Including refugees in disease elimination: challenges observed from a sleeping sickness programme in Uganda.

BACKGROUND: Ensuring equity between forcibly-displaced and host area populations is a key challenge for global elimination programmes. We studied Uganda's response to the recent refugee influx from South Sudan to identify key governance and operational lessons for national sleeping sickness programmes working with displaced populations today. A refugee policy which favours integration of primary healthcare services for refugee and host populations and the availability of rapid diagnostic tests (RDTs) to detect sleeping sickness at this health system level makes Uganda well-placed to include refugees in sleeping sickness surveillance. METHODS: Using ethnographic observations of coordination meetings, review of programme data, interviews with sleeping sickness and refugee authorities and group discussions with health staff and refugees (2013-2016), we nevertheless identified some key challenges to equitably integrating refugees into government sleeping sickness surveillance. RESULTS: Despite fears that refugees were at risk of disease and posed a threat to elimination, six months into the response, programme coordinators progressed to a sentinel surveillance strategy in districts hosting the highest concentrations of refugees. This meant that RDTs, the programme's primary surveillance tool, were removed from most refugee-serving facilities, exacerbating existing inequitable access to surveillance and leading refugees to claim that their access to sleeping sickness tests had been better in South Sudan. This was not intentionally done to exclude refugees from care, rather, four key governance challenges made it difficult for the programme to recognise and correct inequities affecting refugees: (a) perceived donor pressure to reduce the sleeping sickness programme's scope without clear international elimination guidance on surveillance quality; (b) a problematic history of programme relations with refugee-hosting districts which strained supervision of surveillance quality; (c) difficulties that government health workers faced to produce good quality surveillance in a crisis; and (d) reluctant engagement between the sleeping sickness programme and humanitarian structures. CONCLUSIONS: Despite progressive policy intentions, several entrenched governance norms and practices worked against integration of refugees into the national sleeping sickness surveillance system. Elimination programmes which marginalise forced migrants risk unwittingly contributing to disease spread and reinforce social inequities, so new norms urgently need to be established at local, national and international levels

Pathophysiology of hypoperfusion of the precuneus in early Alzheimer’s disease

The earliest decline in cerebral perfusion in Alzheimer's disease (AD) is in the medial parietal cortex (precuneus). We have analyzed precuneus in post‐mortem tissue from 70 AD and 37 control brains to explore the pathophysiology of the hypoperfusion: the contribution of arteriolosclerotic small vessel disease (SVD) and cerebral amyloid angiopathy (CAA), and of the vasoconstrictors endothelin‐1 (EDN1) and angiotensin II (Ang II), and the association with Aβ. The myelin‐associated glycoprotein:proteolipid protein‐1 ratio (MAG:PLP1) was used as an indicator of oxygenation of the precuneus prior to death. MAG:PLP1 was reduced ∼50% in early AD (Braak stage III–IV). Although MAG:PLP1 remained low in advanced AD (stage V–VI), the reduction was less pronounced, possibly reflecting falling oxygen demand. Reduction in cortical MAG:PLP1 correlated with elevation in vascular endothelial growth factor (VEGF), another marker of hypoperfusion. Cortical MAG:PLP1 declined nonsignificantly with increasing SVD and CAA, but significantly with the concentration of EDN1, which was elevated approximately 75% in AD. In contrast, with reduction in cortical MAG:PLP1, Ang II level and angiotensin‐converting enzyme (ACE) activity declined, showing a normal physiological response to hypoperfusion. MAG:PLP1 was reduced in the parietal white matter (WM) in AD but here the decline correlated positively (ie, physiologically) with WM EDN1. However, the decline of MAG:PLP1 in the WM was associated with increasing cortical EDN1 and perhaps reflected vasoconstriction of perforating arterioles, which traverse the cortex to perfuse the WM. EDN1 in the cortex correlated highly significantly with both soluble and insoluble Aβ42, shown previously to upregulate neuronal endothelin‐converting enzyme‐2 (ECE2), but not with Aβ40. Our findings demonstrate reduced oxygenation of the precuneus in early AD and suggest that elevated EDN1, resulting from Aβ42‐mediated upregulation of ECE2, is a contributor

Sensing Sleeping Sickness: Local Symptom-Making in South Sudan.

Programs for neglected tropical diseases (NTDs) such as sleeping sickness increasingly involve patients and community workers in syndromic case detection with little exploration of patient understandings of symptoms. Drawing on concepts from sensorial anthropology, I investigate peoples' experiences of sleeping sickness in South Sudan. People here sense the disease through discourses about four symptoms (pain, sleepiness, confusion and hunger) using biomedical and ethnophysiological concepts and sensations of risk in the post-conflict environment. When identified together, the symptoms interlock as a complete disease, prompting people to seek hospital-based care. Such local forms of sense-making enable diagnosis and help control programs function

Understanding the role of the diagnostic ‘reflex’ in the elimination of human African trypanosomiasis

To successfully eliminate human African trypanosomiasis (HAT), healthcare workers (HCWs) must maintain their diagnostic acuity to identify cases as the disease becomes rarer. HAT experts refer to this concept as a 'reflex' which incorporates the idea that diagnostic expertise, particularly skills involved in recognising which patients should be tested, comes from embodied knowledge, accrued through practice. We investigated diagnostic pathways in the detection of 32 symptomatic HAT patients in South Sudan and found that this 'reflex' was not confined to HCWs. Indeed, lay people suggested patients test for HAT in more than half of cases using similar practices to HCWs, highlighting the importance of the expertise present in disease-affected communities. Three typologies of diagnostic practice characterised patients' detection: 'syndromic suspicion', which closely resembled the idea of an expert diagnostic reflex, as well as 'pragmatic testing' and 'serendipitous detection', which depended on diagnostic expertise embedded in hospital and lay social structures when HAT-specific suspicion was ambivalent or even absent. As we approach elimination, health systems should embrace both expert and non-expert forms of diagnostic practice that can lead to detection. Supporting multidimensional access to HAT tests will be vital for HCWs and lay people to practice diagnosis and develop their expertise

Enhanced Oceanic Operations Human-In-The-Loop In-Trail Procedure Validation Simulation Study

The Enhanced Oceanic Operations Human-In-The-Loop In-Trail Procedure (ITP) Validation Simulation Study investigated the viability of an ITP designed to enable oceanic flight level changes that would not otherwise be possible. Twelve commercial airline pilots with current oceanic experience flew a series of simulated scenarios involving either standard or ITP flight level change maneuvers and provided subjective workload ratings, assessments of ITP validity and acceptability, and objective performance measures associated with the appropriate selection, request, and execution of ITP flight level change maneuvers. In the majority of scenarios, subject pilots correctly assessed the traffic situation, selected an appropriate response (i.e., either a standard flight level change request, an ITP request, or no request), and executed their selected flight level change procedure, if any, without error. Workload ratings for ITP maneuvers were acceptable and not substantially higher than for standard flight level change maneuvers, and, for the majority of scenarios and subject pilots, subjective acceptability ratings and comments for ITP were generally high and positive. Qualitatively, the ITP was found to be valid and acceptable. However, the error rates for ITP maneuvers were higher than for standard flight level changes, and these errors may have design implications for both the ITP and the study's prototype traffic display. These errors and their implications are discussed

Characteristics and survival of patients with advanced cancer and p53 mutations.

P53 mutations are associated with invasive tumors in mouse models. We assessed the p53mutations and survival in patients with advanced cancer treated in the Phase I Program. Of 691 tested patients, 273 (39.5%) had p53 mutations. Patients with p53 mutations were older (p<.0001) and had higher numbers of liver metastases (p=.005). P53 mutations were associated with higher numbers of other aberrations; PTEN (p=.0005) and HER2 (p=.003)aberrations were more common in the p53 mutation group. No survival difference was observed between patients with p53 mutations and those with wild-type p53. In patients with wild-type p53 and other aberrations, patients treated with matched-therapy against the additional aberrations had longer survival compared to those treated with non-matched-therapy or those who received no therapy (median survival, 26.0 vs. 11.8 vs. 9.8 months, respectively; p= .0007). Results were confirmed in a multivariate analysis (p= .0002). In the p53 mutation group with additional aberrations, those who received matched-therapy against the additional aberrations had survival similar to those treated with non-matched-therapy or those who received no therapy (p=.15). In conclusion, our results demonstrated resistance to matched-targeted therapy to the other aberrations in patients with p53 mutations and emphasize the need to overcome this resistance

Outcomes of patients with advanced cancer and KRAS mutations in phase I clinical trials.

BackgroundKRAS mutation is common in human cancer. We assessed the clinical factors, including type of KRAS mutation and treatment, of patients with advanced cancer and tumor KRAS mutations and their association with treatment outcomes.MethodsPatients referred to the Phase I Clinic for treatment who underwent testing for KRAS mutations were analyzed.ResultsOf 1,781 patients, 365 (21%) had a KRAS mutation. The G12D mutation was the most common mutation (29%). PIK3CA mutations were found in 24% and 10% of patients with and without KRAS mutations (p<0.0001). Of 223 patients with a KRAS mutation who were evaluable for response, 56 were treated with a MEK inhibitor-containing therapy and 167 with other therapies. The clinical benefit (partial response and stable disease lasting ≥6 months) rates were 23% and 9%, respectively, for the MEK inhibitor versus other therapies (p=0.005). The median progression-free survival (PFS) was 3.3 and 2.2 months, respectively (p=0.09). The respective median overall survival was 8.4 and 7.0 months (p=0.38). Of 66 patients with a KRAS mutation and additional alterations, higher rates of clinical benefit (p=0.04), PFS (p=0.045), and overall survival (p=0.02) were noted in patients treated with MEK inhibitor-containing therapy (n=9) compared to those treated with targeted therapy matched to the additional alterations (n=24) or other therapy (n=33).ConclusionsMEK inhibitors in patients with KRAS-mutated advanced cancer were associated with higher clinical benefit rates compared to other therapies. Therapeutic strategies that include MEK inhibitors or novel agents combined with other targeted therapies or chemotherapy need further investigation

Functional Allocation with Airborne Self-Separation Evaluated in a Piloted Simulation

A human-in-the-loop simulation experiment was designed and conducted to evaluate an airborne self-separation concept. The activity supports the National Aeronautics and Space Administration s (NASA) research focus on function allocation for separation assurance. The objectives of the experiment were twofold: (1) use experiment design features in common with a companion study of ground-based automated separation assurance to promote comparability, and (2) assess agility of self-separation operations in managing trajectory-changing events in high traffic density, en-route operations with arrival time constraints. This paper describes the experiment and presents initial results associated with subjective workload ratings and group discussion feedback obtained from the experiment s commercial transport pilot participants