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This Guideline, a collaborative effort from the American Thoracic Society, Society of Thoracic Surgeons, and Society of Thoracic Radiology, aims to provide evidence-based recommendations to guide contemporary management of patients with a malignant pleural effusion (MPE). A multidisciplinary panel developed seven questions using the PICO (Population, Intervention, Comparator, and Outcomes) format. The GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach and the Evidence to Decision framework was applied to each question. Recommendations were formulated, discussed, and approved by the entire panel. The panel made weak recommendations in favor of: 1) using ultrasound to guide pleural interventions; 2) not performing pleural interventions in asymptomatic patients with MPE; 3) using either an indwelling pleural catheter (IPC) or chemical pleurodesis in symptomatic patients with MPE and suspected expandable lung; 4) performing large-volume thoracentesis to assess symptomatic response and lung expansion; 5) using either talc poudrage or talc slurry for chemical pleurodesis; 6) using IPC instead of chemical pleurodesis in patients with nonexpandable lung or failed pleurodesis; and 7) treating IPC-associated infections with antibiotics and not removing the catheter. These recommendations, based on the best available evidence, can guide management of patients with MPE and improve patient outcomes.

Metastatic breast cancer remains challenging to treat, and most patients ultimately progress on therapy. This acquired drug resistance is largely due to drug-refractory sub-populations (subclones) within heterogeneous tumors. Here, we track the genetic and phenotypic subclonal evolution of four breast cancers through years of treatment to better understand how breast cancers become drug-resistant. Recurrently appearing post-chemotherapy mutations are rare. However, bulk and single-cell RNA sequencing reveal acquisition of malignant phenotypes after treatment, including enhanced mesenchymal and growth factor signaling, which may promote drug resistance, and decreased antigen presentation and TNF-α signaling, which may enable immune system avoidance. Some of these phenotypes pre-exist in pre-treatment subclones that become dominant after chemotherapy, indicating selection for resistance phenotypes. Post-chemotherapy cancer cells are effectively treated with drugs targeting acquired phenotypes. These findings highlight cancer’s ability to evolve phenotypically and suggest a phenotype-targeted treatment strategy that adapts to cancer as it evolves. In metastatic breast cancer, subclonal evolution can drive drug resistance. Here, the authors genetically and transcriptionally follow the evolution of four breast cancers over time and treatment, and suggest a phenotype-targeted treatment strategy to adapt to cancer as it evolves.

Several randomized trials have compared the efficacy of an indwelling pleural catheter (IPC) versus the more traditional chemical pleurodesis in the management of malignant pleural effusion (MPE). As part of the American Thoracic Society's guidelines for management of MPE, we performed a systematic review and a meta-analysis to compare patient-centered outcomes with the use of a tunneled pleural catheter versus chemical pleurodesis for the first-line treatment of malignant pleural effusions. We performed literature searches in MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials. We included randomized controlled trials comparing IPC and pleurodesis in adult patients with symptomatic MPE. Risk of bias was assessed with the Cochrane Risk of Bias tool recommended by the Cochrane Methods Bias Group. The meta-analysis was performed with Review Manager software, using a random effects model. We used risk ratios (RRs) with 95% confidence interval (CI) as the effect measure for dichotomous outcomes and mean differences for continuous outcomes. We identified five randomized trials, involving 545 patients, that compared IPC and pleurodesis. Lack of blinding and the inevitable attrition of patients due to death resulted in an overall high risk of bias among the studies. No differences in survival or measures of dyspnea were observed in any of the studies. Total hospital length of stay was shorter, and repeat pleural interventions were less common in the IPC group (RR, 0.32; 95% CI, 0.18-0.55). However, the risk of cellulitis was higher with IPC (RR, 5.83; 95% CI, 1.56-21.8). No differences were noted in other adverse events. Compared with chemical pleurodesis, IPC results in shorter hospital length of stay and fewer repeat pleural procedures but carries a higher risk of cellulitis. Careful assessment of individual patient preferences and costs should be considered when choosing between IPC and pleurodesis.

Hydroxychloroquine (HCQ), a drug used to treat lupus and malaria, was proposed as a treatment for SARS-coronavirus-2 (SARS-CoV-2) infection, albeit with controversy. In vitro, HCQ effectively inhibits viral entry, but its use in the clinic has been hampered by conflicting results. A better understanding of HCQ’s mechanism of actions in vitro is needed. Recently, anesthetics were shown to disrupt ordered clusters of monosialotetrahexosylganglioside1 (GM1) lipid. These same lipid clusters recruit the SARS-CoV-2 surface receptor angiotensin converting enzyme 2 (ACE2) to endocytic lipids, away from phosphatidylinositol 4,5 bisphosphate (PIP 2 ) clusters. Here we employed super-resolution imaging of cultured mammalian cells (VeroE6, A549, H1793, and HEK293T) to show HCQ directly perturbs clustering of ACE2 receptor with both endocytic lipids and PIP 2 clusters. In elevated (high) cholesterol, HCQ moves ACE2 nanoscopic distances away from endocytic lipids. In cells with resting (low) cholesterol, ACE2 primarily associates with PIP 2 clusters, and HCQ moves ACE2 away from PIP 2 clusters—erythromycin has a similar effect. We conclude HCQ inhibits viral entry through two distinct mechanisms in high and low tissue cholesterol and does so prior to inhibiting cathepsin-L. HCQ clinical trials and animal studies will need to account for tissue cholesterol levels when evaluating dosing and efficacy. Super-resolution microscopy in cultured cells is employed to dissect the effect of hydroxychloroquine (HCQ) at the plasma membrane and HCQ directly perturbs clustering of the SARS-CoV-2 receptor ACE2 with endocytic lipids and PIP2 clusters.

IntroductionEarly lung cancer screening (LCS) through low-dose CT (LDCT) is crucial but underused due to various barriers, including incomplete or inaccurate patient smoking data in the electronic health record and limited time for shared decision-making. The objective of this trial is to investigate a patient-centred intervention, MyLungHealth, delivered through the patient portal. The intervention is designed to improve LCS rates through increased identification of eligible patients and informed decision-making.Methods and analysisMyLungHealth is a multisite pragmatic trial, involving University of Utah Health and New York University Langone Health primary care clinics. The MyLungHealth intervention was developed using a user-centred design process, informed by patient and provider focus groups and interviews. The intervention’s effectiveness will be evaluated through a patient-randomised trial, comparing the combined use of MyLungHealth and DecisionPrecision+ (a provider-focused shared decision-making intervention) against DecisionPrecision+ alone. The first study hypothesis is that among patients aged 50–79 with uncertain LCS eligibility (eg, 10–19 pack-years or unknown pack-years or unknown quit date for individuals who used to smoke), MyLungHealth eligibility questionnaires will result in increased identification of LCS-eligible patients (n~26 729 patients). The second study hypothesis is that among patients aged 50–79 with documented LCS eligibility (20+ pack-years, quit within the last 15 years if individuals who used to smoke, and no recent screening or screening discussion), MyLungHealth education will result in increased LDCT ordering (n~4574 patients). Primary outcomes will be identification of LCS-eligible patients among individuals with uncertain LCS eligibility and LDCT ordering rates among individuals with documented LCS eligibility.Ethics and disseminationThe protocol was approved by the University of Utah Institutional Review Board (# 00153806). The patient data collected for this study will not be shared publicly due to the sensitive nature of the patient health information and the fact that we will not be obtaining written informed consent to allow public sharing of their data. Results will be disseminated through peer-reviewed publications.Trial registration numberClinicaltrials.gov, NCT06338592.

Because the average survival of patients with MPE is 4 to 7 months (3), treatment should aim to relieve dyspnea in a minimally invasive manner and prevent the need for multiple procedures. The use of ultrasound guidance reduced the risk of pneumothorax after thoracentesis for malignant effusions (1.0% vs. 8.9%; relative risk [RR], 0.10; 95% confidence interval [CI], 0.03-0.37). On the basis of the reduced length of hospital stay and low observed incidence of complications associated with IPCs, as well as abundant clinical experience that chemical pleurodesis is rarely effective in the setting of nonexpandable lung, the panel recommended IPCs over chemical pleurodesis. 3 Porcel JM,GasolA, BielsaS, Civit C, Light RW, Salud A. Clinical features and survival of lung cancer patients with pleural effusions.

The originally published version of this Article contained an error in Figure 4. In panel a, grey boxes surrounding the subclones associated with patients #2 and #4 obscured adjacent portions of the heatmap. This error has now been corrected in both the PDF and HTML versions of the Article.

The objective of this study was to evaluate the antiinflammatory, antiinfective and clinical properties of amniotic membrane (AM) when used for guided tissue regeneration (GTR) in contained interdental defects. A total of 30 subjects participated in this study. Two sites in each subject were randomly assigned into each of the following experimental groups; test group: AM with bone graft and control group: Bone graft only. Clinical parameters included recording site-specific measures of plaque, gingivitis, probing pocket depth (PPD), and clinical attachment loss (CAL). The levels of interleukin-1β (IL-1β) and human beta-defensin-2 (hBD-2) levels in gingival crevicular fluid (GCF) from the test and control sites were measured by using commercially available enzyme linked immunosorbent assay kits. The evaluation of bone fill was performed by using digital subtraction technique and morphometric area analysis. One-way analysis of variance followed by the post-hoc test was used for intragroup and intergroup comparison. A P < 0.05 was considered as statistically significant. Combination therapy using an AM increased bone fill and reduced PPD and CAL when compared to controls. AM also resulted in a significant reduction of GCF IL-1β levels and insignificant increase in the hBD-2 levels. From this trial conducted over a period of 24 weeks, AM demonstrated a marked antiinflammatory effect and its use resulted in an improvement in periodontal parameters. AM has the potential to function as a barrier for GTR and the unique properties associated with this material can augment its potential as a matrix for periodontal regeneration.