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Immediately after its appearance, we at the University of Amsterdam's Institute of Interdisciplinary Studies enthusiastically adopted Allen Repko's "Interdisciplinary Research: Process and Theory" (Repko, 2008) as it was the first textbook that offered systematic explanation of and guidance through the complexities of an interdisciplinary research project. However, several characteristics of the projects conducted by our students made it an uneasy match for their needs and ours. For one thing, the Repko text targets students doing individual research projects whereas our students typically perform interdisciplinary research in teams. Our students also typically bring more disciplinary expertise to their interdisciplinary work than those whom the Repko text targets. And they often undertake empirical research as part of their projects--and not just the research in relevant literature that is emphasized in the Repko texts. Feeling the need for a textbook on interdisciplinary research that would better support students like ours, we decided to develop our own textbook, "Introduction to Interdisciplinary Research: Theory and Practice." In this article, we describe the version of the research process we present in our text, emphasizing the many forms of pluralism involved in the process as reconceived to better suit teams of researchers based in different disciplines, and sometimes pursuing empirical work which may involve extra-academic stakeholders.

When interacting with infants, humans often alter their speech and song in ways thought to support communication. Theories of human child-rearing, informed by data on vocal signalling across species, predict that such alterations should appear globally. Here, we show acoustic differences between infant-directed and adult-directed vocalizations across cultures. We collected 1,615 recordings of infant- and adult-directed speech and song produced by 410 people in 21 urban, rural and small-scale societies. Infant-directedness was reliably classified from acoustic features only, with acoustic profiles of infant-directedness differing across language and music but in consistent fashions. We then studied listener sensitivity to these acoustic features. We played the recordings to 51,065 people from 187 countries, recruited via an English-language website, who guessed whether each vocalization was infant-directed. Their intuitions were more accurate than chance, predictable in part by common sets of acoustic features and robust to the effects of linguistic relatedness between vocalizer and listener. These findings inform hypotheses of the psychological functions and evolution of human communication.

When introduced around 1925, interdisciplinarity, grounded in the notion of the unity of knowledge, was meant to reconnect the fragmented and specialized disciplines of academia. However, interdisciplinary research became more and more challenging as the plurality and heterogeneity of disciplinary perspectives and insights increased. Insisting on this divergence and diversity, Julie Thompson Klein has nevertheless contributed in important ways to convergence in interdisciplinarity with her work on the process of integration as interdisciplinarity's defining feature. Of course Klein is aware that the increasing inclusion of extra-academic stakeholders in "trans"disciplinary research constitutes a fundamental challenge to integrative interdisciplinarity. Along with academic contributions, experiential knowledge, interests, and norms must be recognized as valuable to the process, and stakeholder expectations of applicable results must be met. Exploring the future by extending this crucial development further, this article focuses on the actionability of knowledge as an additional criterion for effective interdisciplinarity and transdisciplinarity, as it is in Action Research. With action options for stakeholders being an important goal for such research, it is argued that joint deliberation about these options must be part of the process, aiming for reflective equilibrium. At the same time, an important role for imagination is defended, enabling adequate consideration of action options with their ramifications and implications. The future of interdisciplinarity, it is concluded, will entail an important role for the actionability criterion and for the related role of imagination of potential outcomes, much greater roles than these now have.

Many colleagues who have become active in AIS have experienced that their membership has entailed friendships with like-minded people, thanks to Bill Newell's creation of a welcoming atmosphere from which both individuals and the organization have benefitted. Musing upon the words behind the acronym AIS, and anticipating its historic first conference outside North America -- in Amsterdam in 2019 (see http://www.aisconference2019.nl ) -- what follows is a brief reflection upon friendship and interdisciplinary studies and the ways that Bill has connected the two.

The inflammatory response to Chlamydia infection is likely to be multifactorial and involve a variety of ligand-dependent and -independent recognition pathways. We previously reported the presence of NOD1/NOD2-dependent endoplasmic reticulum (ER) stress-induced inflammation during Chlamydia muridarum infection in vitro, but the relevance of this finding to an in vivo context is unclear. Here, we examined the ER stress response to in vivo Chlamydia infection. The induction of interleukin 6 (IL-6) production after systemic Chlamydia infection correlated with expression of ER stress response genes. Furthermore, when tauroursodeoxycholate (TUDCA) was used to inhibit the ER stress response, an increased bacterial burden was detected, suggesting that ER stress-driven inflammation can contribute to systemic bacterial clearance. Mice lacking both NOD1 and NOD2 or RIP2 exhibited slightly higher systemic bacterial burdens after infection with Chlamydia Overall, these data suggest a model where RIP2 and NOD1/NOD2 proteins link ER stress responses with the induction of Chlamydia-specific inflammatory responses.IMPORTANCE Understanding the initiation of the inflammatory response during Chlamydia infection is of public health importance given the impact of this disease on young women in the United States. Many young women are chronically infected with Chlamydia but are asymptomatic and therefore do not seek treatment, leaving them at risk of long-term reproductive harm due to inflammation in response to infection. Our manuscript explores the role of the endoplasmic reticulum stress response pathway initiated by an innate receptor in the development of this inflammation.

Interdisciplinary understanding requires integration of insights from different perspectives, yet it appears questionable whether disciplinary experts are well prepared for this. Indeed, psychological and cognitive scientific studies suggest that expertise can be disadvantageous because experts are often more biased than non-experts, for example, or fixed on certain approaches, and less flexible in novel situations or situations outside their domain of expertise. An explanation is that experts' conscious and unconscious cognition and behavior depend upon their learning and acquisition of a set of mental representations or knowledge structures. Compared to beginners in a field, experts have assembled a much larger set of representations that are also more complex, facilitating fast and adequate perception in responding to relevant situations. This article argues how metacognition should be employed in order to mitigate such disadvantages of expertise: By metacognitively monitoring and regulating their own cognitive processes and representations, experts can prepare themselves for interdisciplinary understanding. Interdisciplinary collaboration is further facilitated by team metacognition about the team, tasks, process, goals, and representations developed in the team. Drawing attention to the need for metacognition, the article explains how philosophical reflection on the assumptions involved in different disciplinary perspectives must also be considered in a process complementary to metacognition and not completely overlapping with it. (Disciplinary assumptions are here understood as determining and constraining how the complex mental representations of experts are chunked and structured.) The article concludes with a brief reflection on how the process of Reflective Equilibrium should be added to the processes of metacognition and philosophical refection in order for experts involved in interdisciplinary collaboration to reach a justifiable and coherent form of interdisciplinary integration. An Appendix of "Prompts or Questions for Metacognition" that can elicit metacognitive knowledge, monitoring, or regulation in individuals or teams is included at the end of the article.

Public investment, through both research grants and university funding, plays a crucial role in the research and development (R&D) of novel health technologies, including diagnostics, therapies, and vaccines, to address the coronavirus disease 2019 (COVID-19) pandemic. Using the example of remdesivir, one of the most promising COVID-19 treatments, this paper traces back public contributions to different stages of the innovation process. Applying the Risk-Reward Nexus framework to the R&D of remdesivir, we analyse the role of the public in risk-taking and reward and address inequities in the biomedical innovation system. We discuss the collective, cumulative and uncertain characteristics of innovation, highlighting the lack of transparency in the biomedical R&D system, the need for public investment in the innovation process, and the “time-lag” between risk-taking and reward. Despite the significant public transnational contributions to the R&D of remdesivir, the rewards are extracted by few actors and the return to the public in the form of equitable access and affordable pricing is limited. Beyond the necessity to treat remdesivir as a global public good, we argue that biomedical innovation needs to be viewed in the broader concept of public value to prevent the same equity issues currently seen in the COVID-19 pandemic. This requires the state to take a market-shaping rather than market-fixing role, thereby steering innovation, ensuring that patents do not hinder global equitable access and affordable pricing and safeguarding a global medicines supply.

STUDY QUESTION Does preconceptional exposure to oil-based iodinated contrast media during hysterosalpingography (HSG) impact children's neurodevelopment compared with exposure to water-based alternatives? SUMMARY ANSWER Our study found no large-sized effects for neurodevelopment in children with preconceptional exposure to oil-based iodinated contrast media during HSG compared with water-based alternatives. WHAT IS KNOWN ALREADY HSG is widely used as a diagnostic tool in the female fertility work-up. Tubal flushing with oil-based iodinated contrast has been shown to enhance fertility outcomes in couples with unexplained infertility, increasing the chances of pregnancy and live birth compared with water-based alternatives. However, oil-based contrast contains higher doses of iodine and has a longer half-life, and concerns exist that iodinated contrast media can affect women's iodine status and cause temporary (sub)clinical hypothyroidism in mothers and/or foetuses. Considering that thyroid hormones are vital to embryonal and foetal brain development, oil-based contrast media use could increase the risk of impaired neurodevelopment in children conceived shortly after HSG. Here we examine neurodevelopmental outcomes in school-aged children conceived after HSG. STUDY DESIGN, SIZE, DURATION This is a long-term follow-up of the H2Oil trial in which oil-based or water-based contrast was used during HSG (Netherlands; 2012–2014; NTR3270). Of 369 children born <6 months after HSG in the study, we contacted the mothers of 140 children who gave consent to be contacted for follow-up. The follow-up study took place from January to July 2022 (NCT05168228). PARTICIPANTS/MATERIALS, SETTINGS, METHODS The study included 69 children aged 6–9 years who were conceived after HSG with oil-based (n = 42) or water-based contrast (n = 27). The assessments targeted intelligence (Wechsler Intelligence Scale for Children), neurocognitive outcomes (computerized neurocognitive tests), behavioural functioning (parent and teacher questionnaires), and academic performance. Linear regression models, adjusted for age, sex, and parental educational attainment were employed to compare groups. MAIN RESULTS AND THE ROLE OF CHANCE School-aged children born to mothers after oil-based contrast HSG did not significantly differ from children born to mothers after water-based contrast HSG, in regards to intelligence, neurocognitive functioning, behavioural functioning, or academic performance, with the exception of better performance for visuomotor integration functions in children exposed to oil-based contrast preconception. After exploratory correction for multiple comparisons, none of the group differences was statistically significant. LIMITATIONS, REASONS FOR CAUTION The small sample size of this follow-up study limited statistical power. This study provides evidence for the absence of large-sized differences between preconceptional exposure to the two contrast media types but does not rule out more subtle effects on neurodevelopment compared to naturally conceived children without preconceptional exposure to HSG. WIDER IMPLICATIONS OF THE FINDINGS This study contributes to our knowledge about the long-term effects of different types of iodinated contrast media used in fertility work-up, indicating that choosing oil-based over water-based iodinated contrast media is unlikely to have major effect on the long-term neurodevelopmental outcomes of children conceived shortly after HSG. However, further research should focus on the overall safety of iodine exposure during HSG, comparing children conceived after HSG to those conceived naturally as both types of contrast contain high amounts of iodine. STUDY FUNDING/COMPETING INTEREST(S) The original H2Oil randomized controlled trial was an investigator-initiated study that was funded by the two academic hospitals now merged into the Amsterdam University Medical Centre. The current follow-up study (Neuro-H2Oil) is funded through a research grant awarded to the authors by the Amsterdam Reproduction & Development (AR&D) research institute. S.K. is funded by a AMC MD/PhD Scholarship from the Amsterdam UMC. S.K. reports holding voluntary roles in the civil society organizations Universities Allied for Essential Medicines and People's Health Movement. V.M. reports receiving travel and speaker fees as well as research grants from Guerbet, Merck and Ferring. K.D. reports receiving travel and speaker fees as well as research grants from Guerbet. BWM is supported by a NHMRC Investigator grant (GNT1176437) and reports consultancy, travel support and research funding from Merck, consultancy for Organon and Norgine, and holding stock from ObsEva. The other authors report no conflict of interest. TRIAL REGISTRATION NUMBER NCT05168228 [ABSTRACT FROM AUTHOR]

The inflammasomes are intracellular multimeric protein complexes consisting of an innate immune sensor, the adapter protein ASC and the inflammatory caspases-1 and/or -11 and are important for the host defense against pathogens. Activaton of the receptor leads to formation of the inflammasomes and subsequent processing and activation of caspase-1 that cleaves the proinflammatory cytokines IL-1β and IL-18. Active caspase-1, and in some instances caspase-11, cleaves gasdermin D that translocates to the cell membrane where it forms pores resulting in the cell death program called pyroptosis. Inflammasomes can detect a range of microbial ligands through direct interaction or indirectly through diverse cellular processes including changes in ion fluxes, production of reactive oxygen species and disruption of various host cell functions. In this review, we will focus on the NLRP3, NLRP6, NLRC4 and AIM2 inflammasomes and how they are activated and regulated during infections with Gram-positive bacteria, including Staphylococcus spp., Streptococcus spp. and Listeria monocytogenes.

NOD1 and NOD2 are pattern recognition receptors of the innate immune system with well-established roles in sensing fragments of bacterial peptidoglycan. In addition to their role as microbial sensors, recent evidence indicates that nucleotide-binding oligomerization domains (NODs) can also recognize a broader array of danger signals. Indeed, recent work has expanded the roles of NOD1 and NOD2 to encompass not only sensing of infections with viruses and parasites but also perceiving perturbations of cellular processes such as regulation of the actin cytoskeleton and maintenance of endoplasmic reticulum homeostasis. This review will comment on recent progress and point out emerging questions in these areas.

Background: Three hundred fifty million people worldwide suffer from underactive thyroid conditions, which can lead to infertility, obesity, heart disease, and impaired mental health when poorly managed. Although mobile health (mHealth) applications can be a useful solution for self-managing one's condition, the impact of digital solutions for improving the health of thyroid patients remains unknown. Methods: We used a mixed methods analysis to assess the ways in which a digital approach might benefit thyroid patients. A cross-sectional study was conducted among users of BOOST Thyroid, an mHealth application for patients with an underactive thyroid. We collected data using a modified Short Form 36 Health Survey Questionnaire to measure the impact of in the app on participants' perceived health and quality of life. Participants were asked to (1) score their quality of life before and after using the app, and (2) describe whether and how using the app helped them. Results: We enrolled 406 users (380 females and 26 males), aged 18?78 years. Most participants (95.8%) reported using the app was helpful; of which 68% reported it improved their quality of life and 70.8% reported it had a positive impact on their health. Participants who found the app useful experienced less symptoms and a lower intensity of remaining symptoms. A key factor reported by these participants as helping with managing their health is the information provided in the app. Conclusions: The results support the idea that a patient-centered treatment would benefit from including mHealth tools for a daily self-management of underactive thyroid condition, as it can increase health literacy and improve both one's health status and quality of life.

Abstract Clinical trial transparency forms the foundation of evidence-based medicine, and trial sponsors, especially publicly funded institutions such as universities, have an ethical and scientific responsibility to make the results of clinical trials publicly available in a timely fashion. We assessed whether the thirty UK universities receiving the most Medical Research Council funding in 2017–2018 complied with World Health Organization best practices for clinical trial reporting on the US Clinical Trial Registry ( ClinicalTrials.gov ). Firstly, we developed and evaluated a novel automated tracking tool ( clinical-trials-tracker.com ) for clinical trials registered on ClinicalTrials.gov . This tracker identifies the number of due trials (whose completion lies more than 395 days in the past) that have not reported results on the registry and can now be used for all sponsors. Secondly, we used the tracker to determine the number of due clinical trials sponsored by the selected UK universities in October 2020. Thirdly, using the FDAAA Trials Tracker, we identified trials sponsored by these universities that are not complying with reporting requirements under the Food and Drug Administration Amendments Act 2007. Finally, we quantified the average and median number of days between primary completion date and results posting. In October 2020, the universities included in our study were sponsoring 1634 due trials, only 1.6% (n = 26) of which had reported results within a year of completion. 89.8% (n = 1468) of trials remained unreported, and 8.6% (n = 140) of trials reported results late. We also identified 687 trials that contained inconsistent data, suggesting that UK universities often fail to update their data adequately on ClinicalTrials.gov . The mean reporting delay after primary completion for trials that posted results was 981 days, the median 728 days. Only four trials by UK universities violated the FDAAA 2007. We suggest a number of reasons for the poor reporting performance of UK universities on ClinicalTrials.gov : (i) efforts to improve clinical trial reporting in the UK have to date focused on the European clinical trial registry (EU CTR), (ii) the absence of a tracking tool for timely reporting on ClinicalTrials.gov has limited the visibility of institutions’ reporting performance on the US registry and (iii) there is currently a lack of repercussions for UK sponsors who fail to report results on ClinicalTrials.gov which should be addressed in the future.

Abstract Background Several drugs are being repurposed for the treatment of the coronavirus disease 2019 (COVID-19) pandemic based on in vitro or early clinical findings. As these drugs are being used in varied regimens and dosages, it is important to enable synthesis of existing safety data from clinical trials. However, availability of safety information is limited by a lack of timely reporting of overall clinical trial results on public registries or through academic publication. We aimed to analyse the evidence gap in this data by conducting a rapid review of results posting on ClinicalTrials.gov and in academic publications to quantify the number of trials missing results for drugs potentially being repurposed for COVID-19. Methods ClinicalTrials.gov was searched for 19 drugs that have been identified as potential treatments for COVID-19. Relevant clinical trials for any prior indication were listed by identifier (NCT number) and checked for results and for timely result reporting (within 395 days of the primary completion date). Additionally, PubMed and Google Scholar were searched to identify publications of results not listed on the registry. A second, blinded search of 10% of trials was conducted to assess reviewer concordance. Results Of 3754 completed trials, 1516 (40.4%) did not post results on ClinicalTrials.gov or in the academic literature. Tabular results were available on ClinicalTrials.gov for 1172 (31.2%) completed trials. A further 1066 (28.4%) had published results in the academic literature, but did not report results on ClinicalTrials.gov . Key drugs missing clinical trial results include hydroxychloroquine (37.0% completed trials unreported), favipiravir (77.8%) and lopinavir (40.5%). Conclusions There is an important evidence gap for the safety of drugs being repurposed for COVID-19. This uncertainty could cause unnecessary additional morbidity and mortality during the pandemic. We recommend caution in experimental drug use for non-severe disease and urge clinical trial sponsors to report missing results retrospectively.

BackgroundEarly-life exposures during gestation may permanently alter thyroid physiology and health in adulthood. We investigated whether exposure to the Dutch Famine (1944-1945) in late, mid, or early gestation influences thyroid function (i.e., incidence of thyroid disease, thyroid autoantibodies, thyroid stimulating hormone (TSH), and free thyroxine (FT4) levels) in adulthood. We specifically assessed whether potential effects of famine differed for men and women.MethodsThis study includes 910 men and women born as term singletons in the Wilhelmina Gasthuis in Amsterdam, the Netherlands, shortly before, during, or after the Dutch Famine. We evaluated medical histories for previous diagnosis or current treatment for thyroid dysfunction. At age 50 blood samples were drawn from 728 individuals for tests of thyroid function. We studied the prevalence of overt hypo- and hyperthyroidism and thyroid autoimmunity using medical histories, and measurements of TSH, FT4, anti-TPO and anti-TG, comparing participants exposed to famine at different pregnancy trimesters or born before or conceived after the famine. Additionally, we studied associations of TSH and FT4 levels with in utero famine exposure in a subsample of men and women free of thyroid disease that were exposed in late, mid, or early gestation.ResultsThere were no differences in thyroid dysfunction diagnosis or current treatment between participants at age 50 years who been exposed to famine during different periods of gestation and those born before or conceived after. There was no association between famine exposure and overt hypo- or hyperthyroidism or thyroid autoantibody positivity. Women who had been exposed to famine in mid gestation had slightly lower TSH levels than women who had not been exposed to famine prenatally (b=-0.06; 95%; CI=[-0.11,-0.02]; p

Although viruses have long been known to subvert the endoplasmic reticulum (ER) for their replication, recent work has shown that this strategy is also used by bacterial pathogens and parasites to promote their intracellular growth. The ensuing disruption of cellular processes triggers a condition known as ER stress, which activates the host cell's unfolded protein response (UPR) to restore homeostasis. Recent work has linked the UPR, in particular the arm of this response that depends on the ER-resident sensor IRE1, to innate immunity and inflammation. Surprisingly, two intracellular innate immune receptors, NOD1 and NOD2, previously shown to sense bacterial peptidoglycan, were found to transduce ER stress signals to elicit inflammation. Given the known roles of both ER stress and NOD2 in chronic inflammatory diseases, including inflammatory bowel disease and type 2 diabetes, this new link has important implications for understanding the basis for these pathologies.

Endoplasmic reticulum (ER) stress is a major contributor to inflammatory diseases, such as Crohn disease and type 2 diabetes. ER stress induces the unfolded protein response, which involves activation of three transmembrane receptors, ATF6, PERK and IRE1α. Once activated, IRE1α recruits TRAF2 to the ER membrane to initiate inflammatory responses via the NF-κB pathway. Inflammation is commonly triggered when pattern recognition receptors (PRRs), such as Toll-like receptors or nucleotide-binding oligomerization domain (NOD)-like receptors, detect tissue damage or microbial infection. However, it is not clear which PRRs have a major role in inducing inflammation during ER stress. Here we show that NOD1 and NOD2, two members of the NOD-like receptor family of PRRs, are important mediators of ER-stress-induced inflammation in mouse and human cells. The ER stress inducers thapsigargin and dithiothreitol trigger production of the pro-inflammatory cytokine IL-6 in a NOD1/2-dependent fashion. Inflammation and IL-6 production triggered by infection with Brucella abortus, which induces ER stress by injecting the type IV secretion system effector protein VceC into host cells, is TRAF2, NOD1/2 and RIP2-dependent and can be reduced by treatment with the ER stress inhibitor tauroursodeoxycholate or an IRE1α kinase inhibitor. The association of NOD1 and NOD2 with pro-inflammatory responses induced by the IRE1α/TRAF2 signalling pathway provides a novel link between innate immunity and ER-stress-induced inflammation.

Within the first year of distribution of vaccines against COVID-19, high-income countries (HICs) have achieved vaccination rates of 75-80%, whilst low-income countries (LICs) vaccinated

Nucleotide-binding oligomerization domain protein (NOD)1 and NOD2 participate in signaling pathways that detect pathogen-induced processes, such as the presence of peptidoglycan fragments in the host cell cytosol, as danger signals. Recent work suggests that peptidoglycan fragments activate NOD1 indirectly, through activation of the small Rho GTPase Ras-related C3 botulinum toxin substrate 1 (RAC1). Excessive activation of small Rho GTPases by virulence factors of enteric pathogens also triggers the NOD1 signaling pathway. Many enteric pathogens use virulence factors that alter the activation state of small Rho GTPases, thereby manipulating the host cell cytoskeleton of intestinal epithelial cells to promote bacterial attachment or entry. These data suggest that the NOD1 signaling pathway in intestinal epithelial cells provides an important sentinel function for detecting 'breaking and entering' by enteric pathogens.

Delivery of microbial products into the mammalian cell cytosol by bacterial secretion systems is a strong stimulus for triggering pro-inflammatory host responses. Here we show that Salmonella enterica serovar Typhi (S. Typhi), the causative agent of typhoid fever, tightly regulates expression of the invasion-associated type III secretion system (T3SS-1) and thus fails to activate these innate immune signaling pathways. The S. Typhi regulatory protein TviA rapidly repressed T3SS-1 expression, thereby preventing RAC1-dependent, RIP2-dependent activation of NF-κB in epithelial cells. Heterologous expression of TviA in S. enterica serovar Typhimurium (S. Typhimurium) suppressed T3SS-1-dependent inflammatory responses generated early after infection in animal models of gastroenteritis. These results suggest that S. Typhi reduces intestinal inflammation by limiting the induction of pathogen-induced processes through regulation of virulence gene expression.

Ethnographers frequently allude to alcoholism and related harms in Indigenous hunter-gatherer communities, but very few studies have quantified patterns of alcohol consumption or its health and social impacts. We present a case study of the Mbendjele BaYaka, a Congolese population undergoing socioeconomic transition. 83 adults answered questions about their frequency and quantity of alcohol consumption, underwent biometric measurements and reported whether they were currently experiencing a cough or diarrhoea; 56 participated in structured interviews about their experiences with alcohol. Based on WHO standards, we found 44.3% of the full sample, and 51.5% of drinkers (excluding abstainers), had a hazardous volume of alcohol consumption; and 35.1% of the full sample, and 40.9% of drinkers, engaged in heavy episodic drinking; consumption habits varied with sex and age. Total weekly consumption was a positive predictor of blood pressure and the likelihood of experiencing diarrhoea; associations with other biometric variables were not statistically significant. Interview responses indicated numerous other economic, mental and physical health harms of alcohol use, the prevalence of which demonstrate some variability between forest camps and permanent village settlements. These include high rates of drinking during pregnancy and breastfeeding (~40%); frequent alcohol-induced violence; and considerable exchange of foraged foods and engagement in exploitative labour activities to acquire alcohol or repay associated debts. Our findings demonstrate the prevalence of hazardous alcohol consumption among transitioning hunter-gatherers is higher than other segments of the Congolese population and indicate negative impacts on health and wellbeing, highlighting an urgent need for targeted public health interventions.

Coronavirus disease 2019 (COVID-19) mortality and morbidity have been shown to increase with deprivation and impact non-White ethnicities more severely. Despite the extra risk Black, Asian and Minority Ethnicity (BAME) groups face in the pandemic, our current medical research system seems to prioritise innovation aimed at people of European descent. We found significant difficulties in assessing baseline demographics in clinical trials for COVID-19 vaccines, displaying a lack of transparency in reporting. Further, we found that most of these trials take place in high-income countries, with only 25 of 219 trials (11.4%) taking place in lower middle- or low-income countries. Trials for the current best vaccine candidates (BNT162b2, ChadOx1, mRNA-173) recruited 80.0% White participants. Underrepresentation of BAME groups in medical research will perpetuate historical distrust in healthcare processes, and poses a risk of unknown differences in efficacy and safety of these vaccines by phenotype. Limiting trial demographics and settings will mean a lack of global applicability of the results of COVID-19 vaccine trials, which will slow progress towards ending the pandemic.

Eradication of persistent intracellular bacterial pathogens with antibiotic therapy is often slow or incomplete. However, strategies to augment antibiotics are hampered by our poor understanding of the nutritional environment that sustains chronic infection. Here we show that the intracellular pathogen Brucella abortus survives and replicates preferentially in alternatively activated macrophages (AAMs), which are more abundant during chronic infection. A metabolic shift induced by peroxisome proliferator-activated receptor γ (PPARγ), which increases intracellular glucose availability, is identified as a causal mechanism promoting enhanced bacterial survival in AAMs. Glucose uptake was crucial for increased replication of B. abortus in AAMs, and for chronic infection, as inactivation of the bacterial glucose transporter gluP reduced both intracellular survival in AAMs and persistence in mice. Thus, a shift in intracellular nutrient availability induced by PPARγ promotes chronic persistence of B. abortus within AAMs, and targeting this pathway may aid in eradicating chronic infection.

Our innate immune system distinguishes microbes from self by detecting conserved pathogen-associated molecular patterns. However, these are produced by all microbes, regardless of their pathogenic potential. To distinguish virulent microbes from those with lower disease-causing potential the innate immune system detects conserved pathogen-induced processes, such as the presence of microbial products in the host cytosol, by mechanisms that are not fully resolved. Here we show that NOD1 senses cytosolic microbial products by monitoring the activation state of small Rho GTPases. Activation of RAC1 and CDC42 by bacterial delivery or ectopic expression of SopE, a virulence factor of the enteric pathogen Salmonella, triggered the NOD1 signalling pathway, with consequent RIP2 (also known as RIPK2)-mediated induction of NF-κB-dependent inflammatory responses. Similarly, activation of the NOD1 signalling pathway by peptidoglycan required RAC1 activity. Furthermore, constitutively active forms of RAC1, CDC42 and RHOA activated the NOD1 signalling pathway. Our data identify the activation of small Rho GTPases as a pathogen-induced process sensed through the NOD1 signalling pathway.

Intestinal inflammation changes the luminal habitat for microbes through mechanisms that have not been fully resolved. We noticed that the FepE regulator of very long O-antigen chain assembly in the enteric pathogen Salmonella enterica serotype Typhimurium (S. Typhimurium) conferred a luminal fitness advantage in the mouse colitis model. However, a fepE mutant was not defective for survival in tissue, resistance to complement or resistance to polymyxin B. We performed metabolite profiling to identify changes in the luminal habitat that accompany S. Typhimurium-induced colitis. This analysis suggested that S. Typhimurium-induced colitis increased the luminal concentrations of total bile acids. A mutation in fepE significantly reduced the minimal inhibitory concentration (MIC) of S. Typhimurium for bile acids in vitro. Oral administration of the bile acid sequestrant cholestyramine resin lowered the concentrations of total bile acids in colon contents during S. Typhimurium infection and significantly reduced the luminal fitness advantage conferred by the fepE gene in the mouse colitis model. Collectively, these data suggested that very long O-antigen chains function in bile acid resistance of S. Typhimurium, a property conferring a fitness advantage during luminal growth in the inflamed intestine.

The invasion-associated type III secretion system (T3SS-1) of Salmonella enterica serotype Typhimurium (S. Typhimurium) activates the transcription factor NF-κB in tissue culture cells and induces inflammatory responses in animal models through unknown mechanisms. Here we show that bacterial delivery or ectopic expression of SipA, a T3SS-1-translocated protein, led to the activation of the NOD1/NOD2 signaling pathway and consequent RIP2-mediated induction of NF-κB-dependent inflammatory responses. SipA-mediated activation of NOD1/NOD2 signaling was independent of bacterial invasion in vitro but required an intact T3SS-1. In the mouse colitis model, SipA triggered mucosal inflammation in wild-type mice but not in NOD1/NOD2-deficient mice. These findings implicate SipA-driven activation of the NOD1/NOD2 signaling pathway as a mechanism by which the T3SS-1 induces inflammatory responses in vitro and in vivo.

ABSTRACT The inflammatory response to Chlamydia infection is likely to be multifactorial and involve a variety of ligand-dependent and -independent recognition pathways. We previously reported the presence of NOD1/NOD2-dependent endoplasmic reticulum (ER) stress-induced inflammation during Chlamydia muridarum infection in vitro, but the relevance of this finding to an in vivo context is unclear. Here, we examined the ER stress response to in vivo Chlamydia infection. The induction of interleukin 6 (IL-6) production after systemic Chlamydia infection correlated with expression of ER stress response genes. Furthermore, when tauroursodeoxycholate (TUDCA) was used to inhibit the ER stress response, an increased bacterial burden was detected, suggesting that ER stress-driven inflammation can contribute to systemic bacterial clearance. Mice lacking both NOD1 and NOD2 or RIP2 exhibited slightly higher systemic bacterial burdens after infection with Chlamydia. Overall, these data suggest a model where RIP2 and NOD1/NOD2 proteins link ER stress responses with the induction of Chlamydia-specific inflammatory responses. IMPORTANCE Understanding the initiation of the inflammatory response during Chlamydia infection is of public health importance given the impact of this disease on young women in the United States. Many young women are chronically infected with Chlamydia but are asymptomatic and therefore do not seek treatment, leaving them at risk of long-term reproductive harm due to inflammation in response to infection. Our manuscript explores the role of the endoplasmic reticulum stress response pathway initiated by an innate receptor in the development of this inflammation.

Cultures around the world are converging as populations become more connected. On the one hand this increased connectedness can promote the recombination of existing cultural practices to generate new ones, but on the other it may lead to the replacement of traditional practices and global WEIRDing. Here we examine the process and causes of changes in cultural traits concerning wild plant knowledge in Mbendjele BaYaka hunter–gatherers from Congo. Our results show that the BaYaka who were born in town reported knowing and using fewer plants than the BaYaka who were born in forest camps. Plant uses lost in the town-born BaYaka related to medicine. Unlike the forest-born participants, the town-born BaYaka preferred Western medicine over traditional practices, suggesting that the observed decline of plant knowledge and use is the result of replacement of cultural practices with the new products of cumulative culture.