Atrioventricular Synchrony Delivered by a Dual-Chamber Leadless Pacemaker System.

BACKGROUND: A dual-chamber leadless pacemaker system has been designed for AV synchronous pacing using wireless, beat-to-beat, implant-to-implant (i2i) communication between distinct atrial and ventricular leadless pacemakers. The AV synchrony achieved across various ambulatory scenarios has yet to be systematically evaluated. METHODS: A prospective, single-arm, unblinded, multicenter, international clinical trial of the leadless pacemaker system was conducted in patients with a conventional dual-chamber pacing indication enrolled from February 2022 to March 2023. Leadless pacemaker systems were implanted, and 12-lead Holter electrocardiographic recordings were collected 3 months after implantation over various postures/activities: sitting, supine, left lateral recumbent, right lateral recumbent, standing, normal walk, and fast walk. An independent Holter core laboratory performed a manual adjudication of the percent of AV synchronous beats using the standard 300-millisecond PR interval limit. Atrium-to-ventricle and ventricle-to-atrium i2i communication success rates were also assessed. Post hoc summary statistics describing the relationships between AV synchrony and i2i success, posture/activity, implantation indication, AV event, and heart rate were calculated. RESULTS: In the evaluable population (n=384 of 464 enrolled [83%]; 61% male; age, 70 years; weight, 82 kg; 60% ejection fraction; 95% of beats evaluable), the mean AV synchrony of 98% of beats observed across all postures using the standard 300-millisecond limit was greater than both atrium-to-ventricle i2i (94%) and ventricle-to-atrium i2i (94%; P<0.001), exceeding both i2i values in 95% of patients. AV synchrony was achieved in >95% of evaluable beats across all postures/activities, implantation indications, AV paced/sensed event combinations, and heart rate ranges (including >100 bpm). CONCLUSIONS: This dual-chamber leadless pacemaker system demonstrated AV synchrony in 98% of evaluable beats at 3 months after implantation. AV synchrony was maintained across postures/activities and remained robust for heart rates >100 bpm.

Association between suicidal ideation, negative symptoms and theory of mind in first episode psychosis.

PURPOSE: Suicidal thoughts are common among patients with first episode psychosis (FEP). The impact of symptoms' severity and social cognition on suicidal risk should be a focus of attention. This study aimed at assessment of the severity of suicidal ideation in patients with FEP and its potential association with the theory of mind (ToM) impairment and symptoms' severity. METHODS: Ninety-six participants were recruited consecutively and subdivided into three equal groups: FEP, schizophrenia, and healthy controls (HC). The symptoms' severity was assessed using Positive and Negative Syndrome Scale (PANSS) and Beck Depression Inventory (BDI). Suicidal ideation was evaluated using Beck Scale for Suicidal Ideation (BSSI). Reading the Mind in the Eyes revised version (RMET) was used to assess ToM. RESULTS: Suicidal ideation was significantly higher only in FEP compared to HC (p = 0.001). Both FEP and schizophrenia had substantially lower performance than HC on RMET (p < 0.001). Higher depression (ß = 0.452, p = 0.007) and negative symptoms (ß = 0.433, p = 0.027) appeared to be significantly associated with increased suicidal ideation severity in FEP while RMET did not. CONCLUSION: Patients with FEP and chronic schizophrenia have comparable deficits in theory of mind dimension of social cognition. The severity of negative and depressive symptoms potentially contributes to the increased risk of suicide in FEP.

Impact of Intraprocedural Mitral Regurgitation and Gradient Following Transcatheter Edge-to-Edge Repair for Primary Mitral Regurgitation.

BACKGROUND: The impact of intraprocedural results following transcatheter edge-to-edge repair (TEER) in primary mitral regurgitation (MR) is controversial. OBJECTIVES: This study sought to investigate the prognostic impact of intraprocedural residual mitral regurgitation (rMR) and mean mitral valve gradient (MPG) in patients with primary MR undergoing TEER. METHODS: The PRIME-MR (Outcomes of Patients Treated With Mitral Transcatheter Edge-to-Edge Repair for Primary Mitral Regurgitation) registry included consecutive patients with primary MR undergoing TEER from 2008 to 2022 at 27 international sites. Clinical outcomes were assessed according to intraprocedural rMR and mean MPG. Patients were categorized according to rMR (optimal result: ≤1+, suboptimal result: ≥2+) and MPG (low gradient: ≤5 mm Hg, high gradient: > 5 mm Hg). The prognostic impact of rMR and MPG was evaluated in a Cox regression analysis. The primary endpoint was 2-year all-cause mortality or heart failure hospitalization. RESULTS: Intraprocedural rMR and mean MPG were available in 1,509 patients (median age = 82 years [Q1-Q3: 76.0-86.0 years], 55.1% male). Kaplan-Meier analysis according to rMR severity showed significant differences for the primary endpoint between rMR ≤1+ (29.1%), 2+ (41.7%), and ≥3+ (58.0%; P < 0.001), whereas there was no difference between patients with a low (32.4%) and high gradient (42.1%; P = 0.12). An optimal result/low gradient was achieved in most patients (n = 1,039). The worst outcomes were observed in patients with a suboptimal result/high gradient. After adjustment, rMR ≥2+ was independently linked to the primary endpoint (HR: 1.87; 95% CI: 1.32-2.65; P < 0.001), whereas MPG >5 mm Hg was not (HR: 0.78; 95% CI: 0.47-1.31; P = 0.35). CONCLUSIONS: Intraprocedural rMR but not MPG independently predicted clinical outcomes following TEER for primary MR. When performing TEER in primary MR, optimal MR reduction seems to outweigh the impact of high transvalvular gradients.

Resilience after severe critical illness: a prospective, multicentre, observational study (RESIREA).

BACKGROUND: Critical-illness survivors may experience post-traumatic stress disorder (PTSD) and quality-of-life impairments. Resilience may protect against psychological trauma but has not been adequately studied after critical illness. We assessed resilience and its associations with PTSD and quality of life, and also identified factors associated with greater resilience. METHODS: This prospective, multicentre, study in patients recruited at 41 French ICUs was done in parallel with the NUTRIREA-3 trial in patients given mechanical ventilation and vasoactive amines for shock. Three months to one year after intensive-care-unit admission, survivors completed the Connor-Davidson Resilience Scale (CD-RISC-25), Impact of Event-Revised scale for PTSD symptoms (IES-R), SF-36 quality-of-life scale, Multidimensional Scale of Perceived Social Support (MSPSS), and Brief Illness Perception Questionnaire (B-IPQ). RESULTS: Of the 382 included patients, 203 (53.1%) had normal or high resilience (CD-RISC-25 ≥ 68). Of these resilient patients, 26 (12.8%) had moderate to severe PTSD symptoms (IES-R ≥ 24) vs. 45 (25.4%) patients with low resilience (p = 0.002). Resilient patients had higher SF-36 scores. Factors independently associated with higher CD-RISC-25 scores were higher MSPSS score indicating stronger social support (OR, 1.027; 95%CI 1.008-1.047; p = 0.005) and lower B-IPQ scores indicating a more threatening perception of the illness (OR, 0.973; 95%CI 0.950-0.996; p = 0.02). CONCLUSIONS: Resilient patients had a lower prevalence of PTSD symptoms and higher quality of life scores, compared to patients with low resilience. Higher scores for social support and illness perception were independently associated with greater resilience. Thus, our findings suggest that interventions to strengthen social support and improve illness perception may help to improve resilience. Such interventions should be evaluated in trials with PTSD mitigation and quality-of-life improvement as the target outcomes.

Implementation of a fluid balance control strategy in critically ill patients: POINCARE-2 trial process evaluation.

BACKGROUND: POINCARE-2 trial aimed to assess the effectiveness of a strategy designed to tackle fluid overload through daily weighing and subsequent administration of treatments in critically ill patients. Even in highly standardized care settings, such as intensive care units, effectiveness of such a complex intervention depends on its actual efficacy but also on the extent of its implementation. Using a process evaluation, we aimed to provide understanding of the implementation, context, and mechanisms of change of POINCARE-2 strategy during the trial, to gain insight on its effectiveness and inform the decision regarding the dissemination of the intervention. METHODS: We conducted a mixed-method process evaluation following the Medical Research Council guideline. Both quantitative data derived from the trial, and qualitative data from semi-structured interviews with professionals were used to explain implementation, mechanisms of change of the POINCARE-2 strategy, as well as contextual factors potentially influencing implementation of the strategy. RESULTS: Score of actual exposure to the strategy ranged from 29.1 to 68.2% during the control period, and from 61.9 to 92.3% during the intervention period, suggesting both potential contamination and suboptimal fidelity to the strategy. Lack of appropriate weighing devices, lack of human resources dedicated to research, pre-trial rooted prescription habits, and anticipated knowledge of the strategy have been identified as the main barriers to optimal implementation of the strategy in the trial context. CONCLUSIONS: Both contamination and suboptimal fidelity to POINCARE-2 strategy raised concerns about a potential bias towards the null of intention-to-treat (ITT) analyses. However, optimal fidelity seemed reachable. Consequently, a clinical strategy should not be rejected solely on the basis of the negativity of ITT analyses' results. Our findings showed that, even in highly standardized care conditions, the implementation of clinical strategies may be hindered by numerous contextual factors, which demonstrates the critical importance of assessing the viability of an intervention, prior to any evaluation of its effectiveness. TRIAL REGISTRATION: Number NCT02765009.

Calibration curve for radiation dose estimation using FDXR gene expression biodosimetry - premises and pitfalls.

PURPOSE: Radiation-induced alterations in gene expression show great promise for dose reconstruction and for severity prediction of acute health effects. Among several genes explored as potential biomarkers, FDXR is widely used due to high upregulation in white blood cells following radiation exposure. Nonetheless, the absence of a standardized protocols for gene expression-based biodosimetry is a notable gap that warrants attention to enhance the accuracy, reproducibility and reliability. The objective of this study was to evaluate the sensitivity of transcriptional biodosimetry to differences in protocols used by different laboratories and establish guidelines for the calculation of calibration curve using FDXR expression data. MATERIAL AND METHODS: Two sets of irradiated blood samples generated during RENEB exercise were used. The first included samples irradiated with known doses including: 0, 0.25, 0.5, 1, 2, 3 and 4 Gy. The second set consisted of three 'blind' samples irradiated with 1.8 Gy, 0.4 Gy and a sham-irradiated sample. After irradiation, samples were incubated at 37 °C over 24 h and sent to participating laboratories, where RNA isolation and FDXR expression analysis by qPCR were performed using sets of primers/probes and reference genes specific for each laboratory. Calibration curves based on FDXR expression data were generated using non-linear and linear regression and used for dose estimation of 'blind' samples. RESULTS: Dose estimates for sham-irradiated sample (0.020-0.024 Gy) and sample irradiated with 0.4 Gy (0.369-0.381 Gy) showed remarkable consistency across all laboratories, closely approximating the true doses regardless variation in primers/probes and reference genes used. For sample irradiated with 1.8 Gy the dose estimates were less precise (1.198-2.011 Gy) but remained within an acceptable margin for triage within the context of high dose range. CONCLUSION: Methodological differences in reference genes and primers/probes used for FDXR expression measurement do not have a significant impact on the dose estimates generated, provided that all reference genes performed as expected and the primers/probes target a similar set of transcript variants. The preferred method for constructing a calibration curve based on FDXR expression data involves employing linear regression to establish a function that describes the relationship between the logarithm of absorbed dose and FDXR ΔCt values. However, one should be careful with using non-irradiated sample data as these cannot be accurately represented on a logarithmic scale. A standard curve generated using this approach can give reliable dose estimations in a dose range from 50 mGy to 4 Gy at least.

Brachydactyly type B: a rare case report and literature review.

Brachydactyly is a genetic condition leading to shortened or absent digits in hands or feet. It can occur independently or as part of syndromes. This case focuses on Brachydactyly type B, the rarest form. An 8-month-old from the Philippines was referred due to a missing third toe. Examination revealed a hypoplastic left third toe. X-rays confirmed the finding. Treatment options were discussed, including conservative therapy and follow up. Diagnosis involved history, examination, and imaging. Prenatal diagnosis is limited for isolated cases but useful for syndromic forms if a family mutation is known. Prognosis varies depending on the severity and associated syndromes. Currently there is no definitive treatment; management involves genetic counseling and therapy. Due to limited cases, Type B is underreported, highlighting the need for more research into its genetics.

Voltage-Driven Fluorine Motion for Novel Organic Spintronic Memristor.

Integrating tunneling magnetoresistance (TMR) effect in memristors is a long-term aspiration because it allows to realize multifunctional devices, such as multi-state memory and tunable plasticity for synaptic function. However, the reported TMR in different multiferroic tunnel junctions is limited to 100%. This work demonstrates a giant TMR of -266% in La0.6Sr0.4MnO3(LSMO)/poly(vinylidene fluoride)(PVDF)/Co memristor with thin organic barrier. Different from the ferroelectricity-based memristors, this work discovers that the voltage-driven florine (F) motion in the junction generates a huge reversible resistivity change up to 106% with nanosecond (ns) timescale. Removing F from PVDF layer suppresses the dipole field in the tunneling barrier, thereby significantly enhances the TMR. Furthermore, the TMR can be tuned by different polarizing voltage due to the strong modification of spin-polarization at the LSMO/PVDF interface upon F doping. Combining of high TMR in the organic memristor paves the way to develop high-performance multifunctional devices for storage and neuromorphic applications.

A novel HLA-DQB2::MET gene fusion variant in lung adenocarcinoma with prolonged response to tepotinib: a case report.

Background: MET rearrangements are infrequently observed in non-small cell lung cancer (NSCLC). Advanced genomic detection techniques have unveiled such infrequent genomic variations, particularly MET fusions in approximately 0.5% of NSCLC patients. Tyrosine kinase inhibitors (TKIs) have revolutionized the standard of care in lung cancer and more recently a second generation MET TKI tepotinib received Food and Drug Administration (FDA) approval for MET exon 14 alterations in metastatic NSCLC. Despite this, the therapeutic landscape for MET-rearranged NSCLC patients remains significantly unexplored. The aim of our report is to detail a unique case of a patient with metastatic lung adenocarcinoma with a novel HLA-DQB2::MET fusion detected by next-generation sequencing (NGS) following previous treatment resistance. Case Description: A 73-year-old female was initially started on carboplatin, pemetrexed and pembrolizumab with maintenance, but eventually had progression in the left upper lobe (LUL). Upon progression she was enrolled in a clinical trial of a monoclonal antibody with or without a PD-1 inhibitor, but brain metastasis progression was eventually detected by magnetic resonance imaging (MRI) requiring stereotactic radiosurgery (SRS) and a craniotomy. The trial drug was eventually discontinued due to progression and toxicity and NGS on bronchoscopy tissue revealed HLA-DQB2::MET fusion. The patient was initiated on tepotinib and continues with clinical and radiological stable disease for over 12 months. The patient's response to a MET inhibitor, tepotinib, underscores the potential efficacy of selective MET inhibitors for individuals with previously unexplored MET fusions. Conclusions: The positive response to tepotinib of a patient with NSCLC harboring a novel MET-Fusion underscores the importance of the use of comprehensive next-generational sequencing-based panels and highlights the necessity for additional research and clinical exploration of selective MET inhibitors for managing NSCLC with MET rearrangements.

Serum angiopoietin-2: a promising biomarker for early diabetic kidney disease in children and adolescents with type 1 diabetes.

Albuminuria has been considered the golden standard biomarker for diabetic kidney disease (DKD), but appears once significant kidney damage has already occurred. Angiopoietin-2 (Angpt-2) has been implicated in the development and progression of DKD in adults. We aimed to explore the association of serum Angpt-2 levels with DKD in children and adolescents with type 1 diabetes mellitus (T1DM) of short duration (3-5 years) and to evaluate the predictive power of serum Angpt-2 in the early detection of DKD prior to the microalbuminuric phase. The current cross-sectional study included 90 children divided into three age and sex-matched groups based on urinary albumin-to-creatinine ratio (UACR): microalbuminuric diabetic group (n = 30), non-albuminuric diabetic group (n = 30), and control group (n = 30). All participants were subjected to anthropometric measurements, serum Angpt-2 and fasting lipid profile (total cholesterol, triglycerides, LDL-C, HDL-C, and Non-HDL-C) assessment. Glomerular filtration rate was estimated based on serum creatinine (eGFR-Cr). Higher serum Angpt-2 levels were detected in both diabetic groups compared to controls and in microalbuminuric compared to non-albuminuric diabetic group. There was no detected significant difference in eGFR-Cr values across the study groups. Serum Angpt-2 was positively correlated with triglycerides, LDL, Non-HDL-C, HbA1c, and UACR, while UACR, HbA1c, and Non-HDL-C were independent predictors for serum Angpt-2. Serum Angpt-2 at level of 137.4 ng/L could discriminate between microalbuminuric and non-albuminuric diabetic groups with AUC = 0.960 and at level of 115.95 ng/L could discriminate between the non-albuminuric diabetic group and controls with AUC = 0.976.Conclusion: Serum Angpt-2 is a promising potent biomarker for the detection of early stage of DKD in childhood T1DM before albuminuria emerges. What is Known? • Urine albumin-to-creatinine ratio (UACR) and glomerular filtration rate (GFR) are the golden standard but late biomarkers for DKD. • Angiopoietin-2 has been implicated in the development and progression of DKD in adults with diabetes, but has not been explored in T1DM children with DKD. What is New? • Higher serum angiopoietin-2 was detected in diabetic groups compared to controls and in microalbuminuric compared to non-albuminuric group. • Angiopoietin-2 correlated positively with triglycerides, LDL, Non-HDL-C, HbA1c, and UACR. • Serum angiopoietin-2 is a promising early diagnostic biomarker for DKD in children with T1DM.

Six-month electrical performance of the first dual-chamber leadless pacemaker.

BACKGROUND: The first dual-chamber leadless pacemaker (DC-LP) system consists of 2 separate atrial and ventricular devices that communicate to maintain synchronous atrioventricular pacing and sensing. The initial safety and efficacy were previously reported. OBJECTIVE: The purpose of this study was to evaluate the chronic electrical performance of the DC-LP system. METHODS: Patients meeting standard dual-chamber pacing indications were enrolled and implanted with the DC-LP system (Aveir DR, Abbott), including right atrial and ventricular helix-fixation LPs (atrial leadless pacemaker [ALP], ventricular leadless pacemaker [VLP]). Pacing capture threshold, sensed amplitude, and pacing impedance were collected using the device programmer at prespecified timepoints from 0-6 months postimplant. RESULTS: De novo devices were successfully implanted in 381 patients with complete 6-month data (62% male; age 69 ± 14 years; weight 82 ± 20 kg; 65% sinus nodal dysfunction, 30% atrioventricular block). ALPs were implanted predominantly in the right atrial appendage anterior base and VLPs primarily at the mid-to-apical right ventricular septum. From implant to 1 month, pacing capture thresholds (0.4-ms pulse width) improved in both ALPs (2.4 ± 1.5 V to 0.8 ± 0.8 V; P <.001) and VLPs (0.8 ± 0.6 V to 0.6 ± 0.4 V; P <.001). Sensed amplitudes improved in both ALPs (1.8 ± 1.3 mV to 3.4 ± 1.9 mV; P <.001) and VLPs (8.8 ± 4.0 mV to 11.7 ± 4.2 mV; P <.001). Impedances were stable in ALPs (334 ± 68 Ω to 329 ± 52 Ω; P = .17) and reduced in VLPs (789 ± 351 Ω to 646 ± 190 Ω; P <.001). Electrical measurements remained relatively stable from 1-6 months postimplant. No differences in electrical metrics were observed among ALP or VLP implant locations. CONCLUSION: This first in-human evaluation of the new dual-chamber leadless pacemaker system demonstrated reliable electrical performance throughout the initial 6-month evaluation period.

In vitro study of radiosensitivity in colorectal cancer cell lines associated with Lynch syndrome.

Introduction: Lynch syndrome patients have an inherited predisposition to cancer due to a deficiency in DNA mismatch repair (MMR) genes which could lead to a higher risk of developing cancer if exposed to ionizing radiation. This pilot study aims to reveal the association between MMR deficiency and radiosensitivity at both a CT relevant low dose (20 mGy) and a therapeutic higher dose (2 Gy). Methods: Human colorectal cancer cell lines with (dMMR) or without MMR deficiency (pMMR) were analyzed before and after exposure to radiation using cellular and cytogenetic analyses i.e., clonogenic assay to determine cell reproductive death; sister chromatid exchange (SCE) assay to detect the exchange of DNA between sister chromatids; γH2AX assay to analyze DNA damage repair; and apoptosis analysis to compare cell death response. The advantages and limitations of these assays were assessed in vitro, and their applicability and feasibility investigated for their potential to be used for further studies using clinical samples. Results: Results from the clonogenic assay indicated that the pMMR cell line (HT29) was significantly more radio-resistant than the dMMR cell lines (HCT116, SW48, and LoVo) after 2 Gy X-irradiation. Both cell type and radiation dose had a significant effect on the yield of SCEs/chromosome. When the yield of SCEs/chromosome for the irradiated samples (2 Gy) was normalized against the controls, no significant difference was observed between the cell lines. For the γH2AX assay, 0, 20 mGy and 2 Gy were examined at post-exposure time points of 30 min (min), 4 and 24 h (h). Statistical analysis revealed that HT29 was only significantly more radio-resistant than the MLH1-deficient cells lines, but not the MSH2-deficient cell line. Apoptosis analysis (4 Gy) revealed that HT29 was significantly more radio-resistant than HCT116 albeit with very few apoptotic cells observed. Discussion: Overall, this study showed radio-resistance of the MMR proficient cell line in some assays, but not in the others. All methods used within this study have been validated; however, due to the limitations associated with cancer cell lines, the next step will be to use these assays in clinical samples in an effort to understand the biological and mechanistic effects of radiation in Lynch patients as well as the health implications.

Bioelectrical Impedance Analysis Detects Body Fat Changes After Surgical Subcutaneous Fat Removal.

Background: The risk and metabolic effects of obesity are determined by the distribution of fat throughout the body. It has been proposed that the distribution of abdominal fat is more closely related to the metabolic risks of obesity. High prevalence of overweight and obesity has thereby contributed to an increased uptake of surgical subcutaneous fat removal (SSFR) procedures. The goal of this study was to determine whether bioelectrical impedance analysis (Tanita system) can be used to detect the removal of excess abdominal subcutaneous fat tissue during SSFR when studying the metabolic effects of such procedures. Methods: Study population comprised patients who received body contouring procedures at the Hamad General Hospital's plastic surgery department between November 2020 and December 2022. To evaluate the factors of interest, subjects were prospectively followed up at two time points: within 1 week before the surgery and within 1-2 weeks thereafter. The following factors were measured: body weight, body fat percentage, body fat mass, body mass index (BMI), fat-free mass, estimated muscle mass, total body water, visceral fat score, and basal metabolic rate. Results: In total, 22 patients were included in the study. The two visits' medians for height, weight, BMI, fat percent (fat%), fat mass, visceral fat rating, and Doi's weighted average glucose (dwAG) were compared. Only in the case of Tanita fat% and fat mass, were the preoperative and postoperative medians significantly different. Furthermore, there was no association between these Tanita measures and dwAG or homeostatic model assessment (HOMA; insulin resistance [IR]) changes (before and after surgery). Tanita measures overestimated fat loss, as seen by the mountain plot and Bland-Altman plot agreement methods. Conclusions: Our findings indicated that the only two Tanita measures exhibited meaningful early associations with the amount of tissue excised which were fat mass and fat% differences. Although dwAG and HOMA-IR are not impacted immediately postsurgery, a trend was seen that suggested improvements in those parameters, even though the changes are not clinically significant.

Locoregional delivery of IL-13Rα2-targeting CAR-T cells in recurrent high-grade glioma: a phase 1 trial.

Chimeric antigen receptor T cell (CAR-T) therapy is an emerging strategy to improve treatment outcomes for recurrent high-grade glioma, a cancer that responds poorly to current therapies. Here we report a completed phase I trial evaluating IL-13Rα2-targeted CAR-T cells in 65 patients with recurrent high-grade glioma, the majority being recurrent glioblastoma (rGBM). Primary objectives were safety and feasibility, maximum tolerated dose/maximum feasible dose and a recommended phase 2 dose plan. Secondary objectives included overall survival, disease response, cytokine dynamics and tumor immune contexture biomarkers. This trial evolved to evaluate three routes of locoregional T cell administration (intratumoral (ICT), intraventricular (ICV) and dual ICT/ICV) and two manufacturing platforms, culminating in arm 5, which utilized dual ICT/ICV delivery and an optimized manufacturing process. Locoregional CAR-T cell administration was feasible and well tolerated, and as there were no dose-limiting toxicities across all arms, a maximum tolerated dose was not determined. Probable treatment-related grade 3+ toxicities were one grade 3 encephalopathy and one grade 3 ataxia. A clinical maximum feasible dose of 200 × 106 CAR-T cells per infusion cycle was achieved for arm 5; however, other arms either did not test or achieve this dose due to manufacturing feasibility. A recommended phase 2 dose will be refined in future studies based on data from this trial. Stable disease or better was achieved in 50% (29/58) of patients, with two partial responses, one complete response and a second complete response after additional CAR-T cycles off protocol. For rGBM, median overall survival for all patients was 7.7 months and for arm 5 was 10.2 months. Central nervous system increases in inflammatory cytokines, including IFNγ, CXCL9 and CXCL10, were associated with CAR-T cell administration and bioactivity. Pretreatment intratumoral CD3 T cell levels were positively associated with survival. These findings demonstrate that locoregional IL-13Rα2-targeted CAR-T therapy is safe with promising clinical activity in a subset of patients. ClinicalTrials.gov Identifier: NCT02208362 .

A malignant spiradenoma of the forehead: a case report and literature review.

Spiroadenomas, arising from sweat glands, are rare benign skin tumors primarily found as solitary nodules on the head, neck, and trunk. The malignant subtype, Spiradenocarcinoma (MSA), originating from benign spiradenomas, is extremely rare and occurs mainly in individuals over 50. MSA exhibits aggressiveness with higher metastasis rates and lower survival rates. Surgical excision is the standard management, supported by imaging modalities like MRI, CT-scan, and ultrasound. We present a 69-year-old female with a medical history of diabetes, hypertension, and dyslipidemia who presented in 2014 with multiple swellings on the forehead and left arm. Initial excisions revealed capillary hemangioma lesions. Subsequent visits involved the excision of further facial and body lesions, with some identified as intradermal nevi. In 2022, she presented to plastic surgery clinic with forehead swelling. The biopsy showed MSA lesion with involved margins. Thus, subsequent re-excision was carried out. One year later, she came with recurrent forehead swelling. Excision and direct closure of the lesion showed involvement of part of the subcutaneous tissue (fat globule) showing residual/recurrent MSA that is very close to nerve trunks. Malignant Spiradenomas (MSAs) usually arise from benign spiradenomas. Therefore, consideration is given to preemptive removal of these tumors due to their potential evolution. The primary treatment approach involves surgery, with a focus on wide local excision and a minimum margin of 1 cm to diminish the risk of metastasis. Vigilant follow-up is essential to promptly identify any recurrences or spreading.

Evaluation of Sleep Difficulties in Egyptian Children with Down Syndrome: A Case-Control Study.

Sleep is a major concern in Down syndrome children. Obstructive sleep apnea, delayed sleep onset, night-time and early awakenings have been reported contributing to the cognitive and behavioral outcomes. The aim is to evaluate sleep related difficulties in Down syndrome young children. A questionnaire of sleep related difficulties was translated and validated into Arabic language then was filled in by caregivers of 45 Down syndrome and 48 normal children. The questionnaire consisted of sections related to snoring, breathing difficulties, mouth breathing, upper respiratory tract infections, sleep position, restless sleep and frequent awakening, and daytime behavior. The results show highly significant differences between the total and subtotal questionnaire scores with higher scores in the control group. The questionnaire has a good reliability. Test-retest reliability of the questionnaire revealed a significant positive correlation in the total questionnaire and all the subitems except for the 7th subitem of the daytime behavior which showed no significant correlation. The questionnaire showed 100% sensitivity and 70.8% Specificity with at cut-off value of 8.5. The sleep related difficulties questionnaire has good psychometric properties and could detect significant sleep problems in Down syndrome children. Supplementary Information: The online version contains supplementary material available at 10.1007/s12070-023-04090-9.

Gut dysbiosis is linked to metabolic syndrome in obese Egyptian women: potential treatment by probiotics and high fiber diets regimen.

Metabolic syndrome (MetS) is defined as a cluster of glucose intolerance, hypertension, dyslipidemia, and central obesity with insulin resistance. The role of gut microbiota in metabolic disorders is increasingly considered. To investigate the effects of probiotic supplements and hypocaloric high fiber regimen on MetS in obese Egyptian women. A longitudinal follow-up intervention study included 58 obese Egyptian women, with a mean age of 41.62 ± 10.70 years. They were grouped according to the criteria of MetS into 2 groups; 23 obese women with MetS and 35 ones without MetS. They followed a hypocaloric high fiber regimen weight loss program, light physical exercise, and received a probiotic supplement daily for 3 months. For each participating woman, blood pressure, anthropometric measurements, basal metabolic rate (BMR), dietary recalls, laboratory investigations, and microbiota analysis were acquired before and after 3 months of follow-up. After intervention by the probiotic and hypocaloric high fiber regimen and light exercise, reduction ranged from numerical to significant difference in the anthropometric parameters, blood pressure, and BMR was reported. All the biochemical parameters characterized by MetS decreased significantly at p ≤ 0.05-0.01. Before the intervention, results revealed abundant of Bacteroidetes bacteria over Firmicutes with a low Firmicutes/Bacteroidetes ratio. After the intervention, Log Lactobacillus, Log Bifidobacteria, and Log Bacteroidetes increased significantly in both groups, while Log Firmicutes and the Firmicutes/Bacteroidetes Ratio revealed a significant decrease. In conclusion, this study's results highlight a positive trend of probiotics supplementation with hypocaloric high-fiber diets in amelioration of the criteria of the Mets in obese Egyptian women.

Early real-world implant experience with a helix-fixation ventricular leadless pacemaker.

BACKGROUND: Roughly one in six patients receiving conventional transvenous pacemaker systems experience significant complications within 1 year of implant, mainly due to the transvenous lead and subcutaneous pocket. A new helix-fixation single-chamber ventricular leadless pacemaker (LP) system capable of pre-deployment exploratory electrical mapping is commercially available. Such an LP may mitigate complications while streamlining the implantation. In this study, the initial real-world implant experience of the helix-fixation LP was evaluated following its commercial release. METHODS: In patients indicated for single-chamber right ventricular pacing, helix-fixation Aveir VR LPs (Abbott, Abbott Park, IL) were implanted using the dedicated loading tool, introducer, and delivery catheter. Implant procedural characteristics, electrical parameters, and any 30-day procedure-related adverse events of consecutive implant attempts were retrospectively evaluated. RESULTS: A total of 167 patients with Class I indication for permanent pacing received implants in four North American centers (57% male, 70 years old). Pre-fixation electrical mapping of potential sites allowed repositioning to be avoided in 95.7% of patients. Median [interquartile range] LP procedure and fluoroscopy durations were 25.5 min [20.0, 35.0] and 5.7 min [4.0, 9.2], respectively. Pacing capture threshold, sensed R-wave amplitude, and impedance were 0.8 V [0.5, 1.3], 9.0 mV [6.0, 12.0], and 705 Ω [550, 910], respectively. Implantation was successful in 98.8% of patients, with 98.2% free from acute adverse events. CONCLUSIONS: The initial, real-world experience of the helix-fixation ventricular leadless pacemaker demonstrated safe and efficient implantation with minimal repositioning, viable electrical metrics, and limited acute complications.