Infectious complications are major causes of morbidity and mortality after liver transplantation, despite recent advances in the transplant field. Bacteria, fungi, viruses and parasites can cause infection before and after transplantation. Among them, bacterial infections are predominant during the first two months post-transplantation and affect patient and graft survival. They might cause surgical site infections, including deep intra-abdominal infections, bacteremia, pneumonia, catheter-related infections and urinary tract infections. The risk factors for bacterial infections differ between the periods after transplant, and between centers. Recently, the emergence of multi-drug resistant bacteria is great concern in liver transplant (LT) patients. The instructive data about effects of infections with extended-spectrum beta lactamase producing bacteria, carbapenem-resistant gram-negative bacteria, and glycopeptide-resistant gram-positive bacteria were reported on a center-by-center basis. To prevent post-transplant bacterial infections, proper strategies need to be established based upon center-specific data and evidence from well-controlled studies. This article reviewed the recent epidemiological data, risk factors for each type of infections and important clinical issues in bacterial infection after LT.

<A<em>b</em>stractText>Total neoadjuvant therapy is a new paradigm for rectal cancer treatment. Optimal scheduling of preoperative chemoradiotherapy (CRT) and chemotherapy remains to <em>b</em>e esta<em>b</em>lished.</A<em>b</em>stractText><A<em>b</em>stractText>We conducted a mu<em>lt</em>icenter, randomized, phase II trial using a pick-the-winner design on the <em>b</em>asis of the hypothesis of an increased pathologic complete response (pCR) of 25% after total neoadjuvant therapy compared with standard 15% after preoperative CRT. Patients with stage II or III rectal cancer were assigned to group A for induction chemotherapy using three cycles of fluorouracil, leucovorin, and oxaliplatin <em>b</em>efore fluorouracil/oxaliplatin CRT (50.4 Gy) or to group <em>B</em> for consolidation chemotherapy after CRT. Secondary end points included toxicity, compliance, and surgical mor<em>b</em>idity.</A<em>b</em>stractText><p><div>(<em>b</em>)RESULTS</<em>b</em>)</div>Of the 311 patients enrolled, 306 patients were evalua<em>b</em>le (156 in group A and 150 in group <em>B</em>). CRT-related grade 3 or 4 toxicity was lower (37% <i>v</i> 27%) and compliance with CRT higher in group <em>B</em> (91%, 78%, and 76% <i>v</i> 97%, 87%, and 93% received full-dose radiotherapy, concomitant fluorouracil, and concomitant oxaliplatin in groups A and <em>B</em>, respectively); 92% versus 85% completed all induction/consolidation chemotherapy cycles, respectively. The longer interval <em>b</em>etween completion of CRT and surgery in group <em>B</em> (median 90 <i>v</i> 45 days in group A) did not increase surgical mor<em>b</em>idity. A pCR in the intention-to-treat population was achieved in 17% in group A and in 25% in group <em>B</em>. Thus, only group <em>B</em> (<i>P</i> &<em>lt</em>; .001), <em>b</em>ut not group A (<i>P</i> = .210), fulfilled the predefined statistical hypothesis.</p><A<em>b</em>stractText>Up-front CRT followed <em>b</em>y chemotherapy resu<em>lt</em>ed in <em>b</em>etter compliance with CRT <em>b</em>ut worse compliance with chemotherapy compared with group A. Long-term follow-up will assess whether improved pCR in group <em>B</em> translates to <em>b</em>etter oncologic outcome.</A<em>b</em>stractText>

<A<em>b</em>stractText>Immune-related genes (IRGs) were linked to the prognosis of head and neck squamous cell carcinoma (HNSCC). This study aimed to identify the effects of an immune-related gene signature (IRGS) that can predict the of HNSCC prognosis.</A<em>b</em>stractText><A<em>b</em>stractText>The expression data of 770 HNSCC patients from the TCGA data<em>b</em>ase and the GEO data<em>b</em>ase were used. To explore a predictive model, the Cox proportional hazards model was applied. The Kaplan-Meier survival analysis, as well as univariate and mu<em>lt</em>ivariate analyses were performed to evaluate the independent predictive value of IRGS. To explore <em>b</em>iological functions of IRGS, enrichment analyses and pathway annotation for differentially expressed genes (DEGs) in different immune groups were applied, as well as the immune infi<em>lt</em>ration.</A<em>b</em>stractText><p><div>(<em>b</em>)Resu<em>lt</em>s</<em>b</em>)</div>A prognostic signature comprising 27 IRGs was generated. IRGS significantly stratified HNSCC patients into high and low immune risk groups in regard to overall survival in the training cohort (HR = 3.69, 95% <i>CI</i> 2.73-4.98, <i>P </i>&<em>lt</em>; 0.001). Likewise, IRGS could <em>b</em>e linked to the prognosis of HNSCC in patients of the validation cohort (HR = 1.84, 95% <i>CI</i> 1.21-2.81, <i>P </i>&<em>lt</em>; 0.01). Even after adjusting for TNM stage, IRGS was maintained as an independent predictor in the mu<em>lt</em>ivariate analysis (HR = 3.62, 95% <i>CI</i> 2.58-5.09, <i>P </i>&<em>lt</em>; 0.001), and in the validation cohort (HR = 1.73, 95% <i>CI</i> 1.12-2.67, <i>P </i>= 0.014). The IFN-α response, the IFN-γ response, IL-2/STAT5 signaling, and IL-6/JAK/STAT3 signaling were all negatively correlated with the immune risk (<i>P </i>&<em>lt</em>; 0.01). Immune infi<em>lt</em>ration of the high-risk group was significantly lower than that of the low-risk group (<i>P </i>&<em>lt</em>; 0.01). Most nota<em>b</em>ly, the infi<em>lt</em>ration of CD8 T cells, memory-activated CD4 T cells, and regulatory T cells was strongly upregulated in the low immune risk groups, while memory resting CD4 T cell infi<em>lt</em>ration was downregulated (<i>P </i>&<em>lt</em>; 0.01).</p><A<em>b</em>stractText>Our analysis provides a comprehensive prognosis of the immune microenvironments and outcomes for different individuals. Further studies are needed to evaluate the clinical application of this signature.</A<em>b</em>stractText>

OBJECTIVE

To evaluate the short-term safety and efficacy of the new generation of 70-150 µm drug-eluting beads (M1 DEB) in patients with hepatocellular carcinoma undergoing transarterial chemoembolization (TACE) as a primary therapy or as a bridge to liver transplantation (LT).

METHODS

Forty-five consecutive patients underwent TACE with M1 DEB loaded with doxorubicin (DEBDOX/M1). Clinical data were recorded at 12, 24, and 48 h, 7 and 30 days after treatment. Response was assessed by computed tomographic scan according to the modified response evaluation criteria in solid tumors criteria, and a second DEBDOX/M1 TACE was scheduled within 6 weeks in case of a noncomplete response.

RESULTS

All patients had well-compensated cirrhosis (97.7 % Child A, 44.4 % hepatitis C virus, median age 61 years). Twenty patients (44.4 %) had Barcelona Clinic for Liver Cancer class B disease; the median number of nodules and their sum of diameters were 2 (range 1-6) and 43 mm (range 10-190), respectively. The mean number of TACE procedures per patient was 1.4. Objective response rate (complete + partial response) was 77.7 % with a median time to best response of 3 months (95 % confidence interval 2-4). In 13 patients, DEBDOX/M1 TACE served as a bridge/downstaging to LT/surgery. Pathology showed that more than 90 % necrosis was achieved in 10 of 28 nodules. DEBDOX/M1 TACE was well tolerated, and the grade 3/4 adverse event rate was low (1 of 65 procedures).

CONCLUSIONS

DEBDOX/M1 TACE is an effective procedure with a favorable safety profile and promising results in terms of objective response rate, tumor downstaging, and necrosis.

The characterization of hepatitis B virus (HBV) quasispecies in different compartments in liver transplant (LT) recipients may be helpful in optimizing prophylaxis regimens. The aims of this study were to evaluate liver, peripheral blood mononuclear cells (PBMC), and plasma samples for HBV and to compare the quasispecies in hepatic and extrahepatic sites in LT recipients on long-term prophylaxis. For 12 patients followed for up to 15 years post-LT, liver, plasma, and PBMC samples [all HBV DNA-negative according to conventional polymerase chain reaction (PCR) assays] were evaluated for HBV DNA by a sensitive nested PCR method [covalently closed circular DNA (cccDNA) for liver and PBMC samples] and by the sequencing and phylogenetic analysis of polymerase quasispecies. For the 10 patients on prophylaxis with no clinical recurrence (median time post-LT = 15.5 months, range = 12-96 months), liver samples were HBV DNA-reactive in 9 of 10 cases, plasma samples were HBV DNA-reactive in 3 of 10 cases, and PBMC samples were HBV DNA-reactive in 2 of 7 cases (including 1 case with HBV cccDNA in PBMCs). The sequence analysis showed that all HBV clones had a wild-type (WT) sequence in the liver and PBMCs. In 2 patients with early HBV recurrence post-LT who were treated with nucleosides only, HBV DNA was detected in serum, PBMC, and liver samples, and HBV cccDNA was found in liver samples. An HBV lamivudine-resistant variant with an M204I mutation was identified in liver (70% and 18% of the clones) and plasma samples (100% of the clones), but a WT sequence was found in 70% and 100% of the PBMC clones. In conclusion, despite prophylaxis and the absence of HBV DNA in serum according to conventional assays, HBV is detectable in the serum, liver, and PBMCs of almost all patients, and this supports the use of continued anti-HBV therapy in this group. Antiviral drug-resistant variants are more frequent in the liver versus PBMCs, but both compartments are potential sources of reinfection.

<A<em>b</em>stractText>Oral semaglutide is the first oral glucagon-like peptide-1 (GLP-1) receptor agonist for glycaemic control in patients with type 2 dia<em>b</em>etes. Type 2 dia<em>b</em>etes is commonly associated with renal impairment, restricting treatment options. We aimed to investigate the efficacy and safety of oral semaglutide in patients with type 2 dia<em>b</em>etes and moderate renal impairment.</A<em>b</em>stractText><p><div>(<em>b</em>)METHODS</<em>b</em>)</div>This randomised, dou<em>b</em>le-<em>b</em>lind, phase 3a trial was undertaken at 88 sites in eight countries. Patients aged 18 years and older, with type 2 dia<em>b</em>etes, an estimated glomerular fi<em>lt</em>ration rate of 30-59 mL/min per 1·73 m², and who had <em>b</em>een receiving a sta<em>b</em>le dose of metformin or sulfonylurea, or <em>b</em>oth, or <em>b</em>asal insulin with or without metformin for the past 90 days were eligi<em>b</em>le. Participants were randomly assigned (1:1) <em>b</em>y use of an interactive we<em>b</em>-response system, with stratification <em>b</em>y glucose-lowering medication and renal function, to receive oral semaglutide (dose escalated to 14 mg once daily) or matching place<em>b</em>o for 26 weeks, in addition to <em>b</em>ackground medication. Participants and site staff were masked to assignment. Two efficacy-related estimands were defined: treatment policy (regardless of treatment discontinuation or rescue medication) and trial product (on treatment without rescue medication) in all participants randomly assigned. Endpoints were change from <em>b</em>aseline to week 26 in H<em>b</em>A<su<em>b</em>)1c</su<em>b</em>) (primary endpoint) and <em>b</em>odyweight (confirmatory secondary endpoint), assessed in all participants with sufficient data. Safety was assessed in all participants who received at least one dose of study drug. This trial is registered on ClinicalTrials.gov, num<em>b</em>er NCT02827708, and the European Clinical Trials Registry, num<em>b</em>er EudraCT 2015-005326-19, and is now complete.</p><p><div>(<em>b</em>)FINDINGS</<em>b</em>)</div>Between Sept 20, 2016, and Sept 29, 2017, of 721 patients screened, 324 were eligi<em>b</em>le and randomly assigned to oral semaglutide (n=163) or place<em>b</em>o (n=161). Mean age at <em>b</em>aseline was 70 years (SD 8), and 168 (52%) of participants were female. 133 (82%) participants in the oral semaglutide group and 141 (88%) in the place<em>b</em>o group completed 26 weeks on treatment. At 26 weeks, oral semaglutide was superior to place<em>b</em>o in decreasing H<em>b</em>A<su<em>b</em>)1c</su<em>b</em>) (estimated mean change of -1·0 percentage point (SE 0·1; -11 mmol/mol [SE 0·8]) vs -0·2 percentage points (SE 0·1; -2 mmol/mol [SE 0·8]); estimated treatment difference [ETD]: -0·8 percentage points, 95% CI -1·0 to -0·6; p&<em>lt</em>;0·0001) and <em>b</em>odyweight (estimated mean change of -3·4 kg [SE 0·3] vs -0·9 kg [SE 0·3]; ETD, -2·5, 95% CI -3·2 to -1·8; p&<em>lt</em>;0·0001) <em>b</em>y the treatment policy estimand. Significant differences were seen for the trial product estimand: mean change in H<em>b</em>A<su<em>b</em>)1c</su<em>b</em>) -1·1 percentage points (SE 0·1; -12 mmol/mol [SE 0·8] versus -0·1 percentage points (SE 0·1; -1 mmol/mol [SE 0·8]; ETD -1·0 percentage points, 95% CI -1·2 to -0·8; p&<em>lt</em>;0·0001); mean change in <em>b</em>odyweight -3·7 kg (SE 0·3) versus -1·1 kg (SE 0·3; ETD -2·7 kg, 95% CI -3·5 to -1·9; p&<em>lt</em>;0·0001). More patients taking oral semaglutide than place<em>b</em>o had adverse events (120 [74%] of 163 vs 105 [65%] of 161), and discontinued treatment as a resu<em>lt</em> (24 [15%] vs eight [5%]). Gastrointestinal events, mainly mild-to-moderate nausea, were more common with oral semaglutide than with place<em>b</em>o. Three deaths occurred during the treatment period that were not condsidered to <em>b</em>e treatment related, one in the semaglutide group and two in the place<em>b</em>o group.</p><A<em>b</em>stractText>Oral semaglutide was effective in patients with type 2 dia<em>b</em>etes and moderate renal impairment, potentially providing a new treatment option for this population. Safety, including renal safety, was consistent with the GLP-1 receptor agonist class.</A<em>b</em>stractText><A<em>b</em>stractText>Novo Nordisk A/S.</A<em>b</em>stractText>

<A<em>b</em>stractText>Dia<em>b</em>etes is a risk factor for the progression and prognosis of coronavirus disease (COVID-19), <em>b</em>ut the relationship <em>b</em>etween glycosylated hemoglo<em>b</em>in (H<em>b</em>A1c) level, inflammation, and prognosis of COVID-19 patients has not <em>b</em>een explored.</A<em>b</em>stractText><A<em>b</em>stractText>This was a retrospective study of COVID-19 patients who underwent an H<em>b</em>A1c test. Their demographic data, medical history, signs and symptoms of COVID-19, la<em>b</em>oratory test resu<em>lt</em>s, and final outcomes of COVID-19 treatment were collected and analyzed.</A<em>b</em>stractText><p><div>(<em>b</em>)RESULTS</<em>b</em>)</div>A total of 132 patients were included and divided into three groups <em>b</em>ased on their <em>b</em>lood glucose status. There were significant differences in SaO<su<em>b</em>)2</su<em>b</em>), serum ferritin level, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), fi<em>b</em>rinogen (F<em>b</em>g) level, and IL6 level among the three groups. A pairwise comparison of the groups showed that groups <em>B</em> and C were significantly different from group A in terms of CRP, ESR, and F<em>b</em>g, IL6, and serum ferritin levels (P&<em>lt</em>;0.05). Correlation analysis showed that there was a linear negative correlation <em>b</em>etween SaO<su<em>b</em>)2</su<em>b</em>) and H<em>b</em>A1c (r=-0.22, P=0.01), while there was a linear positive correlation <em>b</em>etween serum ferritin, CRP, F<em>b</em>g, and ESR levels and H<em>b</em>A1c (P&<em>lt</em>;0.05).</p><p><div>(<em>b</em>)CONCLUSIONS</<em>b</em>)</div>High H<em>b</em>A1c level is associated with inflammation, hypercoagula<em>b</em>ility, and low SaO<su<em>b</em>)2</su<em>b</em>) in COVID-19 patients, and the mortality rate (27.7%) is higher in patients with dia<em>b</em>etes. Determining H<em>b</em>A1c level after hospital admission is thus helpful assessing inflammation, hypercoagula<em>b</em>ility, and prognosis of COVID-19 patients.</p>

Studies have found increased rates of dysosmia in patients with Novel Coronavirus disease 2019 (COVID-19). However, the mechanism that causes olfactory loss is unknown. The primary objective of this study was to explore local proinflammatory cytokine levels in the olfactory epithelium in patients with COVID-19. Biopsies of the olfactory epithelium were taken from patients with confirmed COVID-19 as well as uninfected controls. Levels of tumor necrosis factor α (TNF-α) and interleukin-1-beta (IL-1β) were assessed using ELISA and compared between groups. Average TNF-α levels were significantly increased in the olfactory epithelium of the COVID-19 group compared to the control group (P &lt; 0.05). However, no differences in IL-1β were seen between groups. Elevated levels of the proinflammatory cytokine TNF-α were seen in the olfactory epithelium in patients with COVID-19. This suggests that direct inflammation of the olfactory epithelium could play a role in the acute olfactory loss described in many patients with COVID-19.

Keywords: Anosmia; COVID-19; Inflammation; Tumor necrosis factor-alpha.

Chimeric antigen receptor (CAR) T cells have demonstrated clinical benefit in patients with relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). We undertook a multi-center clinical trial to determine toxicity, feasibility, and response for this therapy. A total of 25 pediatric/young adult patients (age 1-22.5 years) with R/R B-ALL were treated with 19-28z CAR T cells. Conditioning chemotherapy included high dose (3 g/m2) cyclophosphamide (HD-Cy) for seventeen (n=17) patients and low dose ({less than or equal to}1.5 g/m2) cyclophosphamide (LD-Cy) for eight (n=8) patients. Fifteen (n=15) patients had pre-treatment minimal residual disease (MRD; &lt;5% blasts in bone marrow) and ten (n=10) patients had pre-treatment morphologic evidence of disease ({greater than or equal to}5% blasts in bone marrow). All toxicities were reversible including severe CRS in 16% (4/25) and severe neurotoxicity in 28% (7/25) of patients. Treated patients were assessed for response and among evaluable patients (n=24), response and peak CAR T cell expansion were superior in the HD-Cy/MRD cohorts as compared to the LD-Cy/morphologic cohorts without an increase of toxicity. Our data supports the safety of CD19-specific CAR T cell therapy for R/R B-ALL. Our data also suggest that dose intensity of conditioning chemotherapy and minimal pre-treatment disease burden have a positive impact on response without a negative effect on toxicity. This trial was registered at www.clinicaltrials.gov as NCT01860937.

(<em>b</em>)O<em>b</em>jective:</<em>b</em>) To estimate the infection rate of close contacts of COVID-19 cases, and to evaluate the risk of COVID-19 under different exposure conditions. (<em>b</em>)Methods:</<em>b</em>) A prospective study was used to conduct continuous quarantine medical o<em>b</em>servations of close contacts of people infected with COVID-19, collect epidemiological, clinical manifestations, and la<em>b</em>oratory test data to estimate the infection rate of close contacts under different exposures. (<em>b</em>)Resu<em>lt</em>s:</<em>b</em>) The epidemiological curve of COVID-19 in Ning<em>b</em>o showed persistent human-to-human characteristics. A total of 2 147 close contacts were tracked and investigated. The total infection rate was 6.15%. The infection rates of confirmed cases and positive contacts were 6.30% and 4.11%, respectively. The difference was not statistically significant (<i>P</i>>0.05). Among close contacts of different relationships, friends/pilgrims (22.31%), family mem<em>b</em>ers (18.01%), and relatives (4.73%) have a higher infection rate, and close contacts of medical staff were not infected. Differences in infection rates among the close contacts were statistically significant (<i>P</i>&<em>lt</em>;0.005). Living with the case (13.26%), taking the same transportation (11.91%), and dining together (7.18%) are high risk factors for infection. Cross-infection in the hospital should not <em>b</em>e ignored (1.94%). The median of incu<em>b</em>ation period is 5 days. (<em>b</em>)Conclusion:</<em>b</em>) The infection rate of close contacts of COVID-19 cases is high, and isolation medical o<em>b</em>servation measures should <em>b</em>e implemented in strict accordance with the close contact management plan.

(<em>b</em>)目的：</<em>b</em>) 估算新型冠状病毒肺炎病例密切接触者的感染率，评估不同暴露状况下新型冠状病毒肺炎的发病风险。 (<em>b</em>)方法：</<em>b</em>) 采用前瞻性研究的方法，对新型冠状病毒肺炎病例和无症状感染者的密切接触者进行持续隔离医学观察，收集流行病学、临床表现和实验室检测资料，估算不同暴露下的密切接触者感染率。 (<em>b</em>)结果：</<em>b</em>) 宁波市新型冠状病毒肺炎发病流行曲线呈现持续的人传人特征。共追踪调查了2 147名密切接触者，总感染率为6.15%，确诊病例、无症状感染者的密切接触者感染率分别为6.30%和4.11%，差异无统计学意义（<i>P</i>>0.05）。不同关系的密切接触者中，以朋友/香客（22.31%）、家庭成员（18.01%）、亲戚（4.73%）感染较高率，医务人员密切接触者未发生感染，各密切接触者人群感染率差异有统计学意义（<i>P</i>&<em>lt</em>;0.005）。与病例同住（13.26%）、乘坐同一个交通工具（11.91%）、聚餐娱乐（7.18%）均是感染高危因素。医院诊疗环境下的交叉感染也不容忽视（1.94%）。潜伏期中位数为5 d。 (<em>b</em>)结论：</<em>b</em>) 新型冠状病毒肺炎病例密切接触者的感染率高，需严格按照密切接触者管理方案实施隔离医学观察措施。.

Keywords: COVID-19; Close contacts; Epidemiological characteristics; Infection rate.

(<em>b</em>)Purpose:</<em>b</em>) To evaluate the performance of radiomic features (RF) derived from PSMA PET for intraprostatic tumor discrimination and non-invasive characterization of Gleason score (GS) and pelvic lymph node status. (<em>b</em>)Patients and methods:</<em>b</em>) Patients with prostate cancer (PCa) who underwent [⁶⁸Ga]-PSMA-11 PET/CT followed <em>b</em>y radical prostatectomy and pelvic lymph node dissection were prospectively enrolled (n=20). Coregistered histopathological gross tumor volume (GTV-Histo) in the prostate served as reference. 133 RF were derived from GTV-Histo and from manually created segmentations of the intraprostatic tumor volume (GTV-Exp). Spearman´s correlation coefficients (ρ) were assessed <em>b</em>etween RF derived from the different GTVs. We additionally analyzed the differences in RF values for PCa and non-PCa tissues. Furthermore, areas under receiver-operating characteristics curves (AUC) were calculated and uni- and mu<em>lt</em>ivariate analyses were performed to evaluate the RF <em>b</em>ased discrimination of GS 7 and ≥8 disease and of patients with nodal spread (pN1) and non-nodal spread (pN0) in surgical specimen. The resu<em>lt</em>s found in the latter analyses were validated <em>b</em>y a retrospective cohort of 40 patients. (<em>b</em>)Resu<em>lt</em>s:</<em>b</em>) Most RF from GTV-Exp showed strong correlations with RF from GTV-Histo (86% with ρ>0.7). 81% and 76% of RF from GTV-Exp and GTV-Histo significantly discriminated <em>b</em>etween PCa and non-PCa tissue. The texture feature QSZHGE discriminated <em>b</em>etween GS 7 and ≥8 considering GTV-Histo (AUC=0.93) and GTV-Exp (prospective cohort: AUC=0.91 / validation cohort: AUC=0.84). QSZHGE also discriminated <em>b</em>etween pN1 and pN0 disease considering GTV-Histo (AUC=0.85) and GTV-Exp (prospective cohort: AUC=0.87 / validation cohort: AUC=0.85). In uni- and mu<em>lt</em>ivariate analyses including patients of <em>b</em>oth cohorts QSZHGE was a statistically significant (p&<em>lt</em>;0.01) predictor for PCa patients with GS ≥8 tumors and pN1 status. (<em>b</em>)Conclusion:</<em>b</em>) RF derived from PSMA PET discriminated <em>b</em>etween PCa and non-PCa tissue within the prostate. Additionally, the texture feature QSZHGE discriminated <em>b</em>etween GS 7 and GS ≥8 tumors and <em>b</em>etween patients with pN1 and pN0 disease. Our resu<em>lt</em>s support the role of RF in PSMA PET as a new tool for non-invasive PCa discrimination and characterization of its <em>b</em>iological properties.

Affinity maturation and Ab class switches occur in lymphoid germinal centers (GCs), in which differentiation and maintenance depend on lymphotoxin (LT) signaling and include differentiation of follicular dendritic cells (FDCs). The events leading to FDC and GC maturation are poorly defined. Using several approaches of functional genomics, we enumerated transcripts affected in mice by suppressing LT beta receptor (LTbetaR) signaling and/or overrepresented in FDC-enriched GC isolates. Protein expression analysis of 3 of 12 genes both enriched in FDCs and down-regulated by LTbetaR signaling suppression validated them as FDC markers. Functional analysis of one of these three, clusterin, suggests a role as an FDC-derived trophic factor for GC B cells. Hence, the set of genes presented in this study includes markers emanating from LTbetaR signaling and transcripts relevant to GC and FDC function.

Rationale: Psychological resilience is characterized as the ability to respond to extreme stress or trauma or adverse experience successfully. While the relation between public emergencies and psychological distress is well known, research on therelationship between psychological resilience and mental health is very limited during the outbreak of public health emergencies.

Objective: This research investigated the relationship between psychological resilience and mental health (depression, anxiety, somatization symptoms) among the general population in China.

Method: Psychological resilience, depression, anxiety, and somatization symptoms of 1770 Chinese citizens were investigated during the epidemic peak of coronavirus disease 2019 (COVID-19) (23rd February 2020 to 2nd March 2020). The analyses were done through the Connor-Davidson Resilience Scale (CD-RISC), the Patient Health Questionnaire-9 (PHQ-9), the Generalized Anxiety Disorder-7 (GAD-7) scale, and the Patient Health Questionnaire-15 (PHQ-15) scale.

Results: The prevalence of depression, anxiety, somatization symptoms was found to be 47.1%, 31.9%, 45.9%, respectively, among all participants. From them, 18.2% showed moderate to severe symptoms of depression, 8.8% showed moderate to severe symptoms of anxiety, and 16.6% showed moderate to severe symptoms of somatization. Psychological resilience was negatively correlated with depression (standardized β = -0.490, P &lt; 0.001), anxiety (standardized β = -0.443, P &lt; 0.001), and somatization symptom scores (standardized β = -0.358, P &lt; 0.001), while controlling for confounding factors. Analysis of the three-factor resilience structure showed that strength and tenacity were correlated with depression (standardized β = -0.256, P &lt; 0.001; standardized β = -0.217, P &lt; 0.001), anxiety (standardized β = -0.268, P &lt; 0.001; standardized β = -0.147, P &lt; 0.001), and somatization symptoms (standardized β = -0.236, P &lt; 0.001; standardized β = -0.126, P &lt; 0.01).

Conclusions: Our results suggest that there is a high prevalence of psychological distresses among the general population at the peak of the COVID-19 epidemic in China, which is negatively correlated with resilience. Psychological resilience represents an essential target for psychological intervention in a public health emergency.

Keywords: Anxiety; China; Coronavirus disease 2019; Depression; Epidemic; Mental health; Psychological resilience; Somatization symptoms.

<A<em>b</em>stractText>A<em>b</em>iraterone acetate plus prednisone and enzalutamide are <em>b</em>oth used for the treatment of metastatic castration-resistant prostate cancer. We aimed to determine the <em>b</em>est sequence in which to use <em>b</em>oth drugs, as well as their second-line efficacy.</A<em>b</em>stractText><A<em>b</em>stractText>In this mu<em>lt</em>icentre, randomised, open-la<em>b</em>el, phase 2, crossover trial done in six cancer centres in <em>B</em>ritish Colum<em>b</em>ia, Canada, we recruited patients aged 18 years or older with newly-diagnosed metastatic castration-resistant prostate cancer without neuroendocrine differentiation and Eastern Cooperative Oncology Group performance status 2 or less. Patients were randomly assigned (1:1) using a computer-generated random num<em>b</em>er ta<em>b</em>le to receive either a<em>b</em>iraterone acetate 1000 mg orally once daily plus prednisone 5 mg orally twice daily until PSA progression followed <em>b</em>y crossover to enzalutamide 160 mg orally once daily (group A), or the opposite sequence (group <em>B</em>). Treatment was not masked to investigators or participants. Primary endpoints were time to second PSA progression and PSA response (≥30% decline from <em>b</em>aseline) on second-line therapy, analysed <em>b</em>y intention-to-treat in all randomly assigned patients and in patients who crossed over, respectively. The trial is registered with ClinicalTrials.gov, NCT02125357.</A<em>b</em>stractText><p><div>(<em>b</em>)FINDINGS</<em>b</em>)</div><em>B</em>etween Oct 21, 2014, and Dec 13, 2016, 202 patients were enrolled and randomly assigned to either group A (n=101) or group <em>B</em> (n=101). At the time of data cutoff, 73 (72%) patients in group A and 75 (74%) patients in group <em>B</em> had crossed over. Time to second PSA progression was longer in group A than in group <em>B</em> (median 19·3 months [95% CI 16·0-30·5] vs 15·2 months [95% CI 11·9-19·8] months; hazard ratio 0·66, 95% CI 0·45-0·97, p=0·036), at a median follow-up of 22·8 months (IQR 10·3-33·4). PSA responses to second-line therapy were seen in 26 (36%) of 73 patients for enzalutamide and three (4%) of 75 for a<em>b</em>iraterone (χ² p&<em>lt</em>;0·0001). The most common grade 3-4 adverse events throughout the trial were hypertension (27 [27%] of 101 patients in group A vs 18 [18%] of 101 patients in group <em>B</em>) and fatigue (six [10%] vs four [4%]). Serious adverse events were reported in 15 (15%) of 101 patients in group A and 20 (20%) of 101 patients in group <em>B</em>. There were no treatment-related deaths.</p><A<em>b</em>stractText>Enzalutamide showed activity as a second-line novel androgen receptor pathway inhi<em>b</em>itor, whereas a<em>b</em>iraterone acetate did not, leading to a longer time to second PSA progression for the sequence of a<em>b</em>iraterone followed <em>b</em>y enzalutamide than with the opposite treatment sequence. Our data suggest that using a sequencing strategy of a<em>b</em>iraterone acetate followed <em>b</em>y enzalutamide provides the greatest clinical <em>b</em>enefit.</A<em>b</em>stractText><A<em>b</em>stractText>Canadian Cancer Society Research Institute, Prostate Cancer Canada, Movem<em>b</em>er Foundation, Prostate Cancer Foundation, Terry Fox New Frontiers Program, <em>B</em>C Cancer Foundation, Jane and Aatos Erkko Foundation, Janssen, and Astellas.</A<em>b</em>stractText>

<A<em>b</em>stractText>For several cardiometa<em>b</em>olic risk factors, values considered within normal range are associated with an increased risk of cardiovascular mor<em>b</em>idity and mortality. We aimed to investigate the short-term and long-term effects of calorie restriction with adequate nutrition on these risk factors in hea<em>lt</em>hy, lean, or slightly overweight young and middle-aged individuals.</A<em>b</em>stractText><p><div>(<em>b</em>)METHODS</<em>b</em>)</div>CALERIE was a phase 2, mu<em>lt</em>icentre, randomised controlled trial in young and middle-aged (21-50 years), hea<em>lt</em>hy non-o<em>b</em>ese (BMI 22·0-27·9 kg/m²) men and women done in three clinical centres in the USA. Participants were randomly assigned (2:1) to a 25% calorie restriction diet or an ad li<em>b</em>itum control diet. Exploratory cardiometa<em>b</em>olic risk factor responses to a prescri<em>b</em>ed 25% calorie restriction diet for 2 years were evaluated (systolic, diastolic, and mean <em>b</em>lood pressure; plasma lipids; high-sensitivity C-reactive protein; meta<em>b</em>olic syndrome score; and glucose homoeostasis measures of fasting insulin, glucose, insulin resistance, and 2-h glucose, area-under-the curve for glucose, and insulin from an oral glucose tolerance test) analysed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, num<em>b</em>er NCT00427193.</p><A<em>b</em>stractText>From May 8, 2007, to Fe<em>b</em> 26, 2010, of 238 participants that were assessed, 218 were randomly assigned to and started a 25% calorie restriction diet (n=143, 66%) or an ad li<em>b</em>itum control diet (n=75, 34%). Individuals in the calorie restriction group achieved a mean reduction in calorie intake of 11·9% (SE 0·7; from 2467 kcal to 2170 kcal) versus 0·8% (1·0) in the control group, and a sustained mean weight reduction of 7·5 kg (SE 0·4) versus an increase of 0·1 kg (0·5) in the control group, of which 71% (mean change in fat mass 5·3 kg [SE 0·3] divided <em>b</em>y mean change in weight 7·5 kg [0·4]) was fat mass loss. Calorie restriction caused a persistent and significant reduction from <em>b</em>aseline to 2 years of all measured conventional cardiometa<em>b</em>olic risk factors, including change scores for LDL-cholesterol (p&<em>lt</em>;0·0001), total cholesterol to HDL-cholesterol ratio (p&<em>lt</em>;0·0001), and systolic (p&<em>lt</em>;0·0011) and diastolic (p&<em>lt</em>;0·0001) <em>b</em>lood pressure. In addition, calorie restriction resu<em>lt</em>ed in a significant improvement at 2 years in C-reactive protein (p=0·012), insulin sensitivity index (p&<em>lt</em>;0·0001), and meta<em>b</em>olic syndrome score (p&<em>lt</em>;0·0001) relative to control. A sensitivity analysis revealed the responses to <em>b</em>e ro<em>b</em>ust after controlling for relative weight loss changes.</A<em>b</em>stractText><A<em>b</em>stractText>2 years of moderate calorie restriction significantly reduced mu<em>lt</em>iple cardiometa<em>b</em>olic risk factors in young, non-o<em>b</em>ese adu<em>lt</em>s. These findings suggest the potential for a su<em>b</em>stantial advantage for cardiovascular hea<em>lt</em>h of practicing moderate calorie restriction in young and middle-aged hea<em>lt</em>hy individuals, and they offer promise for pronounced long-term population hea<em>lt</em>h <em>b</em>enefits.</A<em>b</em>stractText><A<em>b</em>stractText>National Institute on Aging and National Institute of Dia<em>b</em>etes and Digestive and Kidney Diseases, National Institutes of Hea<em>lt</em>h.</A<em>b</em>stractText>

Rotavirus vaccines are delivered early in life, when the immune system is immature. To determine the effects of immaturity on responses to candidate vaccines, neonatal (7 days old) and adult mice were immunized with single doses of either Escherichia coli-expressed rotavirus VP6 protein and the adjuvant LT(R192G) or live rhesus rotavirus (RRV), and protection against fecal rotavirus shedding following challenge with the murine rotavirus strain EDIM was determined. Neonatal mice immunized intranasally with VP6/LT(R192G) were unprotected at 10 days postimmunization (dpi) and had no detectable rotavirus B-cell (antibody) or CD4(+) CD8(+) T-cell (rotavirus-inducible, Th1 [gamma interferon and interleukin-2 {IL-2}]-, Th2 [IL-5 and IL-4]-, or ThIL-17 [IL-17]-producing spleen cells) responses. However, by 28 and 42 dpi, these mice were significantly (P>>or= 0.003) protected and contained memory rotavirus-specific T cells but produced no rotavirus antibody. In contrast, adult mice were nearly fully protected by 10 dpi and contained both rotavirus immunoglobulin G and memory T cells. Neonates immunized orally with RRV were also less protected (P=0.01) than adult mice by 10 dpi and produced correspondingly less rotavirus antibody. Both groups contained few rotavirus-specific memory T cells. Protection levels by 28 dpi for neonates or adults were equal, as were rotavirus antibody levels. This report introduces a neonatal mouse model for active protection studies with rotavirus vaccines. It indicates that, with time, neonatal mice develop full protection after intranasal immunization with VP6/LT(R192G) or oral immunization with a live heterologous rotavirus and supports reports that protection depends on CD4(+) T cells or antibody, respectively.

Operon fusions for the Escherichia coli heat-labile enterotoxin type IIa (LT-IIa) operon were isolated and characterized. The LT-IIa genes are organized in a transcriptional unit similar to those of cholera toxin (CT) and the closely related E. coli heat-labile toxin type I (LT-I, with subtypes LTh-I and LTp-I). The nucleotide sequence of the LT-IIa genes was determined and compared with the sequences of LTh-I and CT. The A subunit gene of LT-IIa was found to be 57% homologous with the A subunit gene of LTh-I and 55% homologous with the A gene of CT. Most of the homology derived from the region of the A gene which encodes the A1 fragment. The B gene of LT-IIa was not homologous with the B gene of LTh-I or CT. DNA probes containing various portions of the LT-IIa genes and adjacent sequences were used for hybridization studies with restriction endonuclease fragments of DNA from a collection of LT-II-producing strains. These studies showed that a probe containing much of the A subunit gene hybridized well to DNA from the various strains, but a probe for the B subunit gene did not.

The bacterial pathogen Clostridium difficle synthesizes two high-molecular-weight toxins (A and B), which exhibit toxic effects in vivo and in vitro. Here, we present evidence that the major intracellular targets of these two toxins are the Rho GTPases. Overexpression of RhoA, RhoB, or RhoC GTPases in transfected HeLa cells conferred an increased resistance to toxins A and B, indicating that these toxins cause their cytopathic effects primarily by affecting Rho proteins. In addition, toxin A and B treatment appeared to result in modification of Rho, since Rho isolated from toxin-treated cells had a decreased ability to be ADP-ribosylated by Clostridium botulinum C3 exoenzyme. In contrast, the lethal toxin (LT) of Clostridium sordellii, although structurally and immunologically related to C. difficile toxin B, appeared to induce cytopathic effects independently of the Rho GTPases. Overexpression of RhoA in transfected HeLa cells did not protect them from the effect of LT, and Rho isolated from lysates of LT-treated cells was not resistant to modification by C3. Immunofluorescence studies showed that LT treatment caused a cytopathic effect that was very different from those described for C. difficile toxins A and B, resulting in an increase in cortical F-actin, with a concomitant decrease in the number of stress fibers, and in the formation of numerous microvilli containing the actin-bundling protein fimbrin/plastin.

The isolated, in vitro whole brain of guinea-pig was used to assess some of the main physiological and pharmacological properties of the vestibulo-ocular pathways in this species. Extracellular and intracellular recordings were obtained from the vestibular, abducens and oculomotor nuclei, as well as from the abducens and oculomotor nerves, while inputs from the vestibular afferents, the visual pathways and the spinal cord were activated. The three main types of medial vestibular nucleus neurons (A, B and B+LTS), previously described on slices, were also identified in the isolated brain. They had similar membrane properties in both preparations. Eighty-five per cent of cells recorded in the vestibular nucleus responded with monosynaptic, excitatory postsynaptic potentials (latency 1.05-1.9 ms) to stimulation of the ipsilateral vestibular nerve, and were thus identified as second-order vestibular neurons. In addition, stimulation of the contralateral vestibular afferents revealed in most cases a disynaptic or trisynaptic, commissural inhibition. Second-order vestibular neurons displayed in the isolated brain a high degree of variability of their spontaneous activity, as in alert guinea-pigs. Type A neurons always exhibited a regular firing, while type B and B+LTS cells could have very irregular patterns of spontaneous discharge. Thus, type A and type B neurons might correspond, respectively, to the tonic and phasic vestibular neurons described in vivo. The regularity of spontaneous discharge was positively correlated with the amplitude of spike after hyperpolarization, and there was a trend for irregular neurons to be excited from ipsilateral vestibular afferents at shorter latencies than regular units. Synaptic activation could trigger subthreshold plateau potentials and low-threshold spikes in some of the second-order vestibular neurons. As a second step, the pharmacology of the synaptic transmission between primary vestibular afferents and second-order neurons was assessed using specific antagonists of the glutamatergic receptors. Both the synaptic field potentials and excitatory postsynaptic potentials elicited in the medial vestibular nucleus by single shock stimulation of the ipsilateral vestibular nerve were largely or, sometimes, totally blocked by 6-cyano-7-nitroquinoxaline-2,3-dione, indicating a dominating role of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor-mediated glutamatergic transmission. The remaining component of the responses was completely or partially suppressed by DL-2-amino-5-phosphonovaleric acid in 35% of the cases, suggesting a concomitant, moderate involvement of N-methyl-D-asparate receptors. In addition, a synaptic response resistant to both antagonists, but sensitive to a zero Ca2+/high Mg(2+)-containing solution, was often observed. Finally, recordings from abducens and oculomotor complexes confirmed the existence in the guinea-pig of strong bilateral, disynaptic excitatory and inhibitory inputs from vestibular afferents to motoneurons of extraocular muscles, which contribute to generation of the vestibulo-ocular reflex. The functional integrity of vestibular-related pathways in the isolated brain was additionally checked by stimulation of the spinal cord and optic tract. Stimulation of the spinal cord evoked, in addition to antidromic responses in the vestibular nucleus, short-latency synaptic responses in both the vestibular nucleus and abducens motoneurons, suggesting possible recruitment of spinal afferents. Activation of visual pathways at the level of the optic chiasm often induced long latency responses in the various structures under study. These results demonstrate that the in vitro isolated brain can be readily used for detailed, functional studies of the neuronal networks underlying gaze and posture control.

BACKGROUND

The outcome of liver transplantation (LT) in patients infected with human immunodeficiency virus (HIV) has been a matter of controversy.

METHODS

A retrospective cohort study was performed to assess the impact of HIV on LT survival by using United Network for Organ Sharing registry Standard Transplant Analysis and Research files.

RESULTS

A total of 138 HIV(+) and 30,520 HIV(-) patients who were>> or =18 years old and underwent LT during the highly active antiretroviral therapy era (starting January 1, 1997) in the United States were included. Among all HIV(+) patients, the estimated 2-year survival probability was lower (70%) than among non-HIV patients (81%). This excess risk appeared entirely among those with coinfections, that is, HIV with hepatitis B virus or hepatitis C virus (HCV), as none of the 24 HIV-infected patients who did not have hepatitis B virus or HCV died during an average of 1.2 years of follow-up per person. Among HCV(+) patients, those with HIV coinfection had significantly lower survival rates than patients without HIV (P=0.006). Controlling for age, coinfection, Model for End-Stage Liver Disease scores, and other potential confounders in a proportional hazards regression analysis, HIV(+) patients had a hazard ratio of 1.41 (P=0.14, 95% confidence interval: 0.90-2.22) for mortality after LT.

CONCLUSIONS

HIV(+) patients without HCV coinfection seemed to have good prognosis, whereas patients who had HIV/HCV coinfection had poor outcomes, which were significantly worse than that seen in those with HCV alone.

OBJECTIVE

Emerging data continue to link carcinogenesis to inflammatory events involving the eicosanoid metabolic pathways. We therefore evaluated the effects of cyclooxygenase (COX)-2 inhibition on leukotriene (LT) B(4) synthesis in the lungs of active smokers, as part of a pilot lung cancer chemoprevention study with celecoxib (Celebrex), an oral COX-2 inhibitor.

METHODS

Bronchoalveolar lavage was performed before celecoxib treatment and after 1 month of celecoxib treatment to recover alveolar macrophages (AMs) and lining fluid for study. After harvest, AMs were immediately stimulated in vitro with the calcium ionophore A23187. AMs obtained from smokers before treatment and from ex-smoker control subjects were also cultured overnight with SC58236, a selective COX-2 inhibitor, with or without lipopolysaccharide stimulation.

RESULTS

Treatment with oral celecoxib only modestly increased LTB(4) levels in bronchoalveolar lavage, without increasing the mRNA transcription of 5-lipoxygenase (5-LOX) or 5-LOX-activating protein in AMs, whereas the acute calcium ionophore-stimulated LTB(4) production from smokers' AMs was markedly increased by 10.6-fold. In addition, smokers' AMs were twice as responsive in producing LTB(4) when exposed to lipopolysaccharide compared with ex-smokers' AMs. Concomitant COX-2 inhibition with SC58236, however, did not significantly impact these changes, whereas the 5-LOX inhibitor Zileuton blocked the generation of LTB(4) in a dose-responsive manner. Finally, cycloheximide increased the production of LTB(4) under all conditions, suggesting a shunting phenomenon and/or the presence of pathway inhibitors.

CONCLUSIONS

Our findings suggest that whereas oral celecoxib is capable of modulating LTB(4) production in the lung microenvironment, under physiologic conditions, this effect is probably not functionally significant.

We report the detection in vivo of precursors to the A and the B subunits of the heat-labile enterotoxin (LT) in Escherichia coli. Both pre-LT A (Mr = 29,500) and pre-LT B (Mr = 13,500) are present in the spheroplast fraction of the bacteria after separation of the cells in spheroplasts and periplasm. Two smaller LT A related polypeptides (17 and 23 kDa) were also detected in the spheroplast fraction. Both were degraded with a half-time of about 40 s. Mature subunits (Mr = 27,500 for LT A, and 11,500 for LT B) are released from the spheroplasts soon after processing and occur freely in the periplasm not associated with the cytoplasmic or the outer membranes. Processing occurs mainly post-translationally for both the A and the B subunits. However, they show different kinetics of processing and subsequent segregation into the periplasm. Whereas pre-LT B is processed and released within seconds after chain termination, pre-LT A is processed and released more slowly, and a subfraction of mature LT A may reside in the cytoplasmic membrane for several minutes.