Loss of stress sensor GADD45A promotes stem cell activity and ferroptosis resistance in LGR4/HOXA9-dependent AML.

The overall prognosis of acute myeloid leukemia (AML) remains dismal, largely due to the inability of current therapies to kill leukemia stem cells (LSCs) with intrinsic resistance. Loss of the stress sensor GADD45A is implicated in poor clinical outcomes but its role in LSCs and AML pathogenesis is unknown. Here we define GADD45A as a key downstream target of LGR4 oncogenic signaling and discover a regulatory role for GADD45A loss in promoting leukemia-initiating activity and oxidative resistance in LGR4/HOXA9-dependent AML, a poor prognosis subset of leukemia. Knockout of GADD45A enhances AML progression in murine and patient-derived xenograft (PDX) mouse models. Deletion of GADD45A induces substantial mutations, increases LSC self-renewal and stemness in vivo and reduces levels of reactive oxygen species (ROS), accompanied by decreased response to ROS-associated genotoxic agents (e.g., ferroptosis inducer RSL3) and acquisition of an increasingly aggressive phenotype upon serial transplantation in mice. Our single-cell CITE-seq analysis on patient-derived LSCs in PDX mice and subsequent functional studies in murine LSCs and primary AML patient cells show that loss of GADD45A is associated with resistance to ferroptosis (an iron-dependent oxidative cell death caused by ROS accumulation) through aberrant activation of antioxidant pathways related to iron and ROS detoxification such as FTH1 and PRDX1, upregulation of which correlates with unfavorable outcomes in AML patients. These results reveal a therapy resistance mechanism contributing to poor prognosis and support a role for GADD45A loss as a critical step for leukemia-initiating activity and as a target to overcome resistance in aggressive leukemia.

Sinoatrial nodal artery fistula to bronchial arteries originating from the right coronary artery in the setting of chronic bronchiectasis and coronary artery disease.

We present a 67-year-old male with past medical history of hyperlipidemia, hypertension, and emphysema, and who was a former smoker, with dyspnea on exertion and chest pain.

Outcomes, Symptomatology, and Mortality of Children Presenting With Bacterial Meningitis at Allied Hospitals of Rawalpindi Medical University, Pakistan: A Cross-Sectional Study.

Introduction Bacterial meningitis (BM) is a neurologic emergency mainly affecting children under the age of two. Clinical symptoms are rarely evident in children, thus making a diagnosis is a challenge. Antibiotic therapy should be started timely to ensure the avoidance of significant morbidity and mortality. This study aims to assess the outcomes, mortality, and symptomatology of children presenting with BM in allied hospitals of Rawalpindi Medical University, Pakistan. Methods It is a cross-sectional study employing a sample size of 201, conducted at the Allied Hospitals of Rawalpindi Medical University, Pakistan from a period of January 2023 to August 2023. Non-probability convenience sampling was used. Children aged between newborns and 14 years of age with a confirmed diagnosis of bacterial meningitis were included in this study. The study population was divided into five different age groups. Three different outcomes were studied including complete recovery, development of complications, and death. Data was entered into and analyzed by Statistical Package for the Social Sciences (SPSS) version 25 (IBM Corp., Armonk, NY, USA). Descriptive statistics were applied to the demographic data. The chi-square analytical test was applied to study the association between the categorical variables. Results One hundred nineteen (59.2%) of the study's population were males. One hundred twenty-six (62.7%) of the patients were born through a spontaneous vaginal delivery (SVD). The majority (54%) of the study population were infants. Twenty-three percent were newborns, 13% were toddlers, 6% were preschool children, and 4% were school-age children. The majority (85%) of the study participants belonged to lower socioeconomic backgrounds. Ninety percent of the cases had symptoms of fever, seizures, and poor feeding. Neck stiffness was significantly associated with death as an outcome (p-value=0.01). The overall mortality amongst the study population was 20%. Forty-nine percent of the study population recovered completely, whereas 31% had complications following the diagnosis. Neonates had a higher mortality rate than infants (45% vs 9% respectively). Conclusion The most common presenting symptoms were fever, vomiting, seizures, and neck stiffness. Poor feeding was also seen in most cases. The rate of complications and death is observed to be relatively higher following the diagnosis of bacterial meningitis as compared to rates in the surrounding and developed countries. Out of all signs and symptoms, the presence of neck stiffness was significantly associated with death as an outcome among children with bacterial meningitis.

Improving the Quality and Completeness of Discharge Summaries at a Tertiary Care Hospital in Pakistan: A Quality Improvement Project.

Introduction Discharge summaries (DS) allow continued patient care after being discharged from the hospital. Only a few quality improvement projects (QIPs) focused on assessing and improving the quality and completeness of DS at tertiary care hospitals have been undertaken in Pakistan. This QIP aimed to evaluate and enhance the quality and completeness of DS at a tertiary care hospital in Pakistan to facilitate seamless healthcare transitions. Methods A QIP was conducted in the medical unit of a tertiary care hospital in Rawalpindi, Pakistan. The DS were assessed using the e-discharge summary self-assessment checklist devised by the Royal College of Physicians (RCP). This QIP was done by the plan, do, study, act (PDSA) cycle. The PDSA cycle comprised two audit cycles and an intervention in between them. The first audit cycle (AC) was conducted on 150 DS. Its duration was from March 2023 to June 2023. An educational workshop was conducted before the re-audit cycle (RAC) to address deficiencies and reinforce the implementation of the guidelines provided by the RCP. The RAC was conducted from June 2023 to August 2023. 100 DS were studied and analyzed to assess for improvement in the completeness of DS. Frequencies and percentages were calculated in each audit cycle. The Chi-squared test was applied to compare the statistical difference between the results of both audit cycles. Results A total of 150 DS were analyzed in the first AC and 100 DS in the RAC. The results of the first AC show that the details of any allergies were recorded only in 3% of the DS; this percentage significantly improved to 51% after the RAC (p-value <0.05). Relevant past medical history was included in 52% and 88% of the DS during the first AC and RAC, respectively (p-value <0.05). Secondary diagnoses were written in 54% and 71% of the DS during the first AC and RAC, respectively (p-value <0.05). Details of relevant investigations were included in 60% and 88% of the DS during the first AC and RAC, respectively (p-value <0.05). The post-discharge management plan was written in 90% and 98% of the DS during the first AC and RAC, respectively (p-value <0.05). The follow-up plan was written clearly in 65% and 93% of the DS during the first AC and RAC, respectively (p-value <0.05).  Conclusion The DS was found to be incomplete after analyzing the results of the first AC. The details related to allergies, medications, operations, and procedures were found to be missing in the majority of the cases. No mention of the patient's concerns or expectations was made in the DS. The results of the RAC showed improvement in the level of completeness of DS. The majority of the weak points observed after the first AC seemed to have improved after the RAC, which shows that intervention proved to be quite effective in improving the completeness and quality of DS. The RAC showed significant improvement in the completeness of the details relating to investigations, allergies, past medical history, secondary diagnoses, and the post-discharge follow-up plan. QIP must be routinely carried out to assess and improve the completeness and quality of DS at hospitals.

Predominance of MGMT promoter methylation among Pakistani glioblastoma patients.

BACKGROUND: Glioblastoma multiforme (GBM), the most prevalent subgroup of neuroepithelial tumors, is characterized by dismal overall survival (OS). Several studies have linked O6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation to OS in GBM patients. However, MGMT methylation frequencies vary geographically and across ethnicities, with limited data for South Asian populations, including Pakistan. This study aimed to analyze MGMT promoter methylation in Pakistani GBM patients. METHODS: Consecutive primary GBM patients diagnosed ≥ 18 years-of-age, with no prior chemotherapy or radiotherapy history, were retrospectively selected. DNA was isolated from formalin-fixed-paraffin-embedded tissues. MGMT promoter methylation was analyzed using methylation-specific PCR. Clinical, pathological, and treatment data were assessed using Fisher's exact/Chi-squared tests. OS was calculated using Kaplan-Meier analysis in SPSS 27.0.1. RESULTS: The study included 48 GBM patients, comprising 38 (79.2%) males and 10 (20.8%) females. The median diagnosis age was 49.5 years (range 18-70). MGMT methylation was observed in 87.5% (42/48) of all cases. Patients with MGMT methylation undergoing radiotherapy or radiotherapy plus chemotherapy exhibited significantly improved median OS of 7.2 months (95% CI, 3.7-10.7; P < 0.001) and 16.9 months (95% CI, 15.9-17.9; P < 0.001), respectively, compared to those undergoing surgical resection only (OS: 2.2 months, 95% CI, 0.8-3.6). CONCLUSION: This is the first comprehensive study highlighting a predominance of MGMT methylation in Pakistani GBM patients. Furthermore, our findings underscore the association of MGMT methylation with improved OS across diverse treatment modalities. Larger studies are imperative to validate our findings for better management of Pakistani GBM patients.

Left Ventricular Pseudoaneurysm: A Rare but Fatal Complication of Myocardial Infarction.

Left ventricular pseudoaneurysm is a ventricular free wall rupture contained within the adjacent adherent pericardium or scar tissue. Myocardial infarction (MI), cardiac surgery, and chest trauma are the common causes. The most common presenting symptoms of pseudoaneurysms are congestive heart failure, chest pain, and dyspnea, but a small percentage of patients may be asymptomatic. Early diagnosis and treatment are of prime importance because of the tendency of pseudoaneurysms to expand and rupture, with a high mortality rate, especially if left untreated. We present a case of a 65-year-old man who was found to have left ventricular pseudoaneurysm on a follow-up echocardiography within three weeks of an MI. He subsequently underwent patch repair and was discharged after medical optimization. Our case highlights the importance of maintaining a high clinical suspicion of pseudoaneurysm in a patient post-MI, as delayed diagnosis and treatment can be fatal.

A Multireader Multicase (MRMC) Receiver Operating Characteristic (ROC) Study Evaluating Noninferiority of Quantitative Transmission (QT) Ultrasound to Digital Breast Tomosynthesis (DBT) on Detection and Recall of Breast Lesions.

RATIONALE AND OBJECTIVES: Quantitative transmission (QT) imaging is an emerging volumetric ultrasound modality for women too young for mammography. QT images tissue without overlap seen in mammography, thereby can potentially improve breast mass detection and characterization and noncancer recall. We compared radiologists' interpretation of QT vs digital breast tomosynthesis (DBT) with a multireader multicase observer performance study. MATERIALS AND METHODS: Study subjects received screening DBT and QT scans in HIPAA-compliant, institutional review board-approved prospective case-collection studies at four clinical sites. Twenty-four Mammography Quality Standards Act-qualified radiologists interpreted 177 cases (66 with cancer, atypia, or solid mass and 111 normal or with nonsolid benign abnormality), first QT, then 2 weeks later DBT synthesized 2D-views. Readers reported up to three findings per case and for each finding a recall or no recall decision and confidence of that decision. The study hypothesis was area under receiver operating characteristic curve (AUC) of QT was noninferior to DBT. Sensitivity and specificity were also compared. RESULTS: AUC of QT (0.746 ± 0.028, mean ± SD) was noninferior to DBT (0.700 ± 0.028) for AUC difference margin of -0.05 (P < .05). AUC difference was 0.046 ± 0.028 (95% CI: [-0.008, 0.101]). Sensitivity was 70.6 ± 7.2% for QT and 85.2 ± 6.4% for DBT, specificity was 60.1 ± 12.3% vs 37.2 ± 11.0%, and both differences were statistically significant. Of a total of 21 cases of cysts, readers recommended recall, on average, in 1.1 ± 1.4 cases with QT, but not with DBT, and 10.6 ± 2.2 cases with DBT, but not with QT. CONCLUSION: QT can be a potential alternative to mammography for breast cancer screening of women too young to undergo mammography.

Successful treatment of early bioprosthetic mitral valve fusion in a patient on VA ECMO with balloon valvuloplasty via direct cannulation of pulmonary vein.

We present a case of a 57-year-old male who underwent bioprosthetic mitral valve replacement (MVR) and developed postoperative cardiogenic shock requiring venoarterial extracorporeal membrane oxygenation (VA ECMO) and Impella 5.5 (Abiomed) hemodynamic support.

Patients with COVID-19 Pneumonia Admitted to an Intensive Care Unit (ICU) at a Community Hospital in Flint, Michigan, in Early 2020: Characteristics and Mortality.

INTRODUCTION: Despite the many studies conducted on the factors affecting mortality in patients with COVID-19, there is ongoing debate about the role of race as a risk factor. Several studies have reported a geographic and racial disparity in COVID-19 cases in Michigan. This study aimed to examine the characteristics of the 2020 first cohort of Intensive Care Unit (ICU) COVID-19 patients admitted to a community teaching hospital in Flint, Michigan, and to determine the factors associated with ICU mortality, including race. METHODS: This cross-sectional study included adult patients (≥ 18 years) with severe COVID-19 pneumonia admitted to the ICU between March and May 2020. Potential risk factors associated with ICU mortality included demographic characteristics, comorbidities, treatments, and complications. RESULTS: The study sample consisted of N = 48 patients, aged 24-85 years, (mean 59.7; SD = 12.8); 56.2% (n=27) were male and 51.1% (n=24) were Black adults. The mortality rate was 51.1%. Age (aOR 1.1, 95% CI [1.01, 1.20]; p =0.03), type 2 diabetes (aOR 5.7, 95% CI [1.2, 29.1]; p =0.03), and essential hypertension (aOR 6.2, 95% CI [1.1, 34.5]; p =0.04) were all found to have statistically significant independent associations with increased risk of ICU mortality in this study sample. On the other hand, race was not found to be associated with ICU mortality. CONCLUSIONS: These findings support the literature regarding the association of comorbid conditions, including type 2 diabetes and hypertension, with poorer outcomes in ICU hospitalized patients with severe COVID-19 pneumonia. This study provides insight into mortality of an ICU patient cohort earlier on during the COVID-19 pandemic in Flint, Michigan.

Anaphylaxis to Lumason Contrast Agent in Echocardiography after Immune Sensitization: A Case Report and Literature Review.

With the continued evolution of echocardiography techniques, novel contrast agents have been introduced to aid in evaluating cardiac structure and function. Lumason is an FDA-approved ultrasound-enhancing agent made of Sulfur hexafluoride lipid-type A microspheres. We report a case of Lumason-induced immune sensitization and subsequent anaphylaxis on re-exposure in a middle-aged male patient presenting with symptoms concerning for a cerebrovascular accident. The patient was successfully treated with steroids and antihistamines. Providers, including physicians, echocardiography technicians, and mid-level providers should be aware of and be prepared to respond to the possibility of anaphylaxis to contrast-enhancing agents used in echocardiography.

COPI-regulated mitochondria-ER contact site formation maintains axonal integrity.

Coat protein complex I (COPI) is best known for its role in Golgi-endoplasmic reticulum (ER) trafficking, responsible for the retrograde transport of ER-resident proteins. The ER is crucial to neuronal function, regulating Ca2+ homeostasis and the distribution and function of other organelles such as endosomes, peroxisomes, and mitochondria via functional contact sites. Here we demonstrate that disruption of COPI results in mitochondrial dysfunction in Drosophila axons and human cells. The ER network is also disrupted, and the neurons undergo rapid degeneration. We demonstrate that mitochondria-ER contact sites (MERCS) are decreased in COPI-deficient axons, leading to Ca2+ dysregulation, heightened mitophagy, and a decrease in respiratory capacity. Reintroducing MERCS is sufficient to rescue not only mitochondrial distribution and Ca2+ uptake but also ER morphology, dramatically delaying neurodegeneration. This work demonstrates an important role for COPI-mediated trafficking in MERC formation, which is an essential process for maintaining axonal integrity.

Low frequency 3D transmission ultrasound tomography: technical details and clinical implications.

A novel 3D ultrasound tomographic (3D UT) method (called volography) that creates a speed of sound (SOS) map and a reflection modality that is co-registered are reviewed and shown to be artifact free even in the presence of high contrast and thus shown to be applicable for breast, orthopedic and pediatric clinical use cases. The 3D UT images are almost isotropic with mm resolution and the reflection image is compounded over 360 degrees to create sub-mm resolution in plane. METHODS: The physics of ultrasound scattering requires 3D modeling and the concomitant high computational cost is ameliorated with a bespoke algorithm (paraxial approximation - discussed here) and Nvidia GPUs. The resulting reconstruction times are tabulated for clinical relevance. The resulting SOS map is used to create a refraction corrected reflection image at ∼3.6 MHz center frequency. The transmission data are highly redundant, collected over 360 degrees and at 2 mm levels by true matrix receiver arrays yielding 3D data. The high resolution SOS and attenuation maps and reflection images are used in a segmentation algorithm that optimally utilizes this information to segment out glandular, ductal, connective tissue, fat and skin. These volumes are used to estimate breast density, an important correlate to cancer. RESULTS: Multiple SOS images of breast, knee and segmentations of breast glandular and ductal tissue are shown. Spearman rho is calculated between our volumetric breast density estimates and Volpara™ from mammograms, as 0.9332. Multiple timing results are shown and indicate the variability of the reconstruction times with breast size and type but are ∼30 minutes for average size breast. The timing results with the 3D algorithm indicate ∼60 minute reconstruction times for pediatrics with two Nvidia GPUs. Characteristic variations of the glandular and ductal volumes over time are shown. The SOS from QT images are compared with literature values. The results of a multi-reader multi-case (MRMC) study are shown that compares the 3D UT with full field digital mammography and resulted in an average increase in ROC AUC of 10%. Orthopedic (knee) 3D UT images compared with MRI indicate regions of zero signal in the MRI are clearly displayed in the QT image. Explicit representation of the acoustic field is shown, indicating its 3D nature. An image of in vivo breast with the chest muscle is shown and speed of sound agreement with literature values are tabulated. Reference is made to a recently published paper validating pediatric imaging. CONCLUSIONS: The high Spearman rho indicates a monotonic (not necessarily linear) relation between our method and industry gold standard Volpara™ density. The acoustic field verifies the need for 3D modeling. The MRMC study, the orthopedic images, breast density study, and references, all indicate the clinical utility of the SOS and reflection images. The QT image of the knee shows its ability to monitor tissue the MRI cannot. The included references and images herein indicate the proof of concept for 3D UT as a viable and valuable clinical adjunct in pediatric and orthopedic situations in addition to the breast imaging.

Deep Ensembles Are Robust to Occasional Catastrophic Failures of Individual DNNs for Organs Segmentations in CT Images.

Deep neural networks (DNNs) have recently showed remarkable performance in various computer vision tasks, including classification and segmentation of medical images. Deep ensembles (an aggregated prediction of multiple DNNs) were shown to improve a DNN's performance in various classification tasks. Here we explore how deep ensembles perform in the image segmentation task, in particular, organ segmentations in CT (Computed Tomography) images. Ensembles of V-Nets were trained to segment multiple organs using several in-house and publicly available clinical studies. The ensembles segmentations were tested on images from a different set of studies, and the effects of ensemble size as well as other ensemble parameters were explored for various organs. Compared to single models, Deep Ensembles significantly improved the average segmentation accuracy, especially for those organs where the accuracy was lower. More importantly, Deep Ensembles strongly reduced occasional "catastrophic" segmentation failures characteristic of single models and variability of the segmentation accuracy from image to image. To quantify this we defined the "high risk images": images for which at least one model produced an outlier metric (performed in the lower 5% percentile). These images comprised about 12% of the test images across all organs. Ensembles performed without outliers for 68%-100% of the "high risk images" depending on the performance metric used.

Comparison of Coronary Artery Bypass Grafting Combined With Mitral Valve Repair Versus Coronary Artery Bypass Grafting Alone in Patients With Moderate Ischemic Mitral Regurgitation: A Meta-Analysis.

The aim of this meta-analysis was to compare clinical outcomes between those who underwent coronary artery bypass grafting (CABG) alone and CABG with mitral valve repair (MVR) in patients with moderate ischemic mitral regurgitation. The present study was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Two authors performed a comprehensive search of international databases, including PubMed, EMBASE, and the Cochrane Library, for relevant studies published from inception to March 1, 2023. The search was performed again before the submission of the manuscript on March 20, 2023. Primary outcomes assessed in the present meta-analysis included early mortality and long-term mortality. Secondary outcomes assessed in the present meta-analysis included change in New York Heart Association (NYHA) score from baseline, change in ejection fraction (EF) from baseline (%), and major cardiovascular events (MACE). A total of 13 studies were included in the present meta-analysis. Out of 13 included studies, four were randomized control trials (RCTs) and nine were retrospective cohort studies. The pooled analysis showed that early mortality was significantly lower in patients in the CABG group compared to the CABG+MVR group (risk ratio [RR]: 0.47, 95% confidence interval [CI]: 0.31, 0.70). Long-term mortality was also lower in patients who underwent CABG compared to patients in the CABG+MVR group. However, the difference was statistically insignificant (RR: 0.88, 95% CI: 0.77, 1.02). No significant differences were reported in the EF score between patients who underwent CABG and patients who underwent CABG plus MVR (mean difference [MD]: 0.40, 95% CI: -1.90, 2.69). NYHA score was significantly lower in patients in the CABG+repair group compared to the CABG alone group (MD: 0.39, 95% CI: 0.06, 0.72). In conclusion, our meta-analysis suggests that concomitant MVR during CABG may not improve clinical outcomes in patients with moderate ischemic mitral regurgitation. Further clinical trials are needed to investigate this intervention in more detail.

Effect of Acetazolamide as Add-On Diuretic Therapy in Patients With Heart Failure: A Meta-Analysis.

The aim of this meta-analysis was to assess the effectiveness of acetazolamide as an add-on diuretic therapy in patients with heart failure. This meta-analysis was conducted in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) guidelines. A systematic literature search was independently performed by two authors using MEDLINE, EMBASE, and the Cochrane Database of Systematic Reviews to identify relevant studies assessing the use of acetazolamide in patients with heart failure. The search keywords included "acetazolamide" and "heart failure". The outcomes assessed in this meta-analysis included natriuresis (mmol/L), diuresis (Liters) and decongestion (absence of signs of volume overload) by 72 hours. Other outcomes assessed in this meta-analysis included hospitalization due to heart failure and all-cause mortality. A total of three studies included a total of 569 heart failure patients. The number of patients achieved decongestion was significantly higher in patients receiving acetazolamide compared to the patients randomized in the control group (RR: 1.34, 95% CI: 1.06-1.67). Compared to patients in the control group, mean natriuresis was significantly higher in acetazolamide patients (MD: 74.91, 95% CI: 39.85-109.97). Diuresis was significantly higher in patients receiving acetazolamide compared to the control group (MD: 0.44, 95% CI: 0.16-0.72). No significant difference was found between the two groups in terms of all-cause mortality and hospitalization due to heart failure. In conclusion, our meta-analysis suggests that acetazolamide may have beneficial impacts on heart failure patients by increasing the number of successful decongestions. Additionally, patients who were treated with acetazolamide had significantly higher natriuresis and diuresis compared to patients in the control group.

Severe asthma ILC2s demonstrate enhanced proliferation that is modified by biologics.

BACKGROUND AND OBJECTIVE: Type 2 (T2) innate lymphoid cells (ILC2s) contribute to airway inflammation and disease in asthma. We hypothesize that ILC2s isolated from people with severe allergic and eosinophilic asthma would exhibit an enhanced T2 inflammatory activity that would be altered following treatment with mepolizumab and omalizumab. We compare peripheral blood (PB) isolated ILC2's proliferative capacity, IL-5 and IL-13 secretion and phenotype between healthy without asthma (HC), non-asthma allergic (NAA), mild asthma (MA) and severe allergic and eosinophilic asthma (SA) subjects. We then determined the impact of 6 months treatment with either mepolizumab or omalizumab on ILC2s physiology of SA subjects. METHODS: ILC2s were sorted and cultured in the presence of IL-2, IL-25, IL-33 and thymic stromal lymphopoietin (TSLP) for 14 days. ILC2s proliferation, phenotypes and functions were assessed using flowcytometry. The ILC2s response was then reassessed following clinically successful treatment of SA subjects with mepolizumab and omalizumab. RESULTS: SA ILC2s demonstrated increased proliferative capacity, TSLP receptor (TSLPR), GATA3 and NFATc1 protein expressions and increased IL-5 and IL-13 release. ILC2s were also capable of releasing IL-6 in response to stimulation. Mepolizumab treatment reduced ILC2s proliferative capacity and expression of TSLPR, GATA3 and NFATc1. Both mepolizumab and omalizumab were associated with reduced ILC2s release of IL-5 and IL-13, only mepolizumab reduced IL-6. CONCLUSION: ILC2s from severe allergic and eosinophilic asthma demonstrated an active phenotype typified by increased proliferation, TSLPR, GATA3 and NFATc1 expression and increased IL-5, IL-13 and IL-6 release. Mepolizumab reduced markers of ILC2s activation.

Whole-Body Imaging Using Low Frequency Transmission Ultrasound.

RATIONALE AND OBJECTIVES: To indicate that 3D low-frequency ultrasound tomography with 3D data acquisition (volography) is a safe, low-cost, high-resolution, whole-body meso-scale medical imaging modality that gives high-resolution quantitatively accurate clinically relevant images. MATERIALS AND METHODS: We compare the speed of sound accuracy in various organs in situ. We validate our 3D ultrasound tomography images using MRI and gross section anatomy as ground truth in 10-day old piglets. Data acquisition is accomplished with the QT Scanner at ∼1 MHz center frequency, and array transceivers for reflection data @3.6 MHz. Images are generated with unique model-based 3D ultrasound tomography algorithms. In reflection, we use 3D refraction-corrected ray tracing to allow 360° compounding with sub-mm resolution. Four 10-12 day old pigs were anesthetized and whole-body images were acquired via low-frequency transmitted ultrasound and 3T MRI. RESULTS: Tissue values were within an average of 1.07% (0.5%) of the literature values. We also show the detailed correlation of our images with MRI images in axial, coronal, and sagittal views. Volography images of a piglet show high resolution and quantitative accuracy, showing more contrast &resolution than 3T MRI, including the kidney showing medulla, cortex and fibrous cover, and small intestines with ileal lumen detail visible. CONCLUSION: We establish that 3D ultrasound tomography (volography), yields high-resolution quantitatively accurate images whole-body images in presence of bone and air which are potentially clinically useful but have not appeared in the literature.

Outcomes of Epi-On Collagen Cross-Linkage Procedure Assessed in Progressive Keratoconus Patients.

INTRODUCTION: Keratoconus is a corneal ectasia that causes astigmatism and reduced vision. Conventional treatment to stop the progression of ectasia involves debridement of corneal epithelium, followed by ultraviolet light and riboflavin drops to reinforce the collagen covalent bonds, called collagen cross-linkage (CXL). Epi-on (epithelium-on) is a modified technique without epithelial debridement and associated complications of pain, infection, and damage to the cornea. However, despite a good safety index and efficacy, Epi-on has not completely replaced the conventional Epi-off (epithelium-off) CXL. We aim to report our five-year experience and outcomes with Epi-on CXL Methods: In this five-year retrospective clinical audit, we included all patients who underwent Epi-on CXL from December 2014 to June 2020 at the Aga Khan University Hospital. Outcomes were based on best-corrected visual acuity (BCVA) and topographic indicators such as keratometry-max (K-max), keratometry mean (K-mean), pachymetry apex (Pachapex), and pachymetry thinnest (Pachthin) performed during pre-CXL clinical visit within one month of the procedure and were compared with the most remote follow up within three years post-CXL. A p-value of <0.05 was considered statistically significant. RESULTS: A total of 223 eyes of 134 patients had undergone CXL of which 32 eyes of 18 patients were included in the study based on the inclusion criteria. The mean age was 26.8 (+/- 6.137) years; nine were males and 16 were right eyes. Mean BCVA was 0.383 logMAR (logarithm of the minimum angle of resolution) units which improved to 0.292 units post CXL (p=0.02) and K-max decreased from 57.4 to 56.60 diopters (p=0.048), both outcomes were statistically significant. Pachapex decreased slightly from 471 to 460 micrometers (p=0.099), K-mean was almost stable from 48.8 to 48.7 diopters (p=0.9), and Pachthin also decreased slightly from 455 to 445 micrometers (p=0.117), however, these outcomes were not statistically significant. Other studies reported similar improvements in K-max and visual acuity. CONCLUSION: Epi-on CXL is an effective treatment for halting the progression of keratoconus. Our results showed significant improvement in visual acuity and K-max readings indicating a halting of the progression of keratoconus in our patients. Long-term follow-up is required for all patients to assess detailed outcomes. Further studies comparing Epi-on CXL with other methods may be carried out.

Reprogramming cultured human fungiform (HBO) taste cells into neuron-like cells through in vitro induction.

Human taste cells are a heterogeneous population of specialized epithelial cells that are constantly generated from progenitor taste cells. Type I and type III taste cells express some neural markers, and studies have reported that direct innervation by neurons is not required for taste cell development. To our knowledge, no previous study has demonstrated that taste cells can differentiate into neuron-like cells or any other non-taste cell type. Here, for the first time, we describe a simple in vitro method that uses a serum-free neural induction medium to differentiate cultured physiologically functional primary human taste (HBO) cells into neuron-like cells in 2-3 wk with high efficiency. We verified neural attributes of these HBO-derived neuron-like with immunocytochemistry, single-cell calcium imaging, and DiI staining and examined cell morphology using transmission electron microscopy. Induced neuron-like cells demonstrated neuron-specific proteins, dendritic and axonal morphology, and networking behaviors. This technique will open new avenues for translational medicine, autologous cell therapy, regenerative medicine, therapy for neurodegenerative disorders, and drug screening.

The role of immunotherapy plus chemotherapy versus chemotherapy alone as first-line treatment for advanced non-small cell lung cancer: an updated systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Recently published randomized controlled trials (RCTs) showed improved overall survival (OS) and progression-free survival (PFS) with the combination of immunotherapy and chemotherapy as compared to chemotherapy alone in advanced non-small cell lung cancer (NSCLC). We aimed to provide a systematic review and meta-analysis of RCTs regarding the efficacy and safety of immunotherapy and chemotherapy combinations for advanced NSCLC. METHODS: On December 23rd, 2021, we searched databases for RCTs that reported PFS and OS as primary outcomes. RESULTS: We included 11 RCTs with 6,386 patients (3,850 in the combination therapy group and 2,536 in the chemotherapy group). Combination therapy was associated with an improvement in PFS (HR: 0.60; 95% CI: 0.54, 0.66; P < 0.00001) andOS (HR: 0.77; 95% CI: 0.68, 0.87; P ≤ 0.0001), compared to chemotherapy. There were no significant differences between both groups in terms of treatment-related adverse events (TRAEs) (RR: 1.07; 95% CI: 0.99, 1.16; P = 0.09). CONCLUSION: The combination of immunotherapy and chemotherapy as first-line treatment for advanced NSCLC significantly improved PFS and OS compared to chemotherapy alone without a significant increase in the overall TRAEs.