Advantages of pooling of human bone marrow-derived mesenchymal stromal cells from different donors versus single-donor MSCs.

Mesenchymal stromal cells (MSC) from adult bone marrow are the most commonly used cells in clinical trials. MSCs from single donors are the preferred starting material but suffer from a major setback of being heterogeneous that results in unpredictable and inconsistent clinical outcomes. To overcome this, we developed a method of pooling MSCs from different donors and created cell banks to cater clinical needs. Initially, the master cell banks (MCBs) were created at passage 1 (P1) from the bone marrow MSCs isolated from of nine different donors. At this stage, MCBs from three different donors were mixed in equal proportion and expanded till P3 to create working cell banks. Further, the pooled cells and individual donor MSCs were expanded till P5 and cryopreserved and extensively characterised. There was a large heterogeneity among the individual donor MSCs in terms of growth kinetics (90% Coefficient of variation (CV) for cell yield and 44% CV for population doubling time at P5), immunosuppressive ability (30% CV at 1:1 and 300% CV at 1:10 ratio), and the angiogenic factor secretion potential (20% CV for VEGF and71% CV for SDF-1). Comparatively, the pooled cells have more stable profiles (60% CV for cell yield and 7% CV for population doubling time at P5) and exhibit better immunosuppressive ability (15% CV at 1:1 and 32% CV at 1:10 ratio ) and consistent secretion of angiogenic factors (16% CV for VEGF and 51% CV for SDF-1). Further pooling does not compromise the trilineage differentiation capacity or phenotypic marker expression of the MSCs. The senescence and in vitro tumourigenicity characteristics of the pooled cells are also similar to those of individual donor MSCs. We conclude that pooling of MSCs from three different donors reduces heterogeneity among individual donors and produces MSCs with a consistent secretion and higher immunosuppressive profile.

Statin prevents cancer development in chronic inflammation by blocking interleukin 33 expression.

Chronic inflammation is a major cause of cancer worldwide. Interleukin 33 (IL-33) is a critical initiator of cancer-prone chronic inflammation; however, its induction mechanism by environmental causes of chronic inflammation is unknown. Herein, we demonstrate that Toll-like receptor (TLR)3/4-TBK1-IRF3 pathway activation links environmental insults to IL-33 induction in the skin and pancreas inflammation. An FDA-approved drug library screen identifies pitavastatin to effectively suppress IL-33 expression by blocking TBK1 membrane recruitment/activation through the mevalonate pathway inhibition. Accordingly, pitavastatin prevents chronic pancreatitis and its cancer sequela in an IL-33-dependent manner. The IRF3-IL-33 axis is highly active in chronic pancreatitis and its associated pancreatic cancer in humans. Interestingly, pitavastatin use correlates with a significantly reduced risk of chronic pancreatitis and pancreatic cancer in patients. Our findings demonstrate that blocking the TBK1-IRF3-IL-33 signaling axis suppresses cancer-prone chronic inflammation. Statins present a safe and effective prophylactic strategy to prevent chronic inflammation and its cancer sequela.

Diffusion tensor brain imaging at 0.55T: A feasibility study.

PURPOSE: To investigate the feasibility of diffusion tensor brain imaging at 0.55T with comparisons against 3T. METHODS: Diffusion tensor imaging data with 2 mm isotropic resolution was acquired on a cohort of five healthy subjects using both 0.55T and 3T scanners. The signal-to-noise ratio (SNR) of the 0.55T data was improved using a previous SNR-enhancing joint reconstruction method that jointly reconstructs the entire set of diffusion weighted images from k-space using shared-edge constraints. Quantitative diffusion tensor parameters were estimated and compared across field strengths. We also performed a test-retest assessment of repeatability at each field strength. RESULTS: After applying SNR-enhancing joint reconstruction, the diffusion tensor parameters obtained from 0.55T data were strongly correlated ( R 2 ≥ 0 . 70 $$ {R}^2\ge 0.70 $$ ) with those obtained from 3T data. Test-retest analysis showed that SNR-enhancing reconstruction improved the repeatability of the 0.55T diffusion tensor parameters. CONCLUSION: High-resolution in vivo diffusion MRI of the human brain is feasible at 0.55T when appropriate noise-mitigation strategies are applied.

Fasting-mimicking diet causes hepatic and blood markers changes indicating reduced biological age and disease risk.

In mice, periodic cycles of a fasting mimicking diet (FMD) protect normal cells while killing damaged cells including cancer and autoimmune cells, reduce inflammation, promote multi-system regeneration, and extend longevity. Here, we performed secondary and exploratory analysis of blood samples from a randomized clinical trial (NCT02158897) and show that 3 FMD cycles in adult study participants are associated with reduced insulin resistance and other pre-diabetes markers, lower hepatic fat (as determined by magnetic resonance imaging) and increased lymphoid to myeloid ratio: an indicator of immune system age. Based on a validated measure of biological age predictive of morbidity and mortality, 3 FMD cycles were associated with a decrease of 2.5 years in median biological age, independent of weight loss. Nearly identical findings resulted from  a second clinical study (NCT04150159). Together these results provide initial support for beneficial effects of the FMD on multiple cardiometabolic risk factors and biomarkers of biological age.

Corrigendum to "Second round statewide sentinel-based population survey for estimation of the burden of active infection and anti-SARS-CoV-2 IgG antibodies in the general population of Karnataka, India, during January-February 2021" [IJID Regions Vol 1(2021) pages 107-116].

[This corrects the article DOI: 10.1016/j.ijregi.2021.10.008.].

Novel technique for laparoscopic common bile duct exploration using flexible videobronchoscope to study on clinical outcomes of single-stage (laparoscopic cholecystectomy and laparoscopic common bile duct exploration) versus dual-stage (endoscopic retrograde cholangiopancreatography followed by laparoscopic cholecystectomy) for cholelithiasis with choledocholithiasis - Prospective study in a tertiary care centre (BRACE study - BRonchoscope Assisted Common bile duct Exploration Study).

INTRODUCTION: This study aimed to study on clinical outcomes of single-stage (laparoscopic cholecystectomy [LC] and laparoscopic common bile duct [CBD] exploration using flexible videobronchoscope) versus dual-stage (endoscopic retrograde cholangiopancreatography followed by laparoscopic cholecystectomy) for cholelithiasis with choledocholithiasis-prospective study in a tertiary care centre (BRACE STUDY-Bronchoscope-Assisted CBD Exploration [CBDE] Study). PATIENTS AND METHODS: Between April 2022 and April 2023, patients who underwent LC with laparoscopic CBDE and endoscopic retrograde cholangiopancreatography (ERCP) followed by LC participated in this single-centre prospective research. The Institute Ethics Committee granted its approval after receiving an ethical review. The primary endpoint of the proposed research was the removal of the gall bladder and CBD stones. The secondary outcomes studied were complications using the Clavien-Dindo score, cost-effectiveness, patient satisfaction score and post-procedure duration of hospital stay. RESULTS: A total of 168 patients were included in the study. The success rate of LC with laparoscopic CBD exploration using a flexible videobronchoscope (Group 1) was significantly higher as compared to ERCP f/b LC (Group 2) (96.4% vs. 84.5%, P value = 0.02). Out of the 84 patients in Group 1, direct choledochotomies were performed on 83 of them. Group 1 had a considerably shorter hospital stay (4.6 ± 2.4 vs. 5.3 ± 6.2 days; P = 0.03). Both the cost (P = 0.002) and the number of procedures per patient (P < 0.001) were considerably higher in Group 2. Major complications (Clavien-Dindo grade 3 and above) were significantly higher in Group 2 (P = 0.04). Patient satisfaction in Group 1 scored more favourably than those in Group 2 (2.26 ± 0.3 vs. 1.92 ± 0.7; P = 0.006). CONCLUSION: For concurrent gall bladder and CBD stones, single-stage management by LCBDE using a flexible videobronchoscope has a significantly better primary outcome and lower major complications than dual-stage management. The single-stage strategy also has advantages in terms of a shorter hospital stay, the need for fewer procedures, cost efficiency and patient satisfaction.

Microstructure and tribological behaviour of CoCrCuFeTi high entropy alloy reinforced SS304 through friction stir processing.

Surface modification by suitable technique aids in improving the characteristics of material to resist severe wear in demanding environments and challenging applications. The present study aims to analyse the tribological performance of Stainless Steel (SS304) reinforced with CoCrCuFeTi High Entropy Alloy (HEA) through friction stir processing and compares the results with annealed specimens. The CoCrCuFeTi HEA was ball milled and revealed irregular fragment particles with Body Centred Cubic (BCC) phase. The processed samples exhibited excellent refinement in grains with uniform HEA reinforcement distribution. The grains were observed to be in nano level post-annealing promoting exceptional microhardness. The pin-on-disc wear test was conducted by varying load (10-40N), sliding velocity (0.5-3.5 m/s) and sliding distance (500-2000 m) and the respective worn surface was analysed. The processed sample with HEA after annealing offered 29.8%, 57.4% and 58.49% improved wear resistance at the minimum level of load, sliding velocity and sliding distance than the processed base samples. The worn morphology revealed delamination, abrasion, adhesion and oxide layer formation to be the predominant wear mechanisms.

Laparoscopic subtotal cholecystectomy in difficult gallbladder: Our experience in a tertiary care center.

Backgrounds/Aims: Open cholecystectomy is becoming obsolete and laparoscopic cholecystectomy has become the treatment of choice in gallstone diseases. Difficult gallbladders are encountered whenever there is a frozen calot's triangle, obliterated cystic plate, or both. Rather than converting to open procedure, there has been a growing preference for laparoscopic subtotal cholecystectomy (LSC) during difficult gallbladders. This study aimed to assess the advantages, indications, and viability of LSC in difficult gallbladders. Methods: The study included patients undergoing laparoscopic cholecystectomy in NIMS Hospital, Jaipur, from January 2021 to January 2023. Data of the patients who underwent LSC for difficult gallbladders included demographics, comorbidities, operative time, conversion to open cholecystectomy, length of hospital stay, and complications. LSC was classified into three types depending on the part of the gallbladder remnant. Results: A total of 728 patients underwent laparoscopic cholecystectomy. Among them, 41 patients (5.6%) were attempted for LSC. However, one patient was converted to an open procedure and the rest 40 underwent LSC. LSC was divided into 3 types, 4 patients underwent LSC type I, 34 patients underwent type II, and 2 patients type III. The average operating time and postoperative length of hospital stay were 86.2 minutes and 2.1 days, respectively. Two patients had surgical site infection. No patient had a bile leak and none required intensive care unit care. Conclusions: LSC is a safe and feasible option for use in difficult gallbladders.

Status of Serum Calcium in Patients with Chronic Obstructive Pulmonary Disease.

Chronic obstructive pulmonary disease (COPD) remains a major public health problem with relatively high prevalence rates worldwide (5-13%). COPD is a major cause of morbidity and mortality worldwide and results in an economic and social burden that is both substantial and increasing. The purpose of the study was to explore the alteration of serum calcium in patients with COPD. This cross-sectional study was carried out in the Department of Biochemistry, Mymensingh Medical College, Bangladesh from January 2021 to December 2021. Data was collected from Medicine Department of Mymensingh Medical College Hospital, Mymensingh. A total number of 120 subjects participated in this study. Out of them, 60 apparently normal healthy individuals were selected as Group I and another 60 diagnosed COPD patients were selected as Group II. Serum calcium was measured by colorimetric method using the test kit. The results were calculated and analyzed by using statistical package for social science (SPSS), windows package version 21.0. Data were expressed in mean ±SD and statistical significance was done by Student's unpaired 't' test. In this study, the mean ±SD values of serum calcium were 9.21±1.06mg/dl and 8.26±0.95mg/dl in Group I and Group II respectively. The results were highly significant (p<0.001). The result suggested that there was significant relation between COPD and alteration of serum calcium. So, by this study we recommended that routine evaluation of serum calcium is important for prevention of exacerbations, reduction of morbidity and mortality in patients with COPD.

Impact of variant subtype on electro-clinical phenotype of Dravet syndrome- a South Indian cohort study.

OBJECTIVE: We aimed to compare the electroclinical correlates of truncating and missense variants of SCN1A variants in children with Dravet syndrome (DS) and to determine phenotypic features in relation to variants identified and seizure outcomes. METHODS: A single center prospective study was carried out on a South Indian cohort. Patients below 18 years of age who met the clinical criteria for DS who had undergone genetic testing and completed a minimum of one year follow up were included. We compared the differences in clinical profile, seizure outcome, developmental characteristics and anti-seizure medication (ASM) responsiveness profiles between patients with missense and truncating variants. RESULTS: Out of a total of 3967 children with drug-resistant epilepsy during the period 2015-2021, 49 patients who fulfilled the inclusion criteria were studied. Thirty-seven had positive genetic tests, out of which 29 were SCN1A variants and 9 were other novel variants. The proportion of missense (14; 48.3%) and truncating SCN1A variants (15; 51.7%) was similar. A significant trend for developing multiple seizure types was noted among children with truncating variants (p = 0.035) and seizure freedom was more likely among children with missense variants (p = 0.042). All patients with truncating variants had ASM resistant epilepsy (p = 0.020). Developmental outcomes did not differ between the variant subtypes. CONCLUSION: Our results show that children harbouring missense variants demonstrated a significantly lower propensity for multiple seizure subtypes and a higher proportion with seizure freedom. However developmental implications appear to be independent of variant subtype.

A study on microstructural, mechanical properties and optimization of wear behavior of friction stir processed AlCrCoFeNi High Entropy Alloy reinforced SS410 using response surface methodology.

The equimolar High Entropy Alloy (HEA) is incorporated on the surface of SS410 steel to enhance the mechanical properties for the current industrial scenario. The objective of the present work is to make a first attempt at surface modification of SS410 steel with gas atomization synthesized AlCrCoFeNi HEA powder through Friction Stir Processing (FSP). The microhardness and ultimate tensile strength of the FSP-HEA sample are increased by 41.3 % and 39.1 % respectively due to the high degree of refined grains with 2.84 µm and evenly distributed HEA particles. The wear rate of FSP-HEA samples is optimized by response surface methodology with process parameters including applied load, sliding distance, and sliding velocity. The most influential factor and regression model are derived from experimental results that predict the wear rate by the analysis of variance technique. The worn surface of FSP-HEA samples is evaluated by morphological analysis with corresponding induced wear mechanisms. The minimum wear rate is achieved by optimum process parameters along with higher hardness through particle-stimulated nucleation mechanism, Hall-Petch relation, and dynamic recrystallization. The grain refinement, barrier effect, and grain growth hindrance of HEA particles lead to enhancement in the strength of processed HEA samples.

Association of Primary Open-Angle Glaucoma with Diabetic Retinopathy among Patients with Type 1 and Type 2 Diabetes: A Large Global Database Study.

PURPOSE: To assess the correlation between primary open-angle glaucoma (POAG) and the risk of developing diabetic retinopathy (DR) in patients with type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). DESIGN: A retrospective cohort study leveraging the global patient database of TriNetX Research Network. PARTICIPANTS: The study included 44 359 patients with diabetes mellitus (DM) with POAG and 4 393 300 patients with DM without any glaucoma ≥ 18 years of age. Propensity score matching harmonized the cohorts to 39 680 patients each, covering diagnoses from January 1, 2005, to January 1, 2023. METHODS: We analyzed data using specific International Classification of Diseases, 10th Revision (ICD-10) codes for DM and glaucoma. We matched the cohorts using propensity score matching, adjusting for age, sex, race/ethnicity, blood markers, relevant medical history, and ophthalmic service use. MAIN OUTCOME MEASURES: The primary outcome was the first-time occurrence of DR, including nonproliferative DR (NPDR) and proliferative DR (PDR), in patients with DM with and without glaucoma at 1-, 5-, and 10-year intervals from their individual index dates. RESULTS: At 10 years, patients with T1DM with POAG exhibited a heightened risk for any DR (adjusted risk ratios [RRs], 4.12; 95% confidence interval [CI], 3.05-5.57, P < 0.0001) and PDR (RR, 7.02; 95% CI, 3.62-13.61, P < 0.0001). Patients with T2DM and POAG also faced an increased 10-year risk for any DR (RR, 2.47; 95% CI, 2.28-2.68, P < 0.0001) and PDR (RR, 3.82; 95% CI, 3.09-4.70, P < 0.0001). The combined association of POAG on DR risk in those with T1DM and T2DM at 10 years was found to be significantly higher among patients with POAG (5.45%) compared with those without glaucoma (2.12%) (adjusted hazard ratio [aHR], 2.33; 95% CI, 2.14-2.53). The cumulative incidence of DR was significantly higher in the POAG group compared with nonglaucoma counterparts after a decade (log-rank P < 0.001). CONCLUSIONS: Our findings underscore a substantial association between POAG and DR development in both T1DM and T2DM patients, emphasizing the need for vigilant screening and comprehensive management in glaucomatous patients with DM to mitigate the risk of DR. Future research should delve into elucidating the causal mechanisms driving these observed associations. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Cardiac MRI at Low Field Strengths.

Cardiac MR imaging is well established for assessment of cardiovascular structure and function, myocardial scar, quantitative flow, parametric mapping, and myocardial perfusion. Despite the clear evidence supporting the use of cardiac MRI for a wide range of indications, it is underutilized clinically. Recent developments in low-field MRI technology, including modern data acquisition and image reconstruction methods, are enabling high-quality low-field imaging that may improve the cost-benefit ratio for cardiac MRI. Studies to-date confirm that low-field MRI offers high measurement concordance and consistent interpretation with clinical imaging for several routine sequences. Moreover, low-field MRI may enable specific new clinical opportunities for cardiac imaging such as imaging near metal implants, MRI-guided interventions, combined cardiopulmonary assessment, and imaging of patients with severe obesity. In this review, we discuss the recent progress in low-field cardiac MRI with a focus on technical developments and early clinical validation studies. EVIDENCE LEVEL: 5 TECHNICAL EFFICACY: Stage 1.

New clinical opportunities of low-field MRI: heart, lung, body, and musculoskeletal.

Contemporary whole-body low-field MRI scanners (< 1 T) present new and exciting opportunities for improved body imaging. The fundamental reason is that the reduced off-resonance and reduced SAR provide substantially increased flexibility in the design of MRI pulse sequences. Promising body applications include lung parenchyma imaging, imaging adjacent to metallic implants, cardiac imaging, and dynamic imaging in general. The lower cost of such systems may make MRI favorable for screening high-risk populations and population health research, and the more open configurations allowed may prove favorable for obese subjects and for pregnant women. This article summarizes promising body applications for contemporary whole-body low-field MRI systems, with a focus on new platforms developed within the past 5 years. This is an active area of research, and one can expect many improvements as MRI physicists fully explore the landscape of pulse sequences that are feasible, and as clinicians apply these to patient populations.

Replication of the bSTAR sequence and open-source implementation.

PURPOSE: The reproducibility of scientific reports is crucial to advancing human knowledge. This paper is a summary of our experience in replicating a balanced SSFP half-radial dual-echo imaging technique (bSTAR) using open-source frameworks as a response to the 2023 ISMRM "repeat it with me" Challenge. METHODS: We replicated the bSTAR technique for thoracic imaging at 0.55T. The bSTAR pulse sequence is implemented in Pulseq, a vendor neutral open-source rapid sequence prototyping environment. Image reconstruction is performed with the open-source Berkeley Advanced Reconstruction Toolbox (BART). The replication of bSTAR, termed open-source bSTAR, is tested by replicating several figures from the published literature. Original bSTAR, using the pulse sequence and image reconstruction developed by the original authors, and open-source bSTAR, with pulse sequence and image reconstruction developed in this work, were performed in healthy volunteers. RESULTS: Both echo images obtained from open-source bSTAR contain no visible artifacts and show identical spatial resolution and image quality to those in the published literature. A direct head-to-head comparison between open-source bSTAR and original bSTAR on a healthy volunteer indicates that open-source bSTAR provides adequate SNR, spatial resolution, level of artifacts, and conspicuity of pulmonary vessels comparable to original bSTAR. CONCLUSION: We have successfully replicated bSTAR lung imaging at 0.55T using two open-source frameworks. Full replication of a research method solely relying on information on a research paper is unfortunately rare in research, but our success gives greater confidence that a research methodology can be indeed replicated as described.

Real-time water/fat imaging at 0.55T with spiral out-in-out-in sampling.

PURPOSE: To develop an efficient and flexible water/fat separated real-time MRI (RT-MRI) method using spiral out-in-out-in (OIOI) sampling and balanced SSFP (bSSFP) at 0.55T. METHODS: A bSSFP sequence with golden-angle spiral OIOI readout was developed, capturing three echoes to allow water/fat separation. A low-latency reconstruction that combines all echoes was available for online visualization. An offline reconstruction provided water and fat RT-MRI in two steps: (1) image reconstruction with spatiotemporally constrained reconstruction (STCR) and (2) water/fat separation with hierarchical iterative decomposition of water and fat with echo asymmetry and least-squares estimation (HIDEAL). In healthy volunteers, spiral OIOI was acquired in the wrist during a radial-to-ulnar deviation maneuver, in the heart without breath-hold and cardiac gating, and in the lower abdomen during free-breathing for visualizing small bowel motility. RESULTS: We demonstrate successful water/fat separated RT-MRI for all tested applications. In the wrist, resulting images provided clear depiction of ligament gaps and their interactions during the radial-to-ulnar deviation maneuver. In the heart, water/fat RT-MRI depicted epicardial fat, provided improved delineation of epicardial coronary arteries, and provided high blood-myocardial contrast for ventricular function assessment. In the abdomen, water-only RT-MRI captured small bowel mobility clearly with improved water-fat contrast. CONCLUSIONS: We have demonstrated a novel and flexible bSSFP spiral OIOI sequence at 0.55T that can provide water/fat separated RT-MRI with a variety of application-specific temporal resolution and spatial resolution requirements.

A Fluorescent Reporter Mouse for In Vivo Assessment of Genome Editing with Diverse Cas Nucleases and Prime Editors.

CRISPR-based genome-editing technologies, including nuclease editing, base editing, and prime editing, have recently revolutionized the development of therapeutics targeting disease-causing mutations. To advance the assessment and development of genome editing tools, a robust mouse model is valuable, particularly for evaluating in vivo activity and delivery strategies. In this study, we successfully generated a knock-in mouse line carrying the Traffic Light Reporter design known as TLR-multi-Cas variant 1 (TLR-MCV1). We comprehensively validated the functionality of this mouse model for both in vitro and in vivo nuclease and prime editing. The TLR-MCV1 reporter mouse represents a versatile and powerful tool for expediting the development of editing technologies and their therapeutic applications.

Pneumocystis jirovecii Pneumonia in a Patient With Newly Diagnosed HIV and a High CD4 Count.

Pneumocystis jirovecii pneumonia (PCP) is a rare, life-threatening opportunistic fungal infection that rarely occurs with CD4 counts greater than 200 cells/mm3. We present a case of PCP in a young male who presented with fever, weakness, dyspnea, and a non-productive cough. He was initially treated for community-acquired pneumonia but was then noted to be HIV positive with signs of immunosuppression such as oral thrush. The CD4 count was found to be very high, at 646 cells/mm3 and 281 cells/mm3 on repeat. The patient was treated with trimethoprim/sulfamethoxazole (TMP/SMX) and fluconazole and further started on highly active antiretroviral therapy (HAART) with TMP/SMX as a means of secondary prophylaxis in the outpatient setting.

Comparison of Pre- and Posttreatment Airway Volume in Patients with Temporomandibular Joint Disorders Treated with Ultra-Low Frequency Transcutaneous Electrical Nerve Stimulation Using Cone Beam Computed Tomography.

Introduction Temporomandibular joint disorders (TMD) present with a multitude of symptoms that can range from headaches to shoulder pain. Patients frequently present with pain in the ear, dizziness, and vertigo. It is noted that some patients who report TMDs also have a history of sleep disturbances, which is noted in cone beam computed tomography (CBCT) as a reduction in the oropharyngeal airway volume. Objective To evaluate the airway volume in pre- and posttreatment of TMD with the use of neuromuscular orthotics made with ultra-low frequency transcutaneous electrical nerve stimulation (ULF-TENS). Methods A total of 15 patients were evaluated for TMDs using the related criteria. Those included were treated with ULF-TENS with evaluation of the airway volume both pre- and posttreatment using CBCT and the Dolphin 3D volume analysis software. Results While the symptoms were shown to be significantly reduced in patients who were treated with this particular modality, the airway volume varied in those who reported a reduction after a period of 3 months and those that reported after a period of 6 months. Conclusion Posttreatment evaluation of the airway should be done after a period of 6 months for a more objective evaluation. A multidisciplinary evaluation of the patient is required in such cases.