Clinical and genetic delineation of autosomal recessive and dominant ACTL6B-related developmental brain disorders

Purpose: This study aims to comprehensively delineate the phenotypic spectrum of ACTL6B-related disorders, previously associated with both autosomal recessive and autosomal dominant neurodevelopmental disorders. Molecularly, the role of the nucleolar protein ACTL6B in contributing to the disease has remained unclear. Methods: We identified 105 affected individuals, including 39 previously reported cases, and systematically analyzed detailed clinical and genetic data for all individuals. Additionally, we conducted knockdown experiments in neuronal cells to investigate the role of ACTL6B in ribosome biogenesis. Results: Biallelic variants in ACTL6B are associated with severe-to-profound global developmental delay/intellectual disability, infantile intractable seizures, absent speech, autistic features, dystonia, and increased lethality. De novo monoallelic variants result in moderate-to-severe global developmental delay/intellectual disability, absent speech, and autistic features, whereas seizures and dystonia were less frequently observed. Dysmorphic facial features and brain abnormalities, including hypoplastic corpus callosum, and parenchymal volume loss/atrophy, are common findings in both groups. We reveal that in the nucleolus, ACTL6B plays a crucial role in ribosome biogenesis, particularly in pre-rRNA processing. Conclusion: This study provides a comprehensive characterization of the clinical spectrum of both autosomal recessive and dominant forms of ACTL6B-associated disorders. It offers a comparative analysis of their respective phenotypes provides a plausible molecular explanation and suggests their inclusion within the expanding category of “ribosomopathies.”<p/

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 &lt; 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

Conception et pilotage de flux d’un réseau de soins stochastique sans attente : Application à la périnatalité

Cette thèse porte sur l’étude d’un réseau de soins hiérarchique stochastique avec rejet où les patients sont transférés lorsque la capacité de l’hôpital d’accueil n’est pas suffisante. Les patients sont alors redirigés vers un autre hôpital, ou hors du réseau. Une application concrète sur les réseaux de périnatalité est proposée, et nous avons identifié plusieurs verrous scientifiques fondamentaux d’un point de vue stratégique et opérationnel. Dans la partie stratégique, nous nous sommes intéressés à un problème de planification de capacité dans le réseau. Nous avons développé un modèle de localisation et de dimensionnement non-linéaire qui tient compte de la nature stochastique du système. La linéarisation du modèle permet de résoudre des problèmes de taille réelle en temps raisonnable. Nous avons développé dans un second temps de nouvelles méthodologies d’approximation permettant d’évaluer la performance du réseau en termes de probabilité de rejet et de transfert entre hôpitaux. Dans la partie opérationnelle, nous avons étudié des politiques de pilotage d’admission optimales pour différentes tailles de réseaux de manière utiliser au mieux les ressources hospitalières. Finalement, nous avons construit un modèle de simulation couplant multi-agents et événements discrets permettant la validation des résultats précédents et l’évaluation de performance du système de manière réaliste.In this thesis, by being motivated from the challenges in perinatal networks, we address design, evaluation and flow control of a stochastic healthcare network where there exist multiple levels of hospitals and different types of patients. Patients are supposed urgent; thus they can be rejected and overflow to another facility in the same network if no service capacity is available at their arrival. Rejection of patients due to the lack of service capacity is the common phenomenon in overflow networks. We approach the problem from both strategic and operational perspectives. In strategic part, we address a location & capacity planning problem for adjusting the network to better meet demographic changes. In operational part, we study the optimal patient admission control policies to increase flexibility in allocation of resources and improve the control of patient flow in the network. Finally, in order to evaluate the performance of the network, we develop new approximation methodologies that estimate the rejection probabilities in each hospital for each arriving patient group, thus the overflow probabilities among hospitals. Furthermore, an agent-based discrete-event simulation model is constructed to adequately represent our main applicationarea: Nord Hauts-de-Seine Perinatal Network. The simulation model is used to evaluate the performance of the complex network and more importantly evaluate the strength of the optimal results of our analytical models. The developed methodologies in this thesis are combined in a decision support tool, foreseen under the project “COVER”, which aims to assist health system managers to effectively plan strategic and operational decisions of a healthcare network and evaluate the performance of their decisions

Yüksek kaliteli üretim süreçlerinin kontrolü

In quality control applications, Time-Between-Events (TBE) type observations may be monitored by using Exponentially Weighted Moving Average (EWMA) control charts. A widely accepted model for the TBE processes is the exponential distribution, and hence TBE EWMA charts are designed under this assumption. Nevertheless, practical applications do not always conform to the theory and it is common that the observations do not fit the exponential model. Therefore, control charts that are robust to departures from the assumed distribution are desirable in practice. In this thesis, robustness of the lower-sided TBE EWMA charts to the assumption of exponentially distributed observations has been investigated. Weibull and lognormal distributions are considered in order to represent the departures from the assumed exponential model and Markov Chain approach is utilized for evaluating the performance of the chart. By analyzing the performance results, design settings are suggested in order to achieve robust lower-sided TBE EWMA charts.M.S. - Master of Scienc

Conception et pilotage de flux d’un réseau de soins stochastique sans attente : Application à la périnatalité

In this thesis, by being motivated from the challenges in perinatal networks, we address design, evaluation and flow control of a stochastic healthcare network where there exist multiple levels of hospitals and different types of patients. Patients are supposed urgent; thus they can be rejected and overflow to another facility in the same network if no service capacity is available at their arrival. Rejection of patients due to the lack of service capacity is the common phenomenon in overflow networks. We approach the problem from both strategic and operational perspectives. In strategic part, we address a location & capacity planning problem for adjusting the network to better meet demographic changes. In operational part, we study the optimal patient admission control policies to increase flexibility in allocation of resources and improve the control of patient flow in the network. Finally, in order to evaluate the performance of the network, we develop new approximation methodologies that estimate the rejection probabilities in each hospital for each arriving patient group, thus the overflow probabilities among hospitals. Furthermore, an agent-based discrete-event simulation model is constructed to adequately represent our main applicationarea: Nord Hauts-de-Seine Perinatal Network. The simulation model is used to evaluate the performance of the complex network and more importantly evaluate the strength of the optimal results of our analytical models. The developed methodologies in this thesis are combined in a decision support tool, foreseen under the project “COVER”, which aims to assist health system managers to effectively plan strategic and operational decisions of a healthcare network and evaluate the performance of their decisions.Cette thèse porte sur l’étude d’un réseau de soins hiérarchique stochastique avec rejet où les patients sont transférés lorsque la capacité de l’hôpital d’accueil n’est pas suffisante. Les patients sont alors redirigés vers un autre hôpital, ou hors du réseau. Une application concrète sur les réseaux de périnatalité est proposée, et nous avons identifié plusieurs verrous scientifiques fondamentaux d’un point de vue stratégique et opérationnel. Dans la partie stratégique, nous nous sommes intéressés à un problème de planification de capacité dans le réseau. Nous avons développé un modèle de localisation et de dimensionnement non-linéaire qui tient compte de la nature stochastique du système. La linéarisation du modèle permet de résoudre des problèmes de taille réelle en temps raisonnable. Nous avons développé dans un second temps de nouvelles méthodologies d’approximation permettant d’évaluer la performance du réseau en termes de probabilité de rejet et de transfert entre hôpitaux. Dans la partie opérationnelle, nous avons étudié des politiques de pilotage d’admission optimales pour différentes tailles de réseaux de manière utiliser au mieux les ressources hospitalières. Finalement, nous avons construit un modèle de simulation couplant multi-agents et événements discrets permettant la validation des résultats précédents et l’évaluation de performance du système de manière réaliste

Conception et pilotage de flux d’un réseau de soins stochastique sans attente : Application à la périnatalité

In this thesis, by being motivated from the challenges in perinatal networks, we address design, evaluation and flow control of a stochastic healthcare network where there exist multiple levels of hospitals and different types of patients. Patients are supposed urgent; thus they can be rejected and overflow to another facility in the same network if no service capacity is available at their arrival. Rejection of patients due to the lack of service capacity is the common phenomenon in overflow networks. We approach the problem from both strategic and operational perspectives. In strategic part, we address a location & capacity planning problem for adjusting the network to better meet demographic changes. In operational part, we study the optimal patient admission control policies to increase flexibility in allocation of resources and improve the control of patient flow in the network. Finally, in order to evaluate the performance of the network, we develop new approximation methodologies that estimate the rejection probabilities in each hospital for each arriving patient group, thus the overflow probabilities among hospitals. Furthermore, an agent-based discrete-event simulation model is constructed to adequately represent our main applicationarea: Nord Hauts-de-Seine Perinatal Network. The simulation model is used to evaluate the performance of the complex network and more importantly evaluate the strength of the optimal results of our analytical models. The developed methodologies in this thesis are combined in a decision support tool, foreseen under the project “COVER”, which aims to assist health system managers to effectively plan strategic and operational decisions of a healthcare network and evaluate the performance of their decisions.Cette thèse porte sur l’étude d’un réseau de soins hiérarchique stochastique avec rejet où les patients sont transférés lorsque la capacité de l’hôpital d’accueil n’est pas suffisante. Les patients sont alors redirigés vers un autre hôpital, ou hors du réseau. Une application concrète sur les réseaux de périnatalité est proposée, et nous avons identifié plusieurs verrous scientifiques fondamentaux d’un point de vue stratégique et opérationnel. Dans la partie stratégique, nous nous sommes intéressés à un problème de planification de capacité dans le réseau. Nous avons développé un modèle de localisation et de dimensionnement non-linéaire qui tient compte de la nature stochastique du système. La linéarisation du modèle permet de résoudre des problèmes de taille réelle en temps raisonnable. Nous avons développé dans un second temps de nouvelles méthodologies d’approximation permettant d’évaluer la performance du réseau en termes de probabilité de rejet et de transfert entre hôpitaux. Dans la partie opérationnelle, nous avons étudié des politiques de pilotage d’admission optimales pour différentes tailles de réseaux de manière utiliser au mieux les ressources hospitalières. Finalement, nous avons construit un modèle de simulation couplant multi-agents et événements discrets permettant la validation des résultats précédents et l’évaluation de performance du système de manière réaliste

Evaluation of the relationship of kinesophobia with functional status, quality of life, pain and depression, modified rodnan skin scoring in patients with systemic sclerosis

Sistemik skleroz, yaygın vaskülerdisfonksiyon ve derinin ve iç organların ilerleyici fibrozu ile karakterize kronik multisistemik veotoimmün bir hastalıktır. Yaşam kalitesini bozan, hastalığa bağlı mortalite ve morbiditesi yüksek otoimmünromatizmal hastalıktırveetyolojisi tam olarak bilinmemektedir. Ağrılı veya tekrar eden yaralanma nedeniyle aşırı hassasiyet ve rahatsız edici duygudan kaynaklanan,fiziksel aktiviteye karşı gelişen korku 'Kinezyofobi' olarak tanımlanır. Bu çalışmada sistemik skleroz ile tanılıhastalarda kinezyofobinin fonksiyonel durum, yaşam kalitesi, ağrı ve depresyon, modifiyerodnan deri skorlaması ile İlişkisinin değerlendirilmesi hedeflenmiştir. Şubat 2022 – Eylül 2022 tarihleri arasında, Dicle Üniversitesi Tıp Fakültesi Fiziksel Tıp ve Rehabilitasyon AnabilimdalıRomatoloji Polikliniğine başvuran; 18-65 yaş arasında, klinik değerlendirme ve radyolojik tetkikler sonucunda çalışmaya katılmayı kabul eden;çalışmaya dahil edilme ve dışlama kriterlerine uygun sistemik skleroz tanısı almış 40 olgu hasta grubunda; çalışmaya dahil edilme ve dışlama kriterlerine uygun, 18-65 yaş arasında sağlıklı sistemik skleroz tanısı bulunmayan 60 olgu kontrol grubunda olmak üzere, toplam 100 olgu çalışmaya dahil edildi. Kinezyofobiyi değerlendirmek için hastalardave kontrol grubunda TAMPA ölçeği kullanıldı.Hasta grubunda anksiyeteyi değerlendirmek için BeckAnksiyete ölçeği(BDÖ); yaşam kalitesini değerlendirmek için Sağlık Değerlendirmeölçeği(HAQ); fonksiyonel durumu değerlendirmek için Skleroderma Sağlık Değerlendirme Anketi(SSc-HAQ); deri kalınlığını değerlendirmek için ModifiyeRodnan Deri Skoru kullanıldı. Hasta grubu ve kontrol grubu karşılaştırıldığında TAMPA ölçeği hastagrubunda anlamlı olarak saptandı. Korelasyon analizine göre hasta grubundaTAMPA ölçeği; yaş, hastalık süresi, VAS, solunum hastalığı, hastalık ciddiyeti ve BeckAnksiyete ölçeği(BDÖ) arasında anlamlı bir korelasyon göstermiş olup, yaşam kalitesi veModifiyeRodnan Deri Skoru ile anlamlı korelasyon göstermemiştir. Sistemik skleroz hastalarında kinezyofobi, artmış anksiyete, hastalığın süresi, ileri yaş, ağrı düzeyi ve solunum sıkıntısı olması ile ilişkili bulunmaktadır.Kinezyofobiden dolayı oluşan hareketkısıtlılığının devam etmesi ve iyileşmenin sürecinde uzama gibi nedenler ile oluşan yapısalbozukluklarla beraber psikolojik faktörlerin de göz ardı edilmemesi gerekmektedir. Bu sebepleSSk'lu hastalar tedavi amaçlı değerlendirildiğindemedikal ve fizik tedavi yanında psikolojik destek tedavilerinin de hastalarauygulanması yararlı olabilir.Systemic sclerosis is a chronic multisystemic and autoimmune disease characterized by widespread vascular dysfunction and progressive skin and internal organs fibrosis. It is an autoimmune rheumatic disease that impairs the quality of life and has the highest mortality and morbidity associated with the disease, and its etiology is not known exactly. Kinesiophobia is defined as the fear of physical activity resulting from excessive sensitivity and uncomfortable feelings due to painful or repeated injury. This study aimed to evaluate the relationship of kinesiophobia with functional status, quality of life, pain, depression, and modified Rodnan skin scoring in patients diagnosed with systemic sclerosis. A total of 100 patients were included in the study, including 40 patients who applied to Dicle University Faculty of Medicine, Department of Physical Medicine and Rehabilitation Rheumatology Polyclinic between February 2022 and September 2022, were aged between 18-65 years and agreed to participate in the study as a result of clinical evaluation and radiological examinations were diagnosed with systemic sclerosis and met the inclusion and exclusion criteria of the study, in addition to 60 healthy subjects aged between 18-65 years, who did not have a diagnosis of systemic sclerosis, and who met the inclusion and exclusion criteria of the study in the control group. The Tampa scale was used to evaluate kinesiophobia in patients and the control group. Beck Anxiety Scale (BDI) was used to assess anxiety in the patient group, Health Assessment Scale (HAQ) was used to assess the quality of life, Scleroderma Health Assessment Questionnaire (SSc-HAQ) was used to assess functional status, and Modified Rodnan Skin Score was used to assess skin thickness. The Tampa scale scores were found to be significantly higher in the patient group than in the control group. According to the correlation analysis, it was determined that there was a positive and significant correlation between the Tampa scale and age, duration of illness, VAS, respiratory disease, disease severity, and Beck Anxiety Scale (BDI) in the patient group, and a negative correlation was found with quality of life and Modified Rodnan Skin Score. Kinesiophobia is associated with increased anxiety, duration of illness, advanced age, pain, and respiratory distress in patients with systemic sclerosis. Structural disorders and psychological factors should be considered among the reasons for prolonging the limitation of movement and delayed recovery. For this reason, when patients with systemic sclerosis are evaluated for therapeutic purposes, it may be beneficial to apply psychological support treatments in addition to medical and physical therapy

Admission Control Policies in Loss Networks

International audienc

Conception et pilotage de flux d un réseau de soins stochastique sans attente (Application à la périnatalité)

Cette thèse porte sur l étude d un réseau de soins hiérarchique stochastique avec rejet où les patients sont transférés lorsque la capacité de l hôpital d accueil n est pas suffisante. Les patients sont alors redirigés vers un autre hôpital, ou hors du réseau. Une application concrète sur les réseaux de périnatalité est proposée, et nous avons identifié plusieurs verrous scientifiques fondamentaux d un point de vue stratégique et opérationnel. Dans la partie stratégique, nous nous sommes intéressés à un problème de planification de capacité dans le réseau. Nous avons développé un modèle de localisation et de dimensionnement non-linéaire qui tient compte de la nature stochastique du système. La linéarisation du modèle permet de résoudre des problèmes de taille réelle en temps raisonnable. Nous avons développé dans un second temps de nouvelles méthodologies d approximation permettant d évaluer la performance du réseau en termes de probabilité de rejet et de transfert entre hôpitaux. Dans la partie opérationnelle, nous avons étudié des politiques de pilotage d admission optimales pour différentes tailles de réseaux de manière utiliser au mieux les ressources hospitalières. Finalement, nous avons construit un modèle de simulation couplant multi-agents et événements discrets permettant la validation des résultats précédents et l évaluation de performance du système de manière réaliste.In this thesis, by being motivated from the challenges in perinatal networks, we address design, evaluation and flow control of a stochastic healthcare network where there exist multiple levels of hospitals and different types of patients. Patients are supposed urgent; thus they can be rejected and overflow to another facility in the same network if no service capacity is available at their arrival. Rejection of patients due to the lack of service capacity is the common phenomenon in overflow networks. We approach the problem from both strategic and operational perspectives. In strategic part, we address a location & capacity planning problem for adjusting the network to better meet demographic changes. In operational part, we study the optimal patient admission control policies to increase flexibility in allocation of resources and improve the control of patient flow in the network. Finally, in order to evaluate the performance of the network, we develop new approximation methodologies that estimate the rejection probabilities in each hospital for each arriving patient group, thus the overflow probabilities among hospitals. Furthermore, an agent-based discrete-event simulation model is constructed to adequately represent our main applicationarea: Nord Hauts-de-Seine Perinatal Network. The simulation model is used to evaluate the performance of the complex network and more importantly evaluate the strength of the optimal results of our analytical models. The developed methodologies in this thesis are combined in a decision support tool, foreseen under the project COVER , which aims to assist health system managers to effectively plan strategic and operational decisions of a healthcare network and evaluate the performance of their decisions.ST ETIENNE-ENS des Mines (422182304) / SudocSudocFranceF