Feasibility of Universal Screening for Preeclampsia Risk and Aspirin Recommendation in the Ultrasound Unit.

OBJECTIVE: To evaluate the feasibility and impact of using the first-trimester ultrasound visit to identify and counsel women at increased risk of preeclampsia about the benefits of low-dose aspirin (LDA) for preventing preeclampsia. We also assessed patient-reported utilization of LDA, perceived risk for preeclampsia, and clinical outcomes. STUDY DESIGN: Women presenting for routine first-trimester nuchal-translucency (NT) ultrasounds were screened for clinical preeclampsia risks using a self-administered risk assessment. Women at moderate or high risk for preeclampsia were counseled to take LDA, if not already taking it. LDA utilization and perceived risk for preeclampsia were assessed during the second-trimester ultrasound. Factors associated with LDA utilization were analyzed. Pregnancy outcomes were compared between those who used LDA and those who did not. RESULTS: Slightly more than 20% of patients (765/3,669) screened at increased risk for developing preeclampsia. Of those, 67.8% (519/765) had not received LDA recommendations from their referring obstetrician and 97 had not been taking LDA despite being advised to do so. Combined, 94.6% (583/616) of these patients eligible to start LDA prophylaxis received the indicated counseling during the ultrasound visit. A total of 61.4% (358/583) of women completed the follow-up form and of those 77.9% (279/358) reported taking LDA. Screening at increased risk for preeclampsia and perception of increased risk were positively associated with LDA utilization, whereas concerns for LDA safety were negatively associated with use. African American/Black patients and Medicaid recipients were less likely to use LDA. Pregnancy outcomes were similar between those who used LDA and those who did not. CONCLUSION: Assessing preeclampsia risk and counseling patients about LDA at the time of the NT ultrasound are feasible in the ultrasound unit and led to good LDA utilization among women at increased risk for preeclampsia. This intervention may standardize patient care and help close the disparity in maternal health. KEY POINTS: · A simple intervention captured 2/3 of eligible patients.. · Aspirin utilization rate was good after the intervention.. · Screening high risk for preeclampsia and self-perception of risk correlated with aspirin use..

Knowledge of the Human Papillomavirus Vaccine and Willingness to Accept Vaccination in the Postpartum Period.

OBJECTIVES: Human papillomavirus (HPV) vaccines prevent cervical cancer. The inpatient postpartum period presents a unique window for vaccination. Our study investigates HPV vaccine knowledge, barriers to vaccination, and willingness to get vaccinated during inpatient postpartum care. MATERIALS AND METHODS: We conducted a cross-sectional survey of 147 participants, age 18 to 26, who delivered at our institution between November 1, 2019, and April 30, 2020. Participants completed a questionnaire that included demographics, vaccine knowledge, hesitancies, and willingness to vaccinate. We used descriptive statistics and compared groups with chi-square or Wilcoxon rank sum for categorical variables and t-test for continuous variables. RESULTS: Of the 147 patients, 58 (39.46%) were fully vaccinated against HPV and 89 (60.54%) of participants were unvaccinated or partially vaccinated. There was a greater proportion of African American and Asian participants among unvaccinated women (28.1% vs 20.7% and 16.9% vs 1.7%, respectively). Most unvaccinated participants (52.9%) were willing to get vaccinated in the postpartum unit. Both vaccinated and unvaccinated groups were similarly aware that the HPV vaccine prevents cervical and oropharyngeal cancers and genital warts. The top barrier to future vaccination was forgetting to complete the vaccination series. CONCLUSIONS: Most women were not fully vaccinated but were willing to receive their first dose while in the postpartum unit. African American women were less likely to be vaccinated and expressed more unwillingness to accept vaccination. We identified barriers to HPV vaccination that can be tackled with the initiation of inpatient postpartum vaccination.

Vitamin A and ß-carotene in pregnant and breastfeeding post-bariatric women in an urban population.

Background As breastfeeding awareness and social acceptance are increased, maternal nutritional deficiency requires more investigation. Methods A prospective cohort study was conducted to determine if vitamin A deficiency is more common in pregnant, lactating post-bariatric surgery women in an inner city population. Antepartum, women after bariatric surgery and controls with no history of malabsorption were recruited. Third trimester, postpartum maternal blood and cord blood were collected as well as three breast milk samples: colostrum, transitional and mature milk. A nutritional survey of diet was completed. Each serum sample was analyzed for total retinol and ß-carotene; breast milk samples were analyzed for retinol and retinyl esters, total retinol and ß-carotene. Results Fifty-three women after bariatric surgery and 66 controls were recruited. Postpartum serum retinol was significantly higher in women after bariatric surgery in the univariate analysis (P<0.0001) and confirmed in the multiple linear mixed model (P=0.0001). Breast milk colostrum retinol and transitional milk total retinol were significantly greater in the bariatric surgery group in the univariate analysis (P=0.03 and P=0.02, respectively), but not after adjusting for confounders. Serum ß-carotene in the third trimester and postpartum were lower (P<0.0001 and P=0.003, respectively) in the bariatric surgery group but not after adjusting for confounders. Vitamin A deficiency was high in both groups in serum and breast milk samples. Conclusion Nutritional deficiencies in breastfeeding women after bariatric surgeries may in fact be less common than in control women in an inner city.

Induction of labor using one dose vs multiple doses of misoprostol: a randomized controlled trial.

BACKGROUND: Misoprostol is a common agent that is used to ripen the cervix and induce labor, yet there is no clear evidence of the optimal number of doses needed to achieve a higher rate of vaginal delivery. OBJECTIVE: Our primary objective was to compare the rate of vaginal delivery within 24 hours between a 1-dose and a multiple-dose regimen of misoprostol for the induction of labor. STUDY DESIGN: A randomized controlled trial was conducted from March 2016 to March 2017 that compared a single dose to up to 4 doses of misoprostol. Randomization was stratified by parity. Women with a singleton pregnancy ≥37 weeks gestation with intact membranes who had been admitted for labor induction with a Bishop score ≤6 were included. Our primary outcome was the rate of vaginal delivery within 24 hours. Secondary outcomes included time to vaginal delivery, cesarean delivery rate, and maternal and neonatal morbidity. Based on a power of 80%, an alpha of .05, and the assumption that 50% of women in the multiple-misoprostol group would deliver vaginally in 24 hours, a sample size of 220 patients was needed to detect a 20% increase in vaginal delivery rate within 24 hours in the 1-misoprostol group. Continuous variables were compared with the use of the Mann-Whitney test. Categoric variables were compared with the use of the Fisher's exact test. Probability values <.05 were considered statistically significant. RESULTS: Two hundred fifty women were assigned randomly. Demographics and clinical characteristics were similar between groups. In the univariate analysis, there was no difference in the rate of vaginal delivery within 24 hours between the 1-misoprostol group and the multiple-dose group (41.7% vs 44.7%, respectively; P=.698) or time to vaginal delivery (1187 min vs 1321 min, respectively; P=.202). The 1-misoprostol group had a greater cesarean delivery rate (35.8% vs 22.8%; P=.034). In a Poisson regression that controlled for Bishop score before the initiation of oxytocin, parity, gestational age, body mass index, estimated fetal weight, artificial rupture of membrane at <6 cm, and Foley balloon placement, the treatment group was no longer associated with cesarean delivery rate. Instead, a Bishop score of <4 before the initiation of oxytocin and nulliparity were associated significantly with cesarean delivery rate. CONCLUSION: In this first randomized controlled trial in the literature to compare a single with a multiple dosing of misoprostol, we found that the 1-dose regimen is an acceptable alternative for the induction for labor, especially for multiparous women and for patients with a Bishop score >4 after the first dose.

Whiteboard Use in Labor and Delivery: A Tool to Improve Patient Knowledge of the Name of the Delivery Provider and Satisfaction with Care.

Introduction The impact of whiteboard use in labor rooms has not previously been studied. This quality improvement study aimed to evaluate patient knowledge of their delivering physician's name and the change in patient satisfaction after the implementation of a whiteboard in labor rooms. Methods A multidisciplinary team designed a dry-erase whiteboard prompting care providers to record their names, roles and patient care information. A questionnaire was administered to patients before and after the whiteboard implementation. Patients who had a planned cesarean or vaginal birth within 1 h of admission were excluded. Categorical variables were compared using Chi square and Fisher's exact tests. A multivariable logistic regression was performed to control for confounders. Results 191 patients completed the questionnaires. Although patients were not randomized, the pre-and post-intervention groups were similar. Post-intervention, we found a significant increase in recalling the delivery resident's name [21/101 (20.8%) vs. 33/90 (36.7%), p = 0.016] and a non-significant increase in recalling the name of the attending and nurse [19/101 (18.8%) vs. 23/90 (25.6%), p = 0.296; 46/101 (45.5%) vs. 53/90 (58.9%), p = 0.082]. Post-intervention, patient satisfaction with care was significantly higher [83/101 (82.2%) vs. 83/89 (93.3%), p = 0.028]. Knowledge of the delivery resident's name was associated with higher patient satisfaction [115/137 (84%) vs. 51/53 (96%), p = 0.03] and attendance of the postpartum care visit [50.4% (69/137) vs. 64.8% (35/54), p = 0.049]. Discussion The use of a well-designed whiteboard increases laboring patients' knowledge of their delivery physician's name and may improve patient satisfaction with care on Labor and Delivery.

Social networks of HIV-positive women and their association with social support and depression symptoms.

Social support is important to the mental health and well-being of HIV-positive women. Limited information exists about the specific structure and composition of HIV-positive women's support networks or associations of these network properties with mental health outcomes. In this pilot study, the authors examine whether support network characteristics were associated with depressive symptoms. Survey and network data were collected from HIV-positive women (N = 46) via a web-based survey and an iPad application in August 2012. Data were analyzed using multivariate linear regression models in SAS. Depressive symptoms were positively associated with a greater number of doctors in a woman's network; having more HIV-positive network members was associated with less symptom reporting. Women who reported more individuals who could care for them had more family support. Those who reported feeling loved were less likely to report disclosure stigma. This work highlighted that detailed social network data can increase our understanding of social support so as to identify interventions to support the mental health of HIV-positive women. Most significant is the ongoing need for support from peers.

Prevalence of high-risk cervical human papillomavirus and squamous intraepithelial lesion in Nigeria.

OBJECTIVE: The prevalence of cervical cancer and high-risk human papillomavirus (HPV) in Nigerian women remains poorly studied. Our objective was to estimate the prevalence of high-risk HPV and associated squamous intraepithelial lesions (SILs) in Nigeria. METHODS: After institutional review board approval, data collection was performed by volunteers of FaithCare, Inc, between 2004 and 2008 in 3 regions of Nigeria (Okene, Katari, and Abuja). Demographic data and ThinPrep Pap smears (Cytyc, Marlborough, MA) were collected from 410 women. Pap smears were analyzed for both the presence of SIL and HPV DNA. RESULTS: The prevalence of high-risk HPV and SIL was 15.6% and 6.8%, respectively. Of the 28 abnormal Pap tests, 42.9% had atypical squamous cells of undetermined significance, 39.3% had low-grade SIL, 14.3% had high-grade SIL, and 3.6% had atypical glandular cells. There was a strong association between high-risk HPV and SIL in both the combined (p < .001) and individual group data (p < .001, p = .013, and p < .001 for Okene, Abuja, and Katari, respectively). However, there were no statistically significant correlations between either high-risk HPV or presence of SIL and known risk factors including age, history of sexually transmitted disease, and the number of sexual partners. There was also no statistical difference in the prevalence of high-risk HPV and SIL among the 3 locations. CONCLUSIONS: A strong association exists between high-risk HPV and SIL. The prevalence of cervical high-risk HPV and SIL, however, did not vary in the 3 different locations and is consistent with reports from other regions in Africa.

Perception of the impact of maternal weight on pregnancy outcomes in overweight and obese women.

OBJECTIVE: The purpose of this study was to assess and compare knowledge, self-awareness, and accuracy of perceived risks and weight status among overweight and obese women. METHODS: This study was a secondary analysis of a cross-sectional questionnaire study of overweight and obese pregnant women who sought a routine first-trimester screening ultrasound. Those with a pre-pregnancy body mass index (BMI) ≥25 kg/m2 (calculated using self-reported height and weight) were included. Perceived associations between estimated weight category and risk of pregnancy complications were assessed and compared in the overweight and obese groups. The perceived weight category was compared to an estimated weight category. A logistic regression identified the demographic and medical factors associated with correct identification of risk factors. RESULTS: A total of 169 participants (88 overweight; 81 obese) were included. Most participants believed their weight did not impact the ultrasound detection of a fetal malformation (92.1% overweight vs. 55.6% obese, p < .01). Few participants associated their weight with pregnancy-related problems (6.8% overweight vs. 24.7% obese, p < .01). Most participants did not associate their weight with specific maternal complications (72.7% overweight vs. 45.7% obese, p < .01) and fetal complications (83.0% overweight vs. 71.6% obese, p = .08). More obese than overweight women underestimated their weight category (64.4% vs 41.3% overweight, p = .01). Women who correctly estimated their weight status, non-Hispanic participants, and those with a history of depression or at least one maternal co-morbidity were more likely to associate their weight with increased risk for pregnancy-related problems. CONCLUSION: Although more obese than overweight women associated excess weight with pregnancy complications, both groups underestimated the impact on their pregnancies. Targeted educational programs are needed to improve the risk perception of these populations prior to pregnancy with the goal of improving their weight statuses and pregnancy outcomes.

Perceived racism or racial discrimination and the risk of adverse obstetric outcomes: a systematic review.

BACKGROUND: Racial disparities are differences among distinct subgroups of the human species; biologically, there are no scientifically proven reasons for them to exist. OBJECTIVE: To assess the impact of racism or racial discrimination on obstetric outcomes. DESIGN AND SETTING: Systematic review conducted at a tertiary/academic hospital. METHODS: The Cochrane Library, SCOPUS/EMBASE, PubMed, Web of Science and ClinicalTrials.gov databases were searched from inception to June 2020. Studies presenting any type of racial discrimination, or any manifestation of racism that was perceived by women of any age in an obstetric scenario were included. Studies that only assessed racial disparities without including direct racism were excluded. The secondary outcomes evaluated included quality of antenatal care, intra and postpartum care, preterm birth and birthweight. The Risk of Bias In Non-randomized Studies - of Interventions (ROBINS-I) scale was used to assess the quality of evidence from non-randomized studies. RESULTS: A total of 508 records were retrieved and 29 were selected for qualitative synthesis. No meta-analysis could be performed due to the high heterogeneity across studies. Perceived racism was associated as a risk factor in 7/10 studies focusing on pregnancy and postpartum maternal outcomes, five studies on preterm birth, one study on small for gestational age and two studies on low birthweight. Overall, among the 29 studies, the risk of bias was classified as moderate. CONCLUSIONS: Perceived racism presented an association with poor obstetric outcomes. Anti-racist measures are needed in order to address the problems that are causing patients to perceive or experience racism. SYSTEMATIC REVIEW REGISTRATION: PROSPERO database, CRD42020194382.

Corrigendum: Children and Adults With Mild COVID-19: Dynamics of the Memory T Cell Response Up to 10 Months.

[This corrects the article DOI: 10.3389/fimmu.2022.817876.].

Children and Adults With Mild COVID-19: Dynamics of the Memory T Cell Response up to 10 Months.

Background: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has led to considerable morbidity/mortality worldwide, but most infections, especially among children, have a mild course. However, it remains largely unknown whether infected children develop cellular immune memory. Methods: To determine whether a memory T cell response is being developed, we performed a longitudinal assessment of the SARS-CoV-2-specific T cell response by IFN-γ ELISPOT and activation marker analyses of peripheral blood samples from unvaccinated children and adults with mild-to-moderate COVID-19. Results: Upon stimulation of PBMCs with heat-inactivated SARS-CoV-2 or overlapping peptides of spike (S-SARS-CoV-2) and nucleocapsid proteins, we found S-SARS-CoV-2-specific IFN-γ T cell responses in infected children (83%) and adults (100%) that were absent in unexposed controls. Frequencies of SARS-CoV-2-specific T cells were higher in infected adults, especially several cases with moderate symptoms, compared to infected children. The S-SARS-CoV-2 IFN-γ T cell response correlated with S1-SARS-CoV-2-specific serum antibody concentrations. Predominantly, effector memory CD4+ T cells of a Th1 phenotype were activated upon exposure to SARS-CoV-2 antigens. Frequencies of SARS-CoV-2-specific T cells were significantly reduced at 10 months after symptom onset, while S1-SARS-CoV-2-specific IgG concentrations were still detectable in 90% of all children and adults. Conclusions: Our data indicate that an antigen-specific T cell and antibody response is developed after mild SARS-CoV-2 infection in children and adults. It remains to be elucidated to what extent this SARS-CoV-2-specific response can contribute to an effective recall response after reinfection.

Ethnic Disparities in Coronavirus Disease 2019 after the Implementation of Universal Screening in Hartford, Connecticut.

Objective The aim of this article was to estimate the prevalence of coronavirus disease 2019 (COVID-19) in Connecticut, examine racial/ethnic disparities, and assess pregnancy outcomes in pregnant women following the implementation of universal screening for the virus. Materials and methods This is a retrospective cohort study of all obstetric patients admitted to our labor and delivery unit during the first 4 weeks of implementation of universal screening of COVID-19. Viral studies were performed in all neonates born to mothers with severe acute respiratory syndrome coronavirus 2. We calculated the prevalence of COVID-19, compared the baseline characteristics and pregnancy outcomes between those who tested positive and negative for the virus, and determined the factors associated with COVID-19. Results A total of 10 (4.6%) of 220 women screened positive for the virus. All were asymptomatic. Week 1 had the highest prevalence of infection, nearing 8%. No neonates were infected. Hispanics were more likely to test positive (odds ratio: 10.23; confidence interval: [2.71-49.1], p = 0.001). Obstetric and neonatal outcomes were similar between the groups ( p > 0.05). Conclusion Although the rate of asymptomatic COVID-19 was low, ethnic disparities were present with Hispanics being more likely to have the infection. Key Points 4.6% of pregnant women in labor and delivery tested positive for COVID-19 while being asymptomatic.Hispanic women were more likely to test positive for severe acute respiratory syndrome coronavirus 2.Pregnancy outcomes were similar between COVID-19 positive and negative women.No vertical transmission was detected.

Releasing the brakes of tumor immunity with anti-PD-L1 and pushing its accelerator with L19-IL2 cures poorly immunogenic tumors when combined with radiotherapy.

BACKGROUND: Poorly immunogenic tumors are hardly responsive to immunotherapies such as immune checkpoint blockade (ICB) and are, therefore, a therapeutic challenge. Combination with other immunotherapies and/or immunogenic therapies, such as radiotherapy (RT), could make these tumors more immune responsive. We have previously shown that the immunocytokine L19-IL2 combined with single-dose RT resulted in 75% tumor remission and a 20% curative abscopal effect in the T cell-inflamed C51 colon carcinoma model. This treatment schedule was associated with the upregulation of inhibitory immune checkpoint (IC) molecules on tumor-infiltrating T cells, leading to only tumor growth delay in the poorly immunogenic Lewis lung carcinoma (LLC) model. METHODS: We aimed to trigger curative therapeutic responses in three tumor models (LLC, C51 and CT26) by "pushing the accelerator" of tumor immunity with L19-IL2 and/or "releasing the brakes" with ICB, such as antibodies directed against cytotoxic T lymphocyte associated protein 4 (CTLA-4), programmed death 1 (PD-1) or its ligand (PD-L1), combined with single-dose RT (10 Gy or 5 Gy). Primary tumor endpoint was defined as time to reach four times the size of tumor volume at start of treatment (4T×SV). Multivariate analysis of 4T×SV was performed using the Cox proportional hazards model comparing each treatment group with controls. Causal involvement of T and natural killer (NK) cells in the anti-tumor effect was assessed by in vivo depletion of T, NK or both cell populations. Immune profiling was performed using flow cytometry on single cell suspensions from spleens, bone marrow, tumors and blood. RESULTS: Combining RT, anti-PD-L1 and L19-IL2 cured 38% of LLC tumors, which was both CD8+ T and NK cell dependent. LLC tumors were resistant to RT +anti-PD-L1 likely explained by the upregulation of other IC molecules and increased T regulatory cell tumor infiltration. RT+L19-IL2 outperformed RT+ICB in C51 tumors; effects were comparable in CT26 tumors. Triple combinations were not superior to RT+L19-IL2 in both these models. CONCLUSIONS: This study demonstrated that combinatorial strategies rationally designed on biological effects can turn immunotherapy-resistant tumors into immunologically responsive tumors. This hypothesis is currently being tested in the international multicentric randomized phase 2 trial: ImmunoSABR (NCT03705403).

A novel co-culture assay to assess anti-tumor CD8+ T cell cytotoxicity via luminescence and multicolor flow cytometry.

T cell immunotherapies have shown great promise in patients with advanced cancer disease, revolutionizing treatment. T cell cytotoxicity is crucial in its efficacy, therefore developing ex vivo methods testing tumor and T cell interactions is pivotal. Increasing efforts have been made in developing co-culture assays with sophisticated materials and platforms aiming to mimic the tumor microenvironment (TME), but its complexity makes it difficult to develop the ideal model. In this study, we developed a simple co-culture assay, reproducible in any lab, but respecting the multicellular nature of the TME. Our goal is to combine in a single assay well-established techniques such as a luciferase assay for target cell viability analysis, a CD107a degranulation assay, and multicolor flow cytometry for the detection of cytokines and cytotoxicity markers. Cell suspensions of whole spleens and tumors containing splenic or tumor-infiltrating effector T cells of mice bearing Lewis lung carcinoma (LLC) or CT26 colon carcinoma tumors treated with radiation alone or in combination with immunotherapies were used for co-culture. LLC and CT26 cell lines transduced with the firefly luciferase gene were used as target cells. We demonstrated that splenocytes and tumor-infiltrating T cells derived from mice treated with combination therapy were able to kill approximately 50% of target cells after 48 h of co-culture. This effect was tumor cell-specific and dependent on CD8+ T cells evidenced by in vitro CD8+ T cell depletion. Flow cytometry demonstrated increased expression of CD107a and production of granzyme B, IFNγ, and TNFα by CD8+ T cells. Our co-culture assay is therefore suitable as proof of principle for in vivo therapeutic studies testing immunotherapies, and specifically to assess the involvement of cytotoxic CD8+ T cells in treatment response in LLC and CT26 tumor models. We also propose this assay as an ex vivo platform for high-throughput screening of immunomodulating agents to be tested in these two murine tumor models. This assay can be adapted to other tumor models after optimizations.

Prenatal Sacrococcygeal Teratoma Diagnosed in a Fetus with Partial Trisomy 13q22.

Sacrococcygeal teratoma is a rare neoplasm that arises from a totipotent stem cell in Henson's node. It has rarely been associated with chromosomal abnormalities. We present a unique case of a 25-year-old primigravida at 19 weeks and 5 days of gestation found to have an exophytic complex mass with cystic and solid components in the sacral region. This mass was consistent with a sacrococcygeal teratoma. The patient had originally declined genetic screening. After the ultrasound and genetic counseling, she opted to have cell-free fetal DNA screening that was positive for Trisomy 13. Amniocentesis was performed to confirm the diagnosis. The karyotype demonstrated an abnormality of chromosome 13 and microarray demonstrated a complex structural abnormality of chromosome 13 with large regions of copy number gain. The patient underwent a dilation and evacuation at 23 weeks and 2 days. No fetal autopsy was done. This is a case of a prenatally diagnosed sacrococcygeal teratoma associated with Trisomy 13. It illustrates the diagnostic importance of amniocentesis in setting of fetal anatomical abnormalities on ultrasound. For patients who are reluctant to undergo amniocentesis, cell-free DNA results may provide the additional evidence of the need for diagnostic tests.

HIF-1α and HIF-2α Differently Regulate the Radiation Sensitivity of NSCLC Cells.

The hypoxia-inducible transcription factors (HIF)-1/2α are the main oxygen sensors which regulate the adaptation to intratumoral hypoxia. The aim of this study was to assess the role of the HIF proteins in regulating the radiation response of a non-small cell lung cancer (NSCLC) in vitro model. To directly assess the unique and overlapping functions of HIF-1α and HIF-2α, we use CRISPR gene-editing to generate isogenic H1299 non-small cell lung carcinoma cells lacking HIF-1α, HIF-2α or both. We found that in HIF1 knockout cells, HIF-2α was strongly induced by hypoxia compared to wild type but the reverse was not seen in HIF2 knockout cells. Cells lacking HIF-1α were more radiation resistant than HIF2 knockout and wildtype cells upon hypoxia, which was associated with a reduced recruitment of γH2AX foci directly after irradiation and not due to differences in proliferation. Conversely, double-HIF1/2 knockout cells were most radiation sensitive and had increased γH2AX recruitment and cell cycle delay. Compensatory HIF-2α activity in HIF1 knockout cells is the main cause of this radioprotective effect. Under hypoxia, HIF1 knockout cells uniquely had a strong increase in lactate production and decrease in extracellular pH. Using genetically identical HIF-α isoform-deficient cells we identified a strong radiosensitizing of HIF1, but not of HIF2, which was associated with a reduced extracellular pH and reduced glycolysis.

Critical Contribution of NK Group 2 Member D Expressed on Invariant Natural Killer T Cells in Concanavalin A-Induced Liver Hepatitis in Mice.

Natural killer group 2D (NKG2D) is a well-characterized activating receptor expressed on many immune cells, including invariant natural killer T (iNKT) cells. These cells were shown to be responsible of liver injury in the model of concanavalin A (Con A)-induced hepatitis, considered to be an experimental model of human autoimmune hepatitis. In this study, we investigated whether NKG2D plays a role in the hepatitis induced by iNKT cell-mediated immune response to Con A. By using killer cell lectin-like receptor subfamily K, member 1 deficient (Klrk1-/-) mice, we found that the absence of NKG2D reduced the hepatic injury upon Con A administration. This was not due to an intrinsic functional defect of NKG2D-deficient iNKT cells as mice missing NKG2D have normal distribution and function of iNKT cells. Furthermore, increased resistance to Con A-induced hepatitis was confirmed using neutralizing anti-NKG2D antibodies. The reduced pathogenic effect of Con A in the absence of NKG2D correlates with a reduction in pathogenic cytokine production and FAS-Ligand (FAS-L) expression by iNKT cells. We also found that Con A administration led to an increase in the retinoic acid early inducible (RAE-1) surface expression on wild-type hepatocytes. Finally, we found that Con A has no direct action on FAS-L expression or cytokine production by iNKT cells and thus propose that NKG2D-L expression on stressed hepatocytes promote cytotoxic activity of iNKT cells via its interaction with NKG2D contributing to hepatic injury. In conclusion, our results highlight NKG2D as an essential receptor required for the activation of iNKT cells in Con A-induced hepatitis and indicate that it represents a potential drug target for prevention of autoimmune hepatitis.

The immunocytokine L19-IL2: An interplay between radiotherapy and long-lasting systemic anti-tumour immune responses.

Recently, we have shown that the administration of the tumour-targeted antibody-based immunocytokine L19-IL2 after radiotherapy (RT) resulted in synergistic anti-tumour effect. Here we show that RT and L19-IL2 can activate a curative abscopal effect, with a long-lasting immunological memory. Ionizing radiation (single dose of 15Gy, 5 × 2Gy or 5 × 5Gy) was delivered to primary C51 colon tumour-bearing immunocompetent mice in combination with L19-IL2 and response of secondary non-irradiated C51 or CT26 colon tumours was evaluated. 15Gy + L19-IL2 triggered a curative (20%) abscopal effect, which was T cell dependent. Moreover, 10Gy + L19-IL2 treated and cured mice were re-injected after 150 days with C51 tumour cells and tumour uptake was assessed. Age-matched controls (matrigel injected mice treated with 10Gy + L19-IL2, mice cured after treatment with surgery + L19-IL2 and mice cured after high dose RT 40Gy + vehicle) were included. Several immunological parameters in blood, tumours, lymph nodes and spleens were investigated. Treatment with 10Gy + L19-IL2 resulted in long-lasting immunological memory, associated with CD44+CD127+ expression on circulating T cells. This combination treatment can induce long-lasting curative abscopal responses, and therefore it has also great potential for treatment of metastatic disease. Preclinical findings have led to the initiation of a phase I clinical trial (NCT02086721) in our institute investigating stereotactic ablative radiotherapy with L19-IL2 in patients with oligometastatic solid tumours.

Perceived racism or racial discrimination and the risk of adverse obstetric outcomes: a systematic review

ABSTRACT BACKGROUND: Racial disparities are differences among distinct subgroups of the human species; biologically, there are no scientifically proven reasons for them to exist. OBJECTIVE: To assess the impact of racism or racial discrimination on obstetric outcomes. DESIGN AND SETTING: Systematic review conducted at a tertiary/academic hospital. METHODS: The Cochrane Library, SCOPUS/EMBASE, PubMed, Web of Science and ClinicalTrials.gov databases were searched from inception to June 2020. Studies presenting any type of racial discrimination, or any manifestation of racism that was perceived by women of any age in an obstetric scenario were included. Studies that only assessed racial disparities without including direct racism were excluded. The secondary outcomes evaluated included quality of antenatal care, intra and postpartum care, preterm birth and birthweight. The Risk of Bias In Non-randomized Studies - of Interventions (ROBINS-I) scale was used to assess the quality of evidence from non-randomized studies. RESULTS: A total of 508 records were retrieved and 29 were selected for qualitative synthesis. No meta-analysis could be performed due to the high heterogeneity across studies. Perceived racism was associated as a risk factor in 7/10 studies focusing on pregnancy and postpartum maternal outcomes, five studies on preterm birth, one study on small for gestational age and two studies on low birthweight. Overall, among the 29 studies, the risk of bias was classified as moderate. CONCLUSIONS: Perceived racism presented an association with poor obstetric outcomes. Anti-racist measures are needed in order to address the problems that are causing patients to perceive or experience racism. SYSTEMATIC REVIEW REGISTRATION: PROSPERO database, CRD42020194382

Combining radiotherapy with immunotherapy: the past, the present and the future.

The advent of immunotherapy is currently revolutionizing the field of oncology, where different drugs are used to stimulate different steps in a failing cancer immune response chain. This review gives a basic overview of the immune response against cancer, as well as the historical and current evidence on the interaction of radiotherapy with the immune system and the different forms of immunotherapy. Furthermore the review elaborates on the many open questions on how to exploit this interaction to the full extent in clinical practice.