSV-1 in tumor cells would enhance the antitumor effect of this virus.MethodsWe systematically identified IFN-stimulated genes induced by HSV-1 by performing functional screens and clarified the mechanism by which BACH1 acts against HSV-1. Then, we tested the effect of BACH1 deficiency on immunogenic cell death induced by HSV-1. Furthermore, we investigated the antitumor effect of BACH1 deficiency on HSV-1 in MCA205 and B16 murine tumor models.ResultsWe identified eight IFN-stimulated genes (ISGs) controlling HSV-1 replication, among which BTB and CNC homology 1 (BACH1) suppressed HSV-1 replication by inhibiting the transcription of ICP4, ICP27, and UL39. Loss of Bach1 function not only increased HSV-1 proliferation but also promoted HSV-1-induced cell apoptosis, HMGB1 secretion, and calreticulin exposure in tumor cells. More importantly, hemin, an FDA-approved drug known to downregulate BACH1, significantly enhanced HSV-1-mediated antitumor activity with increased T lymphocyte infiltration at the tumor site.ConclusionsOur studies uncovered a novel antiviral activity of BACH1 and provided a new strategy for improving the clinical efficiency of the oncolytic virus HSV-1.

Antequera in southern Spain is widely recognised as an outstanding example of the European megalithic phenomenon. One of its remarkable features is the evident relationship between conspicuous natural formations and human-built monuments. Here, the authors report the results of their investigation of a tomb newly discovered at the site of Piedras Blancas at the foot of La Pena de los Enamorados, a limestone massif that dominates the Antequera plain. Excavation and multidisciplinary study, including geological, architectural and archaeoastronomical investigations, have revealed a complex funerary monument that is part natural, part built, part hypogeum, part megalith, The results emphasise that centrality of La Pena in the Neolithic worldview and encourage wider investigation of prehistoric place-making. Keywords: Iberia, Neolithic, Copper Age, Bronze Age, megalithic architecture, geological formations, burial practices, Introduction 'All art is an imitation of nature.' (Seneca) Antequera in Andalusia is one of five European megalithic sites to have been awarded UNESCO World Heritage status, and the only [...]

Abstract Background Irrigated rice cultivation in sub-Saharan Africa not only brings more malaria vectors to nearby communities, but also greater malaria risk. To aid the implementation of mosquito control in rice-growing communities, it is necessary to understand how farmers understand, view and manage their responsibility in mosquito generation and whether they are interested in coordinating to minimize it. Methods Qualitative methods (observation grids, semi-structured in-depth interviews and focus group discussions) were used to reveal the perceptions of mosquitoes and their control in two irrigated rice farming communities in central Côte d’Ivoire near the M’bé and Lokapli irrigation schemes. Results All rice farmers viewed mosquitoes as severe nuisances, and most acknowledged that they caused djèkouadjo (malaria) and were less numerous during harmattan (dry season). Many study participants believed that mosquitoes originated from grasses and stagnant water around villages. Only those living closer in proximity (~ 1 km) to the paddies believed that mosquitoes came from the bas-fonds (irrigated lowlands). However, they did not associate mosquito production with rice cultivation. Some farmers believed that there were more mosquitoes in recent years than historically because of the dam construction, but remarked on the importance of the dam (and bas-fonds) for their livelihood. Many farmers were not convinced that mosquito control could occur at farm-level. Conclusions To enhance accountability amongst rice farmers, there is a need for greater awareness on the rice-mosquito link, and emphasis that the link does not imply a trade-off between food production and health. Training should not only be directed towards farming communities, but also agricultural and health extension workers. Future riceland mosquito control methods must focus on improving crop productivity and address collective action problems that may occur.

House construction is rapidly modernizing across Africa but the potential benefits for human health are poorly understood. We hypothesised that improvements to housing would be associated with reductions in malaria, acute respiratory infection (ARI) and gastrointestinal illness in an area of low malaria endemicity in Uganda. Data were analysed from a cohort study of male and female child and adult residents (n = 531) of 80 randomly-selected households in Nagongera sub-county, followed for 24 months (October 4, 2017 to October 31, 2019). Houses were classified as modern (brick walls, metal roof and closed eaves) or traditional (all other homes). Light trap collections of mosquitoes were done every two weeks in all sleeping rooms. Every four weeks, we measured malaria infection (using microscopy and qPCR to detect malaria parasites), incidence of malaria, ARI and gastrointestinal illness. We collected 15,780 adult female Anopheles over 7,631 nights. We collected 13,277 blood samples of which 10.2% (1,347) were positive for malaria parasites. Over 958 person years we diagnosed 38 episodes of uncomplicated malaria (incidence 0.04 episodes per person-year at risk), 2,553 episodes of ARI (incidence 2.7 episodes per person-year) and 387 episodes of gastrointestinal illness (incidence 0.4 episodes per person-year). Modern houses were associated with a 53% lower human biting rate compared to traditional houses (adjusted incidence rate ratio [aIRR] 0.47, 95% confidence interval [CI] 0.32-0.67, p

The tumor microenvironment (TME), including infiltrated immune cells, is known to play an important role in tumor growth; however, the mechanisms underlying tumor immunogenicity have not been fully elucidated. Here, we discovered an unexpected role for the transcription factor SIX1 in regulating the tumor immune microenvironment. Based on analyses of patient datasets, we found that SIX1 was upregulated in human tumor tissues and that its expression levels were negatively correlated with immune cell infiltration in the TME and the overall survival rates of cancer patients. Deletion of Six1 in cancer cells significantly reduced tumor growth in an immune-dependent manner with enhanced antitumor immunity in the TME. Mechanistically, SIX1 was required for the expression of multiple collagen genes via the TGFBR2-dependent Smad2/3 activation pathway, and collagen deposition in the TME hampered immune cell infiltration and activation. Thus, our study uncovers a crucial role for SIX1 in modulating tumor immunogenicity and provides proof-of-concept evidence for targeting SIX1 in cancer immunotherapy.

A Ni/photoredox-catalyzed enantioselective reductive coupling of styrene oxides and aryl iodides is reported. This reaction affords access to enantioenriched 2,2-diarylalcohols from racemic epoxides via a stereoconvergent mechanism. Multivariate linear regression (MVLR) analysis with 29 bioxazoline (BiOx) and biimidazoline (BiIm) ligands revealed that enantioselectivity correlates with electronic properties of the ligands, with more electron-donating ligands affording higher ee's. Experimental and computational mechanistic studies were conducted, lending support to the hypothesis that reductive elimination is enantiodetermining and the electronic character of the ligands influences the enantioselectivity by altering the position of the transition state structure along the reaction coordinate. This study demonstrates the benefits of utilizing statistical modeling as a platform for mechanistic understanding and provides new insight into an emerging class of chiral ligands for stereoconvergent Ni and Ni/photoredox cross-coupling.

IntroductionKidney failure of unknown aetiology (uESKD) is also heavily location dependent varying between 27% in Egypt to 54% in Aguacalientes, Mexico. There is limited information about the characteristics of people with uESKD in Australia and New Zealand, as well as their clinical outcomes on kidney replacement therapy.MethodsData on people commencing kidney replacement therapy 1989-2021 were received from the Australia and New Zealand Dialysis and Transplant (ANZDATA) registry. Primary exposure was cause of kidney failure-uESKD or non-uESKD (known-ESKD). Primary outcome was mortality. Secondary outcome was kidney transplantation. Dialysis and transplant cohorts were analysed separately. Cox Proportional Hazards Regression models were used to evaluate correlations between cause of kidney failure and mortality risk. Subgroup analyses were completed to compare mortality risk in people with uESKD to those with diabetic nephropathy, autosomal dominant polycystic kidney disease (ADPKD), glomerular disease and other kidney diseases.ResultsThis study included 60,448 people on dialysis and 20,859 transplant recipients. 1-year, 3-year and 5-year mortality rates in people with uESKD on dialysis were 31.6%, 58.7% and 77.2%, respectively. 1-year, 3-year and 5-year mortality rates in transplant recipients with uESKD were 2.8%, 13.8% and 24.0%, respectively. People with uESKD on dialysis had a higher mortality risk compared to those without uESKD on univariable and multivariable analyses (adjusted hazard ratio [AHR] 1.10, 95% CI 1.06-1.16, pConclusionPeople with uESKD on kidney replacement therapy have higher mortality risk compared to people with other kidney diseases. Further studies are required to identify contributing factors to these findings.

BackgroundOsteoarthritis (OA) is a chronic joint disease, with increasing global burden of disability and healthcare utilisation. Recent meta-analyses have shown a range of effects of OA on mortality, reflecting different OA definitions and study methods. We seek to overcome limitations introduced when using aggregate results by gathering individual participant-level data (IPD) from international observational studies and standardising methods to determine the association of knee OA with mortality in the general population.MethodsSeven community-based cohorts were identified containing knee OA-related pain, radiographs, and time-to-mortality, six of which were available for analysis. A two-stage IPD meta-analysis framework was applied: (1) Cox proportional hazard models assessed time-to-mortality of participants with radiographic OA (ROA), OA-related pain (POA), and a combination of pain and ROA (PROA) against pain and ROA-free participants; (2) hazard ratios (HR) were then pooled using the Hartung-Knapp modification for random-effects meta-analysis.Findings10,723 participants in six cohorts from four countries were included in the analyses. Multivariable models (adjusting for age, sex, race, BMI, smoking, alcohol consumption, cardiovascular disease, and diabetes) showed a pooled HR, compared to pain and ROA-free participants, of 1.03 (0.83, 1.28) for ROA, 1.35 (1.12, 1.63) for POA, and 1.37 (1.22, 1.54) for PROA.DiscussionParticipants with POA or PROA had a 35-37% increased association with reduced time-to-mortality, independent of confounders. ROA showed no association with mortality, suggesting that OA-related knee pain may be driving the association with time-to-mortality.FundingVersus Arthritis Centre for Sport, Exercise and Osteoarthritis and Osteoarthritis Research Society International.

Early exposure to psychosocial adversity is among the most potent predictors of depression. Because depression commonly emerges prior to adulthood, we must consider the fundamental principles of developmental neuroscience when examining how experiences of childhood adversity, including abuse and neglect, can lead to depression. Considering that both the environment and the brain are highly dynamic across the period spanning gestation through adolescence, the purpose of this review is to discuss and integrate stress-based models of depression that center developmental processes. We offer a general framework for understanding how psychosocial adversity in early life disrupts or calibrates the biobehavioral systems implicated in depression. Specifically, we propose that the sources and nature of the environmental input shaping the brain, and the mechanisms of neuroplasticity involved, change across development. We contend that the effects of adversity largely depend on the developmental stage of the organism. First, we summarize leading neurobiological models that focus on the effects of adversity on risk for mental disorders, including depression. In particular, we highlight models of allostatic load, acceleration maturation, dimensions of adversity, and sensitive or critical periods. Second, we expound on and review evidence for the formulation that distinct mechanisms of neuroplasticity are implicated depending on the timing of adverse experiences, and that inherent within certain windows of development are constraints on the sources and nature of these experiences. Finally, we consider other important facets of adverse experiences (e.g., environmental unpredictability, perceptions of one's experiences) before discussing promising research directions for the future of the field.

In this paper, we present an overview of a series of 1-credit applied problem solving courses. The goal of these courses was to help students develop their oral and written communication skills, ability to work as a team, and general problem solving skills through preparation and participation in the Mathematical Contest in Modeling (MCM) and Interdisciplinary Contest in Modeling (ICM). In the first part of the course series, teams of students worked on past contest problems to simulate the contest experience over a 15-week semester. We provided feedback and guidance at each step of the modeling process, but students were ultimately responsible for all modeling choices. Students were required to write a 20-page report detailing their solutions (as in the contest) and to present their work orally. In the follow-on course, students participated in the MCM/ICM and shared their work in an oral presentation at a local conference or on campus. Here, we provide course details and share student feedback, positive outcomes (including a winning team!), and plans for future iterations of the course. We suggest that this type of experience provides an opportunity for students to engage with open-ended problems similar to those they may face in their careers.

Transforming an observable phenomenon into a tractable model is a challenging process, from determining the appropriate modeling scale to making realistic simplifying assumptions. However, many modeling texts are anchored around problems that have already been synthesized into a digestible format, which inhibits an opportunity to engage students in the decision-making process that leads to a model's design. In this paper, I discuss course elements that provide opportunities for students to participate in the early stages of a model's construction. These include open-ended projects and deconstructed textbook problems, which I explore within the context of an applied mathematical modeling seminar that emphasizes models from the life sciences.

In this paper, we discuss mathematical modeling opportunities that can be included in an introductory Differential Equations course. In particular, we focus on the development of and extensions to the single salty tank model. Typically, salty tank models are included in course materials with matter-of-fact explanations. These explanations miss the opportunity for students to develop rate of change equations for themselves. In this paper, we highlight an open-ended single salty tank task that provides the foundation for more complicated salty tank models that we also detail herein. Furthermore, we discuss instructional implementation techniques that instructors can use in their classes to meet their specific learning goals.

ObjectiveWith adults working to older ages, occupation is an important, yet less modifiable domain of physical activity to consider in the risk of knee osteoarthritis (OA). This study aimed to investigate the association between predominant lifetime occupation and prevalent knee OA.DesignParticipant-level data were used from five international community-based cohorts: Johnston County Osteoarthritis Project, the Hertfordshire Cohort Study, the Multicenter Osteoarthritis Study, the Tasmanian Cohort Study and Framingham Osteoarthritis Study. Self-reported predominant occupation was categorized into sedentary, light, light manual and heavy manual levels. Cross-sectional associations between predominant lifetime occupation and knee OA outcomes including prevalence of radiographic knee OA (RKOA), symptomatic RKOA and knee pain, were assessed using logistic regression, accounting for cohort clustering.ResultsData for 7391 participants were included. 24.7% reported sedentary lifetime occupation, 30.0% light, 35.9% light manual and 9.4% heavy manual. 43.3% presented with RKOA, 52.1% with knee pain and 29.0% with symptomatic RKOA. There was over a two-fold increase in the odds of having RKOA, knee pain and symptomatic RKOA in those whose with heavy manual compared to sedentary occupations ((odds ratio (OR): 2.14; 95% confidence interval (CI): 1.79, 2.58), (OR: 2.19; 95% CI: 1.78, 2.70), (OR: 2.41; 95% CI: 1.94, 2.99) respectively).ConclusionThis large international multi-cohort study demonstrated an association of heavy manual work with RKOA, symptomatic RKOA and knee pain. Measures that protect workers and are designed to reduce heavy manual related activities remain a priority to reduce the risk of knee OA.