Foreword

In preparation for the turn of the century five years ago, the U.N. presented a comprehensive outlook of its mission in the Millennium Report (Report) entitled: We the Peoples: The Role of the U.N. in the 21st Century. The Report Called on Member States to Commit themselves to certain goals of the U.N. Included in the Report\u27s proposals was the view that globalization is a powerful force offering both opportunities and challenges for nations and people, and must be made to work for all people

Foreword

The Journal, in partnership with the Law of the Sea Institute at the University of California, Berkeley, is therefore proud to present a symposium on Multilateralism in International Ocean Resources Law. The authors represented in this symposium delivered papers last year at a conference organized by the Institute at the Boalt Hall School of Law, UC-Berkeley; and those papers have been extensively revised for publication in this issue

Glucose directly promotes antifungal resistance in the fungal pathogen, Candida spp

Effects of glucose on the susceptibility of antifungal agents are investigated against Candida spp. Increasing the concentration of glucose decreased the activity of antifungal agents, voriconazole was mostly affected drugs followed by amphotericin B. No significant change has been observed for anidulafungin. Biophysical interaction between antifungal agents with glucose molecules were investigated using ITC, FTIR and 1HNMR. Glucose have higher affinity to bind with voriconazole by hydrogen bonding and decrease the susceptibility. In addition to confirm the results observed in vitro, theoretical docking studies demonstrated that voriconazole presented three important hydrogen bonds and amphotericin B presented two hydrogen bonds that stabilized the complex compound-glucose. In vivo results also suggest that the physiologically relevant higher glucose level in blood stream of Diabetes Mellitus (DM) mice might interact with the available selective agents during antifungal therapy, decreased the activity by complex formation. Thus, selection of drugs for DM patient is important to control the infectious diseases

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

A 4Kscore Cut-off of 7.5% for Prostate Biopsy Decisions Provides High Sensitivity and Negative Predictive Value for Significant Prostate Cancer

To evaluate the 4Kscore test's low risk cut-off of 7.5% as the indication to proceed with a prostate biopsy by combining data from 2 independent prospective multicentre trials in the United States which have validated the 4Kscore test as a continuous score to predict clinically significant prostate cancer. We analyzed the data from 2 prospective multicenter trials in the United states to determine the number of men who could safely avoid a prostate biopsy and the presence of clinically significant cancers detected, at a 4Kscore cut-off of 7.5%. We evaluated this in the entire cohort, and 3 subgroups of men aged 45-75 years with a total prostate specific antigen between 3.0 and 10.0 ng/mL, African American, and non-African American men. The analysis included 1378 patients. The combination analysis at a 7.5% threshold to decide upon a prostate biopsy, was associated with a 32% biopsy reduction. A total of 21 men (4.8%) with a low risk 4Kscore had International society of Urological Pathology, prostate cancer Grade group (GG) 2 or 3 cancer, leading to a sensitivity of 94% for detecting GG ≥2 cancer, and a negative predictive value of 95%. There were no GG ≥4 cancers with a low risk 4Kscore. Analyses in various subgroups afforded similar results. A 4Kscore test cut-off of 7.5% allowed a significant biopsy reduction, while maintaining high sensitivity and NPV for detecting and ruling out aggressive prostate cancer

Long-term hepatitis B infection in a scalable hepatic co-culture system.

Volume 8, Issue 1, 1 December 2017, Article number 125, pgs. 1-11. Authors: Benjamin Y. Winer, Tiffany S. Huang, Eitan Pludwinski, Brigitte Heller, Felix Wojcik, Gabriel E. Lipkowitz, Amit Parekh, Cheul Cho, Anil Shrirao, Thomas W. Muir (Tom W. Muir), Eric Novik & Alexander Ploss.Hepatitis B virus causes chronic infections in 250 million people worldwide. Chronic hepatitis B virus carriers are at risk of developing fibrosis, cirrhosis, and hepatocellular carcinoma. A prophylactic vaccine exists and currently available antivirals can suppress but rarely cure chronic infections. The study of hepatitis B virus and development of curative antivirals are hampered by a scarcity of models that mimic infection in a physiologically relevant, cellular context. Here, we show that cell-culture and patient-derived hepatitis B virus can establish persistent infection for over 30 days in a self-assembling, primary hepatocyte co-culture system. Importantly, infection can be established without antiviral immune suppression, and susceptibility is not donor dependent. The platform is scalable to microwell formats, and we provide proof-of-concept for its use in testing entry inhibitors and antiviral compounds.The lack of models that mimic hepatitis B virus (HBV) infection in a physiologically relevant context has hampered drug development. Here, Winer et al. establish a self-assembling, primary hepatocyte co-culture system that can be infected with patient-derived HBV without further modifications

Living multiculture: understanding the new spatial and social relations of ethnicity and multiculture in England

Since 2001, as the social and spatial compositions of multiculture and migration have become more complicated and diverse, geography has moved back to the centre of policy, political and academic arguments about cultural difference and ethnic diversity in England. This spatial turn is most obvious in preoccupations with notions of increasing ethnic segregation but it is also apparent in discussions of the possibility of everyday multicultural exchanges in relationally understood places. Responding to the work of others on these questions and in these places, and informed by data from research exploring Ghanaian and Somali migrant settlement in Milton Keynes this paper reviews some of the quantitative and qualitative evidence being drawn on in academic, policy and political debates about contemporary multiculture. The paper problematises the dominance of the concept of segregation in these debates and examines the value of the concept of conviviality for understanding the ‘in-development’ ways in which multiculture is lived

Prostatic Ductal Adenocarcinoma Controlled for Tumor Grade, Stage, and Margin Status Does Not Independently Influence the Likelihood of Biochemical Recurrence in Localized Prostate Cancer After Radical Prostatectomy

Context.— Prostatic ductal adenocarcinoma (PDA) has historically been considered to be an aggressive subtype of prostate cancer. Objective.— To investigate if PDA is independently associated with worse biochemical recurrence (BCR)–free survival after radical prostatectomy. Design.— A review of 1584 radical prostatectomies was performed to grade, stage, and assess margin status in each tumor nodule. Radical prostatectomies with localized PDA (ie, those lacking metastasis) in the tumor nodule with the highest grade and stage and worst margin status were matched with prostatic acinar adenocarcinoma according to grade, stage, and margin status. The effect of PDA on BCR was assessed by multivariable Cox regression and Kaplan-Meier analyses. Results.— Prostatic ductal adenocarcinoma was present in 171 cases. We excluded 24 cases because of lymph node metastasis (n = 13), PDA not in the highest-grade tumor nodule (n = 9), and positive surgical margin in a lower-grade tumor nodule (n = 2). The remaining 147 cases included 26 Grade Group (GG) 2, 44 GG3, 6 GG4, and 71 GG5 cancers. Seventy-six cases had extraprostatic extension, 33 had seminal vesicle invasion, and 65 had positive margins. Follow-up was available for 113 PDA and 109 prostatic acinar adenocarcinoma cases. Prostate-specific antigen density (odds ratio, 3.7; P = .001), cancer grade (odds ratio, 3.3–4.3; P = .02), positive surgical margin (odds ratio, 1.7; P = .02), and tumor volume (odds ratio, 1.3; P = .02) were associated with BCR in multivariable analysis. Prostatic ductal adenocarcinoma, its percentage, intraductal carcinoma, and cribriform Gleason pattern 4 were not significant independent predictors of BCR. Conclusions.— Advanced locoregional stage, higher tumor grade, and positive surgical margin status rather than the mere presence of PDA are more predictive of worse BCR-free survival outcomes following radical prostatectomy in men with a component of PDA