Circular RNA Cdr1as inhibits proliferation and delays injury-induced regeneration of the intestinal epithelium.

Circular RNAs (circRNAs) are highly expressed in the mammalian intestinal epithelium, but their functions remain largely unknown. Here, we identified the circRNA Cdr1as as a repressor of intestinal epithelial regeneration and defense. Cdr1as levels increased in mouse intestinal mucosa after colitis and septic stress, as well as in human intestinal mucosa from patients with inflammatory bowel disease and sepsis. Ablation of the Cdr1as locus from the mouse genome enhanced renewal of the intestinal mucosa, promoted injury-induced epithelial regeneration, and protected the mucosa against colitis. We found approximately 40 microRNAs, including miR-195, differentially expressed between intestinal mucosa of Cdr1as-knockout (Cdr1as-/-) versus littermate mice. Increasing the levels of Cdr1as inhibited intestinal epithelial repair after wounding in cultured cells and repressed growth of intestinal organoids cultured ex vivo, but this inhibition was abolished by miR-195 silencing. The reduction in miR-195 levels in the Cdr1as-/- intestinal epithelium was the result of reduced stability and processing of the precursor miR-195. These findings indicate that Cdr1as reduces proliferation and repair of the intestinal epithelium at least in part via interaction with miR-195 and highlight a role for induced Cdr1as in the pathogenesis of unhealed wounds and disrupted renewal of the intestinal mucosa.

Laparoscopic surgery for adrenocortical carcinoma: Estimating the risk of margin-positive resection.

BACKGROUND: Over recent years, there has been increasing adoption of minimally invasive surgery (MIS) in the treatment of adrenocortical carcinoma (ACC). However, MIS has been associated with noncurative resection and locoregional recurrence. We aimed to identify risk factors for margin-positivity among patients who undergo MIS resection for ACC. We hypothesized that a simple nomogram can accurately identify patients most suitable for curative MIS resection. METHODS: Curative-intent resections for ACC were identified through the National Cancer Database spanning 2010-2018. Trends in MIS utilization were reported using Pearson correlation coefficients. Factors associated with margin-positive resection were identified among preoperatively available variables using multivariable logistic regression, then incorporated into a predictive model. Model quality was cross validated using an 80% training data set and 20% test data set. RESULTS: Among 1260 ACC cases, 38.6% (486) underwent MIS resection. MIS utilization increased over time at nonacademic centers (R = 0.818, p = 0.007), but not at academic centers (R = 0.009, p = 0.982). Factors associated with margin-positive MIS resection were increasing age, nonacademic center (odds ratio [OR]: 1.8, p = 0.006), cT3 (OR: 4.7, p < 0.001) or cT4 tumors (OR: 14.6, p < 0.001), and right-sided tumors (OR: 2.0, p = 0.006). A predictive model incorporating these four factors produced favorable c-statistics of 0.75 in the training data set and 0.72 in the test data set. A pragmatic nomogram was created to enable bedside risk stratification. CONCLUSIONS: An increasing proportion of ACC are resected via minimally invasive operations, particularly at nonacademic centers. Patient selection based on a few key factors can minimize the risk of noncurative surgery.

Age-stratified comparison of active surveillance versus radiofrequency ablation for papillary thyroid microcarcinoma using decision analysis.

BACKGROUND: Papillary thyroid microcarcinomas may be treated with radiofrequency ablation, active surveillance, or surgery. The objective of this study was to use mathematical modeling to compare treatment alternatives for papillary thyroid microcarcinomas among those who decline surgery. We hypothesized that radiofrequency ablation would outperform active surveillance in avoiding progression and surgery but that the effect size would be small for older patients. METHODS: We engaged stakeholders to identify meaningful long-term endpoints for papillary thyroid microcarcinoma treatment-(1) cancer progression/surgery, (2) need for thyroid replacement therapy, and (3) permanent treatment complication. A Markov decision analysis model was created to compare the probability of these endpoints after radiofrequency ablation or active surveillance for papillary thyroid microcarcinomas and overall cost. Transition probabilities were extracted from published literature. Model outcomes were estimated to have a 10-year time horizon. RESULTS: The primary outcome yielded a number needed to treat of 18.1 for the avoidance of progression and 27.4 for the avoidance of lifelong thyroid replacement therapy for radiofrequency ablation compared to active surveillance. However, as patient age increased, the number needed to treat to avoid progression increased from 5.2 (age 20-29) to 39.1 (age 60+). The number needed to treat to avoid lifelong thyroid replacement therapy increased with age from 7.8 (age 20-29) to 59.3 (age 60+). The average 10-year cost/treatment for active surveillance and radiofrequency ablation were $6,400 and $11,700, respectively, translating to a cost per progression-avoided of $106,500. CONCLUSION: As an alternative to active surveillance, radiofrequency ablation may have a greater therapeutic impact in younger patients. However, routine implementation may be cost-prohibitive for most patients with papillary thyroid microcarcinomas.

Growing Deficit in New Cancer Diagnoses 2 Years Into the COVID-19 Pandemic: A National Multicenter Study.

BACKGROUND: Large decreases in cancer diagnoses were seen early in the COVID-19 pandemic. However, the evolution of these deficits since the end of 2020 and the advent of widespread vaccination is unknown. METHODS: This study examined data from the Veterans Health Administration (VA) from 1 January 2018 through 28 February 2022 and identified patients with screening or diagnostic procedures or new cancer diagnoses for the four most common cancers in the VA health system: prostate, lung, colorectal, and bladder cancers. Monthly procedures and new diagnoses were calculated, and the pre-COVID era (January 2018 to February 2020) was compared with the COVID era (March 2020 to February 2022). RESULTS: The study identified 2.5 million patients who underwent a diagnostic or screening procedure related to the four cancers. A new cancer was diagnosed for 317,833 patients. During the first 2 years of the pandemic, VA medical centers performed 13,022 fewer prostate biopsies, 32,348 fewer cystoscopies, and 200,710 fewer colonoscopies than in 2018-2019. These persistent deficits added a cumulative deficit of nearly 19,000 undiagnosed prostate cancers and 3300 to 3700 undiagnosed cancers each for lung, colon, and bladder. Decreased diagnostic and screening procedures correlated with decreased new diagnoses of cancer, particularly cancer of the prostate (R = 0.44) and bladder (R = 0.27). CONCLUSION: Disruptions in new diagnoses of four common cancers (prostate, lung, bladder, and colorectal) seen early in the COVID-19 pandemic have persisted for 2 years. Although reductions improved from the early pandemic, new reductions during the Delta and Omicron waves demonstrate the continued impact of the COVID-19 pandemic on cancer care.

Control of Paneth cell function by HuR regulates gut mucosal growth by altering stem cell activity.

Rapid self-renewal of the intestinal epithelium requires the activity of intestinal stem cells (ISCs) that are intermingled with Paneth cells (PCs) at the crypt base. PCs provide multiple secreted and surface-bound niche signals and play an important role in the regulation of ISC proliferation. Here, we show that control of PC function by RNA-binding protein HuR via mitochondria affects intestinal mucosal growth by altering ISC activity. Targeted deletion of HuR in mice disrupted PC gene expression profiles, reduced PC-derived niche factors, and impaired ISC function, leading to inhibited renewal of the intestinal epithelium. Human intestinal mucosa from patients with critical surgical disorders exhibited decreased levels of tissue HuR and PC/ISC niche dysfunction, along with disrupted mucosal growth. HuR deletion led to mitochondrial impairment by decreasing the levels of several mitochondrial-associated proteins including prohibitin 1 (PHB1) in the intestinal epithelium, whereas HuR enhanced PHB1 expression by preventing microRNA-195 binding to the Phb1 mRNA. These results indicate that HuR is essential for maintaining the integrity of the PC/ISC niche and highlight a novel role for a defective PC/ISC niche in the pathogenesis of intestinal mucosa atrophy.

miR-542-5p targets c-myc and negates the cell proliferation effect of SphK1 in intestinal epithelial cells.

Intestinal epithelial barrier defects occur commonly during a variety of pathological conditions, though their underlying mechanisms are not completely understood. Sphingosine-1-phosphate (S1P) has been shown to be a critical regulator of proliferation and of maintenance of an intact intestinal epithelial barrier, as is also sphingosine kinase 1 (SphK1), the rate-limiting enzyme for S1P synthesis. SphK1 has been shown to modulate its effect on intestinal epithelial proliferation through increased levels of c-myc. We conducted genome-wide profile analysis to search for differential microRNA expression related to overexpressed SphK1 demonstrating adjusted expression of microRNA 542-5p (miR-542-5p). Here, we show that miR-542-5p is regulated by SphK1 activity and is an effector of c-myc translation that ultimately serves as a critical regulator of the intestinal epithelial barrier. miR-542-5p directly regulates c-myc translation through direct binding to the c-myc mRNA. Exogenous S1P analogs administered in vivo protect murine intestinal barrier from damage due to mesenteric ischemia reperfusion, and damaged intestinal tissue had increased levels of miR-542-5p. These results indicate that miR-542-5p plays a critical role in the regulation of S1P-mediated intestinal barrier function, and may highlight a novel role in potential therapies.

Mid-term Surgery Outcomes in Patients With COVID-19: Results From a Nationwide Analysis.

OBJECTIVE: Determine mid-term postoperative outcomes among coronavirus disease 2019 (COVID-19)-positive (+) patients compared with those who never tested positive before surgery. BACKGROUND: COVID-19 is thought to be associated with prohibitively high rates of postoperative complications. However, prior studies have only evaluated 30-day outcomes, and most did not adjust for demographic, clinical, or procedural characteristics. METHODS: We analyzed data from surgeries performed at all Veterans Affairs hospitals between March 2020 and 2021. Kaplan-Meier curves compared trends in mortality and Cox proportional hazards models estimated rates of mortality and pulmonary, thrombotic, and septic postoperative complications between patients with a positive preoperative severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test [COVID (+)] and propensity score-matched COVID-negative (-) patients. RESULTS: Of 153,741 surgical patients, 4778 COVID (+) were matched to 14,101 COVID (-). COVID (+) status was associated with higher postoperative mortality ( P <0.0001) with a 6-month survival of 94.2% (95% confidence interval: 93.2-95.2) versus 96.0% (95% confidence interval: 95.7.0-96.4) in COVID (-). The highest mortality was in the first 30 postoperative days. Hazards for mortality and postoperative complications in COVID (+) decreased with increasing time between testing COVID (+) and date of surgery. COVID (+) patients undergoing elective surgery had similar rates of mortality, thrombotic and septic complications, but higher rates of pulmonary complications than COVID (-) patients. CONCLUSIONS: This is the first report of mid-term outcomes among COVID-19 patients undergoing surgery. COVID-19 is associated with decreased overall and complication-free survival primarily in the early postoperative period, delaying surgery by 5 weeks or more reduces risk of complications. Case urgency has a multiplicative effect on short-term and long-term risk of postoperative mortality and complications.

Total thyroidectomy is more cost-effective than radioactive iodine as an alternative to antithyroid medication for Graves' disease.

BACKGROUND: Patients with Graves' disease treated with radioactive iodine report worse quality of life than those treated by thyroidectomy. However, radioactive iodine is often selected due to lower risk of complications and lower cost. The objective of this study was to estimate the cost-effectiveness of radioactive iodine versus total thyroidectomy for treatment of Graves' disease. METHODS: A Markov decision-analytic model was created to simulate clinical outcomes and costs of medication-refractory Graves' disease treated with radioactive iodine or total thyroidectomy. Complication rates and utilities were derived from published data. Costs were extracted from national Medicare reimbursement rates. We conducted 1-way, 2-way, and probabilistic sensitivity analyses to identify factors that influence cost-effectiveness and reflect uncertainty in model parameters. The willingness-to-pay threshold was set at $100,000/quality-adjusted life-years. RESULTS: Total thyroidectomy yielded 23.6 quality-adjusted life-years versus 20.9 quality-adjusted life-years for radioactive iodine. The incremental cost-effectiveness ratio was $2,982 per quality-adjusted life-years, indicating that surgery is highly cost-effective relative to radioactive iodine. Surgery was more cost effective than radioactive iodine in 88.2% of model simulations. Sensitivity analyses indicate that the model outcomes are driven predominantly by posttreatment quality of life, with contributing effects from rates of treatment complications and the impact of these complications on quality of life. CONCLUSION: For patients with Graves' disease who either cannot tolerate or are refractory to antithyroid drugs, thyroidectomy is more cost-effective than radioactive iodine. Future research should validate reported differences in quality of life between these 2 treatment modalities.

Partial COVID-19 vaccination associated with reduction in postoperative mortality and SARS-CoV-2 infection.

BACKGROUND: There are currently no data to guide decisions about delaying surgery to achieve full vaccination. METHODS: We analyzed data from patients undergoing surgery at any of the 1,283 VA medical facilities nationwide and compared postoperative complication rates by vaccination status. RESULTS: Of 87,073 surgical patients, 20% were fully vaccinated, 15% partially vaccinated, and 65% unvaccinated. Mortality was reduced in full vaccination vs. unvaccinated (Incidence Rate Ratio 0.77, 95% CI [0.62, 0.94]) and partially vaccinated vs. unvaccinated (0.75 [0.60, 0.94]). Postoperative COVID-19 infection was reduced in fully (0.18 [0.12, 0.26]) and partially vaccinated patients (0.34 [0.24, 0.48]). Fully vaccinated compared to partially vaccinated patients, had similar postoperative mortality (1.02, [0.78, 1.33]), but had decreased COVID-19 infection (0.53 [0.32, 0.87]), pneumonia (0.75 [0.62, 0.93]), and pulmonary failure (0.79 [0.68, 0.93]). CONCLUSIONS: Full and partial vaccination reduces postoperative complications indicating the importance of any degree of vaccination prior to surgery.

Low-Risk Papillary Thyroid Cancer: Treatment De-Escalation and Cost Implications.

INTRODUCTION: The American Thyroid Association (ATA) updated consensus guidelines in 2015 for radioactive iodine (RAI) and resection for low-risk papillary thyroid cancer. The objective of this study was to describe the evolution of institutional practice patterns and estimate the cost implications of these trends. MATERIALS AND METHODS: Patients with cT1-T2N0 papillary thyroid cancer were identified via an institutional tumor registry. Incidences of total thyroidectomy or RAI were tracked longitudinally using cumulative sum. Real-world costs for RAI and each surgical encounter were adjusted for inflation and standardized to national average costs from National Inpatient Sample cost data. RESULTS: Sixty-one patients met inclusion criteria between 2007 and 2018. Among these, 28 patients underwent total thyroidectomies and received RAI treatments based on criteria pre-dating the 2015 ATA guidelines. Cumulative sum revealed significant decreases in the rate of total thyroidectomy following May 2015 (15.8% versus 59.5%, P = 0.002) and RAI following March 2013 (3.0% versus 32.1%, P = 0.002). There were no locoregional recurrences in either period. The average cost savings attributable to these institutional practice changes was $1580 per patient. CONCLUSIONS: De-escalation in surgical and RAI utilization for low-risk papillary thyroid cancer according to 2015 ATA guidelines is associated with a substantial decrease in real-world costs.

miR-195 regulates intestinal epithelial restitution after wounding by altering actin-related protein-2 translation.

Early gut epithelial restitution reseals superficial wounds after acute injury, but the exact mechanism underlying this rapid mucosal repair remains largely unknown. MicroRNA-195 (miR-195) is highly expressed in the gut epithelium and involved in many aspects of mucosal pathobiology. Actin-related proteins (ARPs) are key components essential for stimulation of actin polymerization and regulate cell motility. Here, we reported that miR-195 modulates early intestinal epithelial restitution by altering ARP-2 expression at the translation level. miR-195 directly interacted with the ARP-2 mRNA, and ectopically expressed miR-195 decreased ARP-2 protein without effect on its mRNA content. In contrast, miR-195 silencing by transfection with anti-miR-195 oligo increased ARP-2 expression. Decreased ARP-2 levels by miR-195 overexpression were associated with an inhibition of early epithelial restitution, as indicated by a decrease in cell migration over the wounded area. Elevation of cellular ARP-2 levels by transfection with its transgene restored cell migration after wounding in cells overexpressing miR-195. Polyamines were found to decrease miR-195 abundance and enhanced ARP-2 translation, thus promoting epithelial restitution after wounding. Moreover, increasing the levels of miR-195 disrupted F-actin cytoskeleton organization, which was prevented by ARP2 overexpression. These results indicate that miR-195 inhibits early epithelial restitution by decreasing ARP-2 translation and that miR-195 expression is negatively regulated by cellular polyamines.

COVID-19 Vaccination Associated With Reduced Postoperative SARS-CoV-2 Infection and Morbidity.

OBJECTIVE: The purpose of this study was to determine the effect of COVID-19 vaccination on postoperative mortality, pulmonary and thrombotic complications, readmissions and hospital lengths of stay among patients undergoing surgery in the United States. BACKGROUND: While vaccination prevents COVID-19, little is known about its impact on postoperative complications. METHODS: This is a nationwide observational cohort study of all 1,255 Veterans Affairs facilities nationwide. We compared patients undergoing surgery at least 2 weeks after their second dose of the Pfizer BioNTech or Moderna vaccines, to contemporary propensity score matched controls. Primary endpoints were 30-day mortality and postoperative COVID-19 infection. Secondary endpoints were pulmonary or thrombotic complications, readmissions, and hospital lengths of stay. RESULTS: 30,681 patients met inclusion criteria. After matching, there were 3,104 in the vaccination group (1,903 received the Pfizer BioNTech, and 1,201 received the Moderna vaccine) and 7,438 controls. Full COVID-19 vaccination was associated with lower rates of postoperative 30-day COVID-19 infection (Incidence Rate Ratio and 95% confidence intervals, 0.09 [0.01,0.44]), pulmonary complications (0.54 [0.39, 0.72]), thrombotic complications (0.68 [0.46, 0.99]) and decreased hospital lengths of stay (0.78 [0.69, 0.89]). Complications were also low in vaccinated patients who tested COVID-19 positive before surgery but events were too few to detect a significant difference compared to controls. CONCLUSION: COVID-19 vaccination is associated with lower rates of postoperative morbidity. The benefit is most pronounced among individuals who have never had a COVID-19 infection before surgery.

Increased complications in patients who test COVID-19 positive after elective surgery and implications for pre and postoperative screening.

BACKGROUND: The COVID-19 pandemic has necessitated the adoption of protocols to minimize risk of periprocedural complications associated with SARS-CoV-2 infection. This typically involves a preoperative symptom screen and nasal swab RT-PCR test for viral RNA. Asymptomatic patients with a negative COVID-19 test are cleared for surgery. However, little is known about the rate of postoperative COVID-19 positivity among elective surgical patients, risk factors for this group and rate of complications. METHODS: This prospective multicenter study included all patients undergoing elective surgery at 170 Veterans Health Administration (VA) hospitals across the United States. Patients were divided into groups based on first positive COVID-19 test within 30 days after surgery (COVID[-/+]), before surgery (COVID[+/-]) or negative throughout (COVID[-/-]). The cumulative incidence, risk factors for and complications of COVID[-/+], were estimated using univariate analysis, exact matching, and multivariable regression. RESULTS: Between March 1 and December 1, 2020 90,093 patients underwent elective surgery. Of these, 60,853 met inclusion criteria, of which 310 (0.5%) were in the COVID[-/+] group. Adjusted multivariable logistic regression identified female sex, end stage renal disease, chronic obstructive pulmonary disease, congestive heart failure, cancer, cirrhosis, and undergoing neurosurgical procedures as risk factors for being in the COVID[-/+] group. After matching on current procedural terminology code and month of procedure, multivariable Poisson regression estimated the complication rate ratio for the COVID[-/+] group vs. COVID[-/-] to be 8.4 (C.I. 4.9-14.4) for pulmonary complications, 3.0 (2.2, 4.1) for major complications, and 2.6 (1.9, 3.4) for any complication. DISCUSSION: Despite preoperative COVID-19 screening, there remains a risk of COVID infection within 30 days after elective surgery. This risk is increased for patients with a high comorbidity burden and those undergoing neurosurgical procedures. Higher intensity preoperative screening and closer postoperative monitoring is warranted in such patients because they have a significantly elevated risk of postoperative complications.

Impact of the COVID-19 pandemic on diagnosis of new cancers: A national multicenter study of the Veterans Affairs Healthcare System.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic caused disruptions in treatment for cancer. Less is known about its impact on new cancer diagnoses, where delays could cause worsening long-term outcomes. This study quantifies decreases in encounters related to prostate, lung, bladder and colorectal cancers, procedures that facilitate their diagnosis, and new diagnoses of those cancers in the COVID era compared to pre-COVID era. METHODS: All encounters at Veterans' Affairs facilities nationwide from 2016 through 2020 were reviewed. The authors quantified trends in new diagnoses of cancer and in procedures facilitating their diagnosis, from January 1, 2018 onward. Using 2018 to 2019 as baseline, reductions in procedures and new cancer diagnoses in 2020 were estimated. Calculated absolute and percentage differences in annual volume and observed-to-expected volume ratios were calculated. Heat maps and funnel plots of volume changes were generated. RESULTS: From 2018 through 2020, there were 4.1 million cancer-related encounters, 3.9 million relevant procedures, and 251,647 new cancers diagnosed. Compared to the annual averages in 2018 through 2019, colonoscopies in 2020 decreased by 45% whereas prostate biopsies, chest computed tomography scans, and cystoscopies decreased by 29%, 10%, and 21%, respectively. New cancer diagnoses decreased by 13% to 23%. These drops varied by state and continued to accumulate despite reductions in pandemic-related restrictions. CONCLUSION: The authors identified substantial reductions in procedures used to diagnose cancer and subsequent reductions in new diagnoses of cancer across the United States because of the COVID-19 pandemic. A nomogram is provided to identify and resolve these unmet health care needs and avoid worse long-term cancer outcomes. LAY SUMMARY: The disruptions due to the COVID-19 pandemic have led to substantial reductions in new cancers being diagnosed. This study quantifies those reductions in a national health care system and offers a method for understanding the backlog of cases and the resources needed to resolve them.

A Nation-Wide Review of Elective Surgery and COVID-Surge Capacity.

BACKGROUND: The COVID-19 pandemic has resulted in over 225,000 excess deaths in the United States. A moratorium on elective surgery was placed early in the pandemic to reduce risk to patients and staff and preserve critical care resources. This report evaluates the impact of the elective surgical moratorium on case volumes and intensive care unit (ICU) bed utilization. METHODS: This retrospective review used a national convenience sample to correlate trends in the weekly rates of surgical cases at 170 Veterans Affairs Hospitals around the United States from January 1 to September 30, 2020 to national trends in the COVID-19 pandemic. We reviewed data on weekly number of procedures performed and ICU bed usage, stratified by level of urgency (elective, urgent, emergency), and whether an ICU bed was required within 24 hours of surgery. National data on the proportion of COVID-19 positive test results and mortality rates were obtained from the Center for Disease Control website. RESULTS: 198,911 unique surgical procedures performed during the study period. The total number of cases performed from January 1 to March 16 was 86,004 compared with 15,699 from March 17 to May 17. The reduction in volume occurred before an increase in the percentage of COVID-19 positive test results and deaths nationally. There was a 91% reduction from baseline in the number of elective surgeries performed allowing 78% of surgical ICU beds to be available for COVID-19 positive patients. CONCLUSION: The moratorium on elective surgical cases was timely and effective in creating bed capacity for critically ill COVID-19 patients. Further analyses will allow targeted resource allocation for future pandemic planning.

Periprocedural complications in patients with SARS-CoV-2 infection compared to those without infection: A nationwide propensity-matched analysis.

BACKGROUND: Reports on emergency surgery performed soon after a COVID-19 infection that are not controlled for premorbid risk-factors show increased 30-day mortality and pulmonary complications. This contributed to a virtual cessation of elective surgery during the pandemic surge. To inform evidence-based guidance on the decisions for surgery during the recovery phase of the pandemic, we compare 30-day outcomes in patients testing positive for COVID-19 before their operation, to contemporary propensity-matched COVID-19 negative patients undergoing the same procedures. METHODS: This prospective multicentre study included all patients undergoing surgery at 170 Veterans Health Administration (VA) hospitals across the United States. COVID-19 positive patients were propensity matched to COVID-19 negative patients on demographic and procedural factors. We compared 30-day outcomes between COVID-19 positive and negative patients, and the effect of time from testing positive to the date of procedure (≤10 days, 11-30 days and >30 days) on outcomes. RESULTS: Between March 1 and August 15, 2020, 449 COVID-19 positive and 51,238 negative patients met inclusion criteria. Propensity matching yielded 432 COVID-19 positive and 1256 negative patients among whom half underwent elective surgery. Infected patients had longer hospital stays (median seven days), higher rates of pneumonia (20.6%), ventilator requirement (7.6%), acute respiratory distress syndrome (ARDS, 17.1%), septic shock (13.7%), and ischemic stroke (5.8%), while mortality, reoperations and readmissions were not significantly different. Higher odds for ventilation and stroke persisted even when surgery was delayed 11-30 days, and for pneumonia, ARDS, and septic shock >30 days after a positive test. DISCUSSION: 30-day pulmonary, septic, and ischaemic complications are increased in COVID-19 positive, compared to propensity score matched negative patients. Odds for several complications persist despite a delay beyond ten days after testing positive. Individualized risk-stratification by pulmonary and atherosclerotic comorbidities should be considered when making decisions for delaying surgery in infected patients.

Long Noncoding RNA H19 Impairs the Intestinal Barrier by Suppressing Autophagy and Lowering Paneth and Goblet Cell Function.

BACKGROUND & AIMS: The protective intestinal mucosal barrier consists of multiple elements including mucus and epithelial layers and immune defense; nonetheless, barrier dysfunction is common in various disorders. The imprinted and developmentally regulated long noncoding RNA H19 is involved in many cell processes and diseases. Here, we investigated the role of H19 in regulating Paneth and goblet cells and autophagy, and its impact on intestinal barrier dysfunction induced by septic stress. METHODS: Studies were conducted in H19-deficient (H19-/-) mice, mucosal tissues from patients with sepsis, primary enterocytes, and Caco-2 cells. Septic stress was induced by cecal ligation and puncture (CLP), and gut permeability was detected by tracer fluorescein isothiocyanate-dextran assays. The function of Paneth and goblet cells was examined by immunostaining for lysozyme and mucin 2, respectively, and autophagy was examined by microtubule-associated proteins 1A/1B light chain 3 II immunostaining and Western blot analysis. Intestinal organoids were isolated from H19-/- and control littermate mice and treated with lipopolysaccharide (LPS). RESULTS: Intestinal mucosal tissues in mice 24 hours after exposure to CLP and in patients with sepsis showed high H19 levels, associated with intestinal barrier dysfunction. Targeted deletion of the H19 gene in mice enhanced the function of Paneth and goblet cells and promoted autophagy in the small intestinal mucosa. Knockout of H19 protected Paneth and goblet cells against septic stress, preserved autophagy activation, and promoted gut barrier function after exposure to CLP. Compared with organoids from control littermate mice, intestinal organoids isolated from H19-/- mice had increased numbers of lysozyme- and mucin 2-positive cells and showed increased tolerance to LPS. Conversely, ectopic overexpression of H19 in cultured intestinal epithelial cells prevented rapamycin-induced autophagy and abolished the rapamycin-induced protection of the epithelial barrier against LPS. CONCLUSIONS: In investigations of mice, human tissues, primary organoids, and intestinal epithelial cells, we found that increased H19 inhibited the function of Paneth and goblet cells and suppressed autophagy, thus potentially contributing to barrier dysfunction in intestinal pathologies.

MiR-199a-3p decreases esophageal cancer cell proliferation by targeting p21 activated kinase 4.

Although microRNA (miR) 199a-3p functions as a tumor suppressor in multiple malignancies, its expression and role in esophageal cancer have not been studied. Based on our previous observation that miR-199a-3p is markedly downregulated in esophageal cancer cell lines relative to esophageal epithelial cells, we examined the function of miR-199a-3p in these cells. MiR-199a-3p is predicted to bind with high affinity to the mRNA of p21 activated kinase 4 (PAK4). This kinase has been shown to be overexpressed in several malignancies and to modulate proliferation and motility. The current study is designed to determine whether miR-199a-3p regulates the expression of PAK4 in esophageal cancer cells and to understand the functional consequences of this interaction. Herein, we demonstrate reduced expression of miR-199a-3p in human esophageal cancer specimens and cell lines compared to esophageal epithelial cells, with associated increased expression of PAK4. Forced expression of miR-199a-3p decreases expression of PAK4 in esophageal cancer cell lines. Mechanistic studies reveal that miR-199a-3p binds to the 3'UTR of PAK4 mRNA. This interaction results in reduced levels of PAK4 mRNA due to decreased mRNA stability. Downregulation of PAK4 leads to decreased cyclin D1 (CD1) transcription and protein expression, resulting in markedly impaired cellular proliferation. When PAK4 expression is rescued, both CD1 transcription and protein return to baseline levels. Our results show that miR-199a-3p functions as a tumor suppressor in esophageal cancer cells through repression of PAK4. These findings suggest that both miR-199a-3p and PAK4 may be novel therapeutic targets in the treatment of esophageal cancer.