Restricted access and advanced disease in post-pandemic testicular cancer.

INTRODUCTION: Urologists observed reduced cancer consultations and surgeries during the SARS-CoV-2 pandemic, raising concern about treatment delays. Testicular cancer serves as a particularly sensitive marker of this phenomenon, as the clinical stage of testicular cancer at presentation is predictive of cancer-specific survival. We aimed to investigate whether COVID-related restrictions to primary care access resulted in increased incidence of metastatic germ cell testis cancer. METHODS: A retrospective chart review was conducted on all cases of testicular cancer managed surgically at our center from March 1, 2018, to February 28, 2023. Patients were categorized into temporal cohorts, representing before, during, and following the implementation of COVID-19 public health restrictions in the province of Newfoundland and Labrador. RESULTS: Forty-one cases of testicular germ cell tumors were identified during the study period. The mean age at diagnosis was 40.8 years (standard deviation ±13.7). Demographics did not vary across the cohorts. Clinical stage 3 disease remained stable before and during the pandemic at 10.5% and 9.1% of cases, respectively. In the post-pandemic period, there was an increase to 27.3% (p=0.617). Surgical wait times remained stable across the pandemic (p=0.151). CONCLUSIONS: There was a 16.8% rise in clinical stage III disease from the pre-pandemic to post-pandemic period. Our study failed to identify a statistically significant increase in metastatic testis cancer incidence upon lifting of pandemic restrictions. Further study is necessary to confirm suspicions that pandemic restrictions contributed to increased incidence of metastatic testis cancer.

Recovery following discharge from intensive care: What do patients think is helpful and what services are missing?

BACKGROUND: Recovery following critical illness is complex due to the many challenges patients face which influence their long-term outcomes. We explored patients' views about facilitators of recovery after critical illness which could be used to inform the components and timing of specific rehabilitation interventions. AIMS: To explore the views of patients after discharge from an intensive care unit (ICU) about their recovery and factors that facilitated recovery, and to determine additional services that patients felt were missing during their recovery. METHODS: Qualitative study involving individual face-to-face semi-structured interviews at six months (n = 11) and twelve months (n = 10). Written, informed consent was obtained. [Ethics approval 17/NI/0115]. Interviews were audiotaped, transcribed and analysed using template analysis. FINDINGS: Template analysis revealed four core themes: (1) Physical activity and function; (2) Recovery of cognitive and emotional function; (3) Facilitators to recovery; and (4) Gaps in healthcare services. CONCLUSION: Patient reported facilitators to recovery include support and guidance from others and self-motivation and goal setting, equipment for mobility and use of technology. Barriers include a lack of follow up services, exercise rehabilitation, peer support and personal feedback. Patients perceived that access to specific healthcare services was fragmented and where services were unavailable this contributed to slower or poorer quality of recovery. ICU patient recover could be facilitated by a comprehensive rehabilitation intervention that includes patient-directed strategies and health care services.

Impact of the COVID-19 pandemic on diagnosis of renal cell carcinoma and disease stage at presentation.

INTRODUCTION: Renal cell carcinoma (RCC) is often associated with significant morbidity and mortality, with overall survival contingent on multiple factors - most importantly, disease stage at diagnosis. Disruptions in healthcare delivery during the COVID-19 pandemic have resulted in various reported diagnostic and treatment delays, which have had detrimental impacts on malignancies such as RCC. METHODS: Surgically managed cases of RCC at our center were identified using a retrospective chart review of all nephrectomies conducted from March 1, 2018, to February 28, 2023. Examination of disease characteristics in three time period cohorts (before, during, and following the COVID-19 pandemic) was undertaken. Timeframes were consistent with implementation and abolition of public health restrictions in the province of Newfoundland and Labrador. RESULTS: A total of 483 surgically managed RCC cases were identified during the study period. The median age was 65 years (interquartile range [IQR] 56-71), and 62.3% of patients were male. Demographics did not vary across timeframes. Before and during the pandemic, pathologic stage 3 (pT3) disease was reported in 38.9% and 35.4% of cases, respectively, whereas the post-pandemic period saw this presentation in 50.0% of patients. Surgical wait times increased significantly across study timeframes (p=0.003). CONCLUSIONS: The first year following the COVID-19 pandemic saw an 11.1% increase in patients presenting with pT3 RCC. These findings are suggestive of a clinically significant stage migration, which paired with prolonged wait times for surgery, provide critical consideration in the urgency of diagnostic and treatment decisions for RCC in the immediate future.

Microbial associates of the elm leaf beetle: uncovering the absence of resident bacteria and the influence of fungi on insect performance.

Microbial symbionts play crucial roles in the biology of many insects. While bacteria have been the primary focus of research on insect-microbe symbiosis, recent studies suggest that fungal symbionts may be just as important. The elm leaf beetle (ELB, Xanthogaleruca luteola) is a serious pest species of field elm (Ulmus minor). Using culture-dependent and independent methods, we investigated the abundance and species richness of bacteria and fungi throughout various ELB life stages and generations, while concurrently analyzing microbial communities on elm leaves. No persistent bacterial community was found to be associated with the ELB or elm leaves. By contrast, fungi were persistently present in the beetle's feeding life stages and on elm leaves. Fungal community sequencing revealed a predominance of the genera Penicillium and Aspergillus in insects and on leaves. Culture-dependent surveys showed a high prevalence of two fungal colony morphotypes closely related to Penicillium lanosocoeruleum and Aspergillus flavus. Among these, the Penicillium morphotype was significantly more abundant on feeding-damaged compared with intact leaves, suggesting that the fungus thrives in the presence of the ELB. We assessed whether the detected prevalent fungal morphotypes influenced ELB's performance by rearing insects on (i) surface-sterilized leaves, (ii) leaves inoculated with Penicillium spores, and (iii) leaves inoculated with Aspergillus spores. Insects feeding on Penicillium-inoculated leaves gained more biomass and tended to lay larger egg clutches than those consuming surface-sterilized leaves or Aspergillus-inoculated leaves. Our results demonstrate that the ELB does not harbor resident bacteria and that it might benefit from associating with Penicillium fungi.IMPORTANCEOur study provides insights into the still understudied role of microbial symbionts in the biology of the elm leaf beetle (ELB), a major pest of elms. Contrary to expectations, we found no persistent bacterial symbionts associated with the ELB or elm leaves. Our research thus contributes to the growing body of knowledge that not all insects rely on bacterial symbionts. While no persistent bacterial symbionts were detectable in the ELB and elm leaf samples, our analyses revealed the persistent presence of fungi, particularly Penicillium and Aspergillus on both elm leaves and in the feeding ELB stages. Moreover, when ELB were fed with fungus-treated elm leaves, we detected a potentially beneficial effect of Penicillium on the ELB's development and fecundity. Our results highlight the significance of fungal symbionts in the biology of this insect.

A population-based analysis of the epidemiology of penile cancer in Newfoundland and Labrador.

INTRODUCTION: Penile cancers are a rare subset of carcinomas accounting for <1% of all diagnosed malignancies. There have been recent reports of increasing incidence globally; however, there is limited Canadian literature pertaining to these neoplasms. The province of Newfoundland and Labrador (NL ) represents an important entity to study, possessing the highest national incidence of cancer, along with a plethora of relevant risk factors for penile cancer. METHODS: A retrospective chart analysis of all patients with a diagnosis of penile cancer in NL between the years of 2006 and 2018 was conducted. The main outcomes included overall incidence, proportion with metastatic disease, tumor demographics, and overall survival (OS ). Incidence among the male population was calculated using Statistics Canada annual reports. RESULTS: An identified 81 cases satisfied the inclusion criteria, with a median age at diagnosis of 65 (interquartile range 20) years. Crude incidence of penile cancer ranged from 1.20-4.27/100 000 males in 2007 and 2010, respectively, while the average age-standardized incidence was 2.34/100 000 males across the study timeframe. Metastatic disease was noted in 17 (21.0%) patients, with a five-year OS of 74% for all penile malignancies, decreasing to 66% in those with invasive squamous cell carcinoma. CONCLUSIONS: The incidence of penile cancer in our population was higher than reported Western jurisdictions and showed frequent rates of metastatic spread. These observations are likely multifactorial, resultant of chronic inflammation paired with high rates of modifiable risk factors and diagnostic delays. An evident need for greater examination and improved reporting of these malignancies in the province was identified.

The Utility of Salvage Radiotherapy for an Inoperable Inguinal Recurrence of Squamous Cell Carcinoma of the Penis.

Penile cancer is a rare genitourinary malignancy for which limited treatment options exist beyond primary surgical resection. Metastatic lymphadenopathy represents a particularly poor prognosis with a lack of literature to suggest the effectiveness of radiation or systemic therapies. Our case documents an inguinal recurrence of penile squamous cell carcinoma not amenable to surgical intervention demonstrating complete response to salvage radiotherapy in the palliative setting. These observations propose the need for further research around the utility of radiotherapy in the management of metastatic penile malignancies.

Malignant Mesothelioma of the Testes with Retroperitoneal Recurrence and Resection in an 80-Year-Old Male and Review of the Literature.

Malignant mesothelioma of the testes is an aggressive, yet rare urogenital malignancy, accounting for an infinitesimally small number of oncologic diagnoses. This infrequent occurrence is accompanied by a relative lack of knowledge surrounding this disease, thus limiting management options beyond surgical intervention. Oftentimes, these malignancies present with a poor prognosis despite early intervention and only worsen in the event of metastatic spread with poor survival and limited response to treatment, if any. Our case documents positive patient outcomes following the use of aggressive surgical intervention in the management of a metastatic testicular mesothelioma. A healthy 80-year-old male with sudden painless testicular swelling requiring radical orchidectomy following failed initial conservative management. Pathologically, the specimen was diagnosed as malignant mesothelioma of the right testis with involvement of the tunica albuginea and tunica vaginalis. Following disease recurrence at 82 years of age, the patient subsequently opted for an open right-sided template non-nerve sparing retroperitoneal lymph node dissection which was undertaken without complication. Malignant mesothelioma of the testes remains an ominous diagnosis with historically poor outcomes and for which surgical intervention remains the mainstay of treatment. The retroperitoneal lymphatic drainage represents the most common route of metastatic spread for testicular tumours; however, retroperitoneal lymph node dissection has rarely been employed in this patient population and never in an individual of this age. Our findings contribute to the growing literature surrounding these rare malignancies and outline the importance of considering both patient autonomy and the clinical picture in disease management.

Characterization of allosteric modulators that disrupt androgen receptor co-activator protein-protein interactions to alter transactivation-Drug leads for metastatic castration resistant prostate cancer.

Three series of compounds were prioritized from a high content screening campaign that identified molecules that blocked dihydrotestosterone (DHT) induced formation of Androgen Receptor (AR) protein-protein interactions (PPIs) with the Transcriptional Intermediary Factor 2 (TIF2) coactivator and also disrupted preformed AR-TIF2 PPI complexes; the hydrobenzo-oxazepins (S1), thiadiazol-5-piperidine-carboxamides (S2), and phenyl-methyl-indoles (S3). Compounds from these series inhibited AR PPIs with TIF2 and SRC-1, another p160 coactivator, in mammalian 2-hybrid assays and blocked transcriptional activation in reporter assays driven by full length AR or AR-V7 splice variants. Compounds inhibited the growth of five prostate cancer cell lines, with many exhibiting differential cytotoxicity towards AR positive cell lines. Representative compounds from the 3 series substantially reduced both endogenous and DHT-enhanced expression and secretion of the prostate specific antigen (PSA) cancer biomarker in the C4-2 castration resistant prostate cancer (CRPC) cell line. The comparatively weak activities of series compounds in the H3-DHT and/or TIF2 box 3 LXXLL-peptide binding assays to the recombinant ligand binding domain of AR suggest that direct antagonism at the orthosteric ligand binding site or AF-2 surface respectively are unlikely mechanisms of action. Cellular enhanced thermal stability assays (CETSA) indicated that compounds engaged AR and reduced the maximum efficacy and right shifted the EC50 of DHT-enhanced AR thermal stabilization consistent with the effects of negative allosteric modulators. Molecular docking of potent representative hits from each series to AR structures suggest that S1-1 and S2-6 engage a novel binding pocket (BP-1) adjacent to the orthosteric ligand binding site, while S3-11 occupies the AR binding function 3 (BF-3) allosteric pocket. Hit binding poses indicate spaces and residues adjacent to the BP-1 and BF-3 pockets that will be exploited in future medicinal chemistry optimization studies. Small molecule allosteric modulators that prevent/disrupt AR PPIs with coactivators like TIF2 to alter transcriptional activation in the presence of orthosteric agonists might evade the resistance mechanisms to existing prostate cancer drugs and provide novel starting points for medicinal chemistry lead optimization and future development into therapies for metastatic CRPC.

A quality assurance review of penile cancer diagnostic delays and stage at presentation during the COVID-19 pandemic.

INTRODUCTION: Penile carcinomas represent a rare malignancy associated with significant psychosocial impacts that deter afflicted individuals from seeking medical attention, thus, worsening prognosis. Following the dramatic shift in healthcare delivery to virtual platforms, it is suspected that prevalent psychosocial impacts have been further compounded by the COVID-19 pandemic, resulting in several late-stage presentations and engendering poorer outcomes. METHODS: A retrospective chart review of surgically managed cases of penile cancer was conducted from January 2020 to June 2022 to identify patients that may have been unduly impacted by the COVID-19 pandemic. Included cases were analyzed in quantifying diagnostic and treatment delays, along with patient outcomes. Relevant epidemiological and pathological markers were also examined. RESULTS: Ten patients met the inclusion criteria. Average time delay from first complaint of a penile lesion to surgical management was 75 days, with 60% of patients experiencing a time delay of two months or more. The average delay from first complaint to diagnosis was 62 days in 2020 and 18 days in 2021. Advanced-stage disease was present in six (60%) individuals at presentation, while four (40%) patients perished during the study period. CONCLUSIONS: In cases of concern for penile malignancy, virtual care cannot replace the necessity of physical exams in preventing diagnostic and treatment delays. The present study further highlights the necessity of initial physical examination of penile abnormalities in preventing fatal outcomes for those afflicted. Such consideration warrants urgent examination of referred males with genital abnormalities to prevent further exacerbation of delays.

Complete metamorphosis and microbiota turnover in insects.

The insects constitute the majority of animal diversity. Most insects are holometabolous: during complete metamorphosis their bodies are radically reorganized. This reorganization poses a significant challenge to the gut microbiota, as the gut is replaced during pupation, a process that does not occur in hemimetabolous insects. In holometabolous hosts, it offers the opportunity to decouple the gut microbiota between the larval and adult life stages resulting in high beta diversity whilst limiting alpha diversity. Here, we studied 18 different herbivorous insect species from five orders of holometabolous and three orders of hemimetabolous insects. Comparing larval and adult specimens, we find a much higher beta-diversity and hence microbiota turnover in holometabolous insects compared to hemimetabolous insects. Alpha diversity did not differ between holo- and hemimetabolous insects nor between developmental stages within these groups. Our results support the idea that pupation offers the opportunity to change the gut microbiota and hence might facilitate ecological niche shifts. This possible effect of niche shift facilitation could explain a selective advantage of the evolution of complete metamorphosis, which is a defining trait of the most speciose insect taxon, the holometabola.

Tachykinin-related peptides modulate immune-gene expression in the mealworm beetle Tenebrio molitor L.

Tachykinins (TKs) are a group of conserved neuropeptides. In insects, tachykinin-related peptides (TRPs) are important modulators of several functions such as nociception and lipid metabolism. Recently, it has become clear that TRPs also play a role in regulating the insect immune system. Here, we report a transcriptomic analysis of changes in the expression levels of immune-related genes in the storage pest Tenebrio molitor after treatment with Tenmo-TRP-7. We tested two concentrations (10-8 and 10-6 M) at two time points, 6 and 24 h post-injection. We found significant changes in the transcript levels of a wide spectrum of immune-related genes. Some changes were observed 6 h after the injection of Tenmo-TRP-7, especially in relation to its putative anti-apoptotic action. Interestingly, 24 h after the injection of 10-8 M Tenmo-TRP-7, most changes were related to the regulation of the cellular response. Applying 10-6 M Tenmo-TRP-7 resulted in the downregulation of genes associated with humoral responses. Injecting Tenmo-TRP-7 did not affect beetle survival but led to a reduction in haemolymph lysozyme-like antibacterial activity, consistent with the transcriptomic data. The results confirmed the immunomodulatory role of TRP and shed new light on the functional homology between TRPs and TKs.

Phenotypic characterization of the Hordeum bulbosum derived leaf rust resistance genes Rph22 and Rph26 in barley.

AIMS: Two introgression lines (ILs), 182Q20 and 200A12, which had chromosomal segments introgressed from Hordeum bulbosum in H. vulgare backgrounds, were identified to show seedling resistance against Puccinia hordei, possibly attributed to two resistance genes, Rph22 and Rph26, respectively. This study characterized the phenotypic responses of the two genes against P. hordei over different plant development stages. METHODS AND RESULTS: Using visual and fungal biomass assessments, responses of ILs 182Q20, 200A12 and four other barley cultivars against P. hordei were determined at seedling, tillering, stem elongation and booting stages. Plants carrying either Rph22 or Rph26 were found to confer gradually increasing resistance over the course of different development stages, with partial resistant phenotypes (i.e. prolonged rust latency periods, reduced uredinia numbers but with susceptible infection types) observed at seedling stage and adult plant resistance (APR) at booting stage. A definitive switch between the two types of resistance occurred at tillering stage. CONCLUSIONS: Rph22 and Rph26 derived from H. bulbosum were well characterized and had typical APR phenotypes against P. hordei. SIGNIFICANCE AND IMPACT OF THE STUDY: This study provides important insights on the effectiveness and expression of Rph22 and Rph26 against P. hordei during plant development and underpins future barley breeding programmes using non-host as a genetic resource for leaf rust management.

A Complex Case of Pregnancy-related Left Main Stem Spontaneous Coronary Artery Dissection.

Spontaneous coronary artery dissection (SCAD) is a less common cause of acute coronary syndrome. Pregnancy-related SCAD is uncommon, but often presents with a more severe phenotype. This report describes a 30-year-old woman with an anterior ST elevation MI, presenting 1 day postpartum. Left main stem (LMS) SCAD with extensive intramural haematoma (IMH) and resultant LMS occlusion was confirmed by angiography and intravascular imaging. Given the extent of disease, the patient underwent emergency cardiac surgery. Coronary flow was initially improved by decompressing the IMH using cutting balloons. The coronary wires were successfully left in situ during transfer in an effort to both maintain flow and allow the surgeon to identify true LMS. Ideally, SCAD can be managed conservatively given the risk of intervention worsening IMH, and hence myocardial ischaemia/MI. However, emergency revascularisation is indicated in cases of persistent ischaemia. This case demonstrates percutaneous therapies to bridge towards and help with subsequent surgical revascularisation.

Eating in a losing cause: limited benefit of modified macronutrient consumption following infection in the oriental cockroach Blatta orientalis.

BACKGROUND: Host-pathogen interactions can lead to dramatic changes in host feeding behaviour. One aspect of this includes self-medication, where infected individuals consume substances such as toxins or alter their macronutrient consumption to enhance immune competence. Another widely adopted animal response to infection is illness-induced anorexia, which is thought to assist host immunity directly or by limiting the nutritional resources available to pathogens. Here, we recorded macronutrient preferences of the global pest cockroach, Blatta orientalis to investigate how shifts in host macronutrient dietary preference and quantity of carbohydrate (C) and protein (P) interact with immunity following bacterial infection. RESULTS: We find that B. orientalis avoids diets enriched for P under normal conditions, and that high P diets reduce cockroach survival in the long term. However, following bacterial challenge, cockroaches significantly reduced their overall nutrient intake, particularly of carbohydrates, and increased the relative ratio of protein (P:C) consumed. Surprisingly, these behavioural shifts had a limited effect on cockroach immunity and survival, with minor changes to immune protein abundance and antimicrobial activity between individuals placed on different diets, regardless of infection status. CONCLUSIONS: We show that cockroach feeding behaviour can be modulated by a pathogen, resulting in an illness-induced anorexia-like feeding response and a shift from a C-enriched to a more P:C equal diet. However, our results also indicate that such responses do not provide significant immune protection in B. orientalis, suggesting that the host's dietary shift might also result from random rather than directed behaviour. The lack of an apparent benefit of the shift in feeding behaviour highlights a possible reduced importance of diet in immune regulation in these invasive animals, although further investigations employing pathogens with alternative infection strategies are warranted.

Validation of HDAC8 Inhibitors as Drug Discovery Starting Points to Treat Acute Kidney Injury.

Acute kidney injury (AKI), a sudden loss of kidney function, is a common and serious condition for which there are no approved specific therapies. While there are multiple approaches to treat the underlying causes of AKI, no targets have been clinically validated. Here, we assessed a series of potent, selective competitive inhibitors of histone deacetylase 8 (HDAC8), a promising therapeutic target in an AKI setting. Using biochemical assays, zebrafish AKI phenotypic assays, and human kidney organoid assays, we show that selective HDAC8 inhibitors can lead to efficacy in increasingly stringent models. One of these, PCI-34051, was efficacious in a rodent model of AKI, further supporting the potential for HDAC8 inhibitors and, in particular, this scaffold as a therapeutic approach to AKI.

Detection and impact of hypoxic regions in multicellular tumor spheroid cultures formed by head and neck squamous cell carcinoma cells lines.

In solid tumors like head and neck cancer (HNC), chronic and acute hypoxia have serious adverse clinical consequences including poorer overall patient prognosis, enhanced metastasis, increased genomic instability, and resistance to radiation-, chemo-, or immuno-therapies. However, cells in the two-dimensional monolayer cultures typically used for cancer drug discovery experience 20%-21% O2 levels (normoxic) which are 4-fold higher than O2 levels in normal tissues and ≥10-fold higher than in the hypoxic regions of solid tumors. The oxygen electrodes, exogenous bio-reductive markers, and increased expression of endogenous hypoxia-regulated proteins like HIF-1α generally used to mark hypoxic regions in solid tumors are impractical in large sample numbers and longitudinal studies. We used a novel homogeneous live-cell permeant HypoxiTRAK™ (HPTK) molecular probe compatible with high content imaging detection, analysis, and throughput to identify and quantify hypoxia levels in live HNC multicellular tumor spheroid (MCTS) cultures over time. Accumulation of fluorescence HPTK metabolite in live normoxic HNC MCTS cultures correlated with hypoxia detection by both pimonidazole and HIF-1α staining. In HNC MCTSs, hypoxic cytotoxicity ratios for the hypoxia activated prodrugs (HAP) evofosfamide and tirapazamine were much smaller than have been reported for uniformly hypoxic 2D monolayers in gas chambers, and many viable cells remained after HAP exposure. Cells in solid tumors and MCTSs experience three distinct O2 microenvironments dictated by their distances from blood vessels or MCTS surfaces, respectively; oxic, hypoxic, or intermediate levels of hypoxia. These studies support the application of more physiologically relevant in vitro 3D models that recapitulate the heterogeneous microenvironments of solid tumors for preclinical cancer drug discovery.

Feasibility of conservative fluid administration and deresuscitation compared with usual care in critical illness: the Role of Active Deresuscitation After Resuscitation-2 (RADAR-2) randomised clinical trial.

PURPOSE: Fluid overload is common in critical illness and is associated with mortality. This study investigated the feasibility of a randomised trial comparing conservative fluid administration and deresuscitation (active removal of accumulated fluid using diuretics or ultrafiltration) with usual care in critical illness. METHODS: Open-label, parallel-group, allocation-concealed randomised clinical feasibility trial. Mechanically ventilated adult patients expected to require critical care beyond the next calendar day were enrolled between 24 and 48 h following admission to the intensive care unit (ICU). Patients were randomised to either a 2-stage fluid strategy comprising conservative fluid administration and, if fluid overload was present, active deresuscitation, or usual care. The primary endpoint was fluid balance in the 24 h up to the start of study day 3. Secondary endpoints included cumulative fluid balance, mortality, and duration of mechanical ventilation. RESULTS: One hundred and eighty patients were randomised. After withdrawal of 1 patient, 89 patients assigned to the intervention were compared with 90 patients assigned to the usual care group. The mean plus standard deviation (SD) 24-h fluid balance up to study day 3 was lower in the intervention group (- 840 ± 1746 mL) than the usual care group (+ 130 ± 1401 mL; P < 0.01). Cumulative fluid balance was lower in the intervention group at days 3 and 5. Overall, clinical outcomes did not differ significantly between the two groups, although the point estimate for 30-day mortality favoured the usual care group [intervention arm: 19 of 90 (21.6%) versus usual care: 14 of 89 (15.6%), P = 0.32]. Baseline imbalances between groups and lack of statistical power limit interpretation of clinical outcomes. CONCLUSIONS: A strategy of conservative fluid administration and active deresuscitation is feasible, reduces fluid balance compared with usual care, and may cause benefit or harm. In view of wide variations in contemporary clinical practice, large, adequately powered trials investigating the clinical effectiveness of conservative fluid strategies in critically ill patients are warranted.

Aspirin as a Treatment for ARDS: A Randomized, Placebo-Controlled Clinical Trial.

BACKGROUND: There is no pharmacologic treatment for ARDS. Platelets play an important role in the pathophysiology of ARDS. Preclinical, observational, and clinically relevant models of ARDS indicate aspirin as a potential therapeutic option. RESEARCH QUESTION: Is enteral aspirin (75 mg, once daily) safe and effective in improving surrogate outcomes in adult patients with ARDS? STUDY DESIGN AND METHODS: This randomized, double-blind (patient and investigator), allocation-concealed, placebo-controlled phase 2 trial was conducted in five UK ICUs. Patients fulfilling the Berlin definition of ARDS were randomly assigned at a 1:1 ratio to receive enteral aspirin (75 mg) or placebo, for a maximum of 14 days, using a computer-generated randomization schedule, with variable block size, stratified by vasopressor requirement. The primary end point was oxygenation index (OI) on day 7. Secondary outcomes included safety parameters and other respiratory physiological markers. Analyses were by intention to treat. RESULTS: The trial was stopped early, due to slow recruitment, after 49 of a planned 60 patients were recruited. Twenty-four patients were allocated to aspirin and 25 to placebo. There was no significant difference in day 7 OI [aspirin group: unadjusted mean, 54.4 (SD 26.8); placebo group: 42.4 (SD 25); mean difference, 12.0; 95% CI, -6.1 to 30.1; P = .19]. Aspirin did not significantly impact the secondary outcomes. There was no difference in the number of adverse events between the groups (13 in each; OR, 1.04; 95% CI, 0.56-1.94; P = .56). INTERPRETATION: Aspirin was well tolerated but did not improve OI or other physiological outcomes; a larger trial is not feasible in its current design. TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT02326350; URL: www. CLINICALTRIALS: gov.