Regionshospitalet Herning

Cell-free DNA in the blood provides a non-invasive diagnostic avenue for patients with cancer1. However, characteristics of the origins and molecular features of cell-free DNA are poorly understood. Here we developed an approach to evaluate fragmentation patterns of cell-free DNA across the genome, and found that profiles of healthy individuals reflected nucleosomal patterns of white blood cells, whereas patients with cancer had altered fragmentation profiles. We used this method to analyse the fragmentation profiles of 236 patients with breast, colorectal, lung, ovarian, pancreatic, gastric or bile duct cancer and 245 healthy individuals. A machine learning model that incorporated genome-wide fragmentation features had sensitivities of detection ranging from 57% to more than 99% among the seven cancer types at 98% specificity, with an overall area under the curve value of 0.94. Fragmentation profiles could be used to identify the tissue of origin of the cancers to a limited number of sites in 75% of cases. Combining our approach with mutation-based cell-free DNA analyses detected 91% of patients with cancer. The results of these analyses highlight important properties of cell-free DNA and provide a proof-of-principle approach for the screening, early detection and monitoring of human cancer. Analyses of fragmentation patterns of cell-free DNA in the blood of patients with cancer and healthy individuals using a machine learning algorithm provide a proof-of principle approach for the early detection and screening of human cancer.

Early detection and intervention are likely to be the most effective means for reducing morbidity and mortality of human cancer. However, development of methods for noninvasive detection of early-stage tumors has remained a challenge. We have developed an approach called targeted error correction sequencing (TEC-Seq) that allows ultrasensitive direct evaluation of sequence changes in circulating cell-free DNA using massively parallel sequencing. We have used this approach to examine 58 cancer-related genes encompassing 81 kb. Analysis of plasma from 44 healthy individuals identified genomic changes related to clonal hematopoiesis in 16% of asymptomatic individuals but no alterations in driver genes related to solid cancers. Evaluation of 200 patients with colorectal, breast, lung, or ovarian cancer detected somatic mutations in the plasma of 71, 59, 59, and 68%, respectively, of patients with stage I or II disease. Analyses of mutations in the circulation revealed high concordance with alterations in the tumors of these patients. In patients with resectable colorectal cancers, higher amounts of preoperative circulating tumor DNA were associated with disease recurrence and decreased overall survival. These analyses provide a broadly applicable approach for noninvasive detection of early-stage tumors that may be useful for screening and management of patients with cancer.

IMPORTANCE: Novel sensitive methods for detection and monitoring of residual disease can improve postoperative risk stratification with implications for patient selection for adjuvant chemotherapy (ACT), ACT duration, intensity of radiologic surveillance, and, ultimately, outcome for patients with colorectal cancer (CRC). OBJECTIVE: To investigate the association of circulating tumor DNA (ctDNA) with recurrence using longitudinal data from ultradeep sequencing of plasma cell-free DNA in patients with CRC before and after surgery, during and after ACT, and during surveillance. DESIGN, SETTING, AND PARTICIPANTS: In this prospective, multicenter cohort study, ctDNA was quantified in the preoperative and postoperative settings of stages I to III CRC by personalized multiplex, polymerase chain reaction-based, next-generation sequencing. The study enrolled 130 patients at the surgical departments of Aarhus University Hospital, Randers Hospital, and Herning Hospital in Denmark from May 1, 2014, to January 31, 2017. Plasma samples (n = 829) were collected before surgery, postoperatively at day 30, and every third month for up to 3 years. MAIN OUTCOMES AND MEASURES: Outcomes were ctDNA measurement, clinical recurrence, and recurrence-free survival. RESULTS: A total of 130 patients with stages I to III CRC (mean [SD] age, 67.9 [10.1] years; 74 [56.9%] male) were enrolled in the study; 5 patients discontinued participation, leaving 125 patients for analysis. Preoperatively, ctDNA was detectable in 108 of 122 patients (88.5%). After definitive treatment, longitudinal ctDNA analysis identified 14 of 16 relapses (87.5%). At postoperative day 30, ctDNA-positive patients were 7 times more likely to relapse than ctDNA-negative patients (hazard ratio [HR], 7.2; 95% CI, 2.7-19.0; P < .001). Similarly, shortly after ACT ctDNA-positive patients were 17 times (HR, 17.5; 95% CI, 5.4-56.5; P < .001) more likely to relapse. All 7 patients who were ctDNA positive after ACT experienced relapse. Monitoring during and after ACT indicated that 3 of the 10 ctDNA-positive patients (30.0%) were cleared by ACT. During surveillance after definitive therapy, ctDNA-positive patients were more than 40 times more likely to experience disease recurrence than ctDNA-negative patients (HR, 43.5; 95% CI, 9.8-193.5 P < .001). In all multivariate analyses, ctDNA status was independently associated with relapse after adjusting for known clinicopathologic risk factors. Serial ctDNA analyses revealed disease recurrence up to 16.5 months ahead of standard-of-care radiologic imaging (mean, 8.7 months; range, 0.8-16.5 months). Actionable mutations were identified in 81.8% of the ctDNA-positive relapse samples. CONCLUSIONS AND RELEVANCE: Circulating tumor DNA analysis can potentially change the postoperative management of CRC by enabling risk stratification, ACT monitoring, and early relapse detection.

BACKGROUND: In spite of more than 100 years of investigations the question of whether a reduced sodium intake improves health is still unsolved. OBJECTIVES: To estimate the effects of low sodium intake versus high sodium intake on systolic and diastolic blood pressure (SBP and DBP), plasma or serum levels of renin, aldosterone, catecholamines, cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL) and triglycerides. SEARCH METHODS: The Cochrane Hypertension Information Specialist searched the following databases for randomized controlled trials up to March 2016: the Cochrane Hypertension Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (2016, Issue 3), MEDLINE (from 1946), Embase (from 1974), the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov. We also searched the reference lists of relevant articles. SELECTION CRITERIA: Studies randomising persons to low-sodium and high-sodium diets were included if they evaluated at least one of the above outcome parameters. DATA COLLECTION AND ANALYSIS: Two review authors independently collected data, which were analysed with Review Manager 5.3. MAIN RESULTS: A total of 185 studies were included. The average sodium intake was reduced from 201 mmol/day (corresponding to high usual level) to 66 mmol/day (corresponding to the recommended level).The effect of sodium reduction on blood pressure (BP) was as follows: white people with normotension: SBP: mean difference (MD) -1.09 mmHg (95% confidence interval (CI): -1.63 to -0.56; P = 0.0001); 89 studies, 8569 participants; DBP: + 0.03 mmHg (MD 95% CI: -0.37 to 0.43; P = 0.89); 90 studies, 8833 participants. High-quality evidence. Black people with normotension: SBP: MD -4.02 mmHg (95% CI:-7.37 to -0.68; P = 0.002); seven studies, 506 participants; DBP: MD -2.01 mmHg (95% CI:-4.37 to 0.35; P = 0.09); seven studies, 506 participants. Moderate-quality evidence. Asian people with normotension: SBP: MD -0.72 mmHg (95% CI: -3.86 to 2.41; P = 0.65); DBP: MD -1.63 mmHg (95% CI:-3.35 to 0.08; P =0.06); three studies, 393 participants. Moderate-quality evidence.White people with hypertension: SBP: MD -5.51 mmHg (95% CI: -6.45 to -4.57; P < 0.00001); 84 studies, 5925 participants; DBP: MD -2.88 mmHg (95% CI: -3.44 to -2.32; P < 0.00001); 85 studies, 6001 participants. High-quality evidence. Black people with hypertension: SBP MD -6.64 mmHg (95% CI:-9.00 to -4.27; P = 0.00001); eight studies, 619 participants; DBP -2.91 mmHg (95% CI:-4.52, -1.30; P = 0.0004); eight studies, 619 participants. Moderate-quality evidence. Asian people with hypertension: SBP: MD -7.75 mmHg (95% CI:-11,44 to -4.07; P < 0.0001) nine studies, 501 participants; DBP: MD -2.68 mmHg (95% CI: -4.21 to -1.15; P = 0.0006). Moderate-quality evidence.In plasma or serum, there was a significant increase in renin (P < 0.00001), aldosterone (P < 0.00001), noradrenaline (P < 0.00001), adrenaline (P < 0.03), cholesterol (P < 0.0005) and triglyceride (P < 0.0006) with low sodium intake as compared with high sodium intake. All effects were stable in 125 study populations with a sodium intake below 250 mmol/day and a sodium reduction intervention of at least one week. AUTHORS' CONCLUSIONS: Sodium reduction from an average high usual sodium intake level (201 mmol/day) to an average level of 66 mmol/day, which is below the recommended upper level of 100 mmol/day (5.8 g salt), resulted in a decrease in SBP/DBP of 1/0 mmHg in white participants with normotension and a decrease in SBP/DBP of 5.5/2.9 mmHg in white participants with hypertension. A few studies showed that these effects in black and Asian populations were greater. The effects on hormones and lipids were similar in people with normotension and hypertension. Renin increased 1.60 ng/mL/hour (55%); aldosterone increased 97.81 pg/mL (127%); adrenalin increased 7.55 pg/mL (14%); noradrenalin increased 63.56 pg/mL: (27%); cholesterol increased 5.59 mg/dL (2.9%); triglyceride increased 7.04 mg/dL (6.3%).

BACKGROUND: Social consequences of disease may be subject to register based follow-up. A Danish database, DREAM, allows weekly follow-up of any public transfer payment. This study aimed to evaluate the feasibility of the register for use in public health research. MATERIAL AND METHODS: The DREAM database includes information on all public transfer payments administered by Danish ministries, municipalities, and Statistics Denmark for all Danish citizens on a weekly basis since 1991. The DREAM database was compared with self-reported information on sources of income in a population survey from 2001 with about 5000 participants. RESULTS: According to DREAM, 80.2% of respondents had received some kind of transfer income since 1991. For the week they filled in the questionnaire, 9.0% had a record of labour-market-related benefit (unemployment benefit, social assistance, wage subsidy), 6.4% a health-related benefit (sickness benefit, vocational rehabilitation allowance, salary from subsidized jobs for persons with limited work capacity, anticipatory pension), 10.1% a voluntary retirement pension, while 74.4% had no record of transfer payment for that week. The predictive value of DREAM was 74.8% for health-related transfer payment and 98.2% for self-support. Among persons with a record of sickness benefit, 52.4% reported no transfer payment. CONCLUSION: The DREAM database is feasible for follow-up of social and economic consequences of disease. Respondents may be unaware of payments transferred by the public authorities to the employer, and in such cases DREAM may be the best source of information. The database is useful for public health research, but may also be useful for socioeconomic analyses of selection bias and dropout from other studies.

OBJECTIVE: To quantify the relative contribution of work-related physical and psychosocial factors, individual factors, and health-related factors to the development of more severe musculoskeletal pain in the neck and upper limbs and the back and lower limbs. METHODS: In this cohort study of 5,604 workers from industrial and service companies, we collected information on work-related physical and psychosocial exposures and on individual and health-related factors. Questionnaires were completed at baseline by 4,006 participants (71.5%) and after 24 months by 3,276 (82%). At followup, participants with no or minor pain were included in Cox regression analyses to determine which factors predicted more severe regional pain. RESULTS: Of the 4,006 baseline respondents, only 7.7% were free of regional pain. A total of 1,513 participants were free of severe pain at baseline and completed the 24-month followup. Highly repetitive work predicted arm pain, heavy lifting and prolonged standing predicted low back pain, and heavy pushing or pulling predicted lower limb pain. Low job satisfaction predicted neck/shoulder pain and lower limb pain, whereas other psychosocial work place factors were only of marginal importance. High levels of fear avoidance were associated with arm pain and lower limb pain. A high body mass index was highly associated with lower limb pain. CONCLUSION: Very few workers are totally free of pain in musculoskeletal regions, and we question the concept of incidence of musculoskeletal pain. The transition from no or minor pain to more severe pain was influenced by physical and psychosocial work place factors together with individual and health-related factors.

Non-invasive approaches for cell-free DNA (cfDNA) assessment provide an opportunity for cancer detection and intervention. Here, we use a machine learning model for detecting tumor-derived cfDNA through genome-wide analyses of cfDNA fragmentation in a prospective study of 365 individuals at risk for lung cancer. We validate the cancer detection model using an independent cohort of 385 non-cancer individuals and 46 lung cancer patients. Combining fragmentation features, clinical risk factors, and CEA levels, followed by CT imaging, detected 94% of patients with cancer across stages and subtypes, including 91% of stage I/II and 96% of stage III/IV, at 80% specificity. Genome-wide fragmentation profiles across ~13,000 ASCL1 transcription factor binding sites distinguished individuals with small cell lung cancer from those with non-small cell lung cancer with high accuracy (AUC = 0.98). A higher fragmentation score represented an independent prognostic indicator of survival. This approach provides a facile avenue for non-invasive detection of lung cancer.

OBJECTIVE: The incidence of inflammatory bowel disease (IBD) is increasing in Eastern Europe. The reasons for these changes remain unknown. The aim of this study was to investigate whether an East-West gradient in the incidence of IBD in Europe exists. DESIGN: A prospective, uniformly diagnosed, population based inception cohort of IBD patients in 31 centres from 14 Western and eight Eastern European countries covering a total background population of approximately 10.1 million people was created. One-third of the centres had previous experience with inception cohorts. Patients were entered into a low cost, web based epidemiological database, making participation possible regardless of socioeconomic status and prior experience. RESULTS: 1515 patients aged 15 years or older were included, of whom 535 (35%) were diagnosed with Crohn's disease (CD), 813 (54%) with ulcerative colitis (UC) and 167 (11%) with IBD unclassified (IBDU). The overall incidence rate ratios in all Western European centres were 1.9 (95% CI 1.5 to 2.4) for CD and 2.1 (95% CI 1.8 to 2.6) for UC compared with Eastern European centres. The median crude annual incidence rates per 100,000 in 2010 for CD were 6.5 (range 0-10.7) in Western European centres and 3.1 (range 0.4-11.5) in Eastern European centres, for UC 10.8 (range 2.9-31.5) and 4.1 (range 2.4-10.3), respectively, and for IBDU 1.9 (range 0-39.4) and 0 (range 0-1.2), respectively. In Western Europe, 92% of CD, 78% of UC and 74% of IBDU patients had a colonoscopy performed as the diagnostic procedure compared with 90%, 100% and 96%, respectively, in Eastern Europe. 8% of CD and 1% of UC patients in both regions underwent surgery within the first 3 months of the onset of disease. 7% of CD patients and 3% of UC patients from Western Europe received biological treatment as rescue therapy. Of all European CD patients, 20% received only 5-aminosalicylates as induction therapy. CONCLUSIONS: An East-West gradient in IBD incidence exists in Europe. Among this inception cohort--including indolent and aggressive cases--international guidelines for diagnosis and initial treatment are not being followed uniformly by physicians.

BACKGROUND: Bowel dysfunction after sphincter-preserving surgery for rectal cancer is a common complication, with the potential to affect quality of life (QoL) strongly. The aim of this study was to examine the extent of bowel dysfunction and impact on health-related QoL after curative sphincter-preserving resection for rectal cancer. METHODS: QoL was assessed using the European Organization for Research and Treatment of Cancer QLQ-C30 questionnaire, and bowel function using a validated questionnaire, including the recently developed low anterior resection syndrome (LARS) score. Assessments were carried out at the time of diagnosis, and at 3 and 12 months after surgery. RESULTS: A total of 260 patients were included in the study. At 3 months, 58·0 per cent of patients had a LARS score of 30 or more (major LARS), which declined to 45·9 per cent at 12 months (P < 0·001). The risk of major LARS was significantly increased in patients who received neoadjuvant therapy (odds ratio 2·41, 95 per cent confidence interval 1·00 to 5·83), and after total versus partial mesorectal excision (odds ratio 2·81, 1·35 to 5·88). Global health status was closely associated with LARS, and significant differences in global health status, functional and symptom scales of QoL were found between patients without LARS and those with major LARS. CONCLUSION: Bowel dysfunction is a major problem with an immense impact on QoL following sphincter-preserving resection. The risk of major LARS was significantly increased after neoadjuvant therapy and total mesorectal excision.

BACKGROUND: Prophylaxis for gastrointestinal stress ulceration is frequently given to patients in the intensive care unit (ICU), but its risks and benefits are unclear. METHODS: In this European, multicenter, parallel-group, blinded trial, we randomly assigned adults who had been admitted to the ICU for an acute condition (i.e., an unplanned admission) and who were at risk for gastrointestinal bleeding to receive 40 mg of intravenous pantoprazole (a proton-pump inhibitor) or placebo daily during the ICU stay. The primary outcome was death by 90 days after randomization. RESULTS: A total of 3298 patients were enrolled; 1645 were randomly assigned to the pantoprazole group and 1653 to the placebo group. Data on the primary outcome were available for 3282 patients (99.5%). At 90 days, 510 patients (31.1%) in the pantoprazole group and 499 (30.4%) in the placebo group had died (relative risk, 1.02; 95% confidence interval [CI], 0.91 to 1.13; P=0.76). During the ICU stay, at least one clinically important event (a composite of clinically important gastrointestinal bleeding, pneumonia, Clostridium difficile infection, or myocardial ischemia) had occurred in 21.9% of patients assigned to pantoprazole and 22.6% of those assigned to placebo (relative risk, 0.96; 95% CI, 0.83 to 1.11). In the pantoprazole group, 2.5% of patients had clinically important gastrointestinal bleeding, as compared with 4.2% in the placebo group. The number of patients with infections or serious adverse reactions and the percentage of days alive without life support within 90 days were similar in the two groups. CONCLUSIONS: Among adult patients in the ICU who were at risk for gastrointestinal bleeding, mortality at 90 days and the number of clinically important events were similar in those assigned to pantoprazole and those assigned to placebo. (Funded by Innovation Fund Denmark and others; SUP-ICU ClinicalTrials.gov number, NCT02467621 .).

AIMS: In patients with sick sinus syndrome, bradycardia can be treated with a single-lead pacemaker or a dual-chamber pacemaker. Previous trials have revealed that pacing modes preserving atrio-ventricular synchrony are superior to single-lead ventricular pacing, but it remains unclear if there is any difference between single-lead atrial pacing (AAIR) and dual-chamber pacing (DDDR). METHODS AND RESULTS: We randomly assigned 1415 patients referred for first pacemaker implantation to AAIR (n = 707) or DDDR (n = 708) pacing and followed them for a mean of 5.4 ± 2.6 years. The primary outcome was death from any cause. Secondary outcomes included paroxysmal and chronic atrial fibrillation, stroke, heart failure, and need for pacemaker reoperation. In the AAIR group, 209 patients (29.6%) died during follow-up vs. 193 patients (27.3%) in the DDDR group, hazard ratio (HR) 1.06, 95% confidence interval (CI) 0.88-1.29, P = 0.53. Paroxysmal atrial fibrillation was observed in 201 patients (28.4%) in the AAIR group vs. 163 patients (23.0%) in the DDDR group, HR 1.27, 95% CI 1.03-1.56, P = 0.024. A total of 240 patients underwent one or more pacemaker reoperations during follow-up, 156 (22.1%) in the AAIR group vs. 84 (11.9%) in the DDDR group (HR 1.99, 95% CI 1.53-2.59, P < 0.001). The incidence of chronic atrial fibrillation, stroke, and heart failure did not differ between treatment groups. CONCLUSION: In patients with sick sinus syndrome, there is no statistically significant difference in death from any cause between AAIR pacing and DDDR pacing. AAIR pacing is associated with a higher incidence of paroxysmal atrial fibrillation and a two-fold increased risk of pacemaker reoperation. These findings support the routine use of DDDR pacing in these patients. CLINICAL TRIAL REGISTRATION: URL http://www.clinicaltrials.gov. Unique identifier: NCT00236158.

In a group of 48 patients with completed stroke, 8 patients had viable collaterally perfused brain tissue which was accessible for rCBF recordings with a two dimensional technique. All 8 had deep subcortical infarcts on CT-scan, and angiographic occlusion of the arteries normally supplying the infarcted territory. The brain tissue overlying the deep infarcts appeared normal on CT-scan and was supplied by collateral circulation. rCBF was measured in all within 72 hours after the stroke. The intra-carotid Xe-133 injection method and a 254 multidetector camera were used to study rCBF. Relatively ischemic low flow areas were a constant finding in the collaterally perfused tissue. In 6 of the patients, the collaterally perfused part of the brain had low flow values comparable to those of an "ischemic penumbra" (viable, but functionally depressed brain tissue due to inadequate perfusion). Autoregulation was impaired in all of the collaterally perfused areas while the CO2-response always was preserved. Steal phenomena were not seen. In the surrounding brain tissue, autoregulation was normal in 5 patients and impaired in 3 while the CO2-response seemed to be normal. The results confirm the experimental finding of an ischemic penumbra associated with acute cerebral infarcts and suggest that early restoration of the blood flow in acute stroke patients might improve recovery and prognosis in selected patients.

OBJECTIVE: The Epi-IBD cohort is a prospective population-based inception cohort of unselected patients with inflammatory bowel disease from 29 European centres covering a background population of almost 10 million people. The aim of this study was to assess the 5-year outcome and disease course of patients with Crohn's disease (CD). DESIGN: Patients were followed up prospectively from the time of diagnosis, including collection of their clinical data, demographics, disease activity, medical therapy, surgery, cancers and deaths. Associations between outcomes and multiple covariates were analysed by Cox regression analysis. RESULTS: In total, 488 patients were included in the study. During follow-up, 107 (22%) patients received surgery, while 176 (36%) patients were hospitalised because of CD. A total of 49 (14%) patients diagnosed with non-stricturing, non-penetrating disease progressed to either stricturing and/or penetrating disease. These rates did not differ between patients from Western and Eastern Europe. However, significant geographic differences were noted regarding treatment: more patients in Western Europe received biological therapy (33%) and immunomodulators (66%) than did those in Eastern Europe (14% and 54%, respectively, P<0.01), while more Eastern European patients received 5-aminosalicylates (90% vs 56%, P<0.05). Treatment with immunomodulators reduced the risk of surgery (HR: 0.4, 95% CI 0.2 to 0.6) and hospitalisation (HR: 0.3, 95% CI 0.2 to 0.5). CONCLUSION: Despite patients being treated early and frequently with immunomodulators and biological therapy in Western Europe, 5-year outcomes including surgery and phenotype progression in this cohort were comparable across Western and Eastern Europe. Differences in treatment strategies between Western and Eastern European centres did not affect the disease course. Treatment with immunomodulators reduced the risk of surgery and hospitalisation.

Importance: A daily dose with 6 mg of dexamethasone is recommended for up to 10 days in patients with severe and critical COVID-19, but a higher dose may benefit those with more severe disease. Objective: To assess the effects of 12 mg/d vs 6 mg/d of dexamethasone in patients with COVID-19 and severe hypoxemia. Design, Setting, and Participants: A multicenter, randomized clinical trial was conducted between August 2020 and May 2021 at 26 hospitals in Europe and India and included 1000 adults with confirmed COVID-19 requiring at least 10 L/min of oxygen or mechanical ventilation. End of 90-day follow-up was on August 19, 2021. Interventions: Patients were randomized 1:1 to 12 mg/d of intravenous dexamethasone (n = 503) or 6 mg/d of intravenous dexamethasone (n = 497) for up to 10 days. Main Outcomes and Measures: The primary outcome was the number of days alive without life support (invasive mechanical ventilation, circulatory support, or kidney replacement therapy) at 28 days and was adjusted for stratification variables. Of the 8 prespecified secondary outcomes, 5 are included in this analysis (the number of days alive without life support at 90 days, the number of days alive out of the hospital at 90 days, mortality at 28 days and at 90 days, and ≥1 serious adverse reactions at 28 days). Results: Of the 1000 randomized patients, 982 were included (median age, 65 [IQR, 55-73] years; 305 [31%] women) and primary outcome data were available for 971 (491 in the 12 mg of dexamethasone group and 480 in the 6 mg of dexamethasone group). The median number of days alive without life support was 22.0 days (IQR, 6.0-28.0 days) in the 12 mg of dexamethasone group and 20.5 days (IQR, 4.0-28.0 days) in the 6 mg of dexamethasone group (adjusted mean difference, 1.3 days [95% CI, 0-2.6 days]; P = .07). Mortality at 28 days was 27.1% in the 12 mg of dexamethasone group vs 32.3% in the 6 mg of dexamethasone group (adjusted relative risk, 0.86 [99% CI, 0.68-1.08]). Mortality at 90 days was 32.0% in the 12 mg of dexamethasone group vs 37.7% in the 6 mg of dexamethasone group (adjusted relative risk, 0.87 [99% CI, 0.70-1.07]). Serious adverse reactions, including septic shock and invasive fungal infections, occurred in 11.3% in the 12 mg of dexamethasone group vs 13.4% in the 6 mg of dexamethasone group (adjusted relative risk, 0.83 [99% CI, 0.54-1.29]). Conclusions and Relevance: Among patients with COVID-19 and severe hypoxemia, 12 mg/d of dexamethasone compared with 6 mg/d of dexamethasone did not result in statistically significantly more days alive without life support at 28 days. However, the trial may have been underpowered to identify a significant difference. Trial Registration: ClinicalTrials.gov Identifier: NCT04509973 and ctri.nic.in Identifier: CTRI/2020/10/028731.

OBJECTIVES: To compare the effect of graded physiotherapeutic training of the rotator cuff versus arthroscopic subacromial decompression in patients with subacromial impingement. METHODS: Randomised controlled trial with 12 months' follow up in a hospital setting. Ninety consecutive patients aged 18 to 55 years were enrolled. Symptom duration was between six months and three years. All fulfilled a set of diagnostic criteria for rotator cuff disease, including a positive impingement sign. Patients were randomised either to arthroscopic subacromial decompression, or to physiotherapy with exercises aiming at strengthening the stabilisers and decompressors of the shoulder. Outcome was shoulder function as measured by the Constant score and a pain and dysfunction score. "Intention to treat" analysis was used, with comparison of means and control of confounding variables by general equation estimation analysis. RESULTS: Of 90 patients enrolled, 84 completed follow up (41 in the surgery group, 43 in the training group). The mean Constant score at baseline was 34.8 in the training group and 33.7 in the surgery group. After 12 months the mean scores improved to 57.0 and 52.7, respectively, the difference being non-significant. No group differences in mean pain and dysfunction score improvement were found. CONCLUSIONS: Surgical treatment of rotator cuff syndrome with subacromial impingement was not superior to physiotherapy with training. Further studies are needed to qualify treatment choice decisions, and it is recommended that samples are stratified according to disability level.

AIMS: To quantify the relative contribution of work related physical factors, psychosocial workplace factors, and individual factors and aspects of somatisation to the onset of neck/shoulder pain. METHODS: Four year prospective cohort study of workers from industrial and service companies in Denmark. Participants were 3123 workers, previously enrolled in a cross sectional study, where objective measurement of physical workplace factors was used. Eligible participants were followed on three subsequent occasions with approximately one year intervals. Outcomes of interest were: new onset of neck/shoulder pain (symptom cases); and neck/shoulder pain with pressure tenderness in the muscles of the neck/shoulder region (clinical cases). RESULTS: During follow up, 636 (14.1%) participants reported neck/shoulder pain of new onset; among these, 82 (1.7%) also had clinical signs of substantial muscle tenderness. High shoulder repetition was related to being a future symptom case, and a future clinical case. Repetition was strongly intercorrelated with other physical measures. High job demands were associated with future status as a symptom case, and as a clinical case. A high level of distress predicted subsequent neck/shoulder pain, and neck/shoulder pain with pressure tenderness. CONCLUSIONS: High levels of distress, and physical and psychosocial workplace factors are predictors of onset of pain in the neck and/or shoulders, particularly pain with pressure tenderness in the muscles.

BACKGROUND: Starch is stored in higher plants as granules composed of semi-crystalline amylopectin and amorphous amylose. Starch granules provide energy for the plant during dark periods and for germination of seeds and tubers. Dietary starch is also a highly glycemic carbohydrate being degraded to glucose and rapidly absorbed in the small intestine. But a portion of dietary starch, termed "resistant starch" (RS) escapes digestion and reaches the large intestine, where it is fermented by colonic bacteria producing short chain fatty acids (SCFA) which are linked to several health benefits. The RS is preferentially derived from amylose, which can be increased by suppressing amylopectin synthesis by silencing of starch branching enzymes (SBEs). However all the previous works attempting the production of high RS crops resulted in only partly increased amylose-content and/or significant yield loss. RESULTS: In this study we invented a new method for silencing of multiple genes. Using a chimeric RNAi hairpin we simultaneously suppressed all genes coding for starch branching enzymes (SBE I, SBE IIa, SBE IIb) in barley (Hordeum vulgare L.), resulting in production of amylose-only starch granules in the endosperm. This trait was segregating 3:1. Amylose-only starch granules were irregularly shaped and showed peculiar thermal properties and crystallinity. Transgenic lines retained high-yield possibly due to a pleiotropic upregualtion of other starch biosynthetic genes compensating the SBEs loss. For gelatinized starch, a very high content of RS (65 %) was observed, which is 2.2-fold higher than control (29%). The amylose-only grains germinated with same frequency as control grains. However, initial growth was delayed in young plants. CONCLUSIONS: This is the first time that pure amylose has been generated with high yield in a living organism. This was achieved by a new method of simultaneous suppression of the entire complement of genes encoding starch branching enzymes. We demonstrate that amylopectin is not essential for starch granule crystallinity and integrity. However the slower initial growth of shoots from amylose-only grains may be due to an important physiological role played by amylopectin ordered crystallinity for rapid starch remobilization explaining the broad conservation in the plant kingdom of the amylopectin structure.

Abstract Purpose: Sensitive methods for risk stratification, monitoring therapeutic efficacy, and early relapse detection may have a major impact on treatment decisions and patient management for stage III colorectal cancer patients. Beyond assessing the predictive power of postoperative ctDNA detection, we explored the added benefits of serial analysis: assessing adjuvant chemotherapy (ACT) efficacy, early relapse detection, and ctDNA growth rates. Experimental Design: We recruited 168 patients with stage III colorectal cancer treated with curative intent at Danish and Spanish hospitals between 2014 and 2019. To quantify ctDNA in plasma samples (n = 1,204), 16 patient-specific somatic single-nucleotide variants were profiled using multiplex-PCR, next-generation sequencing. Results: Detection of ctDNA was a strong recurrence predictor postoperatively [HR = 7.0; 95% confidence interval (CI), 3.7–13.5; P &amp;lt; 0.001] and directly after ACT (HR = 50.76; 95% CI, 15.4–167; P &amp;lt; 0.001). The recurrence rate of postoperative ctDNA-positive patients treated with ACT was 80% (16/20). Only patients who cleared ctDNA permanently during ACT did not relapse. Serial ctDNA assessment after the end of treatment was similarly predictive of recurrence (HR = 50.80; 95% CI, 14.9–172; P &amp;lt; 0.001), and revealed two distinct rates of exponential ctDNA growth, slow (25% ctDNA-increase/month) and fast (143% ctDNA-increase/month; P &amp;lt; 0.001). The ctDNA growth rate was prognostic of survival (HR = 2.7; 95% CI, 1.1–6.7; P = 0.039). Serial ctDNA analysis every 3 months detected recurrence with a median lead-time of 9.8 months compared with standard-of-care computed tomography. Conclusions: Serial postoperative ctDNA analysis has a strong prognostic value and enables tumor growth rate assessment. The novel combination of ctDNA detection and growth rate assessment provides unique opportunities for guiding decision-making. See related commentary by Morris and George, p. 438

STUDY DESIGN: Cross-sectional study. OBJECTIVES: To evaluate the effect of individual characteristics and physical and psychosocial workplace factors on neck/shoulder pain with pressure tenderness in the muscles. SUMMARY OF BACKGROUND DATA: Controversy prevails about the importance of workplace factors versus individual factors in the etiology of pain in the neck and/or shoulders. METHODS: Study participants were 3123 workers from 19 plants. Physical risk factors were evaluated via video observations, and psychosocial risk factors were assessed with the job content questionnaire. Other procedures included symptom survey, clinical examination, and assessment of health-related quality of life (SF-36). The main outcome variable, neck/shoulder pain with pressure tenderness, was defined on the basis of subjective pain score and pressure tenderness in muscles of the neck/shoulder region. RESULTS: The prevalence of neck/shoulder pain with pressure tenderness was 7.0% among participants performing repetitive work and 3.8% among the referents. We found an association with high repetitiveness (prevalence ratio 1.8, 95% confidence interval 1.1-2.9), high force (2.0, 1.2-3.3), and high repetitiveness and high force (2.3, 1.4-4.0). The strongest work-related psychosocial risk was high job demands (1.8, 1.2-2.7). Increased risk was also associated with neck/shoulder injury (2.6, 1.6-4.1), female gender (1.8, 1.2-2.8), and low pressure pain threshold (1.6, 1.1-2.3). Neck/shoulder pain was strongly associated with reduced health-related quality of life. CONCLUSIONS: Work-related physical and psychosocial factors, as well as several individual risk factors, are important in the understanding of neck/shoulder pain. The findings suggest that neck/shoulder pain has a multifactorial nature. Reduced health-related quality of life is associated with subjective pain and clinical signs from the neck and shoulders. The physical workplace factors were highly intercorrelated, and so the effect of individual physical exposures could only be disentangled to a minor degree.

It is well established that lncRNAs are aberrantly expressed in cancer where they have been shown to act as oncogenes or tumor suppressors. RNA profiling of 314 colorectal adenomas/adenocarcinomas and 292 adjacent normal colon mucosa samples using RNA-sequencing demonstrated that the snoRNA host gene 16 (SNHG16) is significantly up-regulated in adenomas and all stages of CRC. SNHG16 expression was positively correlated to the expression of Wnt-regulated transcription factors, including ASCL2, ETS2, and c-Myc. In vitro abrogation of Wnt signaling in CRC cells reduced the expression of SNHG16 indicating that SNHG16 is regulated by the Wnt pathway. Silencing of SNHG16 resulted in reduced viability, increased apoptotic cell death and impaired cell migration. The SNHG16 silencing particularly affected expression of genes involved in lipid metabolism. A connection between SNHG16 and genes involved in lipid metabolism was also observed in clinical tumors. Argonaute CrossLinking and ImmunoPrecipitation (AGO-CLIP) demonstrated that SNHG16 heavily binds AGO and has 27 AGO/miRNA target sites along its length, indicating that SNHG16 may act as a competing endogenous RNA (ceRNA) "sponging" miRNAs off their cognate targets. Most interestingly, half of the miRNA families with high confidence targets on SNHG16 also target the 3'UTR of Stearoyl-CoA Desaturase (SCD). SCD is involved in lipid metabolism and is down-regulated upon SNHG16 silencing. In conclusion, up-regulation of SNHG16 is a frequent event in CRC, likely caused by deregulated Wnt signaling. In vitro analyses demonstrate that SNHG16 may play an oncogenic role in CRC and that it affects genes involved in lipid metabolism, possible through ceRNA related mechanisms.