BACKGROUND

Basic laparoscopic skills are initially best taught and practiced in an inanimate setting. Various devices are used to aid in this education of laparoscopic skills. These devices range from simple box trainers to sophisticated virtual reality trainers. This investigation tested the hypothesis that participants would prefer one trainer to another trainer.

METHODS

Preclinical medical students volunteered for this study. All underwent a porcine laboratory. The students were then divided into 3 groups by method of training: group A--a virtual reality trainer (MIST-VR), group B--an inanimate box trainer (LTS 2000), and group C--both trainers. Each group participated in 10 laboratories with the assigned trainer(s). After completion of the laboratories, all students underwent a similar porcine laboratory. During this laboratory, opinions of each trainer and specific tasks were ascertained from each student.

RESULTS

No statistical difference was seen between groups A and B when asked if their specific trainer helped their skills, was realistic, helped in the animal laboratory, and was interesting. When group C was asked the same questions about each trainer, no statistical difference was seen except that 47% thought the MIST-VR was not realistic as opposed to 0% who thought the LTS 2000 was not realistic (P <.003). The level of difficulty of each task correlated with how much the specific task helped in development of skills for both trainers (P <.0001). In group C, 89% of the participants thought the LTS 2000 helped more that the MIST-VR and 56% thought the LTS 2000 was more interesting than the MIST-VR. In addition, 83% of students in group C chose LTS 2000 when asked to pick only one trainer.

CONCLUSIONS

While virtual reality trainers may have some advantages, most participants feel that inanimate box trainers help more, are more interesting, and should be chosen over virtual reality trainers if only one trainer is allowed. Further studies need to investigate if the opinions affect participants' utilization of these trainers.

The binding of the spermatozoon to the oocyte zona pellucida (ZP) occurs via specific receptors localized over the anterior head region of the spermatozoon. Zona pellucida binding stimulates the spermatozoa to undergo the acrosome reaction resulting in the release of hydrolytic enzymes and in the exposure of new membrane domains, both of which are essential for fertilization. We suggest that ZP binds to at least two different receptors in the plasma membrane. One (R) is a Gi-coupled receptor that activates phospholipase C (PLC) beta 1. The other (TK) is a tyrosine kinase receptor coupled to PLC gamma. Binding to R would regulate adenylyl cyclase (AC) leading to elevation of cAMP and protein kinase (PKA) activation. The PKA activates a voltage-dependent Ca2+ channel in the outer acrosomal membrane which releases Ca2+ from the interior of the acrosome to the cytosol. This is the first, relatively small, rise in [Ca2+]i (I) which leads to activation of the PLC gamma. The products of phosphatidyl-inositol bisphosphate (PIP2) hydrolysis by PLC diacylglycerol (DAG) and inositol-trisphosphate (IP3) will lead to PKC translocation to the plasma membrane and its activation. PKC opens a voltage-dependent Ca2+ channel (L) in the plasma membrane, leading to the second (II) higher increase in [Ca2+]i. The Gi or TK can also activate an Na+/H+ exchanger leading to alkalization of the cytosol. PKC also activates phospholipase A2 (PLA2) to generate arachidonic acid (AA) from membrane phospholipids. AA will be converted to prostaglandins (PG) and leukotriens (LT) by the enzymes cyclooxygenase (COX) and lipoxygenase (LOX) respectively. The increase in [Ca2+]i and pH leads to membrane fusion and acrosomal exocytosis.

Lipopolysaccharides of C. jejuni serotypes O:23 and O:36 have been shown to contain structurally variable O polysaccharide chains with repeating units of four closely-related types: ----3)-beta-D-GlcpNAc-(1----3)-alpha-D-Galp-(1----2)-6d-alpha-D-alt-H epp-(1---- , ----3)-beta-D-GlcpNAc-(1----3)-alpha-D-Galp-(1----2)-6d-3-Me-alpha-D-alt -Hepp- (1----, ----3)-beta-D-GlcpNAc-(1----3)-alpha-D-Galp-(1----2)-D-glycero-alpha-D-a lt-Hepp - (1----, and ----3)-beta-D-GlcpNAc-(1----3)-alpha-D-Galp-(1----2)-3-Me-D-glycero-alph a-D-alt - Hepp-(1----. Structural methods included 1H- and 13C-NMR spectroscopy, methylation linkage analysis, fast atom bombardment mass spectrometry of methylated glycans, and selective fragmentations by the Smith degradation and N-deacetylation-nitrous acid deamination.

The actual risk factors that drive hepatic inflammation during the transition from steatosis to steatohepatitis are unknown. We recently demonstrated that hyperlipidemia-prone apolipoprotein E-deficient (ApoE(-/-)) mice exhibit hepatic steatosis and increased susceptibility to hepatic inflammation and advanced fibrosis. Because the proinflammatory 5-lipoxygenase (5-LO) pathway was found to be up-regulated in these mice and given that 5-LO deficiency confers cardiovascular protection to ApoE(-/-) mice, we determined the extent to which the absence of 5-LO would alter liver injury in these mice. Compared with ApoE(-/-) mice, which showed expected hepatic steatosis and inflammation, ApoE/5-LO double-deficient (ApoE(-/-)/5-LO(-/-)) mice exhibited reduced hepatic inflammation, macrophage infiltration, tumor necrosis factor alpha (TNF-alpha), monocyte chemoattractant protein-1 (MCP-1) and interleukin (IL)-18 expression, caspase-3 and nuclear factor-kappaB (NF-kappaB) activities, and serum alanine aminotransferase levels in the absence of changes in hepatic steatosis. The lack of 5-LO produced a remarkable insulin-sensitizing effect in the adipose tissue because peroxisome proliferator-activated receptor gamma, insulin receptor substrate-1, and adiponectin were up-regulated, whereas c-Jun amino-terminal kinase phosphorylation and MCP-1 and IL-6 expression were down-regulated. On the other hand, hepatocytes isolated from ApoE(-/-)/5-LO(-/-) mice were more resistant to TNF-alpha-induced apoptosis. The 5-LO products leukotriene (LT) B(4), LTD(4), and 5-HETE consistently triggered TNF-alpha-induced apoptosis and compromised hepatocyte survival by suppressing NF-kappaB activity in the presence of actinomycin D. Moreover, ApoE(-/-)/5-LO(-/-) mice were protected against sustained high-fat diet (HFD)-induced liver injury and hepatic inflammation, macrophage infiltration and insulin resistance were significantly milder than those of ApoE(-/-) mice. Finally, pharmacological inhibition of 5-LO significantly reduced hepatic inflammatory infiltrate in the HFD and ob/ob models of fatty liver disease.

CONCLUSIONS

These combined data indicate that hyperlipidemic mice lacking 5-LO are protected against hepatic inflammatory injury, suggesting that 5-LO is involved in mounting hepatic inflammation in metabolic disease.

<A<em>b</em>stractText>Near-infrared spectroscopy (NIRS) intravascular u<em>lt</em>rasound imaging can detect lipid-rich plaques (LRPs). LRPs are associated with acute coronary syndromes or myocardial infarction, which can resu<em>lt</em> in revascularisation or cardiac death. In this study, we aimed to esta<em>b</em>lish the relationship <em>b</em>etween LRPs detected <em>b</em>y NIRS-intravascular u<em>lt</em>rasound imaging at unstented sites and su<em>b</em>sequent coronary events from new culprit lesions.</A<em>b</em>stractText><p><div>(<em>b</em>)METHODS</<em>b</em>)</div>In this prospective, cohort study (LRP), patients from 44 medical centres were enrolled in Italy, Latvia, Netherlands, Slovakia, UK, and the USA. Patients with suspected coronary artery disease who underwent cardiac catheterisation with possi<em>b</em>le ad hoc percutaneous coronary intervention were eligi<em>b</em>le to <em>b</em>e enrolled. Enrolled patients underwent scanning of non-culprit segments using NIRS-intravascular u<em>lt</em>rasound imaging. The study had two hierarchal primary hypotheses, patient and plaque, each testing the association <em>b</em>etween maximum 4 mm Lipid Core Burden Index (maxLCBI<su<em>b</em>)4mm</su<em>b</em>)) and non-culprit major adverse cardiovascular events (NC-MACE). Enrolled patients with large LRPs (≥250 maxLCBI<su<em>b</em>)4mm</su<em>b</em>)) and a randomly selected half of patients with small LRPs (&<em>lt</em>;250 maxLCBI<su<em>b</em>)4mm</su<em>b</em>)) were followed up for 24 months. This study is registered with ClinicalTrials.gov, NCT02033694.</p><p><div>(<em>b</em>)FINDINGS</<em>b</em>)</div>Between Fe<em>b</em> 21, 2014, and March 30, 2016, 1563 patients were enrolled. NIRS-intravascular u<em>lt</em>rasound device-related events were seen in six (0·4%) patients. 1271 patients (mean age 64 years, SD 10, 883 [69%] men, 388 [31%]women) with analysa<em>b</em>le maxLCBI<su<em>b</em>)4mm</su<em>b</em>) were allocated to follow-up. The 2-year cumulative incidence of NC-MACE was 9% (n=103). Both hierarchical primary hypotheses were met. On a patient level, the unadjusted hazard ratio (HR) for NC-MACE was 1·21 (95% CI 1·09-1·35; p=0·0004) for each 100-unit increase maxLCBI<su<em>b</em>)4mm</su<em>b</em>)) and adjusted HR 1·18 (1·05-1·32; p=0·0043). In patients with a maxLCBI<su<em>b</em>)4mm</su<em>b</em>) more than 400, the unadjusted HR for NC-MACE was 2·18 (1·48-3·22; p&<em>lt</em>;0·0001) and adjusted HR was 1·89 (1·26-2·83; p=0·0021). At the plaque level, the unadjusted HR was 1·45 (1·30-1·60; p&<em>lt</em>;0·0001) for each 100-unit increase in maxLCBI<su<em>b</em>)4mm</su<em>b</em>). For segments with a maxLCBI<su<em>b</em>)4mm</su<em>b</em>) more than 400, the unadjusted HR for NC-MACE was 4·22 (2·39-7·45; p&<em>lt</em>;0·0001) and adjusted HR was 3·39 (1·85-6·20; p&<em>lt</em>;0·0001).</p><A<em>b</em>stractText>NIRS imaging of non-o<em>b</em>structive territories in patients undergoing cardiac catheterisation and possi<em>b</em>le percutaneous coronary intervention was safe and can aid in identifying patients and segments at higher risk for su<em>b</em>sequent NC-MACE. NIRS-intravascular u<em>lt</em>rasound imaging adds to the armamentarium as the first diagnostic tool a<em>b</em>le to detect vulnera<em>b</em>le patients and plaques in clinical practice.</A<em>b</em>stractText><A<em>b</em>stractText>Infraredx.</A<em>b</em>stractText>

<A<em>b</em>stractText>The <em>b</em>enefits of hip arthroscopic surgery in the setting of femoroaceta<em>b</em>ular impingement (FAI) have <em>b</em>een well esta<em>b</em>lished; however, some patients may experience a greater degree of improvement than others. Identifying positive and negative predictors of outcomes would assist the orthopaedic surgeon's management algorithm for patients with FAI.</A<em>b</em>stractText><A<em>b</em>stractText>The o<em>b</em>jective of this systematic review was to identify demographic, radiographic, and other operative predictors of positive and negative outcomes after hip arthroscopic surgery for patients with FAI. It was hypothesized that factors including FAI morphology, age, <em>b</em>ody mass index (BMI), sex, dysplasia, articular cartilage damage, radiographic joint space, and la<em>b</em>ral treatment would predict outcomes after hip arthroscopic surgery.</A<em>b</em>stractText><A<em>b</em>stractText>Systematic review; Level of evidence, 4.</A<em>b</em>stractText><A<em>b</em>stractText>This systematic review was performed in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Three data<em>b</em>ases (Em<em>b</em>ase, Pu<em>b</em>Med, and Ovid [MEDLINE]) were searched on May 19, 2018, using terms including "hip," "arthroscopy," and "FAI." Studies were screened and data extracted in duplicate.</A<em>b</em>stractText><p><div>(<em>b</em>)Resu<em>lt</em>s</<em>b</em>)</div>A total of 39 studies were included in this systematic review, comprising 9272 hips with a mean age of 36.5 years (47.2% female). Younger age, male sex, lower BMI (&<em>lt</em>;24.5 kg/m²), Tönnis grade 0, and preoperative pain relief from diagnostic intra-articular hip injections predicted positive outcomes. Female sex, older age (>45 years), longer duration of preoperative symptoms (>8 months), elevated BMI, increased Tönnis grade (≥1), chondral defects, decreased joint space (≤2 mm), increased Kellgren-Lawrence grade (>3), increased lateral center-edge angle (LCEA), and undergoing la<em>b</em>ral de<em>b</em>ridement alone were predictors of negative outcomes.</p><p><div>(<em>b</em>)Conclusion</<em>b</em>)</div>In patients with FAI, younger age, male sex, lower BMI (&<em>lt</em>;24.5 kg/m²), Tönnis grade 0, and pain relief from preoperative intra-articular hip injections are significantly more likely to achieve positive outcomes after hip arthroscopic surgery. On the other hand, older age (>45 years), female sex, elevated BMI, osteoarthritic changes, decreased joint space (≤2 mm), chondral defects, increased LCEA, and undergoing la<em>b</em>ral de<em>b</em>ridement compared with la<em>b</em>ral repair are associated with negative outcomes.</p>

BACKGROUND

This study evaluated the validity and inter- and intraclinician reliability of (1) the Japanese Society of Surgery of the Foot (JSSF) standard rating system for four sites [ankle-hindfoot (AH), midfoot (MF), hallux (HL), and lesser toe (LT)] and the rheumatoid arthritis (RA) foot and ankle scale and (2) the Japanese Orthopaedic Association's foot rating scale (JOA scale).

METHODS

Clinicians from the same institute independently evaluated participating patients from their institute by two evaluations at a 1- to 4-week interval. Statistical evaluation was as follows. (1) The intraclass correlation coefficient (ICC) was calculated from data collected from at least two examinations of each patient by at least two evaluating clinicians (Data A). (2) Total scores for the two evaluations were determined from the distribution of differences in data between the two evaluations (Data B); each item was evaluated by determining Cohen's coefficient of agreement. (3) The relation between patient satisfaction and total score was investigated only for patients who underwent surgery (Data C). Spearman's rank correlation coefficient was obtained.

RESULTS

Participants were 65 clinicians and 610 patients, including those with disorders of the AH (313), MF (47), HL (153), and LT (50) and those with RA (47). From Data A, the ICC was high for AH and HL by JSSF scales and for AH, MF, and LT by the JOA scale. From Data B, the coefficient showed high validity for both scales for AH, with almost no difference between the two scales; the validity for HL was higher with the JOA scale than with the JSSF scale. From Data C, correlations were significant between patient satisfaction and outcome for AH and HL by the JSSF scales and for AH, HL, and LT by the JOA scale.

CONCLUSIONS

The validity of both scales was high. Clinical evaluation of the therapeutic results using these scales would be highly reliable.

The cytokine, lymphotoxin [LT, tumor necrosis factor beta (TNF beta)] is a potent mediator of proinflammatory and tumoricidal activities. Soluble lymphotoxin is a complex of three LT alpha chains. Its receptors, TNF-R55 and TNF-R75, bind in clefts formed by adjacent identical LT alpha monomers. LT also exists as membrane anchored heterotrimers comprised of LT alpha and LT beta chains. The major and minor membrane forms, LT alpha 1 beta 2 and LT alpha 2 beta 1, respectively, bind a unique receptor, LT beta-R. As LT alpha 2 beta 1 expresses an LT alpha-alpha cleft, it also binds TNF-R. In this report we have compared the effects of ligand engagement of TNF-R and LT beta-R by evaluating the ability of soluble LT alpha beta complexes to initiate activities of human umbilical vein endothelial cells which are characteristically signalled by TNF. We recently reported that soluble LT alpha 1 beta 2 signals via LT beta-R to mediate cytotoxicity of a subset of gamma interferon (IFN-gamma) treated carcinomas. We now show that human LT alpha beta heterotrimers do not efficiently activate LT beta-R+, TNF-R+ human endothelial cells in vitro and only inefficiently mediates lethal toxicity in mice. We also show that neither LT alpha beta heterotrimer signals via TNF-R; in fact LT alpha 2 beta 1 trimers fail to activate NF-kappa B and rather inhibit ligand-induced TNF-R signalling supporting the role for aggregation in TNF-R signalling. Thus, the ability of LT alpha beta complexes to efficiently initiate tumoricidal but not inflammatory activities distinguishes the LT/LT beta-R from the LT/TNF-R pathways and suggest novel strategies for exploiting the LT ligands in tumor therapy and for inhibiting TNF-R-mediated inflammatory sequellae.

The technical success of cadaveric whole-size liver transplantation and better immunosuppressive drugs has extended the application of this life-saving procedure to include patients with irreversible acute and chronic liver diseases. However, because of the scarcity of cadaveric liver grafts, living-donor liver transplantation (LDLT) has emerged as an alternative to cadaveric-donor liver transplantation (CDLT), especially in Asia. In Korea, 8% of the population are hepatitis B virus (HBV) carriers, and the resultant HBV cirrhosis, with or without hepatocellular carcinoma (HCC), is common in the 40- to 60-year-old generation. Accordingly, many patients require orthotopic liver transplantation (OLT). In 1992, we started performing CDLTs in the Asan Medical Center. In 1994, the first successful pediatric LDLT was performed in Korea, on a 9-monthold infant with biliary atresia. In 1997, the first successful adult LDLT was performed in our department, using a left lobe, on a 37-year-old patient with HBV cirrhosis associated with HCC. Even after the first successful right-lobe LDLT, we faced the obstacle of anterior segment congestion of a right-lobe graft, and initiated reconstruction of the middle hepatic venous tributaries of a right-lobe graft in 1998. In 1999, we performed more than 100 OLTs a year. Insufficient graft size has hindered the expansion of adult LDLT, when the remaining left-lobe of potential donors is too small to assure donor safety. Dual two-left-lobe graft LDLT (transplanting from two donors into one recipient) was developed in 2000 to solve graft-size insufficiency and minimize donor risk. More than 200 OLTs a year have been performed since 2004, while broadening the indications for adult LDLT to near complete obstruction of the portal vein, with the application of intraoperative portography (IOP) and portal vein stenting. In 2007, 320 LTs were performed, including 276 adult LDLTs, 10 pediatric LDLTs, and 34 CDLTs (including 7 adult and 1 pediatric split-liver transplant). There has been no donor mortality in LDLT. With technical refinement and advanced perioperative care, the in-hospital mortality of recipients has dropped to 4%: attributed to the dedication of our liver transplantation team members.

For the induction of mucosal immune responses by intranasal vaccination, cholera toxin B subunits (CTB) and Escherichia coli heat-labile toxin (LT) are often administered as mucosal adjuvants in order to enhance immune responses to mucosally co-administered bystander antigens. However, these toxin also are the causative agents of diarrhea. There is a demand for the establishment of an effective and safer adjuvant or vaccine that elicits mucosal immunity, but does not require the use of CTB or LT adjuvants. In order to induce protective mucosal immune responses in the nasal area against influenza virus infection, we have examined the recombinant protein composed of the complement component, C3d, which is fused to the secreted form of hemagglutinin (sHA-mC3d3) in the influenza-BALB/c mouse model. The fusion protein sHA-mC3d3, the secretory form of hemagglutinin, and the transmembrane form of HA (tmHA) from the influenza virus were intranasally administered to the mice with or without CTB containing a trace amount of holotoxin (CTB*) as an adjuvant. After intranasal administration of these proteins with CTB*, all mice produced nasal IgA and serum IgG antibodies (Abs) against the viral HA. In addition, viral infection was completely inhibited in these mice. In contrast, in the absence of the adjuvant, only sHA-mC3d3-induced locally secreted IgA and serum IgG Abs and provided complete protection against the influenza virus challenge. Thus, C3d fused to the influenza HA antigen is an effective and safe tool for mucosal vaccination.

Over the past quarter-century, liver transplantation (LT) has been established as a durable therapy for all forms of end-stage liver disease. LT appears ideally suited for hepatocellular carcinoma (HCC), as it involves complete oncologic resection and correction of the underlying liver dysfunction. Since LT based on the Milan criteria has been shown to provide good disease-free survival, LT is considered the optimal treatment for small HCC, especially in patients with underlying chronic liver disease. However, because there is a severe shortage of organ donors, not all patients in need can be offered LT. Transplant listing criteria must simultaneously determine the greatest number of suitable candidates for LT while rejecting the smallest number of those who could benefit from LT. The amended model for end-stage liver disease allocation policy has had a positive effect on liver transplant candidates with HCC, and their number has been increasing significantly over the past several years. To minimize dropout from the waiting list, the treatment of HCC with procedures such as chemoembolization, radiofrequency ablation, or ethanol injection in patients awaiting LT have become widespread. It is currently accepted that liver resection is the best option for the treatment of small HCC when liver function is well preserved, and that LT is preferred when liver function is severely impaired (Child-Pugh class B or C). However, the question arises as to what is the best option for Child-Pugh class A patients with early HCC eligible for both resection and LT, especially in Western countries. HCC is a major indication for living donor liver transplantation (LDLT), because the risk of dropout while waiting is negligible. Extension of the Milan criteria in the setting of LDLT may offer more patients a potentially curative treatment without reducing the donor pool of organs for patients on the waiting list with nonmalignant liver disease. However, imprudent expansion of the selection criteria may result in more patients with HCC being cured at the expense of a higher incidence of recurrence.

<A<em>b</em>stractText>Standard of care for patients with high-grade soft-tissue sarcoma (STS) are <em>b</em>eing redefined since neoadjuvant chemotherapy (NAC) has demonstrated a positive effect on patients' outcome. Yet response evaluation in clinical trials still relies on RECIST criteria.</A<em>b</em>stractText><A<em>b</em>stractText>To investigate the added value of a De<em>lt</em>a-radiomics approach for early response prediction in patients with STS undergoing NAC.</A<em>b</em>stractText><A<em>b</em>stractText>Retrospective.</A<em>b</em>stractText><A<em>b</em>stractText>Sixty-five adu<em>lt</em> patients with newly-diagnosed, locally-advanced, histologically proven high-grade STS of trunk and extremities. All were treated <em>b</em>y anthracycline-<em>b</em>ased NAC followed <em>b</em>y surgery and had availa<em>b</em>le MRI at <em>b</em>aseline and after two chemotherapy cycles.</A<em>b</em>stractText><p><div>(<em>b</em>)FIELD STRENGTH/SEQUENCE</<em>b</em>)</div>Pre- and postcontrast enhanced T<su<em>b</em>)1</su<em>b</em>) -weighted imaging (T<su<em>b</em>)1</su<em>b</em>) -WI), tur<em>b</em>o spin echo T<su<em>b</em>)2</su<em>b</em>) -WI at 1.5 T.</p><A<em>b</em>stractText>A threshold of &<em>lt</em>;10% via<em>b</em>le cells on surgical specimens defined good response (Good-HR). Two senior radiologists performed a semantic analysis of the MRI. After 3D manual segmentation of tumors at <em>b</em>aseline and early evaluation, and standardization of voxel-sizes and intensities, a<em>b</em>solute changes in 33 texture and shape features were calculated.</A<em>b</em>stractText><A<em>b</em>stractText>Classification models <em>b</em>ased on logistic regression, support vector machine, k-nearest neigh<em>b</em>ors, and random forests were ela<em>b</em>orated using crossvalidation (training and validation) on 50 patients ("training cohort") and was validated on 15 other patients ("test cohort").</A<em>b</em>stractText><A<em>b</em>stractText>Sixteen patients were good-HR. Neither RECIST status (P = 0.112) nor semantic radiological varia<em>b</em>les were associated with response (range of P-values: 0.134-0.490) except an edema decrease (P = 0.003), a<em>lt</em>hough 14 shape and texture features were (range of P-values: 0.002-0.037). On the training cohort, the highest diagnostic performances were o<em>b</em>tained with random forests <em>b</em>ui<em>lt</em> on three features: Δ_Histogram_Entropy, Δ_Elongation, Δ_Surrounding_Edema, which provided: area under the curve the receiver operating characteristic = 0.86, accuracy = 88.1%, sensitivity = 94.1%, and specificity = 66.3%. On the test cohort, this model provided an accuracy of 74.6% <em>b</em>ut 3/5 good-HR were systematically ill-classified.</A<em>b</em>stractText><p><div>(<em>b</em>)DATA CONCLUSION</<em>b</em>)</div>A T<su<em>b</em>)2</su<em>b</em>) -<em>b</em>ased De<em>lt</em>a-radiomics approach might improve early response assessment in STS patients with a limited num<em>b</em>er of features.</p><A<em>b</em>stractText>3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;50:497-510.</A<em>b</em>stractText>

<A<em>b</em>stractText>The World Hea<em>lt</em>h Organization (WHO) has declared the current out<em>b</em>reak of the novel coronavirus (COVID-19) a glo<em>b</em>al pandemic. Many countries are facing increasing num<em>b</em>ers of COVID-19 cases, which are, in their origin mostly attri<em>b</em>uted to regular international flight connections with China. This study aims to investigate this relation <em>b</em>y analyzing availa<em>b</em>le data on air traffic volume and the spread of COVID-19 cases.</A<em>b</em>stractText><A<em>b</em>stractText>and findings: We analyzed availa<em>b</em>le data on current domestic and international passenger volume and flight routes and compared these to the distri<em>b</em>ution of domestic and international COVID-19 cases.</A<em>b</em>stractText><p><div>(<em>b</em>)RESULTS</<em>b</em>)</div>Our data indicate a strong linear correlation <em>b</em>etween domestic COVID-19 cases and passenger volume for regions within China (r² = 0.92, p = 0.19) and a significant correlation <em>b</em>etween international COVID-19 cases and passenger volume (r² = 0.98, p &<em>lt</em>; 0.01).</p><A<em>b</em>stractText>The num<em>b</em>er of flight routes as well as total passenger volume are highly relevant risk factors for the spread of current COVID-19. Mu<em>lt</em>iple regions within Asia, as well as some in North America and Europe are at serious risk of constant exposure to COVID-19 from China and other highly infected countries. Risk for COVID-19 exposure remains relatively low in South America and Africa. If adequate measures are taken, including on-site disease detection and temporary passenger quarantine, limited <em>b</em>ut not terminated air traffic can <em>b</em>e a feasi<em>b</em>le option to prevent a long-term crisis. Reasona<em>b</em>le risk calculations and case evaluations per passenger volume are crucial aspects which must <em>b</em>e considered when reducing international flights.</A<em>b</em>stractText>

Vibrio cholerae produce a variety of extracellular products that have deleterious effects on eukaryotic cells. The massive diarrhoea produced by V. cholerae is caused by cholera toxin (CT). CT is composed of 1A and 5B units. CT causes a significant amount of fluid secretion and haemorrhage in the ligated rabbit ileal loops. Its action involves the role of various biochemical pathways. CT acts by activation of adenylate cyclase-cAMP system located at the basolateral membrane of intestinal epithelial cells. The increase in cyclic AMP levels is mainly responsible for the altered transport of Na+ and Cl-. Besides activating cAMP, CT is also known to act through release of prostaglandins and involvement of intramural nerves. Besides CT, other bacterial toxins like Escherichia coli LT, Salmonella toxin, Shigella toxin and Campylobacter toxin also possess A-B structure. The structure and function of E. coli LT resembles closely that of CT. Most of the bacterial toxins exert their effect through involvement of ADP-ribosylating proteins whereas other toxins involve guanylate cyclase system, calcium and protein kinases for their ultimate action.

Mice deficient in lymphotoxin (LT)-alpha lack peripheral lymph nodes and Peyer's patches and have profound defects in development of follicular dendritic cell networks, germinal center formation, and T/B cell segregation in the spleen. Although LTalpha is known to be expressed by NK cells as well as T and B lymphocytes, the requirement of LTalpha for NK cell functions is largely unknown. To address this issue, we have assessed NK cell functions in LTalpha-deficient mice by evaluating tumor models with known requirements for NK cells to control their growth and metastasis. Syngeneic BLTalpha-/- mice than in the wild-type littermates, and the formation of experimental pulmonary metastases was significantly enhanced in LTalpha-/- mice. Although LTalpha-/- mice exhibited almost a normal total number of NK cells in spleen, they showed an impaired recruitment of NK cells to lung and liver. Additionally, lytic NK cells were not efficiently produced from LTalpha-/- bone marrow cells in vitro in the presence of IL-2 and IL-15. These data suggest that LTalpha signaling may be involved in the maturation and recruitment of NK cells and may play an important role in antitumor surveillance.

Significant levels of extracellular glutathione (GSH) were detected in aerobically grown cultures of some strains of Salmonella typhimurium LT-2 and in Escherichia coli K-12, B, and B/r but not in cultures of nine freshly isolated clinical isolates of E. coli. Cultures of S. typhimurium generally contained less total GSH (intracellular plus external) than did E. coli cultures. S. typhimurium TA1534 contained about 2 mM intracellular GSH and exported about 30% of its total GSH. The external GSH concentration increased logarithmically during exponential growth and peaked at about 24 microM in early-stationary-phase cultures. External accumulation of GSH was inhibited by 30 mM NaN3. GSH was predominantly exported in the reduced form. Two-dimensional paper chromatography of supernatants from cultures labeled with Na2(35)SO4 confirmed the presence of GSH and revealed five other sulfur-containing compounds in the media of S. typhimurium and E. coli cultures. The five unidentified compounds were not derivatives of GSH.

Aspirin (acetylsalicylic acid)-induced asthma (AIA) consists of the clinical triad of asthma, chronic rhinosinusitis with nasal polyps, and precipitation of asthma and rhinitis attacks in response to aspirin and other NSAIDs. The prevalence of the syndrome in the adult asthmatic populations is approximately 4-10%. Respiratory disease in these patients may be aggressive and refractory to treatment. The aetiology of AIA is complex and not fully understood, but most evidence points towards an abnormality of arachidonic acid (AA) metabolism. Cyclo-oxygenase (COX), the rate-limiting enzyme in AA metabolism, exists as two main isoforms. COX-1 is the constitutive enzyme responsible for synthesis of protective prostanoids, whereas COX-2 is induced under inflammatory conditions. A number of theories regarding its pathogenesis have been proposed. The shunting hypothesis proposes that inhibition of COX-1 shunts AA metabolism away from production of protective prostanoids and towards cysteinyl leukotriene (cys-LT) biosynthesis, resulting in bronchoconstriction and increased mucus production. The COX-2 hypothesis proposes that aspirin causes a structural change in COX-2 that results in the generation of products of the lipoxygenase pathway. It is speculated that this may result in the formation of mediators that cause respiratory reactions in AIA. Related studies provide evidence for abnormal regulation of the lipoxygenase pathway, demonstrating elevated levels of cys-LTs in urine, sputum and peripheral blood, before and following aspirin challenge in AIA patients. These studies suggest that cys-LTs are continually and aggressively synthesised before exposure to aspirin and, during aspirin-induced reactions, acceleration of synthesis occurs. A genetic polymorphism of the LTC4S gene has been identified consisting of an A to C transversion 444 nucleotides upstream of the first codon, conferring a relative risk of AIA of 3.89. Furthermore, carriers of the C444 allele demonstrate a dramatic rise in urinary LTE(4) following aspirin provocation, and respond better to the cys-LT antagonist pranlukast than A444 homozygotes.AIA patients have an aggressive form of disease, and treatment should include combination therapy with inhaled corticosteroids, beta(2)-adrenoceptor agonists and LT modifiers. Furthermore, recently developed inhibitors of COX-2 may be safer in patients with AIA.

In swine, the most common and severe enterotoxigenic Escherichia coli (ETEC) infections are caused by strains that express K88 (F4)(+) fimbriae, heat-labile enterotoxin (LT), heat-stable enterotoxin b (STb), and enteroaggregative E. coli heat-stable toxin 1. Previous studies based on a design that involved enterotoxin genes cloned into a nontoxigenic fimbriated strain have suggested that LT but not STb plays an important role in dehydrating diarrheal disease in piglets <1 week old and also enhances bacterial colonization of the intestine. In the present study, we compared these two toxins in terms of importance for piglets >1 week old with a study design that involved construction of isogenic single- and double-deletion mutants and inoculation of 9-day-old F4ac receptor-positive gnotobiotic piglets. Based on the postinoculation percent weight change per h and serum bicarbonate concentrations, the virulence of the STb(-) mutant (Delta estB) did not significantly differ from that of the parent. However, deletion of the LT genes (Delta eltAB) in the STb(-) mutant resulted in a complete abrogation of weight loss, dehydration, and metabolic acidosis in inoculated pigs, and LT complementation restored the virulence of this strain. These results support the hypothesis that LT is a more significant contributor than STb to the virulence of F4(+) ETEC infections in young F4ac receptor-positive pigs less than 2 weeks old. However, in contrast to previous studies with gnotobiotic piglets, there was no evidence that the expression of LT enhanced the ability of the F4(+) ETEC strain to colonize the small intestine.

Plasma cells isolated from bone marrow (BM) aspirates of 12 patients with multiple myeloma (MM) and nine patients with monoclonal gammopathy of undetermined significance (MGUS) were analyzed for production of cytokines with bone-resorbing activity, such as interleukin-1 (IL-1), tumor necrosis factor (TNF), and lymphotoxin (LT). Culture supernatants of plasma cells from MM, but not from MGUS or normal donor, invariably contained high amounts of IL-1-beta and lower amounts of IL-1-alpha. With a single exception, TNF/LT biologic activity was not detected in the same supernatants. IL-6 was present in two of five supernatants tested. Normal B lymphocytes released both IL-1 and TNF/LT activities for four days after activation in vitro; however, production of these cytokines ceased at the final stage of plasma cell. Unexpectedly, the mRNA extracted from MM plasma cell hybridized with TNF- and LT-specific, as well as IL-1-specific probes, although the culture supernatants did not contain detectable TNF/LT biologic activity. When tested in the fetal rat long bone assay, MM plasma cell supernatants displayed a strong osteoclast-activating factor (OAF) activity, which was greatly reduced but not completely abolished by neutralizing anti-IL-1 antibodies. Anti-TNF or anti-LT antibodies were ineffective in the same test. We conclude that the IL-1 released in vivo by malignant plasma cells has a major role in pathogenesis of lytic bone lesions of human MM.

BACKGROUND

Oxygen consumption at peak exercise (peak VO2) is the most accurate index of aerobic capacity (AC), which reflects the physical condition of an individual and is currently considered the gold standard for cardiorespiratory fitness. Evaluation of peak VO2 to identify high-risk candidates for liver transplantation (LT) may represent an interesting approach. The aims of this study were (a) to describe AC and identify factors independently associated with peak VO2; (b) to analyze the prognostic value of peak VO2 in patients referred for preliminary evaluation of LT; and (c) to provide preliminary data on the influence of peak VO2 on length of hospitalization and the need for oxygen support after LT.

RESULTS

Peak VO2 was determined in patients referred for preliminary evaluation for LT. One hundred thirty-five candidates were included. More than half had severe alterations in peak VO2. Age, gender, model-for-end-stage liver disease (MELD) score, tobacco use, and hemoglobin were independently associated with peak VO2. Candidates with severe alterations in peak VO2 had a lower 1-year survival than others. Model-for-end-stage liver disease score and peak VO2 were independently associated with survival. In patients with a MELD above 17, those with severe alterations of peak VO2 AC had lower 1-year survival than the others. Among patients who underwent LT, those with severe impairment of peak VO2 showed a trend toward a higher mean length of hospitalization after LT and had significantly longer need for oxygen support.

CONCLUSIONS

Peak VO2 is severely impaired in candidates for LT and affects survival and post-LT course. Perioperative respiratory rehabilitation programs validated in lung and heart transplantation must be tested.

<A<em>b</em>stractText>Existing guidelines for management of type 2 dia<em>b</em>etes recommend a patient-centred approach to guide the choice of pharmacological agents. A<em>lt</em>hough glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter-2 (SGLT2) inhi<em>b</em>itors are increasingly used as second-line agents, direct comparisons <em>b</em>etween these treatments are insufficient. In the SUSTAIN 8 trial, we compared the efficacy and safety of semaglutide (a GLP-1 receptor agonist) with canagliflozin (an SGLT2 inhi<em>b</em>itor) in patients with type 2 dia<em>b</em>etes.</A<em>b</em>stractText><p><div>(<em>b</em>)METHODS</<em>b</em>)</div>This was a dou<em>b</em>le-<em>b</em>lind, parallel-group, phase 3<em>b</em>, randomised controlled trial done at 111 centres in 11 countries. Eligi<em>b</em>le patients were at least 18 years old and had uncontrolled type 2 dia<em>b</em>etes (H<em>b</em>A<su<em>b</em>)1c</su<em>b</em>) 7·0-10·5% [53-91 mmol/mol]) on sta<em>b</em>le daily metformin therapy. Patients were randomly assigned (1:1) <em>b</em>y use of an interactive we<em>b</em> response system to su<em>b</em>cutaneous semaglutide 1·0 mg once weekly or oral canagliflozin 300 mg once daily. The primary endpoint was change from <em>b</em>aseline in H<em>b</em>A<su<em>b</em>)1c</su<em>b</em>), and the confirmatory secondary endpoint was change from <em>b</em>aseline in <em>b</em>odyweight, <em>b</em>oth at week 52. The primary analysis population included all randomly assigned patients, using on-treatment data collected <em>b</em>efore initiation of rescue medication. The safety analysis was done on a population that included all patients exposed to at least one dose of trial product. The trial was powered for H<em>b</em>A<su<em>b</em>)1c</su<em>b</em>) and <em>b</em>odyweight superiority under reasona<em>b</em>le assumptions. This trial is registered with ClinicalTrials.gov, NCT03136484.</p><p><div>(<em>b</em>)FINDINGS</<em>b</em>)</div>Between March 15, 2017, and Nov 16, 2018, 788 patients were randomly assigned to semaglutide 1·0 mg (394 patients) or canagliflozin 300 mg (394 patients). 739 patients completed the trial (367 in the semaglutide group and 372 in the canagliflozin group). From overall <em>b</em>aseline mean, patients receiving semaglutide had significantly greater reductions in H<em>b</em>A<su<em>b</em>)1c</su<em>b</em>) and <em>b</em>odyweight than those receiving canagliflozin (H<em>b</em>A<su<em>b</em>)1c</su<em>b</em>) estimated treatment difference [ETD] -0·49 percentage points, 95% CI -0·65 to -0·33; -5·34 mmol/mol, 95% CI -7·10 to -3·57; p&<em>lt</em>;0·0001; and <em>b</em>odyweight ETD -1·06 kg, 95% CI -1·76 to -0·36; p=0·0029). Gastrointestinal disorders, most commonly nausea, were the most frequently reported adverse events with semaglutide, occurring in 184 (47%) of 392 patients; whereas infections and infestations (defined using the Medical Dictionary for Regulatory Activities, version 21.0), most commonly urinary tract infections, occurred more frequently with canagliflozin, in 136 (35%) of 394 patients. Premature treatment discontinuation <em>b</em>ecause of adverse events occurred in 38 (10%) of 392 patients with semaglutide and in 20 (5%) of 394 patients with canagliflozin. One fatal adverse event confirmed unlikely to <em>b</em>e caused <em>b</em>y treatment occurred in the semaglutide group.</p><p><div>(<em>b</em>)INTERPRETATION</<em>b</em>)</div>Once-weekly semaglutide 1·0 mg was superior to daily canagliflozin 300 mg in reducing H<em>b</em>A<su<em>b</em>)1c</su<em>b</em>) and <em>b</em>odyweight in patients with type 2 dia<em>b</em>etes uncontrolled on metformin therapy. These outcomes might guide treatment intensification choices.</p><A<em>b</em>stractText>Novo Nordisk.</A<em>b</em>stractText>

<p><div>(<em>b</em>)OBJECTIVE</<em>b</em>)</div>Gastrointestinal micro<em>b</em>iota may <em>b</em>e involved in <i>Helico<em>b</em>acter pylori-</i>associated gastric cancer development. The aim of this study was to explore the possi<em>b</em>le micro<em>b</em>ial mechanisms in gastric carcinogenesis and potential dys<em>b</em>iosis arising from <i>H. pylori</i> infection.</p><p><div>(<em>b</em>)DESIGN</<em>b</em>)</div>Deep sequencing of the micro<em>b</em>ial 16S ri<em>b</em>osomal RNA gene was used to investigate a<em>lt</em>erations in paired gastric <em>b</em>iopsies and stool samples in 58 su<em>b</em>jects with successful and 57 su<em>b</em>jects with failed anti-<i>H. pylori</i> treatment, relative to 49 <i>H</i><i>.</i><i>pylori</i> negative su<em>b</em>jects.</p><p><div>(<em>b</em>)RESULTS</<em>b</em>)</div>In <i>H. pylori</i> positive su<em>b</em>jects, richness and Shannon indexes increased significantly (<em>b</em>oth p&<em>lt</em>;0.001) after successful eradication and showed no difference to those of negative su<em>b</em>jects (p=0.493 for richness and p=0.420 for Shannon index). Differential taxa analysis identified 18 significantly a<em>lt</em>ered gastric genera after eradication. The com<em>b</em>ination of these genera into a Micro<em>b</em>ial Dys<em>b</em>iosis Index revealed that the dys<em>b</em>iotic micro<em>b</em>iota in <i>H. pylori</i> positive mucosa was associated with advanced gastric lesions (chronic atrophic gastritis and intestinal metaplasia/dysplasia) and could <em>b</em>e reversed <em>b</em>y eradication. Strong coexcluding interactions <em>b</em>etween <i>Helico<em>b</em>acter</i> and <i>Fuso<em>b</em>acterium</i>, <i>Neisseria</i>, <i>Prevotella</i>, <i>Veillonella</i>, <i>Rothia</i> were found only in advanced gastric lesion patients, and were a<em>b</em>sent in normal/superficial gastritis group. Changes in faecal micro<em>b</em>iota included increased <i>Bifido<em>b</em>acterium</i> after successful <i>H. pylori</i> eradication and more upregulated drug-resistant functional orthologs after failed treatment.</p><p><div>(<em>b</em>)CONCLUSION</<em>b</em>)</div><i>H. pylori</i> infection contri<em>b</em>utes significantly to gastric micro<em>b</em>ial dys<em>b</em>iosis that may <em>b</em>e involved in carcinogenesis. Successful <i>H. pylori</i> eradication potentially restores gastric micro<em>b</em>iota to a similar status as found in uninfected individuals, and shows <em>b</em>eneficial effects on gut micro<em>b</em>iota.</p>