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Background: Palliative care services seek to improve the wellbeing of family carers of people living with serious and life-limiting illness. To help achieve this goal, systematic reviews have recommended priority areas for family carer research and the need to improve the quality of study design. Policy makers have also advocated for enhanced family carer support. However, there are specific methodological considerations and challenges in designing and conducting carer research conducted during the course of the serious illness trajectory and in bereavement. Aim: To develop strategies to improve the design and conduct of research with family carers. Design: Expert elicitation study using an adapted version of the ‘Identify, Discuss, Estimate and Aggregate’ elicitation protocol, supplemented with strategies from peer-reviewed literature. Setting/participants: Nine members of the management committee of the European Association for Palliative Care’s Reference group on family carer research, comprising international senior research academics in family caregiving. Results: A compilation of recommended strategies and checklist was created to: (a) help researchers plan research involving family carers focussing on: preparation, conduct and dissemination and (b) assist ethics committees and funding bodies to evaluate proposals. Conclusions: The strategies and checklist for conducting research with family carers may enhance methodologically rigorous research. Consequently, researchers, practitioners and policy makers will not only gain a more comprehensive understanding of the unmet needs of family carers but also promote the development of empirically sound interventions.

It is projected that in 5 years, pancreatic cancer will become the second deadliest cancer in the United States. A unique aspect of pancreatic ductal adenocarcinoma (PDAC) is its stroma; rich in cancer-associated fibroblasts (CAFs) and a dense CAF-generated extracellular matrix (ECM). These pathogenic stroma CAF/ECM units cause the collapse of local blood vessels rendering the tumor microenvironment nutrient-poor. PDAC cells are able to survive this state of nutrient stress via support from CAF-secreted material, which includes small extracellular vesicles (sEV). The tumor-supportive CAFs possess a distinct phenotypic profile, compared with normal-like fibroblasts, expressing NetrinG1 (NetG1) at the plasma membrane, and active Integrin α5β1 localized to the multivesicular bodies; traits indicative of poor patient survival. We herein report that NetG1+ CAFs secrete sEVs that stimulate Akt-mediated survival in nutrient-deprived PDAC cells, protecting them from undergoing apoptosis. Furthermore, we show that NetG1 expression in CAFs is required for the prosurvival properties of sEVs. In addition, we report that the above-mentioned CAF markers are secreted in distinct subpopulations of EVs; with NetG1 being enriched in exomeres, and Integrin α5β1 being enriched in exosomes. Finally, we found that NetG1 and Integrin α5β1 were detected in sEVs collected from plasma of patients with PDAC, while their levels were significantly lower in plasma-derived sEVs of sex/age-matched healthy donors. The discovery of these tumor-supporting CAF-EVs elucidates novel avenues in tumor–stroma interactions and pathogenic stroma detection. Significance: Results from this study identified two unique types of tumor-supporting CAF EVs, with evidence of these being detected in patients. Thus, this study facilitates a novel avenue to further dissect the subtleties of the tumor–stroma interactions responsible for PDAC homeostasis and progression, as well as the possibility of establishing future means to detect and monitor dynamic stroma staging.

STUDY QUESTION Are maternal anthropometrics associated with anogenital distance (AGD) and 2:4 digit ratio (2:4D) in newborns? SUMMARY ANSWER Select maternal anthropometrics indicative of obesity or increased adiposity are associated with elongated AGD in daughters. WHAT IS KNOWN ALREADY Excessive maternal weight or adiposity before or in early pregnancy may impact child reproductive, and other hormonally mediated, development. AGD and 2:4D are proposed markers of in utero reproductive development. STUDY DESIGN, SIZE, DURATION This study includes 450 mother/newborn dyads participating in the Illinois Kids Development Study (I-KIDS), a prospective pregnancy cohort from Champaign-Urbana, IL, USA. Participants included in the current study enrolled between 2013 and 2018. PARTICIPANTS/MATERIALS, SETTING, METHODS Most mothers in this study were college-educated (82%) and non-Hispanic White (80%), and 55% were under- or normal weight before pregnancy. Pregnant women aged 18–40 years reported pre-pregnancy weight and height to calculate pre-pregnancy BMI. At 8–15 weeks gestation, we measured waist and hip circumference, and evaluated weight, % body fat, visceral fat level, % muscle and BMI using bioelectrical impedance analysis. Within 24 h of birth, we measured newborn 2nd and 4th left/right digits to calculate the 2:4D. In daughters, we measured AGDAF (anus to fourchette) and AGDAC (anus to clitoris). In sons, we measured AGDAS (anus to scrotum) and AGDAP (anus to base of the penis). MAIN RESULTS AND THE ROLE OF CHANCE Select maternal anthropometrics were positively associated with AGD in newborn daughters, but not sons. For example, AGDAC was 0.73 mm (95% CI: 0.15, 1.32) longer for every interquartile range (IQR) increase in pre-pregnancy BMI and 0.88 mm (95% CI: 0.18, 1.58) longer for every IQR increase in hip circumference, whereas AGDAF was 0.51 mm (95% CI: 0.03, 1.00) and 0.56 mm (95% CI: 0.03, 1.09) longer for every IQR increase in hip and waist circumference, respectively. Quartile analyses generally supported linear associations, but additional strong associations emerged in Q4 (versus Q1) of maternal % body fat and visceral fat levels with AGDAC. In quartile analyses, we observed only a few modest associations of maternal anthropometrics with 2:4D, which differed by hand (left versus right) and newborn sex. Although there is always the possibility of spurious findings, the associations for both measures of female AGD were consistent across multiple maternal anthropometric measures, which strengthens our conclusions. LIMITATIONS, REASONS FOR CAUTION Our study sample was racially and ethnically homogenous, educated and relatively healthy, so our study may not be generalizable to other populations. Additionally, we may not have been powered to identify some sex-specific associations, especially for 2:4D. WIDER IMPLICATIONS OF THE FINDINGS Increased maternal weight and adiposity before and in early pregnancy may lengthen the female AGD, which warrants further investigation. STUDY FUNDING/COMPETING INTEREST(S) This publication was made possible by the National Institute for Environmental Health Sciences (NIH/NIEHS) grants ES024795 and ES022848, the National Institute of Child Health and Human Development grant R03HD100775, the U.S. Environmental Protection Agency grant RD83543401 and National Institute of Health Office of the Director grant OD023272. Its contents are solely the responsibility of the grantee and do not necessarily represent the official views of the US EPA or NIH. Furthermore, the US EPA does not endorse the purchase of any commercial products or services mentioned in the publication. This project was also supported by the USDA National Institute of Food and Agriculture and Michigan AgBioResearch. The authors declare no competing interests. TRIAL REGISTRATION NUMBER N/A.

Ibrutinib, a Bruton's tyrosine kinase inhibitor, may have clinical benefit when administered in combination with bendamustine and rituximab and followed by rituximab maintenance therapy in older patients with untreated mantle-cell lymphoma.We randomly assigned patients 65 years of age or older to receive ibrutinib (560 mg, administered orally once daily until disease progression or unacceptable toxic effects) or placebo, plus six cycles of bendamustine (90 mg per square meter of body-surface area) and rituximab (375 mg per square meter). Patients with an objective response (complete or partial response) received rituximab maintenance therapy, administered every 8 weeks for up to 12 additional doses. The primary end point was progression-free survival as assessed by the investigators. Overall survival and safety were also assessed.Among 523 patients, 261 were randomly assigned to receive ibrutinib and 262 to receive placebo. At a median follow-up of 84.7 months, the median progression-free survival was 80.6 months in the ibrutinib group and 52.9 months in the placebo group (hazard ratio for disease progression or death, 0.75; 95% confidence interval, 0.59 to 0.96; P = 0.01). The percentage of patients with a complete response was 65.5% in the ibrutinib group and 57.6% in the placebo group (P = 0.06). Overall survival was similar in the two groups. The incidence of grade 3 or 4 adverse events during treatment was 81.5% in the ibrutinib group and 77.3% in the placebo group.Ibrutinib treatment in combination with standard chemoimmunotherapy significantly prolonged progression-free survival. The safety profile of the combined therapy was consistent with the known profiles of the individual drugs. (Funded by Janssen Research and Development and Pharmacyclics; SHINE ClinicalTrials.gov number, NCT01776840.).

Spread sheet including a single tab per Figure panel conveying each graph's statistical analyses. Note that tabs are named accordingly. The tabs include the comprehensive statistical analyses that were performed for each experiment in which statistical significance was given. Each tab contains the full statistical output for its labeled experiment. The statistical test performed for each experiment is identified within the corresponding tab. Statistical tests were carried out using the software, Prism, version 7.05.

Spreadsheet including the metabolomic analyses corresponding to the experiments indicated by the naming of the assorted tabs. Specific analysis parameters for each experiment are provided within the respective main figure legends.

Supplementary Figure 1. Confirmation that CAFs produce ECMs distinct from NLFs. Supplementary Figure 2. Direct co-culture of CAFs support PDAC cells during nutrient-deprivation. Supplementary Figure 3. Additional CAF cell lines generate sEVs that rescue PDAC cells from nutrient deprivation-induced apoptosis. Supplementary Figure 4. NetG1+ CAF-sEVs support PDAC cell survival in a NGL-1 dependent manner. Supplementary Figure 5. NetG1 expression in CAFs is necessary for sEV-mediated survival of nutrient-deprived PDAC cells. Supplementary Figure 6. NetG1 ablation does not affect the uptake of sEV cargo in PDAC cells. Supplementary Figure 7. sEV supernatant contains DNPs enriched with sub-exosome sized EVs. Supplementary Figure 8. Enriched gene ontology clusters from proteomic and metabolomic analysis comparing sEV and DNP fractions. Supplementary Figure 9. EV cargo requires transfer in intact vesicles to provide tumor-supportive effect.

Spreadsheet including the proteomic analyses corresponding to the experiments indicated by the naming of the assorted tabs. Specific analysis parameters for each experiment are provided within the respective main figure legends.

It is projected that in 5 years, pancreatic cancer will become the second deadliest cancer in the United States. A unique aspect of pancreatic ductal adenocarcinoma (PDAC) is its stroma; rich in cancer-associated fibroblasts (CAFs) and a dense CAF-generated extracellular matrix (ECM). These pathogenic stroma CAF/ECM units cause the collapse of local blood vessels rendering the tumor microenvironment nutrient-poor. PDAC cells are able to survive this state of nutrient stress via support from CAF-secreted material, which includes small extracellular vesicles (sEV). The tumor-supportive CAFs possess a distinct phenotypic profile, compared with normal-like fibroblasts, expressing NetrinG1 (NetG1) at the plasma membrane, and active Integrin α5β1 localized to the multivesicular bodies; traits indicative of poor patient survival. We herein report that NetG1+ CAFs secrete sEVs that stimulate Akt-mediated survival in nutrient-deprived PDAC cells, protecting them from undergoing apoptosis. Furthermore, we show that NetG1 expression in CAFs is required for the prosurvival properties of sEVs. In addition, we report that the above-mentioned CAF markers are secreted in distinct subpopulations of EVs; with NetG1 being enriched in exomeres, and Integrin α5β1 being enriched in exosomes. Finally, we found that NetG1 and Integrin α5β1 were detected in sEVs collected from plasma of patients with PDAC, while their levels were significantly lower in plasma-derived sEVs of sex/age-matched healthy donors. The discovery of these tumor-supporting CAF-EVs elucidates novel avenues in tumor–stroma interactions and pathogenic stroma detection.Significance:Results from this study identified two unique types of tumor-supporting CAF EVs, with evidence of these being detected in patients. Thus, this study facilitates a novel avenue to further dissect the subtleties of the tumor–stroma interactions responsible for PDAC homeostasis and progression, as well as the possibility of establishing future means to detect and monitor dynamic stroma staging.

BACKGROUND: Improving breastfeeding rates among African American (AA) families is an important public health goal. Breastfeeding self-efficacy, a known predictor of breastfeeding behavior, has seldom been assessed among AAs, in relation to breastfeeding intensity (% breastfeeding relative to total feeding) or as a protective factor in combating the historical breastfeeding challenges faced by people of color. We aimed to test the association between breastfeeding self-efficacy assessed during pregnancy and breastfeeding intensity assessed in the early postpartum period. METHODS: This was a secondary data analysis of a randomized controlled feasibility trial of breastfeeding support and postpartum weight management. AA women were recruited during pregnancy from a prenatal clinic in Detroit, MI. Data presented, in this study, were collected at enrollment (n = 50) and ∼6 weeks postpartum (n = 31). Linear regression models were used, adjusting for potential confounders. RESULTS: There were no differences in breastfeeding intensity by study arm; data are from all women with complete data on targeted variables. Age ranged from 18 to 43 years, 52% were Women, Infant's, and Children program enrollees, and 62% had ≥ some college. Breastfeeding self-efficacy during pregnancy was a significant predictor of breastfeeding intensity in the early postpartum period (β = 0.125, p

Background: breast cancer has a significant heritable basis, of which ∼60% remains unexplained. Testing for BRCA1/BRCA2 offers useful discrimination of breast cancer risk within families, and identification of additional breast cancer susceptibility genes could offer clinical utility. Patients and methods: we included 2135 invasive breast cancer cases recruited via the Breast and Ovarian Cancer Susceptibility study, a retrospective UK study of familial breast cancer. Eligibility criteria: female, BRCA-negative, white European ethnicity, and one of: (i) breast cancer family history, (ii) bilateral disease, (iii) young age of onset (Results: 159/2135 (7.4%) cases had a qualifying variant in an established breast cancer susceptibility gene, with minimal evidence of signal in other cancer susceptibility genes. Known breast cancer susceptibility genes PALB2, CHEK2, and ATM were the only genes to retain statistical significance after correcting for multiple testing. Due to the enrichment of hereditary cases in the series, we had good power (>80%) to detect a gene of BRCA1-like risk [odds ratio (OR) = 10.6] down to a population minor allele frequency of 4.6 × 10 −5 (1 in 10 799, less than one-tenth that of BRCA1)and of PALB2-like risk (OR = 5.0) down to a population minor allele frequency of 2.8 × 10 −4 (1 in 1779, less than half that of PALB2). Power was lower for identification of novel moderate penetrance genes (OR = 2-3) like CHEK2 and ATM. Conclusions: this is the largest case-control whole-exome analysis of enriched breast cancer published to date. Whilst additional breast cancer susceptibility genes likely exist, those of high penetrance are likely to be of very low mutational frequency. Contention exists regarding the clinical utility of such genes.

Purpose Perceived Social Support (PSS) can impact breastfeeding behaviors, and a lack of PSS potentially contributes to disparities in breastfeeding rates for African American women (AA). Objectives were to describe PSS at two timepoints and test associations between PSS and breastfeeding intensity for AA. Methods Data are from a feasibility trial of breastfeeding support among AA. The Hughes Breastfeeding Support Scale was used to measure PSS (Emotional, Informational, Tangible; total range = 30–120) in pregnancy (T1, n = 32) and early postpartum (T2, n = 31). Scale means were compared with t-tests. Associations between PSS at T1 and breastfeeding intensity (ie, quantitative measure of breastfeeding) were assessed with linear regression. Results Total PSS (mean ± SE) was high at both time points (T1 = 90.5 ± 4.8; T2 = 92.8 ± 3.1). At T2, older participants or those living with a partner had higher total PSS scores compared to those younger or living alone. Emotional PSS was significantly higher at T2 than T1 with no differences in tangible or informational PSS over time. Mixed-feeding, exclusive breastfeeding, and exclusive formula feeding was distributed at 39%, 32%, and 29%, respectively. Total PSS was not associated with breastfeeding intensity. Conclusion Women reported high levels of social support, and emotional PSS increased over time in this small sample of AA. PSS and sources of PSS are understudied, especially among AA, and future studies should explore quantitative methods to assess PSS. The results of such assessments can then be used to design breastfeeding support interventions.

It is projected that in 5 years, pancreatic cancer will become the second deadliest cancer in the United States. A unique aspect of pancreatic ductal adenocarcinoma (PDAC) is its stroma; rich in cancer-associated fibroblasts (CAFs) and a dense CAF-generated extracellular matrix (ECM). These pathogenic stroma CAF/ECM units cause the collapse of local blood vessels rendering the tumor microenvironment nutrient-poor. PDAC cells are able to survive this state of nutrient stress via support from CAF-secreted material, which includes small extracellular vesicles (sEVs). The tumor-supportive CAFs possess a distinct phenotypic profile, compared to normal-like fibroblasts, expressing NetrinG1 (NetG1) at the plasma membrane, and active Integrin α(5)β(1) localized to the multivesicular bodies; traits indicative of poor patient survival. We herein report that NetG1(+) CAFs secrete sEVs that stimulate Akt-mediated survival in nutrient-deprived PDAC cells, protecting them from undergoing apoptosis. Further, we show that NetG1 expression in CAFs is required for the pro-survival properties of sEVs. Additionally, we report that the above-mentioned CAF markers are secreted in distinct subpopulations of EVs; with NetG1 being enriched in exomeres, and Integrin α(5)β(1) being enriched in exosomes. Finally, we found that NetG1 and Integrin α(5)β(1) were detected in sEVs collected from plasma of PDAC patients, while their levels were significantly lower in plasma-derived sEVs of sex/age-matched healthy donors. The discovery of these tumor-supporting CAF-EVs elucidates novel avenues in tumor-stroma interactions and pathogenic stroma detection.

The COVID-19 pandemic had a major impact on UK deceased organ donation and transplantation activity. We used national audit data from NHS Blood and Transplant to explore in detail the effects of the pandemic in comparison with 12 months pre-pandemic, and to consider the impact of the mitigating strategies and challenges placed on ICU by 'waves' of patients with COVID-19. Between 11 March 2020 and 10 March 2021, referrals to NHS Blood and Transplant of potential organ donors were initially inversely related to the number of people with COVID-19 undergoing mechanical ventilation in intensive care (incident rate ratio (95%CI) per 1000 patients 0.93 (0.88-0.99), p = 0.018), although this pattern reversed during the second wave (additional incident rate ratio (95%CI) 1.12 (1.05-1.19), p 0.001). Adjusted numbers of donors (incident rate ratio (95%CI) 0.71 (0.61-0.81), p 0.001) and organs retrieved (incident rate ratio (95%CI) 0.89 (0.82-0.97), p = 0.007) were inversely dependent on COVID-19 workload, though weekly numbers of transplants were unrelated (incident rate ratio (95%CI) 0.95 (0.86-1.04), p = 0.235). Non-COVID-19 mortality fell from 15,007 to 14,087 during the first wave (rate ratio (95%CI) 0.94 (0.92-0.96), p 0.001) but climbed from 18,907 to 19,372 during the second wave (rate ratio (95%CI) 1.02 (1.00-1.05), p = 0.018). There were fewer in-hospital deaths from cardiac arrest and intracranial catastrophes throughout (rate ratio (95%CI) 0.83 (0.81-0.86), p 0.001 and rate ratio (95%CI) 0.88 (0.85-0.91), p 0.001, respectively). There were overall fewer eligible donors (n = 4282) when compared with pre-pandemic levels (n = 6038); OR (95%CI) 0.58 (0.51-0.66), p 0.001. The total number of donations during the year fell from 1620 to 1140 (rate ratio (95%CI) 0.70 (0.65-0.76), p 0.001), but the proportion of eligible donors who proceeded to donation (27%) was unchanged (OR (95%CI) 0.99 (0.91-1.08), p = 0.821). The reduction in donations and transplantation during the pandemic was multifactorial, but these data highlight the impact in the UK of a fall in eligible donors and an inverse relationship of referrals to COVID-19 workload. Despite the challenges faced, the foundations underpinning the UK deceased organ donation programme remained strong.

The B7 family, and their receptors, the CD28 family, are major immune checkpoints that regulate T-cell activation and function. In the present study, we explore the role of two B7 immune-checkpoints: HERV-H LTR-Associating Protein 2 (HHLA2) and B7 Family Member, H4 (B7x), in the progression of gastrointestinal and pancreatic neuroendocrine tumors (GINETs and PNETs). We demonstrated that both HHLA2 and B7x were expressed to a high degree in human GINETs and PNETs. We determined that the expression of B7x and HHLA2 correlates with higher grade and higher incidence of nodal and distant spread. Furthermore, we confirmed that HIF-1α overexpression is associated with the upregulation of B7x both in our in vivo (animal model) and in vitro (cell culture) models. When grown in vitro, islet tumor β-cells lack B7x expression, unless cultured under hypoxic conditions, which results in both hypoxia-inducible factor 1 subunit alpha (HIF-1α) and B7x upregulation. In vivo, we demonstrated that Men1/B7x double knockout (KO) mice (with loss of B7x expression) exhibited decreased islet β-cell proliferation and tumor transformation accompanied by increased T-cell infiltration compared with Men1 single knockout mice. We have also shown that systemic administration of a B7x mAb to our Men1 KO mice with PNETs promotes an antitumor response mediated by increased T-cell infiltration. These findings suggest that B7x may be a critical mediator of tumor immunity in the tumor microenvironment of NETs. Therefore, targeting B7x offers an attractive strategy for the immunotherapy of patients suffering from NETs.

Phthalates and their replacements are endocrine/metabolic disruptors that may impact gestational weight gain (GWG) - a pregnancy health indicator. We investigated overall and fetal sex-specific associations of individual and cumulative phthalate/replacement biomarkers with GWG.Illinois women (n = 299) self-reported their weight pre-pregnancy and at their final obstetric appointment before delivery (median 38 weeks). We calculated pre-pregnancy body mass index and gestational age-specific GWG z-scores (GWGz). We quantified 19 phthalate/replacement metabolites (representing 10 parent compounds) in pools of up-to-five first-morning urine samples, collected approximately monthly between 8 and 40 weeks gestation. We used linear regression, quantile-based g-computation (QGComp), and weighted quantile sum regression (WQSR) to evaluate associations of ten biomarkers (individual metabolites or parent molar-sums) individually or as mixtures (in interquartile range intervals) with GWGz. We evaluated associations in all women and stratified by fetal sex.Individually, sums of metabolites of di(2-ethylhexyl) phthalate (ƩDEHP), di(isononyl) cyclohexane-1,2-dicarboxylate (ƩDiNCH), and di(2-ethylhexyl) terephthalate (ƩDEHTP) had consistent inverse associations with GWGz, and some associations were fetal sex-specific. When evaluating phthalates/replacements as a mixture, QGComp identified ƩDEHP, ƩDEHTP, and mono-(3-carboxypropyl) phthalate, along with sum of di(isononyl) phthalate metabolites (ƩDiNP) and monobenzyl phthalate as notable contributors to lower and higher GWGz, respectively, resulting in a marginal inverse joint association in all women (β: -0.29; 95% CI: -0.70, 0.12). In women carrying females, ƩDEHP contributed to the marginal inverse joint association (β: -0.54; 95% CI: -1.09, 0.03). However, there was no overall association in women carrying males (β: 0.00; 95% CI: -0.60, 0.59), which was explained by approximately equal negative (driven by ƩDEHTP) and positive (driven by ƩDiNP) partial associations. WQSR analyses consistently replicated these QGComp findings.Biomarkers of phthalates/replacements were fetal sex-specifically associated with GWGz. Because ƩDEHTP contributed substantively to mixture associations, additional studies in pregnant women may be needed around this plasticizer replacement.

Pregnancy nutrition is important for maternal and child health and may affect the development of the infant gut microbiome. Our objective was to assess the feasibility of implementing a food-based intervention designed to increase fiber intake among pregnant women in a rural setting. Participants were enrolled (N = 27) mid-pregnancy from a prenatal care clinic in rural Michigan, randomized to intervention (N = 13) or usual care (N = 14), and followed to 6 weeks postpartum. The intervention was designed to be easily replicable and scalable by partnering with hospital foodservices and included non-perishable high fiber foods and recipes, as well as weekly delivery of salads, soup, and fresh fruit. Surveys, maternal blood, urine, and stool were collected at 24- and 36-weeks gestation and at 6 weeks postpartum. Infant stool was collected at 6 weeks. Participants were 100% White (7% Hispanic White, 7% Native American and White); 55% with education < 4-year college degree. Data on dietary intake and urinary trace elements are presented as evidence of feasibility of outcome measurement. Retention was high at 93%; 85% reported high satisfaction. The intervention described here can be replicated and used in larger, longer studies designed to assess the effects of pregnancy diet on the establishment of the infant gut microbiome and related health outcomes.

It is projected that, in 5 years, pancreatic cancer will become the second deadliest cancer in the United States. A unique aspect of pancreatic ductal adenocarcinoma (PDAC) is its stroma; rich in cancer-associated fibroblasts (CAFs) and a dense CAF-generated extracellular matrix (ECM). This fibrous stroma, known as desmoplasia, causes the collapse of local blood vessels rendering a nutrient-deprived milieu. Hence, PDAC cells are nurtured by local CAF-secreted products, which include, among others, CAF-generated small extracellular vesicles (sEVs). It is well-accepted that upon culturing functionally tumor-promoting CAFs under pathophysiological-relevant conditions (e.g., within self-produced ECM), these cells express NetrinG1 (NetG1) and sustain endosomal pools rich in active α5β1-integrin; traits indicative of poor patient survival. We herein report that NetG1+ CAFs generate sEVs that rescue PDAC cells from nutrient-deprived induced apoptosis. Two unique sEVs, NetG1+ and α5β1-integrin+, were uncovered. The former constitutes cargo of CAF-generated exomeres, and the latter is detected in classic exosomes. Proteomic and metabolomic analyses showed that the sEV-dependent PDAC survival is, at least in part, dictated by the cargo packaged within sEVs in a NetG1-dependent manner. Indeed, despite producing a similar number of vesicles, selected key proteins and metabolites (e.g., glutamine) were incorporated within the unique sEVs. Finally, we found that NetG1 and α5β1-integrin were detected in sEVs collected from plasma of PDAC patients, while their concomitant levels were significantly lower in plasma of sex/age-matched healthy donors. The discovery of these tumor-supporting CAF sEVs opens a new investigative avenue in tumor-stroma interactions and stroma staging detection.

Maternal paraben exposure and diet quality are both independently associated with birth outcomes, but whether these interact is unknown. We assessed sex-specific associations of parabens with birth outcomes and differences by maternal diet quality.Illinois pregnant women (n = 458) provided five first-morning urines collected at 8-40 weeks gestation, which we pooled for quantification of ethylparaben, methylparaben, and propylparaben concentrations. We collected/measured gestational age at delivery, birth weight, body length, and head circumference within 24 h of birth, and calculated sex-specific birth weight-for-gestational-age z-scores and weight/length ratio. Women completed three-month food frequency questionnaires in early and mid-to-late pregnancy, which we used to calculate the Alternative Healthy Eating Index (AHEI)-2010. Linear regression models evaluated sex-specific associations of parabens with birth outcomes, and differences in associations by average pregnancy AHEI-2010.In this predominately non-Hispanic white, college-educated sample, maternal urinary paraben concentrations were only modestly inversely associated with head circumference and gestational length. However, methylparaben and propylparaben were inversely associated with birth weight, birth weight z-scores, body length, and weight/length ratio in female, but not male newborns. For example, each 2-fold increase in methylparaben concentrations was associated with -46.61 g (95% CI: -74.70, -18.51) lower birth weight, -0.09 (95% CI: -0.15, -0.03) lower birth weight z-scores, -0.21 cm (95% CI: -0.34, -0.07) shorter body length, and -0.64 g/cm (95% CI: -1.10, -0.19) smaller weight/length ratio in females. These inverse associations were more prominent in females of mothers with poorer diets (AHEI-2010 median), but attenuated in those with healthier diets (AHEI-2010 ≥ median). In newborn males of mothers with healthier diets, moderate inverse associations emerged for propylparaben with gestational length and head circumference.Maternal diet may moderate associations of parabens with birth size in a sex-specific manner. Additional studies may consider understanding the inflammatory and metabolic mechanisms underlying these findings.

Prophylactic antibiotic usage during delivery is a common practice worldwide, especially in low- to middle-income countries. Guidelines have been published to reduce antibiotic overuse, however, data describing the use of prophylactic antibiotics and clinician adherence to guidelines in low- to middle-income countries remain limited. This study aimed to describe the prevalence of prophylactic antibiotic use, factors associated with its use, and clinician adherence to guidelines. A retrospective review was conducted for all deliveries from 1 January 2016 to 31 December 2018 at a tertiary level hospital in Indonesia. The prevalence of prophylactic antibiotic use during delivery was 47.1%. Maternal education level, Ob/Gyn specialist-led delivery, a history of multiple abortions, C-section, premature membrane rupture, and antepartum hemorrhage were independently associated with prophylactic antibiotic use. Clinician adherence to the guidelines was 68.9%. Adherence to guidelines was the lowest in conditions where the patient had only one indication for prophylactic antibiotics (aOR 0.36, 95% CI 0.24–0.54). The findings showed that the prevalence of prophylactic antibiotic use during delivery was moderate to high. Adherence to local guidelines was moderate. Updating the local prescribing guidelines may improve clinician adherence.

Despite a growing number of research outputs on the importance of nature contact during the COVID-19 pandemic, we know of no longitudinal research conducted prior to and during the pandemic among low-income and minority ethnicity populations, i.e., those that might be most affected. Furthermore, we have scant information about how and to what degree contact with nature might protect mental health or mitigate worsening of mental health during the pandemic. We filled these gaps using a subset of a longitudinal study of n = 86 individuals in low-income, predominantly African American, neighborhoods in Detroit, MI, USA. The study addressed the following research questions: (1) did self-reported use and perceived value of nature change during, vs. prior to, the pandemic; (2) did perceived access to outdoor spaces buffer people against mental health issues such as stress, anxiety and depression symptoms; or (3) did objectively measured quality of nature views from home buffer people against mental health issues, taking into account relevant covariates and pandemic experiences (e.g., loss of employment, death of a friend/relative)? While attitudes to nature improved slightly from pre- to during the pandemic, we also observed significant decreases in most types of outdoor physical activity and passive enjoyment of nature (e.g., smelling plants/rain). We found a positive association between visibility of greenspace and perceived stress and anxiety, which not only contradicts previous research findings, but was especially surprising given that overall there was a decrease in perceived stress from 2019–2020. We did not detect associations between perceived access/use of nature and mental health. However, higher depressive symptoms were associated with exposure to more COVID-19-related stressors (lost employment, death of friends from COVID-19, etc.). Taken together, our results indicate that COVID-19 may serve to prolong or exacerbate mental health issues, rather than create them, in this population and that low quality greenspace may perhaps limit the ability for nature view to buffer mental health during the pandemic.

Trio-based whole-exome sequence (WES) data have established confident genetic diagnoses in ∼40% of previously undiagnosed individuals recruited to the Deciphering Developmental Disorders (DDD) study. Here we aim to use the breadth of phenotypic information recorded in DDD to augment diagnosis and disease variant discovery in probands. Median Euclidean distances (mEuD) were employed as a simple measure of similarity of quantitative phenotypic data within sets of ≥10 individuals with plausibly causative de novo mutations (DNM) in 28 different developmental disorder genes. 13/28 (46.4%) showed significant similarity for growth or developmental milestone metrics, 10/28 (35.7%) showed similarity in HPO term usage, and 12/28 (43%) showed no phenotypic similarity. Pairwise comparisons of individuals with high-impact inherited variants to the 32 individuals with causative DNM in ANKRD11 using only growth z-scores highlighted 5 likely causative inherited variants and two unrecognized DNM resulting in an 18% diagnostic uplift for this gene. Using an independent approach, naive Bayes classification of growth and developmental data produced reasonably discriminative models for the 24 DNM genes with sufficiently complete data. An unsupervised naive Bayes classification of 6,993 probands with WES data and sufficient phenotypic information defined 23 in silico syndromes (ISSs) and was used to test a “phenotype first” approach to the discovery of causative genotypes using WES variants strictly filtered on allele frequency, mutation consequence, and evidence of constraint in humans. This highlighted heterozygous de novo nonsynonymous variants in SPTBN2 as causative in three DDD probands.

Premise of research. Flower color polymorphisms provide a type of variability from which floral evolution can occur. Identifying factors that facilitate such variability within populations is a nec...

Dendritic cell (DC) lectins mediate the recognition, uptake, and processing of antigens, but they can also be coopted by pathogens for infection. These distinct activities depend upon the routing of antigens within the cell. Antigens directed to endosomal compartments are degraded, and the peptides are presented on major histocompatibility complex class II molecules, thereby promoting immunity. Alternatively, HIV-1 can avoid degradation, as virus engagement with C-type lectin receptors (CLRs), such as DC-SIGN (DC-specific ICAM-3–grabbing nonintegrin) results in trafficking to surface-accessible invaginated pockets. This process appears to enable infection of T cells in trans . We sought to explore whether antigen fate upon CLR-mediated internalization was affected by antigen physical properties. To this end, we employed the ring-opening metathesis polymerization to generate glycopolymers that each display multiple copies of mannoside ligand for DC-SIGN, yet differ in length and size. The rate and extent of glycopolymer internalization depended upon polymer structure—longer polymers were internalized more rapidly and more efficiently than were shorter polymers. The trafficking, however, did not differ, and both short and longer polymers colocalized with transferrin-labeled early endosomes. To explore how DC-SIGN directs larger particles, such as pathogens, we induced aggregation of the polymers to access particulate antigens. Strikingly, these particulate antigens were diverted to the invaginated pockets that harbor HIV-1. Thus, antigen structure has a dramatic effect on DC-SIGN–mediated uptake and trafficking. These findings have consequences for the design of synthetic vaccines. Additionally, the results suggest strategies for targeting DC reservoirs that harbor viral pathogens.