Identification and characterization of T-cell receptors with therapeutic potential showing conserved specificity against all SARS-CoV 2 strains.

INTRODUCTION: Treatment of severe COVID-19 disease can be challenging in immunocompromized patients due to newly emerging virus variants of concern (VOC) escaping the humoral response. Thus, T cells recognizing to date unmutated epitopes are not only relevant for patients' immune responses against VOC, but might also serve as a therapeutic option for patients with severe COVID-19 disease in the future, e.g. following allogenic stem cell transplantation. METHODS: To this purpose, the activation, cytokine profile and specificity of T-cell clones against unmutated and omicron Spike (S)-protein was analyzed, HLA restriction was determined and most promising T-cell receptor (TCR) was introduced into allogeneic T cells via CRISPR/Cas9-mediated orthotopic TCR replacement. Finally, T-cell responses of engineered T cells was determined and durability of the TCR replacement measured. PERSPECTIVE: SARS-CoV-2 specific engineered T cells recognizing a genomically stable region of the S-protein of all SARS-CoV 2 variants were successfully generated. Such transgenic T cells exhibit favorable effector functions and provide a treatment option of immunocompromised COVID-19 patients.

Risk Factors of Patients With Diarrhea for Having Clostridioides (Clostridium) difficile Infection.

Nosocomial infections with Clostridioides (Clostridium) difficile have become an emergent health threat. We sought to define risk factors for a C. difficile infection (CDI) beyond the widely known ones, such as antibiotic use and prior hospital stay. We therefore focused on a group of patients with diarrhea in order to identify risk factors for C. difficile infection among this symptomatic cohort. A total of 121 hospitalized patients from Seesen/Germany with diarrhea were included who submitted a stool sample and were interviewed about their socio-demographic background, lifestyle and state of health using a standardized questionnaire. Antibiotic potential of diuretics was examined by agar diffusion test. C. difficile was identified in 29 patients resulting in a prevalence of 24.0%. The infection was hospital-acquired in most cases (p < 0.001, 82.1%; n = 23/28, versus 29/91, 31.9%). The generally accepted risk factor previous antibiotic use was confirmed in this study (p = 0.002, n = 23/28 CDI patients, 82.1%, versus n = 44/91 non-CDI patients, 48.4%). The following additional risk factors were identified: regular consumption of proton pump inhibitors; PPI (p = 0.011, n = 24/29, 82.8% vs. n = 52/92, 56.5%), CDI patients ate less vegetables (p = 0.001, n = 12/29, 41.4% vs. 69/92, 75.0%). The intake of the diuretic agent torasemid in patients with CDI (p = 0.005, n = 18/29, 62.1%) was higher than in patients without (n = 30/92, 32.6%). More patients with CDI had to undergo a surgery in the previous year (p = 0.022, n = 13/29, 44.8% vs. n = 21/92, 22.8%) and held more birds (p = 0.056, n = 4/29, 13.8%) than individuals of the negative group (n = 3/92, 3.3%). In conclusion, although no antibiotic potential was detected in diuretics, especially torasemid seems to have significant influence for the occurrence of a CDI as well as a nutrition poor in vegetables. A diet rich in vegetables represented a fourfold lower risk for a CDI (OR 0.240, CI (0.0720 - 0.796]).

The Missing Baby Bust: The Consequences of the COVID-19 Pandemic for Contraceptive Use, Pregnancy, and Childbirth Among Low-Income Women.

Multiple episodes in US history demonstrate that birth rates fall in response to recessions. However, the 2020 COVID-19 recession differed from earlier periods in that employment and access to contraception and abortion fell, as reproductive health centers across the country temporarily closed or reduced their capacity. This paper exploits novel survey and administrative data to examine how reductions in access to reproductive health care during 2020 affected contraceptive efficacy among low-income women. Accounting for 2020's reductions in access to contraception and the economic slowdown, our results predict a modest decline in births of 1.1 percent in 2021 for low-income women. Further accounting for reductions in access to abortion implies that birth rates may even rise for low-income women. These results also suggest that already economically disadvantaged families disproportionately affected by the COVID-19 economy will experience a large increase in unplanned births. Supplementary Information: The online version contains supplementary material available at 10.1007/s11113-022-09703-9.

Successful treatment of COVID-19 infection with convalescent plasma in B-cell-depleted patients may promote cellular immunity.

Treatment with convalescent plasma has been shown to be safe in coronavirus disease in 2019 (COVID-19) infection, although efficacy reported in immunocompetent patients varies. Nevertheless, neutralizing antibodies are a key requisite in the fight against viral infections. Patients depleted of antibody-producing B cells, such as those treated with rituximab (anti-CD20) for hematological malignancies, lack a fundamental part of their adaptive immunity. Treatment with convalescent plasma appears to be of general benefit in this particularly vulnerable cohort. We analyzed clinical course and inflammation markers of three B-cell-depleted patients suffering from COVID-19 who were treated with convalescent plasma. In addition, we measured serum antibody levels as well as peripheral blood CD38/HLA-DR-positive T-cells ex vivo and CD137-positive T-cells after in vitro stimulation with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-derived peptides in these patients. We observed that therapy with convalescent plasma was effective in all three patients and analysis of CD137-positive T-cells after stimulation with SARS-CoV-2 peptides showed an increase in peptide-specific T-cells after application of convalescent plasma. In conclusion, we here demonstrate efficacy of convalescent plasma therapy in three B-cell-depleted patients and present data that suggest that while application of convalescent plasma elevates systemic antibody levels only transiently, it may also boost specific T-cell responses.

Human CD4+ T cells specific for dominant epitopes of SARS-CoV-2 Spike and Nucleocapsid proteins with therapeutic potential.

Since December 2019, Coronavirus disease-19 (COVID-19) has spread rapidly throughout the world, leading to a global effort to develop vaccines and treatments. Despite extensive progress, there remains a need for treatments to bolster the immune responses in infected immunocompromised individuals, such as cancer patients who recently underwent a haematopoietic stem cell transplantation. Immunological protection against COVID-19 is mediated by both short-lived neutralizing antibodies and long-lasting virus-reactive T cells. Therefore, we propose that T cell therapy may augment efficacy of current treatments. For the greatest efficacy with minimal adverse effects, it is important that any cellular therapy is designed to be as specific and directed as possible. Here, we identify T cells from COVID-19 patients with a potentially protective response to two major antigens of the SARS-CoV-2 virus, Spike and Nucleocapsid protein. By generating clones of highly virus-reactive CD4+ T cells, we were able to confirm a set of nine immunodominant epitopes and characterize T cell responses against these. Accordingly, the sensitivity of T cell clones for their specific epitope, as well as the extent and focus of their cytokine response was examined. Moreover, using an advanced T cell receptor (TCR) sequencing approach, we determined the paired TCR-αß sequences of clones of interest. While these data on a limited population require further expansion for universal application, the results presented here form a crucial first step towards TCR-transgenic CD4+ T cell therapy of COVID-19.

Do Adolescent Sexual and Reproductive Attitudes and Knowledge Predict Men and Women's Adult Sexual Partnerships?

PURPOSE: Adolescence is a key stage for forming knowledge and attitudes about sex and reproduction that may have long-term implications for adult sexual behaviors. Gender differences in experiences and socialization processes may affect the links between adolescent characteristics and adult behaviors. METHODS: By following adolescent virgins aged 15 years and older from wave I through wave IV of the National Longitudinal Study of Adolescent to Adult Health (n = 4,152), we test whether adolescent boys' and girls' knowledge about, and attitudes toward, sex and reproduction influence the number of lifetime different-sex sexual partners and the likelihood of having concurrent sexual partners in adulthood, using negative binomial regression and logistic regression, respectively. Models are run separately by gender. RESULTS: Men and women who reported greater physical benefits of sex as adolescents reported more lifetime different-sex sexual partners and were more likely to have concurrent sexual partners in adulthood. For women, adolescent perceptions of more social costs to sex were linked to fewer lifetime sexual partners, whereas greater birth control confidence was linked to more sexual partners. Women who more strongly felt that avoiding sexually transmitted infections was a hassle during adolescence were less likely to have concurrent sexual partners as adults, and men who were more knowledgeable about condoms during adolescence were more likely to have concurrent sexual partners. CONCLUSIONS: Adolescent knowledge and attitudes about sex, contraception, and reproduction have implications for adult sexual behavior, but different aspects emerge as salient for men and women.

Adolescent Fertility Attitudes and Childbearing in Early Adulthood.

Teens' attitudes about adolescent childbearing predict childbearing in the short term. If these attitudes reflect persistent goals and values, they may also be linked to later outcomes. To test long-term linkages, we analyze the association of adolescent fertility attitudes with actual and prospective fertility in adulthood using Waves I (1994-95) and IV (2007-08) of the National Longitudinal Study of Adolescent to Adult Health and focusing on men (N = 4,275) and women (N=4,418) without a teen birth. For women, we find that more negative teen attitudes predict lower hazards of a first birth up to around age 30 but that teens' attitudes are unrelated to planned childlessness among those who have not yet had children. Men's adolescent attitudes are unrelated to actual fertility or prospective intentions. For both men and women, more advantaged individuals are less likely to have had a child by around age 30; socioeconomic advantage is also related to postponement of childbearing rather than planned childlessness, though more so for women than men. We interpret the findings as evidence that, for girls, teens' attitudes toward adolescent childbearing capture an internalization of social schema about childbearing, childrearing, and sequencing with other life outcomes but do not reflect overall preferences about having children. More work is needed to understand the psychosocial factors that influence men's fertility.

Teen Girls' Reproductive Attitudes and the Timing and Sequencing of Sexual Behaviors.

PURPOSE: Teen girls consider not only health outcomes, such as pregnancy or contracting a sexually transmitted infection (STI), but also social outcomes, such as guilt or embarrassment, when making decisions about sexual behaviors. METHODS: Following a sample of female virgins aged 15-18 years from wave I through wave IV of the National Longitudinal Study of Adolescent to Adult Health (N = 2,376), we tested whether adolescent girls' attitudes toward sex, contraception, pregnancy, and STIs influence the timing of coital debut, using discrete time event history logistic regression, and whether oral sex precedes coital debut, using logistic regression. RESULTS: Concerns about negative social consequences of sex were associated with later coital debut (adjusted odds ratio [AOR]=.79, p = .000), whereas perceived physical benefits of sex and positive attitudes toward contraception were associated with earlier coital debut (AOR = 1.09, p = .049 and AOR = 1.17, p = .002, respectively). Worries about pregnancy were not associated with the timing of coital debut but did predict having oral sex before vaginal sex (AOR = 1.33, p = .007). Favorable birth control attitudes and positive attitudes toward sex also increased the odds of oral sex before vaginal sex (AOR = 1.38, p = .008 and AOR = 1.47, p = .000, respectively). CONCLUSIONS: Teen girls' worries about the emotional and social consequences of sex may be a more salient predictor of the timing of coital debut than concerns about the risk of pregnancy or STIs. Teen girls' fears coexist with positive views about sex and contraception, which are associated with earlier sex and sexual sequencing.

Dimensions of Reproductive Attitudes and Knowledge Related to Unintended Childbearing Among U.S. Adolescents and Young Adults.

Measures of attitudes and knowledge predict reproductive behavior, such as unintended fertility among adolescents and young adults. However, there is little consensus as to the underlying dimensions these measures represent, how to compare findings across surveys using different measures, or how to interpret the concepts captured by existing measures. To guide future research on reproductive behavior, we propose an organizing framework for existing measures. We suggest that two overarching multidimensional concepts-reproductive attitudes and reproductive knowledge-can be applied to understand existing research using various measures. We adapt psychometric analytic techniques to analyze two data sets: the National Longitudinal Survey of Adolescent to Adult Health (Add Health) and the Relationship Dynamics and Social Life study (RDSL). Although the specific survey measures and sample composition of the two data sets are different, the dimensionality of the concepts and the content of the items used to measure their latent factors are remarkably consistent across the two data sets, and the factors are predictive of subsequent contraceptive behavior. However, some survey items do not seem strongly related to any dimension of either construct, and some dimensions of the two concepts appear to be poorly measured with existing survey questions. Nonetheless, we argue that the concepts of reproductive attitudes and reproductive knowledge are useful for categorizing and analyzing social psychological measures related to unintended fertility. The results can be used to guide secondary data analyses to predict reproductive behavior, compare results across data sets, and structure future data collection efforts.

Prevalence and Strain Characterization of Clostridioides (Clostridium) difficile in Representative Regions of Germany, Ghana, Tanzania and Indonesia - A Comparative Multi-Center Cross-Sectional Study.

Clostridioides (Clostridium) difficile infections (CDI) are considered worldwide as emerging health threat. Uptake of C. difficile spores may result in asymptomatic carrier status or lead to CDI that could range from mild diarrhea, eventually developing into pseudomembranous colitis up to a toxic megacolon that often results in high mortality. Most epidemiological studies to date have been performed in middle- and high income countries. Beside others, the use of antibiotics and the composition of the microbiome have been identified as major risk factors for the development of CDI. We therefore postulate that prevalence rates of CDI and the distribution of C. difficile strains differ between geographical regions depending on the regional use of antibiotics and food habits. A total of 593 healthy control individuals and 608 patients suffering from diarrhea in communities in Germany, Ghana, Tanzania and Indonesia were selected for a comparative multi-center cross-sectional study. The study populations were screened for the presence of C. difficile in stool samples. Cultured C. difficile strains (n = 84) were further subtyped and characterized using PCR-ribotyping, determination of toxin production, and antibiotic susceptibility testing. Prevalence rates of C. difficile varied widely between the countries. Whereas high prevalence rates were observed in symptomatic patients living in Germany and Indonesia (24.0 and 14.7%), patients from Ghana and Tanzania showed low detection rates (4.5 and 6.4%). Differences were also obvious for ribotype distribution and toxin repertoires. Toxin A+/B+ ribotypes 001/072 and 078 predominated in Germany, whereas most strains isolated from Indonesian patients belonged to toxin A+/B+ ribotype SLO160 and toxin A-/B+ ribotype 017. With 42.9-73.3%, non-toxigenic strains were most abundant in Africa, but were also found in Indonesia at a rate of 18.2%. All isolates were susceptible to vancomycin and metronidazole. Mirroring the antibiotic use, however, moxifloxacin resistance was absent in African C. difficile isolates but present in Indonesian (24.2%) and German ones (65.5%). This study showed that CDI is a global health threat with geographically different prevalence rates which might reflect distinct use of antibiotics. Significant differences for distributions of ribotypes, toxin production, and antibiotic susceptibilities were observed.