54 research outputs found
Alternative strategies for deciphering the genetic architecture of childhood Pre-B acute lymphoblastic leukemia
La leucĂ©mie lymphoblastique aigĂŒe (LLA) est une maladie gĂ©nĂ©tique complexe. MalgrĂ© que cette maladie hĂ©matologique soit le cancer pĂ©diatrique le plus frĂ©quent, ses causes demeurent inconnues. Des Ă©tudes antĂ©rieures ont dĂ©montrĂ©es que le risque Ă la LLA chez lâenfant pourrait ĂȘtre influencĂ© par des gĂšnes agissant dans le mĂ©tabolisme des xĂ©nobiotiques, dans le maintient de lâintĂ©gritĂ© gĂ©nomique et dans la rĂ©ponse au stress oxydatif, ainsi que par des facteurs environnementaux. Au cours de mes Ă©tudes doctorales, jâai tentĂ© de dissĂ©quer davantage les bases gĂ©nĂ©tiques de la LLA de lâenfant en postulant que la susceptibilitĂ© Ă cette maladie serait modulĂ©e, au moins en partie, par des variants gĂ©nĂ©tiques agissant dans deux voies biologiques fondamentales : le point de contrĂŽle G1/S du cycle cellulaire et la rĂ©paration des cassures double-brin de lâADN. En utilisant une approche unique reposant sur lâanalyse dâune cohorte cas-contrĂŽles jumelĂ©e Ă une cohorte de trios enfants-parents, jâai effectuĂ© une Ă©tude dâassociation de type gĂšnes/voies biologiques candidats. Ainsi, jâai Ă©valuer le rĂŽle de variants provenant de la sĂ©quence promotrice de 12 gĂšnes du cycle cellulaire et de 7 gĂšnes de la voie de rĂ©paration de lâADN, dans la susceptibilitĂ© Ă la LLA. De tels polymorphismes dans la rĂ©gion promotrice (pSNPs) pourraient perturber la liaison de facteurs de transcription et mener Ă des diffĂ©rences dans les niveaux dâexpression des gĂšnes pouvant influencer le risque Ă la maladie.
En combinant diffĂ©rentes mĂ©thodes analytiques, jâai Ă©valuĂ© le rĂŽle de diffĂ©rents mĂ©canismes gĂ©nĂ©tiques dans le dĂ©veloppement de la LLA chez lâenfant. Jâai tout dâabord Ă©tudiĂ© les associations avec gĂšnes/variants indĂ©pendants, et des essaies fonctionnels ont Ă©tĂ© effectuĂ©s afin dâĂ©valuer lâimpact des pSNPs sur la liaison de facteurs de transcription et lâactivitĂ© promotrice allĂšle-spĂ©cifique. Ces analyses ont menĂ© Ă quatre publications. Il est peu probable que ces gĂšnes de susceptibilitĂ© agissent seuls; jâai donc utilisĂ© une approche intĂ©grative afin dâexplorer la possibilitĂ© que plusieurs variants dâune mĂȘme voie biologique ou de voies connexes puissent moduler le risque de la maladie; ces travaux ont Ă©tĂ© soumis pour publication. En outre, le dĂ©veloppement prĂ©coce de la LLA, voir mĂȘme in utero, suggĂšre que les parents, et plus particuliĂšrement la mĂšre, pourraient jouer un rĂŽle important dans le dĂ©veloppement de cette maladie chez lâenfant. Dans une Ă©tude par simulations, jâai Ă©valuĂ© la performance des mĂ©thodes dâanalyse existantes de dĂ©tecter des effets fĆto-maternels sous un design hybride trios/cas-contrĂŽles. Jâai Ă©galement investiguĂ© lâimpact des effets gĂ©nĂ©tiques agissant via la mĂšre sur la susceptibilitĂ© Ă la LLA. Cette Ă©tude, rĂ©cemment publiĂ©e, fĂ»t la premiĂšre Ă dĂ©montrer que le risque de la leucĂ©mie chez lâenfant peut ĂȘtre modulĂ© par le gĂ©notype de sa mĂšre.
En conclusions, mes Ă©tudes doctorales ont permis dâidentifier des nouveaux gĂšnes de susceptibilitĂ© pour la LLA pĂ©diatrique et de mettre en Ă©vidence le rĂŽle du cycle cellulaire et de la voie de la rĂ©paration de lâADN dans la leucĂ©mogenĂšse. Ă terme, ces travaux permettront de mieux comprendre les bases gĂ©nĂ©tiques de la LLA, et conduiront au dĂ©veloppement dâoutils cliniques qui amĂ©lioreront la dĂ©tection, le diagnostique et le traitement de la leucĂ©mie chez lâenfant.Childhood acute lymphoblastic leukemia (ALL) is a complex and heterogeneous genetic disease. Although it is the most common pediatric cancer, its etiology remains poorly understood. Previous studies provided evidence that childhood ALL might originate through the collective contribution of different genes controlling the efficiency of carcinogen metabolism, the capacity of maintaining DNA integrity and the response to oxidative stress, as well as environmental factors. In my doctoral research project I attempted to further dissect the genetic intricacies underlying childhood ALL. I postulated that a childâs susceptibility to ALL may be influenced, in part, by functional sequence variation in genes encoding components of two core biologic pathways: G1/S cell cycle control and DNA double-strand break repair. Using a unique two-tiered study design consisting of both unrelated ALL cases and healthy controls, as well as case-parent trios, I performed a pathway-based candidate-gene association study to investigate the role of sequence variants in the promoter regions of 12 candidate cell cycle genes and 7 DNA repair genes, in modulating ALL risk among children. Polymorphisms in promoter regions (pSNPs) could perturb transcription factor binding and lead to differences in gene expression levels that in turn could modify the risk of disease.
To better depict the complex genetic architecture of childhood ALL, I used multiple analytical approaches. First, individual genes/variants were tested for association with disease, while functional in vitro validation was performed to evaluate the impact of the pSNPs on differential transcription factor binding and allele-specific promoter activity. These analyses led to four published articles. Given that these genes are not likely to act alone to confer disease risk I used an integrative approach to explore the possibility that combinations of functionally relevant pSNPs among several components of the same or of interconnected pathways, could contribute to modified childhood ALL risk either through pathway-specific or epistatic effects; this work was recently submitted for publication. Finally, childhood ALL is thought to arise in utero suggesting that the parents, and in particular the mother, may play an important role in shaping disease susceptibility in their offspring. Using simulations, I investigated the performance of existing methods to test for maternal genotype associations using a case-parent trio/case-control hybrid design, and then assessed the impact of maternally-mediated genetic effects on ALL susceptibility among children. This published work was the first to show that the motherâs genotype can indeed influence the risk of leukemia in children, further corroborating the importance of considering parentally-mediated effects in the study of early-onset diseases.
In conclusion, my doctoral work lead to the identification of novel genetic susceptibility loci for childhood ALL and provided evidence for the implication of the cell cycle control and DNA repair pathways in leukemogenesis. Better elucidation of the genetic mechanisms underlying the pathogenesis of ALL in children could be of great diagnostic value and provide data to help guide risk-directed therapy and improve disease management and outcome. Ultimately, this study brings us one step closer to unraveling the genetic architecture of childhood ALL and provides a stepping-stone towards disease prevention
Detection of Fetomaternal Genotype Associations in Early-Onset Disorders: Evaluation of Different Methods and Their Application to Childhood Leukemia
Several designs and analytical approaches have been proposed to dissect offspring from maternal genetic contributions to early-onset diseases. However, lack of parental controls halts the direct verification of the assumption of mating symmetry (MS) required to assess maternally-mediated effects. In this study, we used simulations to investigate the performance of existing methods under mating asymmetry (MA) when parents of controls are missing. Our results show that the log-linear, likelihood-based framework using a case-triad/case-control hybrid design provides valid tests for maternal genetic effects even under MA. Using this approach, we examined fetomaternal associations between 29 SNPs in 12 cell-cycle genes and childhood pre-B acute lymphoblastic leukemia (ALL). We identified putative fetomaternal effects at loci CDKN2A rs36228834 (P = .017) and CDKN2B rs36229158 (P = .022) that modulate the risk of childhood ALL. These data further corroborate the importance of the mother's genotype on the susceptibility to early-onset diseases
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Ancient Human Parasites in Ethnic Chinese Populations
Whilst archaeological evidence for many aspects of life in ancient China is well studied, there has been much less interest in ancient infectious diseases, such as intestinal parasites in past Chinese populations. Here, we bring together evidence from mummies, ancient latrines, and pelvic soil from burials, dating from the Neolithic Period to the Qing Dynasty, in order to better understand the health of the past inhabitants of China and the diseases endemic in the region. Seven species of intestinal parasite have been identified, namely roundworm, whipworm, Chinese liver fluke, oriental schistosome, pinworm, Taenia sp. tapeworm, and the intestinal fluke Fasciolopsis buski. It was found that in the past, roundworm, whipworm, and Chinese liver fluke appear to have been much more common than the other species. While roundworm and whipworm remained common into the late 20th century, Chinese liver fluke seems to have undergone a marked decline in its prevalence over time. The iconic transport route known as the Silk Road has been shown to have acted as a vector for the transmission of ancient diseases, highlighted by the discovery of Chinese liver fluke in a 2,000 year-old relay station in northwest China, 1,500 km outside its endemic range
Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries
Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P < 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely
Increasing frailty is associated with higher prevalence and reduced recognition of delirium in older hospitalised inpatients: results of a multi-centre study
Purpose:
Delirium is a neuropsychiatric disorder delineated by an acute change in cognition, attention, and consciousness. It is common, particularly in older adults, but poorly recognised. Frailty is the accumulation of deficits conferring an increased risk of adverse outcomes. We set out to determine how severity of frailty, as measured using the CFS, affected delirium rates, and recognition in hospitalised older people in the United Kingdom.
Methods:
Adults over 65 years were included in an observational multi-centre audit across UK hospitals, two prospective rounds, and one retrospective note review. Clinical Frailty Scale (CFS), delirium status, and 30-day outcomes were recorded.
Results:
The overall prevalence of delirium was 16.3% (483). Patients with delirium were more frail than patients without delirium (median CFS 6 vs 4). The risk of delirium was greater with increasing frailty [OR 2.9 (1.8â4.6) in CFS 4 vs 1â3; OR 12.4 (6.2â24.5) in CFS 8 vs 1â3]. Higher CFS was associated with reduced recognition of delirium (OR of 0.7 (0.3â1.9) in CFS 4 compared to 0.2 (0.1â0.7) in CFS 8). These risks were both independent of age and dementia.
Conclusion:
We have demonstrated an incremental increase in risk of delirium with increasing frailty. This has important clinical implications, suggesting that frailty may provide a more nuanced measure of vulnerability to delirium and poor outcomes. However, the most frail patients are least likely to have their delirium diagnosed and there is a significant lack of research into the underlying pathophysiology of both of these common geriatric syndromes
La leucĂ©mie de lâenfant
Le cancer affecte 1 enfant sur 500 avant lâĂąge de 14 ans et constitue la cause majeure de mortalitĂ© par maladie dans cette population. LâĂ©tiologie de ce groupe de maladies hĂ©tĂ©rogĂšnes est encore trĂšs mal connue. Du fait de leur plus grande prĂ©valence, les efforts de recherche en oncogĂ©nĂ©tique pĂ©diatrique se sont concentrĂ©s sur les leucĂ©mies, particuliĂšrement sur la leucĂ©mie lymphoblastique aiguĂ« (LLA). Bien que lâimportance de la variabilitĂ© interindividuelle dans la susceptibilitĂ© au cancer soit acceptĂ©e, il existe peu dâĂ©tudes analysant lâimpact des polymorphismes sur la susceptibilitĂ© aux leucĂ©mies de lâenfant. Les principales voies biologiques contribuant Ă la susceptibilitĂ© au cancer peuvent ĂȘtre regroupĂ©es comme suit : (1) croissance et diffĂ©renciation cellulaires, (2) rĂ©plication et rĂ©paration de lâADN, (3) mĂ©tabolisme des xĂ©nobiotiques, (4) apoptose, (5) rĂ©ponse au stress oxydant, (6) cycle cellulaire. Des Ă©tudes dâassociation ciblant des gĂšnes candidats engagĂ©s dans ces processus biologiques ont Ă©tĂ© entreprises afin dâanalyser les dĂ©terminants gĂ©nĂ©tiques de la leucĂ©mogenĂšse chez lâenfant. Nous avons dĂ©montrĂ© que celle-ci est associĂ©e Ă des variants gĂ©nĂ©tiques et que la combinaison des gĂ©notypes a une plus grande valeur prĂ©dictive du risque que les gĂ©notypes pris indĂ©pendamment les uns des autres. La complexitĂ© des interactions entre lâenvironnement et la variabilitĂ© interindividuelle face Ă la susceptibilitĂ© au cancer, que montrent ces rĂ©sultats, suggĂšre que la comprĂ©hension de la physiopathologie des leucĂ©mies de lâenfant passe par lâĂ©tude gĂ©nĂ©tique de plusieurs enzymes (ou voies mĂ©taboliques)
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The surgical admissions proforma: Does it make a difference?
Admissions records are essential in communicating key information regarding unwell patients and at handover of care. We designed, implemented and evaluated the impact of a standardised surgical clerking proforma on documentation and clinician acceptability in comparison to freehand clerking. A clerking proforma was implemented for all acute general surgical admissions. Documentation was assessed according to 32 criteria based on the Royal College of Surgeons of England guidelines, for admissions before (n = 72) and after (n = 96) implementation. Fisher's exact test and regression analysis were used to compare groups. Surgical team members were surveyed regarding attitudes towards the new proforma. Proforma uptake was 73%. After implementation, documentation increased in 28/32 criteria. This was statistically significant in 17 criteria, including past surgical history (p < 0.01), medication history (p = 0.03), ADLs (p = 0.02), systems review (p < 0.01), blood pressure (p < 0.01), blood results (p = 0.02) and advice given to the patient (p = 0.02). The proforma remained beneficial after regression analysis accounted for differences in time of day, seniority of the doctor and nights or weekends (coefficient = 0.12 [p < 0.01]). 89% of the surgical team felt the form improved quality of documentation and preferred its use to freehand clerking. 94% felt it was beneficial on the post-take ward-round. Audit quality control was also more reliable with the proforma (inter-observer agreement = 99.3% [Îș = 0.997]) versus freehand clerking (97.1% [Îș = 0.941]). Our study demonstrates that a standardised surgical clerking proformas improves the quantity and quality of documentation in comparison to freehand clerking, is preferred by health professionals and improves reliability of the audit quality control process
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