Moving toward Equitable Care for Sleep Apnea in the United States: Positive Airway Pressure Adherence Thresholds: An Official American Thoracic Society Policy Statement.

Background: Positive airway pressure (PAP) is a highly effective treatment for obstructive sleep apnea (OSA), but adherence limits its efficacy. In addition, coverage of PAP by CMS (Centers for Medicare & Medicaid Services) and other insurers in the United States depends on adherence. This leaves many beneficiaries without PAP, disproportionally impacting non-white and low socioeconomic position patients with OSA and exacerbating sleep health disparities. Methods: An inter-professional, multidisciplinary, international committee with various stakeholders was formed. Three working groups (the historical policy origins, impact of current policy, and international PAP coverage models) met and performed literature reviews and discussions. Using surveys and an iterative discussion-based consensus process, the policy statement recommendations were created. Results: In this position paper, we advocate for policy change to CMS PAP coverage requirements to reduce inequities and align with patient-centered goals. We specifically call for eradicating repeat polysomnography, eliminating the 4-hour rule, and focusing on patient-oriented outcomes such as improved sleepiness and sleep quality. Conclusions: Modifications to the current policies for PAP insurance coverage could improve health disparities.

HER2 expression identifies dynamic functional states within circulating breast cancer cells.

Circulating tumour cells in women with advanced oestrogen-receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer acquire a HER2-positive subpopulation after multiple courses of therapy. In contrast to HER2-amplified primary breast cancer, which is highly sensitive to HER2-targeted therapy, the clinical significance of acquired HER2 heterogeneity during the evolution of metastatic breast cancer is unknown. Here we analyse circulating tumour cells from 19 women with ER+/HER2- primary tumours, 84% of whom had acquired circulating tumour cells expressing HER2. Cultured circulating tumour cells maintain discrete HER2+ and HER2- subpopulations: HER2+ circulating tumour cells are more proliferative but not addicted to HER2, consistent with activation of multiple signalling pathways; HER2- circulating tumour cells show activation of Notch and DNA damage pathways, exhibiting resistance to cytotoxic chemotherapy, but sensitivity to Notch inhibition. HER2+ and HER2- circulating tumour cells interconvert spontaneously, with cells of one phenotype producing daughters of the opposite within four cell doublings. Although HER2+ and HER2- circulating tumour cells have comparable tumour initiating potential, differential proliferation favours the HER2+ state, while oxidative stress or cytotoxic chemotherapy enhances transition to the HER2- phenotype. Simultaneous treatment with paclitaxel and Notch inhibitors achieves sustained suppression of tumorigenesis in orthotopic circulating tumour cell-derived tumour models. Together, these results point to distinct yet interconverting phenotypes within patient-derived circulating tumour cells, contributing to progression of breast cancer and acquisition of drug resistance.

Evaluation of endocrine resistance using ESR1 genotyping of circulating tumor cells and plasma DNA.

PURPOSE: Therapeutic efficacy of hormonal therapies to target estrogen receptor (ER)-positive breast cancer is limited by the acquisition of ligand-independent ESR1 mutations, which confer treatment resistance to aromatase inhibitors (AIs). Monitoring for the emergence of such mutations may enable individualized therapy. We thus assessed CTC- and ctDNA-based detection of ESR1 mutations with the aim of evaluating non-invasive approaches for the determination of endocrine resistance. PATIENTS AND METHODS: In a prospective cohort of 55 women with hormone receptor-positive metastatic breast cancer, we isolated circulating tumor cells (CTCs) and developed a high-sensitivity method for the detection of ESR1 mutations in these CTCs. In patients with sufficient plasma for the simultaneous extraction of circulating tumor DNA (ctDNA), we performed a parallel analysis of ESR1 mutations using multiplex droplet digital PCR (ddPCR) and examined the agreement between these two platforms. Finally, we isolated single CTCs from a subset of these patients and reviewed RNA expression to explore alternate methods of evaluating endocrine responsiveness. RESULTS: High-sensitivity ESR1 sequencing from CTCs revealed mono- and oligoclonal mutations in 22% of patients. These were concordant with plasma DNA sequencing in 95% of cases. Emergence of ESR1 mutations was correlated both with time to metastatic relapse and duration of AI therapy following such recurrence. The Presence of an ESR1 mutation, compared to ESR1 wild type, was associated with markedly shorter Progression-Free Survival on AI-based therapies (p = 0.0006), but unaltered to other non-AI-based therapies (p = 0.73). Compared with ESR1 mutant cases, AI-resistant CTCs with wild-type ESR1 showed an elevated ER-coactivator RNA signature, consistent with their predicted response to second-line hormonal therapies. CONCLUSION: Blood-based serial monitoring may guide the selection of precision therapeutics for women with AI-resistant ER-positive breast cancer.

A microfluidic device for label-free, physical capture of circulating tumor cell clusters.

Cancer cells metastasize through the bloodstream either as single migratory circulating tumor cells (CTCs) or as multicellular groupings (CTC clusters). Existing technologies for CTC enrichment are designed to isolate single CTCs, and although CTC clusters are detectable in some cases, their true prevalence and significance remain to be determined. Here we developed a microchip technology (the Cluster-Chip) to capture CTC clusters independently of tumor-specific markers from unprocessed blood. CTC clusters are isolated through specialized bifurcating traps under low-shear stress conditions that preserve their integrity, and even two-cell clusters are captured efficiently. Using the Cluster-Chip, we identified CTC clusters in 30-40% of patients with metastatic breast or prostate cancer or with melanoma. RNA sequencing of CTC clusters confirmed their tumor origin and identified tissue-derived macrophages within the clusters. Efficient capture of CTC clusters will enable the detailed characterization of their biological properties and role in metastasis.

Revisiting Femoral vs. Radial access-do vascular closure devices level the playing field?

Previous large randomized multicenter trials have shown superiority of radial to femoral access in reducing major bleeding, vascular complications, and in some cohorts, mortality Vascular closure devices improve time to hemostasis and ambulation, as well as patient comfort, but have not been shown to reduce major complications or mortality consistently in the high level evidence base. The combination of optimal femoral access and closure with a vascular closure device has the potential to narrow the gap between the radial and femoral approaches in high risk patients, but unfortunately this study was too limited to confirm either non-inferiority or equivalence.

Studies on the histopathological changes in selected tissues of fish Labeo rohita exposed to phenol.

Histopathological changes in vital tissues like gills, liver and kidney in the fish Labeo rohita exposed for 8 days to sublethal (5.2 mgl(-1)) and lethal concentration (25.09 mg(-1)) of phenol were studied. The observed histopathological changes in the gills were epithelial hyperplasia with lamellar fusion, epithelial hypertrophy, edema, general necrosis, increased mucous production and degeneration of primary and secondary gill lamellae at sublethal (5.2 mg l(-1)) and degenerated primary and secondary gill lamellae, lamellar fusion and lamellar disorganization at lethal (25.09 mg l(-1)) concentration. In the liver, the changes include as: formation of number of vacuoles, enlargement of nuclei of some cells, enlarged sinusoids with numerous blood cells and atrophic areas at sublethal (5.2 mg I(-1)) concentration and nuclear and cytoplasmic degeneration and melanomacrophages aggregates at lethal (25.09 mg I(-1)) concentration. In case of kidney, the changes were: degeneration of proximal and distal convoluted tubule, vacuolation of renal interstitial tissue and deformation of the nuclear membrane of some cells at sublethal (5.2 mg l(-1)) and occlusion of tubular lumen, cloudy swelling degeneration and hyaline droplets degeneration at lethal (25.09 mg l(-1)) concentration.

Adipose tissue and skeletal muscle wasting precede clinical diagnosis of pancreatic cancer.

Patients with pancreatic cancer commonly develop weight loss and muscle wasting. Whether adipose tissue and skeletal muscle losses begin before diagnosis and the potential utility of such losses for earlier cancer detection are not well understood. We quantify skeletal muscle and adipose tissue areas from computed tomography (CT) imaging obtained 2 months to 5 years before cancer diagnosis in 714 pancreatic cancer cases and 1748 matched controls. Adipose tissue loss is identified up to 6 months, and skeletal muscle wasting is identified up to 18 months before the clinical diagnosis of pancreatic cancer and is not present in the matched control population. Tissue losses are of similar magnitude in cases diagnosed with localized compared with metastatic disease and are not correlated with at-diagnosis circulating levels of CA19-9. Skeletal muscle wasting occurs in the 1-2 years before pancreatic cancer diagnosis and may signal an upcoming diagnosis of pancreatic cancer.

Long-term Survival Following Heart Transplantation for Chagas Versus Non-Chagas Cardiomyopathy: A Single-center Experience in Northeastern Brazil Over 2 Decades.

Data on post-heart transplant (HT) survival of patients with Chagas cardiomyopathy (CC) are scarce. We sought to evaluate post-HT survival in patients with CC as compared with other causes of heart failure across different eras of HT. Methods: We conducted a retrospective, cohort study of 376 adult HT recipients between October 1997 and November 2019. Participants were classified according to the etiology of heart failure as CC (N = 66), nonischemic cardiomyopathy (N = 214), and ischemic cardiomyopathy (N = 96), and according to the era of HT as early (1997-2009), recent (2010-2014), and current era (2015-2019). Results: After a mean follow-up of 5.0 y (0-20.5 y), post-HT survival rates at 1, 5, and 10 y were comparable between groups. One-y survival improved from 70% in the early eras to 80% in the current era (hazard ratio [HR], 0.63; 95% confidence interval [CI], 0.41-0.97; P = 0.034). After adjustment for sex, age, and mechanical circulatory support, time-related improvement in survival was observed only in patients without CC (HR, 0.54; 95% CI, 0.32-0.91; P = 0.019) but not in those with CC (HR, 0.99; 95% CI, 0.36-2.73; P = 0.98). Causes of death were similar between patients with CC and the other etiological subgroups. Conclusions: Posttransplant survival is comparable between patients with CC, nonischemic cardiomyopathy, and ischemic cardiomyopathy. Although survival has improved significantly over years for most HT recipients, it has remained unchanged for those with Chagas disease. These trends underscore the importance of scientific research, policy discussions and a collaborative registry of heart transplantation in Chagas cardiomyopathy.

Successful New Generation LAA Closure Device Implantation After Prior Incomplete Surgical LAA Ligation.

We present a case of percutaneous closure of a prior incomplete surgical left atrial appendage (LAA) ligation after a failed closure attempt using the first-generation Watchman device. The new generation Watchman FLX device (Boston Scientific) was implanted in this technically and anatomically challenging LAA patient using multimodality fusion imaging. (Level of Difficulty: Advanced.).

Aspiration thrombectomy in ST-Elevation myocardial infarction: Further insights from a network meta-analysis of randomized trials.

BACKGROUND: The initial enthusiasm for thrombectomy during percutaneous coronary intervention (PCI) of ST-elevation myocardial infarction (STEMI) patients has given way to restraint. There has been some limited interest whether it is beneficial in a few selected subgroups. Hence, we performed a network meta-analysis to compare conventional PCI (cPCI), Aspiration or manual thrombectomy (AT) and Mechanical thrombectomy (McT) for clarification. METHODS: Electronic databases were searched for randomized studies that compared AT, McT, or cPCI. A network meta-analysis was performed and odd's ratio (OR) with 95% confidence intervals was generated for major adverse cardiac events (MACE), mortality, myocardial infarction (MI), target vessel revascularization (TVR), stent thrombosis (ST), stroke, left ventricular ejection fraction (LVEF), myocardial blush grade (MBG) and ST segment resolution (STR). RESULTS: A total of 43 randomized trials (n = 26,682) were included. The risk of MACE (OR 0.86 95% CI 0.73-1.00), Mortality (OR 0.85 95% CI 0.73-0.99), MI (OR 0.65, 95% CI: 0.44-0.95) and TVR (OR 0.86, 95% CI: 0.74-1.00) were lower with AT compared to cPCI. The risk of ST and stroke was no different with the use of adjunctive AT. MBG, STR, and LVEF improved with the use of AT while the infarct size was no different in the two groups. CONCLUSIONS: Our comprehensive network meta-analysis suggests conflicting outcomes with AT. While Mortality, MACE, MI seem better, there is a suggestion that, Stroke and ST might be worse. Whether AT can still be pursued in any select cases should be further scrutinized.

Hinge point-based annular plane with abnormal aortic cusps in transcatheter aortic valve replacement.

A virtual aortic annular plane that is built using the three hinge points, known as the hinge point-based annular plane (HPAP), is routinely used during transcatheter aortic valve replacement (TAVR). Abnormal aortic cusps (AAC) with unequal length and size influence the relationship of the HPAP to the aortic root axis significantly and pose challenges to valve deployment, leading to paravalvular leak and valve embolisation. Obtaining a centreline-based aortic annular plane in addition may help to understand valve deployment behaviour in AAC better.

Acute toxicity of Nuvan, an organophosphate to freshwater fish Ctenopharyngodon idella and its effect on oxygen consumption.

The acute toxicity of Nuvan to the grass carp Ctenopharyngodon idella was determined using static and continuous flow through system for 24, 48, 72 and 96 hr. The median lethal concentration (LC50) values were 13.1, 10.9, 9.8 and 6.5 mg l(-1) respectively in static system and 10.7, 9.5, 8.0 and 7.5 mg l(-1) respectively in continuous flow through system. A reduction in oxygen consumption is observed when the fish is exposed to the toxicant and the mortality is due to effect of metabolism of energy synthesis.

Effects of alachlor on biochemical parameters of the freshwater fish, Channa punctatus (Bloch).

The fresh water fish Channa punctatus (Bloch) were exposed to lethal and sublethal concentrations of a chloroacetanilide herbicide Alachlor and its commercial formulation Lasso 50% Emulsifiable Concentrate EC to study the impacts on some biochemical parameters - the energy dependent sources: such as glycogen, total proteins and metabolic enzymes: Aspartate amino transferase (AAT), Alanine amino transferase (ALAT), Lactate Dehydrogenase (LDH), Deoxyribonucleic acid (DNA) and Ribonucleic acid (RNA). The glycogen, total proteins, DNA, RNA were all decreased but the activity of the enzymes AAT, ALAT and LDH were all increased which is due to the toxic stress. The percentage decrease being more pronounced at lethal concentrations than at sublethal concentrations.

Studies on histopathological changes in the gill, liver and kidney of Channa punctatus (Bloch) exposed to Alachlor.

Freshwater fish, Channa punctatus was exposed to sublethal concentration of a chloroacetanilide herbicide alachlor technical grade and lasso 50% EC for a period of 10 days. The histopathological changes in the gill include: necrosis, vacuolar degeneration, fusion and atrophy of primary and secondary gill lamellae. The tissue damages like degeneration of cytoplasm in hepatocytes, atrophy formation of vacuoles, rupture in blood vessels and disposition of hepatic cords are the histopathological changes observed in the liver. The changes in the kidney include: necrosis, swelling of renal tubules, cellular hypertrophy and granular cytoplasm.

Postdiagnosis Loss of Skeletal Muscle, but Not Adipose Tissue, Is Associated with Shorter Survival of Patients with Advanced Pancreatic Cancer.

BACKGROUND: Pancreatic cancer is associated with development of cachexia, a wasting syndrome thought to limit survival. Few studies have longitudinally quantified peripheral tissues or identified biomarkers predictive of future tissue wasting. METHODS: Adipose and muscle tissue were measured by computed tomography (CT) at diagnosis and 50 to 120 days later in 164 patients with advanced pancreatic cancer. Tissue changes and survival were evaluated by Cox proportional hazards regression. Baseline levels of circulating markers were examined in relation to future tissue wasting. RESULTS: Compared with patients in the bottom quartile of muscle change per 30 days (average gain of 0.8 ± 2.0 cm2), those in the top quartile (average loss of 12.9 ± 4.9 cm2) had a hazard ratio (HR) for death of 2.01 [95% confidence interval (CI), 1.12-3.62]. Patients in the top quartile of muscle attenuation change (average decrease of 4.9 ± 2.4 Hounsfield units) had an HR of 2.19 (95% CI, 1.18-4.04) compared with those in the bottom quartile (average increase of 2.4 ± 1.6 Hounsfield units). Changes in adipose tissue were not associated with survival. Higher plasma branched chain amino acids (BCAA; P = 0.004) and lower monocyte chemoattractant protein-1 (MCP-1; P = 0.005) at diagnosis were associated with greater future muscle loss. CONCLUSIONS: In patients with advanced pancreatic cancer, muscle loss and decrease in muscle density in 2 to 4 months after diagnosis were associated with reduced survival. BCAAs and MCP-1 levels at diagnosis were associated with subsequent muscle loss. IMPACT: BCAAs and MCP-1 levels at diagnosis could identify a high-risk group for future tissue wasting.

Notch-1 regulates transcription of the epidermal growth factor receptor through p53.

The Notch pathway plays a key role in the development and is increasingly recognized for its importance in cancer. We demonstrated previously the overexpression of Notch-1 and its ligands in gliomas and showed that their knockdown inhibits glioma cell proliferation and survival. To elucidate the mechanisms downstream of Notch-1 in glioma cells, we performed microarray profiling of glioma cells transfected with Notch-1 small interfering RNA. Notable among downregulated transcripts was the epidermal growth factor receptor (EGFR), known to be overexpressed or amplified in gliomas and prominent in other cancers as well. Further studies confirmed that Notch-1 inhibition decreased EGFR messenger RNA (mRNA) and EGFR protein in glioma and other cell lines. Transfection with Notch-1 increased EGFR expression. Additionally, we found a significant correlation in levels of EGFR and Notch-1 mRNA in primary high-grade human gliomas. Subsequent experiments showed that p53, an activator of the EGFR promoter, is regulated by Notch-1. Experiments with p53-positive and -null cell lines confirmed that p53 partially mediates the effects of Notch-1 on EGFR expression. These results show for the first time that Notch-1 upregulates EGFR expression and also demonstrate Notch-1 regulation of p53 in gliomas. These observations have significant implications for understanding the mechanisms of Notch in cancer and development.

Bone marrow cells for myocardial repair-a new therapeutic concept.

AIM: To assess the safety and feasibility of transfusing autologous bone marrow stem cells (ABMSC) into the culprit coronary artery after an acute anterior wall myocardial infarction (MI) and further to see the ability of ABMSC to promote improvement in Left Ventricular lsqb;LV] function at follow-up. METHODS: In an ongoing phase I clinical trial, twenty-seven patients of uncomplicated acute anterior wall MI treated as per the current practicing guidelines have been included. Among these, seventeen patients received intra-coronary unfractionated ABMSCs from 77ndash;15 days after acute MI (ABMSC group) and ten patients acted as controls. RESULTS: All the procedures carried out were without any complications. After 6 months, cardiac function analysis of ten patients from the ABMSC group by LV angiography and Cardiac Magnetic Resonance Imaging (MRI) demonstrated a significant rise of 12.74% (p = 0.001) and 7.1% (p = 0.001), respectively in the LV ejection fraction [LVEF]. There was an improvement in the LV systolic function wherein LV end systolic volume (LVESV) decreased significanty to 28.75% (p = 0.010) and 16.49% (p = 0.022) by LV angiography and cardiac MRI, respectively. LV end diastolic volume (LVEDV) decreased marginally by LV angiography (p = 0.548) and by cardiac MRI (p = 0.514). Five patients of the control group by LV angiography demonstrated non-significant rise of 1.0% (p = 0.706) in LVEF, 12.79% (p = 0.332) in LVEDV and 22.56% (p = 0.308) in LVESV. By cardiac MRI controls demonstrated significant rise in EF of 3.2% (p = 0.0367rpar; but non-significant fall of only 2.32% (p = 0.812) in LVEDV and 6.47% (p 7equals; 0.508) in LVESV. CONCLUSION: This study shows that intracoronary infusion of ABMSC is safe and feasible after acute MI and shows a favourable trend towards the improvement of LV function and prevention of ventricular remodeling which determines long-term survival.

Effect of phenol on haematological components of Indian major carps Catla catla, Labeo rohita and Cirrhinus mrigala.

The effect of phenol on haematological components of Indian major carps, Catla catla, Labeo rohita and Cirrhinus mrigala were observed. After exposure to sublethal concentrations of 5.17 mg l(-1), 6.06 mg l(-1) and 6.99 mg l(-1), the number of red blood cells, haemoglobin content and packed cell volume all decreased but the glucose level increased. The order of decrease in the haematological components of the three fish is in the order of Catla catla > Labeo rohita > Cirrhinus mrigala.

Effects of ammonia, nitrite and nitrate on hemoglobin content and oxygen consumption of freshwater fish, Cyprinus carpio (Linnaeus).

Lethal effects of nitrogenous compounds ammonia, nitrite and nitrate on freshwater fish Cyprinus carpio were studied and the static LC50 values obtained for these 3 toxicants for 24 hr were 0.80 ppb, 171.36 ppm; 1075.10 ppm and continuous flowthrough LC50 values for 24 hr were 0.72 ppb, 154.31 ppm; 967.63 ppm respectively. The fish were exposed to lethal concentrations to study the changes in hematological parameters and the rate of oxygen consumption. During the period of exposure general decline in the content of hemoglobin was observed. Methemoglobin content increased in case of nitrite exposure consequently the hemoglobin levels decreased drastically. It is also observed that rate of oxygen consumption decreased progressively with the increase of toxicant concentration and duration of the exposure.