SARS-CoV-2-specific cellular and humoral immunity after bivalent BA.4/5 COVID-19-vaccination in previously infected and non-infected individuals.

Knowledge is limited as to how prior SARS-CoV-2 infection influences cellular and humoral immunity after booster-vaccination with bivalent BA.4/5-adapted mRNA-vaccines, and whether vaccine-induced immunity may indicate subsequent infection. In this observational study, individuals with prior infection (n = 64) showed higher vaccine-induced anti-spike IgG-antibodies and neutralizing titers, but the relative increase was significantly higher in non-infected individuals (n = 63). In general, both groups showed higher neutralizing activity towards the parental strain than towards Omicron-subvariants BA.1, BA.2 and BA.5. In contrast, CD4 or CD8 T cell levels towards spike from the parental strain and the Omicron-subvariants, and cytokine expression profiles were similar irrespective of prior infection. Breakthrough infections occurred more frequently among previously non-infected individuals, who had significantly lower vaccine-induced spike-specific neutralizing activity and CD4 T cell levels. In summary, we show that immunogenicity after BA.4/5-bivalent vaccination differs between individuals with and without prior infection. Moreover, our results may help to improve prediction of breakthrough infections.

Differences in SARS-CoV-2 specific humoral and cellular immune responses after contralateral and ipsilateral COVID-19 vaccination.

BACKGROUND: Individual doses of dual-dose vaccine-regimens are sequentially administered into the deltoid muscle, but little attention has so far been paid to the immunological effects of choosing the ipsilateral or the contralateral side for the second dose. METHODS: In an observational study, 303 previously naive individuals were recruited, who received the second dose of the COVID-19 vaccine BNT162b2 on either the ipsilateral (n = 147) or the contralateral side (n = 156). Spike-specific IgG, IgG-avidity, and neutralizing antibodies were quantified using ELISA and a surrogate assay 2 weeks after dose 2. A subgroup of 143 individuals (64 ipsilateral, 79 contralateral) was analysed for spike-specific CD4 and CD8 T-cells using flow-cytometry. FINDINGS: Median spike-specific IgG-levels did not differ after ipsilateral (4590 (IQR 3438) BAU/ml) or contralateral vaccination (4002 (IQR 3524) BAU/ml, p = 0.106). IgG-avidity was also similar (p = 0.056). However, neutralizing activity was significantly lower after contralateral vaccination (p = 0.024). Likewise, median spike-specific CD8 T-cell levels were significantly lower (p = 0.004). Consequently, the percentage of individuals with detectable CD8 T-cells was significantly lower after contralateral than after ipsilateral vaccination (43.0% versus 67.2%, p = 0.004). Spike specific CD4 T-cell levels were similar in both groups, but showed significantly higher CTLA-4 expression after contralateral vaccination (p = 0.011). These effects were vaccine-specific, as polyclonally stimulated T-cell levels did not differ. INTERPRETATION: Both ipsilateral and contralateral vaccination induce a strong immune response, but secondary boosting is more pronounced when choosing vaccine administration-routes that allows for drainage by the same lymph nodes used for priming. Higher neutralizing antibody activity and higher levels of spike-specific CD8 T-cells may have implications for protection from infection and severe disease and support general preference for ipsilateral vaccination. FUNDING: Financial support was provided in part by the State chancellery of the Saarland to M.S.

COVID-19 mRNA booster vaccine induces transient CD8+ T effector cell responses while conserving the memory pool for subsequent reactivation.

Immunization with two mRNA vaccine doses elicits robust spike-specific CD8+ T cell responses, but reports of waning immunity after COVID-19 vaccination prompt the introduction of booster vaccination campaigns. However, the effect of mRNA booster vaccination on the spike-specific CD8+ T cell response remains unclear. Here we show that spike-specific CD8+ T cells are activated and expanded in all analyzed individuals receiving the 3rd and 4th mRNA vaccine shots. This CD8+ T cell boost response is followed by a contraction phase and lasts only for about 30-60 days. The spike-specific CD8+ T memory stem cell pool is not affected by the 3rd vaccination. Both 4th vaccination and breakthrough infections with Delta and Omicron rapidly reactivate CD8+ T memory cells. In contrast, neutralizing antibody responses display little boost effect towards Omicron. Thus, COVID-19 mRNA booster vaccination elicits a transient T effector cell response while long-term spike-specific CD8+ T cell immunity is conserved to mount robust memory recall targeting emerging variants of concern.

Grit as a Key Factor in the Ability of Students to Achieve Productive Global Field Research.

Global fieldwork is an invaluable educational experience for students who aspire to pursue careers as global public health professionals and cancer experts. Student-led research projects can be mutually beneficial for students and host institutions by providing opportunities for bilateral learning, sharing resources, building databases, and ultimately creating uniquely informed multi-cultural health research relevant to global communities. The USA-host country partnerships can be delicate, requiring tactful approaches to the investment in the careers of students and the field projects. The US and host institutions must therefore be selective in determining which students have the privilege of participating in global field work. This paper examines the importance of grit as a character trait contributing to the success of student-led global health research projects. Grit has been explored at length as a predictor of student success in domestic educational experiences, yet is underrepresented in the context of global education, field training, and evaluation of research and learning outcomes. This manuscript utilizes testimonials of three public health graduate students recently returned from summer cancer epidemiology education training fellowships to explore the role that grit played in completion of their independent research projects. Ultimately, this paper discusses ways to identify grit in student applicants and to foster an improved capacity for grit before, during, and after their field experiences. We share the experiences with an aim of providing participant perspectives that may be used by educators, students, and administrators at US and international partner institutions to inform global research, experiential learning, and educational and training programs.

Regional Variation of Pancreatic Cancer Incidence in the Nile Delta Region of Egypt over a Twelve-Year Period.

BACKGROUND: Pancreatic cancer is one of the deadliest forms of cancer, with incidence rates rising in many countries around the world. Geographic variation in pancreatic cancer incidence has not been studied extensively, especially in low- and middle-income countries. The aim of this study was to characterize the distribution of pancreatic cancer incidence in the central Nile Delta region of Egypt and to examine differences by urban and rural patient residence using the nation's only population-based cancer registry. METHODS: Utilizing the Gharbiah province population-based cancer registry, data were abstracted for 1,089 pancreatic cancer cases diagnosed over twelve years from 1999 to 2010. Age- and sex-specific incidence rates were calculated and compared for urban and rural areas of the eight districts of Gharbiah. RESULTS: Age-adjusted incidence of pancreatic cancer within Gharbiah varied considerably by urban/rural patient residence and by district. Incidence rates were 1.3 times higher in urban compared to rural areas (4.45 per 100,000 in urban areas and 3.43 per 100,000 in rural areas). The highest incidence rates were observed in urban centers of Kotour, El Santa, and Kafr El-Zayat districts (12.94, 8.32, and 7.89, respectively). CONCLUSION: Incidence rates varied greatly by urban and rural areas and by district of residence in the Nile Delta region of Egypt. Future studies should examine potential environmental risk factors that may contribute to the geographic distribution of pancreatic cancer in this region.

Interventions to increase uptake of cervical screening in sub-Saharan Africa: a scoping review using the integrated behavioral model.

BACKGROUND: Sub-Saharan Africa (SSA) experiences disproportionate burden of cervical cancer incidence and mortality due in part to low uptake of cervical screening, a strategy for prevention and down-staging of cervical cancer. This scoping review identifies studies of interventions to increase uptake of cervical screening among women in the region and uses the Integrated Behavioral Model (IBM) to describe how interventions might work. METHODS: A systematic search of literature was conducted in PubMed, Web of Science, Embase, and CINAHL databases through May 2019. Screening and data charting were performed by two independent reviewers. Intervention studies measuring changes to uptake in screening among women in SSA were included, with no restriction to intervention type, study setting or date, or participant characteristics. Intervention type and implementation strategies were described using behavioral constructs from the IBM. RESULTS: Of the 3704 citations the search produced, 19 studies were selected for inclusion. Most studies were published between 2014 and 2019 (78.9%) and were set in Nigeria (47.4%) and South Africa (26.3%). Studies most often assessed screening with Pap smears (31.6%) and measured uptake as ever screened (42.1%) or screened during the study period (36.8%). Education-based interventions were most common (57.9%) and the IBM construct of knowledge/skills to perform screening was targeted most frequently (68.4%). Willingness to screen was high, before and after intervention. Screening coverage ranged from 1.7 to 99.2% post-intervention, with six studies (31.6%) reporting a significant improvement in screening that achieved ≥60% coverage. CONCLUSIONS: Educational interventions were largely ineffective, except those that utilized peer or community health educators and mHealth implementation strategies. Two economic incentivization interventions were moderately effective, by acting on participants' instrumental attitudes, but resulted in screening coverage less than 20%. Innovative service delivery, including community-based self-sampling, acted on environmental constraints, striving to make services more available, accessible, and appropriate to women, and were the most effective. This review demonstrates that intent to perform screening may not be the major determinant of screening behavior, suggesting other theoretical frameworks may be needed to more fully understand uptake of cervical screening in sub-Saharan Africa, particularly for health systems change interventions.

The Specificity of EGF-Stimulated IQGAP1 Scaffold Towards the PI3K-Akt Pathway is Defined by the IQ3 motif.

Epidermal growth factor receptor (EGFR) and its downstream phosphoinositide 3-kinase (PI3K) pathway are commonly deregulated in cancer. Recently, we have shown that the IQ motif-containing GTPase-activating protein 1 (IQGAP1) provides a molecular platform to scaffold all the components of the PI3K-Akt pathway and results in the sequential generation of phosphatidylinositol-3,4,5-trisphosphate (PI3,4,5P3). In addition to the PI3K-Akt pathway, IQGAP1 also scaffolds the Ras-ERK pathway. To define the specificity of IQGAP1 for the control of PI3K signaling, we have focused on the IQ3 motif in IQGAP1 as PIPKIα and PI3K enzymes bind this region. An IQ3 deletion mutant loses interactions with the PI3K-Akt components but retains binding to ERK and EGFR. Consistently, blocking the IQ3 motif of IQGAP1 using an IQ3 motif-derived peptide mirrors the effect of IQ3 deletion mutant by reducing Akt activation but has no impact on ERK activation. Also, the peptide disrupts the binding of IQGAP1 with PI3K-Akt pathway components, while IQGAP1 interactions with ERK and EGFR are not affected. Functionally, deleting or blocking the IQ3 motif inhibits cell proliferation, invasion, and migration in a non-additive manner to a PIPKIα inhibitor, establishing the functional specificity of IQ3 motif towards the PI3K-Akt pathway. Taken together, the IQ3 motif is a specific target for suppressing activation of the PI3K-Akt but not the Ras-ERK pathway. Although EGFR stimulates the IQGAP1-PI3K and -ERK pathways, here we show that IQGAP1-PI3K controls migration, invasion, and proliferation independent of ERK. These data illustrate that the IQ3 region of IQGAP1 is a promising therapeutic target for PI3K-driven cancer.

Subclinical impairment of lung function is related to mild cardiac dysfunction and manifest heart failure in the general population.

BACKGROUND: Lung function impairment has previously been related to heart failure, although no overt cardiovascular or structural heart disease is present. The extent to which pulmonary function is related to subclinical left ventricular impairment in the general population remains to be investigated. METHODS: 15010 individuals from the general population (mean age 55±11years, 50.5% men) in the Gutenberg Health Study underwent spirometry, transthoracic echocardiography and biomarker measurement. Forced expiratory volume in 1s (FEV1) and forced vital capacity (FVC) in percent of the predicted value and FEV1/FVC ratio were associated with echocardiographic measures of cardiac structure, systolic and diastolic function, biomarkers of cardiac necrosis (high-sensitive troponin I, hsTnI) and stress (N-terminal pro-B-type natriuretic peptide, Nt-proBNP) and heart failure with preserved (HFpEF) and reduced ejection fraction (HFrEF). RESULTS: Percent predicted FEV1 and FVC were significantly associated with hsTnI (P<0.001) and Nt-proBNP (P<0.001). Additionally, FEV1/FVC ratio was significantly related to hsTnI (P=0.0043) and Nt-proBNP (P<0.001). In the multivariable-adjusted linear regression analyses strongest associations were observed for percent predicted FEV1 and FVC with LVESD, E/e', SV and EF. FEV1/FVC ratio was significantly related with SV and EF. The three lung function parameters were significantly (P<0.001) associated with HFpEF and HFrEF. Associations remained statistically significant after exclusion of individuals with COPD. CONCLUSIONS: FEV1, FVC and FEV1/FVC ratio were associated with systolic and diastolic function and manifest heart failure. Our observations could show, that subclinical lung function impairment is related to a measurable reduction of left ventricular filling and cardiac output in the general population.

Low Homoarginine Levels in the Prognosis of Patients With Acute Chest Pain.

BACKGROUND: The endogenous amino acid homoarginine predicts mortality in cerebro- and cardiovascular disease. The objective was to explore whether homoarginine is associated with atrial fibrillation (AF) and outcome in patients with acute chest pain. METHODS AND RESULTS: One thousand six hundred forty-nine patients with acute chest pain were consecutively enrolled in this study, of whom 589 were diagnosed acute coronary syndrome (ACS). On admission, plasma concentrations of homoarginine as well as brain natriuretic peptide (BNP), and high-sensitivity assayed troponin I (hsTnI) were determined along with electrocardiography (ECG) variables. During a median follow-up of 183 days, 60 major adverse cardiovascular events (MACEs; 3.8%), including all-cause death, myocardial infarction, or stroke, were registered in the overall study population and 43 MACEs (7.5%) in the ACS subgroup. Adjusted multivariable Cox regression analyses revealed that an increase of 1 SD of plasma log-transformed homoarginine (0.37) was associated with a hazard reduction of 26% (hazard ratio [HR], 0.74; 95% CI, 0.57-0.96) for incident MACE and likewise of 35% (HR, 0.65; 95% CI, 0.49-0.88) in ACS patients. In Kaplan-Meier survival curves, homoarginine was predictive for patients with high-sensitivity assayed troponin I (hsTnI) above 27 ng/L (P<0.05). Last, homoarginine was inversely associated with QTc duration (P<0.001) and prevalent AF (OR, 0.83; 95% CI, 0.71-0.95). CONCLUSION: Low plasma homoarginine was identified as a risk marker for incident MACEs in patients with acute chest pain, in particular, in those with elevated hsTnI. Impaired homoarginine was associated with prevalent AF. Further studies are needed to investigate the link to AF and evaluate homoarginine as a therapeutic option for these patients.

ADMA and arginine derivatives in relation to non-invasive vascular function in the general population.

OBJECTIVE: Nitric oxide produced from l-arginine is central to vascular homeostasis. Little is known about the relationship between arginine derivatives including asymmetric dimethylarginine (ADMA) and non-invasive vascular function measures in the general population. APPROACH AND RESULTS: In 5000 individuals (median age 56; 25th/75th percentile: 46, 65; 49% women) taking part in the population-based Gutenberg Health Study (Mainz area, Germany), we measured the relationship between the arginine derivatives asymmetric dimethylarginine (ADMA), N-monomethyl l-arginine (NMMA), symmetric dimethylarginine (SDMA) and l-arginine with flow-mediated dilation (FMD) and peripheral arterial tonometry (PAT). Weak bivariate correlations were observed between all measured arginine derivatives and vascular function measures, except of l-arginine and FMD and SDMA and PAT ratio. In multivariate adjusted linear regression analyses we could show statistically significant relationships between arginine derivatives and vascular function measures, which were influenced by age, sex and body mass index (BMI). Thus, a negative relationship between ADMA and FMD in females who were normal (beta: -0.095, P < 0.001) to overweight (beta: -0.071, P < 0.001) and a negative association of SDMA and FMD for middle-aged females was seen. The relationship between ADMA and PAT was negative for males who were normal (beta: -0.089, P < 0.001) to overweight (beta: -0.051, P = 0.007) and positive for obese females (beta: 0.073, P = 0.021). CONCLUSIONS: We showed small but significant correlations between ADMA and related arginine derivatives and non-invasive vascular function measures representative of different vascular regions. The associations were markedly influenced by age, sex and BMI. These findings support a complex interplay of arginine metabolism and vascular function.

Concomitant transcatheter aortic valve and left ventricular assist device implantation.

Relevant aortic regurgitation (AR) requires surgical repair at the time of left ventricular assist device (LVAD) implantation to reduce recirculation and ensure adequate forward flow. We report here on a patient with moderate AR in a noncalcified aortic valve and extensive calcification of the ascending aorta. The latter precluded aortic-crossclamping and, thus, surgical intervention on the aortic valve. Although there were no valvular or annular calcifications, a JenaValve transcatheter heart valve was successfully placed transapically with subsequent LVAD implantation in one operation. We believe concomitant transcatheter aortic valve implantation (TAVI) and LVAD implantation is a promising hybrid procedure, even in patients with pure AR.

Association of systemic inflammation markers with the presence and extent of coronary artery calcification.

BACKGROUND: Coronary artery calcification (CAC) is a marker for the presence and extent of coronary atherosclerotic plaques and can be detected non-invasively by multi-detector row CT (MDCT). Well known predictors of CAC are age, gender, and the classical atherogenic risk factors. CAC is associated with atherosclerotic plaque burden, but it is still elusive if atherosclerosis-relevant cytokines and chemokines are also associated with CAC. METHODS: We conducted a clinical study among 455 consecutive individuals who underwent coronary calcium assessment performed by MDCT. Before MDCT, blood was drawn and subsequently analyzed for 20 different atherosclerosis-relevant cytokines and chemokines using a Luminex-laser-based fluorescence analysis. RESULTS: Using univariate analyses, CAC patients revealed significantly higher levels of the chemokines IP-10 (P=0.047) and eotaxin (P=0.031) as compared to non-CAC patients. In multivariate analyses using common thresholds for calcium burden, the three cytokines interleukin-6 (P=0.028), interleukin-8 (P=0.009), and interleukin-13 (P=0.024) were associated with high coronary calcium levels after adjustment for classical variables and risk factors. CONCLUSIONS: In a large group of individuals with atypical chest pain and a low to intermediate likelihood for coronary artery disease elevated plasma levels of IL-6 and reduced levels of IL-8 and IL-13 were predictive for distinct coronary artery calcification. These findings support a specific role of these cytokines in coronary calcification.