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Collagen-I fibrillogenesis is crucial to health and development, where dysregulation is a hallmark of fibroproliferative diseases. Here, we show that collagen-I fibril assembly required a functional endocytic system that recycles collagen-I to assemble new fibrils. Endogenous collagen production was not required for fibrillogenesis if exogenous collagen was available, but the circadian-regulated vacuolar protein sorting (VPS) 33b and collagen-binding integrin α11 subunit were crucial to fibrillogenesis. Cells lacking VPS33B secrete soluble collagen-I protomers but were deficient in fibril formation, thus secretion and assembly are separately controlled. Overexpression of VPS33B led to loss of fibril rhythmicity and overabundance of fibrils, which was mediated through integrin α11β1. Endocytic recycling of collagen-I was enhanced in human fibroblasts isolated from idiopathic pulmonary fibrosis, where VPS33B and integrin α11 subunit were overexpressed at the fibrogenic front; this correlation between VPS33B, integrin α11 subunit, and abnormal collagen deposition was also observed in samples from patients with chronic skin wounds. In conclusion, our study showed that circadian-regulated endocytic recycling is central to homeostatic assembly of collagen fibrils and is disrupted in diseases.

Abstract Honeycombing is a histological pattern consistent with Usual Interstitial Pneumonia (UIP). Honeycombing refers to cystic airways located at sites of dense fibrosis with marked mucus accumulation. Utilizing laser capture microdissection coupled mass spectrometry (LCM-MS), we interrogated the fibrotic honeycomb airway cells and fibrotic uninvolved airway cells (distant from honeycomb airways and morphologically intact) in specimens from 10 patients with UIP. Non-fibrotic airway cell specimens from 6 patients served as controls. Furthermore, we performed LCM-MS on the mucus plugs found in 6 patients with UIP and 6 patients with mucinous adenocarcinoma. The mass spectrometry data were subject to both qualitative and quantitative analysis and validated by immunohistochemistry. Surprisingly, fibrotic uninvolved airway cells share a similar protein profile to honeycomb airway cells, showing deregulation of the slit and roundabout receptor (Slit and Robo) pathway as the strongest category. We find that (BPI) fold-containing family B member 1 (BPIFB1) is the most significantly increased secretome-associated protein in UIP, whereas Mucin-5AC (MUC5AC) is the most significantly increased in mucinous adenocarcinoma. We conclude that fibrotic uninvolved airway cells share pathological features with fibrotic honeycomb airway cells. In addition, fibrotic honeycomb airway cells are enriched in mucin biogenesis proteins with a marked derangement in proteins essential for ciliogenesis. This unbiased spatial proteomic approach generates novel and testable hypotheses to decipher fibrosis progression.

Usual interstitial pneumonia (UIP) is a histological pattern characteristic of idiopathic pulmonary fibrosis (IPF). The UIP pattern is patchy with histologically normal lung adjacent to dense fibrotic tissue. At this interface, fibroblastic foci (FF) are present and are sites where myofibroblasts and extracellular matrix (ECM) accumulate. Utilizing laser capture microdissection-coupled mass spectrometry, we interrogated the FF, adjacent mature scar, and adjacent alveoli in 6 fibrotic (UIP/IPF) specimens plus 6 nonfibrotic alveolar specimens as controls. The data were subjected to qualitative and quantitative analysis and histologically validated. We found that the fibrotic alveoli protein signature is defined by immune deregulation as the strongest category. The fibrotic mature scar classified as end-stage fibrosis whereas the FF contained an overabundance of a distinctive ECM compared with the nonfibrotic control. Furthermore, FF were positive for both TGFB1 and TGFB3, whereas the aberrant basaloid cell lining of FF was predominantly positive for TGFB2. In conclusion, spatial proteomics demonstrated distinct protein compositions in the histologically defined regions of UIP/IPF tissue. These data revealed that FF are the main site of collagen biosynthesis and that the adjacent alveoli are abnormal. This essential information will inform future mechanistic studies on fibrosis progression.

Background: Utilisation of the Endoscopic Vein Harvesting (EVH) technique has been increasing for coronary artery bypass grafting (CABG) for the last two decades. Some surgeons remain concerned about the long-term patency of the long saphenous vein harvested endoscopically compared to traditional Open Vein Harvesting (OVH). The aim of this study was to perform a retrospective analysis of the outcomes between EVH and OVH from three UK centres with 10 years follow-up. Methods: 27,024 patients underwent CABG with long saphenous vein harvested by EVH (n=13,794) or OVH (n=13,230) in three UK centres between 2007 and 2019. Propensity modelling was used to calculate the Inverse Probability of Treatment Weights (IPTW). The primary endpoint was mortality from all causes and secondary endpoints were length of hospital stay, postoperative complications, and incidence of repeat coronary re-vascularisation for symptomatic patients. IPTW was used to balance the two intervention groups for baseline and preoperative co-morbidities. Results: Median follow-up time was 4.54 years for EVH and 6.00 years for OVH. Death from any cause occurred in 13.8% of the EVH group versus 20.8% in the OVH group over the follow-up period. The hazard ratio of death (EVH to OVH) was 0.823 (95% CI: 0.767, 0.884). Length of hospital stay was similar between the groups (p=0.86). Post-operative pulmonary complications were more common in EVH vs OVH (14.7% vs. 12.8%, p

A simple, disposable and low - cost voltammetric sensor based on the anodized pencil graphite electrode (APGE) for the simultaneous determination of dopamine (DA) and uric acid (UA) is demonstrated. The physico-chemical properties of the pencil graphite electrode (PGE) before and after anodization were analyzed using FT-IR, FT-Raman, SEM and EIS characterization techniques. In comparison to PGE, APGE exhibited excellent electrochemical activity towards the simultaneous detection of DA and UA with peak-to-peak separation of about 0.18 V even in the presence of high concentration (2 mM) of ascorbic acid (AA). The discrimination of APGE towards AA was rationalized through the absence of favorable surface interactions between oxygen rich functional groups on the surface of APGE and AA. Using DPV without any pre-concentration step and under optimized conditions, APGE displayed a linear range of 1 – 80 μM with an estimated limit of detection (LOD, 3σ/m) of 0.008 μM and 0.014 μM for DA and UA, respectively. Moreover, a higher sensitivity in comparison to other previously reported pretreated pencil graphite electrodes was observed for DA (34.32 μA/μM) and UA (12.33 μA/μM). The practical applicability of APGE was demonstrated through the estimation of DA in human blood serum and UA in urine samples.

Background A proposed cause of dyspnea induced by ticagrelor is an increase in adenosine blood levels. Because caffeine is an adenosine antagonist, it can potentially improve drug tolerability with regard to dyspnea. Furthermore, association between caffeine and cardiovascular events is of clinical interest. Methods and Results This prespecified analysis used data from the PEGASUS TIMI 54 (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin–Thrombolysis in Myocardial Infarction 54) trial, which randomized 21 162 patients with prior myocardial infarction to ticagrelor 60 mg or 90 mg or matching placebo (twice daily). Baseline caffeine intake in cups per week was prospectively collected for 9694 patients. Outcomes of interest included dyspnea, major adverse cardiovascular events (ie, the composite of cardiovascular death, myocardial infarction, or stroke), and arrhythmias. Dyspnea analyses considered the pooled ticagrelor group, whereas cardiovascular outcome analyses included patients from the 3 randomized arms. After adjustment, caffeine intake, compared with no intake, was not associated with lower rates of dyspnea in patients taking ticagrelor (adjusted hazard ratio (HR), 0.91; 95% CI, 0.76–1.10; P=0.34). There was no excess risk with caffeine for major adverse cardiovascular events (adjusted HR, 0.78; 95% CI, 0.63–0.98; P=0.031), sudden cardiac death (adjusted HR, 0.98; 95% CI, 0.57–1.70; P=0.95), or atrial fibrillation (adjusted odds ratio, 1.07; 95% CI, 0.56–2.04; P=0.84). Conclusions In patients taking ticagrelor for secondary prevention after myocardial infarction, caffeine intake at baseline was not associated with lower rates of dyspnea compared with no intake. Otherwise, caffeine appeared to be safe in this population, with no apparent increase in atherothrombotic events or clinically significant arrhythmias. Registration URL: https://www.clini​caltr​ials.gov; Unique identifier: NCT01225562.

Osteomyelitis complicates 20% of patients with infected diabetic foot ulcers. In this study, 2 strategies for treating pedal osteomyelitis were compared in a pilot study. This was a retrospective, non-randomized, single center 2 arm cohort study, conducted between 2020 and 2022 involving 53 patients at a tertiary limb salvage unit. All patients were managed with debridement and proximal bone biopsy. Group A was treated with systemic antibiotics for up to 6 weeks. Group B had vancomycin or gentamycin eluting bone void filler implanted into the diseased bone medullary cavity(s) and 1 week of oral antibiotics. Patients were followed independently for the primary endpoint of osteomyelitis treatment failure and secondary endpoints of amputation free survival, wound healing, minor amputation, and treatment-limiting side-effects. Survival analysis demonstrated no significant difference in treatment failure (p = .35) or amputation free survival (p = .46). Limb salvage rates were 88% in Group A and 89% in Group B. Wounds healed in 85% in Group A and 89% in Group B. Minor amputations occurred in 21% in Group A and 11% in Group B. Treatment limiting side effects occurred in 6% in Group A and were absent in Group B. In conclusion, the use of antibiotic eluting bone void filler appeared safe without extended systemic antibiotics in this study. Group B had fewer intravenous lines, requirement for home nursing, and treatment limiting side effects. A larger randomized controlled trial examining longer term clinical and radiological efficacy, treatment costs and side effects is warranted., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Venous thromboembolism (VTE) is a significant contributor to morbidity and mortality, with large disparities in incidence rates between Black and White Americans. Polygenic risk scores (PRSs) limited to variants discovered in genome-wide association studies in European-ancestry samples can identify European-ancestry individuals at high risk of VTE. However, there is limited evidence on whether high-dimensional PRS constructed using more sophisticated methods and more diverse training data can enhance the predictive ability and their utility across diverse populations. We developed PRSs for VTE using summary statistics from the International Network against Venous Thrombosis (INVENT) consortium genome-wide association studies meta-analyses of European- (71 771 cases and 1 059 740 controls) and African-ancestry samples (7482 cases and 129 975 controls). We used LDpred2 and PRS-CSx to construct ancestry-specific and multi-ancestry PRSs and evaluated their performance in an independent European- (6781 cases and 103 016 controls) and African-ancestry sample (1385 cases and 12 569 controls). Multi-ancestry PRSs with weights tuned in European-ancestry samples slightly outperformed ancestry-specific PRSs in European-ancestry test samples (e.g. the area under the receiver operating curve [AUC] was 0.609 for PRS-CSx_combinedEUR and 0.608 for PRS-CSxEUR [P = 0.00029]). Multi-ancestry PRSs with weights tuned in African-ancestry samples also outperformed ancestry-specific PRSs in African-ancestry test samples (PRS-CSxAFR: AUC = 0.58, PRS-CSx_combined AFR: AUC = 0.59), although this difference was not statistically significant (P = 0.34). The highest fifth percentile of the best-performing PRS was associated with 1.9-fold and 1.68-fold increased risk for VTE among European- and African-ancestry subjects, respectively, relative to those in the middle stratum. These findings suggest that the multi-ancestry PRS might be used to improve performance across diverse populations to identify individuals at highest risk for VTE., (© The Author(s) 2024. Published by Oxford University Press.)

Background: The management of pain after shoulder surgery typically includes the use of cryotherapy and the prescription of opioid analgesics. Much focus has been placed lately on the opioid epidemic, which in part is fueled by excessive prescription of opioid medication. Previous studies have found a combination of cryotherapy and compression effective at reducing analgesic consumption and increasing recovery in patients undergoing knee and spine surgery; however, efficacy in patients undergoing shoulder surgery has not been evaluated., Purpose: To evaluate the effectiveness of a cryo-pneumatic compression device on postoperative shoulder pain, narcotic use, and quality of life when compared with standard care cryotherapy., Study Design: Randomized controlled trial; Level of evidence, 2., Methods: In total, 200 patients older than 18 years scheduled for unilateral shoulder surgery were enrolled. Patients were randomized to receive either postoperative cryo-pneumatic compression or standard care. The intervention group received a cryo-pneumatic device, while the standard care group received the treating surgeon's preferred method of postoperative care, including standard cryotherapy. Narcotic use was evaluated by the number of oral morphine milligram equivalents consumed during the postoperative period, as well as the time to cessation of narcotic use. Patient-reported outcome measures consisted of a numeric rating scale pain score, 36-item Short Form Survey, patient experience assessed using the net promoter score, and adverse events. Outcomes were evaluated at 2, 6, and 12 weeks postoperatively., Results: Patients receiving cryo-pneumatic compression reported a significant decrease in opioid consumption when compared with standard care (oral morphine milligram equivalents median, 56.1 vs 112; P = .02468). A significant increase in self-reported function was seen in the cryo-pneumatic compression group at 2 weeks when compared with standard care (mean, 61.2 vs 54.2; P = .0412)., Conclusion: In patients undergoing unilateral shoulder surgery, the use of cryotherapy with pneumatic compression, when compared with standard care, resulted in significantly decreased opioid consumption as well as increased function at 2 weeks., Registration: NCT04185064 (ClinicalTrials.gov identifier)., Competing Interests: The authors declared that they have no conflicts of interest in the authorship and publication of this contribution. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto.

An essential adaptive strategy in insects is the evolution of olfactory receptors (ORs) to recognize important volatile environmental chemical cues. Our model species, Ceratosolen fusciceps, a specialist wasp pollinator of Ficus racemosa, likely possesses an OR repertoire that allows it to distinguish fig-specific volatiles in highly variable environments. Using a newly assembled genome-guided transcriptome, we annotated 63 ORs in the species and reconstructed the phylogeny of Ceratosolen ORs in conjunction with other hymenopteran species. Expression analysis showed that though ORs were mainly expressed in the female antennae, 20% were also expressed in nonantennal tissues such as the head, thorax, abdomen, legs, wings, and ovipositor. Specific upregulated expression was observed in OR30C in the head and OR60C in the wings. We identified OR expression from all major body parts of female C. fusciceps, suggesting novel roles of ORs throughout the body. Further examination of the OR expression of C. fusciceps in widely separated geographical locations, that is, South (urban) and Northeast (rural) India, revealed distinct OR expression levels in different locations. This discrepancy likely parallels the observed variation in fig volatiles between these regions and provides new insights into the evolution of insect ORs and their expression across geographical locations and tissues., (© 2024 Institute of Zoology, Chinese Academy of Sciences.)

Polygenic scores (PGSs) summarize the combined effect of common risk variants and are associated with breast cancer risk in patients without identifiable monogenic risk factors. One of the most well-validated PGSs in breast cancer to date is PGS 313 , which was developed from a Northern European biobank but has shown attenuated performance in non-European ancestries. We further investigate the generalizability of the PGS 313 for American women of European (EA), African (AFR), Asian (EAA), and Latinx (HL) ancestry within one institution with a singular electronic health record (EHR) system, genotyping platform, and quality control process. We found that the PGS 313 achieved overlapping areas under the receiver operator characteristic (ROC) curve (AUCs) in females of HL (AUC = 0.68, 95% confidence interval [CI] = 0.65-0.71) and EA ancestry (AUC = 0.70, 95% CI = 0.69-0.71) but lower AUCs for the AFR and EAA populations (AFR: AUC = 0.61, 95% CI = 0.56-0.65; EAA: AUC = 0.64, 95% CI = 0.60-0.680). While PGS 313 is associated with hormone-receptor-positive (HR+) disease in EA Americans (odds ratio [OR] = 1.42, 95% CI = 1.16-1.64), this association is lost in African, Latinx, and Asian Americans. In summary, we found that PGS 313 was significantly associated with breast cancer but with attenuated accuracy in women of AFR and EAA descent within a singular health system in Los Angeles. Our work further highlights the need for additional validation in diverse cohorts prior to the clinical implementation of PGSs., Competing Interests: Declaration of interests The authors declare no competing interests., (Published by Elsevier Inc.)

Tobacco use is a major risk factor for many diseases and is heavily influenced by environmental factors with significant underlying genetic contributions. Here, we evaluated the predictive performance, risk stratification, and potential systemic health effects of tobacco use disorder (TUD) predisposing germline variants using a European- ancestry-derived polygenic score (PGS) in 24,202 participants from the multi-ancestry, hospital-based UCLA ATLAS biobank. Among genetically inferred ancestry groups (GIAs), TUD-PGS was significantly associated with TUD in European American (EA) (OR: 1.20, CI: [1.16, 1.24]), Hispanic/Latin American (HL) (OR:1.19, CI: [1.11, 1.28]), and East Asian American (EAA) (OR: 1.18, CI: [1.06, 1.31]) GIAs but not in African American (AA) GIA (OR: 1.04, CI: [0.93, 1.17]). Similarly, TUD-PGS offered strong risk stratification across PGS quantiles in EA and HL GIAs and inconsistently in EAA and AA GIAs. In a cross-ancestry phenome-wide association meta-analysis, TUD-PGS was associated with cardiometabolic, respiratory, and psychiatric phecodes (17 phecodes at P < 2.7E-05). In individuals with no history of smoking, the top TUD-PGS associations with obesity and alcohol-related disorders (P = 3.54E-07, 1.61E-06) persist. Mendelian Randomization (MR) analysis provides evidence of a causal association between adiposity measures and tobacco use. Inconsistent predictive performance of the TUD-PGS across GIAs motivates the inclusion of multiple ancestry populations at all levels of genetic research of tobacco use for equitable clinical translation of TUD-PGS. Phenome associations suggest that TUD-predisposed individuals may require comprehensive tobacco use prevention and management approaches to address underlying addictive tendencies., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Insects are a diverse group of organisms that provide important ecosystem services like pollination, pest control, and decomposition and rely on olfaction to perform these services. In the Anthropocene, increasing concentrations of oxidant pollutants such as ozone have been shown to corrupt odor-driven behavior in insects by chemically degrading e.g. flower signals or insect pheromones. The degradation, however, does not only result in a loss of signals, but also in a potential enrichment of oxidation products, predominantly small carbonyls. Whether and how these oxidation products affect insect olfactory perception remains unclear. We examined the effects of ozone-generated small carbonyls on the olfactory behavior of the vinegar fly Drosophila melanogaster. We compiled a broad collection of neurophysiologically relevant odorants for the fly from databases and literature and predicted the formation of the types of stable small carbonyl products resulting from the odorant's oxidation by ozone. Based on these predictions, we evaluated the olfactory detection and behavioral impact of the ten most frequently predicted carbonyl products in the fly using single sensillum recordings (SSRs) and behavioral tests. Our results demonstrate that the fly's olfactory system can detect the oxidation products, which then elicit either attractive or neutral behavioral responses, rather than repulsion. However, certain products alter behavioral choices to an attractive odor source of balsamic vinegar. Our findings suggest that the enrichment of small carbonyl oxidation products due to increased ozone levels can affect olfactory guided insect behavior. Our study underscores the implications for odor-guided foraging in insects and the essential ecosystem services they offer under carbonyl enriched environments., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

Background: Bilirubin is a potent antioxidant with a protective role in many diseases. We examined the relationships between serum bilirubin (SB) levels, tobacco smoking (a known cause of low SB), and aerodigestive cancers, grouped as lung cancers (LC) and head and neck cancers (HNC)., Methods: We examined the associations between SB, LC, and HNC using data from 393,210 participants from a real-world, diverse, de-identified data repository and biobank linked to the UCLA Health system. We employed regression models, propensity score matching, and polygenic scores to investigate the associations and interactions between SB, tobacco smoking, LC, and HNC., Results: Current tobacco smokers showed lower SB (-0.04mg/dL, 95% CI: [-0.04, -0.03]), compared to never-smokers. Lower SB levels were observed in HNC and LC cases (-0.10 mg/dL, [-0.13, -0.09] and - 0.09 mg/dL, CI [-0.1, -0.07] respectively) compared to cancer-free controls with the effect persisting after adjusting for smoking. SB levels were inversely associated with HNC and LC risk (ORs per SD change in SB: 0.64, CI [0.59,0.69] and 0.57, CI [0.43,0.75], respectively). Lastly, a polygenic score (PGS) for SB was associated with LC (OR per SD change of SB-PGS: 0.71, CI [0.67, 0.76])., Conclusions: Low SB levels are associated with an increased risk of both HNC and LC, independent of the effect of tobacco smoking. Additionally, tobacco smoking demonstrated a strong interaction with SB on LC risk. Lastly, genetically predicted low SB (using a polygenic score) is negatively associated with LC. These findings suggest that SB could serve as a potential early and low-cost biomarker for LC and HNC. The interaction with tobacco smoking suggests that smokers with lower bilirubin could likely be at higher risk for LC compared to never smokers, suggesting the utility of SB in risk stratification for patients at risk for LC. Lastly, the results of the polygenic score analyses suggest potential shared biological pathways between the genetic control of SB and the risk of LC development., Competing Interests: Competing interests The authors declare that they have no competing interests

Purpose: Latent grade group ≥2 prostate cancer can impact the performance of active surveillance protocols. To date, molecular biomarkers for active surveillance have relied solely on RNA or protein. We trained and independently validated multimodal (mRNA abundance, DNA methylation, and/or DNA copy number) biomarkers that more accurately separate grade group 1 from grade group ≥2 cancers., Materials and Methods: Low- and intermediate-risk prostate cancer patients were assigned to training (n=333) and validation (n=202) cohorts. We profiled the abundance of 342 mRNAs, 100 DNA copy number alteration loci, and 14 hypermethylation sites at 2 locations per tumor. Using the training cohort with cross-validation, we evaluated methods for training classifiers of pathological grade group ≥2 in centrally reviewed radical prostatectomies. We trained 2 distinct classifiers, PRONTO-e and PRONTO-m, and validated them in an independent radical prostatectomy cohort., Results: PRONTO-e comprises 353 mRNA and copy number alteration features. PRONTO-m includes 94 clinical, mRNAs, copy number alterations, and methylation features at 14 and 12 loci, respectively. In independent validation, PRONTO-e and PRONTO-m predicted grade group ≥2 with respective true-positive rates of 0.81 and 0.76, and false-positive rates of 0.43 and 0.26. Both classifiers were resistant to sampling error and identified more upgrading cases than a well-validated presurgical risk calculator, CAPRA (Cancer of the Prostate Risk Assessment; P < .001)., Conclusions: Two grade group classifiers with superior accuracy were developed by incorporating RNA and DNA features and validated in an independent cohort. Upon further validation in biopsy samples, classifiers with these performance characteristics could refine selection of men for active surveillance, extending their treatment-free survival and intervals between surveillance.

How to cite this article: Venkateswaran V, Soni KD, Trikha A. "There is No Easy Way to Say This…": Communication Challenges in the COVID-19 Intensive Care Unit. Indian J Crit Care Med 2023;27(1):79-81., Competing Interests: Source of support: Nil Conflict of interest: None, (Copyright © 2023; The Author(s).)

Background: Large medical centers in urban areas, like Los Angeles, care for a diverse patient population and offer the potential to study the interplay between genetic ancestry and social determinants of health. Here, we explore the implications of genetic ancestry within the University of California, Los Angeles (UCLA) ATLAS Community Health Initiative-an ancestrally diverse biobank of genomic data linked with de-identified electronic health records (EHRs) of UCLA Health patients (N=36,736)., Methods: We quantify the extensive continental and subcontinental genetic diversity within the ATLAS data through principal component analysis, identity-by-descent, and genetic admixture. We assess the relationship between genetically inferred ancestry (GIA) and >1500 EHR-derived phenotypes (phecodes). Finally, we demonstrate the utility of genetic data linked with EHR to perform ancestry-specific and multi-ancestry genome and phenome-wide scans across a broad set of disease phenotypes., Results: We identify 5 continental-scale GIA clusters including European American (EA), African American (AA), Hispanic Latino American (HL), South Asian American (SAA) and East Asian American (EAA) individuals and 7 subcontinental GIA clusters within the EAA GIA corresponding to Chinese American, Vietnamese American, and Japanese American individuals. Although we broadly find that self-identified race/ethnicity (SIRE) is highly correlated with GIA, we still observe marked differences between the two, emphasizing that the populations defined by these two criteria are not analogous. We find a total of 259 significant associations between continental GIA and phecodes even after accounting for individuals' SIRE, demonstrating that for some phenotypes, GIA provides information not already captured by SIRE. GWAS identifies significant associations for liver disease in the 22q13.31 locus across the HL and EAA GIA groups (HL p-value=2.32×10 -16 , EAA p-value=6.73×10 -11 ). A subsequent PheWAS at the top SNP reveals significant associations with neurologic and neoplastic phenotypes specifically within the HL GIA group., Conclusions: Overall, our results explore the interplay between SIRE and GIA within a disease context and underscore the utility of studying the genomes of diverse individuals through biobank-scale genotyping linked with EHR-based phenotyping., (© 2022. The Author(s).)

Background and Aims: There is a marked inclination towards cesarean sections as the preferred mode of delivery in parturients with COVID-19 disease. However, the challenges associated with planning and performing a surgery in the COVID-19 setup are considerable. These factors may lead to widespread changes in obstetric decision-making, operative planning, and perioperative outcomes. Thus, our study aimed to study the clinical and logistical factors involved in cesarean sections in COVID-19 parturients., Material and Methods: This was a retrospective observational study performed at a dedicated COVID-19 tertiary care center in India. All women undergoing cesarean section in the specially earmarked operating room between 1 st May 2020 and 31 st December 2020 were included in the study. The clinical characteristics, operative details, and neonatal details, along with maternal and fetal outcomes were noted and analyzed., Results: A total of 44 women underwent cesarean section during the study period, with elective and emergency surgeries numbering 22 each. No indication, apart from COVID-19 status, was listed in over one-fourth of the women (13/44). The most common preoperative comorbidity was hypothyroidism (12/44). Median surgical duration was 117.5 min (IQR 100-133), with a median of 7.5 (IQR 6-8.25) healthcare personnel in the OT. Over one-fourth (12/44) of the delivered babies had low birth weight, while 4.5% (2/44) tested positive for SARS-CoV-2., Conclusion: COVID-19 status alone continues to be a common indication for cesarean section. Operative time is increased, but the number of healthcare personnel involved can be trimmed with proper planning. Maternal and fetal outcomes are largely positive, with low transmission rates, but a considerable proportion of low-birth-weight neonates., Competing Interests: There are no conflicts of interest., (Copyright: © 2022 Journal of Anaesthesiology Clinical Pharmacology.)

Introduction: Alveolar arterial (A-a) oxygen gradient and respiratory index can be of immense help for the critical care physician in clinical decision making. This study aimed to evaluate the potential application of A-a oxygen gradient and respiratory index in predicting the survival of COVID-19 patients in intensive care unit (ICU)., Method: This is a retrospective cross-sectional study involving 215 adult patients with COVID-19 disease, admitted to the ICU between 1 st April 2020 and 30 June 2021. Details regarding demographic variables, comorbidities, laboratory and arterial blood gas (ABG) findings were recorded. Alveolar-arterial gradient and respiratory index were calculated and tested as predictors of survival., Result: The mean age of the patients was 51.92 years (65.6 % male). Hypertension was the most common comorbidity and oxygen via non-rebreathing mask was the most common modality used at the time of ICU admission. Mortality was 28.37% and average length of stay was 12.84 days. Patients who died were older (p=0.02), mostly male (p=0.017), had at least one comorbidity (p<0.001), and higher heart rate and respiratory rate (<0.001 and p=0.03, respectively), lower pH on arterial blood gas (ABG) (p=0.002), higher FiO2 requirement (p<0.001), and increased A-a oxygen gradient on admission compared to survivors. According to receiver operating characteristic (ROC) curve analysis, A-a oxygen gradient and respiratory index were not sensitive or specific in predicting mortality in the studied patient subset., Conclusion: A-a oxygen gradient and respiratory index calculated at time of admission to ICU in patients with COVID-19 were poor predictors of survival., Competing Interests: None.

Insects detect volatile chemicals using antennae, which house a vast variety of olfactory sensory neurons (OSNs) that innervate hair-like structures called sensilla where odor detection takes place. In addition to OSNs, the antenna also hosts various support cell types. These include the triad of trichogen, tormogen, and thecogen support cells that lie adjacent to their respective OSNs. The arrangement of OSN supporting cells occurs stereotypically for all sensilla and is widely conserved in evolution. While insect chemosensory neurons have received considerable attention, little is known about the functional significance of the cells that support them. For instance, it remains unknown whether support cells play an active role in odor detection, or only passively contribute to homeostasis, e.g., by maintaining sensillum lymph composition. To investigate the functional interaction between OSNs and support cells, we used optical and electrophysiological approaches in Drosophila . First, we characterized the distribution of various supporting cells using genetic markers. By means of an ex vivo antennal preparation and genetically-encoded Ca 2+ and K + indicators, we then studied the activation of these auxiliary cells during odor presentation in adult flies. We observed acute responses and distinct differences in Ca 2+ and K + fluxes between support cell types. Finally, we observed alterations in OSN responses upon thecogen cell ablation in mature adults. Upon inducible ablation of thecogen cells, we notice a gain in mechanical responsiveness to mechanical stimulations during single-sensillum recording, but a lack of change to the neuronal resting activity. Taken together, these results demonstrate that support cells play a more active and responsive role during odor processing than previously thought. Our observations thus reveal that support cells functionally interact with OSNs and may be important for the extraordinary ability of insect olfactory systems to dynamically and sensitively discriminate between odors in the turbulent sensory landscape of insect flight., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Prelic, Pal Mahadevan, Venkateswaran, Lavista-Llanos, Hansson and Wicher.)

Background: There is increased incidence of barotrauma in COVID-19 patients, probably due to disease pathology, oxygen therapy and coughing. We aimed to retrospectively compare the characteristics, associations and outcomes of COVID-19 patients with and without barotrauma in the intensive care unit (ICU)., Methods: All adults admitted between October 1st and December 31st 2020 in the ICUs of a COVID-19 hospital were retrospectively analysed for presence of a 'barotrauma event' (presence of at least one of pneumothorax, pneumomediastinum, subcutaneous emphysema or bronchopleural fistula). A control group was formed by matching each case to a patient belonging to the same gender and age range from the remaining patients in the cohort, i.e., those without barotrauma. Demographic details, ICU stay details, details of oxygen therapy and ventilation, and outcomes were noted and compared., Results: Of 827 patients, 30 patients (3.6%) developed barotrauma events. The typical patient was middle aged (median age 55.5 years) and male (73.3%). The mortality rate was significantly higher in the barotrauma group (83.3% vs. 43.3%, P < 0.001), and odds of survival decreased by 85% if barotrauma occurred (OR 0.15; 95% CI: 0.46-0.51). Patients who developed barotrauma spent a longer time on a high-flow nasal cannula (median 6.7 vs. 1.73 days, P = 0.04), and mechanical ventilation (median 9.54 vs. 0.867 days, P < 0.001), and had a longer ICU stay (median 15.5 vs. 9 days, P = 0.014). The most common event was pneumothorax (26/30)., Conclusions: Barotrauma in the COVID-19 ICU is associated with prolonged ICU stay, higher odds of mortality and longer duration spent on mechanical ventilation and a high-flow nasal cannula. Key words: barotrauma, ICU, COVID-19, mortality, pneumothorax.

Trikha A, Venkateswaran V, Soni KD. Extracorporeal Membrane Oxygenation in COVID-19 Patients: More Hype than Substance? Indian J Crit Care Med 2021;25(11):1322-1323., Competing Interests: Source of support: Nil Conflict of interest: None, (Copyright © 2021; Jaypee Brothers Medical Publishers (P) Ltd.)

How to cite this article: Venkateswaran V, Chaturvedi A, Soni KD, Aggarwal R, Trikha A. Bronchopleural Fistula after High-flow Nasal Cannula Use in Patient with COVID-19. Indian J Crit Care Med 2021;25(7):830-831., Competing Interests: Source of support: Nil Conflict of interest: None, (Copyright © 2021; Jaypee Brothers Medical Publishers (P) Ltd.)

Background and Objective: A large number of studies describing the clinicoepidemiological features of coronavirus disease-2019 (COVID-19) patients are available but very few studies have documented similar features of the deceased. This study was aimed to describe the clinicoepidemiological features and the causes of mortality of COVID-19 deceased patients admitted in a dedicated COVID center in India., Methodology: This was a retrospective study done in adult deceased patients admitted in COVID ICU from April 4 to July 24, 2020. The clinical features, comorbidities, complications, and causes of mortality in these patients were analyzed. Pediatric deceased were analyzed separately., Results: A total of 654 adult patients were admitted in the ICU during the study period and ICU mortality was 37.7% (247/654). Among the adult deceased, 65.9% were males with a median age of 56 years [interquartile range (IQR), 41.5-65] and 94.74% had one or more comorbidities, most common being hypertension (43.3%), diabetes mellitus (34.8%), and chronic kidney disease (20.6%). The most common presenting features in these deceased were fever (75.7%), cough (68.8%), and shortness of breath (67.6%). The mean initial sequential organ failure assessment score was 9.3 ± 4.7 and 24.2% were already intubated at the time of admission. The median duration of hospital stay was 6 days (IQR, 3-11). The most common cause of death was sepsis with multi-organ failure (55.1%) followed by severe acute respiratory distress syndrome (ARDS) (25.5%). All pediatric deceased had comorbid conditions and the most common cause of death in this group was severe ARDS., Conclusion: In this cohort of adult deceased, most were young males with age less than 65 years with one or more comorbidities, hypertension being the most common. Only 5% of the deceased had no comorbidities. Sepsis with multi-organ dysfunction syndrome was the most common cause of death., How to Cite This Article: Aggarwal R, Bhatia R, Kulshrestha K, Soni KD, Viswanath R, Singh AK, et al. Clinicoepidemiological Features and Mortality Analysis of Deceased Patients with COVID-19 in a Tertiary Care Center. Indian J Crit Care Med 2021; 25(6):622-628., Competing Interests: Source of support: Nil Conflict of interest: None, (Copyright © 2021; Jaypee Brothers Medical Publishers (P) Ltd.)

Anti-glomerular basement membrane (anti-GBM) disease is a rare autoimmune disease affecting the kidneys and lungs. COVID-19 infection in a patient with pre-existing anti-GBM disease presents a unique set of clinical challenges. The formulation of a judicious treatment plan balancing both disease processes is tricky, especially with regard to anticoagulation. We present the case of a young patient with anti-GBM disease who acquired COVID-19 infection and eventually succumbed to his illness., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Venkateswaran et al.)

Metacommunity membership is influenced by habitat availability and trophic requirements. However, for multitrophic horizontally transmitted symbiont communities that are closely associated with hosts, symbiont-host interactions may affect membership criteria in novel ways. For example, failure of beneficial services from symbionts could influence the host, and in turn, the entire community. Understanding such host-symbiont feedback effects on symbiont community membership, symbiont community structure, and function is important for understanding if host-symbiont communities are fundamentally different from more traditional ecological communities. We investigate the membership criteria for a multitrophic insect symbiont community that colonizes host inflorescences at specific developmental stages termed colonization windows. The inflorescences serve as microcosm habitats. Symbionts exhibit a range of interactions from mutualism to parasitism. Hosts exhibit feedback by aborting inflorescences not pollinated by mutualistic symbionts. Habitats are consequently lost for all other symbiont species in such host-derived organs whose development is mutualist-dependent. Using empirical measurements to characterize inflorescence development, we simulate symbiont dispersal colonization across hosts. We vary host densities and lengths of symbiont colonization windows, and track the persistence of each symbiont species in the metacommunity based on its trophic requirements and resource availability within the microcosm. Since the persistence of the microcosm habitat is dictated by pollination performed by the mutualist, the mutualist fared better than all other symbionts. The length of symbiont colonization windows was positively related with colonization success and symbiont persistence. The cumulative length of the colonization windows of prey dictated predator success; diet breadth or prey colonization success did not influence predator persistence. Predators also had a greater host-plant density requirement than prey for persistence in the community. These results offer valuable insights into host densities required for maintaining symbionts, and have implications for multitrophic symbiont community stability. Special constraints can govern symbiont community membership, function and structure and symbiont persistence when host-symbiont feedback impacts host microcosm development., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: There is a lack of evidence regarding the success of ulnar collateral ligament (UCL) revision reconstruction. Understanding outcomes after UCL revision reconstruction is important in clinical decision making for overhead athletes., Purpose: To evaluate return to play and patient-reported outcomes after UCL revision reconstruction., Study Design: Case series; Level of evidence, 4., Methods: All patients who underwent UCL revision reconstruction, attributed to retear of the ligament or pain, between June 2004 and July 2016 at 2 surgical centers were identified. Charts were reviewed for age, sex, date of primary and revision reconstruction, sport played, level of play, graft type, and complications. Patients were contacted by telephone to determine time to return to play, current level of participation, Conway score, Kerlan-Jobe Orthopaedic Clinic (KJOC) Shoulder and Elbow Score, and satisfaction., Results: Of the 65 consecutive baseball players who underwent revision UCL reconstruction, 40 (62%) were contacted at a minimum 22 months after surgery. Of these, 38 (95%) were pitchers and 2 (5%) were position players. Time to return to throwing was 6.2 ± 2.3 months (mean ± SD), and the KJOC score was 74.2 ± 20.7. Based on the Conway score, 50% (20/40) had an excellent result, indicating a return to the previous competition level for at least 1 year, and 30% (12/40) had a good result, indicating a return to a lower level for at least 1 year. For those who were able to return to competition, it took 12.7 ± 3.6 months. In pitchers, 47% (18/38) returned to their previous competition levels for at least 1 year, with a KJOC score of 73.7 ± 21.1. Pitchers were able to return to throwing at 6.3 ± 2.3 months and competition at 12.8 ± 3.7 months., Conclusion: Only half of baseball players undergoing UCL revision reconstruction were able to return to their previous levels of competition. Outcomes for revision reconstructions are not as promising as primary procedures. Baseball players should be cautioned that they may not return to their previous levels of play after a revision reconstruction.

Background: Gleason grade is among the most powerful clinicopathological classification systems used to assess risk of lethal potential in prostate cancer, yet its biologic basis is poorly understood. Notably, pure low-grade cancers, comprised predominantly of Gleason pattern 3 (G3) are typically indolent, with lethal potential emerging with the progression of higher-grade Gleason patterns 4 (G4) or 5. One of the hallmarks of more aggressive cancer phenotypes is the stereotyped set of metabolic characteristics that transformed cells acquire to facilitate unregulated growth. In the present study, we profiled expression signatures of metabolic genes that are differentially expressed between G3 and G4 cancer foci and investigated the functional role of two of the profiled genes, PGRMC1 and HSD17B4, in prostate cancer cells., Methods: Gene expression profiling was conducted using 32 G3 and 32 G4 cancer foci from patients with 3+3 and ≥4+3 tumors, respectively. A 95-gene Nanostring probe set was used to probe genes associated with energy metabolism. Two out of five genes (PGRMC1 and HSD17B4) that significantly distinguish between G3 and G4 were functionally validated in vitro using established prostate cancer cells (PC3, DU145). Expression of PGRMC1 and HSD17B4 was knocked down and subsequent studies were performed to analyze cell proliferation, migration, invasion, and apoptosis. Mechanistic studies that explored the epidermal growth factor receptor (EGFR) pathway were performed by Western blot., Results: Multivariate analysis identified five metabolic genes that were differentially expressed between G3 and G4 stroma (P < .05). Functional validation studies revealed that knockdown of PGRMC1 and HSD17B4 significantly decreased cell proliferation, migration, and invasion, and increased apoptosis in PC3 and DU145 cells. Mechanistic studies showed that these effects, after PGRMC1 knockdown, were possibly mediated through alterations in downstream components of the EGFR, protein kinase B, and nuclear factor kappa-light-chain-enhancer of activated B cells pathways., Conclusion: The following study provides evidence supporting the use of metabolic genes PGRMC1 and HSD17B4 as a prognostic biomarker for the distinction between G3 and G4 prostate cancers., (© 2019 Wiley Periodicals, Inc.)

Optofluidic nano/microsystems have advanced the realization of Boolean circuits, with drastic progression to achieve extensive scale integration of desirable optoelectronics to investigate multiple logic switches. In this context, we demonstrate the optofluidic logic operations with interfacial piezophototronic effect to promote multiple operations of electronic analogues. We report an optofluidic Y-channeled logic device with tunable metal-semiconductor-metal interfaces through mechanically induced strain elements. We investigate the configuration of an OR gate in a semiconductor-piezoelectric zinc oxide nanorod-manipulated optofluidic sensor, and its direct reconfiguration to logic AND through compressive strain-induced (-1%) piezoelectric negative polarizations. The exhibited strategy in optofluidic systems implemented with piezophototronic concept enables direct-on chip working of OR and AND logic with switchable photocurrent under identical analyte. Featured smart intrinsic switching between the Boolean optoelectronic gates (OR↔AND) ultimately reduces the need for cascaded logic circuits to operate multiple logic switches on-a-chip.

Airway management remains a challenge in children, and the presence of a cleft palate further complicates the scenario. Endotracheal intubation, although definitive and most preferred, may be avoided for certain short-duration procedures wherein the use of laryngeal mask airway can allow quicker emergence. We present the successful airway management of 2 pediatric patients with cleft palate undergoing ophthalmological surgery, using AMBU® LMA® as the airway device of choice, which was further used as a rescue airway device in an emergent situation of "difficult to ventilate."

Background: Cannabinoids have demonstrated anticarcinogenic properties in a variety of malignancies, including in prostate cancer. In the present study, we explored the anti-cancer effects of the synthetic cannabinoid WIN 55,212-2 (WIN) in prostate cancer., Methods: Established prostate cancer cells (PC3, DU145, LNCaP) were treated with varying concentrations of WIN. Cell proliferation was determined by the MTS assay. The anti-migration and anti-invasive potential of WIN was examined by the wound healing assay and the matrigel invasion assay. Cell cycle analysis was performed by flow cytometry, and mechanistic studies were performed by Western blot. Athymic mice (n = 10) were inoculated with human PC3 cells. Once tumors reached 100 mm 3 , animals were randomized into two groups: saline control and WIN (5 mg/kg), delivered by intraperitoneal injection three times per week for 3 weeks., Results: WIN significantly reduced prostate cancer cell proliferation, migration, invasion, induced apoptosis, and arrested cells in Go/G1 phase in a dose-dependent manner. Mechanistic studies revealed these effects were mediated through a pathway involving cell cycle regulators p27, Cdk4, and pRb. Pre-treatment with a CB 2 antagonist, AM630, followed by treatment with WIN resulted in a reversal of the anti-proliferation and cell cycle arrest previously seen with WIN alone. In vivo, administration of WIN resulted in a reduction in the tumor growth rate compared to control (P < 0.05)., Conclusions: The following study provides evidence supporting the use of WIN as a novel therapeutic for prostate cancer., (© 2018 Wiley Periodicals, Inc.)

Background/aim: Desmopressin is a synthetic analogue of the antidiuretic hormone vasopressin. It has recently been demonstrated to inhibit tumor progression and metastasis in breast cancer models. Docetaxel is a chemotherapy agent for castrate-resistant prostate cancer (CRPC). In this study, the ability of CRPC cells to grow and develop in vivo tumors in an animal model was evaluated, in order to investigate the anti-tumor effect of desmopressin in combination with docetaxel., Materials and Methods: The CRPC cell line PC3 was used for orthotopic inoculation in male athymic nude mice. The mice were randomly assigned to one of the four treatment groups: Control, docetaxel, desmopressin or combination therapy. Following the last treatment, tumors were excised and measured. Blood samples were processed for CTC analysis., Results: Docetaxel treatment resulted in a significant reduction in tumor volume compared to control. The combination therapy resulted in even more significant reduction (31.2%) in tumor volume. There was a complete absence of CTCs in the combination group., Conclusion: Our pilot study demonstrated an enhanced efficacy of docetaxel-based therapy in combination with desmopressin., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Communities in which species are obligately associated with a single host are ideal to test adaptive responses of community traits to host-imposed selection because such communities are often highly insulated. Fig species provide oviposition resources to co-evolved fig-wasp communities. Dispersing fig-wasp communities move from one host plant to another for oviposition. We compared the spatial dispersion of two fig species and the dispersal capacities of their multitrophic wasp communities. Dispersal capacities were assessed by measuring vital dispersal correlates, namely tethered flight durations, somatic lipid contents and resting metabolic rates. We suggest that dispersal-trait distributions of congeneric wasp species across the communities are an adaptive response to host plant dispersion. Larger dispersal capacities of the entire multitrophic community are related to more widely dispersed resources. Our results provide evidence and a novel perspective for understanding the potential role of adaptation in whole-community dispersal-trait distributions., (© 2018 The Author(s).)

Background: Research examining the association between physical activity (PA) and prostate cancer (PCa) has accumulated; however, few studies have examined this association in the context of active surveillance. The current study examines this among men initially diagnosed with favorable-risk PCa and managed by active surveillance at Sunnybrook Health Sciences Centre in Canada and the Royal Marsden Hospital in the United Kingdom., Methods: Participants completed a questionnaire on daily participation in non-leisure, transport, and recreational PA. A logistic regression was employed using PA as the independent variable and whether the patient reclassified to higher-risk PCa while on active surveillance as the dependent variable. Demographic and lifestyle covariates were incorporated in the analysis to assess potential confounding and effect modification., Results: Men from both hospitals presented with similar clinical and demographic characteristics. Total PA was inversely associated with odds of reclassification while on active surveillance (p-trend = 0.027). A weaker inverse association was observed with recreational PA (p-trend = 0.30). Men who participated in weekly vigorous PA were less likely to reclassify than those who did not (odds ratio (95% confidence interval): 0.42 (0.20-0.85))., Conclusions: Total and vigorous PA were inversely associated with odds of reclassification in two active surveillance cohorts. Given the limitations of this study, more robust prospective observational studies involving objective PA measures are warranted to confirm findings.

Background: The combined influence of life-history strategy and resource dispersion on dispersal evolution of a biological community, and by extension, on community assemblage, has received sparse attention. Highly specialized fig wasp communities are ideal for addressing this question since the life-history strategies that affect their pace of life and the dispersion of their oviposition resources vary. We compared dispersal capacities of the wasp community of a widespread tropical fig, Ficus racemosa , by measuring flight durations, somatic lipid content and resting metabolic rates., Results: Wasp species exhibiting greater flight durations had higher energy reserves and resting metabolic rates. "Fast"-paced species showed higher dispersal capacities reflecting requirements for rapid resource location within short adult lifespans. Longer-lived "slow"-paced species exhibited lower dispersal capacities. Most dispersal traits were negatively related with resource dispersion while their variances were positively related with this variable, suggesting that resource dispersion selects for dispersal capacity. Dispersal traits exhibited a phylogenetic signal., Conclusions: Using a combination of phylogeny, trait functionality and community features, we explain how dispersal traits may have co-evolved with life-history strategies in fig wasps and influenced a predisposition for dispersal. We speculate how processes influencing dispersal trait expression of community members may affect resource occupancy and community assemblage.

Background/aim: Docetaxel, the first-line chemotherapy for metastatic castration-resistant prostate cancer (mCRPC), provides certain survival benefits, but is associated with significant toxicity. A novel therapeutic approach for mCRPC is combining docetaxel with a chemosensitizing agent. We hypothesized that metformin, a potential chemosensitizer, would improve docetaxel efficacy in CRPC cells., Materials and Methods: MTS assays were used to determine the effect of metformin-docetaxel treatment on PC3 and DU145 cell viability. Wound-healing and ATP concentration assays were used to evaluate cell migration and intracellular ATP levels following metformin-docetaxel treatment. Western blotting was used for mechanistic evaluation., Results: Metformin-docetaxel treatment significantly reduced PC3 cell viability. Metformin-docetaxel treatment did not significantly affect cell migration or intracellular ATP levels. Western blotting revealed metformin-docetaxel treatment did not significantly change AMPK or P-AMPK expression patterns., Conclusion: Metformin may be an effective chemosensitizer for certain types of CRPC cells, but further investigation is needed., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Purpose: Docetaxel is the first line chemotherapy currently used to treat patients with symptomatic metastatic castration resistant prostate cancer. Although it provides survival benefits, it is associated with significant side effects. Novel therapeutic options are needed for patients with metastatic castration resistant prostate cancer and an approach is combining docetaxel with chemosensitizing agents. Metformin has been shown to improve the survival of patients with breast, lung and endometrial cancer receiving chemotherapy, and enhance chemotherapeutic efficacy in breast cancer and colon cancer cells. However, to our knowledge the chemosensitizing effect of metformin in prostate cancer has not been explored. Therefore, the hypothesis for our study was that diabetic patients with metastatic castration resistant prostate cancer who were administered metformin during docetaxel chemotherapy would have improved prostate cancer specific and overall survival., Materials and Methods: This retrospective cohort study used data from several Ontario administrative health care databases. Men older than 65 years diagnosed with metastatic castration resistant prostate cancer and treated with docetaxel were stratified into groups based on diabetes status and use of antidiabetic medications. We evaluated the effect of metformin use with docetaxel on prostate cancer specific survival and overall survival using Kaplan-Meier survival curves, the log rank test and multivariate Cox proportional HRs., Results: Survival curves showed that metformin use with docetaxel did not improve prostate cancer specific survival (p = 0.9562) or overall survival (p = 0.9927). HRs showed no significant effect of metformin use with docetaxel on prostate cancer specific survival (HR = 0.96, p = 0.66) or overall survival (HR = 0.94, p = 0.39)., Conclusions: Metformin use during docetaxel chemotherapy did not significantly improve prostate cancer specific or overall survival in diabetic patients with metastatic castration resistant prostate cancer. This study indicates that metformin may not be an effective chemosensitizer for metastatic castration resistant prostate cancer., (Copyright © 2017 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: Patients with prostate cancer on active surveillance are monitored by repeat prostate specific antigen measurements, digital rectal examinations and prostate biopsies. A subset of patients on active surveillance will later reclassify with disease progression, prompting definitive treatment. To minimize the risk of under treating such patients on active surveillance minimally invasive tests are urgently needed incorporating biomarkers to identify patients who will reclassify., Materials and Methods: We assessed post-digital rectal examination urine samples of patients on active surveillance for select DNA methylation biomarkers that were previously investigated in radical prostatectomy specimens and shown to correlate with an increasing risk of prostate cancer. Post-digital rectal examination urine samples were prospectively collected from 153 men on active surveillance who were diagnosed with Gleason score 6 disease. Urinary sediment DNA was analyzed for 8 DNA methylation biomarkers by multiplex MethyLight assay. Correlative analyses were performed on gene methylation and clinicopathological variables to test the ability to predict patient risk reclassification., Results: Using backward logistic regression a 4-gene methylation classifier panel (APC, CRIP3, GSTP1 and HOXD8) was identified. The classifier panel was able to predict patient reclassification (OR 2.559, 95% CI 1.257-5.212). We observed this panel to be an independent and superior predictor compared to current clinical predictors such as prostate specific antigen at diagnosis or the percent of tumor positive cores in the initial biopsy., Conclusion: We report that a urine based classifier panel of 4 methylation biomarkers predicts disease progression in patients on active surveillance. Once validated in independent active surveillance cohorts, these promising biomarkers may help establish a less invasive method to monitor patients on active surveillance programs., (Copyright © 2017 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Although much research has examined the relationship between lifestyle and prostate cancer (PCa) risk, few studies focus on the relationship between lifestyle and PCa progression. The present study examines this relationship among men initially diagnosed with low- to intermediate-risk PCa and managed with active surveillance (AS)., Methods: Men enrolled in two separate AS programs were recruited for this study. Data regarding clinical, demographic and lifestyle characteristics were collected. Results were then compared between men whose disease remained low- to intermediate-risk and men whose disease progressed., Results: Demographic, clinical and physical characteristics were similar between comparative groups and cohorts, with the exception that age at the time of diagnosis and questionnaire was increased among men whose disease progressed. Lifestyle scores among men who remained low- to intermediate-risk were higher than those whose risk progressed; however, scores were only significant in one cohort on univariable analysis. On multivariable analysis, the only predictor of progression was age at diagnosis. Physical activity was consistently higher in both low risk groups, although this difference was insignificant. Consistent differences in other lifestyle variables were not observed., Conclusions: Age remains an important predictor of PCa progression. Improving lifestyle characteristics among men initially managed with AS might help to reduce the risk of progression. Given the limitations of this study, more rigorous investigation is required to confirm whether lifestyle characteristics influence the progression of low- to intermediate-risk PCa.

Cancer arises in the context of an in vivo tumor microenvironment. This microenvironment is both a cause and consequence of tumorigenesis. Tumor and host cells co-evolve dynamically through indirect and direct cellular interactions, eliciting multiscale effects on many biological programs, including cellular proliferation, growth, and metabolism, as well as angiogenesis and hypoxia and innate and adaptive immunity. Here we highlight specific biological processes that could be exploited as targets for the prevention and therapy of cancer. Specifically, we describe how inhibition of targets such as cholesterol synthesis and metabolites, reactive oxygen species and hypoxia, macrophage activation and conversion, indoleamine 2,3-dioxygenase regulation of dendritic cells, vascular endothelial growth factor regulation of angiogenesis, fibrosis inhibition, endoglin, and Janus kinase signaling emerge as examples of important potential nexuses in the regulation of tumorigenesis and the tumor microenvironment that can be targeted. We have also identified therapeutic agents as approaches, in particular natural products such as berberine, resveratrol, onionin A, epigallocatechin gallate, genistein, curcumin, naringenin, desoxyrhapontigenin, piperine, and zerumbone, that may warrant further investigation to target the tumor microenvironment for the treatment and/or prevention of cancer., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Targeted therapies and the consequent adoption of "personalized" oncology have achieved notable successes in some cancers; however, significant problems remain with this approach. Many targeted therapies are highly toxic, costs are extremely high, and most patients experience relapse after a few disease-free months. Relapses arise from genetic heterogeneity in tumors, which harbor therapy-resistant immortalized cells that have adopted alternate and compensatory pathways (i.e., pathways that are not reliant upon the same mechanisms as those which have been targeted). To address these limitations, an international task force of 180 scientists was assembled to explore the concept of a low-toxicity "broad-spectrum" therapeutic approach that could simultaneously target many key pathways and mechanisms. Using cancer hallmark phenotypes and the tumor microenvironment to account for the various aspects of relevant cancer biology, interdisciplinary teams reviewed each hallmark area and nominated a wide range of high-priority targets (74 in total) that could be modified to improve patient outcomes. For these targets, corresponding low-toxicity therapeutic approaches were then suggested, many of which were phytochemicals. Proposed actions on each target and all of the approaches were further reviewed for known effects on other hallmark areas and the tumor microenvironment. Potential contrary or procarcinogenic effects were found for 3.9% of the relationships between targets and hallmarks, and mixed evidence of complementary and contrary relationships was found for 7.1%. Approximately 67% of the relationships revealed potentially complementary effects, and the remainder had no known relationship. Among the approaches, 1.1% had contrary, 2.8% had mixed and 62.1% had complementary relationships. These results suggest that a broad-spectrum approach should be feasible from a safety standpoint. This novel approach has potential to be relatively inexpensive, it should help us address stages and types of cancer that lack conventional treatment, and it may reduce relapse risks. A proposed agenda for future research is offered., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Prostate cancer is the second most frequently diagnosed cancer in the world. Localized disease can be effectively treated with radiation therapy or radical prostatectomy. However, advanced prostate cancer is more difficult to treat and if metastatic, is incurable. There is a need for more effective therapy for advanced prostate cancer. One potential target is the cancer stem cell (CSC). CSCs have been described in several solid tumors, including prostate cancer, and contribute to therapeutic resistance and tumor recurrence. Metformin, a common oral biguanide used to treat type 2 diabetes, has been demonstrated to have anti-neoplastic effects. Specifically, metformin targets CSCs in breast cancer, pancreatic cancer, glioblastoma and colon cancer. Metformin acts directly on the mitochondria to inhibit oxidative phosphorylation and reduce mitochondrial ATP production. This forces tumor cells to compensate by increasing the rate of glycolysis. CSCs rely heavily on mitochondrial oxidative phosphorylation for energy production. The glycolytic switch results in an energy crisis in these cells. Metformin could be used to exploit this metabolic weakness in CSCs. This would increase CSC sensitivity to conventional cancer therapies, circumventing treatment resistance and enhancing treatment efficacy. This review will explore the characteristics of prostate CSCs, their role in tumor propagation and therapeutic resistance and the role of metformin as a potential prostate CSC sensitizer to current anticancer therapies.