Clonal origin of KMT2A wild-type lineage-switch leukemia following CAR-T cell and blinatumomab therapy

Children with acute lymphoblastic leukemia (ALL) undergoing anti-CD19 therapy occasionally develop acute myeloid leukemia (AML). The clonal origin of such lineage-switch leukemias 1–4 remains unresolved. Here, we reconstructed the phylogeny of multiple leukemias in a girl who, following multiply relapsed ALL, received anti-CD19 cellular and antibody treatment and subsequently developed AML. Whole genome sequencing unambiguously revealed the AML derived from the initial ALL, with distinct driver mutations that were detectable before emergence. Extensive prior diversification and subsequent clonal selection underpins this fatal lineage switch. Genomic monitoring of primary leukemias and recurrences may predict therapy resistance, especially regarding anti-CD19 treatment

Cross-subsidies are a viable option to fund formal pit latrine emptying services: Evidence from Kigali, Rwanda

Pit latrines are the most common household sanitation system in East African cities. Urbanisation reduces the space available for new latrines to be constructed when pits fill and they increasingly require emptying. But formal services that empty and transport sludge to safe disposal or treatment are often unaffordable to low-income households. Cross-subsidies have been suggested to fund services for low-income households but there are no academic studies assessing this funding mechanism. This study analyses empirical financial and operational data shared by a formal service provider in Kigali, Rwanda who is establishing a cross-subsidy model between corporate and high-income households, and low-income households in informal settlements. A semi-mechanical method is used to serve households which cannot be accessed from the road by an exhauster truck. We find that mechanical emptying is gross profitable when exhauster trucks are fully used, particularly large volume and corporate customers. Transferring sludge between vehicles for efficient transport reduces average cost. Cross-subsidies are found to be a viable funding method and a ten-fold increase in mechanical emptying by the service provider would generate 466,876 Int$ (2022 international dollars) gross profit to fund a cross-subsidy for all low-income households in Kigali which require semi-mechanical emptying. This study highlights the opportunities that city authorities have to organise funding to cross-subsidise emptying for low-income households. In addition, by using data from operational records rather than self-reported estimates the reliability of cost estimates is in improved. Further research is required to understand customer group size, demand and emptying frequencies to determine the structure of a citywide cross-subsidy

Assessing the impact of drinking water and sanitation on diarrhoeal disease in low- and middle-income settings: Systematic review and meta-regression

Objective: To assess the impact of inadequate water and sanitation on diarrhoeal disease in low- and middle-income settings. Methods: The search strategy used Cochrane Library, MEDLINE & PubMed, Global Health, Embase and BIOSIS supplemented by screening of reference lists from previously published systematic reviews, to identify studies reporting on interventions examining the effect of drinking water and sanitation improvements in low- and middle-income settings published between 1970 and May 2013. Studies including randomised controlled trials, quasi-randomised trials with control group, observational studies using matching techniques and observational studies with a control group where the intervention was well defined were eligible. Risk of bias was assessed using a modified Ottawa-Newcastle scale. Study results were combined using meta-analysis and meta-regression to derive overall and intervention-specific risk estimates. Results: Of 6819 records identified for drinking water, 61 studies met the inclusion criteria, and of 12 515 records identified for sanitation, 11 studies were included. Overall, improvements in drinking water and sanitation were associated with decreased risks of diarrhoea. Specific improvements, such as the use of water filters, provision of high-quality piped water and sewer connections, were associated with greater reductions in diarrhoea compared with other interventions. Conclusions: The results show that inadequate water and sanitation are associated with considerable risks of diarrhoeal disease and that there are notable differences in illness reduction according to the type of improved water and sanitation implemented

Standardized next-generation sequencing of immunoglobulin and T-cell receptor gene recombinations for MRD marker identification in acute lymphoblastic leukaemia; a EuroClonality-NGS validation study

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Kisspeptin-neuron control of LH pulsatility and ovulation

Feedback from oestradiol (E2) plays a critical role in the regulation of major events in the physiological menstrual cycle including the release of gonadotrophins to stimulate follicular growth, and the mid-cycle luteinising hormone (LH) surge that leads to ovulation. E2 predominantly exerts its action via oestrogen receptor-alpha (ERα), however, as gonadotrophin releasing hormone (GnRH) neurons lack ERα, E2-feedback is posited to be indirectly mediated via upstream neurons. Kisspeptin (KP) is a neuropeptide expressed in hypothalamic KP-neurons that control GnRH secretion and plays a key role in the central mechanism regulating the hypothalamic-pituitary-gonadal (HPG) axis. In the rodent arcuate (ARC) nucleus, KP is co-expressed with Neurokinin B and Dynorphin; and thus, these neurons are termed ‘Kisspeptin-Neurokinin B-Dynorphin’ (KNDy) neurons. ARC KP-neurons function as the ‘GnRH pulse generator’ to regulate GnRH pulsatility, as well as mediating negative feedback from E2. A second KP neuronal population is present in the rostral periventricular area of the third ventricle (RP3V), which includes anteroventral periventricular (AVPV) nucleus and preoptic area neurons. These RP3V KP-neurons mediate positive feedback to induce the mid-cycle luteinising hormone (LH) surge and subsequent ovulation. Here, we describe the role of KP-neurons in these two regions in mediating this differential feedback from oestrogens. We conclude by considering reproductive diseases for which exploitation of these mechanisms could yield future therapies

Household water use and greywater management in Khulna city, Bangladesh

While substantial progress has been made in improving water and sanitation services in low- and middle-income countries, aligned basic services such as greywater, stormwater, and solid waste management have progressed little in recent decades. Data was collected in Khulna city, Bangladesh via a household survey (n = 192) of low-income areas exploring domestic water use and greywater volumes, characteristics, and disposal practices. Most households (71%) use a piped water supply for domestic purposes, supplemented by seasonal rainwater harvesting (26%) and greywater use (13%). Of the total water used by households (mean: 594 L/household/day and equivalent to 116 L/person/day), approximately 58% becomes greywater through bathing, dishwashing, religious practices, handwashing, laundry, and mopping. Greywater produced ranges from 61-1274 L/household/day, with a mean of 345 L/household/day and equivalent to 78.4 L/person/day. Greywater characteristics vary depending on the activity, individual behaviours and any products used during cooking, bathing, or cleaning. After generation, households dispose greywater to open drains (67%), nearby waterbodies (17%) directly to the ground (9%), or decentralised wastewater treatment system (7%). Without services for greywater management, greywater disposal may have considerable public and environmental health implications, necessitating careful attention and oversight from service-providers and stakeholders beyond the household-level

Use of PDV to measure the overdriven products equation of state in PBX 9502 and PBX 9501 and the EOS in shocked foams

Author Institution: Los Alamos National LaboratorySlides presented at the 2014 Photonic Doppler Velocimetry (PDV) Workshop Hosted by National Security Technologies, LLC, and the University of Nevada Las Vegas, June 24-26, 2014, Las Vegas, Nevada

Economic motives to attend university: a cross-country study

This paper considers students’ economic motives to attend university. Drawing on selected results from a tri-national survey involving online questionnaires and interviews with students at English, German and Portuguese universities, it examines and compares this particular extrinsic motivational dimension, alongside the influence of the national economic contexts within which the students are located. The findings suggest a strong consensus across all three settings in relation to high levels of motivation driven by the students’ economic goals – careers, qualifications and future income – irrespective of background variables and fee structures. An exploration of the impact of the broader economic climate, however, reveals a more fragmented picture. The differences revealed between national settings offer tentative evidence that the students’ perceptions of their country’s economic situation does have a differential impact on their decision to take up university studies

Impact Evaluation of Training Natural Leaders during a Community-Led Total Sanitation Intervention: A Cluster-Randomized Field Trial in Ghana

We used a cluster-randomized field trial to evaluate training natural leaders (NLs) as an addition to a community-led total sanitation (CLTS) intervention in Ghana. NLs are motivated community members who influence their peers’ behaviors during CLTS. The outcomes were latrine use and quality, which were assessed from surveys and direct observation. From October 2012, Plan International Ghana (Plan) implemented CLTS in 60 villages in three regions in Ghana. After 5 months, Plan trained eight NLs from a randomly selected half of the villages, then continued implementing CLTS in all villages for 12 more months. The NL training led to increased time spent on CLTS by community members, increased latrine construction, and a 19.9 percentage point reduction in open defecation (p < 0.001). The training had the largest impact in small, remote villages with low exposure to prior water and sanitation projects, and may be most effective in socially cohesive villages. For both interventions, latrines built during CLTS were less likely to be constructed of durable materials than pre-existing latrines, but were equally clean, and more often had handwashing materials. CLTS with NL training contributes to three parts of Goal 6 of the Sustainable Development Goals: eliminating open defecation, expanding capacity-building, and strengthening community participation