Intellectual disability (ID) is a major health problem mostly with an unknown etiology. Recently exome sequencing of individuals with ID identified novel genes implicated in the disease. Therefore ...the purpose of the present study was to identify the genetic cause of ID in one syndromic and two non-syndromic Pakistani families. Whole exome of three ID probands was sequenced. Missense variations in two plausible novel genes implicated in autosomal recessive ID were identified: lysine (K)-specific methyltransferase 2B (KMT2B), zinc finger protein 589 (ZNF589), as well as hedgehog acyltransferase (HHAT) with a de novo mutation with autosomal dominant mode of inheritance. The KMT2B recessive variant is the first report of recessive Kleefstra syndrome-like phenotype. Identification of plausible causative mutations for two recessive and a dominant type of ID, in genes not previously implicated in disease, underscores the large genetic heterogeneity of ID. These results also support the viewpoint that large number of ID genes converge on limited number of common networks i.e. ZNF589 belongs to KRAB-domain zinc-finger proteins previously implicated in ID, HHAT is predicted to affect sonic hedgehog, which is involved in several disorders with ID, KMT2B associated with syndromic ID fits the epigenetic module underlying the Kleefstra syndromic spectrum. The association of these novel genes in three different Pakistani ID families highlights the importance of screening these genes in more families with similar phenotypes from different populations to confirm the involvement of these genes in pathogenesis of ID.
Global approval of the use of fluid viscous dampers to control the buildings response against dynamic loadings is growing. The idea behind incorporating additional dampers is that they will reduce ...most of the energy that is transmitted to the building during shaking event. The objective of this work is to identify and enhance the design parameters that control the nonlinear behaviour of fluid viscous damper subjected to sinusoidal excitation. For this, a numerical model of the flow inside the dissipater has been carried out based on finite volume method. A novel approach has been adopted to simulate elastic behaviour of the fluid, taking into account its compressibility by using the Murnaghan equation of state. A comparison between the calculations of the proposed model and the experimental tests was carried out. The model proved to be sufficiently accurate. A fluid flow analysis was then conducted to fully understand the internal mechanism of the damper. A parametric study was then performed by varying aspects such as dimensions, geometric relationships between components and fluid properties in order to better understand their effect on the non-linear behaviour of the device. The results highlight the relationship between the parameters governing the shear thinning behaviour of the fluid and the non-linearity exponent of the damper. This makes it possible to better control the non-linear behaviour of the device by selecting the appropriate silicone oil and the appropriate geometric dimensions of its components.
To evaluate the impact of high-resolution contrast-enhanced ultrasound (CEUS) in combination with Color Coded and Power Doppler Sonography (CCDS/PD) in the preoperative differentiation of thyroid ...adenomas and thyroid carcinomas.
A total of 101 patients (55 female, median age 54 years) underwent surgery for thyroid adenoma and thyroid carcinoma. CCDS/PD and CEUS were performed in all patients by an experienced examiner using a multifrequency linear transducer (6-9 or 6-15 MHz) and were digitally stored. Reading of the ultrasound images was performed by two experienced radiologists in consensus. A histopathological evaluation was obtained as standard of reference in all patients.
Altogether, 75 thyroid adenomas and 26 thyroid carcinomas were detected. Mean diameter of thyroid adenomas and thyroid carcinomas was 27 mm and 32 mm, respectively. The differences in microcirculation of thyroid adenomas and thyroid carcinomas were statistically highly significant (p < 0.01). Representative features for thyroid adenomas were either no wash-out or wash-out with persisting edge in late phase, for thyroid carcinomas a complete wash-out in late phase. Thus, a calculation of sensitivity, specificity, positive and negative predictive value of 81% , 92% , 97% and 63%, respectively, for the differentiation of benignity and malignancy was possible.
Dynamic evaluation of microcirculation using CEUS and CCDS/PD enables a more reliable preoperative discrimination between thyroid adenomas and thyroid carcinomas.
The adoptive transfer of antigen-specific T cells to establish immunity is an effective therapy for viral infections and tumors in animal models. The application of this approach to human disease ...would require the isolation and in vitro expansion of human antigen-specific T cells and evidence that such T cells persist and function in vivo after transfer. Cytomegalovirus-specific CD8$^+$ cytotoxic T cell (CTL) clones could be isolated from bone marrow donors, propagated in vitro, and adoptively transferred to immunodeficient bone marrow transplant recipients. No toxicity developed and the clones provided persistent reconstitution of CD8$^+$ cytomegalovirus-specific CTL responses.
Cilta-cel is a CAR-T cell therapy that expresses 2 BCMA-targeting single-domain antibodies, designed to confer avidity. In the multicohort, phase 2 CARTITUDE-2 study (NCT04133636), the safety and ...efficacy of cilta-cel in various clinical settings and suitability of outpatient administration was explored in patients with multiple myeloma.
Patients enrolled in Cohort A had progressive MM after 1–3 prior lines of therapy (LOT), including a proteasome inhibitor (PI) and immunomodulatory drug (IMiD), were lenalidomide refractory, and were naïve to BCMA-targeting agents. A single cilta-cel infusion (target dose: 0.75 × 106 CAR+ viable T cells/kg) was given 5–7 days after start of lymphodepletion (daily cyclophosphamide 300 mg/m2 and fludarabine 30 mg/m2 for 3 days). The primary outcome was minimal residual disease (MRD) 10-5 negativity. Secondary outcomes were response rates (per IMWG criteria) and safety (per CTCAE; CRS and ICANS by ASTCT).
As of the February 2021 data cutoff (median follow-up: 5.8 months 2.5–9.8), 20 patients (65% male; median age 60 years 38–75) received cilta-cel; 1 patient was treated in an outpatient setting. Patients (n = 12: <3 prior LOT; n = 8: 3 prior LOT) received a median of 2 (1–3) prior LOT. All patients were exposed to PI, IMiD, and dexamethasone, 95% to alkylating agents, and 65% to daratumumab. The majority (95%) were refractory to the last LOT; 40% were triple-class refractory. Overall response rate was 95% (95% CI: 75–100), 75% (95% CI: 51–91) achieved stringent CR/CR, and 85% (95% CI: 62–97) achieved ≥VGPR. Median time to first response was 1.0 month (0.7–3.3); median time to best response was 1.9 month (0.9–5.1). Median duration of response was not reached. All patients (n = 4) with MRD-evaluable samples at 10-5 at data cutoff were MRD-negative. Hematologic AEs ≥20% were neutropenia (95%; grade 3/4: 90%), thrombocytopenia (80%; grade 3/4: 35%), anemia (65%; grade 3/4: 40%), lymphopenia (60%; grade 3/4: 55%), and leukopenia (55%; all grade 3/4). 85% of patients had CRS; 10% were grade 3/4. Median time to CRS onset was 7 days (5–9), with a median duration of 3.5 days (2–11). CAR-T cell neurotoxicity occurred in 20% of patients (all grade 1/2). Three patients had ICANS (n = 1: grade 1; n = 2: grade 2); median time to onset was 8 days (7–11) and median duration was 2 days (1–2). One patient had grade 2 facial paralysis; time to onset was 29 days with a duration of 51 days. One death occurred due to Covid-19 (assessed as treatment-related by investigator). The safety profile was manageable in the patient who was treated in an outpatient setting.
Updated efficacy and safety findings will inform suitability of outpatient treatment in this and other cohorts of CARTITUDE-2 as well as the CARTITUDE-4 study.
A single cilta-cel infusion at the recommended phase 2 dose led to early and deep responses with a manageable safety profile in patients with MM who had 1–3 prior LOT.
Background Data regarding multidrug-resistant (MDR) Acinetobacter baumannii infections among cancer patients are limited. Methods We conducted a case-control study to investigate the risk factors for ...acquisition of MDR A baumannii and the outcomes among cancer patients. Cases were inpatients with malignancy who had MDR A baumannii from any cultures between 2008 and 2011. Controls were inpatients with malignancy but no MDR A baumannii. Results A total of 31 case patients were matched with 62 control patients. Hematologic malignancy ( P = .036), need for dialysis ( P = .01), admission for other reasons except elective surgery ( P = .03), transfer from other health care facilities ( P = .02), prolonged intensive care unit stay ( P = .004), mechanical ventilation ( P < .001), pressor use ( P = .001), tube feeding ( P < .001), transfusion ( P = .009), and prior antimicrobial use ( P < .001) were identified as significant risk factors in univariate analysis. Need for dialysis (odds ratio OR, 18.23; P = .04) and prolonged intensive care unit stay (OR, 19.28; P = .01) remained significant in multivariate analysis. Lengths of stay were 28 days for the case patients and 10 days for the control patients ( P = .001). The 90-day mortality rates were 41.9% and 29.0%, respectively ( P = .20). Conclusions Acquisition of MDR A baumannii among cancer patients appears to be associated with general nosocomial infection risk factors rather than underlying malignancies.
The aim of this study is to describe the image findings of contrast-enhanced ultrasound (CEUS) after irreversible electroporation (IRE), and to assess its usefulness in relation to the evaluation of ...the ablation status using a dynamic recording of the microvascularisation.
In this prospectively designed study, a percutaneous IRE was performed for the treatment of malignant hepatic lesions in a total of 15 patients following the interdisciplinary diagnosis. The lesions were documented using CEUS before, immediately after and 20 minutes after the ablation. The acquired CEUS image data was subsequently independently retrospectively evaluated by 2 experienced radiologists and assessed in relation to microvascularisation using a 5 point scale.
Using CEUS, a significant reduction in the microcirculation of the lesions, both centrally and marginally, could be detected following IRE (p < 0.001 and p < 0.001). The mean evaluation of the central microcirculation was reduced from 3.13 ± 1.38 to 0.47 ± 0.64 (p < 0.01). For the peripheral area of the lesion and the ablation margin, there was a reduction of 3.37 ± 1.13 to 1.57 ± 0.46 (p = 0.001). There was no significant reduction in the macrocirculation.
Within the framework of this study, it could be demonstrated that, in the course of IRE, a rapid significant reduction of the microcirculation in the ablation area occurred.
To evaluate the impact of high-resolution contrast-enhanced ultrasound (CEUS), Color Coded and Power Doppler Sonography (CCDS/PD), in the preoperative recognition of thyroid adenomas. A total of 64 ...patients (36 female, median age 54 years) underwent surgery for thyroid adenoma. CEUS with linear multifrequency probes (6-9 or 6-15 MHz) and CCDS/PD was performed in all patients preoperatively by an experienced examiner and images were stored in PACS. Reading of the ultrasound images was performed in consensus by two experienced radiologists. Histopathology was achieved as standard of reference in all patients. Median diameter of the tumor lesions was 27 mm. 31 nodules were found on the left side. In B-Scan mode 13 (20%) adenomas showed complex cystic echo pattern and 44 (69%) had a complete and sharp hypoechoic edge. 43 (67%) thyroid adenomas had strong hypervascularization in CCDS/PD. In 61 (95%) adenomas early contrast enhancement was present in CEUS and 50 (78%) adenomas proved no wash-out or central wash-out with persisting edge enhancement. In 47 (73%) cases early contrast enhancement was combined with no washout or with central wash-out with persisting edge enhancement. 45 (70%) thyroid lesions had preoperatively been classified as benign lesions correctly. Dynamic evaluation of microcirculation by CEUS and CCDS/PD enables a more reliable preoperative characterization of thyroid adenomas.
Sinusoidal obstruction syndrome, also known as veno-occlusive disease (SOS/VOD), is a potentially life threatening complication that can develop after hematopoietic cell transplantation. Although ...SOS/VOD progressively resolves within a few weeks in most patients, the most severe forms result in multi-organ dysfunction and are associated with a high mortality rate (>80%). Therefore, careful attention must be paid to allow an early detection of SOS/VOD, particularly as drugs have now proven to be effective and licensed for its treatment. Unfortunately, current criteria lack sensitivity and specificity, making early identification and severity assessment of SOS/VOD difficult. The aim of this work is to propose a new definition for diagnosis, and a severity-grading system for SOS/VOD in adult patients, on behalf of the European Society for Blood and Marrow Transplantation.
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