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The opioid crisis is a national health emergency with immense morbidity, mortality, and socioeconomic cost. Emergency department (ED) pain management is tightly linked to the issue of opioid use disorder (OUD), because opioid exposure is necessary for development of OUD. Emergency nurses are on the frontlines of this complex problem, yet little, if any, attention has been paid to the role they play in the prevention and management of either pain or OUD in this unique and important setting. A framework that conceptualizes and optimizes emergency nurses as change agents in the opioid epidemic is urgently needed. While ED pain management and OUD prevention is dependent on the entire care team, this innovative study qualitatively characterizes emergency nurse perceptions of pain management, OUD prevention, and their potential role in each. Content analysis produced 14 categories that were clustered into two themes, “nurses influence ED pain management” and “adjustments in ED pain management”, and an overarching message that “pain management depends on the care team.” By generating a more comprehensive and nuanced understanding of the role played by emergency nurses, our findings provide essential insights into potential interventions and frameworks.

Introduction Cytokines might play a key role in the pathophysiology of major depressive disorder (MDD). The speed of onset of depressive episodes has been discussed as an important clinical parameter in MDD. The aim of this study was to investigate a potential influence of the speed of onset of the depressive episode on cytokine serum levels. Method Serum level of the cytokines interleukin (IL)-2, IL-4, IL-6, IL-8, IL-10, tumor necrosis factor alpha (TNF-α), interferon-gamma (IFN-γ) granulocyte and monocyte colony stimulating factor (GM-CSF) were measured in a total of 92 patients with MDD that did not respond to at least one previous antidepressant treatment. Patients were retrospectively divided in two groups: Faster (≤4 weeks) and slower (>4 weeks) onset of the depressive episode defined as the time passing from the first depressive symptoms to a full-blown depressive episode by using information from a clinical interview. Results We found significantly lower serum levels of IL-2, IL-4, IL-6, IL-10, TNF-α and IFN-γ in patients with a faster onset compared to patients with a slower onset of the depressive episodes. Furthermore, lower cytokine serum levels of IL-2, IL-8, IL-10 and IFN-γ were found in patients with a shorter duration (less than 6 months) compared to a longer duration (6–24 months) of the current depressive episode. This effect on cytokines was independent from the effect of the speed of onset of the depressive episode. Conclusions Patients with faster onset of the depressive episode might represent a biological subtype of MDD with lower serum levels of IL-2, IL-4, IL-6, IL-10, TNF-α and IFN-γ.

Salt-inducible kinases (SIKs) are key metabolic regulators. The imbalance in SIK function is associated with the development of diverse cancers, including breast, gastric, and ovarian cancers. Chemical tools to clarify the roles of SIK in different diseases are, however, sparse and are generally characterized by poor kinome-wide selectivity. Here, we have adapted the pyrido[2,3-d]pyrimidin-7-one-based p21-activated kinase (PAK) inhibitor G-5555 for the targeting of SIK, by exploiting differences in the back-pocket region of these kinases. Optimization was supported by high-resolution crystal structures of G-5555 bound to the known off-targets, MST3 and MST4, leading to a chemical probe, MRIA9, with dual SIK/PAK activity and excellent selectivity over other kinases. Furthermore, we show that MRIA9 sensitizes ovarian cancer cells to treatment with the mitotic agent paclitaxel, confirming earlier data from genetic knockdown studies and suggesting a combination therapy with SIK inhibitors and paclitaxel for the treatment of paclitaxel-resistant ovarian cancer.

BACKGROUND The US Preventive Services Task Force (USPSTF) includes multitarget stool DNA (mt-sDNA) testing as a colorectal cancer (CRC) screening option in average-risk individuals, but data on colonoscopy outcomes after positive mt-sDNA tests in community settings are needed. AIM The aim of this study was to investigate colonoscopy outcomes and quality following positive mt-sDNA in the population-based New Hampshire Colonoscopy Registry. METHODS We compared colonoscopy outcomes and quality between age-matched, sex-matched, and risk-matched patients from 30 endoscopy practices with and without a preceding positive mt-sDNA test. Main outcomes were colonoscopy findings of CRC, advanced noncancerous neoplasia, nonadvanced neoplasia, or normal examination. Quality measures included withdrawal time, bowel preparation quality, examination completion, and percentage of average-risk individuals with normal colonoscopies receiving a USPSTF-recommended 10 year rescreening interval. RESULTS Individuals with positive mt-sDNA tests (N=306, average age 67.0 y; 61.8% female) were significantly more likely than colonoscopy-only patients (N=918, 66.2 y; 61.8% female) to have CRC (1.3% vs. 0.4%) or advanced noncancerous neoplasia (27.1% vs. 8.2%) (P

Amino acid (AA) metabolism is severely disturbed in critically ill ICU patients. To be able to make a more scientifically based decision on the type of protein or AA nutrition to deliver in ICU patients, comprehensive AA phenotyping with measurements of plasma concentrations and whole body production (WBP) is needed. Therefore, we studied ICU patients and matched control subjects using a novel pulse isotope method to obtain in-depth metabolic analysis. In 51 critically ill ICU patients (SOFA~6.6) and 49 healthy controls, we measured REE and body composition/phase-angle using BIA. In the postabsorptive state, we collected arterial (ized) blood for CRP and AA. Then, we administered an 8 mL solution containing 18 stable AA tracers as a pulse and calculated WBP. Enrichments: LC-MS/MS and statistics: t-test, ANCOVA. Compared to healthy, critically ill ICU patients had lower phase-angle (p 0.00001), and higher CRP (p 0.0001). Most AA concentrations were lower in ICU patients (p 0.0001), except tau-methylhistidine and phenylalanine. WBP of most AA were significantly (p 0.0001) higher with increases in glutamate (160%), glutamine (46%), and essential AA. Remarkably, net protein breakdown was lower. There were only weak relationships between AA concentrations and WBP. Critically ill ICU patients (SOFA 8-16) had lower values for phase angle (p = 0.0005) and small reductions of most plasma AA concentrations, but higher tau-methylhistidine (p = 0.0223) and hydroxyproline (p = 0.0028). Remarkably, the WBP of glutamate and glutamine were lower (p 0.05), as was their clearance, but WBP of tau-methylhistidine (p = 0.0215) and hydroxyproline (p = 0.0028) were higher. Our study in critically ill ICU patients shows that comprehensive metabolic phenotyping was able to reveal severe disturbances in specific AA pathways, in a disease severity dependent way. This information may guide improving nutritional compositions to improve the health of the critically ill patient. CLINICAL TRIAL REGISTRY: Data are from the baseline measurements of study NCT02770092 (URL: https://clinicaltrials.gov/ct2/show/NCT02770092) and NCT03628365 (URL: https://clinicaltrials.gov/ct2/show/NCT03628365).

Cardiovascular diseases (CVDs) are the most common cause of death in patients with nonalcoholic fatty liver disease (NAFLD) and dyslipidemia is considered at least partially responsible for the increased CVD risk in NAFLD patients. The aim of the present study is to understand how hepatic de novo lipogenesis influences hepatic cholesterol content as well as its effects on the plasma lipid levels. Hepatic lipogenesis was induced in mice by feeding a fat-free/high-sucrose (FF/HS) diet and the metabolic pathways associated with cholesterol were then analyzed. Both liver triglyceride and cholesterol contents were significantly increased in mice fed an FF/HS diet. Activation of fatty acid synthesis driven by the activation of sterol regulatory element binding protein (SREBP)-1c resulted in the increased liver triglycerides. The augmented cholesterol content in the liver could not be explained by an increased cholesterol synthesis, which was decreased by the FF/HS diet. HMG-CoA reductase protein level was decreased in mice fed an FF/HS diet. We found that the liver retained more cholesterol through a reduced excretion of bile acids, a reduced fecal cholesterol excretion, and an increased cholesterol uptake from plasma lipoproteins. Very low-density lipoprotein-triglyceride and -cholesterol secretion were increased in mice fed an FF/HS diet, which led to hypertriglyceridemia and hypercholesterolemia in Ldlr-/- mice, a model that exhibits a more human like lipoprotein profile. These findings suggest that dietary cholesterol intake and cholesterol synthesis rates cannot only explain the hypercholesterolemia associated with NAFLD, and that the control of fatty acid synthesis should be considered for the management of dyslipidemia.

BACKGROUND & AIMS: Hypophosphatemia (HypoP) is associated with organ dysfunction and mortality. Despite its potential severe consequences, HypoP remains poorly characterized in terms of real prevalence and timing of onset. The primary objective was to determine the prevalence of HypoP defined as blood phosphate

Background or objectives Breast cancer is the most frequent cancer in women. Chronic pain following mastectomy remains a significant problem. This study aimed to evaluate risk factors associated with postoperative chronic pain. Methods Medical records were analyzed retrospectively for 147 consecutive patients with breast cancer who underwent mastectomy between July 2016 and February 2018 with one-year follow-up. All patients received a paravertebral block pre-operatively and then general anesthesia for the surgery. Results The median postoperative pain score was 1.3 on the verbal analgesic score. The average total dose of opioids administered postoperatively was 10.4 mg, expressed in morphine milligram equivalents. The incidence of chronic pain after mastectomy was 16.7% at 6 months and 13.3% at 1 year. The satisfaction rate for anesthesia and surgery was 95.7%. Conclusions The data suggested that preoperative paravertebral nerve blocks, appropriate adjuvants, and a balanced general anesthetic may contribute to better postoperative pain control and decreased the incidence of chronic pain. A history of preoperative use of opioids and/or a history of alcohol consumption were both associated with significant increased levels of postoperative pain, and this subgroup warrants attention to diminish the risk of developing chronic pain.

Objective: Evidence is scant regarding symptom clusters and quality of life (QOL) over 1 year in women who receive adjuvant breast cancer chemotherapy (CTX). Our purpose was to identify the prevalence and severity of individual symptoms, symptom clusters, and QOL in women receiving adjuvant breast cancer CTX from baseline over 1 year. Methods: Symptoms were identified in a sample (n = 219) at three times: baseline (prior to the first adjuvant CTX treatment), 1 month after the last CTX (approximately 6 months after baseline), and 1 year after baseline. The Hospital Anxiety and Depression Scale and Symptom Experience Scale measured symptoms. The Medical Outcomes Study, Short-Form Survey, measured QOL. Exploratory factor analysis identified symptom clusters at each time and core symptoms in clusters over time. Results: The prevalence and severity of 10 symptoms decreased over time (P < 0.05). Fatigue, sleep disturbance, and pain were most prevalent; all were of mild severity. Two symptom clusters were identified at baseline and one met internal consistency reliability criteria at the later times. Core symptoms were identified. Both the physical and mental component scores of QOL improved over time (P < 0.01), but physical was below the general population norms 1 year after baseline. Conclusions: The symptom experience was dynamic, and symptom clusters changed over 1 year. Despite mild severity, core symptoms and clusters persisted over 1 year, and physical health was below the general population norms. Breast cancer survivors with persistent single and co-occurring symptoms need to be taught to manage the patterns of symptoms over time because they may not resolve by 1 year.

Background & Aims We aimed to compare the incidence of aerodigestive cancers in persons with negative results from colonoscopies and positive vs negative results from multitarget stool DNA tests for colorectal cancer and vs expected incidence. Methods We performed a retrospective cohort study of 1216 subjects with comprehensive patient records and/or cancer registry data from 3 medical centers in North America. Subjects had no neoplasia or only nonadvanced adenomas, based on screening colonoscopy, and either negative results (concordant with colonoscopy, n = 1011) or positive results (discordant colonoscopy, n = 205) from the multitarget stool DNA test. Outcomes included aerodigestive cancers in discordant vs concordant groups and comparison of observed aerodigestive cancer incidence between the groups and compared with expected incidence for the population, based on the Surveillance, Epidemiology, and End Results (SEER) data. Results Median follow-up times were comparable between subjects in the discordant (5.3 y; interquartile range, 3.5–5.8 y) and concordant (5.4 y; interquartile range, 3.7–5.8 y) groups. Aerodigestive cancers developed in 5 subjects in the discordant group vs 11 subjects in the concordant group (crude risk ratio, 2.3; 95% CI, 0.8–6.6; adjusted risk ratio, 2.2; 95% CI, 0.8–6.2; P = .151). The incidence of aerodigestive cancer was lower in the concordant group than the expected incidence based on SEER data (risk ratio, 0.4; 95% CI, 0.2–0.6; P = .0008). The incidence of aerodigestive cancer was not significantly greater in the population in the discordant group than the expected incidence based on SEER data (risk ratio, 0.8; 95% CI, 0.3–1.9; P = .599). Conclusions In a retrospective study with a median follow-up time of 5.4 years, incident aerodigestive cancers were uncommon among subjects with negative findings from colonoscopies, regardless of discordant or concordant results from multitarget stool DNA tests. Patients with negative results from high-quality colonoscopies therefore should not undergo further testing.

To examine if selected demographic (age, gender), clinical (diabetes, coronary artery disease, hyperlipidemia, myocardial infarction, stroke, lung disease, smoking history, alcohol intake), and biomarker [blood pressure (BP), heart rate, body mass index (BMI), neck circumference, Mallampati score] variables are predictors of apnea-hypopnea index (AHI) from polysomnography (PSG). This cross-sectional study recruited a sample of adults (N = 170) who were being evaluated for OSA. Participants completed self-reported demographic and clinical questionnaires, and then completed PSG (n = 142). Multi-collinearity was assessed. Confounding factors, correlations, and potential interactions were explored. The final regression model was performed on 130 participants; 61 (46.9%) had an AHI ≥ 15. Systolic and diastolic BPs were highly correlated. Interactions were tested between gender and other variables (high cholesterol, BMI, neck circumference, systolic BP) and between systolic BP and other variables (high cholesterol, BMI, neck circumference, and lung disease). No interactions occurred between gender or systolic BP and other variables, meaning that the effects of the variables on AHI levels from PSG did not vary depending on gender or systolic BP. BMI, systolic BP, and absence of lung disease were predictors for AHI levels ≥ 15 from PSG. BMI and systolic BP were significant predictors of OSA in this study. The absence of lung disease as a significant predictor was unique and may be due to the small number of participants who self-reported lung disease. To our knowledge, this is the first study to report this combination of variables to predict AHI levels ≥ 15 from PSG.

Purpose Ascent to high altitude increases right ventricular (RV) afterload and decreases myocardial energy supply. This study evaluates physiologic variables and comprehensive echocardiographic indices of RV and right atrial (RA) function following rapid ascent to high altitude. Methods Fifty healthy volunteers actively ascended from 1130 to 4559 m in Results sPAP increased from baseline (24 ± 4 mmHg) to the first altitude examination (39 ± 8 mmHg, p p = 0.07) secondary to a significant increase of RA contraction strain (19.2 ± 6.4 vs. 25.4 ± 9.6%, p Conclusion Active and rapid ascent of healthy individuals to 4559 m is associated with an increased contractile performance of the RA that compensates for the increased workload of the RV.

Purpose of review Mitochondrial dysfunction seems to be the common denominator of several critical care conditions and particularly of sepsis. Faced with relative failure, and limited progress of sepsis therapies aiming at blocking some oxidative and/or inflammatory pathways, the question of antioxidants micronutrient therapy, particularly of selenium, ascorbic acid and thiamine remains open. Recent findings The rationale for the essentiality of numerous micronutrients within the mitochondria is well established. Many studies have tested single micronutrients in animal and in-vitro models and provide positive evidences in favor of reduction of organ failure (cardiac and renal mainly). In clinical settings, high-dose selenium administration in sepsis has been disappointing. The most recent high dose, short-term ascorbic acid trial in sepsis is promising though, with an associated reduction of mortality, but analysis of the impact of this intervention on the various organs remains to be conducted. Summary Results from animal and human studies indicate that there are indeed intervention options at the level of the mitochondria, but neither the optimal dose nor the optimal combination of micronutrients is yet identified.

OBJECTIVES: Multitarget stool DNA (MT-sDNA) testing has grown as a noninvasive screening modality for colorectal cancer (CRC), but real-world clinical data are limited in the post-FDA approval setting. The effect of previous colonoscopy on MT-sDNA performance is not known. We aimed to evaluate findings of colorectal neoplasia (CRN) at diagnostic colonoscopy in patients with positive MT-sDNA testing, stratified by patient exposure to previous colonoscopy. METHODS: We identified consecutive patients completing MT-sDNA testing over a 39-month period and reviewed the records of those with positive tests for neoplastic findings at diagnostic colonoscopy. MT-sDNA test positivity rate, adherence to diagnostic colonoscopy, and the positive predictive value (PPV) of MT-sDNA for any CRN and neoplastic subtypes were calculated. RESULTS: Of 16,469 MT-sDNA tests completed, testing returned positive in 2,326 (14.1%) patients. After exclusion of patients at increased risk for CRC, 1,801 patients remained, 1,558 (87%) of whom underwent diagnostic colonoscopy; 918 of 1,558 (59%) of these patients had undergone previous colonoscopy, whereas 640 (41%) had not. Any CRN was found in 1,046 of 1,558 patients (PPV = 67%). More neoplastic lesions were found in patients without previous colonoscopy (73%); however, the rates remained high among those who had undergone previous colonoscopy (63%, P < 0.0001). The large majority (79%) of patients had right-sided neoplasia. DISCUSSION: MT-sDNA has a high PPV for any CRN regardless of exposure to previous colonoscopy. Right-sided CRN was found at colonoscopy in most patients with positive MT-sDNA testing, representing a potential advantage over other currently available screening modalities for CRC.

PURPOSE/BACKGROUND Lithium augmentation of antidepressants represents a common strategy to overcome treatment resistance in patients with major depressive disorder. The use of lithium has been associated with cardiovascular adverse effects such as QTc prolongation and tachyarrhythmia. Although the previous studies investigated monotherapy with lithium, the aim of this study was to investigate electrocardiographic changes in LA. METHODS/PROCEDURES A 12-lead surface electrocardiogram (ECG) was obtained from 38 patients with major depressive disorder before and during LA. Changes in heart rate, PQ, QRS and QTc interval, QT dispersion, ST segment, and T- and U-wave alterations were analyzed using a linear mixed model. FINDINGS/RESULTS The ECG readings of 33 patients were evaluated. Lithium augmentation was not significantly associated with changes in heart rate, QTc, PQ, or QRS interval. We found a significant decrease in QT dispersion. These results were independent of sex, age, stable comedication, and comorbidities. During LA, we observed 9 cases of T-wave alterations and 2 cases of new U waves. CONCLUSIONS Our data provide no evidence for serious ECG abnormalities at therapeutic serum lithium levels in patients treated with LA. In particular, we did not find evidence for QTc time lengthening or tachyarrhythmia, such as torsades des pointes. The recommended intervals for ECG checks should be considered to detect long-term effects of LA.

Objective: To examine glycemic variability within 1 month and 1 year following surgery among adult patients, with and without Type 2 Diabetes (T2D), treated for stage II-III colon cancer. Method: A retrospective analysis of electronic health record data was conducted. Glycemic variability (i.e., standard deviation [SD] and coefficient of variation [CV] of > 2 blood glucose measures) was assessed within 1 month and within 1 year following colon surgery. Chi-square (χ2), Fisher’s exact, and Mann-Whitney U tests were used for the analyses. Results: Among the sample of 165 patients with stage II–III colon cancer, those with T2D had higher glycemic variability compared to patients without T2D ( p < .001), with values within 1 month following surgery (SD = 44.69 mg/dL, CV = 27.4%) vs (SD = 20.55 mg/dL, CV = 17.53%); and within 1 year following surgery (SD = 45.04 mg/dL, CV = 29.04%) vs (SD = 21.36 mg/dL, CV = 18.6%). Associations were found between lower body mass index and higher glycemic variability (i.e., SD [r = −.413, p < .05] and CV [r = −.481, p < .01]) within 1 month following surgery in patients with T2D. Higher preoperative glucose was associated with higher glycemic variability (i.e., SD r = .448, p < .01) within 1 year in patients with T2D. Demographic and clinical characteristics were weakly associated with glycemic variability in patients without T2D. Conclusions: Patients with stage II–III colon cancer with T2D experienced higher glycemic variability within 1 month and within 1 year following surgery compared to those without T2D. Associations between glycemic variability and demographic and clinical characteristics differed by T2D status. Further research in prospective studies is warranted.

Background The long-term frequencies of cardiac arrhythmias in hospitalized coronavirus disease 2019 (COVID-19) patients have not been thoroughly investigated. Purpose To describe the prevalence of cardiac arrhythmias, 3–4 months after hospitalization for COVID-19. Methods and results Participants with COVID-19 discharged from five large Norwegian hospitals were invited to participate in a prospective cohort study. We examined 201 participants (44% females, mean age 58.5 years) with 24-hour electrocardiogram 3–4 months after discharge. Body mass index (BMI) was 28.3±4.5 kg/m2 (mean ± SD), and obesity (BMI >30) was found in 70 participants (34%). Clinically significant arrhythmias were defined as; ventricular tachycardia (non-sustained or sustained), premature ventricular contractions (PVC) exceeding 200/24 h, or coupled PVC, atrial fibrillation/flutter, second-degree atrioventricular block (AV-block) type 2, complete AV-block, sinoatrial (SA) block exceeding 3 s, premature AV-nodal beats in bigeminy, supraventricular tachycardia (SVT) exceeding 30 s, and sinus bradycardia with less than 30 beats/min. High-sensitive cardiac troponin T (hs-cTnT) was measured at the 3-month follow-up. Results Cardiac arrhythmias were found in 27% (n=54) of the participants. Ventricular premature contractions and non-sustained ventricular tachycardia were the most common arrhythmias, found in 22% (n=44) of the participants. Premature ventricular contractions were the most frequent cardiac arrhythmia. More than 200 PVCs per day were observed in 37 participants (18%) with a mean of 1300 PVC/day, and in 35 (95%) of these participants, the PVCs were polymorphic. Among 10 patients experiencing NSVT, 5 participants had previous CVD, including coronary heart disease (n=1), 1 atrial fibrillation, 2 venous thromboembolism, 4 heart failure. Atrial fibrillation was found in seven patients (3%), none of them of new-onset. SA block >3 seconds was only observed in one patient, and no incidence of high degree AV block was discovered. Pre-existing cardiovascular disease or hypertension (CVDH) were reported in 40% (n=81) of the participants. The CVDH group had an increased amount of arrhythmia compared to the group free of CVDH (p=0.04). High PVCs showed a fair correlation with hs-cTnT levels at 3 months (ρ=0.21 p=0.048). Conclusions Three months following hospital discharge with COVID-19, cardiac arrhythmia was found in every fourth participant and was associated with a higher concentration of hs-cTnT at 3 months. The clinical implications of persistent ventricular arrhythmia following COVID-19 is not clear, but ventricular ectopy has been linked to increased risk of cardiac disease, including cardiomyopathy and sudden cardiac death. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): The National Association for Heart, Lung diseases and the Norwegian Health Association and Akershus University Hospital.

Importance: To our knowledge, little is known about antibody development after SARS-CoV-2 vaccination in immunocompromised individuals, such as patients with cancer. Objective: To determine whether hematooncological patients develop anti-SARS-CoV-2 antibodies after vaccination. Design, Setting, and Participants: This retrospective cohort study included 2 independent cohorts of patients who were treated for hematological and solid malignant tumors between October 2020 and May 2021, comprising 901 samples from 595 patients and 58 health care workers (HCWs). Serum samples were collected from patients who were treated at an academic center and a community hospital in a rural area and a control group of HCWs, all of whom received SARS-CoV-2 vaccination. Main Outcomes and Measures: Total anti-SARS-CoV-2 nucleocapsid (anti-NC) and antispike protein (anti-S) antibodies were measured retrospectively. Results: In total, 595 patients (320 women [53.8%] and 275 men [46.2%]; median [range] age, 67 [19-96] years) and 58 HCWs (40 women [69.0%] and 18 men [31.0%]; median [range] age, 42 [24-60] years) were included. Previous SARS-CoV-2 infection was documented in 43 of 595 (7.2%), while anti-NC antibodies that suggested previous infections were observed in 49 of 573 evaluable patients (8.6%). In both cohorts, anti-S antibody levels were higher in fully vaccinated patients compared with patients who received 1 dose. After the first vaccination, patients with hematological cancer who received B cell-targeting agents had lower anti-S levels (median, 1.6 AU/mL; range: 0-17 244 AU/mL) than patients who received other therapies (median, 191.6 AU/mL; range, 0-40 000; P < .001) or patients with solid tumors (median, 246.4 AU/mL; range, 0-40 000 AU/mL; P < .001). Anti-S levels after the first vaccination differed according to ongoing antineoplastic treatment modalities, with the lowest median levels in patients who received chemotherapy alone (157.7 AU/mL; range, 0-40 000 AU/mL) or in combination with immunotherapy (118.7 AU/mL; range, 14.1-38 727 AU/mL) and the highest levels in patients with no ongoing antineoplastic treatment (median, 634.3 AU/mL; range, 0-40 000 AU/mL; P = .01). Antibody levels after full immunization were higher in HCWs (median, 2500 U/mL; range, 485-2500 U/mL) than in patients with cancer (median, 117.0 U/mL; range, 0-2500 U/mL; P < .001). Conclusions and Relevance: In this cohort study of patients with hematooncological diseases and a control group of HCWs, anti-SARS-CoV-2 antibodies after vaccination could be detected in patients with cancer. Lower antibody levels compared with HCWs and differences in seroconversion in specific subgroups underscore the need for further studies on SARS-CoV-2 vaccination in patients with hematooncological disease.

Psychoneurological symptom clusters are co-occurring and interrelated physiological symptoms that may include cancer-related fatigue, pain, depressive symptoms, cognitive disturbances, and sleep disturbances. These symptoms are hypothesized to share a common systemic proinflammatory etiology. Thus, an investigation of systemic immune biomarkers is an important approach to test this hypothesis. Here, we investigated the associations between extracellular vesicle (EV)-associated and soluble cytokines with immune markers and symptom clusters in men with non-metastatic prostate cancer. This observational study included 40 men with non-metastatic prostate cancer at the start (T1) of external beam radiation therapy (EBRT) and 3 months post treatment (T2), as well as 20 men with non-metastatic prostate cancer on active surveillance (AS) seen at one time point. Collected questionnaires assessed patient-reported fatigue, sleep disturbances, depressive symptoms, and cognitive fatigue. In total, 45 soluble and EV-associated biomarkers in plasma were determined by multiplex assays. Principal component analysis (PCA) was used to identify psychoneurological symptom clusters for each study group and their time points. Bivariate correlation analysis was run for each identified PCA cluster with the concentrations of EV-associated and soluble cytokines and immune markers. Both EV-associated and soluble forms of RANTES significantly correlated with the symptom cluster for EBRT at T1, whereas, at T2, soluble IFNα2, IL-9, and IL-17 correlated with the corresponding symptom cluster. For the AS group, soluble survivin correlated with psychoneurological symptoms. Linking specific inflammatory cytokines with psychoneurological symptom clusters in men receiving prostate cancer treatment can enhance understanding of the underlying mechanisms of this phenomenon and aid in developing targeted interventions.

Salt-inducible kinases (SIKs) are key metabolic regulators. Imbalance of SIK function is associated with the development of diverse cancers, including breast, gastric and ovarian cancer. Chemical tools to clarify the roles of SIK in different diseases are, however, sparse and are generally characterized by poor kinome-wide selectivity. Here, we have adapted the pyrido[2,3-d]pyrimidin-7-one-based PAK inhibitor G-5555 for the targeting of SIK, by exploiting differences in the back-pocket region of these kinases. Optimization was supported by high-resolution crystal structures of G-5555 bound to the known off-targets MST3 and MST4, leading to a chemical probe, MRIA9, with dual SIK/PAK activity and excellent selectivity over other kinases. Furthermore, we show that MRIA9 sensitizes ovarian cancer cells to treatment with the mitotic agent paclitaxel, confirming earlier data from genetic knockdown studies and suggesting a combination therapy with SIK inhibitors and paclitaxel for the treatment of paclitaxel-resistant ovarian cancer.

Complement plays important roles in both ischemia-reperfusion injury (IRI) and antibody-mediated rejection (AMR) of solid organ allografts. One approach to possibly improve outcomes after transplantation is the use of C1 inhibitor (C1-INH), which blocks the first step in both the classical and lectin pathways of complement activation and also inhibits the contact, coagulation, and kinin systems. C1-INH can also directly block leukocyte-endothelial cell adhesion. C1-INH contrasts with eculizumab and other distal inhibitors, which do not affect C4b or C3b deposition or noncomplement pathways. Authors of reports on trials in kidney transplant recipients have suggested that C1-INH treatment may reduce IRI and delayed graft function, based on decreased requirements for dialysis in the first month after transplantation. This effect was particularly marked with grafts with Kidney Disease Profile Index ≥ 85. Other clinical studies and models suggest that C1-INH may decrease sensitization and donor-specific antibody production and might improve outcomes in AMR, including in patients who are refractory to other modalities. However, the studies have been small and often only single-center. This article reviews clinical data and ongoing trials with C1-INH in transplant recipients, compares the results with those of other complement inhibitors, and summarizes potentially productive directions for future research.

Objective Neuroimaging studies of hematologic cancer patients report altered activity in dorsal attention and central executive networks. To determine the consequences of these altered brain networks, we evaluated neurophysiological correlates of attention and working memory in hematologic cancer patients prior to initiating treatment. Methods Hematologic cancer patients (19–80 years) were excluded for premorbid cognitive impairment, prior non-hematologic cancer diagnosis, and prior chemotherapy. Attention was manipulated by presenting an irrelevant spatial cue prior to visual search displays. Working memory was manipulated by presenting irrelevant distractors within memory displays. Electroencephalogram was recorded during task performance. Results Patients (n = 28) and controls (n = 15) were balanced on age, gender, and education. Spatial cues evoked larger N2pc amplitudes, a correlate of spatial attention, in patients than controls (p 0.7). Memory distractors evoked larger contralateral delay activity amplitudes, a correlate of working memory load, in patients (p = .028; Cohen’s d = 1.1) but not controls (p = .64). Conclusions Prior to initiating treatment, hematologic cancer patients demonstrated poor control over spatial attention and working memory, consistent with altered dorsal attention and central executive network activity. Significance Hematologic cancer patients may be at a higher risk for selecting, processing, and storing distracting information that would compete with more immediate goal-related behaviors.

Throughout the cancer continuum, patients are faced with the cancer- and treatment-related side effects that can have a negative impact on their overall quality of life. Cancer-related fatigue (CRF) and sleep deficiency are among the symptoms that patients and their caregivers most often experience. An increasing body of literature suggests that a strong correlation between CRF and sleep deficiency exists, indicating that they may be reciprocally related and that they may have similar underlying etiology. This paper aims at bringing together the opinions of leading cancer control (i.e., CRF and sleep) and oncology experts in order to increase the understanding of CRF and sleep deficiency's assessment, associated symptom clustering, symptom burden shared by caregivers, and CRF and sleep deficiency management in the cancer care context.

Cardiologic assessment was conducted on a 78-year-old male patient scheduled for elective aortic valve surgery who complained of angina and dyspnea that had arisen over the previous few months. Evaluation showed stable coronary artery disease and iron deficiency anemia (hemoglobin, 7.7 g/dL). Colonoscopy revealed a non-stenosing carcinoma of the right colonic flexure that was causing chronic blood loss. The interdisciplinary tumor board of the hospital decided that his need for an extended right hemicolectomy followed by resection of two pulmonary nodules that were suspicious of metastatic lesions had priority over his cardiac surgery. Prior to abdominal surgery, the patient received 4 × 500 mg intravenous iron (Ferric-Carboxymaltose) over 2 weeks, for correction of iron deficiency and optimization of hemoglobin concentration. This treatment led to rapid improvement of his angina and exertion-induced dyspnea. His hemoglobin concentration continued to rise even after completion of the iron supplementation, and reached normal levels before thoracoscopic removal of the lung nodules, which took place 1 month after resection of the colon tumor. The patient remained in good clinical condition without any need for blood transfusions. As follow-up visits showed persistent abatement of angina and dyspnea, aortic valve surgery and other cardiac interventions were no longer deemed necessary.

Purpose/Objective(s) Standard of care for surgical candidates with locally advanced esophageal/gastroesophageal junction (E/GEJ) cancers is trimodality therapy. Similar to other groups, we have previously demonstrated the strong prognostic significance of pathological complete response (pCR) at the time of esophagectomy. Little is known about the prognostic significance of nodal clearance alone, however. We sought to determine the prognostic significance of nodal clearance in the subgroup of node positive E/GEJ (N+ E/GEJ), hypothesizing that nodal clearance drives the improved outcomes seen in patients with pCR as the primary tumor is more completely removed at esophagectomy. Materials/Methods Patients undergoing TMT for a primary N+ E/GEJ cancer from 1993-2020 within a single institution were retrospectively analyzed. All patients had either clinically involved nodal disease prior to nCRT and/or pathologically confirmed residual nodal disease at time of esophagectomy. Cancer and demographic features were collected. Direct comparisons were made between pCR versus no pCR and nodal clearance (ypN0) versus persistent nodal disease (ypN+) using the Kaplan-Meier method to estimate progression free survival (PFS) and overall survival (OS). Results One hundred eighty-one patients with median follow up of 140 months were included for analysis. Median age at diagnosis was 60.1 years (30.1-80.9), 142 (78.5%) were adenocarcinomas, 102 (56.4%) were AJCC stage IIIA. Fifty-one (28.2%) had pCR, 103 (56.9%) had ypN0 (including 52 [28.7%] with nodal clearance and residual tumor) and 78 (43.1%) had ypN+. Median OS and PFS for the entire cohort were 26.4 (95% CI, 20.5-32.3) and 18.0 months (95% CI, 12.7-23.4), respectively; 2-year local control rate was 87.4% (95% CI, 84.6-90.2). When comparing ypN0 to ypN+, there were statistically significant improvements in OS and PFS. In contrast, there were no significant differences in OS and PFS when comparing patients with pCR to no pCR (Table 1). Conclusion While pCR is a known prognostic factor in E/GEJ regardless of nodal status, in the high-risk subset of N+ E/GEJ patients, nodal clearance was associated with significantly improved OS and PFS regardless of primary tumor response. This is a novel observation and warrants similar hypothesis testing in other data sets and may have implications for therapy in node positive patients.

Problem identification Self-efficacy for symptom management plays a key role in outcomes, such as quality of life (QOL), functional status, and symptom distress, for adults with cancer. This integrative review identified and assessed evidence regarding self-efficacy for management of symptoms and symptom distress in adults with cancer. Literature search The authors performed a search of literature published from 2006-2018, and articles that examined the relationship among self-reported self-efficacy, symptom management, symptom distress or frequency, and severity in adults with cancer were selected for inclusion. Data evaluation 22 articles met the inclusion criteria. All articles were critically appraised and met standards for methodologic quality. Synthesis Evidence from this review showed that high self-efficacy was associated with low symptom occurrence and symptom distress and higher general health and QOL. High self-efficacy predicted physical and emotional well-being. Low self-efficacy was associated with higher symptom severity, poorer outcomes, and better overall functioning. Implications for research Self-efficacy can be assessed using developed instruments. Presence of a theoretical model and validated instruments to measure self-efficacy for symptom management have set the groundwork for ongoing research.

Hypoxia challenges left ventricular (LV) function due to reduced energy supply. Conflicting results exist whether high‐altitude exposure impairs LV diastolic function and thus contributes to the high altitude‐induced increase in systolic pulmonary artery pressure (sPAP) and reduction in stroke volume (SV). This study aimed to assess LV diastolic function, LV end‐diastolic pressure (LVEDP), and LA mechanics using comprehensive echocardiographic imaging in healthy volunteers at 4559 m. Fifty subjects performed rapid (

SummaryBackgroundDuring the second wave of the coronavirus disease 2019 (COVID-19) pandemic Austria suffered one of the highest severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) rates worldwide. We report performance parameters of a SARS-CoV‑2 screening program established for cancer outpatients at our center.MethodsInstitutional policy recommended routine biweekly SARS-CoV‑2 testing. Adherence to the testing recommendation during the second wave of the COVID-19 pandemic between 1 October and 30 November 2020 was analyzed. The SARS-CoV‑2 infection rate during first wave period (21 March to 4 May 2020) was compared to the one during second wave.ResultsA total of 1577 cancer patients were seen at our outpatient clinic during the second wave. In 1079/1577 (68.4%) patients, at least 1 SARS-CoV2 test was performed. Overall 2833 tests were performed, 23/1577 (1.5%, 95% confidence interval, CI 1.0–2.2%) patients were tested positive for SARS-CoV‑2, which indicates a significant increase compared to the first wave (4/1016; 0.4%, 95% CI 0.1–1.0%) with an odds ratio of 3.9 (95% CI 1.5–10.1;p p p ConclusionWe identified clinical patient parameters influencing SARS-CoV‑2 testing coverage in cancer outpatients. Our data can provide information on generation of standard operating procedures and resource allocation during subsequent infection waves.

Objectives Age, sedentary activity, central adiposity, and inflammation have all been independently associated with bone mineral density (BMD). We assessed how the effects of sedentary activity and central adiposity on BMD of the lumbar spine and femoral neck change across early to late adulthood and whether these relationships are mediated by inflammation. Methods We analyzed data from 7135 women and men 20 years of age and older from NHANES 2007 to 2010. Anthropometrics, sedentary activity (min/day), serum CRP (mg/dl), and BMD (gm/cm2 measured by DXA scans) at the femoral neck and lumbar spine. Data were compared by age and sex groups and through causal mediation analysis. Results The effect of waist circumference on BMD was significantly mediated by serum CRP at both skeletal sites in men and at the femoral neck in women. Sedentary activity did not have a direct relationship to BMD but was mediated by waist circumference in men. Least square means differed significantly by sex and age groups with a general age-related decline in BMD at both skeletal sites. Conclusions We found that central adiposity, independent of overall body size and composition as measured through BMI, has an inverse relationship with BMD that is mediated by serum CRP. In addition, the negative impact of increased sedentism acted through changes in central adiposity (waist circumference) but only in men. Although low bone density and osteoporosis are often considered degenerative diseases that primarily impact postmenopausal women, our findings show that sedentary activity and central adiposity impact bone density beginning in early adulthood in both women and men.

BACKGROUND & AIMS Critically ill patients requiring prolonged intensive care (ICU) treatment are at high risk of malnutrition, which latter contributes to worsening outcome. Having observed that despite the presence of a nutrition protocol and dieticians, the patients with persistent critical illness (PCI) had been underfed during their ICU stay and particularly during the first 10 days, the aim was to analyse the impact of the organisational changes that were proposed to prevent the observed malnutrition. METHODS Before (Period A) and after (Period B) study enrolling critically ill patients consecutively admitted, requiring >10 days of ICU treatment. The intervention consisted in increasing the early morning interactions between dieticians, nurses, and physicians, while modifying the computer visualisation of the dietician proposals. The primary endpoint was a reduction in the cumulative energy balance in period B. The ICU stay was divided in early ICU stay (first 10 days) and late ICU stay (day 11 to day 30). Other variables: protein, glucose, and prealbumin. RESULTS Altogether, 205 patients (150 and 55 in period A and B respectively) were enrolled in the PCI program. Patient characteristics were similar over both periods except for lower SAPSII score in period B. There was no difference in nutritional pattern in the first 10 days between periods. The cumulate energy balance was less negative from day 11-30 in period B than in A (-884 vs -1566 kcal; p = 0.033). There was a one-day reduction in the median duration of fasting in period B (p

Purpose of review Micronutrients have essential antioxidant and immune functions, while low blood concentrations are frequently observed in critically ill patients. This has led to the concepts of complementation, repletion, or even pharmacological supplementation. Over the last three decades, many clinical studies have tested the latter strategy, with controversial or negative results. Therefore, this review aims at evaluating micronutrient-related interventions that are mandatory or need to be assessed in future trials or clinical registries in all or specific critically ill patients. Recent findings In the critically ill, low plasma/serum micronutrient levels not always reflect a true deficiency in the absence of demonstrable losses. Current practices of micronutrient provision and monitoring in critical care, vary substantially across the world. Also, recent clinical trials testing high dose as monotherapy (selenium, thiamine, vitamin C, vitamin D) or in combination have failed to demonstrate clinical benefits in sepsis. However, these studies have not applied a physiological integrative approach of micronutrient action. Summary Micronutrients are essential in nutrition but their administration and monitoring are difficult. So far, different well designed RCTs on intravenous and oral high dose micronutrient supplementation have been conducted. Nevertheless, very high-dose single micronutrients cannot be advocated at this stage in sepsis, or any other critical condition. By contrast, studies using combination of moderate doses of micronutrients in specific diseases, such as burns and trauma have been associated with improved outcomes. Intravenous administration seems to be the most efficient route. Future clinical trials need to integrate the physiology underlying the interconnected micronutrient activity, and choose more specific primary and secondary endpoints.

Background: Appropriate nutritional support is a key component of care for critically ill patients. While malnutrition increases complications, impacting long term outcomes and healthcare-related costs, uncertainties persist regarding optimal provision of nutritional support in this setting.Methods: An international group of healthcare providers (HCPs) from critical care specialties and nutrition researchers convened to identify knowledge gaps and learnings from studies in critical care nutrition. Clinical research needs were identified in order to better inform future nutrition practices.Results: Challenges in critical care nutrition arise, in part, from inconsistent outcomes in several large-scale studies regarding the optimal amount of calories and protein to prescribe, the optimal time to initiate nutritional support and the role of parental nutrition to support critically ill patients. Furthermore, there is uncertainty on how best to identify patients at nutritional risk, and the appropriate outcome measures for ICU nutrition studies. Given HCPs have a suboptimal evidence base to inform the nutritional management of critically ill patients, further well-designed clinical trials capturing clinically relevant endpoints are needed to address these knowledge gaps.Conclusions: The identified aspects for future research could be addressed in studies designed and conducted in collaboration with an international team of interdisciplinary nutrition experts. The aim of this collaboration is to address the unmet need for robust clinical data needed to develop high-quality evidence-based nutritional intervention recommendations to better inform the future management of critically ill patients. (C) 2020 The Authors. Published by Elsevier Ltd on behalf of European Society for Clinical Nutrition and Metabolism. This is an open access article under the CC BY license.

Background During the COVID-19 outbreak, healthcare professionals (HCP) are at the frontline of clinical management and at increased risk for infection. The SARS-CoV-2 seroprevalence of oncological HCP and their patients has significant implications for oncological care. Methods HCP and patients with cancer at the Division of Oncology, Medical University of Vienna were included between 21 March and 4 June and tested for total antibodies against SARS-CoV-2 employing the Roche Elecsys Anti-SARS-CoV-2 immunoassay. Reactive samples were confirmed or disproved by the Abbott SARS-CoV-2 IgG test. Additionally, a structured questionnaire regarding basic demographic parameters, travel history and COVID-19-associated symptoms had to be completed by HCP. Results 146 subjects (62 HCP and 84 patients with cancer) were enrolled. In the oncological HCP cohort, 20 (32.3%) subjects were medical oncologists, 28 (45.2%) nurses at our ward and 14 (22.6%) fulfil other functions such as study coordinators. In the patient cohort, most individuals are on active anticancer treatment (96.4%). 26% of the HCP and 6% of the patients had symptoms potentially associated with COVID-19 since the end of February 2020. However, only in 2 (3.2%) HCP and in 3 (3.6%) patients, anti-SARS-Cov-2 total antibodies were detected. The second assay for anti-SARS-Cov-2 IgG antibodies confirmed the positive result in all HCP and in 2 (2.4%) patients, suggesting an initial assay’s unspecific reaction in one case. In individuals with a confirmed test result, an active COVID-19 infection was documented by a positive SARS-CoV-2 RNA PCR test. Conclusion Specific anti-SARS-CoV-2 antibodies were found solely in persons after a documented SARS-CoV-2 viral infection, thus supporting the test methods’ high sensitivity and specificity. The low prevalence of anti-SARS-CoV-2 antibodies in our cohorts indicates a lack of immunity against SARS-CoV-2. It highlights the need for continued strict safety measures to prevent uncontrolled viral spread among oncological HCPs and patients with cancer.

BackgroundMost colorectal cancer (CRC) screening tests have not been rigorously studied in younger age groups.AimsTo estimate sensitivity of the multi-target stool DNA (mt-sDNA) test in patients ages 45-49 years.MethodsWe identified archived stool samples (Exact Sciences; Madison, WI) from individuals ages 45-49 years who had completed an index colonoscopy and had confirmed diagnoses of CRC or advanced precancerous lesions (APL; defined as high-grade dysplasia, >25% villous morphology, or ≥1 cm in size [conventional adenoma or serrated lesion]). Data annotation referent to potential CRC risk factors, other than age, was limited. Stool samples were collected at least 7 days after the index colonoscopy, prior to lesion excision or treatment. Stool samples were processed and analyzed per established laboratory protocols for the mt-sDNA assay. Mt-sDNA test sensitivity for CRC, APL, and CRC+APL was estimated from the available sample set. Samples were collected from 2010-2013 (NCT01260168) and 2014-2017 (NCT02503631), with sample testing and analysis in 2019.ResultsStool samples were analyzed from 19 eligible subjects, 13 with CRC and 6 with APL. Estimated mt-sDNA test sensitivity for CRC, APL, and CRC+APL were 92%, 83%, and 89%, respectively.ConclusionsIn this small pilot study using existing archived stool samples from subjects ages 45-49 years, mt-sDNA test sensitivity was similar to previously reported estimates for individuals ages ≥50 years. These results support the application of mt-sDNA screening to 76 average-risk patients beginning at age 45 years. Larger studies are needed to confirm and extend these findings.

PURPOSE To analyze the prevalence of SARS-CoV-2 infection in patients with cancer in hospital care after implementation of institutional and governmental safety measurements. METHODS Patients with cancer routinely tested for SARS-CoV-2 RNA by nasal swab and real-time polymerase chain reaction between March 21 and May 4, 2020, were included. The results of this cancer cohort were statistically compared with the SARS-CoV-2 prevalence in the Austrian population as determined by a representative nationwide random sample study (control cohort 1) and a cohort of patients without cancer presenting to our hospital (control cohort 2). RESULTS A total of 1,688 SARS-CoV-2 tests in 1,016 consecutive patients with cancer were performed. A total of 270 of 1,016 (26.6%) of the patients were undergoing active anticancer treatment in a neoadjuvant/adjuvant and 560 of 1,016 (55.1%) in a palliative setting. A total of 53 of 1,016 (5.2%) patients self-reported symptoms potentially associated with COVID-19. In 4 of 1,016 (0.4%) patients, SARS-CoV-2 was detected. At the time of testing at our department, all four SARS-CoV-2–positive patients were asymptomatic, and two of them had recovered from symptomatic COVID-19. Viral clearance was achieved in three of the four patients 14-56 days after testing positive. The estimated odds ratio of SARS-CoV-2 prevalence between the cancer cohort and control cohort 1 was 1.013 (95% CI, 0.209 to 4.272; P = 1), and between control cohort 2 and the cancer cohort it was 18.333 (95% CI, 6.056 to 74.157). CONCLUSION Our data indicate that continuation of active anticancer therapy and follow-up visits in a large tertiary care hospital are feasible and safe after implementation of strict population-wide and institutional safety measures during the current COVID-19 pandemic. Routine SARS-CoV-2 testing of patients with cancer seems advisable to detect asymptomatic virus carriers and avoid uncontrolled viral spread.

BACKGROUND & AIMS: Phosphate is the main intracellular anion essential for numerous biological processes. Symptoms of hypophosphatemia are non-specific, yet potentially life-threatening. This systematic review process was initiated to gain a global insight into hypophosphatemia, associated morbidity and treatments. METHODS: A systematic review was conducted (PROSPERO CRD42020163191). Nine clinically relevant questions were generated, seven for adult and two for pediatric critically ill patients, and prevalence of hypophosphatemia was assessed in both groups. We identified trials through systematic searches of Medline, EMBASE, Scopus, Cochrane Central Register of Controlled Trials, CINAHL, and Web of Science. Quality assessment was performed using the Cochrane risk of bias tool for randomized controlled trials and the Newcastle-Ottawa Scale for observational studies. RESULTS: For all research questions, we identified 2727 titles in total, assessed 399 full texts, and retained 82 full texts for evidence synthesis, with 20 of them identified for several research questions. Only 3 randomized controlled trials were identified with two of them published only in abstract form, as well as 28 prospective and 31 retrospective studies, and 20 case reports. Relevant risk of bias regarding selection and comparability was identified for most of the studies. No meta-analysis could be performed. The prevalence of hypophosphatemia varied substantially in critically ill adults and children, but no study assessed consecutive admissions to intensive care. In both critically ill adults and children, several studies report that hypophosphatemia is associated with worse outcome (prolonged length of stay and the need for respiratory support, and higher mortality). However, there was insufficient evidence regarding the optimal threshold upon which hypophosphatemia becomes critical and requires treatment. We found no studies regarding the optimal frequency of phosphate measurements, and regarding the time window to correct hypophosphatemia. In adults, nutrient restriction on top of phosphate repletion in patients with refeeding syndrome may improve survival, although evidence is weak. CONCLUSIONS: Evidence on the definition, outcome and treatment of clinically relevant hypophosphatemia in critically ill adults and children is scarce and does not allow answering clinically relevant questions. High quality clinical research is crucial for the development of respective guidelines. ispartof: CLINICAL NUTRITION vol:40 issue:4 pages:1744-1754 ispartof: location:England status: published

PURPOSE OF REVIEW In critical care, micronutrients remain perceived as 'quantum' part, that is, a little pertinent component of therapy. Some micronutrients have attracted more attention because of their antioxidant properties. During the last decade, some large size trials have tested their therapeutic potential, generally as 'single high-dose micronutrient intervention', with variable success. This review aims at taking stock of most recent. RECENT FINDINGS Micronutrient blood levels are generally low in ICU patients, which has prompted the concept of replenishing or compensating deficits, or even realizing a pharmacological action. Single micronutrient trials have been conducted in large cohorts with selenium (≥1000 μg/day), with limited success but no harm. Other trials have tested high-dose vitamin D (>400 000 IU), with nonconvincing results despite selecting patients with very low blood levels. High-dose vitamin C has been tested in septic shock (+/- thiamine, hydrocortisone) with variable results. A problem encountered in all studies is definition of deficiency based on blood levels as majority of the patients suffer inflammation, which causes redistribution of the micronutrients away from the circulating compartment in the absence of real deficiency. SUMMARY Micronutrients are essential in the ICU. Due to their antioxidant properties and to the high prevalence of low blood concentrations suggestive of deficiency, several large-size RCTs have been conducted with variable success. Further research must clarify the respective importance of deficiency and inflammation.

High-specificity colorectal cancer screening is desirable to triage patients Prevention Relevance: This study shows that mt-sDNA has high specificity among average-risk 45–49 year olds, supporting its use as a non-invasive option for colorectal cancer screening.

Critically ill (intensive care unit [ICU]) patients are characterized by organ failure, intense inflammatory response, insulin resistance, and altered metabolic response. The sicker the patient, the higher the threat to nutrition and micronutrient status. In addition, many patients start the ICU stay with an altered nutrition status, which requires assessment upon admission. Nutrition needs vary among patients as well as during hospitalization, as the metabolic response changes over time. Shock and acute organ failure result in a metabolic shift toward intense catabolism: endogenous glucose production aiming at ensuring the basal adenosine triphosphate production starts immediately and occurs at the expense of the lean body mass using amino acids for neoglucogenesis. Later, the stabilization and recovery phases are characterized by higher energy and substrate needs. Indirect calorimetry is the only tool enabling determination of the metabolic level. When and how should feeding be started? Recent research shows that the route does not matter much, with equipoise between enteral and parenteral nutrition (PN) as long as overfeeding is avoided. As micronutrients are an integral part of metabolism and antioxidant defenses, their delivery must be ensured: whereas needs are well defined for healthy individuals, needs for illness remain poorly defined. PN that contains only macrosubstrates requires the daily prescription of multimicronutrient complements to qualify as total PN. Achievement of goals requires minimal monitoring, consisting of the daily verification of energy and protein goal delivery achievement and daily follow-up determining blood glucose and phosphate levels and insulin requirements.

AIMS OF THE STUDY Based on an incidental observation made in the context of the Swiss National Science Foundation (SNSF) Project 67 “End-of-life decision-making in extremely low birth weight infants in Switzerland”, this retrospective multicentre observational study aimed to analyse circumstances of delivery room deaths after late termination of pregnancy (LTOP) in Switzerland over a 3-year period. METHODS All delivery room deaths (including live and stillbirths) following LTOP among infants with a gestational age between 22 0/7 and 27 6/7 weeks at the nine Swiss level III perinatal centres between 1 July 2012 and 30 June 2015 were analysed. Indications for LTOP were classified as either (a) maternal emergencies or (b) fetal anomalies severe enough to cause significant maternal psychological distress. Whenever possible, specific diagnoses were recorded. Spontaneous intrapartum death and fetal death caused by injection of a cardioplegic drug were distinguished for stillborn infants. RESULTS A total of 465 delivery room deaths among extremely low gestational age newborns (ELGANs) were identified over the 3-year study period of the SNSF project. Of these, 195 (42%) occurred in the context of LTOP. Central nervous system malformations, chromosomal anomalies, severe congenital heart disease, multiple malformations and maternal emergencies accounted for 70% of all LTOPs. LTOPs resulted in live births in 76 (39%) cases. No correlation between gestational age and rate of live births was observed. Fetal death caused by injection of a cardioplegic drug was documented in only three cases. All infants born alive after LTOP died in the delivery room without resuscitation attempts. The use of drugs for palliative care in these patients was either rare or, alternatively, incompletely documented. CONCLUSION LTOPs contribute significantly to mortality rates among ELGANs and should therefore be included in perinatal registries. Uniform reporting of LTOPs should be established. Infants born alive after LTOP are entitled to comprehensive palliative care like any other infant born under different circumstances. Development of national guidelines for LTOPs (including the role of fetal death caused by injection of a cardioplegic drug and palliative birth as an alternative to induced abortion) would be highly desirable to guarantee acceptable standards of care.

Background: Exaggerated pulmonary arterial hypertension (PAH) is a hallmark of high-altitude pulmonary edema (HAPE). The objective of this study was therefore to investigate genetic predisposition ...

Preventing the progression to acute respiratory distress syndrome (ARDS) in COVID-19 is an unsolved challenge. The involvement of T cell immunity in this exacerbation remains unclear. To identify predictive markers of COVID-19 progress and outcome, we analyzed peripheral blood of 10 COVID-19-associated ARDS patients and 35 mild/moderate COVID-19 patients, not requiring intensive care. Using multi-parametric flow cytometry, we compared quantitative, phenotypic and functional characteristics of circulating bulk immune cells, and SARS-CoV-2 S-protein reactive T cell between the two groups. ARDS patients demonstrated significantly higher S-protein reactive CD4+ and CD8+ T cells compared to non-ARDS patients. Of interest, comparison of circulating bulk T cells in ARDS patients to non-ARDS patients demonstrated decreased frequencies of CD4+ and CD8+ T cell subsets with activated memory/effector T cells expressing tissue migration molecule CD11a++. Importantly, survival from ARDS (4/10) was accompanied by a recovery of the CD11a++ T cell subsets in peripheral blood. Conclusively, data on S-protein reactive polyfunctional T cells indicate the ability of ARDS patients to generate antiviral protection. Furthermore, decreased frequencies of activated memory/effector T cells expressing tissue migratory molecule CD11a++ observed in circulation of ARDS patients might suggest their involvement in ARDS development and propose CD11a-based immune signature as a possible prognostic marker., Graphical Abstract, This study shows a strong SARS-CoV-2 S-protein T-cell response and decreased frequencies of activated memory/effector T-cells expressing migratory molecule CD11a++ in ARDS patients. The data suggest the involvement of the analyzed T-cell subsets in ARDS development and propose CD11a-based immune signature as a possible prognostic marker for COVID-19 progression.

Background Multitarget stool DNA (mt-sDNA) is an approved method for colon cancer screening that is especially relevant for patients who cannot undergo colonoscopy. Although the test performance has been evaluated in a large clinical trial, it was limited to a predominantly white population. Given differences in the epidemiology and biology of colon cancer in African American individuals, the authors sought to compare the performance of mt-sDNA between racial groups. Methods The authors prospectively identified patients aged ≥40 years who were referred for colonoscopy at an academic medical center and 2 satellite facilities. Prior to the colonoscopy, the authors collected stool for mt-sDNA and fecal immunochemical testing (FIT). They compared the sensitivity, specificity, and receiver operating characteristic curve between African American and white patients for the detection of advanced lesions or any adenoma. Results A total of 760 patients were included, 34.9% of whom were African American. The prevalence of any adenoma (38.9% for African American patients and 33.9% for white patients) and that for advanced lesions (6.8% and 6.7%, respectively) were similar between groups. The overall sensitivities of mt-sDNA for the detection of advanced lesions and any adenoma were 43% and 19%, respectively, and the specificities were 91% and 93%, respectively. In general, mt-sDNA was more sensitive and less specific than FIT. When stratified by race, the sensitivity, specificity, and receiver operating characteristic curve area were similar between African American and white patients for both mt-sDNA and FIT. Conclusions Test performance characteristics of mt-sDNA were comparable in African American and white patients. Given the lower uptake of colonoscopy in African American individuals, mt-sDNA may offer a promising screening alternative in this patient population.

Sleep deficiency is common and distressing for women with breast cancer throughout the care continuum. This article describes the scope and quality of evidence related to exercise interventions to improve sleep in women with breast cancer. Fifteen studies met the criteria and 12 were judged to be excellent quality. The most frequent intervention was walking, primarily during the time of chemotherapy. Eleven studies reported postintervention improvement in sleep deficiency. Most yoga, qigong, and dance intervention studies reported no differences between groups. Emerging evidence exists for the effectiveness of aerobic exercise to improve various sleep outcomes in women with breast cancer.

PURPOSE: Assess systemic vascular endothelial growth factor-A (VEGF) levels after treatment with intravitreous aflibercept, bevacizumab or ranibizumab. DESIGN: Comparative-effectiveness trial with participants randomly assigned to 2-mg aflibercept, 1.25-mg bevacizumab, or 0.3-mg ranibizumab following a retreatment algorithm. PARTICIPANTS: Participants with available plasma samples (N=436) METHODS: Plasma samples were collected before injections at baseline, 4-week, 52-week and 104-week visits. In a pre-planned secondary analysis, systemic free-VEGF levels from an ELISA immunoassay were compared across anti-VEGF agents and correlated with systemic side effects. MAIN OUTCOME MEASURES: Changes in the natural log (ln) of plasma VEGF levels. RESULTS: Baseline free-VEGF levels were similar across all 3 groups. At 4 weeks, mean ln(VEGF) changes were −0.30±0.61, −0.31±0.54, −0.02±0.44 pg/ml for the aflibercept, bevacizumab, and ranibizumab groups, respectively. The adjusted differences between treatment groups (adjusted CI; P-value) were −0.01 (−0.12, +0.10; P=0.89), −0.31 (−0.44, −0.18; P

There is uncertainty as to the appropriate follow-up of patients who test positive on multimarker stool DNA (sDNA) testing and have a colonoscopy without neoplasia. To determine the prevalence of missed colonic or occult upper gastrointestinal neoplasia in patients with an apparent false positive sDNA. We prospectively identified 30 patients who tested positive with a commercially available sDNA followed by colonoscopy without neoplastic lesions. Patients were invited to undergo repeat sDNA at 11–29 months after the initial test followed by repeat colonoscopy and upper endoscopy. We determined the presence of neoplastic lesions on repeat evaluation stratified by results of repeat sDNA. Twelve patients were restudied. Seven patients had a negative second sDNA test and a normal second colonoscopy and upper endoscopy. In contrast, 5 of 12 subjects had a persistently positive second sDNA test, and 3 had positive findings, including a 3-cm sessile transverse colon adenoma with high-grade dysplasia, a 2-cm right colon sessile serrated adenoma with dysplasia, and a nonadvanced colon adenoma (p = 0.045). These corresponded to a positive predictive value of 0.60 (95% CI 0.17–1.00) and a negative predictive value of 1.00 (95% CI 1.00–1.00) for the second sDNA test. In addition, the medical records of all 30 subjects with apparent false positive testing were reviewed and no documented cases of malignant tumors were recorded. Repeat positive sDNA testing may identify a subset of patients with missed or occult colorectal neoplasia after negative colonoscopy for an initially positive sDNA. High-quality colonoscopy with careful attention to the right colon in patients with positive sDNA is critically important and may avoid false negative colonoscopy.

Cardioprotection by postconditioning requires activation of mitochondrial large-conductance Ca2+-sensitive potassium (mBKCa) channels. The involvement of these channels in milrinone-induced postconditioning is unknown. The authors determined whether cardioprotection by milrinone-induced postconditioning involves activation of mBKCa channels in the rat heart in vitro. Randomized, prospective, blinded laboratory investigation. Experimental laboratory. Male Wistar rats. Hearts of male Wistar rats were randomized, placed on a Langendorff system, and perfused with Krebs-Henseleit buffer at a constant pressure of 80 mmHg. All hearts were subjected to 33 minutes of global ischemia and 60 minutes of reperfusion. At the onset of reperfusion, hearts were perfused with different concentrations of milrinone (0.3-100 μM) for determination of a dose-effect curve. In a second set of experiments, 3 μM milrinone was administered in combination with the mBKCa channel inhibitor paxilline (1 μM). Infarct size was determined by triphenyltetrazoliumchloride staining. In control animals, infarct size was 37 ± 7%. Milrinone at a concentration of 3 μM reduced infarct size to 22 ± 7% (p < 0.05 v control). Higher milrinone concentrations did not confer stronger protection. Paxilline completely blocked milrinone-induced cardioprotection whereas paxilline alone had no effect on infarct size. This study shows that activation of mBKCa channels plays a pivotal role in milrinone-induced postconditioning

Decreased oxygen saturation (SO2) at high altitude is associated with potentially life-threatening diseases, e.g., high-altitude pulmonary edema. Wearable devices that allow continuous monitoring of peripheral oxygen saturation (SpO2), such as the Garmin Fēnix® 5X Plus (GAR), might provide early detection to prevent hypoxia-induced diseases. We therefore aimed to validate GAR-derived SpO2 readings at 4559 m. SpO2 was measured with GAR and the medically certified Covidien Nellcor SpO2 monitor (COV) at six time points in 13 healthy lowlanders after a rapid ascent from 1130 m to 4559 m. Arterial blood gas (ABG) analysis served as the criterion measure and was conducted at four of the six time points with the Radiometer ABL 90 Flex. Validity was assessed by intraclass correlation coefficients (ICCs), mean absolute percentage error (MAPE), and Bland–Altman plots. Mean (±SD) SO2, including all time points at 4559 m, was 85.2 ± 6.2% with GAR, 81.0 ± 9.4% with COV, and 75.0 ± 9.5% with ABG. Validity of GAR was low, as indicated by the ICC (0.549), the MAPE (9.77%), the mean SO2 difference (7.0%), and the wide limits of agreement (−6.5; 20.5%) vs. ABG. Validity of COV was good, as indicated by the ICC (0.883), the MAPE (6.15%), and the mean SO2 difference (0.1%) vs. ABG. The GAR device demonstrated poor validity and cannot be recommended for monitoring SpO2 at high altitude.