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Food insecurity poses a serious threat to children's development, but the mechanisms through which food insecurity undermines child development are far less clear. Specifically, food insecurity may influence children through its effect on parents' psychological well-being and parent--child interactions as a result, but past research on the role of parents is correlational and undermined by omitted variable bias. Using a partially rural, low-income sample of parents living in Pennsylvania (N = 272, 90% mother, M[subscript age] = 35) and their school-aged children (ages 4-11, 50% female) alongside daily measures of parent-reported food insecurity and parent and child mood and behavior, we examine how daily changes in food insecurity predict daily changes in parent and child well-being, and the extent to which food insecurity operates through parents to affect children. This method not only explores families' daily, lived experiences of food insecurity, but improves upon the methodological issues undermining past research. Findings indicate that food insecurity influences parent and child well-being on a daily basis, but that associations are stronger and sustain longer for parents than children. Further, parent mood and behavior partially explain the association between daily food insecurity and child mood and behavior, but food insecurity is also independently associated with child well-being. This study is the first to examine daily associations between food insecurity and parent and child well-being. Its implications for food assistance programs, policies, and the future of food insecurity research are discussed.

This paper examines changes from 1996-2019 in U.S. parents' time investment at their children's schools using data from the National Household Education Survey (N [approximately equal to] 116,000). The most common way parents spend time at their child's school is by attending a general school meeting, which rose from 76% to 85% over this period. The proportion who volunteered at school rose slightly over time (36% to 38%), whereas the frequency of participating in school activities decreased slightly. Little change emerged in the proportion who attend a PTA/PTO meeting ([approximately 50%), whereas the proportion who spent time fundraising decreased (60% to 54%). Differences in time investment between high- versus low-income parents either narrowed significantly (attended school meetings, frequency of participation) or remained stable (attended PTO/PTA meeting, volunteered) over time, except for income-based differences in time spent fundraising for their child's school, which grew significantly. We discuss factors possibly related to these narrowing and persistent gaps.

Solar eclipses are a rare phenomenon that everyone should have the opportunity to explore in depth. This article describes two programs developed by a science, technology, engineering, and mathematics (STEM) outreach center with the goal of bringing the excitement of eclipses to all learners. The STEM outreach center collaborated with local schools to provide a learning opportunity about eclipses in the weeks leading up to the October 14, 2023, annular solar eclipse, and with a local library to provide a free public viewing event for the eclipse. Students and community members engaged in various activities including modeling lunar phases and eclipses, learning about why and how often eclipses happen in a mobile planetarium, exploring magnetism and sunspots with the use of a solar telescope, and measuring and graphing light intensity and ultraviolet radiation throughout the solar eclipse. Post-event evaluations and anecdotal evidence indicate that participants could make connections on a variety of topics including how sunspots occur; why eclipses are predictable; and the differences between annular, total, and partial eclipses. The article also includes adaptations for classroom teachers and other STEM outreach centers to use the ideas presented here for the April 8, 2024, solar eclipse.

Abstract Sarcoidosis is a rare and elusive chronic inflammatory disease. It can manifest itself in any organ, but preferentially affects the lungs and the skin. Our case of an elderly woman with cutaneous and pulmonary sarcoidosis presented with exacerbated itchy, scaly skin changes to our department. The clinical and histopathological findings were consistent with sarcoidosis and eczematized psoriasis. The case represents a unique presentation of sarcoidosis with cutaneous involvement and poses diagnostic and therapeutic challenges due to overlapping clinical features and histology covering the three diagnoses. We discuss the immunological complexities underlying this overlap and resulting possible treatment options, highlighting the role of dermatology in systemic autoimmune diseases involving the skin and the need for pathophysiology-based tailored management approaches in these diseases.

Abstract Background Lack of access to risk-appropriate maternity services, particularly for rural residents, is thought to be a leading contributor to disparities in maternal morbidity and mortality. There are several existing measures of access to obstetric care in the literature and popular media. In this study, we explored how current measures of obstetric access inform the number and location of additional obstetric care facilities required to improve access. Methods We formulated two facility location optimization models to determine the number of new facilities required to minimize the number of reproductive-aged women who lack access to obstetric care. We define regions with a lack of access as either maternity care deserts, designated by the March of Dimes to be counties with no obstetric care facility or obstetric providers, or regions further than 50 miles from critical care obstetric (CCO) services. We gathered information on hospitals with obstetric services from Georgia Department of Public Health public reports and estimated the female reproductive-age population by census block group using the American Community Survey. Results Out of the 1,910,308 reproductive-aged women who live in Georgia, 104,158 (5.5%) live in maternity care deserts, 150,563 (7.9%) reproductive-aged women live further than 50 miles from CCO services, and 38,202 (2.0%) live in both maternity care desert and further than 50 miles from CCO services. Our optimization analysis suggests that at least 56 new obstetric care facilities (a 67% increase) would be required to eliminate maternity care deserts in Georgia. However, the expansion of 8 facilities would ensure all women in Georgia live within 50 miles of CCO services. Conclusions Current measures of access to obstetric care may not be sufficient for evaluating access and planning action toward improvements. In a state like Georgia with a large number of small counties, eliminating maternity care deserts would require a prohibitively large number of new obstetric care facilities. This work suggests that additional measures and tools are needed to estimate the number and type of obstetric care facilities that best match practical resources to meet obstetric care needs.

Abstract Ivermectin (IVM) is a commonly prescribed antiparasitic treatment with pharmacological effects on invertebrate glutamate ion channels resulting in paralysis and death of invertebrates. However, it can also act as a modulator of some vertebrate ion channels and has shown promise in facilitating L-DOPA treatment in preclinical models of Parkinson’s disease. The pharmacological effects of IVM on dopamine terminal function were tested, focusing on the role of two of IVM’s potential targets: purinergic P2X4 and nicotinic acetylcholine receptors. Ivermectin enhanced electrochemical detection of dorsal striatum dopamine release. Although striatal P2X4 receptors were observed, IVM effects on dopamine release were not blocked by P2X4 receptor inactivation. In contrast, IVM attenuated nicotine effects on dopamine release, and antagonizing nicotinic receptors prevented IVM effects on dopamine release. IVM also enhanced striatal cholinergic interneuron firing. L-DOPA enhances dopamine release by increasing vesicular content. L-DOPA and IVM co-application further enhanced release but resulted in a reduction in the ratio between high and low frequency stimulations, suggesting that IVM is enhancing release largely through changes in terminal excitability and not vesicular content. Thus, IVM is increasing striatal dopamine release through enhanced cholinergic activity on dopamine terminals.

PURPOSECancers are a growing cause of mortality especially in low- and middle-income countries in Africa. Rwanda is no exception. Two cancer centers currently provide care to the public, but there are both political and human interest in expanding access to tertiary cancer care. Improved geographic access could lead to both better patient outcomes and a better understanding of the existing cancer burden across Rwanda.METHODSTo identify cost-aware ways of expanding geographic access, we adopt an optimization approach and identify expansion plans that minimize the average travel time to a cancer center across the country while remaining under a given monetary budget.RESULTSThree additional hospitals could reduce average travel times by 40%, with the largest decrease in travel times observed in populations with long travel times. However, such an expansion would require a 50% increase in the number of in-country oncologists. We find that oncologist scarcity, as opposed to monetary constraints, is likely to be a limiting factor for improved access to cancer care.CONCLUSIONWe present an array of expansion plans and suggest that further modeling approaches that incorporate oncologist scarcity can help deliver better policy recommendations.

Background: Despite the successes of the Global Polio Eradication Initiative, substantial challenges remain in eradicating the poliovirus. The Sabin-strain (live-attenuated) virus in oral poliovirus vaccine (OPV) can revert to circulating vaccine-derived poliovirus (cVDPV) in under-vaccinated communities, regain neurovirulence and transmissibility, and cause paralysis outbreaks. Since the cessation of type 2-containing OPV (OPV2) in 2016, there have been cVDPV type 2 (cVDPV2) outbreaks in four out of six geographical World Health Organization regions, making these outbreaks a significant public health threat. Preparing for and responding to cVDPV2 outbreaks requires an updated understanding of how different factors, such as outbreak responses with the novel type of OPV2 (nOPV2) and the existence of under-vaccinated areas, affect the disease spread. Methods: We built a differential-equation-based model to simulate the transmission of cVDPV2 following reversion of the Sabin-strain virus in prolonged circulation. The model incorporates vaccinations by essential (routine) immunization and supplementary immunization activities (SIAs), the immunity induced by different poliovirus vaccines, and the reversion process from Sabin-strain virus to cVDPV. The model’s outcomes include weekly cVDPV2 paralytic case counts and the die-out date when cVDPV2 transmission stops. In a case study of Northwest and Northeast Nigeria, we fit the model to data on the weekly cVDPV2 case counts with onset in 2018–2021. We then used the model to test the impact of different outbreak response scenarios during a prediction period of 2022–2023. The response scenarios included no response, the planned response (based on Nigeria’s SIA calendar), and a set of hypothetical responses that vary in the dates at which SIAs started. The planned response scenario included two rounds of SIAs that covered almost all areas of Northwest and Northeast Nigeria except some under-vaccinated areas (e.g., Sokoto). The hypothetical response scenarios involved two, three, and four rounds of SIAs that covered the whole Northwest and Northeast Nigeria. All SIAs in tested outbreak response scenarios used nOPV2. We compared the outcomes of tested outbreak response scenarios in the prediction period. Results: Modeled cVDPV2 weekly case counts aligned spatiotemporally with the data. The prediction results indicated that implementing the planned response reduced total case counts by 79% compared to no response, but did not stop the transmission, especially in under-vaccinated areas. Implementing the hypothetical response scenarios involving two rounds of nOPV2 SIAs that covered all areas further reduced cVDPV2 case counts in under-vaccinated areas by 91–95% compared to the planned response, with greater impact from completing the two rounds at an earlier time, but it did not stop the transmission. When the first two rounds were completed in early April 2022, implementing two additional rounds stopped the transmission in late January 2023. When the first two rounds were completed six weeks earlier (i.e., in late February 2022), implementing one (two) additional round stopped the transmission in early February 2023 (late November 2022). The die out was always achieved last in the under-vaccinated areas of Northwest and Northeast Nigeria. Conclusions: A differential-equation-based model of poliovirus transmission was developed and validated in a case study of Northwest and Northeast Nigeria. The results highlighted (i) the effectiveness of nOPV2 in reducing outbreak case counts; (ii) the need for more rounds of outbreak response SIAs that covered all of Northwest and Northeast Nigeria in 2022 to stop the cVDPV2 outbreaks; (iii) that persistent transmission in under-vaccinated areas delayed the progress towards stopping outbreaks; and (iv) that a quicker outbreak response would avert more paralytic cases and require fewer SIA rounds to stop the outbreaks.

Background Chimeric antigen receptor (CAR) T-cell therapy target receptor tyrosine kinase-like orphan receptor 1 (ROR1) is broadly expressed in hematologic and solid tumors, however clinically-characterized ROR1-CAR T cells with single chain variable fragment (scFv)-R12 targeting domain failed to induce durable remissions, in part due to the immunosuppressive tumor microenvironment (TME). Herein, we describe the development of an improved ROR1-CAR with a novel, fully human scFv9 targeting domain, and augmented with TGFβRIIDN armor protective against a major TME factor, transforming growth factor beta (TGFβ).Methods CAR T cells were generated by lentiviral transduction of enriched CD4+ and CD8+ T cells, and the novel scFv9-based ROR1-CAR-1 was compared with the clinically-characterized ROR1-R12-scFv-based CAR-2 in vitro and in vivo.Results CAR-1 T cells exhibited greater CAR surface density than CAR-2 when normalized for %CAR+, and produced more interferon (IFN)-γ tumor necrosis factor (TNF)-α and interleukin (IL)-2 in response to hematologic (Jeko-1, RPMI-8226) and solid (OVCAR-3, Capan-2, NCI-H226) tumor cell lines in vitro. In vivo, CAR-1 and CAR-2 both cleared hematologic Jeko-1 lymphoma xenografts, however only CAR-1 fully rejected ovarian solid OVCAR-3 tumors, concordantly with greater expansion of CD8+ and CD4+CAR T cells, and enrichment for central and effector memory phenotype. When equipped with TGFβ-protective armor TGFβRIIDN, CAR-1 T cells resisted TGFβ-mediated pSmad2/3 phosphorylation, as compared with CAR-1 alone. When co-cultured with ROR-1+ AsPC-1 pancreatic cancer line in the presence of TGFβ1, armored CAR-1 demonstrated improved recovery of killing function, IFN-γ, TNF-α and IL-2 secretion. In mouse AsPC-1 pancreatic tumor xenografts overexpressing TGFβ1, armored CAR-1, in contrast to CAR-1 alone, achieved complete tumor remissions, and yielded accelerated expansion of CAR+ T cells, diminished circulating active TGFβ1, and no apparent toxicity or weight loss. Unexpectedly, in AsPC-1 xenografts without TGFβ overexpression, TGFβ1 production was specifically induced by ROR-1-CAR T cells interaction with ROR-1 positive tumor cells, and the TGFβRIIDN armor conferred accelerated tumor clearance.Conclusions The novel fully human TGFßRIIDN-armored ROR1-CAR-1 T cells are highly potent against ROR1-positive tumors, and withstand the inhibitory effects of TGFß in solid TME. Moreover, TGFβ1 induction represents a novel, CAR-induced checkpoint in the solid TME, which can be circumvented by co-expressing the TGβRIIDN armor on T cells.

ABSTRACTInflammatory bowel disease (IBD) is a group of inflammatory conditions of the gastrointestinal tract. The etiology of IBD remains elusive, but the disease is suggested to arise from the interaction of environmental and genetic factors that trigger inadequate immune responses and inflammation in the intestine. The gut microbiome majorly contributes to disease as an environmental variable, and although some causative bacteria are identified, little is known about which specific members of the microbiome aid in the intestinal epithelial barrier function to protect from disease. While chemically inducing colitis in mice from two distinct animal facilities, we serendipitously found that mice in one facility showed remarkable resistance to disease development, which was associated with increased markers of epithelial barrier integrity. Importantly, we show that Akkermansia muciniphila and Parabacteroides distasonis were significantly increased in the microbiota of resistant mice. To causally connect these microbes to protection against disease, we colonized susceptible mice with the two bacterial species. Our results demonstrate that A. muciniphila and P. distasonis synergistically drive a protective effect in both acute and chronic models of colitis by boosting the frequency of type 3 innate lymphoid cells in the colon and by improving gut epithelial integrity. Altogether, our work reveals a combined effort of commensal microbes in offering protection against severe intestinal inflammation by shaping gut immunity and by enhancing intestinal epithelial barrier stability. Our study highlights the beneficial role of gut bacteria in dictating intestinal homeostasis, which is an important step toward employing microbiome-driven therapeutic approaches for IBD clinical management.IMPORTANCEThe contribution of the gut microbiome to the balance between homeostasis and inflammation is widely known. Nevertheless, the etiology of inflammatory bowel disease, which is known to be influenced by genetics, immune response, and environmental cues, remains unclear. Unlocking novel players involved in the dictation of a protective gut, namely, in the microbiota component, is therefore crucial to develop novel strategies to tackle IBD. Herein, we revealed a synergistic interaction between two commensal bacterial strains, Akkermansia muciniphila and Parabacteroides distasonis, which induce protection against both acute and chronic models of colitis induction, by enhancing epithelial barrier integrity and promoting group 3 innate lymphoid cells in the colonic mucosa. This study provides a novel insight on how commensal bacteria can beneficially act to promote intestinal homeostasis, which may open new avenues toward the use of microbiome-derived strategies to tackle IBD.

Abstract The first Harm Reduction DACH Conference [DACH = D (Germany), A (Austria), CH (Switzerland)] took place in Vienna on June 23rd, 2023, and focused on tobacco harm reduction. It is the first conference bringing together various experts of all three German-speaking countries to shed light on the subject of destigmatization and tobacco harm reduction and to share their experiences with the audience. All in all, the first German-speaking harm reduction conference has the goal to discuss and expand harm reduction in the German-speaking countries. This meeting report gives a brief overview of the conference.

Abstract Background Darier’s disease (DD) is a genodermatosis caused by mutations of the ATP2A2 gene leading to disrupted keratinocyte adhesion. Recurrent episodes of skin inflammation and infections with a typical malodour in DD indicate a role for microbial dysbiosis. Here, for the first time, we investigated the DD skin microbiome using a metabarcoding approach of 115 skin swabs from 14 patients and 14 healthy volunteers. Furthermore, we analyzed its changes in the context of DD malodour and the cutaneous DD transcriptome. Results We identified a disease-specific cutaneous microbiome with a loss of microbial diversity and of potentially beneficial commensals. Expansion of inflammation-associated microbes such as Staphylococcus aureus and Staphylococcus warneri strongly correlated with disease severity. DD dysbiosis was further characterized by abundant species belonging to Corynebacteria, Staphylococci and Streptococci groups displaying strong associations with malodour intensity. Transcriptome analyses showed marked upregulation of epidermal repair, inflammatory and immune defence pathways reflecting epithelial and immune response mechanisms to DD dysbiotic microbiome. In contrast, barrier genes including claudin-4 and cadherin-4 were downregulated. Conclusions These findings allow a better understanding of Darier exacerbations, highlighting the role of cutaneous dysbiosis in DD inflammation and associated malodour. Our data also suggest potential biomarkers and targets of intervention for DD. Video Abstract

ObjectivesTo determine how pre-existing conditions contribute to racial disparities in adverse maternal outcomes and incorporate these conditions into models to improve risk prediction for racial minority subgroups.Study designWe used data from the "Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-be (nuMoM2b)" observational cohort study. We defined multimorbidity as the co-occurrence of two or more pre-pregnancy conditions. The primary outcomes of interest were severe preeclampsia, postpartum readmission, and blood transfusion during pregnancy or up to 14 days postpartum. We used weighted Poisson regression with robust variance to estimate adjusted risk ratios and 95% confidence intervals, and we used mediation analysis to evaluate the contribution of the combined effects of pre-pregnancy conditions to racial/ethnic disparities. We also evaluated the predictive performance of our regression models by racial subgroup using the area under the receiver operating characteristic curve (AUC) metric.ResultsIn the nuMoM2b cohort (n = 8729), accounting for pre-existing conditions attenuated the association between non-Hispanic Black race/ethnicity and risk of severe preeclampsia. Cardiovascular and kidney conditions were associated with risk for severe preeclampsia among all women (aRR, 1.77; CI, 1.61-1.96, and aRR, 1.27; CI, 1.03-1.56 respectively). The mediation analysis results were not statistically significant; however, cardiovascular conditions explained 36.6% of the association between non-Hispanic Black race/ethnicity and severe preeclampsia (p = 0.07). The addition of pre-pregnancy conditions increased model performance for the prediction of severe preeclampsia.ConclusionsPre-existing conditions may explain some of the association between non-Hispanic Black race/ethnicity and severe preeclampsia. Specific pre-pregnancy conditions were associated with adverse maternal outcomes and the incorporation of comorbidities improved the performance of most risk prediction models.

IntroductionA crisis can be described as subjective experience that threatens and overwhelms a person's ability to handle a specific situation. In dealing with crises some people are looking for support from professionals. The "professional relationship" between people experiencing a crisis and professionals plays an important role in the successful management of a crisis which has been widely researched in many contexts. However, regarding outpatient services (e. g. crisis resolution home treatment teams), yet empirical evidence remains limited.ObjectiveWe aim to explore descriptions of supportive professional relationships during outpatient crisis interventions in empirical literature. Accordingly, a scoping review was conducted to identify types of evidence, map the key concepts, and point out research gaps.MethodsMEDLINE, PsycINFO, CINAHL and Social Science Citation Index were searched for studies reporting empirical data on the professional relationship between people experiencing a crisis (18+) and professionals (e. g. social workers, psychiatrists) during a crisis intervention, defined as a short-term, face-to-face, low threshold, time-limited, outpatient, and voluntary intervention to cope with crises. Studies were excluded if they were published before 2007, in languages other than English and German, and if they couldn't be accessed. Included studies were summarized, compared, and synthesized using qualitative content analyses.Results3.741 records were identified, of which 8 met the eligibility criteria. Only one study directly focused on the relationship; the others addressed varied aspects. Two studies explored the perspectives of service users, five focused on those of the professionals and one study examined both. The empirical literature was categorized into three main themes: strategies used to develop a supportive professional relationship, factors influencing the relationship and the nature of these relationships.DiscussionThe results reveal a gap in understanding the nature of supportive professional relationships from the service users' perspective, as well as how professionals construct these relationships.

Abstract Background DC are among the first antigen presenting cells encountering bacteria at mucosal surfaces, and play an important role in maintenance of regular homeostasis in the intestine. Upon stimulation DC undergo activation and maturation and as initiators of T cell responses they have the capacity to stimulate naïve T cells. However, stimulation of naïve murine DC with B. vulgatus or LPS at low concentration drives DC to a semimature (sm) state with low surface expression of activation-markers and a reduced capacity to activate T-cells. Additionally, semimature DC are nonresponsive to subsequent TLR stimulation in terms of maturation, TNF-α but not IL-6 production. Ligation of CD40 is an important mechanism in enhancing DC maturation, function and capacity to activate T-cells. We investigated whether the DC semimaturation can be overcome by CD40 ligation. Results Upon CD40 ligation smDC secreted IL-12p40 but not the bioactive heterodimer IL-12p70. Additionally, CD40 ligation of smDC resulted in an increased production of IL-6 but not in an increased expression of CD40. Analysis of the phosphorylation pattern of MAP kinases showed that in smDC the p38 phosphorylation induced by CD40 ligation is inhibited. In contrast, phosphorylation of ERK upon CD40 ligation was independent of the DC maturation state. Conclusion Our data show that the semimature differentiation state of DC can not be overcome by CD40 ligation. We suggest that the inability of CD40 ligation in overcoming DC semimaturation might contribute to the tolerogenic phenotype of semimature DC and at least partially account for maintenance of intestinal immune homeostasis.

Summary: Mechanisms underlying distinct specification, commitment, and differentiation phases of cell fate determination remain undefined due to difficulties capturing these processes. Here, we interrogate the activity of ETV2, a transcription factor necessary and sufficient for hematoendothelial differentiation, within isolated fate intermediates. We observe transcriptional upregulation of Etv2 and opening of ETV2-binding sites, indicating new ETV2 binding, in a common cardiac-hematoendothelial progenitor population. Accessible ETV2-binding sites are active at the Etv2 locus but not at other hematoendothelial regulator genes. Hematoendothelial commitment coincides with the activation of a small repertoire of previously accessible ETV2-binding sites at hematoendothelial regulators. Hematoendothelial differentiation accompanies activation of a large repertoire of new ETV2-binding sites and upregulation of hematopoietic and endothelial gene regulatory networks. This work distinguishes specification, commitment, and sublineage differentiation phases of ETV2-dependent transcription and suggests that the shift from ETV2 binding to ETV2-bound enhancer activation, not ETV2 binding to target enhancers, drives hematoendothelial fate commitment.

Infectious diseases, like COVID-19, pose serious challenges to university campuses, which typically adopt closure as a non-pharmaceutical intervention to control spread and ensure a gradual return to normalcy. Intervention policies, such as remote instruction (RI) where large classes are offered online, reduce potential contact but also have broad side-effects on campus by hampering the local economy, students’ learning outcomes, and community wellbeing. In this paper, we demonstrate that university policymakers can mitigate these tradeoffs by leveraging anonymized data from their WiFi infrastructure to learn community mobility—a methodology we refer to as WiFi mobility models (WiMob). This approach enables policymakers to explore more granular policies like localized closures (LC). WiMob can construct contact networks that capture behavior in various spaces, highlighting new potential transmission pathways and temporal variation in contact behavior. Additionally, WiMob enables us to design LC policies that close super-spreader locations on campus. By simulating disease spread with contact networks from WiMob, we find that LC maintains the same reduction in cumulative infections as RI while showing greater reduction in peak infections and internal transmission. Moreover, LC reduces campus burden by closing fewer locations, forcing fewer students into completely online schedules, and requiring no additional isolation. WiMob can empower universities to conceive and assess a variety of closure policies to prevent future outbreaks.

Raster-Scanning-Optoacoustic Mesoscopy can be used to image the vasculature in skin cancer lesions but is limited by a long exposure time. Here; the authors increase the speed of the imaging using co-axial illumination and a high-sensitivity ultrasound detector path.