Genomic profiling of post-transplant lymphoproliferative disorders using cell-free DNA

Diagnosing post-transplant lymphoproliferative disorder (PTLD) is challenging and often requires invasive procedures. Analyses of cell-free DNA (cfDNA) isolated from plasma is minimally invasive and highly effective for genomic profiling of tumors. We studied the feasibility of using cfDNA to profile PTLD and explore its potential to serve as a screening tool. We included seventeen patients with monomorphic PTLD after solid organ transplantation in this multi-center observational cohort study. We used low-coverage whole genome sequencing (lcWGS) to detect copy number variations (CNVs) and targeted next-generation sequencing (NGS) to identify Epstein-Barr virus (EBV) DNA load and somatic single nucleotide variants (SNVs) in cfDNA from plasma. Seven out of seventeen (41%) patients had EBV-positive tumors, and 13/17 (76%) had stage IV disease. Nine out of seventeen (56%) patients showed CNVs in cfDNA, with more CNVs in EBV-negative cases. Recurrent gains were detected for 3q, 11q, and 18q. Recurrent losses were observed at 6q. The fraction of EBV reads in cfDNA from EBV-positive patients was 3-log higher compared to controls and EBV-negative patients. 289 SNVs were identified, with a median of 19 per sample. SNV burden correlated significantly with lactate dehydrogenase levels. Similar SNV burdens were observed in EBV-negative and EBV-positive PTLD. The most commonly mutated genes were TP53 and KMT2D (41%), followed by SPEN, TET2 (35%), and ARID1A, IGLL5, and PIM1 (29%), indicating DNA damage response, epigenetic regulation, and B-cell signaling/NFkB pathways as drivers of PTLD. Overall, CNVs were more prevalent in EBV-negative lymphoma, while no difference was observed in the number of SNVs. Our data indicated the potential of analyzing cfDNA as a tool for PTLD screening and response monitoring.</p

Dust Devil Sediment Transport: From Lab to Field to Global Impact

The impact of dust aerosols on the climate and environment of Earth and Mars is complex and forms a major area of research. A difficulty arises in estimating the contribution of small-scale dust devils to the total dust aerosol. This difficulty is due to uncertainties in the amount of dust lifted by individual dust devils, the frequency of dust devil occurrence, and the lack of statistical generality of individual experiments and observations. In this paper, we review results of observational, laboratory, and modeling studies and provide an overview of dust devil dust transport on various spatio-temporal scales as obtained with the different research approaches. Methods used for the investigation of dust devils on Earth and Mars vary. For example, while the use of imagery for the investigation of dust devil occurrence frequency is common practice for Mars, this is less so the case for Earth. Modeling approaches for Earth and Mars are similar in that they are based on the same underlying theory, but they are applied in different ways. Insights into the benefits and limitations of each approach suggest potential future research focuses, which can further reduce the uncertainty associated with dust devil dust entrainment. The potential impacts of dust devils on the climates of Earth and Mars are discussed on the basis of the presented research results

The global retinoblastoma outcome study : a prospective, cluster-based analysis of 4064 patients from 149 countries

DATA SHARING : The study data will become available online once all analyses are complete.BACKGROUND : Retinoblastoma is the most common intraocular cancer worldwide. There is some evidence to suggest that major differences exist in treatment outcomes for children with retinoblastoma from different regions, but these differences have not been assessed on a global scale. We aimed to report 3-year outcomes for children with retinoblastoma globally and to investigate factors associated with survival. METHODS : We did a prospective cluster-based analysis of treatment-naive patients with retinoblastoma who were diagnosed between Jan 1, 2017, and Dec 31, 2017, then treated and followed up for 3 years. Patients were recruited from 260 specialised treatment centres worldwide. Data were obtained from participating centres on primary and additional treatments, duration of follow-up, metastasis, eye globe salvage, and survival outcome. We analysed time to death and time to enucleation with Cox regression models. FINDINGS : The cohort included 4064 children from 149 countries. The median age at diagnosis was 23·2 months (IQR 11·0–36·5). Extraocular tumour spread (cT4 of the cTNMH classification) at diagnosis was reported in five (0·8%) of 636 children from high-income countries, 55 (5·4%) of 1027 children from upper-middle-income countries, 342 (19·7%) of 1738 children from lower-middle-income countries, and 196 (42·9%) of 457 children from low-income countries. Enucleation surgery was available for all children and intravenous chemotherapy was available for 4014 (98·8%) of 4064 children. The 3-year survival rate was 99·5% (95% CI 98·8–100·0) for children from high-income countries, 91·2% (89·5–93·0) for children from upper-middle-income countries, 80·3% (78·3–82·3) for children from lower-middle-income countries, and 57·3% (52·1-63·0) for children from low-income countries. On analysis, independent factors for worse survival were residence in low-income countries compared to high-income countries (hazard ratio 16·67; 95% CI 4·76–50·00), cT4 advanced tumour compared to cT1 (8·98; 4·44–18·18), and older age at diagnosis in children up to 3 years (1·38 per year; 1·23–1·56). For children aged 3–7 years, the mortality risk decreased slightly (p=0·0104 for the change in slope). INTERPRETATION : This study, estimated to include approximately half of all new retinoblastoma cases worldwide in 2017, shows profound inequity in survival of children depending on the national income level of their country of residence. In high-income countries, death from retinoblastoma is rare, whereas in low-income countries estimated 3-year survival is just over 50%. Although essential treatments are available in nearly all countries, early diagnosis and treatment in low-income countries are key to improving survival outcomes.The Queen Elizabeth Diamond Jubilee Trust and the Wellcome Trust.https://www.thelancet.com/journals/langlo/homeam2023Paediatrics and Child Healt

Childbirth and Birth Care

Pregnancy and birth are physical, biological processes taking place in individual human bodies, but the lived experience of pregnancy and birth is co-constituted by the historical, social, political, and economic context. Birth care is similarly context dependent, despite calls for “evidence-based” medicine. Care is inevitably infused with societal discourses, ideologies, and local logics rather than purely based on neutral and universal science. These social discourses and practices contribute to inequalities and inequities in people’s reproductive possibilities and care experiences. Moreover, birth care is at times experienced as violent, especially by members of marginalized communities. In order to understand and improve lived experiences of childbirth and birth care, we must go beyond the objectifying “medical gaze” and apply social science lenses to broaden and deepen an understanding. To this effect, this chapter will provide an overview of selected anthropological, sociological, and science and technology studies literature on birth and maternity care. It will provide examples of qualitative and ethnographic studies maternity care to illustrate how social science concepts (e.g., reproductive governance, logic of care, and social capital) and social science methodologies like (hospital) ethnography can illuminate childbirth and birth care as both political and situated, social practices, enmeshed with the reproduction of inequities. The chapter will conclude with a discussion of how the social sciences can help improve birth care experiences and address inequities, and identify the field’s strengths, blind spots, and opportunities for growth.<br/

Between orchestrated and organic: Accountability for loss and the moral landscape of childbearing in Malawi

This paper explores loss in childbearing in Malawi (miscarriages, perinatal deaths and maternal mortality) as a lens to understand accountability and health system functioning. In low-income countries, maternal and perinatal mortality reflects poor health system functioning, to be improved in part through accountability. Understanding how accountability plays out on the ground requires examination of the existing, ‘organic’ accountability relationships and mechanisms. Thematic and discourse analysis of interviews and observations illuminates vocabularies of responsibility and practices of accountability concerning loss. Women are especially held accountable for loss, by a range of social actors. They use existing ‘organic’ accountability relationships and mechanisms to manage their own interests, but arguably also to care for pregnant women, even though negative birth experiences may ensue. Instances of disrespectful care appear a by-product of the convergence of organic and orchestrated, policy-driven accountability for numeric outcomes (deaths averted) rather than process (quality of care). Moreover, in the absence of essential physical resources, providers and relatives mobilize the social resources at their disposal to keep women and babies alive. Improving quality of care requires acknowledgment that providers' actions are both systemic and situational, and embedded in local moral landscapes and uneven webs of accountability

Childbirth and Birth Care

Pregnancy and birth are physical, biological processes taking place in individual human bodies, but the lived experience of pregnancy and birth is co-constituted by the historical, social, political, and economic context. Birth care is similarly context dependent, despite calls for “evidence-based” medicine. Care is inevitably infused with societal discourses, ideologies, and local logics rather than purely based on neutral and universal science. These social discourses and practices contribute to inequalities and inequities in people’s reproductive possibilities and care experiences. Moreover, birth care is at times experienced as violent, especially by members of marginalized communities. In order to understand and improve lived experiences of childbirth and birth care, we must go beyond the objectifying “medical gaze” and apply social science lenses to broaden and deepen an understanding. To this effect, this chapter will provide an overview of selected anthropological, sociological, and science and technology studies literature on birth and maternity care. It will provide examples of qualitative and ethnographic studies maternity care to illustrate how social science concepts (e.g., reproductive governance, logic of care, and social capital) and social science methodologies like (hospital) ethnography can illuminate childbirth and birth care as both political and situated, social practices, enmeshed with the reproduction of inequities. The chapter will conclude with a discussion of how the social sciences can help improve birth care experiences and address inequities, and identify the field’s strengths, blind spots, and opportunities for growth