Past as global trade governance prelude: reconfiguring debate about reform of the multilateral trading system

This paper peers backwards into the history of the multilateral trading system and its development over the past half century as a means of considering what may lie beyond the horizon for the future of global trade governance. Its purpose is to underscore the necessity and urgency for root-and-branch reform of the multilateral trading system. It achieves this by comparing and contrasting the global trading system of 50 years ago with its modern-day equivalent and its likely future counterpart half-a-century hence. In so doing, the paper throws into sharp relief not only the inadequacies of global trade governance today but also the damaging consequences of not fundamentally reforming the system in the near future, with a particular emphasis on the past, present and future development of the world’s poorest and most marginalised countries

Consensus statement from the 2014 International Microdialysis Forum.

Microdialysis enables the chemistry of the extracellular interstitial space to be monitored. Use of this technique in patients with acute brain injury has increased our understanding of the pathophysiology of several acute neurological disorders. In 2004, a consensus document on the clinical application of cerebral microdialysis was published. Since then, there have been significant advances in the clinical use of microdialysis in neurocritical care. The objective of this review is to report on the International Microdialysis Forum held in Cambridge, UK, in April 2014 and to produce a revised and updated consensus statement about its clinical use including technique, data interpretation, relationship with outcome, role in guiding therapy in neurocritical care and research applications.We gratefully acknowledge financial support for participants as follows: P.J.H. - National Institute for Health Research (NIHR) Professorship and the NIHR Biomedical Research Centre, Cambridge; I.J. – Medical Research Council (G1002277 ID 98489); A. H. - Medical Research Council, Royal College of Surgeons of England; K.L.H.C. - NIHR Biomedical Research Centre, Cambridge (Neuroscience Theme; Brain Injury and Repair Theme); M.G.B. - Wellcome Trust Dept Health Healthcare Innovation Challenge Fund (HICF-0510-080); L. H. - The Swedish Research Council, VINNOVA and Uppsala Berzelii Technology Centre for Neurodiagnostics; S. M. - Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico; D.K.M. - NIHR Senior Investigator Award to D.K.M., NIHR Cambridge Biomedical Research Centre (Neuroscience Theme), FP7 Program of the European Union; M. O. - Swiss National Science Foundation and the Novartis Foundation for Biomedical Research; J.S. - Fondo de Investigación Sanitaria (Instituto de Salud Carlos III) (PI11/00700) co-financed by the European Regional Development; M.S. – NIHR University College London Hospitals Biomedical Research Centre; N. S. - Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico.This is the final version of the article. It first appeared from Springer via http://dx.doi.org/10.1007/s00134-015-3930-

Community Surveillance of Omicron in Ontario: Wastewater-based Epidemiology Comes of Age

Wastewater-based surveillance of SARS-CoV-2 RNA has been implemented at building, neighbourhood, and city levels throughout the world. Implementation strategies and analysis methods differ, but they all aim to provide rapid and reliable information about community COVID-19 health states. A viable and sustainable SARS-CoV-2 surveillance network must not only provide reliable and timely information about COVID-19 trends, but also provide for scalability as well as accurate detection of known or unknown emerging variants. Emergence of the SARS-CoV-2 variant of concern Omicron in late Fall 2021 presented an excellent opportunity to benchmark individual and aggregated data outputs of the Ontario Wastewater Surveillance Initiative in Canada; this public health-integrated surveillance network monitors wastewaters from over 10 million people across major population centres of the province. We demonstrate that this coordinated approach provides excellent situational awareness, comparing favourably with traditional clinical surveillance measures. Thus, aggregated datasets compiled from multiple wastewater-based surveillance nodes can provide sufficient sensitivity (i.e., early indication of increasing and decreasing incidence of SARS-CoV-2) and specificity (i.e., allele frequency estimation of emerging variants) with which to make informed public health decisions at regional- and state-levels.Ontario Ministry of the Environment, Conservation and Parks|| Genome Canada and Ontario Genomics (OGI-209)||NSERC (ALLRP 555041-20 to C.O.)||Ontario Clean Water Agenc

Multifaceted highly targeted sequential multidrug treatment of early ambulatory high-risk SARS-CoV-2 infection (COVID-19)

The SARS-CoV-2 virus spreading across the world has led to surges of COVID-19 illness, hospitalizations, and death. The complex and multifaceted pathophysiology of life-threatening COVID-19 illness including viral mediated organ damage, cytokine storm, and thrombosis warrants early interventions to address all components of the devastating illness. In countries where therapeutic nihilism is prevalent, patients endure escalating symptoms and without early treatment can succumb to delayed in-hospital care and death. Prompt early initiation of sequenced multidrug therapy (SMDT) is a widely and currently available solution to stem the tide of hospitalizations and death. A multipronged therapeutic approach includes 1) adjuvant nutraceuticals, 2) combination intracellular anti-infective therapy, 3) inhaled/oral corticosteroids, 4) antiplatelet agents/anticoagulants, 5) supportive care including supplemental oxygen, monitoring, and telemedicine. Randomized trials of individual, novel oral therapies have not delivered tools for physicians to combat the pandemic in practice. No single therapeutic option thus far has been entirely effective and therefore a combination is required at this time. An urgent immediate pivot from single drug to SMDT regimens should be employed as a critical strategy to deal with the large numbers of acute COVID-19 patients with the aim of reducing the intensity and duration of symptoms and avoiding hospitalization and death

Consensus statement from the 2014 International Microdialysis Forum

This is the final version of the article. It first appeared from Springer via http://dx.doi.org/10.1007/s00134-015-3930-yMicrodialysis enables the chemistry of the extracellular interstitial space to be measured. Use of this technique in patients with acute brain injury has increased our understanding of the pathophysiology of several acute neurological disorders. In 2004 a consensus document on the clinical application of cerebral microdialysis was published. Since then there have been significant advances in the clinical use of microdialysis in neurocritical care. The objective of this review is to report on the International Microdialysis Forum held in Cambridge, UK, in April 2014 and to produce a revised and updated consensus statement about its clinical use including technique, data interpretation, relationship with outcome, role in guiding therapy in neurocritical care and research applications.We gratefully acknowledge financial support for participants as follows: P.J.H. - National Institute for Health Research (NIHR) Professorship and the NIHR Biomedical Research Centre, Cambridge; I.J. ? Medical Research Council (G1002277 ID 98489); A. H. - Medical Research Council, Royal College of Surgeons of England; K.L.H.C. - NIHR Biomedical Research Centre, Cambridge (Neuroscience Theme; Brain Injury and Repair Theme); M.G.B. - Wellcome Trust Dept Health Healthcare Innovation Challenge Fund (HICF-0510-080); L. H. - The Swedish Research Council, VINNOVA and Uppsala Berzelii Technology Centre for Neurodiagnostics; S. M. - Fondazione IRCCS C? Granda Ospedale Maggiore Policlinico; D.K.M. - NIHR Senior Investigator Award to D.K.M., NIHR Cambridge Biomedical Research Centre (Neuroscience Theme), FP7 Program of the European Union; M. O. - Swiss National Science Foundation and the Novartis Foundation for Biomedical Research; J.S. - Fondo de Investigaci?n Sanitaria (Instituto de Salud Carlos III) (PI11/00700) co-financed by the European Regional Development; M.S. ? NIHR University College London Hospitals Biomedical Research Centre; N. S. - Fondazione IRCCS C? Granda Ospedale Maggiore Policlinico

The IDENTIFY study: the investigation and detection of urological neoplasia in patients referred with suspected urinary tract cancer - a multicentre observational study

Objective To evaluate the contemporary prevalence of urinary tract cancer (bladder cancer, upper tract urothelial cancer [UTUC] and renal cancer) in patients referred to secondary care with haematuria, adjusted for established patient risk markers and geographical variation. Patients and Methods This was an international multicentre prospective observational study. We included patients aged ≥16 years, referred to secondary care with suspected urinary tract cancer. Patients with a known or previous urological malignancy were excluded. We estimated the prevalence of bladder cancer, UTUC, renal cancer and prostate cancer; stratified by age, type of haematuria, sex, and smoking. We used a multivariable mixed-effects logistic regression to adjust cancer prevalence for age, type of haematuria, sex, smoking, hospitals, and countries. Results Of the 11 059 patients assessed for eligibility, 10 896 were included from 110 hospitals across 26 countries. The overall adjusted cancer prevalence (n = 2257) was 28.2% (95% confidence interval [CI] 22.3–34.1), bladder cancer (n = 1951) 24.7% (95% CI 19.1–30.2), UTUC (n = 128) 1.14% (95% CI 0.77–1.52), renal cancer (n = 107) 1.05% (95% CI 0.80–1.29), and prostate cancer (n = 124) 1.75% (95% CI 1.32–2.18). The odds ratios for patient risk markers in the model for all cancers were: age 1.04 (95% CI 1.03–1.05; P < 0.001), visible haematuria 3.47 (95% CI 2.90–4.15; P < 0.001), male sex 1.30 (95% CI 1.14–1.50; P < 0.001), and smoking 2.70 (95% CI 2.30–3.18; P < 0.001). Conclusions A better understanding of cancer prevalence across an international population is required to inform clinical guidelines. We are the first to report urinary tract cancer prevalence across an international population in patients referred to secondary care, adjusted for patient risk markers and geographical variation. Bladder cancer was the most prevalent disease. Visible haematuria was the strongest predictor for urinary tract cancer

Managing hypertension in rural Uganda: Realities and strategies 10 years of experience at a district hospital chronic disease clinic.

The literature on the global burden of noncommunicable diseases (NCDs) contrasts a spiraling epidemic centered in low-income countries with low levels of awareness, risk factor control, infrastructure, personnel and funding. There are few data-based reports of broad and interconnected strategies to address these challenges where they hit hardest. Kisoro district in Southwest Uganda is rural, remote, over-populated and poor, the majority of its population working as subsistence farmers. This paper describes the 10-year experience of a tri-partite collaboration between Kisoro District Hospital, a New York teaching hospital, and a US-based NGO delivering hypertension services to the district. Using data from patient and pharmacy registers and a random sample of charts reviewed manually, we describe both common and often-overlooked barriers to quality care (clinic overcrowding, drug stockouts, provider shortages, visit non-adherence, and uninformative medical records) and strategies adopted to address these barriers (locally-adapted treatment guidelines, patient-clinic-pharmacy cost sharing, appointment systems, workforce development, patient-provider continuity initiatives, and ongoing data monitoring). We find that: 1) although following CVD risk-based treatment guidelines could safely allocate scarce medications to the highest-risk patients first, national guidelines emphasizing treatment at blood pressures over 140/90 mmHg ignore the reality of "stockouts" and conflict with this goal; 2) often-overlooked barriers to quality care such as poor quality medical records, clinic disorganization and local employment practices are surmountable; 3) cost-sharing initiatives partially fill the gap during stockouts of government supplied medications, but still may be insufficient for the poorest patients; 4) frequent prolonged lapses in care may be the norm for most known hypertensives in rural SSA, and 5) ongoing data monitoring can identify local barriers to quality care and provide the impetus to ameliorate them. We anticipate that our 10-year experience adapting to the complex challenges of hypertension management and a granular description of the solutions we devised will be of benefit to others managing chronic disease in similar rural African communities

Pertuzumab Plus Trastuzumab in Patients With Endometrial Cancer With

Purpose: The TAPUR Study is a pragmatic basket trial evaluating antitumor activity of commercially available targeted agents in patients with advanced cancers harboring potentially actionable genomic alterations. Data from a cohort of patients with endometrial cancer (EC) with ERBB2 or ERBB3 (ERBB2/3) amplification, overexpression, or mutation treated with pertuzumab plus trastuzumab (P + T) are reported. Methods: Eligible patients had advanced EC, no standard treatment options, measurable disease (RECIST v1.1), Eastern Cooperative Oncology Group performance status 0-2, adequate organ function, and tumors with ERBB2/3 amplification, overexpression, or mutation. Simon\u27s two-stage design was used with a primary end point of disease control (DC), defined as objective response (OR) or stable disease (SD) of at least 16 weeks (SD16+) duration. Secondary end points include safety, duration of response, duration of SD, progression-free survival (PFS), and overall survival (OS). Results: Twenty-eight patients were enrolled from March 2017 to November 2019; all patients were evaluable for efficacy and toxicity. Seventeen patients had tumors with ERBB2/3 amplification and/or overexpression, eight with both ERBB2 amplification and ERBB2/3 mutations, and three with only ERBB2 mutations. Ten patients had DC (two partial response and eight SD16+); all 10 had ERBB2 amplification, and 6 of the 10 patients with DC had \u3e1 ERBB2/3 alteration. DC and OR rates were 37% (95% CI, 21 to 50) and 7% (95% CI, 1 to 24), respectively; the median PFS and median OS were 16 weeks (95% CI, 10-28) and 61 weeks (95% CI, 24-105), respectively. One patient experienced a grade 3 serious adverse event (muscle weakness) at least possibly related to P + T. Conclusion: P + T has antitumor activity in heavily pretreated patients with EC with ERBB2 amplification and warrants additional study. Trial registration: ClinicalTrials.gov NCT02693535

Abstract CT231: Temsirolimus (T) in patients (pts) with solid tumors with PTEN mutation (mut): results from the Targeted Agent and Profiling Utilization Registry (TAPUR) Study

Abstract Background: TAPUR is a phase II basket study evaluating antitumor activity of commercially available targeted agents in pts with advanced cancers with specific genomic alterations. Results in a cohort of pts with solid tumors with PTEN mut treated with T are reported. Methods: Eligible pts had no standard treatment (tx) options, measurable disease, ECOG performance status (PS) 0-2, and adequate organ function. Genomic testing was performed in CLIA-certified, CAP-accredited site selected labs. After antihistamine pre-tx, 25 mg T was infused over 30-60 minutes once weekly until disease progression. Low accruing histology-specific cohorts with PTEN mut were collapsed into 1 histology-pooled cohort for analysis. Primary end point was disease control (DC), defined as complete or partial response (PR) or stable disease (SD) of at least 16+ weeks (wks) duration (SD16+) per RECIST v1.1. The primary end point was summarized as a proportion and the hypothesized null DC rate of 15% was evaluated by a 1-sided exact binomial test with alpha 0.10. Other end points were progression-free survival (PFS), overall survival (OS), duration of response (DOR), duration of SD and safety. DOR is defined as time from pt’s first documented objective response (OR) until progressive disease (PD). Duration of SD is defined as time from tx start to PD. Results: 34 pts with solid tumors (10 tumor types; 20/34 pts had prostate, soft tissue sarcoma [STS] or lung) with PTEN mut were enrolled. 6 pts were unevaluable for efficacy, 1 was ineligible. Table shows demographics, outcomes and toxicity. 2 pts obtained PR (prostate and STS) and 5 had SD16+ (lung, head and neck, breast, uterine, and site unspecified) for DC rate of 26% (1-sided 90% CI: 15.1%, 100%) and OR rate of 7% (95% CI: 1%, 24%). The null DC rate was rejected. Median PFS was 10 wks and median OS was 32 wks. Conclusions: T met prespecified criteria to declare a signal of activity in pts with solid tumors with PTEN mut. Table: Baseline Characteristics (N=34); Efficacy Outcomes (n=27); Toxicity Outcomes (N=34) Median (Med) age, years (range) 65 (42, 84) Female, % 14 (41) ECOG PS, % 0 13 (38) 1 18 (53) 2 3 (9) Prior systemic regimens, % 1 3 (9) 2 5 (15) ≥3 26 (77) DC rate, % (OR and SD16+) (1-sided 90% CI) 26 (15.1, 100) OR rate, % (95% CI) 7 (1, 24) Med PFS, wks (95% CI) 10 (7, 17) Med OS, wks (95% CI) 32 (13, 42) DOR, wks (n=2) 11 and 55 Med duration SD, wks (n=5) 27 (24, 36) Number of pts1 with tx-related grade 3-4 AE or SAE AE2 12 (35) SAE3 6 (18) 1Pts may have experienced one or more events 2alkaline phosphatase increase, anemia, chronic kidney disease, diarrhea, fatigue, hyperglycemia, hypokalemia, hypophosphatemia, lung infection, oral pain and all SAEs 3acute kidney injury, dyspnea, generalized muscle weakness, hypophosphatemia, lung infection, oral mucositis, pericardial effusion Citation Format: Kristopher Wentzel, Michael Rothe, Pam K. Mangat, Elizabeth Garrett-Mayer, Li Ding, Evan Pisick, Mridula Krishnan, Deepti Behl, Olatunji B. Alese, Carmen J. Calfa, Kathrine A. Cooper, Herbert L. Duvivier, Raghava Reddy Induru, Janet C. Ruzich, Song Zhao, Gina N. Grantham, Abigail Gregory, Susan Halabi, Richard L. Schilsky. Temsirolimus (T) in patients (pts) with solid tumors with PTEN mutation (mut): results from the Targeted Agent and Profiling Utilization Registry (TAPUR) Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT231