Wnt/ß-catenin pathway and cell adhesion deregulation in CSDE1-related intellectual disability and autism spectrum disorders.

Among the genetic factors playing a key role in the etiology of intellectual disabilities (IDs) and autism spectrum disorders (ASDs), several encode RNA-binding proteins (RBPs). In this study, we deciphered the molecular and cellular bases of ID-ASD in a patient followed from birth to the age of 21, in whom we identified a de novo CSDE1 (Cold Shock Domain-containing E1) nonsense variation. CSDE1 encodes an RBP that regulates multiple cellular pathways by monitoring the translation and abundance of target transcripts. Analyses performed on the patient's primary fibroblasts showed that the identified CSDE1 variation leads to haploinsufficiency. We identified through RNA-seq assays the Wnt/ß-catenin signaling and cellular adhesion as two major deregulated pathways. These results were further confirmed by functional studies involving Wnt-specific luciferase and substrate adhesion assays. Additional data support a disease model involving APC Down-Regulated-1 (APCDD1) and cadherin-2 (CDH2), two components of the Wnt/ß-catenin pathway, CDH2 being also pivotal for cellular adhesion. Our study, which relies on both the deep phenotyping and long-term follow-up of a patient with CSDE1 haploinsufficiency and on ex vivo studies, sheds new light on the CSDE1-dependent deregulated pathways in ID-ASD.

Changes in serum PSA after endoscopic enucleation of the prostate are predictive for the future diagnosis of prostate cancer.

PURPOSE: After Endoscopic Enucleation of the Prostate (EEP) for benign prostatic obstruction (BPO), men remain at risk for prostate cancer (PCa). Significant PSA changes occur after enucleation, which interfere with later screening for PCa. It remains unclear which patients need further diagnostic investigations for PCa after EEP. The goal of this study was to identify an independent predictor for PCa diagnosis after Holmium Laser Enucleation of the Prostate (HoLEP) in patients whose HoLEP resection specimen did not show PCa. METHODS: Data of 773 patients who underwent HoLEP for BPO between 2010 and 2018 in a referral center were analyzed. Exclusion criteria were PCa detection in the HoLEP specimen or absence of post-operative PSA values. Patients were divided in a PCa group and Control group depending on whether or not PCa was detected during follow-up after HoLEP. The predictive value for future diagnosis of PCa of different forms of PSA-change after HoLEP was analyzed by multivariate Cox regression and ROC analysis. RESULTS: Overall, 24 (4.2%) patients developed PCa after HoLEP. At 5 year follow-up, the PCa-free survival rate was 85%. First post-operative PSA was an independent predictor of PCa diagnosis after HoLEP (HR 1.106, 95% CI 1.074-1.139, p < 0.001, ROC AUC 0.903) with an optimal cut-off value of 1.73 ng/ml (sensitivity 83.3%, specificity 82.3%). CONCLUSIONS: For patients who underwent HoLEP for BPO, post-operative PSA after HoLEP is an independent predictor for future PCa diagnosis. When PSA is > 1.73 ng/ml within the first year after HoLEP, rigorous follow-up and diagnostic investigations for PCa are indicated.

Coverage determinants of breast cancer screening in Flanders: an evaluation of the past decade.

BACKGROUND: Breast cancer (BC) is the most common cancer in women in the developed world. In order to find developing cancers in an early stage, BC screening is commonly used. In Flanders, screening is performed in and outside an organized breast cancer screening program (BCSP). However, the determinants of BC screening coverage for both screening strategies are yet unknown. OBJECTIVE: To assess the determinants of BC screening coverage in Flanders. METHODS: Reimbursement data were used to attribute a screening status to each woman in the target population for the years 2008-2016. Yearly coverage data were categorized as screening inside or outside BCSP or no screening. Data were clustered by municipality level. A generalized linear equation model was used to assess the determinants of screening type. RESULTS: Over all years and municipalities, the median screening coverage rate inside and outside BCSP was 48.40% (IQR: 41.50-54.40%) and 14.10% (IQR: 9.80-19.80%) respectively. A higher coverage rate outside BSCP was statistically significantly (P < 0.001) associated with more crowded households (OR: 3.797, 95% CI: 3.199-4.508), younger age, higher population densities (OR: 2.528, 95% CI: 2.455-2.606), a lower proportion of unemployed job seekers (OR: 0.641, 95% CI: 0.624-0.658) and lower use of dental care (OR: 0.969, 95% CI: 0.967-0.972). CONCLUSION: Coverage rate of BC screening is not optimal in Flanders. Women with low SES that are characterized by younger age, living in a high population density area, living in crowded households, or having low dental care are less likely to be screened for BC in Flanders. If screened, they are more likely to be screened outside the BCSP.

Pain-related fear in adolescents with chronic musculoskeletal pain: process evaluation of an interdisciplinary graded exposure program.

BACKGROUND: For studying the effectiveness of treatment, it is important to check whether a new treatment is performed as originally described in the study-protocol. OBJECTIVES: To evaluate whether an interdisciplinary graded exposure program, for adolescents with chronic musculoskeletal pain reporting pain-related fear, was performed according to protocol, and whether it is feasible to implement the program in rehabilitation care. METHODS: A process evaluation where quantitative and qualitative data on participant characteristics (adolescents, parents and therapists), attendance and participants' opinion on the program were collected, by means of registration forms, questionnaires and group interviews. To evaluate treatment fidelity, audio and video recordings of program sessions were analyzed. RESULTS: Thirty adolescents were offered the program, of which 23 started the program. Adolescents attended on average 90% of the sessions. At least one parent per adolescent participated in the program. Analysis of 20 randomly selected recordings of treatment sessions revealed that treatment fidelity was high, since 81% of essential treatment elements were offered to the adolescents. The program was considered client-centered by adolescents and family-centered by parents. Treatment teams wished to continue offering the program in their center. CONCLUSION: The interdisciplinary graded exposure program was performed largely according to protocol, and therapists, adolescents and their parents had a favorable opinion on the program. Implementation of the program in rehabilitation care is considered feasible. TRIAL REGISTRATION: Clinicaltrials.gov ID: NCT02181725 (7 February 2014).

Flemish breast cancer screening programme: 15 years of key performance indicators (2002-2016).

BACKGROUND: We examined 15 years of key performance indicators (KPIs) of the population-based mammography screening programme (PMSP) in Flanders, Belgium. METHODS: Individual screening data were linked to the national cancer registry to obtain oncological follow-up. We benchmarked crude KPI results against KPI-targets set by the European guidelines and KPI results of other national screening programmes. Temporal trends were examined by plotting age-standardised KPIs against the year of screening and estimating the Average Annual Percentage Change (AAPC). RESULTS: PMSP coverage increased significantly over the period of 15 years (+ 7.5% AAPC), but the increase fell to + 1.6% after invitation coverage was maximised. In 2016, PMSP coverage was at 50.0% and opportunistic coverage was at 14.1%, resulting in a total coverage by screening of 64.2%. The response to the invitations was 49.8% in 2016, without a trend. Recall rate decreased significantly (AAPC -1.5% & -5.0% in initial and subsequent regular screenings respectively) while cancer detection remained stable (AAPC 0.0%). The result was an increased positive predictive value (AAPC + 3.8%). Overall programme sensitivity was stable and was at 65.1% in 2014. In initial screens of 2015, the proportion of DCIS, tumours stage II+, and node negative invasive cancers was 18.2, 31.2, and 61.6% respectively. In subsequent regular screens of 2015, those proportions were 14.0, 24.8, and 65.4% respectively. Trends were not significant. CONCLUSION: Besides a suboptimal attendance rate, most KPIs in the Flemish PMSP meet EU benchmark targets. Nonetheless, there are several priorities for further investigation such as a critical evaluation of strategies to increase screening participation, organising a biennial radiological review of interval cancers, analysing the effect that preceding opportunistic screening has on the KPI for initial screenings, and efforts to estimate the impact on breast cancer mortality.

Maternal quality of life in routine labor epidural analgesia versus labor analgesia on request: results of a randomized trial.

INTRODUCTION: The purpose of this study was to evaluate the changes in maternal quality of life (QOL) from pregnancy to 6 weeks after delivery between routine labor epidural analgesia (EA) and pain relief on maternal request only. METHODS: \Women delivering of a singleton in cephalic presentation beyond 36 + 0 weeks' gestation were randomly allocated to EA as a routine during labor (routine EA group), or to any kind of analgesia on request only (control group). The Short Form health survey (SF-36) was used to assess women's QOL before randomization, and 6 weeks postpartum. Data were analyzed according to the intention to treat principle. RESULTS: A total of 488 women were included, and antepartum as well as postpartum SF-36 questionnaires were filled in by 356 (73.0%) women, 176 (49.4%) in the routine EA group, and 180 (50.6%) in the control group. Changes from the QOL antepartum to the QOL 6 weeks postpartum were comparable between both groups, also in the subgroup of women in the control group who gave birth without any pain medication (n = 41, 22.8%). Maternal age and the incidence of adverse events related to EA, which were both higher in the routine EA group, had no influence on the changes in QOL. Differences in request for pain relief were comparable with other studies. CONCLUSION: Routine administration of EA during labor and pain relief on maternal request only are associated with comparable changes of women's QOL antepartum to 6 weeks postpartum.

Practitioner review: evidence-based practice guidelines on alcohol and drug misuse among adolescents: a systematic review.

BACKGROUND: Context-specific evidence-based guidelines on how to prevent and treat substance misuse among adolescents are currently lacking in many countries. Due to the time consuming nature of de novo guideline development, the ADAPTE collaboration introduced a methodology to adapt existing guidelines to a local context. An important step in this method is a systematic review to identify relevant high-quality evidence-based guidelines. This study describes the results of this step for the development of guidelines on adolescent alcohol and drug misuse in Belgium. METHODS: Rigorous systematic review methodology was used. This included searches of electronic databases (Medline, Embase, Cinahl, PsychInfo, and ERIC in June 2011), websites of relevant organizations, and reference lists of key publications. Experts in the field were also contacted. Included were Dutch, English, French, or German evidence-based practice guidelines from 2006 or later on the prevention, screening, assessment, or treatment of alcohol or illicit drug misuse in persons aged 12-18 years. Two independent reviewers assessed the quality of the guidelines using the AGREE II (Appraisal of Guidelines for Research and Evaluation) instrument. SCOPE: This overview provides a framework of current knowledge in adolescent alcohol and drug misuse prevention and treatment. RESULTS: This systematic review identified 32 relevant evidence-based guidelines on substance misuse among adolescents. Nine guidelines were judged to be of high quality; of which four had recommendations specifically on adolescents: one on school-based prevention, one on substance misuse prevention in vulnerable young people and two on alcohol misuse with specific sections for the adolescent population. There were few commonalities as guidelines focused on different target groups, professional disciplines and type and level of substance misuse. Evidence to support the recommendations was sparse, and many recommendations were based on expert consensus or on studies among adults. Also, the link between evidence and recommendations was often unclear. CONCLUSIONS: There are a substantial number of guidelines addressing substance misuse in adolescents. However, only four high-quality guidelines included recommendations specific for adolescents. The current level of evidence that underpins the recommendations in these high-quality guidelines is low.

Quantifying independent risk factors for failing to rescreen in a breast cancer screening program in Flanders, Belgium.

BACKGROUND: Mammographic screening may reduce breast cancer mortality by about 20%, provided participation is high and women screen regularly. We quantified independent risk factors for failing to rescreen and built a model to predict how rescreening rates change if these risk factors would be modified. METHODS: Multivariate analysis was used to analyze data from a prospective study which included a self-administered questionnaire and rescreening status 30months after a t0 mammogram, using a random sample of women 50-67years (Belgium 2010-2013). RESULTS: A false positive result at the most recent past mammogram (Odds Ratio=5.0, 95% Confidence Interval 3.6-6.8), an interval until new invitation greater than 25months (Odds Ratio=4.8 for >29months, 95% Confidence Interval 2.9-8.1), waiting times in the mammography unit >1h (Odds Ratio=2.1, 95% Confidence Interval 1.2-3.7) and difficulties in reaching the unit (Odds Ratio=2.5, 95% Confidence Interval 1.4-4.4) were the strongest independent predictors for failing to rescreen. The area under the curve of the receiver operating characteristic analysis was 0.705 for the model development stage and 0.717 for the validation stage and goodness-of-fit was good. CONCLUSIONS: Maintaining an invitation cycle of maximum 25months, limiting waiting time in the mammography unit and lowering the number of false positives could increase breast cancer screening compliance.

Antimicrobial resistance to benzylpenicillin in invasive pneumococcal disease in Belgium, 2003-2010: the effect of altering clinical breakpoints.

The Belgian data (2003-2010) for the European Antimicrobial Resistance Surveillance Network (EARS-Net) showed a significant decreasing trend in the proportion of penicillin non-susceptible Streptococcus pneumoniae (9·4% to <1%) from blood and CSF isolates. We found that 75% of this decrease was explained by a change in Clinical and Laboratory Standards Institute (CLSI) breakpoints as the trend disappeared if only the new breakpoints were applied. Applying only European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints also resulted in a relatively stable proportion of penicillin non-susceptibility (average 5%), but this proportion was 7-13 times higher than with the new CLSI breakpoints. When the new CLSI breakpoints alone are used, fewer than 1% of bacteraemia isolates were penicillin non-susceptible during the entire period, but the proportion of non-susceptible meningitis isolates rose from 6·3% in 2003 to 15·9% between 2003 and 2010. Changing breakpoints should lead to retrospective analysis of historical data to minimize wrongly interpreting resistance trends.

A missense mutation in the rod domain of keratin 14 associated with recessive epidermolysis bullosa simplex.

Epidermolysis bullosa simplex (EBS) is a group of epidermal blistering diseases almost invariably transmitted as a dominant trait, which has recently been shown to arise from mutations in keratins 14 and 5 (K14 and K5). We describe a family with recessive EBS in which the disease is tightly linked to the substitution of the highly conserved glutamic acid-144 to alanine in the first helical segment of the rod domain of keratin 14. In contrast, linkage with keratin 5 was excluded. The loss of an ionic interaction with keratin 5 is likely to affect K14-K5 heterodimer formation. Our data suggest that this mutation underlies EBS in our family, and that mutations in keratin genes may impair the mechanical integrity of basal keratinocytes in a recessive as well as dominant fashion.

A homozygous insertion-deletion in the type VII collagen gene (COL7A1) in Hallopeau-Siemens dystrophic epidermolysis bullosa.

The Hallopeau-Siemens type of recessive dystrophic epidermolysis bullosa (HS-RDEB) is a life-threatening autosomal disease characterized by loss of dermal-epidermal adherence with abnormal anchoring fibrils (AF). We recently linked HS-RDEB to the type VII collagen gene (COL7A1) which encodes the major component of AF. We describe a patient who is homozygous for an insertion-deletion in the FN-4A domain of the COL7A1 gene. This defect causes a frameshift mutation which leads to a premature stop codon in the FN-5A domain, resulting in a marked diminution in mutated mRNA levels, with no detectable type VII collagen polypeptide in the patient. Our data suggest strongly that this null allele prevents normal anchoring fibril formation in homozygotes and is the underlying cause of HS-RDEB in this patient.

Mutations in LHX3 result in a new syndrome revealed by combined pituitary hormone deficiency.

Combined pituitary hormone deficiency (CPHD) has been linked with rare abnormalities in genes encoding transcription factors necessary for pituitary development. We have isolated LHX3, a gene involved in a new syndrome, using a candidate-gene approach developed on the basis of documented pituitary abnormalities of a recessive lethal mutation in mice generated by targeted disruption of Lhx3 (ref. 2). LHX3, encoding a member of the LIM class of homeodomain proteins, consists of at least six exons located at 9q34. We identified a homozygous LHX3 defect in patients of two unrelated consanguineous families displaying a complete deficit in all but one (adrenocorticotropin) anterior pituitary hormone and a rigid cervical spine leading to limited head rotation. Two of these patients also displayed a severe pituitary hypoplasia, whereas one patient presented secondarily with an enlarged anterior pituitary. These LHX3 mutations consist of a missense mutation (Y116C) in the LIM2 domain at a phylogenetically conserved residue and an intragenic deletion predicting a severely truncated protein lacking the entire homeodomain. These data are consistent with function of LHX3 in the proper development of all anterior pituitary cell types, except corticotropes, and extrapituitary structures.

SOX10 mutations in patients with Waardenburg-Hirschsprung disease.

Waardenburg syndrome (WS; deafness with pigmentary abnormalities) and Hirschsprung's disease (HSCR; aganglionic megacolon) are congenital disorders caused by defective function of the embryonic neural crest. WS and HSCR are associated in patients with Waardenburg-Shah syndrome (WS4), whose symptoms are reminiscent of the white coat-spotting and aganglionic megacolon displayed by the mouse mutants Dom (Dominant megacolon), piebald-lethal (sl) and lethal spotting (ls). The sl and ls phenotypes are caused by mutations in the genes encoding the Endothelin-B receptor (Ednrb) and Endothelin 3 (Edn3), respectively. The identification of Sox10 as the gene mutated in Dom mice (B.H. et al., manuscript submitted) prompted us to analyse the role of its human homologue SOX10 in neural crest defects. Here we show that patients from four families with WS4 have mutations in SOX10, whereas no mutation could be detected in patients with HSCR alone. These mutations are likely to result in haploinsufficiency of the SOX10 product. Our findings further define the locus heterogeneity of Waardenburg-Hirschsprung syndromes, and point to an essential role of SOX10 in the development of two neural crest-derived human cell lineages.

Array comparative genomic hybridization analysis of small supernumerary marker chromosomes in human infertility.

Small supernumerary marker chromosomes (sSMC) are structurally abnormal chromosomes that cannot be unambiguously identified by conventional banding cytogenetics. This study describes four patients with sSMC in relation with infertility. Patient 1 had primary infertility. His brother, fertile, carried the same sSMC (patient 2). Patient 3 presented polycystic ovary syndrome and patient 4 primary ovarian insufficiency. Cytogenetic studies, array comparative genomic hybridization (CGH) and sperm analyses were compared with cases previously reported. sSMC corresponded to the 15q11.2 region (patients 1 and 2), the centromeric chromosome 15 region (patient 3) and the 21p11.2 region (patient 4). Array CGH showed 3.6-Mb gain for patients 1 and 2 and 0.266-Mb gain for patient 4. Sperm fluorescent in-situ hybridization analyses found ratios of 0.37 and 0.30 of sperm nuclei with sSMC(15) for patients 1 and 2, respectively (P < 0.001). An increase of sperm nuclei with disomy X, Y and 18 was noted for patient 1 compared with control and patient 2 (P < 0.001). Among the genes mapped in the unbalanced chromosomal regions, POTE B and BAGE are related to the testis and ovary, respectively. The implication of sSMC in infertility could be due to duplication, but also to mechanical effects perturbing meiosis.

Physiotherapists' knowledge, attitude and practice behavior to prevent chronification in patients with non-specific, non-traumatic, acute- and subacute neck pain: A qualitative study.

BACKGROUND: The purpose of this study was to explore physiotherapists' knowledge, attitude, and practice behavior in assessing and managing patients with non-specific, non-traumatic, acute- and subacute neck pain, with a focus on prognostic factors for chronification. METHOD: A qualitative study using in-depth semi-structured interviews was conducted with 13 physiotherapists working in primary care. A purposive sampling method served to seek the broadest perspectives. The knowledge-attitude and practice framework was used as an analytic lens throughout the process. Textual data were analyzed using qualitative content analysis with an inductive approach and constant comparison. RESULTS: Seven main themes emerged from the data; physiotherapists self-estimated knowledge and attitude, role clarity, therapeutic relationship, internal- and external barriers to practice behavior, physiotherapists' practice behaviors, and self-reflection. These findings are presented in an adjusted knowledge-attitude and practice behavior framework. CONCLUSION: A complex relationship was found between a physiotherapist's knowledge about, attitude, and practice behavior concerning the diagnostic process and interventions for non-specific, non-traumatic, acute, and subacute neck pain. Overall, physiotherapists used a biopsychosocial view of patients with non-specific neck pain. Physiotherapists' practice behaviors was influenced by individual attitudes towards their professional role and therapeutic relationship with the patient, and individual knowledge and skills, personal routines and habits, the feeling of powerlessness to modify patients' external factors, and patients' lack of willingness to a biopsychosocial approach influenced physiotherapists' clinical decisions. In addition, we found self-reflection to have an essential role in developing self-estimated knowledge and change in attitude towards their therapeutic role and therapist-patient relationship.

Irregular screening participation increases advanced stage breast cancer at diagnosis: A population-based study.

OBJECTIVE: To evaluate the effect of irregular screening behaviour on the risk of advanced stage breast cancer at diagnosis in Flanders. METHODS: All women aged 50-69 who were invited to the organized breast cancer screening and diagnosed with breast cancer before age 72 from 2001 to 2018 were included. All prevalent screen and interval cancers within 2 years of a prevalent screen were excluded. Screening behaviour was categorized based on the number of invitations and performed screenings. Four groups were defined: regular, irregular, only-once, and never attenders. Advanced stage cancer was defined as a stage III + breast cancer. The association between screening regularity and breast cancer stage at diagnosis was evaluated in multivariable logistic regression models, taking age of diagnosis and socio-economic status into account. RESULTS: In total 13.5% of the 38,005 breast cancer cases were diagnosed at the advanced stage. Compared to the regular attenders, the risk of advanced stage breast cancer for the irregular attenders, women who participated only-once, and never attenders was significantly higher with ORadjusted:1.17 (95%CI:1.06-1.29) and ORadjusted:2.18 (95%CI:1.94-2.45), and ORadjusted:5.95 (95%CI:5.33-6.65), respectively. CONCLUSIONS: In our study, never attenders were nearly six times more likely to be diagnosed with advanced stage breast cancer than regular attenders, which was much higher than the estimates published thus far. An explanation for this is that the ever screened women is a heterogeneous group regarding the participation profiles which also includes irregular and only-once attenders. The benefit of regular screening should be informed to all women invited for screening.

Determinants of Non-Participation in Population-Based Breast Cancer Screening: A Systematic Review and Meta-Analysis.

Background: Breast cancer (BC) screening can be performed in a screening program (BCSP) or in opportunistic screening. The existing reviews on the determinants of non-participation depend on self-reported data which may be biased. Furthermore, no distinction was made between the probably different determinants of both screening strategies. Objective: To find the determinants of non-participation in BCSP by means of a meta-analysis. Methods: PubMed, Embase, and Web of Science were searched for observational studies which quantified factors associated with non-participation in BCSP in a general population. Studies on opportunistic screening and studies using self-reported data were excluded. A random-effect model was used to calculate pooled odds ratios (ORs) and 95% confidence intervals (CIs). Potential sources of heterogeneity were explored by stratification of the results. Results: Twenty-nine studies with in a total of 20,361,756 women were included. Low income (OR: 1.20, 95% CI: 1.10-1.30), low education (OR: 1.18, 95% CI: 1.05-1.32), living far from an assigned screening unit (OR: 1.15, 95% CI: 1.07-1.24), being immigrant (OR: 2.64, 95% CI: 2.48-2.82), and having a male family doctor (OR: 1.43, 95% CI: 1.20-1.61) was associated with higher non-participation in screening. Reminders sent to non-attenders and estimations of ORs (adjusted or not) partly explained substantial heterogeneity. Conclusion: In this meta-analysis excluding studies on the non-participation in opportunistic screening, or with self-reported data on non-participation, the well-known determinants for non-participation are still significant, but less strong. This analysis only supports the relevance of meta-analysis of studies with registered non-participation in a BCSP. Systematic Review Registration: PROSPERO, CRD42020154016.

Contacts between general practitioners and migrants without a residence permit and the use of "urgent" medical care.

AIMS: To examine the extent to which general practitioners (GPs) are consulted by migrants without a residence permit (MRP), their use of the government sponsored reimbursement system and the difficulties encountered therewith. To study what hurdles the care recipients (MRP) experience in using healthcare and the reimbursement system. METHODS: A written survey of GPs in the Brussels Capital region and semi-structured interviews with MRP in the same area. Bivariate analysis of the GP data (two-sided independent t-test, two-sided Fisher's exact test). Recording, transcription, coding and categorizing of MRP interviews. RESULTS: Overall GP response rate was 71%. The average number of MRP contacts per month was 1.1 for all, representing 0.26% of all GP contacts. GPs working in community health centres (CHC) 4.4 MRP per month (p=0.042). The mean probability that the GP will not use the reimbursement programme is 0.66--there is less non-use in CHC (p=0.042). The main barrier for GPs is insufficient knowledge of the system, followed by its complex and time consuming paperwork. Barriers experienced by MRP include fear of deportation, lack of funds, insufficient healthcare related knowledge and communication barriers. CONCLUSIONS: Primary care is an active channel in healthcare for MRP, with CHC taking the lead. With the reimbursement system, there should hardly be financial barriers to access the healthcare system. However, due to the high probability of non-use (0.66), this system cannot substantially contribute to lowering financial barriers. The complexity of the system prevents it from being used properly and leads to undesirable alternatives.

Reduced humoral immune response after BNT162b2 coronavirus disease 2019 messenger RNA vaccination in cancer patients under antineoplastic treatment.

BACKGROUND: Cancer patients are at a higher risk of developing severe coronavirus disease 2019 (COVID-19). However, the safety and efficacy of COVID-19 vaccination in cancer patients undergoing treatment remain unclear. PATIENTS AND METHODS: In this interventional prospective multicohort study, priming and booster doses of the BNT162b2 COVID-19 vaccine were administered 21 days apart to solid tumor patients receiving chemotherapy, immunotherapy, targeted or hormonal therapy, and patients with a hematologic malignancy receiving rituximab or after allogeneic hematopoietic stem cell transplantation. Vaccine safety and efficacy (until 3 months post-booster) were assessed. Anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor-binding domain (RBD) antibody levels were followed over time (until 28 days after the booster) and in vitro SARS-CoV-2 50% neutralization titers (NT50) toward the wild-type Wuhan strain were analyzed 28 days after the booster. RESULTS: Local and systemic adverse events (AEs) were mostly mild to moderate (only 1%-3% of patients experienced severe AEs). Local, but not systemic, AEs occurred more frequently after the booster dose. Twenty-eight days after the booster vaccination of 197 cancer patients, RBD-binding antibody titers and NT50 were lower in the chemotherapy group {234.05 IU/ml [95% confidence interval (CI) 122.10-448.66] and 24.54 (95% CI 14.50-41.52), respectively} compared with healthy individuals [1844.93 IU/ml (95% CI 1383.57-2460.14) and 122.63 (95% CI 76.85-195.67), respectively], irrespective of timing of vaccination during chemotherapy cycles. Extremely low antibody responses were seen in hematology patients receiving rituximab; only two patients had RBD-binding antibody titers necessary for 50% protection against symptomatic SARS-CoV-2 infection (<200 IU/ml) and only one had NT50 above the limit of detection. During the study period, five cancer patients tested positive for SARS-CoV-2 infection, including a case of severe COVID-19 in a patient receiving rituximab, resulting in a 2-week hospital admission. CONCLUSION: The BNT162b2 vaccine is well-tolerated in cancer patients under active treatment. However, the antibody response of immunized cancer patients was delayed and diminished, mainly in patients receiving chemotherapy or rituximab, resulting in breakthrough infections.

The very low penetrance of cystic fibrosis for the R117H mutation: a reappraisal for genetic counselling and newborn screening.

BACKGROUND: Cystic fibrosis (CF) is caused by compound heterozygosity or homozygosity of CF transmembrane conductance regulator gene (CFTR) mutations. Phenotypic variability associated with certain mutations makes genetic counselling difficult, notably for R117H, whose disease phenotype varies from asymptomatic to classical CF. The high frequency of R117H observed in CF newborn screening has also introduced diagnostic dilemmas. The aim of this study was to evaluate the disease penetrance for R117H in order to improve clinical practice. METHODS: The phenotypes in all individuals identified in France as compound heterozygous for R117H and F508del, the most frequent CF mutation, were described. The allelic prevalences of R117H (p(R117H)), on either intron 8 T5 or T7 background, and F508del (p(F508del)) were determined in the French population, to permit an evaluation of the penetrance of CF for the [R117H]+[F508del] genotype. RESULTS: Clinical details were documented for 184 [R117H]+[F508del] individuals, including 72 newborns. The disease phenotype was predominantly mild; one child had classical CF, and three adults' severe pulmonary symptoms. In 5245 healthy adults, p(F508del) was 1.06%, p(R117H;T7) 0.27% and p(R117H;T5)<0.01%. The theoretical number of [R117H;T7]+[F508del] individuals in the French population was estimated at 3650, whereas only 112 were known with CF related symptoms (3.1%). The penetrance of classical CF for [R117H;T7]+[F508del] was estimated at 0.03% and that of severe CF in adulthood at 0.06%. CONCLUSIONS: These results suggest that R117H should be withdrawn from CF mutation panels used for screening programmes. The real impact of so-called disease mutations should be assessed before including them in newborn or preconceptional carrier screening programmes.