Recombinant fusion protein identified by lepromatous sera mimics native Mycobacterium leprae in T-cell responses across the leprosy spectrum

Pooled polyvalent sera from lepromatous leprosy patients were used to screen a lambda gt11 recombinant DNA expression library of Mycobacterium leprae in order to identify the relevant antigens recognized by the human immune response. Of the 300,000 phages screened, 4 clones were identified that coded for fusion proteins of the same molecular mass. The fusion protein from clone LSR2 was tested for immunoreactivity in assays using peripheral blood cells and sera from 11 laboratory personnel and 105 patients across the leprosy spectrum. LSR2 protein appears to be predominantly a T-cell antigen. It evokes similar lymphoproliferative responses as the native bacillus both at the individual level and in the leprosy spectrum as a whole. Though only 50% of patient sera with anti-M. leprae antibodies reacted with the fusion protein, the pattern of reactivity in the antibody responses was also similar for the various clinical types. The coding regions of clones LSR1 and LSR2 are identical. They show no homology with sequences stored in data banks and encode a protein of 89 amino acids with a calculated molecular mass of approximately 10 kDa

A service evaluation of FIT and anaemia for risk stratification in the two week wait pathway for colorectal cancer

Introduction: New national guidance on urgent referral for investigation for Colorectal Cancer (CRC) included faecal occult blood testing in 2015. We evaluated faecal immunochemical testing (FIT) and anaemia as risk stratification tools in symptomatic patients suspected of having CRC.Methods: Postal FIT was incorporated into the CRC two week wait (2WW) pathway for all patients without rectal bleeding in 2016. Patients were investigated in the 2WW pathway as normal and outcomes of investigations were prospectively recorded. Anaemia was defined as haemoglobin less than 120g/L in women and less than 130g/L in men.Results: FIT kits were sent to 1106 patients with an 80.9% return rate; 810 patients completed investigation with 40 CRCs diagnosed (4.9%). Median FIT results were significantly higher in patients who were anaemic (median 4.8 iqr 0.8-34.1 versus 1.2 iqr 0-6.4, Mann-Whitney p less than 0.001).Some 538 (60.4%) had a result of less than 4 µgHb/gFaeces (limit of detectability) and 621 (69.7%) a result less than 10 µgHb/gFaeces. Sixty per cent of CRCs had a FIT reading of >150 µgHb/gFaeces. Five CRCs diagnosed in patients with a FIT4 µgHb/gFaeces had 97.5% sensitivity and 64.5% specificity for CRC diagnosis. A FIT result of >4 µgHb/gFaeces and/or anaemia had a 100% sensitivity and 45.3% specificity for CRC diagnosis.Conclusion: FIT is most useful at the extremes of detectability; strongly positive readings predict high rates of CRC and other significant pathology, whilst very low readings in the absence of anaemia or palpable rectal mass identify a group with very low risk. High return rates for FIT within this 2WW pathway indicate its acceptability

"In the interests of justice?" The International Criminal Court, peace talks and the failed quest for war crimes accountability in northern Uganda

This article analyzes the first peace talks to take place against the backdrop of an International Criminal Court (ICC) investigation: the Juba Talks between the Lord’s Resistance Army and the Government of Uganda (2006–2008). Drawing on field research and original source material, it departs from well-worn peace versus justice debates and provides new empirical material to explore how the presence of the court shaped domestic political dynamics at Juba. It argues that at the level of broad rhetoric, the presence of the court created significant discord between negotiating parties. On a practical level, however, it created space for consensus, but not the type envisaged by international justice promoters. The court came to be seen by both sides as an intervention that needed to be contained and controlled. This resulted in the politically expedient Agreement on Accountability and Reconciliation, which showcased a transitional justice “tool-kit,” but was based on a shared desire to evade the jurisdiction of international criminal justice. Given its practical complexity, the transitional justice agreement was ultimately rejected by Joseph Kony, who became increasingly distrustful of his own negotiating team at Juba. In findings relevant to other contexts, the article presents in-depth analyses of how domestic political dynamics around the ICC intervention produced a national transitional justice framework designed to protect both parties from war crimes accountability

Novel Anemia Therapies in CKD: Conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference

Anemia is common in patients with chronic kidney disease (CKD) and is associated with a high burden of morbidity and adverse clinical outcomes. In 2012, Kidney Disease: Improving Global Outcomes (KDIGO) published a guideline for the diagnosis and management of anemia in CKD. Since then, new data from studies assessing established and emerging therapies for the treatment of anemia and iron deficiency have become available. Beginning in 2019, KDIGO planned two Controversies Conferences to review the new evidence and its potential impact on the management of anemia in clinical practice. Here we report on the second of these conferences held virtually in December 2021 which focused on a new class of agents, the hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHIs). This report provides a review of the consensus points and controversies from this second conference and highlights areas that warrant prioritization for future research

Risk of cardiovascular events and death associated with initiation of SGLT2 inhibitors compared with DPP-4 inhibitors:an analysis from the CVD-REAL 2 multinational cohort study

Background Cardiovascular outcome trials have shown cardiovascular benefit with sodium-glucose co-transporter-2 (SGLT2) inhibitors in patients with type 2 diabetes, whereas dipeptidyl peptidase-4 (DPP-4) inhibitors have not shown an effect. We aimed to address knowledge gaps regarding the comparative effectiveness of SGLT2 inhibitor use in clinical practice (with DPP-4 inhibitor use as an active comparator) across a range of cardiovascular risks and in diverse geographical settings. Methods In this comparative cohort study, we used data from clinical practice from 13 countries in the Asia-Pacific, Middle East, European, and North American regions to assess the risk of cardiovascular events and death in adult patients with type 2 diabetes newly initiated on SGLT2 inhibitors compared with those newly initiated on DPP-4 inhibitors. De-identified health records were used to select patients who were initiated on these drug classes between Dec 1, 2012, and May 1, 2016, with follow-up until Dec 31, 2014, to Nov 30, 2017 (full range; dates varied by country). Non-parsimonious propensity scores for SGLT2 inhibitor initiation were developed for each country and patients who were initiated on an SGLT2 inhibitor were matched with those who were initiated on a DPP-4 inhibitor in a 1:1 ratio. Outcomes assessed were hospitalisation for heart failure, all-cause death, myocardial infarction, and stroke. Hazard ratios (HRs) were estimated by country and then pooled in a weighted meta-analysis. Findings Following propensity score matching, 193 124 new users of SGLT2 inhibitors and 193 124 new users of DPP-4 inhibitors were included in the study population. Participants had a mean age of 58 years (SD 12.2), 170 335 (44.1%) of 386 248 were women, and 111933 (30.1%) of 372 262 had established cardiovascular disease. Initiation of an SGLT2 inhibitor versus a DPP-4 inhibitor was associated with substantially lower risks of hospitalisation for heart failure (HR 0.69, 95% CI 0. 61-0. 77; p Interpretation In this large, international, observational study, initiation of SGLT2 inhibitors versus DPP-4 inhibitors was associated with lower risks of heart failure, death, myocardial infarction, and stroke, providing further support for the cardiovascular benefits associated with use of SGLT2 inhibitors in patients with type 2 diabetes. Copyright (C) 2020 Elsevier Ltd. All rights reserved

The Acute Phase Protein Ceruloplasmin as a Non-Invasive Marker of Pseudopregnancy, Pregnancy, and Pregnancy Loss in the Giant Panda

After ovulation, non-pregnant female giant pandas experience pseudopregnancy. During pseudopregnancy, non-pregnant females exhibit physiological and behavioral changes similar to pregnancy. Monitoring hormonal patterns that are usually different in pregnant mammals are not effective at determining pregnancy status in many animals that undergo pseudopregnancy, including the giant panda. Therefore, a physiological test to distinguish between pregnancy and pseudopregnancy in pandas has eluded scientists for decades. We examined other potential markers of pregnancy and found that activity of the acute phase protein ceruloplasmin increases in urine of giant pandas in response to pregnancy. Results indicate that in term pregnancies, levels of active urinary ceruloplasmin were elevated the first week of pregnancy and remain elevated until 20–24 days prior to parturition, while no increase was observed during the luteal phase in known pseudopregnancies. Active ceruloplasmin also increased during ultrasound-confirmed lost pregnancies; however, the pattern was different compared to term pregnancies, particularly during the late luteal phase. In four out of the five additional reproductive cycles included in the current study where females were bred but no birth occurred, active ceruloplasmin in urine increased during the luteal phase. Similar to the known lost pregnancies, the temporal pattern of change in urinary ceruloplasmin during the luteal phase deviated from the term pregnancies suggesting that these cycles may have also been lost pregnancies. Among giant pandas in captivity, it has been presumed that there is a high rate of pregnancy loss and our results are the first to provide evidence supporting this notion