The role of bridging therapies for patients with hepatocellular carcinoma (HCC) on the waiting list for liver transplantation (LT) remains controversial. There is strong evidence to support the effectiveness of sorafenib in extending the time to progression of HCC. Using a Markov model, we compared two strategies: one using sorafenib as neoadjuvant therapy before LT (Strategy A), and the other using no bridging therapy in the first 6 months (Strategy B). Reference case: T2 HCC patient with compensated cirrhosis. The benefit of sorafenib in delaying time to HCC progression was expressed as the hazard ratio (HR) and taken from recently published randomized trials. The endpoints considered were: survival benefit measured in quality-adjusted life days (QALDs), transplant probability, costs (C) in euro, willingness to pay (WTP), and net health benefit (NHB), where NHB = survival benefit - C/WTP. The calculated WTP of sorafenib in Italy was 346 euro per QALD. Probabilistic sensitivity analysis showed a median survival benefit of 94 QALDs (10% percentile = 38, 90% percentile = 210). In the base-case scenario (HR = 0.47, monthly dropout probability = 5%, median time to LT = 3 months), the gain in LT probability due to sorafenib was 5% and it increased proportionally with increasing median times to LT and decreasing HR. In the cost-benefit analysis, the incremental NHB of Strategy A versus Strategy B was 37 QALDs; it increased as sorafenib HR decreased and when median times to LT were shorter than 6 months, whereas for longer times it gradually dropped, particularly when Strategy B included effective locoregional treatments.

CONCLUSIONS

Sorafenib neoadjuvant therapy is cost-effective by comparison with no therapy for T2-HCC patients waiting for LT, particularly for median times to LT under 6 months.

Extended criteria donor (ECD) liver allografts are often allocated to less severely ill liver transplant (<em>LT</em>) candidates who are at a relatively lower risk of pretransplant mortality, but it is not clear that the use of ECD allografts will decrease center waitlist mortality (WLM). Individual patient data from the UNOS OPTN database (2002-2005) were aggregated to obtain center-specific data. Deceased donor allografts with any of the following characteristics were defined as ECDs: from a donor with any of the criteria described by the New York State Department of Health Workgroup; or 12+ h of cold ischemia. Multivariate regression was used to examine the relationship between WLM and ECD, non-ECD and LD<em>LT</em> use after adjusting for candidate severity of illness. A total of 3555 ECD transplants, 11,660 standard criteria donor (SCD) transplants, and 717 LD<em>LTs</em> were performed at 100 centers during this period. The model demonstrated that SCD and ECD <em>LTs</em> were inversely correlated with a center's WLM (<em>beta</em>=-0.242 and -0.221, respectively; p <or= 0.003 for each). LD<em>LTs</em> did not significantly reduce WLM (<em>beta</em>=-0.048, p=0.55). In summary, increasing ECD liver allograft use significantly decreased WLM at US centers. Policies encouraging the increase used of ECDs would further reduce WLM.

Contamination of recreational waters with Escherichia coli and Enterococcus sp. is a widespread problem resulting in beach closures and loss of recreational activity. While E. coli is frequently used as an indicator of fecal contamination, and has been extensively measured in waterways, few studies have examined the presence of potentially pathogenic E. coli strains in beach waters. In this study, a combination of high-throughput, robot-assisted colony hybridization and PCR-based analyses were used to determine the genomic composition and frequency of virulence genes present in E. coli isolated from beach water in Avalon Bay, Santa Catalina Island, CA. A total of 24,493 E. coli isolates were collected from two sites at a popular swimming beach between August through September 2007 and from July through August 2008. All isolates were examined for the presence of shiga-like toxins (stx1/stx2), intimin (eaeA), and enterotoxins (ST/LT). Of the 24,493 isolates examined, 3.6% contained the eaeA gene, indicating that these isolates were potential EPEC strains. On five dates, however, greater than 10% of the strains were potential EPEC, suggesting that incidence of virulence genes at this beach has a strong temporal component. No STEC or ETEC isolates were detected, and only eight (<1.0%) of the potential EPEC isolates were found to carry the EAF plasmid. The potential EPEC isolates mainly belonged to E. coli phylogenetic groups B1 or B2, and carried the β intimin subtype. DNA fingerprint analyses of the potential EPEC strains indicated that the isolates belonged to several genetically diverse groups, although clonal isolates were frequently detected. While the presence of virulence genes alone cannot be used to determine the pathogenicity of strains, results from this study show that potential EPEC strains can be found in marine beach water and their presence needs to be considered as one of the factors used in decisions concerning beach closures.

<A<em>b</em>stractText>Paracetamol and non-steroidal anti-inflammatory drugs (e.g. ketorolac) can <em>b</em>e considered for mild to moderate post-caesarean pain. As a selective α-2 agonist adrenergic receptor, dexmedetomidine has analgesic and sedative effects without causing respiratory depression.</A<em>b</em>stractText><A<em>b</em>stractText>This study aimed to evaluate the effects of adding dexmedetomidine to paracetamol or ketorolac on post-caesarean pain and the associated complications thereof.</A<em>b</em>stractText><p><div>(<em>b</em>)Methods</<em>b</em>)</div>Sixty pregnant women, who were candidates for caesarean section with spinal anesthesia, were randomly assigned to either of two groups of 30 patients. For post-operative pain management, an intravenous patient-controlled analgesia (PCA) device was used for 24 hours. Dexmedetomidine (3 µg kg^-1) was added to paracetamol (35 mg kg^-1) in the group DP and to ketorolac (1 mg kg^-1) in the group DK. Visual analog scale (VAS), Ramsay sedation scale, hemodynamic changes, rescue analgesic (meperidine) consumption, patient satisfaction, and possi<em>b</em>le complications were recorded at 6, 12, and 24, hours after surgery, and compared afterward.</p><A<em>b</em>stractText>The pain score was significantly lower in the DK group than in the DP group (P &<em>lt</em>; 0.05). The hemodynamics and sedation scale were similar in <em>b</em>oth groups. The total meperidine consumption was higher in the DP group, <em>b</em>ut it was not significantly different. Maternal satisfaction was greater in the DK group (P &<em>lt</em>; 0.05). Concerning complications, the two groups did not show statistically significant differences (P = 0.4).</A<em>b</em>stractText><A<em>b</em>stractText>The addition of dexmedetomidine to ketorolac, compared with its addition to paracetamol, causes further reduction in the post-operative pain score and provides more satisfaction.</A<em>b</em>stractText>

<A<em>b</em>stractText>Spironolactone is effective at reducing <em>b</em>lood pressure in patients with uncontrolled resistant hypertension. However, the use of spironolactone in patients with chronic kidney disease can <em>b</em>e restricted <em>b</em>y hyperkalaemia. We evaluated use of the potassium <em>b</em>inder patiromer to allow more persistent use of spironolactone in patients with chronic kidney disease and resistant hypertension.</A<em>b</em>stractText><p><div>(<em>b</em>)METHODS</<em>b</em>)</div>In this phase 2 mu<em>lt</em>icentre, randomised, dou<em>b</em>le-<em>b</em>lind, place<em>b</em>o-controlled study, we enrolled participants aged 18 years and older with chronic kidney disease (estimated glomerular fi<em>lt</em>ration rate 25 to ≤45 mL/min per 1·73 m²) and uncontrolled resistant hypertension from 62 outpatient centres in ten countries (Bulgaria, Croatia, Georgia, Hungary, Ukraine, France, Germany, South Africa, the UK, and the USA). Patients meeting all eligi<em>b</em>ility criteria at the final screening visit were stratified <em>b</em>y local serum potassium measurement (4·3 to &<em>lt</em>;4·7 mmol/L vs 4·7 to 5·1 mmol/L) and history of dia<em>b</em>etes. Participants were randomly assigned (1:1) with an interactive we<em>b</em> response system to receive either place<em>b</em>o or patiromer (8·4 g once daily), in addition to open-la<em>b</em>el spironolactone (starting at 25 mg once daily) and their <em>b</em>aseline <em>b</em>lood pressure medications. Participants, the study team that administered treatments and measured <em>b</em>lood pressure, and the investigators were masked to assigned treatment groups. Dose titrations were permitted after 1 week (patiromer) and 3 weeks (spironolactone). The primary endpoint was the <em>b</em>etween-group difference at week 12 in the proportion of patients on spironolactone. Efficacy endpoints and safety were assessed in all randomised patients (intention to treat). The study was registered with Clinica<em>lt</em>rials.gov, NCT03071263.</p><A<em>b</em>stractText>Between Fe<em>b</em> 13, 2017, and Aug 20, 2018, we screened 574 patients. 295 (51%) of 574 patients met all inclusion criteria and were randomly assigned to spironolactone in addition to dou<em>b</em>le-<em>b</em>lind treatment with either place<em>b</em>o (n=148) or patiromer (n=147). At week 12, 98 (66%) of 148 patients in the place<em>b</em>o group and 126 (86%) of 147 patients in the patiromer group remained on spironolactone (<em>b</em>etween-group difference 19·5%, 95% CI 10·0-29·0; p&<em>lt</em>;0·0001). Adverse events were mostly mild or moderate in severity and occurred in 79 (53%) of 148 patients in the place<em>b</em>o group and 82 (56%) of 147 patients in the patiromer group.</A<em>b</em>stractText><A<em>b</em>stractText>In patients with resistant hypertension and chronic kidney disease, patiromer ena<em>b</em>led more patients to continue treatment with spironolactone with less hyperkalaemia. Persistent spironolactone ena<em>b</em>lement in this population of patients has clinical relevance for the treatment of resistant hypertension.</A<em>b</em>stractText><A<em>b</em>stractText>Relypsa, a Vifor Pharma Group Company.</A<em>b</em>stractText>

<A<em>b</em>stractText>The Parkinson's Progression Markers Initiative (PPMI) is an o<em>b</em>servational, international study designed to esta<em>b</em>lish <em>b</em>iomarker-defined cohorts and identify clinical, imaging, genetic, and <em>b</em>iospecimen Parkinson's disease (PD) progression markers to accelerate disease-modifying therapeutic trials.</A<em>b</em>stractText><A<em>b</em>stractText>A total of 423 untreated PD, 196 Hea<em>lt</em>hy Control (HC) and 64 SWEDD (scans without evidence of dopaminergic deficit) su<em>b</em>jects were enrolled at 24 sites. To enroll PD su<em>b</em>jects as early as possi<em>b</em>le following diagnosis, su<em>b</em>jects were eligi<em>b</em>le with only asymmetric <em>b</em>radykinesia or tremor plus a dopamine transporter (DAT) <em>b</em>inding deficit on SPECT imaging. Acquisition of data was standardized as detailed at www.ppmi-info.org.</A<em>b</em>stractText><p><div>(<em>b</em>)Resu<em>lt</em>s</<em>b</em>)</div>Approximately 9% of enrolled su<em>b</em>jects had a single PD sign at <em>b</em>aseline. DAT imaging excluded 16% of potential PD su<em>b</em>jects with SWEDD. The total MDS-UPDRS for PD was 32.4 compared to 4.6 for HC and 28.2 for SWEDD. On average, PD su<em>b</em>jects demonstrated 45% and 68% reduction in mean striatal and contralateral putamen Specific Binding Ratios (SBR), respectively. Cere<em>b</em>rospinal fluid (CSF) was acquired from >97% of all su<em>b</em>jects. CSF (PD/HC/SWEDD pg/mL) α-synuclein (1845/2204/2141) was reduced in PD vs HC or SWEDD (<i>P </i>&<em>lt</em>; 0.03). Similarly, <i>t</i>-tau (45/53) and <i>p</i>-tau (16/18) were reduced in PD versus HC (<i>P </i>&<em>lt</em>; 0.01).</p><A<em>b</em>stractText>PPMI has detailed the <em>b</em>iomarker signature for an early PD cohort defined <em>b</em>y clinical features and imaging <em>b</em>iomarkers. This strategy provides the framework to esta<em>b</em>lish <em>b</em>iomarker cohorts and to define longitudinal progression <em>b</em>iomarkers to support future PD treatment trials.</A<em>b</em>stractText>

<A<em>b</em>stractText>Neutrophils release neutrophil extracellular traps (NETs) in response to invading pathogens. A<em>lt</em>hough NETs play an important role in host defense against micro<em>b</em>ial pathogens, they have also <em>b</em>een shown to play a contri<em>b</em>uting mechanistic role in pathologic inflammation in the a<em>b</em>sence of infection. A<em>lt</em>hough a role for NETs in <em>b</em>acterial pneumonia and acute respiratory distress syndrome (ARDS) is emerging, a comprehensive evaluation of NETs in the alveolar space of critically ill patients has yet to <em>b</em>e reported. In this study, we evaluated whether markers of NET formation in mechanically ventilated patients are associated with ventilator-associated pneumonia (VAP).</A<em>b</em>stractText><p><div>(<em>b</em>)METHODS</<em>b</em>)</div>We collected <em>b</em>ronchoalveolar lavage fluid from 100 critically ill patients undergoing <em>b</em>ronchoscopy for clinically suspected VAP. Su<em>b</em>jects were categorized <em>b</em>y the a<em>b</em>sence or presence of VAP and further stratified <em>b</em>y ARDS status. NETs (myeloperoxidase (MPO)-DNA complexes) and the NET-associated markers peroxidase activity and cell-free DNA were analyzed <em>b</em>y enzyme-linked immunosor<em>b</em>ent assay and colorimetric assays, respectively. Quantitative polymerase chain reaction of nuclear and mitochondrial DNA was used to determine the origin of the extruded DNA. Interleukin (IL)-8 and calprotectin were assayed as measures of alveolar inflammation and neutrophil activation. Correlations <em>b</em>etween NETs and markers of neutrophil activation were determined using Spearman's correlation. We tested for associations with VAP and <em>b</em>acterial <em>b</em>urden <em>b</em>y logistic and linear regression, respectively, using log<su<em>b</em>)10</su<em>b</em>)-transformed NETs.</p><A<em>b</em>stractText>MPO-DNA concentrations were highly correlated with other measures of NET formation in the alveolar space, including cell-free DNA and peroxidase activity (r = 0.95 and r = 0.87, p &<em>lt</em>; 0.0001, respectively). Alveolar concentrations of MPO-DNA were higher in su<em>b</em>jects with VAP and ARDS compared with those with ARDS alone (p &<em>lt</em>; 0.0001), and higher MPO-DNA was associated with increased odds of VAP (odds ratio 3.03, p &<em>lt</em>; 0.0001). In addition, NET concentrations were associated with <em>b</em>acterial <em>b</em>urden (p &<em>lt</em>; 0.0001) and local alveolar inflammation as measured <em>b</em>y IL-8 (r = 0.89, p &<em>lt</em>; 0.0001).</A<em>b</em>stractText><A<em>b</em>stractText>Alveolar NETs measured <em>b</em>y MPO-DNA complex are associated with VAP, and markers of NETosis are associated with local inflammation and <em>b</em>acterial <em>b</em>urden in the lung. These resu<em>lt</em>s suggest that NETs contri<em>b</em>ute to inflammatory responses involved in the pathogenesis of VAP.</A<em>b</em>stractText>

<A<em>b</em>stractText>This trial compared the efficacy and safety of the first oral glucagon-like peptide 1 (GLP-1) receptor agonist, oral semaglutide, as monotherapy with place<em>b</em>o in patients with type 2 dia<em>b</em>etes managed <em>b</em>y diet and exercise alone. Two estimands addressed two efficacy-related questions: a treatment policy estimand (regardless of trial product discontinuation or rescue medication use) and a trial product estimand (on trial product without rescue medication use) in all randomized patients.</A<em>b</em>stractText><p><div>(<em>b</em>)RESEARCH DESIGN AND METHODS</<em>b</em>)</div>This was a 26-week, phase 3a, randomized, dou<em>b</em>le-<em>b</em>lind, place<em>b</em>o-controlled, parallel-group trial conducted in 93 sites in nine countries. Adu<em>lt</em>s with type 2 dia<em>b</em>etes insufficiently controlled with diet and exercise were randomized (1:1:1:1) to once-daily oral semaglutide 3 mg, 7 mg, 14 mg, or place<em>b</em>o. The primary end point was change from <em>b</em>aseline to week 26 in H<em>b</em>A<su<em>b</em>)1c</su<em>b</em>). The confirmatory secondary end point was change from <em>b</em>aseline to week 26 in <em>b</em>ody weight.</p><p><div>(<em>b</em>)RESULTS</<em>b</em>)</div>In the 703 patients randomized (mean age 55 years, 50.8% male, and mean <em>b</em>aseline H<em>b</em>A<su<em>b</em>)1c</su<em>b</em>) 8.0% [64 mmol/mol]), oral semaglutide reduced H<em>b</em>A<su<em>b</em>)1c</su<em>b</em>) (place<em>b</em>o-adjusted treatment differences at week 26: treatment policy estimand, -0.6% [3 mg], -0.9% [7 mg], and -1.1% [14 mg]; trial product estimand, -0.7% [3 mg], -1.2% [7 mg], and -1.4% [14 mg]; <i>P</i> &<em>lt</em>; 0.001 for all) and <em>b</em>ody weight (treatment policy, -0.1 kg [3 mg], -0.9 kg [7 mg], and -2.3 kg [14 mg, <i>P</i> &<em>lt</em>; 0.001]; trial product, -0.2 kg [3 mg], -1.0 kg [7 mg, <i>P</i> = 0.01], and -2.6 kg [14 mg, <i>P</i> &<em>lt</em>; 0.001]). Mild-to-moderate transient gastrointestinal events were the most common adverse events with oral semaglutide. Trial product discontinuations occurred in 2.3-7.4% with oral semaglutide and 2.2% with place<em>b</em>o.</p><p><div>(<em>b</em>)CONCLUSIONS</<em>b</em>)</div>In patients with type 2 dia<em>b</em>etes, oral semaglutide monotherapy demonstrated superior and clinically relevant improvements in H<em>b</em>A<su<em>b</em>)1c</su<em>b</em>) (all doses) and <em>b</em>ody weight loss (14 mg dose) versus place<em>b</em>o, with a safety profile consistent with other GLP-1 receptor agonists.</p>

<p><div>(<em>b</em>)BACKGROUND</<em>b</em>)</div>Prostate cancer (PCa) is one of the most frequently diagnosed cancers in the world. Emerging evidence suggests that inflammatory cells such as M2 macrophages and regulatory T cells (T<su<em>b</em>)regs</su<em>b</em>) ) can contri<em>b</em>ute to cancer progression <em>b</em>y suppressing the anti-tumor immune response. This study investigated the num<em>b</em>er of CD163-positive M2 macrophages in PCa tissue. It also investigated the correlation and interaction of M2 macrophages and T<su<em>b</em>)regs</su<em>b</em>) .</p><p><div>(<em>b</em>)METHODS</<em>b</em>)</div>This nested case-control study included su<em>b</em>jects from a cohort of men diagnosed with PCa as an incidental finding during transurethral resection of the prostate. The cases were 225 men who died from PCa, and the controls were 367 men who survived more than 10 years after PCa diagnosis without disease progression. Infi<em>lt</em>rating CD163-positive M2 macrophages and FOXP3/CD4-positive T<su<em>b</em>)regs</su<em>b</em>) in PCa tissue were identified using immunohistochemistry. The correlation and interaction of M2 macrophages and T<su<em>b</em>)regs</su<em>b</em>) were assessed using Spearman's rank-order correlation and a likelihood test, respectively. Logistic regression was used to estimate odds ratios (ORs) for lethal PCa and macrophage counts.</p><p><div>(<em>b</em>)RESULTS</<em>b</em>)</div>The num<em>b</em>er of M2 macrophages and T<su<em>b</em>)regs</su<em>b</em>) showed a significant correlation (P &<em>lt</em>; 0.001) <em>b</em>ut no interactions. The OR for lethal PCa was 1.93 (95%CI: 1.23-3.03) for men with high num<em>b</em>ers of M2 macrophages. Also for cases with uncertain outcome (GS categories 3 + 4 and 4 + 3) high num<em>b</em>ers of M2 macrophages does predict a poorer prognosis.</p><p><div>(<em>b</em>)CONCLUSIONS</<em>b</em>)</div>Our data showed that men with high num<em>b</em>ers of M2 macrophages in the prostate tumor environment had increased odds of dying of PCa. It is possi<em>b</em>le that M2 macrophages, together with other suppressor cells such as T<su<em>b</em>)regs</su<em>b</em>) , promote an immunosuppressive environment.</p>

<p><div>(<em>b</em>)PURPOSE</<em>b</em>)</div>Targeted next-generation sequencing of DNA has <em>b</em>ecome more widely used in the management of patients with lung adenocarcinoma; however, no clear mitogenic driver a<em>lt</em>eration is found in some cases. We evaluated the incremental <em>b</em>enefit of targeted RNA sequencing (RNAseq) in the identification of gene fusions and <i>MET</i> exon 14 (<i>MET</i>ex14) a<em>lt</em>erations in DNA sequencing (DNAseq) driver-negative lung cancers.</p><A<em>b</em>stractText>Lung cancers driver negative <em>b</em>y MSK-IMPACT underwent further analysis using a custom RNAseq panel (MSK-Fusion). Tumor mutation <em>b</em>urden (TMB) was assessed as a potential prioritization criterion for targeted RNAseq.</A<em>b</em>stractText><p><div>(<em>b</em>)RESULTS</<em>b</em>)</div>As part of prospective clinical genomic testing, we profiled 2,522 lung adenocarcinomas using MSK-IMPACT, which identified 195 (7.7%) fusions and 119 (4.7%) <i>MET</i>ex14 a<em>lt</em>erations. Among 275 driver-negative cases with availa<em>b</em>le tissue, 254 (92%) had sufficient material for RNAseq. A previously undetected a<em>lt</em>eration was identified in 14% (36/254) of cases, 33 of which were actiona<em>b</em>le (27 in-frame fusions, 6 <i>MET</i>ex14). Of these 33 patients, 10 then received matched targeted therapy, which achieved clinical <em>b</em>enefit in 8 (80%). In the 32% (81/254) of DNAseq driver-negative cases with low TMB [0-5 mutations/Mega<em>b</em>ase (mut/M<em>b</em>)], 25 (31%) were positive for previously undetected gene fusions on RNAseq, whereas, in 151 cases with TMB >5 mut/M<em>b</em>, only 7% were positive for fusions (<i>P</i> &<em>lt</em>; 0.0001).</p><p><div>(<em>b</em>)CONCLUSIONS</<em>b</em>)</div>Targeted RNAseq assays should <em>b</em>e used in all cases that appear driver negative <em>b</em>y DNAseq assays to ensure comprehensive detection of actiona<em>b</em>le gene rearrangements. Furthermore, we o<em>b</em>served a significant enrichment for fusions in DNAseq driver-negative samples with low TMB, supporting the prioritization of such cases for additional RNAseq.<i>See related commentary <em>b</em>y Davies and Aisner, p. 4586</i>.</p>

<A<em>b</em>stractText>Individuals with type 2 dia<em>b</em>etes have an a<em>lt</em>ered <em>b</em>acterial composition of their gut micro<em>b</em>iota compared with non-dia<em>b</em>etic individuals. However, these a<em>lt</em>erations may <em>b</em>e confounded <em>b</em>y medication, nota<em>b</em>ly the <em>b</em>lood-glucose-lowering <em>b</em>iguanide, metformin. We undertook a clinical trial in hea<em>lt</em>hy and previously drug-free men with the primary aim of investigating metformin-induced compositional changes in the non-dia<em>b</em>etic state. A secondary aim was to examine whether the pre-treatment gut micro<em>b</em>iota was related to gastrointestinal adverse effects during metformin treatment.</A<em>b</em>stractText><p><div>(<em>b</em>)METHODS</<em>b</em>)</div>Twenty-seven hea<em>lt</em>hy young Danish men were included in an 18-week one-armed crossover trial consisting of a pre-intervention period, an intervention period and a post-intervention period, each period lasting 6 weeks. Inclusion criteria were men of age 18-35 years, BMI <em>b</em>etween 18.5 kg/m² and 27.5 kg/m², H<em>b</em>A<su<em>b</em>)1c</su<em>b</em>) &<em>lt</em>; 39 mmol/mol (5.7%) and plasma creatinine within the normal range. No prescri<em>b</em>ed medication, including anti<em>b</em>iotics, for 2 months prior to recruitment were allowed and no previous gastrointestinal surgery, discounting appendectomy or chronic illness requiring medical treatment. During the intervention the participants were given metformin up to 1 g twice daily. Participants were examined five times in the fasting state with <em>b</em>lood sampling and recording of gastrointestinal symptoms. Examinations took place at Frederiks<em>b</em>erg Hospital, Denmark <em>b</em>efore and after the pre-intervention period, halfway through and immediately after the end of intervention and after the wash-out period. Faecal samples were collected at nine evenly distri<em>b</em>uted time points, and <em>b</em>acterial DNA was extracted and su<em>b</em>jected to 16S rRNA gene amplicon sequencing in order to evaluate gut micro<em>b</em>iota composition. Su<em>b</em>jective gastrointestinal symptoms were reported at each visit.</p><A<em>b</em>stractText>Data from participants who completed visit 1 (n=23) are included in analyses. For the primary outcome the relative a<em>b</em>undance of 11 <em>b</em>acterial genera significantly changed during the intervention <em>b</em>ut returned to <em>b</em>aseline levels after treatment cessation. In line with previous reports, we o<em>b</em>served a reduced a<em>b</em>undance of Intestini<em>b</em>acter spp. and Clostridium spp., as well as an increased a<em>b</em>undance of Escherichia/Shigella spp. and Bilophila wadsworthia. The relative a<em>b</em>undance at <em>b</em>aseline of 12 <em>b</em>acterial genera predicted self-reported gastrointestinal adverse effects.</A<em>b</em>stractText><A<em>b</em>stractText>Intake of metformin changes the gut micro<em>b</em>iota composition in normoglycaemic young men. The micro<em>b</em>iota changes induced <em>b</em>y metformin extend and validate previous reports in individuals with type 2 dia<em>b</em>etes. Secondary analyses suggest that pre-treatment gut micro<em>b</em>iota composition may <em>b</em>e a determinant for development of gastrointestinal adverse effects following metformin intake. These resu<em>lt</em>s require further investigation and replication in larger prospective studies.</A<em>b</em>stractText><A<em>b</em>stractText>Clinica<em>lt</em>rialsregister.eu 2015-000199-86 and ClinicalTrials.gov NCT02546050 FUNDING: This project was funded <em>b</em>y Danish Dia<em>b</em>etes Association and The Novo Nordisk Foundation.</A<em>b</em>stractText>

<A<em>b</em>stractText>Previous approaches using deep learning (DL) algorithms to classify glaucomatous damage on fundus photographs have <em>b</em>een limited <em>b</em>y the requirement for human la<em>b</em>eling of a reference training set. We propose a new approach using quantitative spectral-domain (SD) OCT data to train a DL algorithm to quantify glaucomatous structural damage on optic disc photographs.</A<em>b</em>stractText><A<em>b</em>stractText>Cross-sectional study.</A<em>b</em>stractText><A<em>b</em>stractText>A total of 32 820 pairs of optic disc photographs and SD OCT retinal nerve fi<em>b</em>er layer (RNFL) scans from 2312 eyes of 1198 participants.</A<em>b</em>stractText><A<em>b</em>stractText>The sample was divided randomly into validation plus training (80%) and test (20%) sets, with randomization performed at the patient level. A DL convolutional neural network was trained to assess optic disc photographs and predict SD OCT average RNFL thickness.</A<em>b</em>stractText><A<em>b</em>stractText>The DL algorithm performance was evaluated in the test sample <em>b</em>y evaluating correlation and agreement <em>b</em>etween the predictions and actual SD OCT measurements. We also assessed the a<em>b</em>ility to discriminate eyes with glaucomatous visual field loss from hea<em>lt</em>hy eyes with area under the receiver operating characteristic (ROC) curves.</A<em>b</em>stractText><p><div>(<em>b</em>)RESULTS</<em>b</em>)</div>The mean prediction of average RNFL thickness from all 6292 optic disc photographs in the test set was 83.3±14.5 μm, whereas the mean average RNFL thickness from all corresponding SD OCT scans was 82.5±16.8 μm (P = 0.164). There was a very strong correlation <em>b</em>etween predicted and o<em>b</em>served RNFL thickness values (Pearson r = 0.832; R² = 69.3%; P &<em>lt</em>; 0.001), with mean a<em>b</em>solute error of the predictions of 7.39 μm. The area under the ROC curves for discriminating glaucomatous from hea<em>lt</em>hy eyes with the DL predictions and actual SD OCT average RNFL thickness measurements were 0.944 (95% confidence interval [CI], 0.912-0.966) and 0.940 (95% CI, 0.902-0.966), respectively (P = 0.724).</p><A<em>b</em>stractText>We introduced a novel DL approach to assess fundus photographs and provide quantitative information a<em>b</em>out the amount of neural damage that can <em>b</em>e used to diagnose and stage glaucoma. In addition, training neural networks to predict SD OCT data o<em>b</em>jectively represents a new approach that overcomes limitations of human la<em>b</em>eling and could <em>b</em>e useful in other areas of ophthalmology.</A<em>b</em>stractText>

<p><div>(<em>b</em>)BACKGROUND</<em>b</em>)</div>In dou<em>b</em>le-<em>b</em>lind, place<em>b</em>o-controlled trials, <em>b</em>udesonide-formoterol used on an as-needed <em>b</em>asis resu<em>lt</em>ed in a lower risk of severe exacer<em>b</em>ation of asthma than as-needed use of a short-acting <em>β</em><su<em>b</em>)2</su<em>b</em>)-agonist (SABA); the risk was similar to that of <em>b</em>udesonide maintenance therapy plus as-needed SABA. The availa<em>b</em>ility of data from clinical trials designed to <em>b</em>etter reflect clinical practice would <em>b</em>e <em>b</em>eneficial.</p><A<em>b</em>stractText>We conducted a 52-week, randomized, open-la<em>b</em>el, parallel-group, controlled trial involving adu<em>lt</em>s with mild asthma. Patients were randomly assigned to one of three treatment groups: al<em>b</em>uterol (100 μg, two inhalations from a pressurized metered-dose inhaler as needed for asthma symptoms) (al<em>b</em>uterol group); <em>b</em>udesonide (200 μg, one inhalation through a Tur<em>b</em>uhaler twice daily) plus as-needed al<em>b</em>uterol (<em>b</em>udesonide maintenance group); or <em>b</em>udesonide-formoterol (200 μg of <em>b</em>udesonide and 6 μg of formoterol, one inhalation through a Tur<em>b</em>uhaler as needed) (<em>b</em>udesonide-formoterol group). Electronic monitoring of inhalers was used to measure medication use. The primary outcome was the annualized rate of asthma exacer<em>b</em>ations.</A<em>b</em>stractText><A<em>b</em>stractText>The analysis included 668 of 675 patients who underwent randomization. The annualized exacer<em>b</em>ation rate in the <em>b</em>udesonide-formoterol group was lower than that in the al<em>b</em>uterol group (a<em>b</em>solute rate, 0.195 vs. 0.400; relative rate, 0.49; 95% confidence interval [CI], 0.33 to 0.72; P&<em>lt</em>;0.001) and did not differ significantly from the rate in the <em>b</em>udesonide maintenance group (a<em>b</em>solute rate, 0.195 in the <em>b</em>udesonide-formoterol group vs. 0.175 in the <em>b</em>udesonide maintenance group; relative rate, 1.12; 95% CI, 0.70 to 1.79; P = 0.65). The num<em>b</em>er of severe exacer<em>b</em>ations was lower in the <em>b</em>udesonide-formoterol group than in <em>b</em>oth the al<em>b</em>uterol group (9 vs. 23; relative risk, 0.40; 95% CI, 0.18 to 0.86) and the <em>b</em>udesonide maintenance group (9 vs. 21; relative risk, 0.44; 95% CI, 0.20 to 0.96). The mean (±SD) dose of inhaled <em>b</em>udesonide was 107±109 μg per day in the <em>b</em>udesonide-formoterol group and 222±113 μg per day in the <em>b</em>udesonide maintenance group. The incidence and type of adverse events reported were consistent with those in previous trials and with reports in clinical use.</A<em>b</em>stractText><A<em>b</em>stractText>In an open-la<em>b</em>el trial involving adu<em>lt</em>s with mild asthma, <em>b</em>udesonide-formoterol used as needed was superior to al<em>b</em>uterol used as needed for the prevention of asthma exacer<em>b</em>ations. (Funded <em>b</em>y AstraZeneca and the Hea<em>lt</em>h Research Council of New Zealand; Novel START Australian New Zealand Clinical Trials Registry num<em>b</em>er, ACTRN12615000999538.).</A<em>b</em>stractText>

<A<em>b</em>stractText>To report relia<em>b</em>le estimates of short term and long term survival rates for people with a diagnosis of heart failure and to assess trends over time <em>b</em>y year of diagnosis, hospital admission, and socioeconomic group.</A<em>b</em>stractText><A<em>b</em>stractText>Population <em>b</em>ased cohort study.</A<em>b</em>stractText><A<em>b</em>stractText>Primary care, United Kingdom.</A<em>b</em>stractText><A<em>b</em>stractText>Primary care data for 55 959 patients aged 45 and overwith a new diagnosis of heart failure and 278 679 age and sex matched controls in the Clinical Practice Research Datalink from 1 January 2000 to 31 Decem<em>b</em>er 2017 and linked to inpatient Hospital Episode Statistics and Office for National Statistics mortality data.</A<em>b</em>stractText><A<em>b</em>stractText>Survival rates at one, five, and 10 years and cause of death for people with and without heart failure; and temporal trends in survival <em>b</em>y year of diagnosis, hospital admission, and socioeconomic group.</A<em>b</em>stractText><p><div>(<em>b</em>)RESULTS</<em>b</em>)</div>Overall, one, five, and 10 year survival rates increased <em>b</em>y 6.6% (from 74.2% in 2000 to 80.8% in 2016), 7.2% (from 41.0% in 2000 to 48.2% in 2012), and 6.4% (from 19.8% in 2000 to 26.2% in 2007), respectively. There were 30 906 deaths in the heart failure group over the study period. Heart failure was listed on the death certificate in 13 093 (42.4%) of these patients, and in 2237 (7.2%) it was the primary cause of death. Improvement in survival was greater for patients not requiring admission to hospital around the time of diagnosis (median difference 2.4 years; 5.3 <i>v</i> 2.9 years, P&<em>lt</em>;0.001). There was a deprivation gap in median survival of 2.4 years <em>b</em>etween people who were least deprived and those who were most deprived (11.1 <i>v</i> 8.7 years, P&<em>lt</em>;0.001).</p><A<em>b</em>stractText>Survival after a diagnosis of heart failure has shown only modest improvement in the 21st century and lags <em>b</em>ehind other serious conditions, such as cancer. New strategies to achieve timely diagnosis and treatment initiation in primary care for all socioeconomic groups should <em>b</em>e a priority for future research and policy.</A<em>b</em>stractText>

<A<em>b</em>stractText>Alliance/CALG<em>B</em> 50303 (NCT00118209), an intergroup, phase III study, compared dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxoru<em>b</em>icin, and rituxima<em>b</em> (DA-EPOCH-R) with standard rituxima<em>b</em>, cyclophosphamide, doxoru<em>b</em>icin, vincristine, and prednisone (R-CHOP) as frontline therapy for diffuse large <em>B</em>-cell lymphoma.</A<em>b</em>stractText><A<em>b</em>stractText>Patients received six cycles of DA-EPOCH-R or R-CHOP. The primary o<em>b</em>jective was progression-free survival (PFS); secondary clinical o<em>b</em>jectives included response rate, overall survival (OS), and safety.</A<em>b</em>stractText><p><div>(<em>b</em>)RESULTS</<em>b</em>)</div><em>B</em>etween 2005 and 2013, 524 patients were registered; 491 eligi<em>b</em>le patients were included in the final analysis. Most patients (74%) had stage III or IV disease; International Prognostic Index (IPI) risk groups included 26% IPI 0 to 1, 37% IPI 2, 25% IPI 3, and 12% IPI 4 to 5. At a median follow-up of 5 years, PFS was not statistically different <em>b</em>etween the arms (hazard ratio, 0.93; 95% CI, 0.68 to 1.27; <i>P</i> = .65), with a 2-year PFS rate of 78.9% (95% CI, 73.8% to 84.2%) for DA-EPOCH-R and 75.5% (95% CI, 70.2% to 81.1%) for R-CHOP. OS was not different (hazard ratio, 1.09; 95% CI, 0.75 to 1.59; <i>P</i> = .64), with a 2-year OS rate of 86.5% (95% CI, 82.3% to 91%) for DA-EPOCH-R and 85.7% (95% CI, 81.4% to 90.2%) for R-CHOP. Grade 3 and 4 adverse events were more common (<i>P</i> &<em>lt</em>; .001) in the DA-EPOCH-R arm than the R-CHOP arm, including infection (16.9% <i>v</i> 10.7%, respectively), fe<em>b</em>rile neutropenia (35.0% <i>v</i> 17.7%, respectively), mucositis (8.4% <i>v</i> 2.1%, respectively), and neuropathy (18.6% <i>v</i> 3.3%, respectively). Five treatment-related deaths (2.1%) occurred in each arm.</p><A<em>b</em>stractText>In the 50303 study population, the more intensive, infusional DA-EPOCH-R was more toxic and did not improve PFS or OS compared with R-CHOP. The more favora<em>b</em>le resu<em>lt</em>s with R-CHOP compared with historical controls suggest a potential patient selection <em>b</em>ias and may preclude generaliza<em>b</em>ility of resu<em>lt</em>s to specific risk su<em>b</em>groups.</A<em>b</em>stractText>

<A<em>b</em>stractText>Lung cancer has the highest mor<em>b</em>idity and mortality worldwide, and lung adenocarcinoma (LADC) is the most common pathological su<em>b</em>type. Accumulating evidence suggests the tumor microenvironment (TME) is correlated with the tumor progress and the patient's outcome. As the major components of TME, the tumor-infi<em>lt</em>rated immune cells and stromal cells have attracted more and more attention. In this study, differentially expressed immune and stromal signature genes were used to construct a TME-related prognostic model for predicting the outcomes of LADC patients.</A<em>b</em>stractText><A<em>b</em>stractText>The expression profiles of LADC samples with clinical information were o<em>b</em>tained from The Cancer Genome Atlas (TCGA) and Gene Expression Omni<em>b</em>us (GEO). The differentially expressed genes (DEGs) related to the TME of LADC were identified using TCGA dataset <em>b</em>y Wilcoxon rank sum test. The prognostic effects of TME-related DEGs were analyzed using univariate Cox regression. Then, the least a<em>b</em>solute shrinkage and selection operator (LASSO) regression was performed to reduce the overfit and the num<em>b</em>er of genes for further analysis. Next, the prognostic model was constructed <em>b</em>y step mu<em>lt</em>ivariate Cox regression and risk score of each sample was calculated. Then, survival and Receiver Operating Characteristic (ROC) analyses were conducted to validate the model using TCGA and GEO datasets, respectively. The Kyoto Encyclopedia of Genes and Genomes analysis of gene signature was performed using Gene Set Enrichment Analysis (GSEA). Finally, the overall immune status, tumor purity and the expression profiles of HLA genes of high- and low-risk samples was further analyzed to reveal the potential mechanisms of prognostic effects of the model.</A<em>b</em>stractText><p><div>(<em>b</em>)Resu<em>lt</em>s</<em>b</em>)</div>A total of 93 TME-related DEGs were identified, of which 23 DEGs were up-regulated and 70 DEGs were down-regulated. The univariate cox analysis indicated that 23 DEGs has the prognostic effects, the hazard ratio ranged from 0.65 to 1.25 (<i>p</i> &<em>lt</em>; 0.05). Then, seven genes were screened out from the 23 DEGs <em>b</em>y LASSO regression method and were further analyzed <em>b</em>y step mu<em>lt</em>ivariate Cox regression. Finally, a three-gene (ADAM12, Bruton Tyrosine Kinase (BTK), ERG) signature was constructed, and ADAM12, BTK can <em>b</em>e used as independent prognostic factors. The three-gene signature well stratified the LADC patients in <em>b</em>oth training (TCGA) and testing (GEO) datasets as high-risk and low-risk groups, the 3-year area under curve (AUC) of ROC curves of three GEO sets were 0.718 (GSE3141), 0.646 (GSE30219) and 0.643 (GSE50081). The GSEA analysis indicated that highly expressed ADAM12, BTK, ERG mainly correlated with the activation of pathways involving in focal adhesion, immune regulation. The immune analysis indicated that the low-risk group has more immune activities and higher expression of HLA genes than that of the high-risk group. In sum, we identified and constructed a three TME-related DEGs signature, which could <em>b</em>e used to predict the prognosis of LADC patients.</p>

<A<em>b</em>stractText>To determine the impact of <em>b</em>asal-like and classical su<em>b</em>types in advanced PDAC and to explore GATA6 expression as a surrogate <em>b</em>iomarker.</A<em>b</em>stractText><p><div>(<em>b</em>)EXPERIMENTAL DESIGN</<em>b</em>)</div>Within the COMPASS trial patients proceeding to chemotherapy for advanced PDAC undergo tumour <em>b</em>iopsy for RNA sequencing. Overall response rate (ORR) and overall survival (OS) were stratified <em>b</em>y su<em>b</em>types and according to chemotherapy received. Correlation of <i>GATA6</i> with the su<em>b</em>types using gene expression profiling, in situ hy<em>b</em>ridization (ISH) were explored.</p><p><div>(<em>b</em>)RESULTS</<em>b</em>)</div>Between Decem<em>b</em>er 2015-May 2019, 195 patients (95%) had enough tissue for RNA sequencing; 39 (20%) were classified as <em>b</em>asal-like and 156 (80%) as classical. RECIST response data were availa<em>b</em>le for 157 patients; 29 <em>b</em>asal-like and 128 classical where the ORR was 10% vs. 33% respectively (p=0.02). In patients with <em>b</em>asal-like tumours treated with modified FOLFIRINOX (mFFX) (n=22) the progression rate was 60% compared to 15% in classical PDAC (p= 0.0002). Median OS in the intention to treat population (n=195) was 9.3 months for classical vs. 5.9 months for <em>b</em>asal-like PDAC (HR 0.47 95% CI 0.32-0.69, p=0.0001). <i>GATA6</i> expression <em>b</em>y RNAseq highly correlated with the classifier (p&<em>lt</em>;0.001) and ISH predicted the su<em>b</em>types with sensitivity of 89% and specificity of 83%. In a mu<em>lt</em>ivaria<em>b</em>le analysis, GATA6 expression was prognostic (p=0.02). In exploratory analyses, <em>b</em>asal-like tumours, could <em>b</em>e identified <em>b</em>y keratin 5, were more hypoxic and enriched for a T cell inflamed gene expression signature.</p><A<em>b</em>stractText>The <em>b</em>asal-like su<em>b</em>type is chemoresistant and can <em>b</em>e distinguished from classical PDAC <em>b</em>y GATA6 expression.</A<em>b</em>stractText>

<A<em>b</em>stractText>Merkel cell carcinoma (MCC) is a rare, aggressive cutaneous malignancy, which has demonstrated sensitivity to immune checkpoint inhi<em>b</em>itor therapy. Here, we perform the largest genomics study in MCC to date to characterize the molecular landscape and evaluate for clinical and molecular correlates to immune checkpoint inhi<em>b</em>itor response.</A<em>b</em>stractText><A<em>b</em>stractText>Comprehensive molecular profiling was performed on 317 tumors from patients with MCC, including the evaluation of oncogenic mutations, tumor mutational <em>b</em>urden (TMB), mutational signatures, and the Merkel cell polyomavirus (MCPyV). For a su<em>b</em>set of 57 patients, a retrospective analysis was conducted to evaluate for clinical and molecular correlates to immune checkpoint inhi<em>b</em>itor response and disease survival.</A<em>b</em>stractText><p><div>(<em>b</em>)RESULTS</<em>b</em>)</div>Genomic analyses revealed a <em>b</em>imodal distri<em>b</em>ution in TMB, with 2 molecularly distinct su<em>b</em>groups. Ninety-four percent (<i>n</i> = 110) of TMB-high specimens exhi<em>b</em>ited an u<em>lt</em>raviolet light (UV) mutational signature. MCPyV genomic DNA sequences were not identified in any TMB-high cases (0/117), <em>b</em>ut were in 63% (110/175) of TMB-low cases. For 36 evalua<em>b</em>le patients treated with checkpoint inhi<em>b</em>itors, the overall response rate was 44% and response correlated with survival at time of review (100% vs. 20%, <i>P</i> &<em>lt</em>; 0.001). Response rate was 50% in TMB-high/UV-driven and 41% in TMB-low/MCPyV-positive tumors (<i>P</i> = 0.63). Response rate was significantly correlated with line of therapy: 75% in first-line, 39% in second-line, and 18% in third-line or <em>b</em>eyond (<i>P</i> = 0.0066). PD-1, <em>b</em>ut not PD-L1, expression was associated with immunotherapy response (77% vs. 21%, <i>P</i> = 0.00598, for PD-1 positive and negative, respectively).</p><A<em>b</em>stractText>We provide a comprehensive genomic landscape of MCC and demonstrate clinicogenomic associates of immunotherapy response.</A<em>b</em>stractText>

<A<em>b</em>stractText>This study aimed to evaluate the prevalence and related factors of post-traumatic stress disorder (PTSD) symptoms among doctors and nurses who were exposed to H7N9 patients during the H7N9 influenza epidemic. To provide scientific <em>b</em>asis for promoting the physical and psychological hea<em>lt</em>h of these staff mem<em>b</em>ers.</A<em>b</em>stractText><p><div>(<em>b</em>)Method</<em>b</em>)</div>The 102 medical staff workers who were exposed to H7N9 patients were recruited through convenient sampling <em>b</em>etween January 2015 and May 2016. We used a self-reported questionnaire, the PTSD Checklist-Civilian Version (PCL-C), to evaluate the PTSD symptoms among doctors and nurses from an intensive care unit (<i>n</i> = 61), a respiratory department (<i>n</i> = 20), and an emergency department (<i>n</i> = 21). We then analyzed the related factors.</p><p><div>(<em>b</em>)Resu<em>lt</em>s</<em>b</em>)</div>Around 20.59% of the tested doctors and nurses showed PTSD symptoms. The sample had a mean PCL-C score of 30.00 ± 9.95. The differences in the scores of doctors and nurses with different genders, ages, professional titles, contact frequencies, trainings, and experiences were statistically significant (<i>P</i> &<em>lt</em>; 0.05, <i>P</i> &<em>lt</em>; 0.01). Moreover, t-tests and one-way analysis of variance showed that nurses received higher scores than doctors, female participants received higher scores than male participants, and the participants with low professional title and high contact frequency, aged <em>b</em>etween 20 years and 30 years, with less than five years of work experience, having not received related training and with no related experience o<em>b</em>tained higher PCL-C scores than the others (<i>P</i> &<em>lt</em>; 0.05, <i>P</i> &<em>lt</em>; 0.01).</p><A<em>b</em>stractText>The PTSD level of doctors and nurses after their exposure to H7N9 patients was high, which warrant further research. Hea<em>lt</em>h and medical institutions should pay attention to the physical and psychological hea<em>lt</em>h of these staff mem<em>b</em>ers.</A<em>b</em>stractText>

Secondary lymphoid organs provide the necessary microenvironment for the cooperation of antigen-specific T- and B-lymphocytes and antigen-presenting cells in order to initiate an efficient immune response. Remarkable progress in understanding of the mechanisms of lymphoid organogenesis was achieved due to the analysis of various gene-targeted mice. This review primarily focuses on the role of lymphotoxin (LT) in development, maturation and maintenance of secondary lymphoid organs.

Infection of chicken embryo cells with vesicular stomatitis (VS) virus resulted in variable production of three classes of intracellular viral ribonucleocapsids with sedimentation coefficients of approximately 140S, 110S, and 80S, as well as three corresponding classes of released virions designated B, LT, and T. Intracellular nucleocapsids of each class contained three proteins of which the major N protein was firmly bound, and the minor L and NS1 proteins were readily dissociated with 0.5 m NaCl. The ribonucleic acid (RNA) species extracted from B, LT, and T virions, and from corresponding intracellular nucleocapsids, contained RNA species with approximate molecular weights of 3.2 x 10(6), 2.0 x 10(6), and 10(6), respectively, as determined by polyacrylamide gel electrophoresis. These values are roughly equivalent to sedimentation coefficients of 42S, 28S, and 23S for each of the virion and nucleocapsid RNA species. Cells infected at high multiplicity with undiluted passage VS virus gave rise primarily to virions and nucleocapsids containing 23S RNA, whereas cells productively infected with purified B virions produced predominantly B and LT virions and nucleocapsids. At late stages in the productive cycle of infection, more virions containing 42S RNA were produced, but the intracellular pool of nucleocapsids containing 28S and 23S RNA remained relatively constant. Additional studies by more refined techniques are required to test the hypothesis that nucleocapsids containing 28S and 23S RNA are precursors of the 42S RNA in infectious VS-B virions and that production of defective T and LT virions results from failure of ligation of the RNA precursors.