A live attenuated RSV vaccine, process development studies

Respiratory Syncytial Virus (RSV) is the leading cause of lower respiratory tract disease in infants and young children. A vaccine to prevent the high burden of disease caused by RSV is urgently needed, but not available. A live attenuated respiratory syncytial virus (RSV) vaccine for intranasal delivery is currently under development at Intravacc. The vaccine concept comprises a live Glycoprotein-complemented RSVΔG virus. This G-RSVΔG virus is generated by proliferation of an RSVΔG on G-expressing Vero cells. The vaccine thus contains virus particles that have the G-protein on their surface but not in their RNA genomes. This recombinant virus is highly attenuated compared to wild type RSV and therefore presents a live attenuated vaccine candidate for RSV infection. A vaccine production process has been setup for the production of Phase I clinical lots. In short, the production process steps are: cell and virus culture, clarification, continuous flow density gradient ultracentrifugation, ultra/diafiltration, filling and lyophilization. An example of process development is the design of the cell and virus culture method. Using the statistical design of experiment approach the virus culture has been optimized to both virus yield and harvest quality. As RSV is a filamentous virus, the optimization of harvest quality with respect to purification opportunities is pivotal. This DoE was done at lab-scale bioreactors (2-L) and the chosen conditions were successfully scaled-up to 50-L single use bioreactors. Preparation of preclinical and clinical lots is done at this scale. The pre-clinical studies were successful. In the cotton rat model, the G-RSVΔG vaccine is safe, immunogenic and protects against challenge with wild type RSV. The following step, a clinical Phase I study, is planned

Clinical usefulness of splanchnic oxygenation in predicting necrotizing enterocolitis in extremely preterm infants:a cohort study

Background: Impaired intestinal microcirculation seems to play an important role in the pathogenesis of necrotizing enterocolitis (NEC). A previous study showed that a SrSO2 &lt; 30% is associated with an increased risk of developing of NEC. We aimed to determine the clinical usefulness of the cut off &lt; 30% for SrSO2 in predicting NEC in extremely preterm neonates.Methods: This is a combined cohort observational study. We added a second cohort from another university hospital to the previous cohort of extremely preterm infants. SrSO2 was measured for 1–2 h at days 2–6 after birth. To determine clinical usefulness we assessed sensitivity, specificity, positive and negative predictive values for mean SrSO2 &lt; 30. Odds ratio to develop NEC was assessed with generalized linear model analysis, adjusting for center.Results: We included 86 extremely preterm infants, median gestational age 26.3 weeks (range 23.0-27.9). Seventeen infants developed NEC. A mean SrSO2 &lt; 30% was found in 70.5% of infants who developed NEC compared to 33.3% of those who did not (p = 0.01). Positive and negative predictive values were 0.33 CI (0.24–0.44) and 0.90 CI (0.83–0.96), respectively. The odds of developing NEC were 4.5 (95% CI 1.4–14.3) times higher in infants with SrSO2 &lt; 30% compared to those with SrSO2 ≥ 30%.Conclusions: A mean SrSO2 cut off ≥ 30% in extremely preterm infants between days 2–6 after birth may be useful in identifying infants who will not develop NEC.</p

Cerebrovascular Autoregulation in Preterm Infants During and After Surgical Ligation of the Ductus Arteriosus, a Comparison Between Two Surgical Approaches

Objective: During ligation of the ductus arteriosus, cerebrovascular autoregulation (CAR) may deteriorate. It is unknown whether different surgical approaches affect changes in CAR differently. The objective of this study was to compare the potential change in CAR in preterm infants during and after ligation comparing two surgical approaches: sternotomy and posterolateral thoracotomy. Design: This was an observational cohort pilot study. Setting: Level III NICU. Patients: Preterm infants (GA < 32 weeks) requiring ductal ligation were eligible for inclusion. Interventions: Halfway the study period, our standard surgical approach changed from a posterolateral thoracotomy to sternotomy. We analyzed dynamic CAR, using an index of autoregulation (COx) correlating cerebral tissue oxygen saturation and invasive arterial blood pressure measurements, before, during, and after ligation, in relation to the two approaches. Measurements and Main Results: Of nine infants, four were approached by thoracotomy and five by sternotomy. Median GA was 26 (range: 24.9–27.9) weeks, median birth weight (BW) was 800 (640–960) grams, and median post-natal age (PNA) was 18 (15–30) days, without differences between groups. COx worsened significantly more during and after thoracotomy from baseline (Δρ from baseline: during surgery: Δ + 0.32, at 4 h: Δ + 0.36, at 8 h: Δ + 0.32, at 12 h: Δ + 0.31) as compared with sternotomy patients (Δρ from baseline: during surgery: Δ + 0.20, at 4 h: Δ + 0.05, at 8 h: Δ + 0.15, at 12 h: Δ + 0.11) (F = 6.50; p = 0.038). Conclusions: In preterm infants, CAR reduced significantly during and up to 12 h after ductal ligation in all infants, but more evident during and after posterolateral thoracotomy as compared with sternotomy. These results need to be confirmed in a larger population

Involutory reflection groups and their models

AbstractA finite subgroup G of GL(n,C) is involutory if the sum of the dimensions of its irreducible complex representations is given by the number of absolute involutions in the group, i.e. elements g∈G such that gg¯=1, where the bar denotes complex conjugation. A uniform combinatorial model is constructed for all non-exceptional irreducible complex reflection groups which are involutory including, in particular, all infinite families of finite irreducible Coxeter groups

A family-based study into penetrance in facioscapulohumeral muscular dystrophy type 1

Functional Genomics of Muscle, Nerve and Brain Disorder

Necrotizing Enterocolitis Associated with Congenital Heart Disease:a Different Entity?

Background: Necrotizing enterocolitis (NEC) predominantly occurs in preterm infants (PT-NEC). In term neonates, NEC occurs more frequently when a congenital heart disease is present (CHDNEC). Our aim was to evaluate differences and similarities in disease characteristics of PT-NEC versus CHD-NEC.Methods: In this retrospective case-control study we identified all CHD infants who developed NEC Bell's stage &gt;= 2 in our center from 2004 to 2014. We randomly selected (1:2 ratio) PT-NEC infants from the same period. Biochemical and clinical variables were retrieved from patient files.Results: We found 18 CHD-NEC infants and selected 36 PT-NEC infants (gestational age 28.3 [25-35.6] weeks vs. 38.6 [31.7-40.7] weeks). Postnatal age at onset was significantly lower in CHD-NEC patients (4 [2-24] vs. 11 [4-41] days, p &lt;0.001). Lowest pH levels were lower (7.21 [7.01-7.47] vs. 7.27 [6.68-7.39], p = 0.02), and highest CRP levels were higher (112.5 mg/L [5.0-425.0] vs. 66.0 [52-189.0], p = 0.05) in PT-NEC vs. CHD-NEC. Anatomic localisation of the disease differed: the colon was significantly more often involved in CHD-NEC versus PT-NEC (86% vs. 33%, p = 0.03). Mortality caused by NEC was not different (22% vs. 11%, p = 0.47).Conclusion: While outcome of NEC in both groups is similar, the predominant NEC localisation differed between CHD-NEC and PT-NEC patients. This suggests that both variants of the disease have a different underlying pathophysiological mechanism that predisposes different intestinal regions to develop NEC.Type of Study: Retrospective Case-Control Study. (C) 2018 Elsevier Inc. All rights reserved.</p

Health-related quality of life in Dutch adult survivors of childhood cancer:A nation-wide cohort study

Aim: To investigate the health-related quality of life (HRQOL) of Dutch adult childhood cancer survivors (CCS) and to identify risk factors of impaired HRQOL. Methods: Adult CCS (age >18, diagnosed <18, ≥5 years since diagnosis) from the Dutch LATER registry completed the Medical Outcome Study Short Form 36 (SF-36) to measure HRQOL and provided sociodemographic characteristics. Age-adjusted mean SF-36 scale scores of CCS were compared to the Dutch general population for men and women separately using t-tests, with effect size d. Multivariate logistic regression models were built to identify sociodemographic and cancer-related risk factors for impaired physical and mental HRQOL. Results: Both male and female CCS (N = 2301, mean age = 35.4 years, 49.6% female) reported significantly (p ≤ .005) worse HRQOL than the general population on almost all scales of the SF-36 (−.11 ≤ d ≤ −.56). Largest differences were found on vitality and general health perceptions. Significant risk factors (p ≤ .05) for impaired physical HRQOL were female sex, older age at diagnosis, not having a partner, low educational attainment, disease recurrence and exposure to radiotherapy, specifically to lower extremity radiation. Odds ratios (ORs) ranged from 1.6 to 3.7. Significant risk factors for impaired mental HRQOL were age 26–35 years, male sex, not having a partner and low educational attainment. ORs ranged from 1.3 to 2.0. Conclusion: Adult CCS had worse HRQOL than the general population. CCS most at risk were those with low educational attainment and without a partner. Adult CCS could benefit from routine surveillance of their HRQOL. Special attention for CCS’ vitality and health perceptions and beliefs is warranted

Regional splanchnic oxygen saturation for preterm infants in the first week after birth:reference values

BACKGROUND: Near-infrared spectroscopy is used in the assessment of regional splanchnic oxygen saturation (rsSO2), but solid reference values are scarce. We aimed to establish reference values of rsSO2 for preterm infants during the first week after birth, both crude and modeled based on predictors. METHODS: We included infants with gestational age (GA) <32 weeks and/or birth weight <1200 g. We excluded infants who developed necrotizing enterocolitis or sepsis or who died. In the first week after birth, we determined a daily 2-h mean of rsSO2 to assess its associations with sex, GA, postnatal age (PNA), small-for-gestational age (SGA) status, patent ductus arteriosus, hemoglobin, nutrition, and head circumference at birth and translated those into a prediction model. RESULTS: We included 220 infants. On day 1, the mean ± SD rsSO2 value was 48.2% ± 16.6. The nadir of rsSO2 was on day 4 (38.7% ± 16.6 smoothed line) to 5 (37.4%±17.3, actual data), after which rsSO2 increased to 44.2% ± 16.6 on day 7. The final model of the reference values of rsSO2 included the following coefficients: rsSO2 = 3.2 - 7.0 × PNA + 0.8 × PNA2 - 4.0 × SGA + 1.8 × GA. CONCLUSIONS: We established reference values of rsSO2 for preterm infants during the first week after birth. GA, PNA, and SGA affect these values and need to be taken into account. IMPACT: Regional splanchnic oxygen saturation is lower in infants with a lower gestational age and in small-for-gestational age infants. Regional splanchnic oxygen saturation decreases with a higher postnatal age until day 4 after birth and then increases until day 7 after birth. Gestational age, postnatal age, and small-for-gestational age status affect regional splanchnic oxygen saturation and need to be taken into account when interpreting regional splanchnic oxygen saturations using NIRS. Reference values for infant regional splanchnic oxygen saturation can be computed with a formula based on these variables, as provided by this study