Long-Term Exposure to AIR Pollution and COVID-19 Mortality and Morbidity in DENmark: Who Is Most Susceptible? (AIRCODEN).

INTRODUCTION: Early ecological studies have suggested a link between air pollution and Coronavirus Diseases 2019 (COVID-19); however, the evidence from individual-level prospective cohort studies is still sparse. Here, we have examined, in a general population, whether long-term exposure to air pollution is associated with the risk of contracting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and developing severe COVID-19, resulting in hospitalization or death and who is most susceptible. We also examined whether long-term exposure to air pollution is associated with hospitalization or death due to COVID-19 in those who have tested positive for SARS-CoV-2. METHODS: We included all Danish residents 30 years or older who resided in Denmark on March 1, 2020. and followed them in the National COVID-19 Surveillance System until first positive test (incidence), COVID-19 hospitalization, or death until April 26, 2021. We estimated mean levels of nitrogen dioxide (NO2), particulate matter with an aerodynamic diameter <2.5 µm (PM2.5), black carbon (BC), and ozone (O3) at cohort participants' residence in 2019 by the Danish Eulerian Hemispheric Model/Urban Background Model. We used Cox proportional hazard models to estimate the associations of air pollutants with COVID-19 incidence, hospitalization, and mortality adjusting for age, sex, and socioeconomic status (SES) at the individual and area levels. We examined effect modification by age, sex, SES (education, income, wealth, employment), and comorbidities with cardiovascular disease, respiratory disease, acute lower respiratory infections, diabetes, lung cancer, and dementia. We used logistic regression to examine association of air pollutants with COVID-19-related hospitalization or death among SARS-CoV-2 positive patients, adjusting for age, sex, individual- and area-level SES. RESULTS: Of 3,721,810 people, 138,742 were infected, 11,270 hospitalized, and 2,557 died from COVID-19 during 14 months of follow-up. We detected strong positive associations with COVID-19 incidence, with hazard ratio (HR) and 95% confidence interval (CI) of 1.10 (CI: 1.05-1.14) per 0.5-µg/m3 increase in PM2.5 and 1.18 (CI: 1.14-1.23) per 3.6-µg/m3 increase in NO2. For COVID-19 hospitalizations and for COVID-19 deaths, corresponding HRs and 95% CIs were 1.09 (CI: 1.01-1.17) and 1.19 (CI: 1.12-1.27), respectively for PM2.5, and 1.23 (CI: 1.04-1.44) and 1.18 (CI: 1.03-1.34), respectively for NO2. We also found strong positive and statistically significant associations with BC and negative associations with O3. Associations were strongest in those aged 65 years old or older, participants with the lowest SES, and patients with chronic cardiovascular, respiratory, metabolic, lung cancer, and neurodegenerative disease. Among 138,742 individuals who have tested positive for SARS-Cov-2, we detected positive association with COVID-19 hospitalizations (N = 11,270) with odds ratio and 95% CI of 1.04 (CI: 1.01- 1.08) per 0.5-µg/m3 increase in PM2.5 and 1.06 (CI: 1.01-1.12) per 3.6-µg/m3 increase in NO2, but no association with PM with an aerodynamic diameter <10 µm (PM10), BC, or O3, and no association between any of the pollutants and COVID-19 mortality (N = 2,557). CONCLUSIONS: This large nationwide study provides strong new evidence in support of association between long-term exposure to air pollution and COVID-19.

ESE Clinical Practice Guideline on functioning and nonfunctioning pituitary adenomas in pregnancy.

Pregnancies are rare in women with pituitary adenomas, which may relate to hormone excess from secretory subtypes such as prolactinomas or corticotroph adenomas. Decreased fertility may also result from pituitary hormone deficiencies due to compression of the gland by large tumours and/or surgical or radiation treatment of the lesion. Counselling premenopausal women with pituitary adenomas about their chance of conceiving spontaneously or with assisted reproductive technology, and the optimal pre-conception treatment, should start at the time of initial diagnosis. The normal physiological changes during pregnancy need to be considered when interpreting endocrine tests in women with pituitary adenomas. Dose adjustments in hormone substitution therapies may be needed across the trimesters. When medical therapy is used for pituitary hormone excess, consideration should be given to the known efficacy and safety data specific to pregnant women for each therapeutic option. In healthy women, pituitary gland size increases during pregnancy. Since some pituitary adenomas also enlarge during pregnancy, there is a risk of visual impairment, especially in women with macroadenomas or tumours near the optic chiasm. Pituitary apoplexy represents a rare acute complication of adenomas requiring surveillance, with surgical intervention needed in some cases. This guideline describes the choice and timing of diagnostic tests and treatments from the pre-conception stage until after delivery, taking into account adenoma size, location and endocrine activity. In most cases, pregnant women with pituitary adenomas should be managed by a multidisciplinary team in a centre specialised in the treatment of such tumours.

Stoma reversal after intended restorative rectal cancer resection in Denmark: nationwide population-based study.

BACKGROUND: Data on stoma reversal following restorative rectal resection (RRR) with a diverting stoma are conflicting. This study investigated a Danish population-based cohort of patients undergoing RRR to evaluate factors predictive of stoma reversal during 3 years of follow-up. METHODS: Patients from national registries with rectal cancer undergoing RRR or Hartmann's procedure with curative intent between May 2001 and April 2012 were included. Patients with a diverting stoma were followed from the time of primary rectal cancer resection to date of stoma reversal, death, emigration, or end of 3-year follow-up. The cumulative incidence proportion (CIP) of stoma reversal at 1 and 3 years was calculated, treating death as a competing risk. Factors predictive of stoma reversal were explored using Cox regression analysis. RESULTS: Of 6859 patients included, 35·7, 41·9 and 22·4 per cent respectively had a RRR with a diverting stoma, RRR without a stoma, and Hartmann's procedure with an end-colostomy. In patients with a diverting stoma, the CIP of stoma reversal was 70·3 (95 per cent c.i. 68·4 to 72·1) per cent after 1 year, and 74·3 (72·5 to 76·0) per cent after 3 years. Neoadjuvant treatment (hazard ratio (HR) 0·75, 95 per cent c.i. 0·66 to 0·85), blood loss greater than 300 ml (HR 0·86, 0·76 to 0·97), anastomotic leak (HR 0·41, 0·33 to 0·50), T3 category (HR 0·63, 0·47 to 0·83), T4 category (HR 0·62, 0·42 to 0·90) and UICC stage IV (HR 0·57, 0·41 to 0·80) were possible predictors of delayed stoma reversal. CONCLUSION: In one-quarter of the patients the diverting stoma had not been reversed 3 years after the intended RRR procedure.

ANTECEDENTES: Los datos sobre el cierre del estoma (stoma reversal, SR) tras la exéresis el recto con intención reconstructiva (restorative rectal resection, RRR) y estoma derivativo (diverting stoma, DS) son contradictorios. Este estudio analizó los factores predictivos del SR en una cohorte danesa de base poblacional de pacientes sometidos a RRR con un seguimiento de 3 años. MÉTODOS: Los pacientes con cáncer de recto a los que se realizó una RRR o una operación de Hartmann (Hartmann's operation, HO) con intención curativa desde mayo de 2001 hasta abril de 2012, se seleccionaron a partir de registros nacionales. Los pacientes con SD fueron seguidos desde la resección primaria del cáncer rectal hasta la fecha del SR, del fallecimiento, de su cambio de residencia o hasta el final del seguimiento (3 años). Se calculó la tasa de incidencia acumulada (cumulative incidence proportion, CIP) de RS a 1 y 3 años utilizando la muerte como factor de riesgo competitivo. Se identificaron los factores predictivos de SR mediante regresión múltiple de Cox. RESULTADOS: De los 6.859 pacientes incluidos, el 35,7%, 41,9% y 22,4% tenían una RRR con DS, una RRR sin estoma y una HO con colostomía terminal, respectivamente. En pacientes con SD, el CIP de SR fue del 70,3% (i.c. del 95%: 68,4-72,1) al año y del 74,3% (i.c. del 95%: 72,5-76,0) a los 3 años. Se identificaron como posibles factores predictivos relacionados con el retraso del SR, el tratamiento neoadyuvante (cociente de riesgos instantáneos, hazard ratio, HR 0,75; i.c. del 95% 0,66-0,85), una pérdida de sangre > 300 mL (HR 0,86; i.c. del 95% 0,76-0,97), la fuga anastomótica (HR 0,41; i.c. del 95% 0,33-0,50), las categorías T3 (HR 0,63; i.c. del 95% 0,47-0,83) y T4 (HR 0,62; i.c. del 95% 0,42-0,90) y el estadio IV UICC (HR 0,57; i.c. del 95%: 0,41-0,80). CONCLUSIÓN: En una cuarta parte de los pacientes no se había cerrado el estoma derivativo tres años después de la resección de cáncer rectal con intención reconstructiva.

Immune status and the efficacy of adjuvant radiotherapy for patients with localized Merkel cell carcinoma of the head and neck.

PURPOSE: Immunosuppressed (IS) patients are at increased risk for developing Merkel cell carcinoma (MCC) with worsened outcomes compared to immunocompetent (IC) patients. We sought to determine the effects of immune status on the efficacy of adjuvant RT regarding OS for patients with stage I, II or III (localized) MCC of the head and neck. METHODS/PATIENTS: The National Cancer Database was queried for patients with resected, localized MCC of the head and neck with known immune status. Kaplan-Meier methods were used to describe OS. Log-rank tests, multivariable Cox regression models and interaction effect testing were used to compare OS by subgroup categorized by patient and treatment factors including immune status and adjuvant RT receipt. RESULTS: A total of 892 (89.6%) IC and 104 (10.4%) IS patients with MCC of the head and neck were included. Adjuvant RT was associated with improved 3-year OS rate for both IS patients (49.4% vs. 35.5%, p = 0.0467) and stage I/II IC patients (72.4% vs. 62.9%, p = 0.0092). Adjuvant RT was associated with decreased hazard of death (HR 0.77, 95% CI 0.62-0.95). Interaction effect testing did not demonstrate a difference in the efficacy of adjuvant RT on OS between IC and IS status (p = 0.157). CONCLUSIONS: In this NCDB analysis, adjuvant RT was associated with decreased hazard of death for patients with localized MCC of the head and neck regardless of immune status and should be considered for both IS and IC patients.

Development and Implementation of a Culturally Appropriate Education Program to Increase Cervical Cancer Screening among Maasai Women in Rural Tanzania.

Background: In Tanzania, the incidence of cervical cancer is nearly ten times that found in the US. Tanzanian women of the traditional Maasai tribe are financially and educationally marginalized and face a language barrier that reduces access to health care. While cervical cancer (CACX) screening programs are available locally, in our experience, Maasai women were less likely to use these services compared to local women of other tribal backgrounds. Objectives: A novel patient education program was designed to teach Maasai women about the natural history of cervical cancer and available screening and treatment. The program addressed the importance of preventative health and informed consent. Additionally, we sought to better understand the specific barriers Maasai women face in accessing and utilizing CACX screening services. Methods: The program used simple, scripted language translated into Maa language, the Maasai native language, with accompanying culturally appropriate 3D models. The effectiveness of the program was evaluated through pre and post-intervention surveys administered to Maasai and non-Maasai women as well as local healthcare providers, assessing knowledge of cervical cancer, screening, and treatment. Paired t-test analyses were used to analyze significance. Extensive question and answer sessions followed the education sessions from which additional barriers to screening were identified. Findings: Maasai women had minimal understanding of preventative health services prior to the intervention. While all groups showed an increase in knowledge following the education program, Maasai women demonstrated the greatest statistically significant improvement in knowledge. The proportion of Maasai women in attendance to CACX screening clinics increased by 18% after the intervention. Conclusions: Through a culturally sensitive and accessible patient education program, Maasai women gained knowledge of cervical cancer screening and treatment. This program serves as an adaptable model for other marginalized populations to increase patient understanding and informed consent, and to address issues that pertain to underutilization of health care services.

Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) and Subsequent Central Diabetes Insipidus: A Rare Presentation of Pituitary Apoplexy.

Pituitary apoplexy (PA) is a rare endocrine emergency that occasionally presents with sodium disturbances. Here we present a rare case with a previously healthy 41-year-old female who presented with acute onset headache and nausea without visual impairment or overt pituitary dysfunction. Plasma sodium concentrations declined abruptly during the first two days of admission to a nadir of 111 mmol/l. Urine and blood chemistry were consistent with syndrome of inappropriate antidiuretic hormone secretion (SIADH). Magnetic resonance imaging revealed recent bleeding into a pituitary cystic process. Hyponatremia was successfully corrected with fluid restriction and both visual function and anterior pituitary function remained intact. Subsequently, the patient developed central diabetes insipidus (CDI), which responded well to desmopressin substitution. To our knowledge, this is the first case of PA presenting predominantly with posterior pituitary dysfunction that transitioned from SIADH to permanent CDI.

Up-front rituximab maintenance improves outcome in patients with follicular lymphoma: a collaborative Nordic study.

The introduction of the anti-CD20 antibody rituximab in combination with chemotherapy (R-chemo) has improved the prognosis of patients with follicular lymphoma (FL). During the last decade, the addition of a maintenance treatment with rituximab (MR) after R-chemo has been tested with the hope of further improving the outcome of these patients. Using 2 independent population-based cohorts, we investigated the effect of up-front MR on time related end points as well as the risk of histological transformation (HT). FL patients were included if they: (1) completed first-line induction treatment with R-chemo, (2) were alive after induction treatment and eligible for MR, and (3) had no evidence of HT at this time point. The training cohort consisted of 733 Danish patients of whom 364 were consolidated with MR; 369 were not. Patients receiving MR more often had advanced clinical stage (90% vs 78%), high Follicular Lymphoma International Prognostic Index (FLIPI) score (64% vs 55%), and bone marrow infiltration (49% vs 40%). Those consolidated with MR had an improved 5-year overall survival (OS; 89% vs 81%; P = .001) and progression-free survival (PFS; 72% vs 60%; P < .001). In the training cohort, MR was associated with a reduction of HT risk (P = .049). Analyses of an independent validation cohort of 190 Finnish patients confirmed the favorable impact of MR on 5-year OS (89% vs 81%; P = .046) and PFS (70% vs 57%; P = .005) but did not find a reduced risk of HT. The present population-based data suggest that the outcome of patients with FL has improved after consolidation of R-chemo with MR.

Echinococcus multilocularis in Denmark 2012-2015: high local prevalence in red foxes.

In Western Europe, the Echinococcus multilocularis lifecycle is predominantly sylvatic, typically involving red foxes (Vulpes vulpes) as the main definitive hosts with Microtus spp. and Arvicola spp. as intermediate hosts. During a 4-year surveillance study (2012-2015), Danish red foxes and raccoon dogs (n = 1345) were examined for E. multilocularis. Moreover, 134 insectivores and rodents collected in South Jutland during spring and summer 2016 were examined for the presence of metacestodes. The sedimentation and counting technique and molecular typing were used to identify E. multilocularis infections in the carnivores, while the rodent livers were examined macro- and microscopically for parasite lesions. Following morphological identification of E. multilocularis adult worms, the identity was verified by sequence analysis of the 12S rRNA gene in most cases (n = 13). Echinococcus multilocularis infection was demonstrated in 19 red foxes (Vulpes vulpes) originating from only two specific areas of South Jutland, namely Højer and Grindsted, and in two raccoon dogs (Nyctereutes procyonoides), originating from Højer. In Højer, 28.5% (CI 95% 11.7-45.3) of the examined red foxes were E. multilocularis positive per year. Moreover, positive red foxes were identified each year from 2012 to 2015, while E. multilocularis positive red foxes were only identified in Grindsted in 2013 (4.0%) and 2014 (6.4%). In contrast, all collected rodents were negative for E. multilocularis. We conclude that E. multilocularis is locally endemic in South Jutland with a high local prevalence in Højer.

Pelvic insufficiency fractures frequently occur following preoperative chemo-radiotherapy for rectal cancer - a nationwide MRI study.

AIM: The aim of this prospective case-control study was to evaluate the rate of pelvic insufficiency fractures (PIFs) in Denmark using MRI at the 3-year follow-up. All patients had rectal cancer and had undergone surgery with or without preoperative chemo-radiotherapy (CRT). METHOD: Patients registered with primary rectal cancer in the Danish Colorectal Cancer Group database, who underwent rectal cancer resection from April 2011 through August 2012, were invited to participate in a national MRI study aiming to detect local recurrence and evaluate quality of the surgical treatment. Pelvic MRI including bone-specific sequences 3 years after treatment was obtained. The primary outcome was the rate of PIFs; secondary outcome was risk factors of PIFs evaluated in multivariate analysis. RESULTS: During the study period, 890 patients underwent rectal cancer surgery. Of these, 403 patients were included in the MRI study and had a 3-year follow-up MRI. PIFs were detected in 49 (12.2%; 95% CI 9.0-15.4) patients by MRI. PIFs were detected in 39 patients (33.6%; 95% CI 24.9-42.3) treated with preoperative CRT compared to 10 (3.5%; 95% CI 1.3-5.6) non-irradiated patients (P < 0.001). In a multivariate analysis female gender (OR = 3.52; 95% CI 1.7-7.5), age above 65 years (OR = 3.20; 95% CI 1.5-6.9) and preoperative CRT (OR = 14.20; 95% CI 6.1-33.1) were significant risk factors for PIFs. CONCLUSION: Preoperative CRT in the treatment of rectal cancer was associated with a 14-fold higher risk of PIFs after 3 years, whereas female gender and age above 65 years each tripled the risk of PIFs.

Editor's Choice - The National Norwegian Carotid Study: Time from Symptom Onset to Surgery is too Long, Resulting in Additional Neurological Events.

OBJECTIVE/BACKGROUND: The objective was to observe for 1 year all patients in Norway operated on for symptomatic carotid stenosis with respect to (i) the time from the index event to surgery and neurological events during this time; (ii) the level in the healthcare system causing delay of surgical treatment; and (iii) the possible relationship between peri-operative use of platelet inhibitors and neurological events while awaiting surgery. METHODS: This was a prospective national multicentre study of a consecutive series of symptomatic patients. Patients were eligible for inclusion when referred for surgery. An index event was defined as the neurological event prompting contact with the healthcare system. All 15 departments in Norway performing carotid endarterectomy (CEA) participated. RESULTS: Three hundred and seventy one patients were eligible for inclusion between 1 April 2014 and 31 March 2015, and 368 patients (99.2%) were included. Fifty-four percent of the patients contacted their general practitioner on the day of the index event. Primary healthcare referred 84.2% of the patients to hospital on the same day as examined. In hospital median time from admission to referral for vascular surgery was 3 days. Median time between referral to the operating unit and actual CEA was 5 days. Overall, 61.7% of the patients were operated on within 2 weeks of the index event. Twelve patients (3.3%) suffered a new neurological event while awaiting surgery. The percentage of patients on dual antiplatelet therapy was lower (25.0%) in this group than among the other patients (62.6%) (p = .008). The combined 30 day mortality and stroke rate was 3.8%. CONCLUSION: This national study with almost complete inclusion and follow-up shows that the delays occur mainly at patient level and in hospital. The delay is associated with new neurological events. Dual antiplatelet therapy is associated with reduced risk of having a new neurological event before surgery.

Multi-center analysis of the effect of T-cell acute lymphoblastic leukemia subtype and minimal residual disease on allogeneic stem cell transplantation outcomes.

This study aims to provide a detailed analysis of allogeneic stem cell transplantation (allo-SCT) outcomes in a large T-cell acute lymphoblastic leukemia (T-ALL) cohort with a specific emphasis on the effects of pre-transplant minimal residual disease (MRD) and disease subtype, including the aggressive early-thymic precursor (ETP) subtype. Data from 102 allo-SCT patients with a diagnosis of T-ALL from three centers were retrospectively analyzed. Patients were grouped into four T-ALL subtypes: ETP, early, cortical and mature. At 3 years, overall survival (OS), PFS, non-relapse mortality and cumulative incidence (CI) progression were 35, 33, 11 and 55%, respectively. Patients transplanted in first complete remission (CR1) had a 3-year OS of 62% versus those transplanted in CR2 or greater (24%) (hazards ratio 1.6, P=0.2). Patients with MRD positivity at the time of transplant had significantly higher rates of progression compared with those with MRD negativity (76 vs 34%, hazards ratio 2.8, P=0.006). There was no difference in OS, PFS or cumulative incidence (CI) progression between disease subtypes, including ETP (n=16). ETP patients transplanted in CR1 (n=10) had OS of 47%, comparable to other disease subtypes, suggesting that allo-SCT can overcome the poor prognosis associated with ETP. MRD status at transplant was highly predictive of disease relapse, suggesting novel therapies are necessary to improve transplant outcomes.

Bendamustine added to allogeneic conditioning improves long-term outcomes in patients with CLL.

Bendamustine has shown a favorable safety profile when included in chemotherapy regimens for several types of lymphoma, including CLL. This study investigated the long-term effect of adding bendamustine to a conditioning regimen on survival, rate of engraftment, immune recovery and GvHD after allogeneic stem cell transplantation (alloSCT) in CLL patients. These outcomes were compared with the fludarabine, cyclophosphamide and rituximab (FCR) conditioning regimen. We reviewed the data for 89 CLL patients treated on three trials at our institution. Twenty-six (29%) patients received bendamustine, fludarabine and rituximab (BFR) and 63 (71%) received FCR. Patient characteristics were similar in both groups. Ten (38%) BFR-treated patients vs only two (3%) FCR-treated patients did not experience severe neutropenia (P=<0.001). The 3-year overall survival estimates for the BFR and FCR groups were 82 and 51% (P=0.03), and the 3-year PFS estimates were 63% and 27% (P=0.001), respectively. The 2-year treatment-related mortality was 8 and 23% and the incidence of grade 3 or 4 GvHD was 4% and 10%, respectively. This study is the first to report that addition of bendamustine to alloSCT conditioning for CLL patients is associated with improved survival and lower mortality, myelosuppression, and GvHD.

The association between angiogenic markers and fetal sex: Implications for preeclampsia research.

OBJECTIVE: Current research suggests sexual dimorphism between the male and female fetoplacental units, but with unknown relevance for preeclampsia. We investigated the association between fetal sex and concentrations of the angiogenic markers soluble Fms-like kinase 1 (sFlt-1), placental growth factor (PlGF), and sFlt-1/PlGF ratio in first and second-third trimester in women with/without preeclampsia, and the impact of fetal sex on the prognostic value of angiogenic markers for preeclampsia. STUDY DESIGN: Observational study in a prospective, population-based cohort of 2110 singleton pregnancies with 150 preeclampsia cases. RESULTS: Higher sFlt-1 concentrations were observed for women carrying female fetuses in first trimester (all, 1107.65 vs. 992.27pg/ml; preeclampsia cases, 1118.79 vs. 934.49pg/ml, p<0.05) and in second-third trimester (all, 1130.03 vs. 1043.15pg/ml; preeclampsia, 1480.30 vs. 1152.86pg/ml, p<0.05), with similar findings for the sFlt-1/PlGF ratio concentrations in first (29.67 vs. 27.39 p<0.05) and second-third trimester (3.56 vs. 3.22, p<0.05). In first trimester, log transformed concentrations of PlGF, sFlt-1 and sFlt-1/PlGF (all participants) and sFlt-1 (preeclampsia cases) associated with fetal sex in adjusted analyses (p<0.05). In second-third trimester, only log(sFlt-1) associated with fetal sex (all, p=0.028; preeclampsia, p=0.067) In receiver operating curve analysis, prediction of early-onset preeclampsia by sFlt-1/PlGF tended to be superior in pregnancies with female vs. male fetuses (p=0.06). CONCLUSION: Sexual dimorphism was observed for concentrations of angiogenic markers. Female fetal sex was associated to higher sFlt-1 and sFlt-1/PlGF ratio concentrations in both healthy pregnancies and women developing preeclampsia. Fetal sex should be considered in research and clinical use of angiogenic markers.

Amino acid supplementation is anabolic during the acute phase of endotoxin-induced inflammation: A human randomized crossover trial.

BACKGROUND & AIMS: Inflammation is catabolic and causes muscle loss. It is unknown if amino acid supplementation reverses these effects during the acute phase of inflammation. The aim was to test whether amino acid supplementation counteracts endotoxin-induced catabolism. METHODS: Eight young, healthy, lean males were investigated three times in randomized order: (i) normal conditions (Placebo), (ii) endotoxemia (LPS), and (iii) endotoxemia with amino acid supplementation (LPS + A). Protein kinetics were determined using phenylalanine, tyrosine, and urea tracers. Each study day consisted of a four-hour non-insulin stimulated period and a two-hour hyperinsulinemic euglycemic clamp period. Muscle biopsies were collected once each period. RESULTS: Endotoxin administration created a significant inflammatory response (cytokines, hormones, and vital parameters) without significant differences between LPS and LPS + A. Whole body protein breakdown was elevated during LPS compared with Placebo and LPS + A (p < 0.05). Whole body protein synthesis was higher during LPS + A than both Placebo and LPS (p < 0.003). Furthermore, protein synthesis was higher during LPS than during Placebo (p < 0.02). Net muscle phenylalanine release was markedly decreased during LPS + A (p < 0.004), even though muscle protein synthesis and breakdown rates did not differ significantly between interventions. LPS + A increased mammalian target of rapamycin (mTOR) phosphorylation (p < 0.05) and eukaryotic translation factor 4E-binding protein 1 (4EBP1) phosphorylation (p = 0.007) without activating AMPK or affecting insulin signaling through Akt. During insulin stimulation net muscle phenylalanine release and protein degradation were further reduced. CONCLUSIONS: Amino acid supplementation in the acute phase of inflammation reduces whole body and muscle protein loss, and this effect is associated with activation of mTOR and downstream signaling to protein synthesis through mTORC1, suggesting a therapeutic role for intravenous amino acids in inflammatory states. CLINICAL TRIAL REGISTRY: The Central Denmark Region Ethics Commitee (1-10-71-410-12) www.clinicaltrials.gov (identification number NCT01705782).