Artificial thymic organoids represent a reliable tool to study T-cell differentiation in patients with severe T-cell lymphopenia

The study of early T-cell development in humans is challenging because of limited availability of thymic samples and the limitations of in vitro T-cell differentiation assays. We used an artificial thymic organoid (ATO) platform generated by aggregating a DLL4-expressing stromal cell line (MS5-hDLL4) with CD34+ cells isolated from bone marrow or mobilized peripheral blood to study T-cell development from CD34+ cells of patients carrying hematopoietic intrinsic or thymic defects that cause T-cell lymphopenia. We found that AK2 deficiency is associated with decreased cell viability and an early block in T-cell development. We observed a similar defect in a patient carrying a null IL2RG mutation. In contrast, CD34+ cells from a patient carrying a missense IL2RG mutation reached full T-cell maturation, although cell numbers were significantly lower than in controls. CD34+ cells from patients carrying RAG mutations were able to differentiate to CD4+CD8+ cells, but not to CD3+TCRαβ+ cells. Finally, normal T-cell differentiation was observed in a patient with complete DiGeorge syndrome, consistent with the extra-hematopoietic nature of the defect. The ATO system may help determine whether T-cell deficiency reflects hematopoietic or thymic intrinsic abnormalities and define the exact stage at which T-cell differentiation is blocked

Patients with adenosine deaminase deficiency surviving after hematopoietic stem cell transplantation are at high risk of CNS complications

Adenosine deaminase (ADA) deficiency is a systemic metabolic disease that causes an autosomal recessive variant of severe combined immunodeficiency (SCID) and less consistently other complications including neurologic abnormalities. Hematopoietic stem cell transplantation (HSCT) is able to correct the immunodeficiency, whereas control of nonimmunologic complications has not been extensively explored. We applied HSCT in 15 ADA-deficient patients consecutively treated at our institutions since 1982 and analyzed long-term outcome. Seven patients received transplants without conditioning from HLA-matched family donors (MFDs); the other 8 patients received conditioning and were given transplants either from HLA-mismatched family donors (MMFDs; n = 6) or from matched unrelated donors (MUDs; n = 2). At a mean follow-up period of 12 years (range, 4-22 years), 12 patients are alive with stable and complete immune reconstitution (7 of 7 after MFD, 4 of 6 after MMFD, and 1 of 2 after MUD transplantation). Six of 12 surviving patients show marked neurologic abnormalities, which include mental retardation, motor dysfunction, and sensorineural hearing deficit. We were unable to identify disease or transplantation-related factors correlating with this divergent neurologic outcome. The high rate of neurologic abnormalities observed in long-term surviving patients with ADA deficiency indicates that HSCT commonly fails to control CNS complications in this metabolic disease

Allogeneic hematopoietic stem cell transplantation from unrelated donors is associated with higher infection rates in children with acute lymphoblastic leukemia—A prospective international multicenter trial on behalf of the BFM-SG and the EBMT-PDWP

Severe infections (SI) significantly impact on non-relapse mortality after hematopoietic stem cell transplantation (HSCT). We assessed 432 children and adolescents with acute lymphoblastic leukemia (ALL) after total body irradiation based myeloablative HSCT within the multicenter ALL-BFM-SCT 2003 trial for SI grade 3 or higher according to common terminology criteria for adverse events. A total 172 patients experienced at least one SI. Transplantation from matched unrelated donors (MUD) was associated with any type of SI in the pre-engraftment period (hazard ratio [HR]: 2.57; P < .001), and with any SI between day +30 and + 100 (HR: 2.91; P = .011). Bacterial (HR: 2.24; P = .041) and fungal infections (HR: 4.06; P = .057) occurred more often in the pre-engraftment phase and viral infections more often before day +30 (HR: 2.66; P = .007) or between day +30 and + 100 (HR: 3.89; P = .002) after HSCT from MUD as compared to matched sibling donors. Chronic GvHD was an independent risk factor for any type of SI after day +100 (HR: 2.57; P < .002). We conclude that allogeneic HSCT from MUD in children and adolescents with pediatric ALL is associated with higher infection rates, which seems attributable to an intensified GvHD prophylaxis including serotherapy and methotrexate

Supportive Care During Pediatric Hematopoietic Stem Cell Transplantation: Prevention of Infections. A Report From Workshops on Supportive Care of the Paediatric Diseases Working Party (PDWP) of the European Society for Blood and Marrow Transplantation (EBMT)

Specific protocols define eligibility, conditioning, donor selection, graft composition and prophylaxis of graft vs. host disease for children and young adults undergoing hematopoietic stem cell transplant (HSCT). However, international protocols rarely, if ever, detail supportive care, including pharmaceutical infection prophylaxis, physical protection with face masks and cohort isolation or food restrictions. Supportive care suffers from a lack of scientific evidence and implementation of practices in the transplant centers brings extensive restrictions to the child's and family's daily life after HSCT. Therefore, the Board of the Pediatric Diseases Working Party (PDWP) of the European Society for Blood and Marrow Transplantation (EBMT) held a series of dedicated workshops since 2017 with the aim of initiating the production of a set of minimal recommendations. The present paper describes the consensus reached within the field of infection prophylaxis. Keywords: allogeneic hematological stem cell transplantation; antibiotic prophylactic therapy; children; infection precaution; vaccination

Association between the magnitude of intravenous busulfan exposure and development of hepatic veno-occlusive disease in children and young adults undergoing myeloablative allogeneic hematopoietic cell transplantation

BACKGROUND Intravenous busulfan is widely used as part of myeloablative conditioning regimens in children and young adults undergoing allogeneic hematopoietic cell transplantation (HCT). Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a serious clinical problem observed with busulfan-based conditioning HCT. The development of VOD/SOS may be associated with busulfan exposure. Getting more insight in the association between busulfan exposure and the development of VOD/SOS enables further optimization of dosing and treatment strategies. OBJECTIVE The objective of this study was to assess the association between the magnitude of busulfan exposure and the occurrence of VOD/SOS in children and young adults undergoing myeloablative conditioning with a busulfan-containing regimen prior to allogeneic HCT. STUDY DESIGN In this observational study we included all patients who received an allogeneic HCT with intravenous busulfan as part of the conditioning regimen at 15 pediatric transplantation centers between 2000 and 2015. The endpoint was the development of VOD/SOS. The magnitude of busulfan exposure was estimated using non-linear mixed effect modelling and expressed as the maximal concentration (Cmax; day 1 and day 1-4 Cmax), cumulative area under the curve (AUC; day 1, highest 1-day AUC in 4 days, and 4-day cumulative AUC), cumulative time above a concentration of 300 µg/L, and clearance on day 1. RESULTS A total of 88 out of 697 patients (12.6%) developed VOD/SOS. The number of alkylators in the conditioning regimen was a strong effect modifier, therefore, we stratified the regression analysis for the number of alkylators. For patients receiving only busulfan as one alkylator (36.3%, n = 253), cumulative busulfan exposure (>78 mg*h/L) was associated with increased VOD/SOS risk (12.6% vs. 4.7%; odds ratio (OR) = 2.95, 95% CI 1.13-7.66). For individuals receiving busulfan with one or two additional alkylators (63.7%, n = 444), cumulative busulfan exposure (≤78 and >78 mg*h/L) did not further increase the risk of VOD/SOS (15.4% vs. 15.2%; OR = 1.03, 95% CI 0.61-1.75). CONCLUSION The effect of the magnitude of busulfan exposure on VOD/SOS risk in children and young adults undergoing HCT is dependent on the number of alkylators. In patients receiving busulfan as the only alkylator, higher cumulative busulfan exposure increased the risk of VOD/SOS, whereas in those receiving multiple alkylators, the magnitude of busulfan exposure did not further increase this risk

Sugammadeks

Genel anestezide steroid yapıdaki nöromüsküler bloker ajanlar (NMBA); hızlı ve kolay endotrakeal entübasyon ve ventilasyon uygulamasındaki etkilerinden dolayı kullanımı artmaktadır. NMBA’ın kullanımından kaynaklanan postoperatif rezidüel blok; hipoventilasyon, havayolu obstrüksiyonu, hipoksi ve ölüm gibi komplikasyonlara neden olmaktadır. Sugammadeks steroid yapıda NMBA’ın etkisini geri çeviren, gamma-siklodektrin yapıda ve sekiz glukoz molekülü içeren ilk seçici bağlayıcı ajandır. Sugammadeks uygulamasının kolay, etkisinin yüksek ve hızlı olması ve yan etkisinin az olması sebebiyle kullanımı yaygınlaşmaktadır. Sugammadeksin yapısı, uygulama dozu, yan etkisi ve terapotik etkisi hakkında bilği vermeyi amaçladık.In general anesthesia, steroidal neuromusculer blocking agents(NMBAs), use increasing of guickly and facilitate endotracheal intubation and effects of ventilation application. The use of NMBAs may be associated with complications attributable to the development of postoperative residual curarisation, resulting in hipoventilation, airway obstruction, hypoxia, and death. Sugammadex is the first selective relaxant-binding agent designed to reverse the efffect of steroidal NMBAs, is gamma-cyclodextrins and have got eight glucose molecule. Sugammadeks the effect of high and fast and have less side effects and easy application, due to the usage is exploding. We aimed to give information about sugammadex, dosage, side effects and therapeutic effects

Sugammadeks

Genel anestezide steroid yapıdaki nöromüsküler bloker ajanlar (NMBA); hızlı ve kolay endotrakeal entübasyon ve ventilasyon uygulamasındaki etkilerinden dolayı kullanımı artmaktadır. NMBA’ın kullanımından kaynaklanan postoperatif rezidüel blok; hipoventilasyon, havayolu obstrüksiyonu, hipoksi ve ölüm gibi komplikasyonlara neden olmaktadır. Sugammadeks steroid yapıda NMBA’ın etkisini geri çeviren, gamma-siklodektrin yapıda ve sekiz glukoz molekülü içeren ilk seçici bağlayıcı ajandır. Sugammadeks uygulamasının kolay, etkisinin yüksek ve hızlı olması ve yan etkisinin az olması sebebiyle kullanımı yaygınlaşmaktadır. Sugammadeksin yapısı, uygulama dozu, yan etkisi ve terapotik etkisi hakkında bilği vermeyi amaçladık.In general anesthesia, steroidal neuromusculer blocking agents(NMBAs), use increasing of guickly and facilitate endotracheal intubation and effects of ventilation application. The use of NMBAs may be associated with complications attributable to the development of postoperative residual curarisation, resulting in hipoventilation, airway obstruction, hypoxia, and death. Sugammadex is the first selective relaxant-binding agent designed to reverse the efffect of steroidal NMBAs, is gamma-cyclodextrins and have got eight glucose molecule. Sugammadeks the effect of high and fast and have less side effects and easy application, due to the usage is exploding. We aimed to give information about sugammadex, dosage, side effects and therapeutic effects

Comparison of pericapsular nerve group (peng) block with intra-articular and quadratus lumborum block in primary total hip arthroplasty: a randomized controlled trial

PMID: 37013389Background: Pericapsular nerve group (PENG) block, quadratus lumborum block (QLB) and intra-articular (IA) local anesthetic injection have all been shown to provide effective analgesia in total hip arthroplasty (THA). The aim of this randomized study was to compare PENG block, QLB, and IA injection in terms of analgesic efficacy, motor protection, and quality of recovery. Methods: A total of 89 patients who underwent unilateral primary THA under spinal anesthesia were randomly assigned to the groups of PENG block (n = 30), QLB (n = 30), and IA (n = 29). The primary outcome was the numerical rating scale (NRS) over 48 hours. Secondary outcomes were postoperative opioid use, quadriceps and adductor muscle strength, and quality of recovery (QoR-40). Results: The 3-hour and 6-hour dynamic NRS scores were significantly different in the PENG and QLB group compared to the IA group (P = 0.002 and P < 0.001, respectively). The time to the first requirement for opioid analgesia was longer in the PENG and QLB groups than in the IA group (P = 0.009, P = 0.016, respectively). There was a significant difference between the PENG and QLB groups in terms of quadriceps muscle strength (QMS) at 3 hours (P = 0.007) and mobilization time (P = 0.003). There was no significant difference in QoR-40. Conclusions: The PENG block and QLB showed more effective analgesia at 6 hours postoperatively compared to IA applications. The PENG block and QLB applications showed similar analgesic effects. All the groups were similar in terms of postoperative recovery