Profound Treg perturbations correlate with COVID-19 severity.

The hallmark of severe COVID-19 is an uncontrolled inflammatory response, resulting from poorly understood immunological dysfunction. We hypothesized that perturbations in FoxP3+ T regulatory cells (Treg), key enforcers of immune homeostasis, contribute to COVID-19 pathology. Cytometric and transcriptomic profiling revealed a distinct Treg phenotype in severe COVID-19 patients, with an increase in Treg proportions and intracellular levels of the lineage-defining transcription factor FoxP3, correlating with poor outcomes. These Tregs showed a distinct transcriptional signature, with overexpression of several suppressive effectors, but also proinflammatory molecules like interleukin (IL)-32, and a striking similarity to tumor-infiltrating Tregs that suppress antitumor responses. Most marked during acute severe disease, these traits persisted somewhat in convalescent patients. A screen for candidate agents revealed that IL-6 and IL-18 may individually contribute different facets of these COVID-19-linked perturbations. These results suggest that Tregs may play nefarious roles in COVID-19, by suppressing antiviral T cell responses during the severe phase of the disease, and by a direct proinflammatory role.

An Exploratory Analysis of the Association Between Catechol-O-Methyltransferase and Response to a Randomized Open-Label Placebo Treatment for Cancer-Related Fatigue.

Previous studies have identified catechol-O-methyltransferase (COMT), as a key enzyme influencing sympathetic function. Although the COMT SNP rs4680 and rs4818, are well-studied, little is known about their influence on cancer-related fatigue (CrF) and placebo response. In this study, we examined whether genetic variation in COMT, at the functional SNP rs4680 and linked rs4818, influenced open-label placebo (OLP) responses found in cancer survivors reporting moderate to severe CrF. We randomized cancer survivors (N = 74) reporting moderate-to-severe CrF to receive OLP or to treatment-as-usual (TAU) and assessed if rs4680 and rs4818 were associated with changes in fatigue severity and fatigue-distressed quality of life. At the end of the initial 21 days, the treatments were crossed over and both groups were re-assessed. Participants with the rs4680 high-activity G-allele (G/G or G/A) or rs4818 C/G genotypes reported significant decreases in fatigue severity and improvements in fatigue-distressed quality of life. The COMT rs4818 findings replicated findings in a similar study of OLP in cancer fatigue. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT02522988.

Profound Treg perturbations correlate with COVID-19 severity.

The hallmark of severe COVID-19 disease has been an uncontrolled inflammatory response, resulting from poorly understood immunological dysfunction. We explored the hypothesis that perturbations in FoxP3+ T regulatory cells (Treg), key enforcers of immune homeostasis, contribute to COVID-19 pathology. Cytometric and transcriptomic profiling revealed a distinct Treg phenotype in severe COVID-19 patients, with an increase in both Treg proportions and intracellular levels of the lineage-defining transcription factor FoxP3, which correlated with poor outcomes. Accordingly, these Tregs over-expressed a range of suppressive effectors, but also pro-inflammatory molecules like IL32. Most strikingly, they acquired similarity to tumor-infiltrating Tregs, known to suppress local anti-tumor responses. These traits were most marked in acute patients with severe disease, but persisted somewhat in convalescent patients. These results suggest that Tregs may play nefarious roles in COVID-19, via suppressing anti-viral T cell responses during the severe phase of the disease, and/or via a direct pro-inflammatory role.

SARS-CoV-2 viral load is associated with increased disease severity and mortality.

The relationship between SARS-CoV-2 viral load and risk of disease progression remains largely undefined in coronavirus disease 2019 (COVID-19). Here, we quantify SARS-CoV-2 viral load from participants with a diverse range of COVID-19 disease severity, including those requiring hospitalization, outpatients with mild disease, and individuals with resolved infection. We detected SARS-CoV-2 plasma RNA in 27% of hospitalized participants, and 13% of outpatients diagnosed with COVID-19. Amongst the participants hospitalized with COVID-19, we report that a higher prevalence of detectable SARS-CoV-2 plasma viral load is associated with worse respiratory disease severity, lower absolute lymphocyte counts, and increased markers of inflammation, including C-reactive protein and IL-6. SARS-CoV-2 viral loads, especially plasma viremia, are associated with increased risk of mortality. Our data show that SARS-CoV-2 viral loads may aid in the risk stratification of patients with COVID-19, and therefore its role in disease pathogenesis should be further explored.

Validation of the Khorana Score to Assess Venous Thromboembolism and Its Association with Mortality in Cancer Patients: A Retrospective Community-based Observational Experience.

INTRODUCTION: Khorana score (KS) stratifies patients into low, intermediate, and high risk groups for venous thromboembolism (VTE). We examined the generalizability of the KS to risk of VTE and association with mortality. METHODS: A retrospective cohort study was conducted at Mount Auburn Hospital, Cambridge, Massachusetts. Patients aged 18 years or older undergoing chemotherapy were included. All patients were evaluated for a six-month period. Primary study endpoints were VTE or mortality. RESULTS: Some 277 participants were included with a mean age of 63.95 (standard deviation, SD ± 12.47). The incidence proportion was 6.13% and a total of 17 VTE events were reported over a 2.5-year period. Compared to those with a low KS (0), those with a high KS (3 or above) had 6.4 times (p=0.032) while with an intermediate KS (1-2) had 2.6 times the odds of having a VTE event (p=0.22). Those who had a VTE had 4.03 times the odds of death compared to those who did not have a VTE (p=0.006). Compared to those with a low KS, those with a high KS had 5.7 times (p=0.02) the odds of six-month mortality and 5.04 odds (p=0.001) of mortality at any time. CONCLUSION: High KS was associated with increased odds of VTE and mortality in our study.

Plasmacytoid dendritic cells orchestrate innate and adaptive anti-tumor immunity induced by oncolytic coxsackievirus A21.

BACKGROUND: The oncolytic virus, coxsackievirus A21 (CVA21), has shown promise as a single agent in several clinical trials and is now being tested in combination with immune checkpoint blockade. Combination therapies offer the best chance of disease control; however, the design of successful combination strategies requires a deeper understanding of the mechanisms underpinning CVA21 efficacy, in particular, the role of CVA21 anti-tumor immunity. Therefore, this study aimed to examine the ability of CVA21 to induce human anti-tumor immunity, and identify the cellular mechanism responsible. METHODS: This study utilized peripheral blood mononuclear cells from i) healthy donors, ii) Acute Myeloid Leukemia (AML) patients, and iii) patients taking part in the STORM clinical trial, who received intravenous CVA21; patients receiving intravenous CVA21 were consented separately in accordance with local institutional ethics review and approval. Collectively, these blood samples were used to characterize the development of innate and adaptive anti-tumor immune responses following CVA21 treatment. RESULTS: An Initial characterization of peripheral blood mononuclear cells, collected from cancer patients following intravenous infusion of CVA21, confirmed that CVA21 activated immune effector cells in patients. Next, using hematological disease models which were sensitive (Multiple Myeloma; MM) or resistant (AML) to CVA21-direct oncolysis, we demonstrated that CVA21 stimulated potent anti-tumor immune responses, including: 1) cytokine-mediated bystander killing; 2) enhanced natural killer cell-mediated cellular cytotoxicity; and 3) priming of tumor-specific cytotoxic T lymphocytes, with specificity towards known tumor-associated antigens. Importantly, immune-mediated killing of both MM and AML, despite AML cells being resistant to CVA21-direct oncolysis, was observed. Upon further examination of the cellular mechanisms responsible for CVA21-induced anti-tumor immunity we have identified the importance of type I IFN for NK cell activation, and demonstrated that both ICAM-1 and plasmacytoid dendritic cells were key mediators of this response. CONCLUSION: This work supports the development of CVA21 as an immunotherapeutic agent for the treatment of both AML and MM. Additionally, the data presented provides an important insight into the mechanisms of CVA21-mediated immunotherapy to aid the development of clinical biomarkers to predict response and rationalize future drug combinations.

Systems pharmacogenomics - gene, disease, drug and placebo interactions: a case study in COMT.

Disease, drugs and the placebos used as comparators are inextricably linked in the methodology of the double-blind, randomized controlled trial. Nonetheless, pharmacogenomics, the study of how individuals respond to drugs based on genetic substrate, focuses primarily on the link between genes and drugs, while the link between genes and disease is often overlooked and the link between genes and placebos is largely ignored. Herein, we use the example of the enzyme catechol-O-methyltransferase to examine the hypothesis that genes can function as pharmacogenomic hubs across system-wide regulatory processes that, if perturbed in andomized controlled trials, can have primary and combinatorial effects on drug and placebo responses.

COMT and Alpha-Tocopherol Effects in Cancer Prevention: Gene-Supplement Interactions in Two Randomized Clinical Trials.

BACKGROUND: Vitamins are among the most frequently used supplements (48% of US adults). However, little is known about contributions of genetic variation to their efficacy and safety. Multiple pathways link catechol-O-methyltransferase (COMT) to the vitamin E supplement, alpha-tocopherol, and cancer. METHODS: Here we determined if COMT exerted pharmacogenetic effects on cancer prevention in two randomized trials of alpha-tocopherol supplementation. Pharmacogenetic effects of common COMT rs4680 (val158met), which encodes a nonsynonymous valine-to-methionine substitution, were examined in the trial plus a 10-year post-trial follow-up (overall) period of The Women's Genome Health Study (WGHS, N = 23 294), a 10-year alpha-tocopherol and aspirin trial with 10 years post-trial follow-up. Results were validated in a case/control (N = 2396/2235) subset of the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study (ATBC, N = 29 133). The primary outcome was total cancers. Rates of cancer types prevalent in women (colorectal, breast, lung, uterine, and lymphoma/leukemia) were also examined. All statistical tests were two-sided. RESULTS: Random-effects meta-analysis of rs4680 genotype strata, in WGHS and ATBC overall periods, revealed differential alpha-tocopherol effects compared with placebo: met/met (hazard ratio [HR] = 0.88; 95% confidence interval [CI] = 0.80 to 0.97; P = .01), val/met (HR = 0.99; 95% CI = 0.92 to 1.06; P = .74), and val/val (HR = 1.18; 95% CI = 1.06 to 1.31; P = .002) with a statistically significant COMT by alpha-tocopherol interaction (Pinteraction <.001). Timing of effects differed, with stronger effects in WGHS trial and ATBC post-trial. CONCLUSION: Pharmacogenetic analysis of COMT and cancer prevention in two large randomized trials revealed statistically significant COMT by alpha-tocopherol interaction, such that alpha-tocopherol was beneficial among rs4680 met-allele (28.0%), but not val-allele (22.8%) homozygotes. These effects indicate the need for additional studies of genetic variation as a determinant of the benefits and possible harms of over-the-counter supplements, like alpha-tocopherol, used for health promotion.

Open-label placebo reduces fatigue in cancer survivors: a randomized trial.

PURPOSE: Cancer-related fatigue (CRF) is a common and challenging late effect for many cancer survivors. Clinical trials demonstrate robust placebo effects on CRF in blinded trials. Recently, open-label placebo (OLP) has been shown to improve a variety of symptoms in other populations. We conducted a randomized controlled trial to investigate the effect of OLP on CRF in cancer survivors, and to explore biologic and psychological correlates of placebo efficacy. METHODS: Forty cancer survivors (92.5% female; mean age 47.3 years) were randomized to OLP or no treatment control. OLP participants were prescribed two placebo tablets twice daily, for 3 weeks. All participants completed assessments at Baseline, Day 8, and Day 22. The primary endpoint was change in CRF (FACIT-F), and secondary outcomes included exercise frequency, mood, and quality of life. We examined whether personality characteristics or a genetic variation important in dopamine catabolism (catechol-O-methyltransferase; COMT) affected the placebo response. RESULTS: The OLP group reported significantly improved CRF at both Day 8 (p = 0.005) and Day 22 (p = .02), while the control group did not (ps > .05). CRF improvement differed by COMT genotype, but was not associated with personality characteristics. Marginal improvements were noted in the placebo group for some secondary outcomes (exercise frequency and quality of life), but not in the control group. CONCLUSIONS: Results demonstrate that even when administered openly, placebos improve CRF in cancer survivors and dopaminergic systems may be associated with this response. This novel research has meaningful implications for the use of OLP in symptom management for cancer survivors.

Transversus abdominis block utilizing liposomal bupivacaine as a non-opioid analgesic for postoperative pain management.

INTRODUCTION: The use of non-narcotic modalities for postoperative analgesia may decrease exposure to opioids, thereby limiting their deleterious effects. The objective of this study was to determine the effectiveness of a liposomal bupivacaine transverse abdominis plane (TAP) block prior to laparoscopic sleeve gastrectomy (LSG) and laparoscopic gastric bypass (LRYGB). The primary outcome was total postoperative morphine equivalents. METHODS: A single-surgeon, IRB-approved retrospective chart review was performed on consecutive patients who underwent LRYGB or LSG from 2010 to 2016. Patients were grouped according to those who received TAP blocks immediately preoperatively with rescue opioids (TAP group) and those who received PCA only (PCA group). Total parenteral morphine equivalents (PME) were calculated. Numerical pain scores were collected immediately following surgery, 12 h postoperatively, and on the day of discharge. Median length of stay (LOS) and 30-day readmissions were also calculated. RESULTS: There were 440 patients who met inclusion criteria. The TAP group had significantly less opioid use (total PME) than the PCA, irrespective of surgical approach (70.4 ± 2.7 PCA LRYGB and 26.5 ± 1.5 TAP block LRYGB, p value ≤ 0.0001; 60.0 ± 3.5 PCA LSG vs. and 24.1 ± 2.0 TAP block LSG, p value < 0.0001). Median LOS was 2.0 days for both PCA groups, whereas LOS decreased to 1.0 day for both groups of patients receiving TAP blocks (p < 0.0001). Pain scores immediately following and 12 h after surgery were significantly elevated in the TAP LRYGB versus PCA LRYGB (p < 0.05) and immediately following surgery for PCA versus TAP block for LSG (p = 0.0109). CONCLUSIONS: TAP blocks with liposomal bupivacaine lead to significantly less use of parenteral morphine equivalents and decreased LOS compared to PCA alone. Pain scores were higher in the TAP LRYGB group compared to the LRYGB PCA group, with no differences in pain scores noted in the LSG groups.

The Association Between C-Reactive Protein and Postoperative Delirium Differs by Catechol-O-Methyltransferase Genotype.

OBJECTIVE: Catechol-O-methyltransferase (COMT), a key enzyme in degrading catecholamines associated with the stress response, may influence susceptibility to delirium. Individuals with the COMT (rs4680) Val/Val genotype (designated "warriors") withstand the onset of neuropsychiatric disorders and cognitive decline, whereas individuals with Met/Met and Val/Met genotypes ("nonwarriors") are more susceptible to these conditions. We evaluated whether COMT genotype modifies the established association between acute phase reactant (stress marker) C-reactive protein (CRP) and postoperative delirium. METHODS: This was a prospective cohort study conducted at two academic medical centers. The study involved 547 patients aged 70 or older undergoing major noncardiac surgery. We collected blood, extracted DNA, and performed COMT genotyping using allele-specific polymerase chain reaction assays, considering warriors versus nonwarriors. High plasma CRP, measured on postoperative day 2 using enzyme-linked immunosorbent assay, was defined by the highest sample-based quartile (≥234.12 mg/L). Delirium was determined using the Confusion Assessment Method, augmented by a validated chart review. We used generalized linear models adjusted for age, sex, surgery type, and race/ethnicity, stratified by COMT genotype, to determine whether the association between CRP and delirium differed by COMT. RESULTS: Prevalence of COMT warriors was 26%, and postoperative delirium occurred in 23%. Among COMT warriors, high CRP was not associated with delirium (relative risk [RR] 1.0, 95% confidence interval [CI] 0.4-2.6). In contrast, among nonwarriors, we found the expected relationship of high CRP and delirium (RR 1.5, 95% CI 1.1-2.2). CONCLUSION: COMT warriors may be protected against the increased risk of delirium associated with high CRP on postoperative day 2. With further confirmation, COMT genotype may help target interventions for delirium prevention in the vulnerable nonwarrior group.

Endoscopic Corneal Neurotization: Cadaver Feasibility Study.

PURPOSE: The authors describe a cadaver feasibility study investigating a minimally invasive technique for corneal neurotization with the supraorbital nerve harvested endoscopically. METHODS: A cadaver study was performed to investigate the technical feasibility of corneal neurotization via endoscopic supraorbital nerve transfer to the corneoscleral limbus. RESULTS: Endoscopic corneal neurotization was successfully performed on each cadaveric hemiface. CONCLUSION: The use of an endoscope allows for a minimally invasive approach to corneal neurotization with the supraorbital nerve.

Value of Patient-Directed Brain Magnetic Resonance Imaging Scan with a Diagnosis of Migraine.

BACKGROUND: The objective of this study was to determine whether a brain magnetic resonance imaging (MRI) scan in patients with a diagnosis of migraine, who insist on the performance of imaging, is of more benefit in detecting clinically significant unsuspected structural abnormalities than would be expected by chance. METHODS: This prospective, observational, single-center study was performed from January 1, 2010 to December 31, 2012 and included 100 subjects with a diagnosis of migraine and normal results on neurologic examination. A brain MRI scan was performed on all patients, solely at their request, to detect an unsuspected clinically significant structural lesion. RESULTS: Of the 100 patients, 86 were female, and the average age was 31.5 years. Forty-five patients experienced migraine without aura, 41 chronic migraine, and 14 migraine with aura. All of the patients had normal results on neurologic examination. The duration of headaches ranged from 4 months to 40 years. In all, 82 of the MRI scans showed normal results, and 17 revealed clinically insignificant abnormalities. One MRI in a patient with chronic migraine without aura revealed a meningioma that subsequently required surgery and radiation therapy. The 1% prevalence of tumor in this study was then compared with 2 large cohorts of MRI abnormalities in the general asymptomatic population, in which tumor was found in 35 out of 3000. Fisher's exact test was used to compare the prevalence of tumor in the study population with the combined cohorts, and there was no statistical difference between these rates (P > .99). CONCLUSIONS: Brain MRI obtained at the specific request of patients with a diagnosis of migraine in the presence of normal neurologic examination results has a yield that is equivalent to that of the general asymptomatic population. Patients do not seem to have more insight than the examining clinician with regard to detecting underlying structural abnormalities, and brain MRI should not performed as part of the routine evaluation of migraine without a clear clinical indication.

Dopaminergic tone does not influence pain levels during placebo interventions in patients with chronic neuropathic pain.

Placebo effects have been reported in patients with chronic neuropathic pain. Expected pain levels and positive emotions are involved in the observed pain relief, but the underlying neurobiology is largely unknown. Patients with neuropathic pain are highly motivated for pain relief, and as motivational factors such as expectations of reward, as well as pain processing in itself, are related to the dopaminergic system, it can be speculated that dopamine release contributes to placebo effects in neuropathic pain. Nineteen patients with neuropathic pain after thoracic surgery were tested during a placebo intervention consisting of open and hidden applications of the pain-relieving agent lidocaine (2 mL) and no treatment. The dopamine antagonist haloperidol (2 mg) and the agonist levodopa/carbidopa (100/25 mg) were administered to test the involvement of dopamine. Expected pain levels, desire for pain relief, and ongoing and evoked pain were assessed on mechanical visual analog scales (0-10). Significant placebo effects on ongoing (P ≤ 0.003) and evoked (P ≤ 0.002) pain were observed. Expectancy and desire accounted for up to 41.2% and 71.5% of the variance in ongoing and evoked pain, respectively, after the open application of lidocaine. We found no evidence for an effect of haloperidol and levodopa/carbidopa on neuropathic pain levels (P = 0.071-0.963). Dopamine seemed to influence the levels of expectancy and desire, yet there was no evidence for indirect or interaction effects on the placebo effect. This is the first study to suggest that dopamine does not contribute to placebo effects in chronic neuropathic pain.

Cytotoxic Guanidine Alkaloids from a French Polynesian Monanchora n. sp. Sponge.

Four bicyclic and three pentacyclic guanidine alkaloids (1-7) were isolated from a French Polynesian Monanchora n. sp. sponge, along with the known alkaloids monalidine A (8), enantiomers 9-11 of known natural product crambescins, and the known crambescidins 12-15. Structures were assigned by spectroscopic data interpretation. The relative and absolute configurations of the alkaloids were established by analysis of (1)H NMR and NOESY spectra and by circular dichroism analysis. The new norcrambescidic acid (7) corresponds to interesting biosynthetic variation within the pentacyclic core. All compounds exhibited antiproliferative and cytotoxic efficacy against KB, HCT116, HL60, MRC5, and B16F10 cancer cells, with IC50 values ranging from 4 nM to 10 µM.

The Effect of Anesthetic Choice (Sevoflurane Versus Desflurane) and Neuromuscular Management on Speed of Airway Reflex Recovery.

BACKGROUND: Nonintubated patients receiving sevoflurane have slower protective airway reflex recovery after anesthesia compared with patients receiving desflurane. We asked whether this difference would remain significant among intubated patients receiving rocuronium or whether the impact of variable neuromuscular recovery would predominate and thus minimize differences between anesthetics. METHODS: After obtaining written informed consent, patients were randomly assigned to receive sevoflurane (n = 41) or desflurane (n = 40), with neuromuscular monitoring by quantitative train-of-four (TOF) method using accelerometry. Intubation was facilitated by administration of 1 mg/kg rocuronium. Neuromuscular block was produced, with the goal of maintaining 10% to 15% of baseline function. After surgery, neostigmine 70 µg/kg + glycopyrrolate 14 µg/kg was administered. When TOF ratio reached ≥ 0.7, anesthetic was discontinued and fresh gas flow was raised to 15 L/m. The time of first response to command was noted, after which patients were given a 20-mL water swallowing test at 2, 6, 14, 22, 30, and 60 minutes. The following average time intervals were compared between the 2 intervention groups: anesthetic discontinuation to first response to command (T1); first response to command to first successful passing of swallow test (T2); and anesthetic discontinuation to first successful passing of swallow test (T3). We also compared the rates of successful swallow tests at 2 minutes after first response to command in the 2 groups, first categorizing as failures all those who were unable to take the test at 2 minutes, and then excluding 10 patients unable to take the test at this time for reasons other than somnolence (n = 10). RESULTS: Patients receiving desflurane passed the swallowing test at shorter time intervals after first response to command than did patients receiving sevoflurane (Wilcoxon-Mann-Whitney odds = 1.60; 95% confidence interval [CI], 1.01-2.69; P = 0.054). Two minutes after the first response to command, among all 81 patients, the chance of passing the swallowing test was higher after desflurane compared with sevoflurane anesthesia (relative risk = 1.6; 95% CI, 1.0-2.5; P = 0.04). Of the 71 patients (as above), we observed a significantly higher chance of passing at 2 minutes after first response to command (relative risk = 1.8; 95% CI, 1.2-2.7; P = 0.006) in patients receiving desflurane (25/33) compared with those receiving sevoflurane (16/38). In 18 of 81 and 16 of 71 patients, the neuromuscular monitoring and reversal protocols were not followed (neostigmine underdosed, extubation at TOF <0.7, or reliance on tactile as opposed to quantitative TOF measurement). In both the total cohort and the subset of 71, neuromuscular protocol adherence increased the chance of passing the swallow test, independent of anesthetic assignment in multivariable logistic regression (P = 0.02 and P = 0.006, respectively), demonstrating significant effect on airway reflex recovery independent of chosen anesthetic. CONCLUSIONS: Compared with sevoflurane, desflurane allowed faster recovery of airway reflexes after anesthesia in intubated patients. Clinical management of neuromuscular block, including full reversal and the use of quantitative TOF, affects airway reflex recovery-an effect that may be at least as profound as the choice of potent inhaled anesthetic.

Enteral nutrition: what the dietitian prescribes is not what the burn patient gets!

Enteral nutrition (EN) is commonly interrupted in burn patients for many reasons, which leads to discrepancies between prescribed and actual EN delivery. The magnitude and origin of these discrepancies have never been well documented among burn patients. The purpose of this study was to examine differences between prescribed and actual EN delivery and to identify the specific causes of EN interruption and to quantify these. Retrospective review of patients treated between June 6, 2009 and June 6, 2012 at an adult regional American Burn Association-verified burn center who had ≥10% TBSA burns and who were prescribed EN for at least 24 hours. On postburn days (PBD) 0 to 14 the daily volume of EN prescribed by the dietitian was compared with the actual volume received by the patient. The cause and duration of interruptions to EN delivery were recorded. A total of 90 subjects, [mean (± SD) age 47 ± 18 years, 32% female, median %TBSA burn size 28, median %TBSA full-thickness burn size 11, and a 54% incidence of inhalation injury], were studied. EN was initiated at a median of 9.5 hours after burn center admission. Received calories were significantly less than prescribed calories on every study day. The median daily caloric deficit ranged between 172 and 930 kcal. The median percent of prescribed calories received each day ranged from 19% on PBD 0 to 91% on PBD 14. The mean (± SD) total duration of EN interruption was 8.9 ± 3.0 hours per day. Gradually increasing the feed rate to reach the prescribed EN goal rate ("ramping-in") was the most common cause of a discrepancy between prescribed and actual EN delivery, accounting for 35% of total discrepancy time. Interruptions for surgery accounted for 24% of total discrepancy time. Other causes of discrepancies were physician- or nurse-directed interruptions (16% of time), planned extubation (7%), feed intolerance (11%), tube malfunction (2%), bedside procedures (2%), and dressing changes (3%).Enterally fed burn patients received significantly less nutrition than prescribed. Some of the causes for discrepancies between prescribed and received EN are unavoidable, but many are not, suggesting the need for careful review and possible alteration of existing EN practices.

The frontotemporal-orbitozygomatic approach: reconstructive technique and outcome.

BACKGROUND: The frontotemporal-orbitozygomatic (FTOZ) approach, also known as "the workhorse of skull base surgery," has captured the interest of many researchers throughout the years. Most of the studies published have focused on the surgical technique and the gained exposure. However, few studies have described reconstructive techniques or functional and cosmetic outcomes. The goal of this study was to describe the surgical reconstruction after the FTOZ approach and analyze the functional and cosmetic outcomes. METHODS: Seventy-five consecutive patients who had undergone FTOZ craniotomy for different reasons were selected. The same surgical (one-piece FTOZ) and reconstructive techniques were applied in all patients. The functional outcome was measured by complications related to the surgical approach: retro-orbital pain, exophthalmos, enophthalmos, ocular movement restriction, cranial nerve injuries, pseudomeningocele (PMC) and secondary surgeries required to attain a reconstructive closure. The cosmetic outcome was evaluated by analyzing the satisfaction of the patients and their families. Questionnaires were conducted later in the postoperative period. A statistical analysis of the data obtained from the charts and questions was performed. RESULTS: Of the 75 patients studied, 59 had no complications whatsoever. Ocular movement restriction was found in two patients (2.4 %). Cranial nerve injury was documented in seven patients (8.5 %). One patient (1.2 %) underwent surgical repair of a cerebrospinal fluid (CSF) leak from the initial surgery. Two patients (2.4 %) developed delayed postoperative pseudomenigocele. One patient (1.2 %) developed intraparenchymal hemorrhage (IPH). Full responses to the questionnaires were collected from 28 patients giving an overall response rate of 34 %. Overall, 22 patients (78.5 %) were satisfied with the cosmetic outcome of surgery. CONCLUSION: The reconstruction after FTOZ approach is as important as the performance of the surgical technique. Attention to anatomical details and the stepwise reconstruction are a prerequisite to the successful preservation of function and cosmesis. In our series, the orbitozygomatic osteotomy did not increase surgical complications or alter cosmetic outcomes.

Impact of human adenovirus type 3 dodecahedron on host cells and its potential role in viral infection.

During human adenovirus type 3 (Ad3) infection, an excess of penton base and fiber proteins are produced which form dodecahedral particles composed of 12 pentamers of penton base and 12 trimers of fiber protein. No biological functions have yet been ascribed to Ad3 dodecahedra. Here, we show that dodecahedra compete with Ad3 virions for binding to the cell surface and trigger cell remodeling, giving new insights into possible biological functions of dodecahedra in the Ad3 infectious cycle.

Reovirus-mediated cytotoxicity and enhancement of innate immune responses against acute myeloid leukemia.

Reovirus is a naturally occurring oncolytic virus that has shown preclinical efficacy in the treatment of a wide range of tumor types and has now reached phase III testing in clinical trials. The anti-cancer activity of reovirus has been attributed to both its direct oncolytic activity and the enhancement of anti-tumor immune responses. In this study, we have investigated the direct effect of reovirus on acute myeloid leukemia (AML) cells and its potential to enhance innate immune responses against AML, including the testing of primary samples from patients. Reovirus was found to replicate in and kill AML cell lines, and to reduce cell viability in primary AML samples. The pro-inflammatory cytokine interferon alpha (IFNα) and the chemokine (C-C motif) ligand 5 (known as RANTES [regulated upon activation, normal T-cell expressed, and secreted]) were also secreted from AML cells in response to virus treatment. In addition, reovirus-mediated activation of natural killer (NK) cells, within the context of peripheral blood mononuclear cells, stimulated their anti-leukemia response, with increased NK degranulation and IFNγ production and enhanced killing of AML targets. These data suggest that reovirus has the potential as both a direct cytotoxic and an immunotherapeutic agent for the treatment of AML.