Long-term colchicine for the prevention of vascular recurrent events in non-cardioembolic stroke (CONVINCE): a randomised controlled trial.

BACKGROUND: Anti-inflammatory therapy with long-term colchicine prevented vascular recurrence in coronary disease. Unlike coronary disease, which is typically caused by atherosclerosis, ischaemic stroke is caused by diverse mechanisms including atherosclerosis and small vessel disease or is frequently due to an unknown cause. We aimed to investigate the hypothesis that long-term colchicine would reduce recurrent events after ischaemic stroke. METHODS: We did a randomised, parallel-group, open-label, blinded endpoint assessed trial comparing long-term colchicine (0·5 mg orally per day) plus guideline-based usual care with usual care only. Hospital-based patients with non-severe, non-cardioembolic ischaemic stroke or high-risk transient ischaemic attack were eligible. The primary endpoint was a composite of first fatal or non-fatal recurrent ischaemic stroke, myocardial infarction, cardiac arrest, or hospitalisation (defined as an admission to an inpatient unit or a visit to an emergency department that resulted in at least a 24 h stay [or a change in calendar date if the hospital admission or discharge times were not available]) for unstable angina. The p value for significance was 0·048 to adjust for two prespecified interim analyses conducted by the data monitoring committee, for which the steering committee and trial investigators remained blinded. The trial was registered at ClinicalTrials.gov (NCT02898610) and is completed. FINDINGS: 3154 patients were randomly assigned between Dec 19, 2016, and Nov 21, 2022, with the last follow-up on Jan 31, 2024. The trial finished before the anticipated number of outcomes was accrued (367 outcomes planned) due to budget constraints attributable to the COVID-19 pandemic. Ten patients withdrew consent for analysis of their data, leaving 3144 patients in the intention-to-treat analysis: 1569 (colchicine and usual care) and 1575 (usual care alone). A primary endpoint occurred in 338 patients, 153 (9·8%) of 1569 patients allocated to colchicine and usual care and 185 (11·7%) of 1575 patients allocated to usual care alone (incidence rates 3·32 vs 3·92 per 100 person-years, hazard ratio 0·84; 95% CI 0·68-1·05, p=0·12). Although no between-group difference in C-reactive protein (CRP) was observed at baseline, patients treated with colchicine had lower CRP at 28 days and at 1, 2, and 3 years (p<0·05 for all timepoints). The rates of serious adverse events were similar in both groups. INTERPRETATION: Although no statistically significant benefit was observed on the primary intention-to-treat analysis, the findings provide new evidence supporting the rationale for anti-inflammatory therapy in further randomised trials. FUNDING: Health Research Board Ireland, Deutsche Forschungsgemeinschaft (German Research Foundation), and Fonds Wetenschappelijk Onderzoek Vlaanderen (Research Foundation Flanders), Belgium.

Fever education for caregivers in the emergency room (The FEVER study)-an interventional trial.

BACKGROUND: Despite the vast majority of fevers representing benign self-limiting illnesses, caregiver anxiety regarding fever is high. Empowering caregivers with knowledge to safely and appropriately manage fever at home has the potential to reduce demands upon healthcare services. AIM: To improve caregiver knowledge about fever and its management in children via an educational intervention. METHODS: Caregivers of children over 6 months presenting with fever to a Paediatric Emergency Department were recruited. A pre-intervention survey was completed to ascertain caregiver knowledge about fever and its management. The intervention of (i) an infographic about fever, with (ii) a short video on fever was viewed. A post-intervention survey re-assessed knowledge. The primary outcome was the correct definition of fever as a temperature ≥38 °C. RESULTS: Caregivers (n = 51) who correctly defined fever increased from 41% (n = 21) pre-intervention to 94% (n = 48) post-intervention. There was a reduction in common misconceptions about fever, including a higher fever representing a more serious infection (76% vs. 8%). Caregivers reported they were less likely to seek emergency healthcare due to the height and nature of the fever alone. CONCLUSIONS: A simple brief educational intervention can rapidly increase caregiver knowledge about fever in children. There is a continuing need for clear, easily-accessible information for caregivers on this topic. IMPACT: Parental knowledge about fever and how to manage it in their children is low. A simple brief educational intervention can significantly increase caregiver knowledge about fever. A combined written and audiovisual approach is effective and well-received by parents. Educating caregivers has the potential to improve the management of childhood fever at home and to reduce the burden on healthcare services, as well as reduce unpleasant hospital visits for children and their caregivers.

Postoperative Capnocytophaga Sputigena Presenting as Diffuse Recalcitrant Intra-abdominal Abscesses.

Capnocytophaga sputigena is rarely implicated as the cause of postsurgical intra-abdominal abscess because it is almost exclusively found in oral flora. Despite its rarity in intra-abdominal infection, there are examples of this atypical presentation, and an awareness of this organism as a potential etiology of surgical infection is relevant for both obstetric and general surgeons. We report a case of a young female who presented just over a week after an uncomplicated C-section with complaint of abdominal discomfort and fevers. Imaging revealed multiple intra-abdominal fluid collections and cultures revealed the presence of C. sputigena. Percutaneous drainage and intravenous antibiotics were unable to provide significant source control, so she underwent surgical exploration with a multi-specialty team of obstetric and acute care surgeons. Although postsurgical pelvic abscesses are rarely due to C. sputigena, this organism has been documented to serve as a source of intra-abdominal infection.

Limited transmission of SARS-CoV-2 in schools in Ireland during the 2020-2021 school year.

BackgroundThe role of schools in SARS-CoV-2 transmission has been a debated topic since the beginning of the COVID-19 pandemic.AimTo examine SARS-CoV-2 transmission in all schools in Ireland during the 2020-21 school year.MethodsIn a national descriptive cross-sectional study, we investigated PCR-confirmed cases of COVID-19 among students (aged < 20 years) and staff (aged ≥ 20 years) who attended school during their infectious period to identify school close contacts. SARS-CoV-2 PCR test results of all school close contacts were pooled to obtain an overall positivity rate and to stratify positivity rate by school setting and role (i.e. student or staff).ResultsIn total, 100,474 individuals were tested as close contacts in 1,771 schools during the 2020-21 school year. An overall close contact positivity rate of 2.4% was observed across all schools (n = 2,373 secondary cases). The highest positivity rate was seen in special schools (3.4%), followed by primary (2.5%) and post-primary schools (1.8%) (p < 0.001). Of the close contacts identified, 90.5% (n = 90,953) were students and 9.5% (n = 9,521) were staff. Overall, students had a significantly higher positivity rate than staff (2.4% vs 1.8%, p < 0.001).ConclusionThis study demonstrated that a low level of SARS-CoV-2 transmission occurred in Irish schools during the 2020-21 academic year. In the event of future pandemics, and as the COVID-19 pandemic continues, there is a need to carefully weigh up the harms and benefits associated with disrupted education to mitigate infectious disease transmission before reflexively closing classes or schools.

Designing a large-scale track-based monitoring program to detect changes in species distributions in arid Australia.

Monitoring trends in animal populations in arid regions is challenging due to remoteness and low population densities. However, detecting species' tracks or signs is an effective survey technique for monitoring population trends across large spatial and temporal scales. In this study, we developed a simulation framework to evaluate the performance of alternative track-based monitoring designs at detecting change in species distributions in arid Australia. We collated presence-absence records from 550 2-ha track-based plots for 11 vertebrates over 13 years and fitted ensemble species distribution models to predict occupancy in 2018. We simulated plausible changes in species' distributions over the next 15 years and, with estimates of detectability, simulated monitoring to evaluate the statistical power of three alternative monitoring scenarios: (1) where surveys were restricted to existing 2-ha plots, (2) where surveys were optimized to target all species equally, and (3) where surveys were optimized to target two species of conservation concern. Across all monitoring designs and scenarios, we found that power was higher when detecting increasing occupancy trends compared to decreasing trends owing to the relatively low levels of initial occupancy. Our results suggest that surveying 200 of the existing plots annually (with a small subset resurveyed twice within a year) will have at least an 80% chance of detecting 30% declines in occupancy for four of the five invasive species modeled and one of the six native species. This increased to 10 of the 11 species assuming larger (50%) declines. When plots were positioned to target all species equally, power improved slightly for most compared to the existing survey network. When plots were positioned to target two species of conservation concern (crest-tailed mulgara and dusky hopping mouse), power to detect 30% declines increased by 29% and 31% for these species, respectively, at the cost of reduced power for the remaining species. The effect of varying survey frequency depended on its trade-off with the number of sites sampled and requires further consideration. Nonetheless, our research suggests that track-based surveying is an effective and logistically feasible approach to monitoring broad-scale occupancy trends in desert species with both widespread and restricted distributions.

Mid-Arm Point in PAEDiatrics (MAPPAED): An effective procedural aid for safe pleural decompression in trauma.

OBJECTIVE: Life-threatening thoracic trauma requires emergency pleural decompression and thoracostomy and chest drain insertion are core trauma procedures. Reliably determining a safe site for pleural decompression in children can be challenging. We assessed whether the Mid-Arm Point (MAP) technique, a procedural aid proposed for use with injured adults, would also identify a safe site for pleural decompression in children. METHODS: Children (0-18 years) attending four EDs were prospectively recruited. The MAP technique was performed, and chest wall skin marked bilaterally at the level of the MAP; no pleural decompression was performed. Radio-opaque markers were placed over the MAP-determined skin marks and corresponding intercostal space (ICS) reported using chest X-ray. RESULTS: A total of 392 children participated, and 712 markers sited using the MAP technique were analysed. Eighty-three percentage of markers were sited within the 'safe zone' for pleural decompression (4th to 6th ICSs). When sited outside the 'safe zone', MAP-determined markers were typically too caudal. However, if the site for pleural decompression was transposed one ICS cranially in children ≥4 years, the MAP technique performance improved significantly with 91% within the 'safe zone'. CONCLUSIONS: The MAP technique reliably determines a safe site for pleural decompression in children, albeit with an age-based adjustment, the Mid-Arm Point in PAEDiatrics (MAPPAED) rule: 'in children aged ≥4 years, use the MAP and go up one ICS to hit the safe zone. In children <4 years, use the MAP.' When together with this rule, the MAP technique will identify a site within the 'safe zone' in 9 out of 10 children.

Potential Oncogenic Effect of the MERTK-Dependent Apoptotic-Cell Clearance Pathway in Starry-Sky B-Cell Lymphoma.

The histological architecture of certain aggressive B-cell lymphomas (prototypically Burkitt's lymphoma, BL) is characterized by a "starry-sky" (SS) appearance. This is caused by tumor-associated macrophages (TAMs), which appear in standard histological preparations as "stars" in a darkly stained "sky" of lymphoma cells. SS-TAMs accumulate in response to constitutive apoptosis in these tumors and are activated by the apoptotic tumor cells to a pro-oncogenic phenotype. The extent to which SS-TAMs contribute to lymphoma growth through responses generated by interactions with apoptotic tumor cells is unknown. Here, we demonstrate a role for the receptor tyrosine kinase, MERTK, in the oncogenic activity of SS-TAMs. We show that MERTK expression is largely restricted to the macrophages of human BL and of murine models of SS B-cell lymphoma and that it is upregulated in SS-TAMs as compared to the germinal center or paracortical macrophages of normal lymph nodes. Our results further demonstrate that MERTK is active in the phagocytosis of apoptotic lymphoma cells by macrophages and, most significantly, that SS lymphoma growth is markedly inhibited in Mertk-/- mice. These results point toward the MERTK apoptotic-cell clearance/response pathway playing a key role in growth of aggressive B-cell lymphoma and identifies MERTK as a novel potential antilymphoma target.

Alpha Omega Alpha Honor Medical Society: A Commitment to Inclusion, Diversity, Equity, and Service in the Profession of Medicine.

With a motto of "Be Worthy to Serve the Suffering," Alpha Omega Alpha Honor Medical Society (AΩA) supports the importance, inclusion, and development of a culturally and ethnically diverse medical profession with equitable access for all. The underrepresentation of minorities in medical schools and medicine continues to be a challenge for the medical profession, medical education, and AΩA. AΩA has worked, and continues to work, to ensure the development of diverse leaders, fostering within them the objectivity and equity to be inclusive servant leaders who understand and embrace diversity in all its forms.Inclusion of talented individuals from different backgrounds benefits patient care, population health, education, and scientific discovery. AΩA values an inclusive, diverse, fair, and equitable work and learning environment for all and supports the medical profession in its work to achieve a welcoming, inclusive environment in teaching, learning, caring for patients, and collaboration.The diversity of medical schools is changing and will continue to change. AΩA is committed to continuing to work with its members, medical school deans, and AΩA chapters to assure that AΩA elections are unbiased and based on the values of AΩA and the profession of medicine in service to patients and the profession.Progress toward diversity, inclusion, and equity is more than simply checking off a box or responding to criticism-it is about being and developing diverse excellent physicians. AΩA and all those in the medical profession must continue to guide medicine to be unbiased, open, accepting, inclusive, and culturally aware in order to "Be Worthy to Serve the Suffering."

External electrical stimulation compared with intravaginal electrical stimulation for the treatment of stress urinary incontinence in women: A randomized controlled noninferiority trial.

AIMS: To compare the efficacy and safety of a neuromuscular external electrical stimulation device (INNOVO; "NMES") with an FDA-approved intravaginal device (iTouch sure; "comparator device") for the treatment of stress urinary incontinence (SUI). METHODS: This prospective, single-blind, multicenter, noninferiority study randomized women with SUI to treatment with the NMES or the comparator device for 12 weeks. The primary endpoint was the proportion achieving >50% reduction in pad weight from baseline to 12 weeks in the provocative pad weight test. RESULTS: Most subjects in both groups achieved >50% reduction in pad weight in the provocative pad test at week 12 (NMES 56.3%; comparator 63.0%), although noninferiority was not established. Significant improvements in pad tests, number of incontinence episodes, and pads used per day, and incontinence quality of life score were seen with both devices at week 12, with no clinically relevant between-group differences. Adverse events were predominantly mild/moderate and there were few discontinuations due to adverse events. The incidence of urinary tract/vaginal infections was higher with the comparator device than the NMES (7.7% versus 0%). The most common device-related adverse effect with the NMES was device discomfort (9.0%), which was generally manageable by modifying the stimulation intensity. CONCLUSIONS: The NMES significantly improved objective and subjective measures of SUI, although statistical noninferiority was not established. The NMES was well tolerated and associated with fewer urinary tract infections than the comparator. The NMES provides a safe, clinically effective, conservative treatment option for female SUI and a low-risk alternative to intravaginal devices.

Epidemiology of congenital cerebral anomalies in Europe: a multicentre, population-based EUROCAT study.

OBJECTIVES: To describe the epidemiology and geographical differences in prevalence of congenital cerebral anomalies in Europe. DESIGN AND SETTING: Congenital cerebral anomalies (International Classification of Diseases, 10th Revision code Q04) recorded in 29 population-based EUROCAT registries conducting surveillance of 1.7 million births per annum (29% of all European births). PARTICIPANTS: All birth outcomes (live births, fetal deaths from 20 weeks gestation and terminations of pregnancy after prenatal diagnosis of a fetal anomaly (TOPFA)) from 2005 to 2014. MAIN OUTCOME MEASURES: Prevalence, proportion of associated non-cerebral anomalies, prenatal detection rate. RESULTS: 4927 cases with congenital cerebral anomalies were identified; a prevalence (adjusted for under-reporting) of 9.8 (95% CI: 8.5 to 11.2) per 10 000 births. There was a sixfold difference in prevalence across the registries. Registries with higher proportions of prenatal diagnoses had higher prevalence. Overall, 55% of all cases were liveborn, 3% were fetal deaths and 41% resulted in TOPFA. Forty-eight per cent of all cases were an isolated cerebral anomaly, 25% had associated non-cerebral anomalies and 27% were chromosomal or part of a syndrome (genetic or teratogenic). The prevalence excluding genetic or chromosomal conditions increased by 2.4% per annum (95% CI: 1.3% to 3.5%), with the increases occurring only for congenital malformations of the corpus callosum (3.0% per annum) and 'other reduction deformities of the brain' (2.8% per annum). CONCLUSIONS: Only half of the cases were isolated cerebral anomalies. Improved prenatal and postnatal diagnosis may account for the increase in prevalence of congenital cerebral anomalies from 2005 to 2014. However, major differences in prevalence remain between regions.

External Use of an Oxidized Regenerated Cellulose Agent in the Treatment of Labial Agglutination in Postmenopausal Women.

BACKGROUND: Vulvovaginal diseases affect women of all ages. Vaginal atrophy and vulvar lichen sclerosus are common etiologies for chronic vulvovaginal pruritus and labial agglutination in both prepubertal and postmenopausal women. CASES: We present two cases of a novel approach in management of symptomatic labial agglutination in postmenopausal women. At the time of surgical intervention, an oxidized regenerated cellulose gauze was sutured in place within the operative field of separation of the labia minora and clitoral hood adhesions. At more than 18-months' follow-up, no recurrence of agglutination has been noted. CONCLUSION: The use of an oxidized regenerated cellulose agent may create an effective barrier to recurrence of labial agglutination in postmenopausal women.

A national measles outbreak in Ireland linked to a single imported case, April to September, 2016.

Endemic measles transmission was interrupted for the first time in Ireland in 2015. In May 2016, a case of measles was confirmed in an adult who had travelled from Hungary to Ireland (index case). Cases subsequently arose in five of the eight public health regions around the country. There were 40 confirmed cases in Ireland between April and September 2016. All sequenced cases were genotype B3. Vaccination status was known for 34 cases, of whom 31 were unvaccinated. Median age was 8 years (range: 3 months to 40 years). Ten cases were nosocomial, and three cases were infected on separate international flights. One linked case occurred in a resident of Slovenia. Nineteen cases were hospitalised; median duration of hospitalisation was 5 days (range: 2-8 days). The primary case was a child who travelled from Romania to Ireland via Budapest, and infected the index adult case on the same flight. This was the first reported outbreak of measles genotype B3 in Ireland. This outbreak demonstrated that Ireland remains at risk of measles outbreaks due to persistent suboptimal vaccination rates.

Epidemiology of septo-optic dysplasia with focus on prevalence and maternal age - A EUROCAT study.

Septo-optic nerve dysplasia is a rare congenital anomaly with optic nerve hypoplasia, pituitary hormone deficiencies and midline developmental defects of the brain. The clinical findings are visual impairment, hypopituitarism and developmental delays. The aim of this study was to report prevalence, associated anomalies, maternal age and other epidemiological factors from a large European population based network of congenital anomaly registries (EUROCAT). Data from 29 full member registries for the years 2005-2014 were included, covering 6.4 million births. There were 99 cases with a diagnosis of septo-optic dysplasia. The prevalence of septo-optic dysplasia in Europe was calculated to lie between 1.9 and 2.5 per 100,000 births after adjusting for potential under-reporting in some registries. The prevalence was highest in babies of mothers aged 20-24 years of age and was significantly higher in UK registries compared with other EUROCAT registries (P = 0.021 in the multilevel model) and the additional risk for younger mothers was significantly greater in the UK compared to the rest of Europe (P = 0.027). The majority of septo-optic dysplasia cases were classified as an isolated cerebral anomaly (N = 76, 77%). Forty percent of diagnoses occurred in fetuses with a prenatal diagnosis. The anomaly may not be visible at birth, which is reflected in that 57% of the postnatal diagnoses occurred over 1 month after birth. This is the first population based study to describe the prevalence of septo-optic dysplasia in Europe. Septo-optic dysplasia shares epidemiological patterns with gastroschisis and this strengthens the hypothesis of vascular disruption being an aetiological factor for septo-optic dysplasia.

Prevalence of valproate syndrome in Europe from 2005 to 2014: A registry based multi-centre study.

Women with epilepsy need to continue to take anticonvulsants during their pregnancies to prevent seizures from occurring. Since the 1980's, it has been known that the use of valproate (an anticonvulsant) in the first trimester of pregnancy is associated with an increased risk of spina bifida. Recent studies have also demonstrated increased risks of other congenital anomalies as well as a risk of cognitive impairment. Doctors in the EU are now advised not to prescribe valproate in pregnant women, in women who can become pregnant or in girls unless other treatments are ineffective or not tolerated. This study aimed to determine if there has been a reduction in the numbers of babies born with valproate syndrome in Europe from 2005 to 2014. Data from 15 European congenital anomaly registries, who are members of EUROCAT (A European network of population-based registries for the epidemiologic surveillance of congenital anomalies), identified 28 cases of valproate syndrome in 2.74 million births from 2005 to 2014. The prevalence of valproate syndrome in Europe significantly decreased from 0.22 per 10,000 births in 2005/6 to 0.03 per 10,000 births in 2013/14. One registry, Ile de la Reunion, had the majority of cases (17). After excluding these cases there still remained a decreasing trend even though it no longer reached statistical significance due to the small number of cases. This study emphasises the continued need for European collaboration in analysing rare exposures and rare anomalies.

Trends in congenital anomalies in Europe from 1980 to 2012.

BACKGROUND: Surveillance of congenital anomalies is important to identify potential teratogens. METHODS: This study analysed the prevalence of 61 congenital anomaly subgroups (excluding chromosomal) in 25 population-based EUROCAT registries (1980-2012). Live births, fetal deaths and terminations of pregnancy for fetal anomaly were analysed with multilevel random-effects Poisson regression models. RESULTS: Seventeen anomaly subgroups had statistically significant trends from 2003-2012; 12 increasing and 5 decreasing. CONCLUSIONS: The annual increasing prevalence of severe congenital heart defects, single ventricle, atrioventricular septal defects and tetralogy of Fallot of 1.4% (95% CI: 0.7% to 2.0%), 4.6% (1.0% to 8.2%), 3.4% (1.3% to 5.5%) and 4.1% (2.4% to 5.7%) respectively may reflect increases in maternal obesity and diabetes (known risk factors). The increased prevalence of cystic adenomatous malformation of the lung [6.5% (3.5% to 9.4%)] and decreased prevalence of limb reduction defects [-2.8% (-4.2% to -1.5%)] are unexplained. For renal dysplasia and maternal infections, increasing trends may be explained by increased screening, and deceases in patent ductus arteriosus at term and increases in craniosynostosis, by improved follow up period after birth and improved diagnosis. For oesophageal atresia, duodenal atresia/stenosis and ano-rectal atresia/stenosis recent changes in prevalence appeared incidental when compared with larger long term fluctuations. For microcephaly and congenital hydronephrosis trends could not be interpreted due to discrepancies in diagnostic criteria. The trends for club foot and syndactyly disappeared once registries with disparate results were excluded. No decrease in neural tube defects was detected, despite efforts at prevention through folic acid supplementation.

Occupational therapy private practice workforce: Issues in the 21st century: La main-œuvre en ergothérapie dans le secteur privé : Les enjeux du 21e siècle.

BACKGROUND: The number of occupational therapists working in the private sector in British Columbia (BC) has risen steadily since 2008, employing approximately 25.7% of occupational therapists by 2012. Processes used to determine workforce needs for occupational therapists in BC have previously overlooked this growing sector. PURPOSE: This study aims to describe the supply, demand, and workforce needs for occupational therapists in BC's private sector. METHOD: This exploratory study used a sample of occupational therapists and employers of occupational therapists in BC's private sector. Data collection included an online survey that collected information about the workplace and supply and demand needs. Descriptive data analysis was conducted on the survey data, and thematic analysis was used to organize participants' comments into categories. FINDINGS: In addition to identifying current supply, this study identifies barriers, facilitators, projected movement in and out of the sector, and current and future demand for occupational therapists. IMPLICATIONS: This study supports the need for an increase in supply of occupational therapists in the private sector to fulfill the current and future workforce demands.

Beta-Blocker Use in Pregnancy and Risk of Specific Congenital Anomalies: A European Case-Malformed Control Study.

INTRODUCTION: The prevalence of chronic hypertension is increasing in pregnant women. Beta-blockers are among the most prevalent anti-hypertensive agents used in early pregnancy. OBJECTIVE: The objective of this study was to investigate whether first-trimester use of beta-blockers increases the risk of specific congenital anomalies in offspring. METHODS: A population-based case-malformed control study was conducted in 117,122 registrations of congenital anomalies from 17 European Concerted Action on Congenital Anomalies and Twins (EUROCAT) registries participating in EUROmediCAT with data for all or part of the period between 1995 and 2013. Associations previously reported in the literature (signals) were tested and an exploratory analysis was performed to identify new signals. Odds ratios of exposure to any beta-blocker or to a beta-blocker subgroup were calculated for each signal anomaly compared with two control groups (non-chromosomal, non-signal anomalies and chromosomal anomalies). The exploratory analyses were performed for each non-signal anomaly compared with all the other non-signal anomalies. RESULTS: The signals from the literature (congenital heart defects, oral clefts, neural tube defects and hypospadias) were not confirmed. Our exploratory analysis revealed that multi-cystic renal dysplasia had significantly increased odds of occurring after maternal exposure to combined alpha- and beta-blockers (adjusted odds ratio 3.8; 95% confidence interval 1.3-11.0). CONCLUSION: Beta-blocker use in the first trimester of pregnancy was not found to be associated with a higher risk of specific congenital anomalies in the offspring, but a new signal between alpha- and beta-blockers and multi-cystic renal dysplasia was found. Future large epidemiological studies are needed to confirm or refute our findings.

Extracellular Vesicles Arising from Apoptotic Cells in Tumors: Roles in Cancer Pathogenesis and Potential Clinical Applications.

It is known that apoptotic cells can have diverse effects on the tumor microenvironment. Emerging evidence indicates that, despite its renowned role in tumor suppression, apoptosis may also promote oncogenic evolution or posttherapeutic relapse through multiple mechanisms. These include immunomodulatory, anti-inflammatory, and trophic environmental responses to apoptosis, which drive tumor progression. Our group has introduced the term "onco-regenerative niche (ORN)" to describe a conceptual network of conserved cell death-driven tissue repair and regeneration mechanisms that are hijacked in cancer. We propose that, among the key elements of the ORN are extracellular vesicles (EVs), notably those derived from apoptotic tumor cells. EVs are membrane-delimited subcellular particles, which contain multiple classes of bioactive molecules including markers of the cell from which they are derived. EVs are implicated in an increasing number of physiological and pathological contexts as mediators of local and systemic intercellular communication and detection of specific EVs may be useful in monitoring disease progression. Here, we discuss the mechanisms by which EVs produced by apoptotic tumor cells-both constitutively and as a consequence of therapy-may mediate host responsiveness to cell death in cancer. We also consider how the monitoring of such EVs and their cargoes may in the future help to improve cancer diagnosis, staging, and therapeutic efficacy.