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.

NVX-CoV2373-induced cellular and humoral immunity towards parental SARS-CoV-2 and VOCs compared to BNT162b2 and mRNA-1273-regimens.

BACKGROUND: The NVX-CoV2373-vaccine has recently been licensed, although knowledge on vaccine-induced humoral and cellular immunity towards the parental strain and variants of concern (VOCs) in comparison to mRNA-regimens is limited. METHODS: In this observational study, 66 individuals were recruited to compare immunogenicity and reactogenicity of NVX-CoV2373 with BNT162b2 or mRNA-1273. Vaccine-induced antibodies were analyzed using ELISA and neutralization assays, specific CD4 and CD8 T-cells were characterized based on intracellular cytokine staining using flow-cytometry after antigen-specific stimulation with parental spike or VOCs. RESULTS: Two doses of NVX-CoV2373 strongly induced anti-spike IgG, although IgG-levels were lower than after vaccination with BNT162b2 or mRNA-1273 (p = 0.006). Regardless of the vaccine and despite different IgG-levels, neutralizing activity towards VOCs was highest for Delta, followed by BA.2 and BA.1. The protein-based vaccine failed to induce any spike-specific CD8 T-cells which were detectable in 3/22 (14%) individuals only. In contrast, spike-specific CD4 T-cells were induced in 18/22 (82%) individuals, although their levels were lower (p<0.001), had lower CTLA-4 expression (p<0.0001) and comprised less multifunctional cells co-expressing IFNγ, TNFα and IL-2 (p = 0.0007). Unlike neutralizing antibodies, NVX-CoV2373-induced CD4 T-cells equally recognized all tested VOCs from Alpha to Omicron. In individuals with a history of infection, one dose of NVX-CoV2373 had similar immunogenicity as two doses in non-infected individuals. The vaccine was overall well tolerated. CONCLUSION: NVX-CoV2373 strongly induced spike-specific antibodies and CD4 T-cells, albeit at lower levels as mRNA-regimens. Cross-reactivity of CD4 T-cells towards the parental strain and all tested VOCs may hold promise to protect from severe disease.

Comparative immunogenicity and reactogenicity of heterologous ChAdOx1-nCoV-19-priming and BNT162b2 or mRNA-1273-boosting with homologous COVID-19 vaccine regimens.

Comparative analyses of the immunogenicity and reactogenicity of homologous and heterologous SARS-CoV-2 vaccine-regimens will inform optimized vaccine strategies. Here we analyze the humoral and cellular immune response following heterologous and homologous vaccination strategies in a convenience cohort of 331 healthy individuals. All regimens induce immunity to the vaccine antigen. Immunity after vaccination with ChAdOx1-nCoV-19 followed by either BNT162b2 (n = 66) or mRNA-1273 (n = 101) is equivalent to or more pronounced than homologous mRNA-regimens (n = 43 BNT162b2, n = 59 mRNA-1273) or homologous ChAdOx1-nCoV-19 vaccination (n = 62). We note highest levels of spike-specific CD8 T-cells following both heterologous regimens. Among mRNA-containing combinations, spike-specific CD4 T-cell levels in regimens including mRNA-1273 are higher than respective combinations with BNT162b2. Polyfunctional T-cell levels are highest in regimens based on ChAdOx1-nCoV-19-priming. All five regimens are well tolerated with most pronounced reactogenicity upon ChAdOx1-nCoV-19-priming, and ChAdOx1-nCoV-19/mRNA-1273-boosting. In conclusion, we present comparative analyses of immunogenicity and reactogenicity for heterologous vector/mRNA-boosting and homologous mRNA-regimens.

Immunogenicity and reactogenicity of heterologous ChAdOx1 nCoV-19/mRNA vaccination.

Heterologous priming with the ChAdOx1 nCoV-19 vector vaccine followed by boosting with a messenger RNA vaccine (BNT162b2 or mRNA-1273) is currently recommended in Germany, although data on immunogenicity and reactogenicity are not available. In this observational study we show that, in healthy adult individuals (n = 96), the heterologous vaccine regimen induced spike-specific IgG, neutralizing antibodies and spike-specific CD4 T cells, the levels of which which were significantly higher than after homologous vector vaccine boost (n = 55) and higher or comparable in magnitude to homologous mRNA vaccine regimens (n = 62). Moreover, spike-specific CD8 T cell levels after heterologous vaccination were significantly higher than after both homologous regimens. Spike-specific T cells were predominantly polyfunctional with largely overlapping cytokine-producing phenotypes in all three regimens. Recipients of both the homologous vector regimen and the heterologous vector/mRNA combination reported greater reactogenicity following the priming vector vaccination, whereas heterologous boosting was well tolerated and comparable to homologous mRNA boosting. Taken together, heterologous vector/mRNA boosting induces strong humoral and cellular immune responses with acceptable reactogenicity profiles.

Magnetic resonance diffusion tensor tractography of a midbrain auditory circuit in Alligator.

Knowledge of brain circuitry is critical for understanding the organization, function, and evolution of central nervous systems. Most commonly, brain connections have been elucidated using histological and experimental methods that require animal sacrifice. On the other hand, magnetic resonance diffusion tensor imaging and associated tractography have emerged as a preferred method to noninvasively visualize brain white matter tracts. However, existing studies have primarily examined large, heavily myelinated fiber tracts. Whether tractography can visualize fiber bundles that contain thin and poorly myelinated axons is uncertain. To address this question, the midbrain auditory pathway to the thalamus was investigated in Alligator. This species was chosen because of its evolutionary importance as it is the reptilian group most closely related to birds and because its brain contains many thin and poorly myelinated tracts. Furthermore, this auditory pathway is well documented in other reptiles, including a related crocodilian. Histological observations and experimental determination of anterograde connections confirmed this path in Alligator. Tractography identified these tracts in Alligator and provided a 3-dimensional picture that accurately identified the neural elements of this circuit. In addition, tractography identified one possible unrecognized pathway. These results demonstrate that tractography can visualize circuits containing thin, poorly myelinated fibers. These findings open the door for future studies to examine these types of pathways in other vertebrates.

Development of a Biological Science Quantitative Reasoning Exam (BioSQuaRE).

Multiple reports highlight the increasingly quantitative nature of biological research and the need to innovate means to ensure that students acquire quantitative skills. We present a tool to support such innovation. The Biological Science Quantitative Reasoning Exam (BioSQuaRE) is an assessment instrument designed to measure the quantitative skills of undergraduate students within a biological context. The instrument was developed by an interdisciplinary team of educators and aligns with skills included in national reports such as BIO2010, Scientific Foundations for Future Physicians, and Vision and Change Undergraduate biology educators also confirmed the importance of items included in the instrument. The current version of the BioSQuaRE was developed through an iterative process using data from students at 12 postsecondary institutions. A psychometric analysis of these data provides multiple lines of evidence for the validity of inferences made using the instrument. Our results suggest that the BioSQuaRE will prove useful to faculty and departments interested in helping students acquire the quantitative competencies they need to successfully pursue biology, and useful to biology students by communicating the importance of quantitative skills. We invite educators to use the BioSQuaRE at their own institutions.

Analyzing the severity of accidents on the German Autobahn.

We study the severity of accidents on the German Autobahn in the state of North Rhine-Westphalia using data for the years 2009 until 2011. We use a multinomial logit model to identify statistically relevant factors explaining the severity of the most severe injury, which is classified into the four classes fatal, severe injury, light injury and property damage. Furthermore, to account for unobserved heterogeneity we use a random parameter model. We study the effect of a number of factors including traffic information, road conditions, type of accidents, speed limits, presence of intelligent traffic control systems, age and gender of the driver and location of the accident. Our findings are in line with studies in different settings and indicate that accidents during daylight and at interchanges or construction sites are less severe in general. Accidents caused by the collision with roadside objects, involving pedestrians and motorcycles, or caused by bad sight conditions tend to be more severe. We discuss the measures of the 2011 German traffic safety programm in the light of our results.

Physician intervention for medication reduction in a nursing home: the polypharmacy outcomes project.

OBJECTIVE: To examine the effects of a medication review project by geriatricians and geriatric medicine fellows on polypharmacy in a teaching nursing home. DESIGN: Quality improvement intervention study SETTING: Long-term care facility in Honolulu, HI PARTICIPANTS: Seventy-four patients with the Minimum Data Set quality indicator criteria of polypharmacy (9 or more medications). INTERVENTION: Geriatric medicine fellows and faculty reviewed each patient's medication list, consulted the updated Beers Criteria and Epocrates online drug-drug interaction program, and recommended medication changes to the patients' primary care physicians. MEASUREMENTS: Descriptive statistics, including means, standard deviations, and sums of variables were obtained for the number of medications in the following categories: total number, scheduled, pro re nata, high risk, contraindicated, with potential drug-drug interactions, and with no indication. RESULTS: Of 160 patients residing in a nursing home, 74 were on 9 or more medications. After the intervention, the mean number of medications per patient in the following categories decreased significantly: total number (16.64 to 15.54, P < .001), scheduled (11.3 to 10.99, P < .001), pro re nata (5.33 to 4.56, P < .001), high risk (0.94 to 0.73, P < .001), contraindicated (0.29 to 0.13, P = .004), with potential drug-drug interactions (6.1 to 4.83, P < .001), and with no indication (3.34 to 3.29, P = .045). CONCLUSION: Polypharmacy in long-term care is prevalent and can lead to increased adverse effects and potentially inappropriate prescriptions. This study demonstrates an effective geriatrician-led intervention that both reduced polypharmacy and provided core competency training for geriatric medicine fellows.

Statistical relevance of ultrasonographic criteria in the assessment of diffuse liver disease in dogs and cats.

OBJECTIVE: To determine whether objectively applied ultrasonographic interpretive criteria are statistically useful in differentiating among 7 defined categories of diffuse liver disease in dogs and cats. SAMPLE POPULATION: Ultrasonographic images of 229 dogs and 104 cats. PROCEDURES: Liver parenchymal or related sonographic criteria established by the authors were retrospectively and independently applied by 3 radiologists who were not aware of patient status or patient laboratory data. Seven histologic or cytologic categories of diffuse (infiltrative but not nodular) liver diseases were jointly established by the authors and included normal liver; inflammation; round-cell neoplasia; non-round-cell infiltrative, prenodular (early) metastatic neoplasia; lipidosis; vacuolar hepatopathy; and other. Liver parenchymal sonographic criteria included parenchymal sound attenuation with increasing depth, comparative organ echogenicity (liver, spleen, and kidneys), diffuse or patchy hyperechoic or hypoechoic echotexture, uniform or coarse echotexture, portal venous clarity, and liver lobe geometry. Related extrahepatic criteria included gallbladder wall thickness, bile duct diameter, amount and character of gallbladder precipitate, nondependent shadowing in the gallbladder, hepatic vein diameter versus caudal vena cava diameter, peritoneal fluid, spleen echotexture (normal vs abnormal [characterized]), and kidney echotexture. Ultrasonographic criteria were statistically compared to the 7 categories of diffuse liver disease in search of clinically exploitable relationships. RESULTS: Statistical evaluation of the applied ultrasonographic criteria did not yield clinically acceptable accuracy for discrimination among the 7 categories of diffuse liver diseases (including normal liver) in either species. CONCLUSIONS AND CLINICAL RELEVANCE: Criterion-based ultrasonographic appearance was insufficient to discriminate among canine and feline diffuse infiltrative liver diseases.

Computed tomographic evaluation of canine and feline mediastinal masses in 14 patients.

A 15-year retrospective analysis of histologically proven canine and feline mediastinal malignancies at the University of Minnesota was conducted to identify patients imaged by computed tomography (CT). The goal of the study was to characterize the CT appearance, to determine if there were any tumor type-specific appearances, and to clarify the role of CT in patients with mediastinal masses. Fourteen patients meeting these criteria were available for evaluation. The masses were characterized based on the presence or absence of contrast enhancement, internal architecture, size, extent of local invasion, the presence of pleural fluid, and the presence of regional vascular invasion. Within the limits of this study and the histopathologic information available, there appeared to be no clinically exploitable relationship between the CT appearance and the histologic characterization of the mass. However, CT does provide reasonably accurate local staging information.

Quantitative contrast harmonic ultrasound imaging of normal canine liver.

Eight adult dogs with no evidence of liver disease, weighing between 8 and 25 kg were imaged after injection of a microbubble contrast medium using harmonic ultrasound imaging. All dogs received three separate bolus contrast injections, and six dogs also received three separate constant rate infusions each. Time/Mean Pixel Value curves were generated for selected regions of the liver. Upslope, downslope, baseline, peak, change, and time to peak were calculated. For bolus injection (averaging all subjects), upslope was 3.85 +/- 1.50 Mean Pixel Values/s, downslope was -0.71 +/- 0.30 Mean Pixel Values/s, baseline was 72.38 +/- 17.82 Mean Pixel Values, peak was 120.26 +/- 17.44 Mean Pixel Value, change from baseline to peak was 47.88 +/- 6.92 Mean Pixel Values, time to peak (from injection) was 22.88 +/- 6.79 s, and time to peak (from first upslope) was 13.88 +/- 1.55 s. Data acquisition and analysis from constant rate infusions was more cumbersome than for bolus, and results were less repeatable. There were significant differences (p < .005) in upslope, downslope, peak values, and time to peak between the two methods. These baseline data may prove useful in the evaluation of dogs with diffuse hepatic disease.

Harmonic ultrasound: a review.

Harmonic ultrasound is a technique based on the principle of transmitting at frequency f and receiving at frequency 2f (or 1/2f). This technology has become available through the development of wide-bandwidth transducers. Microbubble contrast media produce a large amount of harmonic signal. Contrast harmonic ultrasound provides the opportunity to image patterns of high flow vasculature and overall perfusion. Regions of poor perfusion, including necrosis or infarction, can be identified with contrast harmonic ultrasound. While proportionately lower, tissues also produce harmonic signals. Tissue harmonic ultrasound sequences often improve subjective image quality compared to fundamental ultrasound in echocardiographic and abdominal examinations. This review will discuss the physical principles of harmonic ultrasound signal generation, medical and animal research applications, and an overview of current veterinary experiences.