T-bet and Eomes Are Differentially Linked to the Exhausted Phenotype of CD8+T Cells in HIV Infection

CD8+ T cell exhaustion represents a major hallmark of chronic HIV infection. Two key transcription factors governing CD8+ T cell differentiation, T-bet and Eomesodermin (Eomes), have previously been shown in mice to differentially regulate T cell exhaustion in part through direct modulation of PD-1. Here, we examined the relationship between these transcription factors and the expression of several inhibitory receptors (PD-1, CD160, and 2B4), functional characteristics and memory differentiation of CD8+ T cells in chronic and treated HIV infection. The expression of PD-1, CD160, and 2B4 on total CD8+ T cells was elevated in chronically infected individuals and highly associated with a T-betdimEomeshi expressional profile. Interestingly, both resting and activated HIV-specific CD8+ T cells in chronic infection were almost exclusively T-betdimEomeshi cells, while CMV-specific CD8+ T cells displayed a balanced expression pattern of T-bet and Eomes. The T-betdimEomeshi virus-specific CD8+ T cells did not show features of terminal differentiation, but rather a transitional memory phenotype with poor polyfunctional (effector) characteristics. The transitional and exhausted phenotype of HIV-specific CD8+ T cells was longitudinally related to persistent Eomes expression after antiretroviral therapy (ART) initiation. Strikingly, these characteristics remained stable up to 10 years after ART initiation. This study supports the concept that poor human viral-specific CD8+ T cell functionality is due to an inverse expression balance between T-bet and Eomes, which is not reversed despite long-term viral control through ART. These results aid to explain the inability of HIV-specific CD8+ T cells to control the viral replication post-ART cessation

Maternal risk factors for gastroschisis: A population‐based case–control study

BackgroundGastroschisis is an open abdominal wall defect with low mortality but significant morbidity. The prevalence has been increasing worldwide for the past decades. Several risk factors for gastroschisis have been identified, but no clear reason for increasing prevalence has been found. In our study, we aimed to assess and identify maternal risk factors for gastroschisis.MethodsIn our nationwide register‐based case–control study, we identified all gastroschisis cases in the Finnish Register of Congenital Malformations from 2004 to 2014. Information on drug prescriptions and purchases was received from Drugs and Pregnancy database. Five healthy age‐matched controls from the same geographical region were randomly selected for each case. Conditional logistic regression was used to evaluate different risk factors.ResultsOne‐hundred‐eighty‐eight cases of gastroschisis were identified and compared with 910 matched controls. Nulliparity was a significant risk factor for gastroschisis, aOR 2.00 (95% CI 1.29–3.11) whereas obesity was protective, aOR 0.35 (95% CI 0.15–0.83). Smoking appeared to increase the risk for gastroschisis, aOR 1.32 (95% CI 0.88–1.97). The mean maternal age of newborns with gastroschisis was significantly lower than average (p  ConclusionAs in previous studies, nulliparity and young maternal age were significant risk factors for gastroschisis. Maternal obesity significantly reduced the risk of gastroschisis regardless of maternal age and gestational diabetes.</p

Omphalocele in Finland from 1993 to 2014: Trends, Prevalence, Mortality, and Associated Malformations-A Population-Based Study

Introduction The aim of this study is to assess the changes in prevalence, mortality and termination pregnancy of omphalocele, and to identify associated anomalies.Materials and Methods A population-based nationwide register study. All cases with omphalocele were identified in the Finnish Register of Congenital Malformations and the Care Register for Health Care from 1993 to 2014 including live births, stillbirths, and terminations of pregnancy due to fetal anomalies. Associated anomalies were recorded and analyzed, and perinatal and infant mortality and prevalence were calculated.Results There were 600 cases with omphalocele including 229 live births, 39 stillbirths, and 332 (55%) abortions. Birth prevalence in Finland was 1.96 per 10,000 births with no consistent trend over time. However, total prevalence was much higher (4.71/10,000) because more than half of these families chose option for the termination of pregnancy. Omphalocele is often complicated with other anomalies; most commonly chromosomal abnormalities (9.3%), heart defects (6.3%), central nervous system anomalies (3.0%), gastrointestinal, and urogenital malformations (both 2.0%). Proportion of chromosomal and central nervous system abnormalities were even higher in terminated pregnancies. Overall infant mortality was 22%. Total 1-year survival rates for isolated omphalocele, cases with multiple anomalies and neonates with chromosomal defects were 80, 88, and 17%, respectively.Conclusion Omphalocele is a rare congenital anomaly, often associated with other malformations. Our data suggest that isolated cases may be more common than previously thought. In the absence of chromosomal defects, survival is reasonably good. Regardless, more than half of these pregnancies are often terminated.</p

Comparative Analysis of Prothrombin Complex Concentrate and Fresh Frozen Plasma in the Management of Perioperative Bleeding after Coronary Artery Bypass Grafting

Background and Aim: Recent studies suggested that prothrombin complex concentrate (PCC) might be more effective than fresh frozen plasma (FFP) to reduce red blood cell (RBC) transfusion requirement after cardiac surgery. The benefits and risks associated with the use of PCC over FFP have been investigated in this study including patients undergoing isolated coronary artery bypass grafting(CABG) from a prospective, multicenter registry. Methods: This is a comparative analysis of 416 patients who received postoperatively FFP and 119 patients who received PCC with or without FFP after isolated CABG. Results: Mixed-effects regression analyses adjusted for multiple covariates and participating centers showed that PCC significantly decreased RBC transfusion (67.2% vs. 87.5%, adjusted OR 0.319, 95%CI 0.136-0.752) and platelet transfusion requirements (11.8% vs. 45.2%, adjusted OR 0.238, 95%CI 0.097-0.566) compared with FFP. The PCC cohort received a mean of 2.7\ub13.7 (median, 2.0, IQR 4) units of RBC and the FFP cohort received a mean of 4.9\ub16.3 (median, 3.0, IQR 4) units of RBC (adjusted coefficient, -1.926, 95%CI -3.357-0.494). The use of PCC increased the risk of KDIGO acute kidney injury (41.4% vs. 28.2%, adjusted OR 2.300, 1.203-4.400), but not of KDIGO acute kidney injury stage 3 (6.0% vs. 8.0%, OR 0.850, 95%CI 0.258-2.796) when compared with the FFP cohort. Conclusions: These results suggest that the use of PCC compared with FFP may reduce the need of blood transfusion after CABG. In view of the observational nature of this study, these results shoul

A protease-based biosensor for the detection of schistosome cercariae

Parasitic diseases affect millions of people worldwide, causing debilitating illnesses and death. Rapid and cost-effective approaches to detect parasites are needed, especially in resource-limited settings. A common signature of parasitic diseases is the release of specific proteases by the parasites at multiple stages during their life cycles. To this end, we engineered several modular Escherichia coli and Bacillus subtilis whole-cell-based biosensors which incorporate an interchangeable protease recognition motif into their designs. Herein, we describe how several of our engineered biosensors have been applied to detect the presence and activity of elastase, an enzyme released by the cercarial larvae stage of Schistosoma mansoni. Collectively, S. mansoni and several other schistosomes are responsible for the infection of an estimated 200 million people worldwide. Since our biosensors are maintained in lyophilised cells, they could be applied for the detection of S. mansoni and other parasites in settings without reliable cold chain access

COVID-19 mRNA vaccine induced antibody responses against three SARS-CoV-2 variants

As SARS-CoV-2 has been circulating for over a year, dozens of vaccine candidates are under development or in clinical use. The BNT162b2 mRNA COVID-19 vaccine induces spike protein-specific neutralizing antibodies associated with protective immunity. The emergence of the B.1.1.7 and B.1.351 variants has raised concerns of reduced vaccine efficacy and increased re-infection rates. Here we show, that after the second dose, the sera of BNT162b2-vaccinated health care workers (n=180) effectively neutralize the SARS-CoV-2 variant with the D614G substitution and the B.1.1.7 variant, whereas the neutralization of the B.1.351 variant is five-fold reduced. Despite the reduction, 92% of the seronegative vaccinees have a neutralization titre of >20 for the B.1.351 variant indicating some protection. The vaccinees' neutralization titres exceeded those of recovered non-hospitalized COVID-19 patients. Our work provides evidence that the second dose of the BNT162b2 vaccine induces cross-neutralization of at least some of the circulating SARS-CoV-2 variants. Emerging SARS-CoV-2 variants contain mutations in the spike protein that may affect vaccine efficacy. Here, Jalkanen et al. show, using sera from 180 BNT162b2-vaccinated health care workers, that neutralization of SARS-CoV2 variant B.1.1.7 is not affected, while neutralization of B.1.351 variant is five-fold reduced.Peer reviewe

COVID-19 mRNA vaccine induced antibody responses against three SARS-CoV-2 variants

As SARS-CoV-2 has been circulating for over a year, dozens of vaccine candidates are under development or in clinical use. The BNT162b2 mRNA COVID-19 vaccine induces spike protein-specific neutralizing antibodies associated with protective immunity. The emergence of the B.1.1.7 and B.1.351 variants has raised concerns of reduced vaccine efficacy and increased re-infection rates. Here we show, that after the second dose, the sera of BNT162b2-vaccinated health care workers (n = 180) effectively neutralize the SARS-CoV-2 variant with the D614G substitution and the B.1.1.7 variant, whereas the neutralization of the B.1.351 variant is five-fold reduced. Despite the reduction, 92% of the seronegative vaccinees have a neutralization titre of >20 for the B.1.351 variant indicating some protection. The vaccinees’ neutralization titres exceeded those of recovered non-hospitalized COVID-19 patients. Our work provides evidence that the second dose of the BNT162b2 vaccine induces cross-neutralization of at least some of the circulating SARS-CoV-2 variants

Meta-Analysis of the Outcome After Postcardiotomy Venoarterial Extracorporeal Membrane Oxygenation in Adult Patients

ObjectiveThis study was planned to pool existing data on outcome and to evaluate the efficacy of postcardiotomy venoarterial extracorporeal membrane oxygenation (VA-ECMO) in adult patients.DesignSystematic review of the literature and meta-analysis.SettingMulti-institutional study.ParticipantsAdult patients with acute heart failure immediately after cardiac surgery.InterventionsVA-ECMO after cardiac surgery. Studies evaluating only heart transplant patients were excluded from this analysis.Measurements and Main ResultsA literature search was performed to identify studies published since 2000. Thirty-one studies reported on 2,986 patients (mean age, 58.1 years) who required postcardiotomy VA-ECMO. The weaning rate from VA-ECMO was 59.5% and hospital survival was 36.1% (95% CI 31.5-40.8). The pooled rate of reoperation for bleeding was 42.9%, major neurological event 11.3%, lower limb ischemia 10.8%, deep sternal wound infection/mediastinitis 14.7%, and renal replacement therapy 47.1%. The pooled mean number of transfused red blood cell units was 17.7 (95% CI 13.3-22.1). The mean stay in the intensive care unit was 13.3 days (95% CI 10.2-16.4). Survivors were significantly younger (mean, 55.7 v 63.6 years, p = 0.015) and their blood lactate level before starting VA-ECMO was lower (mean, 7.7 v 10.7 mmol/L, p = 0.028) than patients who died. One-year survival rate was 30.9% (95% CI 24.3-37.5).ConclusionsPooled data showed that VA-ECMO may salvage one-third of patients unresponsive to any other resuscitative treatment after adult cardiac surgery.</div