Eliminating first trimester combined testing: Consequences for early detection of significant fetal anomalies.

OBJECTIVE: To determine whether implementation of cell-free DNA (cfDNA) testing for aneuploidy as a first-tier test and subsequent abolition of first trimester combined testing (FCT) affected the first trimester detection (<14 weeks) of certain fetal anomalies. METHODS: We performed a geographical cohort study in two Fetal Medicine Units between 2011 and 2020, including 705 fetuses with prenatally detected severe brain, abdominal wall and congenital heart defects. Cases were divided into two groups: before (n = 396) and after (n = 309) cfDNA introduction. The primary outcome was the first trimester detection rate (<14 weeks) overall and for non-chromosomal anomalies solely. RESULTS: Overall, gastroschisis, AVSD and HLHS were detected more often in the first trimester in the before group compared to the after group, respectively 54.5% versus 18.5% (p = 0.004), 45.9% versus 26.9% (p = 0.008) and 30% versus 3.4% (p = 0.005). After exclusion of chromosomal anomalies identifiable through cfDNA testing, the detection of AVSD remained higher in the before group (43.3% vs. 9.5%, p = 0.02), leading to a possible earlier gestation at termination. The termination of pregnancy (TOP) rate did not differ among the groups. In the after group, referrals for suspected anomalies following a dating scan between 11 and 14 weeks significantly increased from 17.4% to 29.1% (p < 0.001). CONCLUSION: This study underscores the value of a scan dedicated to fetal anatomy in the first trimester as we observed a decline in the early detection of certain fetal anomalies (detectable in the first trimester) subsequent to the abolition of FCT.

Adverse pregnancy outcome in fetuses with early increased nuchal translucency: prospective cohort study.

OBJECTIVES: An increased nuchal translucency (NT) ≥3.5mm is a well-established marker for congenital anomalies and adverse pregnancy outcome between 11 and 14 weeks of gestation. Little is known about its performance as a screening tool before 11 weeks of gestation. We aimed to investigate in a prospective setting whether fetuses with an increased NT before 11 weeks of gestation are at risk for an adverse pregnancy outcome. METHODS: This is a prospective cohort study including pregnant women with a viable fetus with a NT≥2.5mm and a crown-rump-length (CRL) <45mm. All women were referred to our fetal medicine unit (FMU) and scheduled for a follow-up scan where the NT was remeasured after one week when the CRL was >45mm. Two groups were evaluated: cases with a normalized NT(<3.5mm) and cases with a persistently increased NT (≥3.5mm). We monitored the cases until four weeks after delivery. The main outcome was a composite adverse outcome of aneuploidies, other genetic disorders, structural anomalies and pregnancy loss. We performed subgroup analyses of NT thickness at inclusion and normalized or persistently increased NT at follow-up. RESULTS: We included 109 cases of which 35.8% (39/109) had an adverse pregnancy outcome. Of these 64.1% (25/39) were aneuploidies which corresponds to 22.9% (25/109) aneuploidies in total. The subgroups of NT thickness at inclusion of 2.5-3.4, 3.5-4.4 and ≥4.5mm showed abnormal outcomes in 22.0% (9/41), 40.0% (18/45), 52.2% (12/23) respectively. In fetuses with a normalized NT and without ultrasound abnormalities at follow-up scan, the incidence of adverse outcome was 8.5% (5/59), of which 5.1% (3/59) were aneuploidies. CONCLUSION: Fetuses with an early increased NT thickness are at considerable risk of an adverse pregnancy outcome, even if the NT normalizes after 11 weeks. Not all congenital anomalies can be diagnosed with routine first-trimester screening such as non-invasive prenatal testing and/or a first-trimester anomaly scan. Therefore, expectant parents should always be referred to a FMU for detailed ultrasonography. Invasive prenatal testing should be offered if an increased nuchal translucency of ≥2.5mm is observed before 11 weeks of gestation. This article is protected by copyright. All rights reserved.

Congenital small bowel obstruction: Prenatal detection and outcome.

OBJECTIVE: To evaluate and compare the outcome of fetuses and neonates with congenital small bowel obstructions (SBO), evaluate the screening performance of prenatal ultrasound for SBO and identify possible risk factors for adverse outcomes. METHODS: All cases referred to the Amsterdam University Medical Centers between 2007 and 2021 for a prenatal suspected SBO, supplemented by cases of postnatal diagnosis of SBO, were included. The primary outcome was survival after 24 weeks of gestation until the first year of life. RESULTS: 147 cases of SBO were included with a survival rate of 86.2% (119/138) after 24 weeks of gestation until the first year of age. Additional structural or chromosomal anomalies were found to have an increased risk of adverse outcomes. Intrauterine fetal demise occurred in 10/147 (6.8%) cases and 9/147 (6.1%) cases died during postnatal follow-up. The overall positive predictive value of all prenatally diagnosed cases was 91.5%. Surgical correction was performed in 123/128 (96.0%) of the live-born cases. CONCLUSIONS: Congenital SBO has an overall favorable prognosis, but the outcome is negatively impacted by the possible presence of additional structural or chromosomal anomalies. Fetal monitoring in the early third trimester should be considered, since all cases of Intrauterine fetal demise occurred between 30 and 35 weeks of gestation.

Fetal premature atrial contractions: natural course, risk factors and adverse outcomes.

OBJECTIVE: Fetal premature atrial contractions (PACs) are usually benign, but are associated with congenital heart defects (CHDs) and tachyarrhythmias, which in turn carry a risk of cardiac failure and fetal death. We aimed to explore the frequency of adverse outcomes and to identify risk factors for tachyarrhythmias in pregnancies complicated by fetal PACs. METHODS: Fetuses diagnosed with PACs at two academic centres in Amsterdam between 2007 and 2022 were included in this retrospective cohort study. Cases with congenital anomalies or a prior diagnosis of CHD or other arrhythmias were excluded. M-mode and Doppler tracings were reanalysed and the PACs frequency recorded. We explored the incidence of adverse outcomes defined as: underlying CHDs not identified during the 20 weeks fetal anomaly scan, tachyarrhythmias, other arrhythmias, administration of antiarrhythmic therapy and death. Risk factors for tachyarrhythmias were analysed using odds ratios (OR). RESULTS: In 24% of the referred cases, PACs resolved before confirmation at the fetal medicine unit (FMU). Of the 939 included cases with proven PACs, the total incidence of adverse outcome was 6.8% (64/939). CHDs were diagnosed in 14 cases (1.5%, 95%-CI 0.9-2.5%) of which eight prenatally and six postnatally. Compared to baseline, the incidence of CHD in the presence of fetal PACs was increased (OR 1.8, 95%-CI 1.0-3.3, p=0.034). Tachyarrhythmias occurred prenatally and/or postnatally in 32 cases (3.4%) of which eight (25.0%) showed signs of cardiac failure and in 23 (71.9%) antiarrhythmic therapy was required. None of the tachyarrhythmias led to fetal or neonatal death. Risk factors for a tachyarrhythmia were: PACs with short runs of supraventricular tachycardia (OR 99), blocked PACs (OR 30), PACs in bigeminy (OR 22), frequent PACs (1 per 5-10 beats) (OR 6.9), signs of cardiac failure (OR 14) and the presence of a foramen ovale aneurysm (OR 5.0). CONCLUSIONS: PACs are generally benign and resolve often spontaneously. However, fetuses with irregular heart rate should be referred for advanced ultrasonography, which should focus on the type of PACs and risk classification. When risk factors for tachyarrhythmias are identified, weekly heart rate monitoring is advised until the PACs resolve. In the absence of risk factors, standard obstetric care may be sufficient with additional instructions to report reduced fetal movements. Should tachyarrhythmias or cardiac failure develop, referral back to the FMU is then indicated. This article is protected by copyright. All rights reserved.

The interplay between susceptibility and vaccine effectiveness control the timing and size of an emerging seasonal influenza wave in England.

Relaxing social distancing measures and reduced level of influenza over the last two seasons may lead to a winter 2022 influenza wave in England. We used an established model for influenza transmission and vaccination to evaluate the rolled out influenza immunisation programme over October to December 2022. Specifically, we explored how the interplay between pre-season population susceptibility and influenza vaccine efficacy control the timing and the size of a possible winter influenza wave. Our findings suggest that susceptibility affects the timing and the height of a potential influenza wave, with higher susceptibility leading to an earlier and larger influenza wave while vaccine efficacy controls the size of the peak of the influenza wave. With pre-season susceptibility higher than pre-COVID-19 levels, under the planned vaccine programme an early influenza epidemic wave is possible, its size dependent on vaccine effectiveness against the circulating strain. If pre-season susceptibility is low and similar to pre-COVID levels, the planned influenza vaccine programme with an effective vaccine could largely suppress a winter 2022 influenza outbreak in England.

Implications of fetal premature atrial contractions: systematic review.

OBJECTIVE: Fetal heart-rate irregularities occur in 1-2% of pregnancies and are usually caused by premature atrial contractions (PAC). Although PAC are considered benign, they may be associated with cardiac defects and tachyarrhythmia. We aimed to determine the incidence of congenital heart defects (CHDs) and complications in fetuses with PAC. METHODS: This was a systematic review and meta-analysis conducted in accordance with the PRISMA statement for reporting items for systematic reviews and meta-analyses. MEDLINE and EMBASE were searched from 1990 to June 2021 to identify studies on fetuses with PAC. The primary outcome was CHD; secondary outcomes were complications using the endpoints supraventricular tachyarrhythmia (SVT), cardiac failure and intrauterine fetal demise. Meta-analysis of proportions was performed, subdivided into high-risk and low-risk populations based on reason for referral. Pooled incidences with 95% CIs were calculated. RESULTS: Of 2443 unique articles identified, 19 cohort studies including 2260 fetuses were included. The pooled incidence of CHD in fetuses with PAC was 2.8% (95% CI, 1.5-4.1%), when 0.6% is the incidence expected in the general population. The pooled incidence of CHD was 7.2% (95% CI, 3.5-10.9%) in the high-risk population and 0.9% (95% CI, 0.0-2.0%) in the low-risk population. SVT occurred in 1.4% (95% CI, 0.6-3.4%) of fetuses diagnosed with PAC. Cardiac failure was described in 16 fetuses (1.4% (95% CI, 0.5-3.5%)), of which eight were CHD-related. Intrauterine fetal demise occurred in four fetuses (0.9% (95% CI, 0.5-1.7%)) and was related to CHD in two cases. CONCLUSIONS: Our findings suggest that the risk of CHD in fetuses with PAC is 4-5 times higher than that in the general population. CHD was present more frequently in the high-risk population. Consequently, an advanced ultrasound examination to diagnose PAC correctly and exclude CHD is recommended. Complications of PAC are rare but can result in fetal demise, thus weekly fetal heart-rate monitoring remains advisable to enable early detection of SVT and to prevent cardiac failure. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Moral reasoning perspectives of community pharmacists in situations of drug shortages.

BACKGROUND: Drug shortages affect health systems worldwide. Research in community pharmacy has focused on the nature, extent and impact of these shortages on patients and pharmacists. However, pharmacists' moral reasoning in situations of drug shortages has not been addressed. OBJECTIVE: To explore the moral reasoning perspectives of Dutch community pharmacists in situations of drug shortages. METHOD: An electronic survey was developed around three drug shortage scenarios with a varying impact on patient outcomes: a Contraceptive, a Parkinson's and an Osteoporosis scenario. Pharmacists rated the likelihood of nine handling options and rated and ranked 13 considerations that may have played a role therein. The considerations represented three moral reasoning perspectives (MRPs): a business orientation (BO), a rules and regulations (RR), and a professional ethics (PE) MRP. Principle component analysis (PCA) was used to investigate construct validity of the MRPs. MRP rating and MRP ranking scores measured the relative importance of the different MRPs of pharmacists in the three shortages. RESULTS: Results from 267 Pharmacists were obtained. They reported mostly similar handling in the three shortages, except for the likelihood to make agreements with prescribers or other pharmacists and regarding the decision to import a product. The PCA analysis confirmed the three MRPs that accounted for 29% of variance in the data. Both the MRP rating and especially the MRP ranking scores indicated that PE-MRP considerations were most influential on pharmacists' intended handling of the shortages. In the Contraceptive and the Osteoporosis scenarios, the relative importance of a BO-MRP was higher than in the Parkinson's scenario. CONCLUSION: Pharmacists predominantly reason with a PE-MRP when handling drug shortages. However, this perspective can be compromised when the drug shortage is perceived to have a lower impact on patient outcomes and when alternative drugs or therapy are expensive.

[Revised multidisciplinary guidelines 'Varicella'; broader indication for post-exposure prophylaxis]. / Herziene multidisciplinaire richtlijn 'Varicella'.

Post-exposure prophylaxis (PEP) with varicella zoster immunoglobulins (VZIG) should be administered as soon as possible after exposure to the virus, but always within ten days; in the previous guidelines this was within 96 hours. In cases of perinatal exposure, PEP with VZIG should be administered to neonates if the mother develops clinical chickenpox between seven days before delivery and seven days after delivery; in the previous guidelines this was between five days before delivery and two days after delivery. A new chapter on the treatment of chickenpox has been added to the guidelines.

International consensus: ovarian tissue cryopreservation in young Turner syndrome patients: outcomes of an ethical Delphi study including 55 experts from 16 different countries.

STUDY QUESTION: What is the standpoint of an international expert panel on ovarian tissue cryopreservation (OTC) in young females with Turner syndrome (TS)? SUMMARY ANSWER: The expert panel states that OTC should be offered to young females with TS, but under strict conditions only. WHAT IS KNOWN ALREADY: OTC is already an option for preserving the fertility of young females at risk of iatrogenic primary ovarian insufficiency (POI). Offering OTC to females with a genetic cause of POI could be the next step. One of the most common genetic disorders related to POI is TS. Due to an early depletion of the ovarian reserve, most females with TS are confronted with infertility before reaching adulthood. However, before offering OTC as an experimental fertility preservation option to young females with TS, medical and ethical concerns need to be addressed. STUDY DESIGN, SIZE, DURATION: A three-round ethical Delphi study was conducted to systematically discuss whether the expected benefits exceed the expected negative consequences of OTC in young females with TS. The aim was to reach group consensus and form an international standpoint based on selected key statements. The study took place between February and December 2018. PARTICIPANTS/MATERIALS, SETTING, METHODS: Anonymous panel selection was based on expertise in TS, fertility preservation or medical ethics. A mixed panel of 12 gynaecologists, 13 (paediatric) endocrinologists, 10 medical ethicists and 20 patient representatives from 16 different countries gave consent to participate in this international Delphi study. In the first two rounds, experts were asked to rate and rank 38 statements regarding OTC in females with TS. Participants were offered the possibility to adjust their opinions after repetitive feedback. The selection of key statements was based on strict inclusion criteria. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 46 participants completed the first Delphi round (response rate 84%). Based on strict selection criteria, six key statements were selected, and 13 statements were discarded. The remaining 19 statements and two additional statements submitted by the expert panel were re-evaluated in the second round by 41 participants (response rate 75%). The analysis of the second survey resulted in the inclusion of two additional key statements. After the approval of these eight key statements, the majority of the expert panel (96%) believed that OTC should be offered to young females with TS, but in a safe and controlled research setting first, with proper counselling and informed consent procedures, before offering this procedure in routine care. The remaining participants (4%) did not object but did not respond despite several reminders. LIMITATIONS, REASONS FOR CAUTION: The anonymous nature of this study may have led to lack of accountability. The selection of experts was based on their willingness to participate. The fact that not all panellists took part in all rounds may have resulted in selection bias. WIDER IMPLICATIONS OF THE FINDINGS: This international standpoint is the first step in the global acceptance of OTC in females with TS. Future collaborative research with a focus on efficacy and safety and long-term follow-up is urgently needed. Furthermore, we recommend an international register for fertility preservation procedures in females with TS. STUDY FUNDING/COMPETING INTEREST(S): Unconditional funding (A16-1395) was received from Merck B.V., The Netherlands. The authors declare that they have no conflict of interest.

Follow-up ultrasound in second-trimester low-positioned anterior and posterior placentae: prospective cohort study.

OBJECTIVES: The majority of cases of placenta previa or a low-lying placenta in the second trimester will have a normal placental position in the third trimester. The aim of this study was to assess the accuracy of the distance between the placenta and the internal os of the cervix (IOD) in the second trimester for the prediction of third-trimester low-positioned placenta, and to define a cut-off value at which all cases of third-trimester low-positioned placenta are identified. METHODS: This was a prospective cohort study including women undergoing a transvaginal ultrasound examination between 18 and 24 weeks' gestation who had a low-positioned placenta, defined as an IOD of < 20 mm. Low-positioned placenta included placenta previa, defined as a placenta covering the internal os of the cervix, and a low-lying placenta, defined as a placenta lying near to (within 20 mm) but not overlying the internal os. All women were re-evaluated in the third trimester. Relative risks for a low-positioned placenta in the third trimester were calculated for women with placenta previa vs a low-lying placenta, posterior vs anterior placenta and positive vs negative history of Cesarean section. Multilevel likelihood ratios for ranges of IOD in the prediction of a low-positioned placenta in the third trimester were calculated separately for anteriorly and posteriorly located placentae. Corresponding receiver-operating-characteristics curves were constructed. RESULTS: In total, 958 women were included in the study. In the second trimester, placentae were more frequently located on the posterior side (62.0%) than on the anterior side (38.0%). In the third trimester, 48/958 (5.0%) placentae persisted as a low-positioned placenta. Women with placenta previa in the second trimester had a higher risk of a low-positioned placenta in the third trimester than did those with a low-lying placenta in the second trimester (37/181 (20.4%) vs 11/777 (1.4%); relative risk (RR), 17.9 (95% CI, 8.9-36.0)). Women with a posterior placenta had a higher risk of a low-positioned placenta in the third trimester than did those with an anterior placenta (38/594 (6.4%) vs 10/364 (2.7%); RR, 2.4 (95% CI, 1.2-4.9)), as did women with a history of Cesarean section compared with those without such a history (14/105 (13.3%) vs 34/853 (4.0%); RR, 3.7 (95% CI, 1.9-7.2)). The cut-off value of IOD in the second trimester to identify all cases of an abnormally located placenta in the third trimester was 15.5 mm for posteriorly located placentae, while for anteriorly located placentae the IOD cut-off was lower, namely -4.5 mm, representing a 4.5-mm overlap of the placental edge over the internal os of the cervix. CONCLUSIONS: With incorporation of a safety margin of 5 mm and ensuring that all women with placenta previa undergo a follow-up scan, we recommend lowering the IOD cut-off value for follow-up in cases of an anterior low-positioned placenta from 20 to 5 mm, which would decrease the number of unnecessary follow-up ultrasound examinations without missing any high-risk women. © 2019 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

[Ethical decision making in dental care for frail older people]. / Ethische kwesties in de mondzorg voor kwetsbare ouderen.

Vurnerable older people often need intensive preventive and curative oral health care. However, their physical and cognitive decline does not always allow for lege artis implementation of dental treatments. This causes practical problems often with related moral issues. Including these moral issues in planning and implementation will make oral healthcare more effective and will also alleviate moral pressure on oral healthcare providers. Mostly the moral issues relate to every day ethics, which can be solved by all persons involved collectively, in open consultation and with an ethics of care approach. This means aiming at 'doing the right thing in the right way', including all the relevant aspects of the person of the patient and his/her environment. To achieve this, oral health care should be embedded in the overall care process for the elderly and care providers should feel involved with the older person and have reflective skills.

Moral reasoning among Dutch community pharmacists: testing the applicability of the Australian Professional Ethics in Pharmacy test.

Background Moral reasoning competency is essential in healthcare practice, especially in situations of moral dilemmas when a professional has to choose a morally justifiable action among several suboptimal action options. The Australian Professional Ethics in Pharmacy test (PEP test) measures moral reasoning among pharmacists. In Australia three levels of moral reasoning (schemas) were measured (1) business orientation (2) rules and regulations, and (3) patient rights (i.e. most advanced schema). Objective To test the applicability of the PEP test to pharmacists working in the Netherlands. Setting Dutch community pharmacy. Methods The PEP test consists of 36 statements (items) accompanying 3 moral dilemma scenarios. It was translated into Dutch and completed by 390 pharmacists. Principle component analysis (PCA) was used to investigate construct validity and Cronbach's Alpha was used to indicate internal consistency of the Dutch version of the PEP test. The eligible grouped statements and perceived possible moral reasoning schemas were compared to the Australian findings. Main outcome measure Moral reasoning schemas. Results The PCA analysis resulted in 3 components (i.e. possible moral reasoning schemas) that together accounted 27% variance in the data. The statements that represented the moral reasoning schemas 'business orientation' and 'rules and regulations' were somewhat similar when comparing these with the statements that represented these schemas in the PEP test study. The most advanced moral reasoning schema identified in Dutch pharmacists contained different statements compared to the statements that represented that schema among Australian pharmacists. This schema was labelled 'professional ethics'. Conclusion The PEP test needs further adaptation to the Dutch pharmacy practice context: especially the statements that should reflect the most advanced moral reasoning schema, need more accurate representations of professional pharmacy ethics that guide pharmacists in the Netherlands. Moral reasoning tests for a specific professional setting or country should be developed and adapted by experts who share the same professional values and practice as the respondents.

Vaginal delivery in women with a low-lying placenta: a systematic review and meta-analysis.

BACKGROUND: Low-lying placentas are positioned close to the internal os of the cervix. The preferred way of delivery within this group is unclear. OBJECTIVES: To review the literature on the success of a vaginal delivery with a low-lying placenta. SEARCH STRATEGY: We searched OVID EMBASE and MEDLINE for studies on vaginal delivery with a low-lying placenta. DATA COLLECTION AND ANALYSES: Data was extracted on successful vaginal delivery and emergency caesarean section due to haemorrhage. We distinguished between different distances between the cervical os and the placenta (internal os distance, IOD); 0-10, 11-20, and >20 mm. A meta-analysis of proportions was made for successful vaginal delivery and emergency caesarean section at every cut-off value. Maternal morbidity (i.e. antepartum blood loss, postpartum haemorrhage and blood transfusion) at different cut-off values was evaluated. MAIN RESULTS: Of the 999 articles retrieved, 10 articles met our inclusion criteria. A vaginal delivery was successful at an IOD of 0-10 mm in 43%, at an IOD of 11-20 mm in 85%, and at an IOD of >20 mm in 82%. A shorter IOD had a higher chance of antepartum haemorrhage, whereas a larger IOD needed postpartum blood transfusion more often. Postpartum haemorrhage did not depend on IOD. CONCLUSION: A low-lying placenta is not a contraindication for a trial of labour, and the morbidity in these women is not increased. However, women with a low-lying placenta have a higher chance of an emergency caesarean section compared with women with a placenta outside the lower uterine segment. Therefore, shared decision-making is mandatory in case of a trial of labour. TWEETABLE ABSTRACT: This systematic review demonstrates the possibility of a vaginal delivery in women with a low-lying placenta within 20 mm of the cervix.

Exome-sequencing in a large population-based study reveals a rare Asn396Ser variant in the LIPG gene associated with depressive symptoms.

Despite a substantial genetic component, efforts to identify common genetic variation underlying depression have largely been unsuccessful. In the current study we aimed to identify rare genetic variants that might have large effects on depression in the general population. Using high-coverage exome-sequencing, we studied the exonic variants in 1265 individuals from the Rotterdam study (RS), who were assessed for depressive symptoms. We identified a missense Asn396Ser mutation (rs77960347) in the endothelial lipase (LIPG) gene, occurring with an allele frequency of 1% in the general population, which was significantly associated with depressive symptoms (P-value=5.2 × 10-08, ß=7.2). Replication in three independent data sets (N=3612) confirmed the association of Asn396Ser (P-value=7.1 × 10-03, ß=2.55) with depressive symptoms. LIPG is predicted to have enzymatic function in steroid biosynthesis, cholesterol biosynthesis and thyroid hormone metabolic processes. The Asn396Ser variant is predicted to have a damaging effect on the function of LIPG. Within the discovery population, carriers also showed an increased burden of white matter lesions (P-value=3.3 × 10-02) and a higher risk of Alzheimer's disease (odds ratio=2.01; P-value=2.8 × 10-02) compared with the non-carriers. Together, these findings implicate the Asn396Ser variant of LIPG in the pathogenesis of depressive symptoms in the general population.

17D yellow fever vaccine elicits comparable long-term immune responses in healthy individuals and immune-compromised patients.

BACKGROUND: The 17D live attenuated yellow fever (YF) vaccine is contra-indicated in immune-compromised individuals and may elicit a suboptimal immunologic response. The aim of this study is to assess whether long-term immune responses against the YF vaccine are impaired in immune-compromised patients. MATERIALS AND METHODS: Fifteen patients using different immunosuppressive drugs and 30 healthy individuals vaccinated 0-22 years ago were included. The serological response was measured using the plaque reduction neutralization test (PRNT). CD8(+) and CD4(+) T-cell responses were measured following proliferation and re-stimulation with YFV peptide pools. Phenotypic characteristics and cytokine responses of CD8(+) T-cells were determined using class I tetramers. RESULTS: The geometric mean titre of neutralizing antibodies was not different between the groups (p = 0.77). The presence of YFV-specific CD4(+) and CD8(+) T-cell did not differ between patients and healthy individuals (15/15, 100.0% vs. 29/30, 96.7%, p = 0.475). Time since vaccination correlated negatively with the number of YFV-specific CD8(+) T-cells (r = -0.66, p = 0.0045). Percentages of early-differentiated memory cells increased (r = 0.67, p = 0.017) over time. CONCLUSION: These results imply that YF vaccination is effective despite certain immunosuppressive drug regimens. An early-differentiated memory-like phenotype persisted, which is associated with effective expansion upon re-encounter with antigen, suggesting a potent memory T-cell pool remains.

Antibody response to a T-cell-independent antigen is preserved after splenic artery embolization for trauma.

Splenic artery embolization (SAE) is increasingly being used as a nonoperative management strategy for patients with blunt splenic injury following trauma. The aim of this study was to assess the splenic function of patients who were embolized. A clinical study was performed, with splenic function assessed by examining the antibody response to polysaccharide antigens (pneumococcal 23-valent polysaccharide vaccine), B-cell subsets, and the presence of Howell-Jolly bodies (HJB). The data were compared to those obtained from splenectomized patients and healthy controls (HC) who had been included in a previously conducted study. A total of 30 patients were studied: 5 who had proximal SAE, 7 who had distal SAE, 8 who had a splenectomy, and 10 HC. The median vaccine-specific antibody response of the SAE patients (fold increase, 3.97) did not differ significantly from that of the HC (5.29; P = 0.90); however, the median response of the splenectomized patients (2.30) did differ (P = 0.003). In 2 of the proximally embolized patients and none of the distally embolized patients, the ratio of the IgG antibody level postvaccination compared to that prevaccination was <2. There were no significant differences in the absolute numbers of lymphocytes or B-cell subsets between the SAE patients and the HC. HJB were not observed in the SAE patients. The splenic immune function of embolized patients was preserved, and therefore routine vaccination appears not to be indicated. Although the median antibody responses did not differ between the patients who underwent proximal SAE and those who underwent distal SAE, 2 of the 5 proximally embolized patients had insufficient responses to vaccination, whereas none of the distally embolized patients exhibited an insufficient response. Further research should be done to confirm this finding.

Upregulation of CXCR3 expression on CD8+ T cells due to the pervasive influence of chronic hepatitis B and C virus infection.

Chronic systemic 'latent' viral infections such as Cytomegalovirus infection (CMV) are known to leave a fingerprint in the total T-cell population. We investigated whether chronic infections with a 'persistent' viremia, such as chronic hepatitis B and C (CHB, CHC), characterized by local organ-specific inflammation, also impact the total peripheral T-cell population or other virus specific T-cells that do not target hepatitis viruses. No phenotypic or functional differences were found between CD8(+) T-cells or CMV- or Epstein-Barr virus specific T-cells in viral hepatitis and healthy controls (HC). However, expression of chemokine-receptor CXCR3 was significantly higher on total peripheral CD8(+) T-cells of CHB or CHC patients compared to HC (p<0.005) which may reflect the pervasive influence of a persistent viral infection, even when restricted to the liver. In CHB higher CXCR3 expression was associated with positive HBeAg-status and correlated with the percentage of HBsAg expressing hepatocytes found in liver biopsies, both pointing to a relation between CXCR3 expression and disease activity. In fact chemokine-receptors such as CXCR3 are important for T-cell recruitment to the liver and chemokine-ligands specific for CXCR3 are upregulated in chronic hepatitis. Modulating chemokine(receptor) expression could be a potential target for future therapy to optimize the anti-viral immunologic environment in the liver.

A generalized functional response for predators that switch between multiple prey species.

We develop a theory for the food intake of a predator that can switch between multiple prey species. The theory addresses empirical observations of prey switching and is based on the behavioural assumption that a predator tends to continue feeding on prey that are similar to the prey it has consumed last, in terms of, e.g., their morphology, defences, location, habitat choice, or behaviour. From a predator's dietary history and the assumed similarity relationship among prey species, we derive a general closed-form multi-species functional response for describing predators switching between multiple prey species. Our theory includes the Holling type II functional response as a special case and makes consistent predictions when populations of equivalent prey are aggregated or split. An analysis of the derived functional response enables us to highlight the following five main findings. (1) Prey switching leads to an approximate power-law relationship between ratios of prey abundance and prey intake, consistent with experimental data. (2) In agreement with empirical observations, the theory predicts an upper limit of 2 for the exponent of such power laws. (3) Our theory predicts deviations from power-law switching at very low and very high prey-abundance ratios. (4) The theory can predict the diet composition of a predator feeding on multiple prey species from diet observations for predators feeding only on pairs of prey species. (5) Predators foraging on more prey species will show less pronounced prey switching than predators foraging on fewer prey species, thus providing a natural explanation for the known difficulties of observing prey switching in the field.