Normalizing granuloma vasculature and matrix improves drug delivery and reduces bacterial burden in tuberculosis-infected rabbits.

Host-directed therapies (HDTs) represent an emerging approach for bacterial clearance during tuberculosis (TB) infection. While most HDTs are designed and implemented for immuno-modulation, other host targets-such as nonimmune stromal components found in pulmonary granulomas-may prove equally viable. Building on our previous work characterizing and normalizing the aberrant granuloma-associated vasculature, here we demonstrate that FDA-approved therapies (bevacizumab and losartan, respectively) can be repurposed as HDTs to normalize blood vessels and extracellular matrix (ECM), improve drug delivery, and reduce bacterial loads in TB granulomas. Granulomas feature an overabundance of ECM and compressed blood vessels, both of which are effectively reduced by losartan treatment in the rabbit model of TB. Combining both HDTs promotes secretion of proinflammatory cytokines and improves anti-TB drug delivery. Finally, alone and in combination with second-line antitubercular agents (moxifloxacin or bedaquiline), these HDTs significantly reduce bacterial burden. RNA sequencing analysis of HDT-treated lung and granuloma tissues implicates up-regulated antimicrobial peptide and proinflammatory gene expression by ciliated epithelial airway cells as a putative mechanism of the observed antitubercular benefits in the absence of chemotherapy. These findings demonstrate that bevacizumab and losartan are well-tolerated stroma-targeting HDTs, normalize the granuloma microenvironment, and improve TB outcomes, providing the rationale to clinically test this combination in TB patients.

Losartan controls immune checkpoint blocker-induced edema and improves survival in glioblastoma mouse models.

Immune checkpoint blockers (ICBs) have failed in all phase III glioblastoma trials. Here, we found that ICBs induce cerebral edema in some patients and mice with glioblastoma. Through single-cell RNA sequencing, intravital imaging, and CD8+ T cell blocking studies in mice, we demonstrated that this edema results from an inflammatory response following antiprogrammed death 1 (PD1) antibody treatment that disrupts the blood-tumor barrier. Used in lieu of immunosuppressive corticosteroids, the angiotensin receptor blocker losartan prevented this ICB-induced edema and reprogrammed the tumor microenvironment, curing 20% of mice which increased to 40% in combination with standard of care treatment. Using a bihemispheric tumor model, we identified a "hot" tumor immune signature prior to losartan+anti-PD1 therapy that predicted long-term survival. Our findings provide the rationale and associated biomarkers to test losartan with ICBs in glioblastoma patients.

Dendritic cell paucity in mismatch repair-proficient colorectal cancer liver metastases limits immune checkpoint blockade efficacy.

Liver metastasis is a major cause of mortality for patients with colorectal cancer (CRC). Mismatch repair-proficient (pMMR) CRCs make up about 95% of metastatic CRCs, and are unresponsive to immune checkpoint blockade (ICB) therapy. Here we show that mouse models of orthotopic pMMR CRC liver metastasis accurately recapitulate the inefficacy of ICB therapy in patients, whereas the same pMMR CRC tumors are sensitive to ICB therapy when grown subcutaneously. To reveal local, nonmalignant components that determine CRC sensitivity to treatment, we compared the microenvironments of pMMR CRC cells grown as liver metastases and subcutaneous tumors. We found a paucity of both activated T cells and dendritic cells in ICB-treated orthotopic liver metastases, when compared with their subcutaneous tumor counterparts. Furthermore, treatment with Feline McDonough sarcoma (FMS)-like tyrosine kinase 3 ligand (Flt3L) plus ICB therapy increased dendritic cell infiltration into pMMR CRC liver metastases and improved mouse survival. Lastly, we show that human CRC liver metastases and microsatellite stable (MSS) primary CRC have a similar paucity of T cells and dendritic cells. These studies indicate that orthotopic tumor models, but not subcutaneous models, should be used to guide human clinical trials. Our findings also posit dendritic cells as antitumor components that can increase the efficacy of immunotherapies against pMMR CRC.

Comparison of Urinary Biomarkers in Diagnosis of Ureteropelvic Junction Obstruction and Differentiation from Nonobstructive Dilatation.

Background and Aims: Differentiation of nonobstructive dilatation (NOD) from ureteropelvic junction obstruction (UPJO) is a challenge in children with antenatally detected hydronephrosis. The aim of this study is to compare the utility of urinary biomarkers: carbohydrate antigen (CA 19-9), neutrophil gelatinase-associated lipocalin (NGAL), and kidney injury molecule (KIM) in diagnosing UPJO. Methods: A prospective study was conducted after obtaining ethical clearance between 2021 and 2022. Group 1 - control group (n = 30): children with normal antenatal ultrasound with no urinary symptoms. Group 2 - study group (n = 48): children with unilateral hydronephrosis: Group 2a - NOD (n = 24): children stable on ultrasound and diuretic renogram and Group 2b - UPJO (n = 24): children who worsened to Grade 4 hydronephrosis on ultrasound/worsening of differential renal function (10% drop) on renogram who underwent pyeloplasty. Urinary biomarkers NGAL, KIM-1, and CA 19-9 were measured using the enzyme-linked immune absorbent assay method. Results: The urine CA 19-9 level was 128.05 ± 4.08 U/mL in the UPJO group, and this was significantly higher (P = 0.001) than NOD, 70.29 ± 4.41, and controls, 1.91 ± 1.57. The urine NGAL level was 21.41 ± 4.44 pg/mL in UPJO, and this was significantly higher than controls, 2.669 ± 0.513, but not NOD, 24.55 ± 2.67. The urine KIM level was 817 ± 15.84 pg/mL in the UPJO group, and this was significantly higher than controls, 285 ± 8.10, but not NOD, 768.23 ± 15.12. Receiver operating characteristic analysis of CA 19-9 revealed a urine biomarker cutoff of 95 U/mL for diagnosing UPJO (sensitivity 95%; specificity 96%; and area under the curve 0.99). Conclusions: CA 19-9 is a superior marker compared to NGAL and KIM in differentiating UPJO from NOD. Further studies with larger numbers are warranted.

Post-cardiac injury syndrome after surgical repair of atrial septal defect: Reporting a rare occurrence.

A 16-year-old male with past medical history of congenital atrial septal defect surgical repair, presented with recurrent pericarditis secondary to post-cardiotomy injury syndrome (PCIS), After failing medical therapy, he ultimately underwent pericardiectomy for symptom resolution, PCIS is underdiagnosed in children and should be considered in patients with recurrent chest, pain.

Pericardial mesothelioma presenting as constrictive pericarditis.

A 46-year-old woman underwent pericardiocentesis and pericardial window for recurrent pericardial effusion. She presented 17 months later with signs and symptoms consistent with constrictive pericarditis. Cardiac magnetic resonance imaging revealed an infiltrative mass surrounding the pericardium. A transcutaneous core needle biopsy of the pericardium confirmed the diagnosis of pericardial mesothelioma.

Effect of heat treatments on quinoa germ quality and its storage study.

Quinoa is a potential crop to address the situation as it offers a plethora of benefits as it is nutritionally rich and can adapt to extreme climatic and salt conditions. Quinoa germ consists of almost 25-30% of whole grain. Quinoa germ obtained using roller milling has remarkable nutritional properties with high protein, fat and mineral content. Presence higher fat content limits shelf-life of quinoa germ. The objective of the present investigation is to study the effect of different treatment on stabilization of quinoa germ and its storge study. Quinoa germ was subjected to microwave and infrared treatment for shelf-life extension. Colour properties of the germ has not changed drastically by both treatments. Sorption behavior of quinoa germ stored at different RH was studied and results showed typical sigmoid curve for all samples. Sorption studies revealed that treated quinoa germ were stable at 64% RH. The storage study was carried out at accelerated conditions using PET/PE packaging material. Based on the results of the study, it can be inferred that the quinoa germ can be kept up to three months at accelerated conditions. Study demonstrated that microwave treatments of quinoa germ showed highest shelf life of three months at accelerated conditions.

Rapid simultaneous acquisition of macromolecular tissue volume, susceptibility, and relaxometry maps.

PURPOSE: A major obstacle to the clinical implementation of quantitative MR is the lengthy acquisition time required to derive multi-contrast parametric maps. We sought to reduce the acquisition time for QSM and macromolecular tissue volume by acquiring both contrasts simultaneously by leveraging their redundancies. The joint virtual coil concept with GRAPPA (JVC-GRAPPA) was applied to reduce acquisition time further. METHODS: Three adult volunteers were imaged on a 3 Tesla scanner using a multi-echo 3D GRE sequence acquired at 3 head orientations. Macromolecular tissue volume, QSM, R2∗ , T1 , and proton density maps were reconstructed. The same sequence (GRAPPA R = 4) was performed in subject 1 with a single head orientation for comparison. Fully sampled data was acquired in subject 2, from which retrospective undersampling was performed (R = 6 GRAPPA and R = 9 JVC-GRAPPA). Prospective undersampling was performed in subject 3 (R = 6 GRAPPA and R = 9 JVC-GRAPPA) using gradient blips to shift k-space sampling in later echoes. RESULTS: Subject 1's multi-orientation and single-orientation macromolecular tissue volume maps were not significantly different based on RMSE. For subject 2, the retrospectively undersampled JVC-GRAPPA and GRAPPA generated similar results as fully sampled data. This approach was validated with the prospectively undersampled images in subject 3. Using QSM, R2∗ , and macromolecular tissue volume, the contributions of myelin and iron content to susceptibility were estimated. CONCLUSION: We have developed a novel strategy to simultaneously acquire data for the reconstruction of 5 intrinsically coregistered 1-mm isotropic resolution multi-parametric maps, with a scan time of 6 min using JVC-GRAPPA.

Losartan treatment enhances chemotherapy efficacy and reduces ascites in ovarian cancer models by normalizing the tumor stroma.

In ovarian cancer patients, tumor fibrosis and angiotensin-driven fibrogenic signaling have been shown to inversely correlate with survival. We sought to enhance drug delivery and therapeutic efficacy by remodeling the dense extracellular matrix in two orthotopic human ovarian carcinoma xenograft models. We hypothesized that targeting the angiotensin signaling axis with losartan, an approved angiotensin system inhibitor, could reduce extracellular matrix content and the associated "solid stress," leading to better anticancer therapeutic effect. We report here four translatable findings: (i) losartan treatment enhances the efficacy of paclitaxel-a drug used for ovarian cancer treatment-via normalizing the tumor microenvironment, resulting in improved vessel perfusion and drug delivery; (ii) losartan depletes matrix via inducing antifibrotic miRNAs that should be tested as candidate biomarkers of response or resistance to chemotherapy; (iii) although losartan therapy alone does not reduce tumor burden, it reduces both the incidence and the amount of ascites formed; and (iv) our retrospective analysis revealed that patients receiving angiotensin system inhibitors concurrently with standard treatment for ovarian cancer exhibited 30 mo longer overall survival compared with patients on other antihypertensives. Our findings provide the rationale and supporting data for a clinical trial on combined losartan and chemotherapy in ovarian cancer patients.

Providing Care: Intrinsic Human-Machine Teams and Data.

Despite the many successes of artificial intelligence in healthcare applications where human-machine teaming is an intrinsic characteristic of the environment, there is little work that proposes methods for adapting quantitative health data-features with human expertise insights. A method for incorporating qualitative expert perspectives in machine learning training data is proposed. The method implements an entropy-based consensus construct that minimizes the challenges of qualitative-scale data such that they can be combined with quantitative measures in a critical clinical event (CCE) vector. Specifically, the CCE vector minimizes the effects where (a) the sample size is too small, (b) the data may not be normally distributed, or (c) The data are from Likert scales, which are ordinal, so parametric statistics cannot be used. The incorporation of human perspectives in machine learning training data provides encoding of human considerations in the subsequent machine learning model. This encoding provides a basis for increasing explainability, understandability, and ultimately trust in AI-based clinical decision support system (CDSS), thereby improving human-machine teaming concerns. A discussion of applying the CCE vector in a CDSS regime and implications for machine learning are also presented.

Application and effect of hybrid grinding techniques on the quality of stone chakki atta (whole wheat flour) and flat bread.

Industrially packaged whole wheat flour (atta) is manufactured in motorized stone chakkis, which consumes more electric power. Present study is aimed towards evaluating the effect of hybrid grinding technique of wheat using roller mill on its grinding characteristics and quality of chakki atta and chapatti. Wheat was passed through the pair of first break rolls in MLU 202 with the roll gaps of 1 and 0.9 mm for two different samples. Electrical parameters for grinding energy were compared and the pre-milled wheat was ground in the stone chakki. Atta obtained from 2 different variations and control stone chakki atta were compared for physico-chemical, rheological and chapati making quality. Damaged starch increased from 15.25 for control atta to 17.3% for 0.9 mm sample, whereas, farinograph water absorption increased from 75.9 to 78.9% respectively. Chapatis were prepared and sensory studies were carried out. Chapati colour was found to be brighter for 0.9 mm sample.

Effect of grinding techniques and supplementation of quinoa on the carbohydrate profile of tortillas.

With an aim of studying the implication of the milling interventions and supplementation of non-wheat grains on the effect of the carbohydrate digestive profile of wheat flour the present study was conducted. Quinoa grain was selected for the study due its higher protein content and better amino acid profile than that of cereal grains. Milling of grains to produce atta (whole wheat flour) was carried out using traditional method of stone chakki mill and the other method of separation and recombination of different stream using roller mill. The atta flour was then supplemented with the quinoa flour in different combinations and the physico-chemical, rheological and product making characteristics were studied. The milling technique has an impact on the damaged starch with the difference of around 6% across the flour samples which further impacted the water absorption capacity and the gelatinization temperature of the flour. Carbohydrate digestive profile of the prepared tortillas have shown significant difference when the atta from roller mill substituted with quinoa flour upto 15%. Starch digestibility index of stone chakki atta was higher SDI (78.71) than that of roller milled quiooa supplemented flours (38.52 and 36.74). The rapidly digestible sugar decreased and the slow digestible sugar increased as compared to stone chakki atta tortillas which combinedly is responsible for lower glycaemic index. In the commercial point of view this will open a new avenue for food manufacturer to produce value added and healthy products from quinoa. Supplementary Information: The online version contains supplementary material available at 10.1007/s13197-022-05365-9.

Venoarterial Extracorporeal Membrane Oxygenation is Effective in Severe Aluminum Phosphide Overdose Despite Delayed Presentation.

Aluminum phosphide (ALP) is a potentially lethal poison. The mortality rate in ALP overdose is close to 100%. ALP has no specific antidote, and only supportive therapy is possible, with timely extracorporeal support mentioned as a modality. We present a case of severe ALP overdose in a young female with delayed presentation (>24 hours) and multiorgan failure (MOF)/shock successfully managed with veno-arterial extracorporeal membrane oxygenation (VA-ECMO). Unique features of this case include consumption of lethal quantity of ALP (5 g), severe toxicity with MOF, and shock secondary to a delayed presentation, all of which incrementally added to a high mortality. This was managed with the help of VA-ECMO as a last option with a successful outcome. This highlights the fact that late ECMO deployment, despite absorption of a large quantity and MOF/shock/acidosis, can still be salvageable with appropriate management. HOW TO CITE THIS ARTICLE: Kumar PHG, Kalluraya MA, Jithendra C, Kumar A, Kanavehalli SP, Furtado AD, et al. Venoarterial Extracorporeal Membrane Oxygenation is Effective in Severe Aluminum Phosphide Overdose Despite Delayed Presentation. Indian J Crit Care Med 2021;25(12):1459-1461.

Eligibility for PCSK9 treatment in 734 Hypercholesterolemic patients referred to a regional cholesterol treatment center with LDL cholesterol ≥ 70 mg/dl despite maximal tolerated cholesterol lowering therapy.

BACKGROUND: LDL cholesterol (LDLC) lowering has been revolutionized by PCSK9 inhibitors, Alirocumab (Praluent) and Evolocumab (Repatha), approved as adjuncts to maximally tolerated cholesterol lowering therapy in heterozygous (HeFH) or homozygous (HoFH) familial hypercholesterolemia, and/or clinical atherosclerotic cardiovascular disease (CVD) where LDLC lowering is insufficient. METHODS: We applied FDA and insurance eligibility criteria for PCSK9 inhibitor use in 734 hypercholesterolemic patients serially referred over 3 years who then received ≥ 2 months maximally tolerated LDLC lowering therapy with follow up LDLC ≥ 70 mg/dl, and in 50 patients approved by insurance for PCSK9 inhibitors. We documented the percentage of patients with HeFH and/or CVD who met FDA and insurance criteria for PCSK9 inhibitor therapy using LDLC goal-based guidelines. RESULTS: Of 734 patients with LDLC ≥ 70 mg/dl after ≥ 2 months maximally tolerated LDLC lowering therapy, 220 (30%) had HeFH and/or CVD with LDLC > 100 mg/dl, meeting FDA-insurance criteria for PCSK9 inhibitor therapy. Another 66 (9%) patients were statin intolerant, without HeFH or CVD. Of the 50 patients whose PCSK9 inhibitor therapy was approved for insurance coverage, 45 (90%) had LDLC > 100 mg/dl after ≥ 2 months on maximally tolerated LDLC lowering therapy. Seventeen of these 50 patients (34%) had HeFH without CVD (LDLC on treatment 180 ± 50 mg/dl), 15 (30%) had CVD without HeFH (LDLC on treatment 124 ± 26 mg/dl), 14 (28%) had both HeFH and CVD (LDLC on treatment 190 ± 53 mg/dl), and 4 (8%) had neither HeFH nor CVD (LCLC 142 ± 11 mg/dl). CONCLUSION: Of 734 patients referred for LDLC reduction, with LDLC ≥ 70 mg/dl after ≥ 2 months on maximally tolerated therapy, 220 (30%) had HeFH and/or CVD with LDLC > 100 mg/dl, meeting FDA-insurance criteria for PCSK9 inhibitor therapy as an adjunct to diet-maximally tolerated cholesterol lowering therapy in HeFH or CVD. If 30% of patients with high LDLC and HeFH-CVD are eligible for PCSK9 inhibitors, then specialty pharmaceutical pricing models (~$14,300/year) will collide with tens of millions of HeFH-CVD patients. We speculate that if there was a 50 % reduction in CVD, then there would be savings of $245 billion, in the middle of the range of estimated PCSK9 inhibitor costs of $185-342 billion. Whether the health care savings arising from the anticipated reduction of CVD events by PCSK9 inhibitors justify their extraordinary costs in broad population use remains to be determined.

Quality of Life in Recurrent Pericarditis.

Recurrent pericarditis (RP) poses a significant burden on individuals' quality of life. The psychosocial impact of RP is not well understood. It cannot be overlooked, as it can impact the psychosocial well-being of the patients due to the chronicity of the symptoms and multiple flare-ups. Addressing the multifaceted challenges posed by RP requires a comprehensive approach that not only focuses on symptom control but also emphasizes patient education, psychological support, and shared decision-making to optimize both physical and emotional well-being. Therefore, we aim to share our perspective on the effect of RP on the quality of life of the patients.

Nonalcoholic Fatty Liver Disease (NAFLD) and Cardiovascular Risk: Is Imaging Helpful?

Nonalcoholic Fatty Liver Disease (NAFLD) is proving to be a globally prevalent condition. Moreover, NAFLD may be an independent risk factor associated with higher cardiovascular (CVD) morbidity and mortality. Further studies are needed to assess whether NAFLD needs to be included in the atherosclerotic risk score algorithms or whether patients with NAFLD need to be screened early on to assess their CVD risk especially since imaging such as positron emission tomography can be used to assess both NAFLD and CV disease at the same time. Therefore employing cardiovascular imaging modalities to investigate the incidence, extent, and nature of atherosclerotic lesions in NAFLD may be beneficial. Additionally, whether treating NAFLD halts the progression of CVD on imaging remains to be seen. Further research to delineate NAFLD and CVD associations, deciphering screening imaging modalities, and investigating targeted interventions could improve CVD morbidity and mortality in NAFLD.

Exercise intensity governs tumor control in mice with breast cancer.

Introduction: Exercise is recommended as an adjunct therapy in cancer, but its effectiveness varies. Our hypothesis is that the benefit depends on the exercise intensity. Methods: We subjected mice to low intensity (Li), moderate intensity (Mi) or high intensity (Hi) exercise, or untrained control (Co) groups based on their individual maximal running capacity. Results: We found that exercise intensity played a critical role in tumor control. Only Mi exercise delayed tumor growth and reduced tumor burden, whereas Li or Hi exercise failed to exert similar antitumor effects. While both Li and Mi exercise normalized the tumor vasculature, only Mi exercise increased tumor infiltrated CD8+ T cells, that also displayed enhanced effector function (higher proliferation and expression of CD69, INFγ, GzmB). Moreover, exercise induced an intensity-dependent mobilization of CD8+ T cells into the bloodstream. Conclusion: These findings shed light on the intricate relationship between exercise intensity and cancer, with implications for personalized and optimal exercise prescriptions for tumor control.

Optimal antiplatelet strategy following coronary artery bypass grafting: a meta-analysis.

OBJECTIVE: Coronary artery bypass grafting (CABG) is an established revascularisation strategy for multivessel and left main coronary artery disease. Although aspirin is routinely recommended for patients with CABG, the optimal antiplatelet regimen after CABG remains unclear. We evaluated the efficacies and risks of different antiplatelet regimens (dual (DAPT) versus single (SAPT), and dual with clopidogrel (DAPT-C) versus dual with ticagrelor or prasugrel (DAPT-T/P)) after CABG. METHODS: We followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and performed a comprehensive literature search using PubMed, Ovid Medline, Ovid Embase and Cochrane Central Register of Controlled Trials. Data were extracted and pooled using random-effects models and Review Manager (V.5.4). RESULTS: Among the 2970 article abstracts screened, 215 full-text articles were reviewed and 38 studies totaling 77 447 CABG patients were included for analyses. DAPT compared with SAPT was associated with significantly lower all-cause mortality (OR 0.65 with 95% CI 0.50 to 0.86; p=0.002), cardiovascular mortality (OR 0.53, 95% CI 0.33 to 0.84; p=0.008), and major adverse cardiac and cerebrovascular events (MACCE) (OR 0.68, 95% CI 0.51 to 0.91; p=0.01), but higher rates of major (OR 1.30, 95% CI 1.08 to 1.56; p=0.007) and minor bleeding (OR 1.87, 95% CI 1.28 to 2.74; p=0.001) after CABG. DAPT-T/P compared with DAPT-C was associated with significantly lower all-cause (OR 0.43, 95% CI 0.29 to 0.65; p≤0.0001) and cardiovascular mortality (OR 0.44, 95% CI 0.24 to 0.80; p=0.008), and no differences on other cardiovascular or bleeding outcomes after CABG. CONCLUSION: In patients with CABG, DAPT compared with SAPT and DAPT-T/P compared with DAPT-C were associated with reduction in all-cause and cardiovascular mortality, especially in patients with acute coronary syndrome. Additionally, DAPT was associated with reduction in MACCE, but higher rates of major and minor bleeding. An individualised approach to choosing antiplatelet regimen is necessary for patients with CABG based on ischaemic and bleeding risks.

Immune checkpoint inhibitors and pericardial disease: a systematic review.

INTRODUCTION: Despite the growing use of immune checkpoint inhibitors (ICI) in cancer treatment, data regarding ICI-associated pericardial disease are primarily derived from case reports and case series. ICI related pericardial disease can be difficult to diagnose and is associated with significant morbidity. We conducted a systematic review to further characterize the epidemiology, clinical presentation, and outcomes of this patient population. METHODS: A search of four databases resulted in 31 studies meeting inclusion criteria. Patients > 18 years old who presented with ICI mediated pericardial disease were included. Intervention was medical + surgical therapy and outcomes were development of cardiac tamponade, morbidity, and mortality. RESULTS: Thirty- eight patients across 31 cases were included. Patients were majority male (72%) with a median age of 63. Common symptoms included dyspnea (59%) and chest pain (32%), with 41% presenting with cardiac tamponade. Lung cancer (81%) was the most prevalent, and nivolumab (61%) and pembrolizumab (34%) were the most used ICIs. Pericardiocentesis was performed in 68% of patients, and 92% experienced symptom improvement upon ICI cessation. Overall mortality was 16%. DISCUSSION: This study provides the most comprehensive analysis of ICI-mediated pericardial disease to date. Patients affected were most commonly male with lung cancer treated with either Nivolumab or Pembrolizumab. Diagnosis may be challenging in the setting of occult presentation with normal EKG and physical exam as well as delayed onset from therapy initiation. ICI-associated pericardial disease demonstrates high morbidity and mortality, as evidenced by a majority of patients requiring pericardiocentesis.