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Models are widely used to research hydrological change and risk. However, the power embedded in the modelling process and outcomes is often concealed by claiming their neutrality. Our review shows that in the scientific literature relatively little attention is given to the influence of models on development processes and outcomes in water governance. At the same time, an emerging body of work offering critical insights into the political implications of hydrological models and a nuanced understanding of their application in context has begun to flourish. Drawing on this work, we call for power-sensitive modelling which includes the following considerations: take a holistic approach to modelling beyond programming and coding; foster accountability; work towards just and equitable water distributions; be transparent about the expectations and choices made; and democratise modelling by giving space to and being mindful of representations of multiple bodies of knowledge and multiple stakeholders and by incorporating marginalised people and nature into the modelling process. Our call should not be understood as a suggestion to do away with modelling altogether, but rather as an invitation to interrogate how quantitative models may help to foster transformative pathways towards more just and equitable water distributions.

Background: Since the beginning of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, patients with chronic kidney disease vulnerable to suffering more severe COVID-19 disease and worse outcomes have been identified. Objectives: Our study’s aim was to determine the incidence, characteristics, and outcomes of SARS-CoV-2 infection in patients of hemodialysis (HD) units in Mexico and to describe the availability of confirmatory testing. Methods: This study was multicentric study of 19 HD units, conducted between March 2020 and March 2021. Results: From a total of 5779 patients, 955 (16.5%) cases of suspicious COVID-19 were detected; a SARS-CoV-2 reverse transcription polymerase chain reaction test was done in only 50.6% of patients. Forty-five percentages were hospitalized and 6% required invasive mechanical ventilation (IMV). There was no significant difference in mortality between confirmed (131/483) and suspicious (124/472) cases (p = 0.74). The percentage of patients in need of hospitalization, IMV, and deceased was greater than in the rest of the study population. Conclusions: The study revealed that 49.4% of the cases were not confirmed, a worrisome observation given that this is a highly vulnerable population (higher probability of contagion and worse outcomes), in which 100% of patients should have a confirmatory test.

Managers of urban water systems constantly make decisions to guarantee water services by overcoming problems related to supply–demand imbalances. A preferred strategy has been supply augmentation through hydraulic infrastructure development. However, despite considerable investments, many systems seem to be trapped in lacklustre development pathways making some problems seem like an enduring, almost stubborn, characteristic of the systems: overexploitation and pollution of water sources, distribution networks overwhelmed by leakages and non-revenue water, and unequal water insecurity. Because of these strategies and persistent problems, water conflicts have emerged, whereby social actors oppose these strategies and propose alternative technologies and strategies. This can create development pathway crossroads of the urban water system, defined as a critical point whereby actors in conflict will either reinforce the current business-as-usual pathway based on large supply augmentation or implement alternative solutions for the urban water system. To study this development pathway crossroads, we selected the Zapotillo conflict in Mexico where a large supply augmentation project for two cities experiencing water shortages is at stake. The paper concludes that urban water systems that are engaged in a trajectory characterized by supply-side strategies may experience a temporal relief but neglect equally pressing issues that stymie the human right to water in the medium and long run. However, there is not a straightforward, self-evident development pathway to choose from, only a range of multiple alternatives with multiple trade-offs that need to be thoroughly discussed and negotiated between the stakeholders. We argue that this development pathway crossroads can cross-fertilize contrasting disciplines such as socio-hydrology and critical studies on water because both can complement technical and socio-political analyses to make their knowledge actionable and relevant.

The development of large infrastructure to address the water challenges of cities around the world can be a financial and social burden for many cities because of the hidden costs these works entail and social conflicts they often trigger. When conflicts erupt, science is often expected to play a key role in informing policymakers and social actors to clarify controversies surrounding policy responses to water scarcity. However, managing conflicts is a sociopolitical process, and often quantitative models are used as an attempt to depoliticize such processes, conveying the idea that optimal solutions can be objectively identified despite the many perspectives and interests at play. This raises the question as to whether science depoliticizes water conflicts or whether instead conflicts politicize science–policy processes. We use the Zapotillo dam and water transfer project in Mexico to analyze the role of science–policy processes in water conflicts. The Zapotillo project aims at augmenting urban water supply to Guadalajara and León, two large cities in western Mexico, but a social and legal conflict has stalled the project until today. To analyze the conflict and how stakeholders make sense of it, we interviewed the most relevant actors and studied the negotiations between different interest groups through participant observation. To examine the role of science–policy processes in the conflict, we mobilized concepts of epistemic uncertainty and ambiguity and analyzed the design and use of water resources models produced by key actors aiming to resolve the conflict. While the use of models is a proven method to construct future scenarios and test different strategies, the parameterization of scenarios and their results are influenced by the knowledge and/or interests of actors behind the model. We found that in the Zapotillo case, scenarios reflected the interests and strategies of actors on one side of the conflict, resulting in increased distrust of the opposing actors. We conclude that the dilemma of achieving urban water security through investing in either large infrastructure (supply augmentation) or alternative strategies (demand-side management) cannot be resolved if some key interested parties have not been involved in the scientific processes framing the problem and solution space.

BackgroundAllogeneic haematopoietic cell transplantation (HCT) is a curative therapy for severe haematological disorders. However, it carries significant risk of morbidity and mortality. To improve patient outcomes, better graft selection strategies are needed, incorporating HLA matching with clinically important graft characteristics. Studies have shown that the cellular content of HCT grafts, specifically higher ratios of T regulatory (Tregs)/T cells, are important factors influencing outcomes when using adult peripheral blood mobilised grafts. So far, no equivalent study exists in umbilical cord blood (CB) transplantation due to the limitations of cryopreserved CB samples.Study design and methodsTo establish the most robust and efficient way to measure the Treg content of previously cryopreserved CB units, we compared the enumeration of Treg and CD3+ cells using flow cytometry and an epigenetic, DNA-based methodology. The two methods were assessed for their agreement, consistency and susceptibility to error when enumerating Treg and CD3+ cell numbers in both fresh and cryopreserved CB samples.ResultsEpigenetic enumeration gave consistent and comparable results in both fresh and frozen CB samples. By contrast, assessment of Tregs and CD3+ cells by flow cytometry was only possible in fresh samples due to significant cell death following cryopreservation and thawing.ConclusionEpigenetic assessment offers significant advantages over flow cytometry for analysing cryopreserved CB; similar cell numbers were observed both in fresh and frozen samples. Furthermore, multiple epigenetic assessments can be performed from DNA extracted from small cryopreserved CB segments; often the only CB sample available for clinical studies.

Mexico is considered a regional economic and political powerhouse because of the size of its economy, and a large population in constant growth. However, this same growth accompanied by management and governance failures are causing several water crises across the country. The paper aims at identifying and analyzing the drivers of water crises. Water authorities seem to focus solely on large infrastructural schemes to counter the looming water crises, but fail to structure a set of policies for the improvement of management and governance institutions. The paper concludes with the implications of a business-as-usual policy based on infrastructure for solving water problems, which include a non-compliance to the human right to water and sanitation, ecosystem collapses and water conflicts.

We previously reported that cord blood plasma (CBP) contains significantly more soluble NKG2D ligands (sNKG2DLs), such as sMICB and sULBP1, than healthy adult plasma. Viral infection or malignant transformation upregulates expression of NKG2D ligand on affected cells, leading to NK group 2, member D (NKG2D)-mediated natural killer (NK) cell lysis. Conversely, sNKG2DL engagement of NKG2D decreases NK cell cytotoxicity leading to viral or tumour immune escape. We hypothesised that sNKG2DLs detected in CBP may represent an additional fetal–maternal tolerance mechanism. To further understand the role of sNKG2DL in pregnancy and individual contributions of the various ligand types, we carried out functional analysis using 181 CBP samples. To test the ability of CBP to suppress the function of NK cells in vitro, we measured expression of NKG2D, CD107a, and IFN-γ in NK cells from control donors after exposure to 181 individual CBP samples and characterised the sMICA, sMICB, and sULBP1 content of each one. Furthermore, to detect possible allelic differences between samples that may also affect function, we carried out umbilical cord blood typing for MHC class I-related chain A (MICA) and MHC class I-related chain B (MICB) coding and promoter allelic types. Strongest functional correlations related to increasing concentration of exosomal sULBP1, which was present in all CBP samples tested. In addition, common MICB alleles, such as MICB*005:02, resulted in increased concentration of sMICB. Interestingly, MICB*005:02 uniquely associated with eight different promoter types. Among promoter polymorphisms, P2 resulted in the highest expression of sMICB and P9 the least and was confirmed using luciferase reporter assays. Higher levels of sMICB associated with lower IFN-γ production, indicating that sMICB also suppressed NK cell function. We also examined the MICA functional dimorphism encoding methionine (met) or valine (val) at residue 129 associated with strong or weak NKG2D binding, respectively. Most sMICA associated with val/val, some with met/val but none with met/met and, counter-intuitively, the presence of sMICA in CBP increased NK cell cytotoxicity. We propose a model for fetal–maternal tolerance, whereby NK cell activity is limited by sULBP1 and sMICB in CBP. The release of 129val sMICA with weak NKG2D signalling may reduce the overall net suppressive signal and break tolerance thus allowing fetal NK cells to overcome immunological threats in utero.

Regulatory T cells (Tregs) are CD4+ T cells that are key players of immune tolerance. They are powerful suppressor cells, able to impact the function of numerous immune cells, including key effectors of inflammation such as effector T cells. For this reason, Tregs are an ideal candidate for the development of cell therapy approaches to modulate immune responses. Treg therapy has shown promising results so far, providing key knowledge on the conditions in which these cells can provide protection and demonstrating that they could be an alternative to current pharmacological immunosuppressive therapies. However, a more comprehensive understanding of their characteristics, isolation, activation, and expansion is needed to be able design cost effective therapies. Here, we review the practicalities of making Tregs a viable cell therapy, in particular, discussing the challenges faced in isolating and manufacturing Tregs and defining what are the most appropriate applications for this new therapy.

Donation of haematopoietic stem cells, either through bone marrow (BM) or peripheral blood stem cell (PBSC) collection, is a generally safe procedure for healthy donors, although side effects are a known risk. Previous research, including our recent quantitative study, has shown that the psychosocial response to donating is usually a positive one and most donors would be willing to donate again in the future. This is often despite experiencing significant side effects during the donation process. Due to the relative recent introduction of PBSC, a comprehensive understanding of the range of physical and emotional issues donors may experience is lacking, as well as an understanding of specific donor characteristics Qualitative research can provide rich narrative data into these areas. This study was set up in order to identify specific donor characteristics and to further explore the relationship between pre-donation physical health and the donation experience, as previously identified in our quantitative study.It involved in-depth telephone interviews with 14 PBSC donors who participated in our original quantitative study. Thematic analysis was used to analyse the findings and the results provide a summary of participants' characteristics using themes and constituent codes.We identified several donor characteristics, including strong intrinsic motivation, altruism, sense of duty, determination, low levels of ambivalence and the ability to develop a strong emotional relationship with an (unknown/anonymous) recipient whilst being able to manage strong feelings and emotions.These personality traits may explain the resilience that has been observed previously in haematopoietic stem cells donors. Significant feelings of grief were reported after a recipient's death. Possibilities to alleviate these symptoms may include raising awareness of potential poor outcomes in the recipient and offering improved counselling services if the recipient dies. We acknowledge several limitations including the sampling frame.

Transforming growth factor β-1, encoded by the TGFB1 gene, is a cytokine that plays a central role in many physiological and pathogenic processes. We have sequenced TGFB1 regulatory region and assigned allelic genotypes in a large cohort of hematopoietic stem cell transplantation patients and donors. In this study, we analyzed 522 unrelated donor-patient pairs and examined the combined effect of all the common polymorphisms in this genomic region. In univariate analysis, we found that patients carrying a specific allele, ‘p001’, showed significantly reduced overall survival (5-year overall survival 30.7% for p001/p001 patients vs. 41.6% others; P=0.032) and increased non-relapse mortality (1-year non-relapse mortality: 39.0% vs. 25.4%; P=0.039) after transplantation. In multivariate analysis, the presence of a p001/p001 genotype in patients was confirmed as an independent factor for reduced overall survival [hazard ratio=1.53 (1.04–2.24); P=0.031], and increased non-relapse mortality [hazard ratio=1.73 (1.06–2.83); P=0.030]. In functional experiments we found a trend towards a higher percentage of surface transforming growth factor β-1-positive regulatory T cells after activation when the cells had a p001 allele (P=0.07). Higher or lower production of transforming growth factor β-1 in the inflammatory context of hematopoietic stem cell transplantation may influence the development of complications in these patients. Findings indicate that TGFB1 genotype could potentially be of use as a prognostic factor in hematopoietic stem cell transplantation risk assessment algorithms.

Allele-level resolution data at primary HLA typing is the ideal for most histocompatibility testing laboratories. Many high-throughput molecular HLA typing approaches are unable to determine the phase of observed DNA sequence polymorphisms, leading to ambiguous results. The use of higher resolution methods is often restricted due to cost and time limitations. Here we report on the feasibility of using Pacific Biosciences' Single Molecule Real-Time (SMRT) DNA sequencing technology for high-resolution and high-throughput HLA typing. Seven DNA samples were typed for HLA-A, -B and -C. The results showed that SMRT DNA sequencing technology was able to generate sequences that spanned entire HLA Class I genes that allowed for accurate allele calling. Eight novel genomic HLA class I sequences were identified, four were novel alleles, three were confirmed as genomic sequence extensions and one corrected an existing genomic reference sequence. This method has the potential to revolutionize the field of HLA typing. The clinical impact of achieving this level of resolution HLA typing data is likely to considerable, particularly in applications such as organ and blood stem cell transplantation where matching donors and recipients for their HLA is of utmost importance.

Approximately 1 in 20 unrelated donors are asked to make a second donation of hematopoietic progenitor cells, the majority for the same patient. Anthony Nolan undertook a study of subsequent hematopoietic progenitor cell donations made by its donors from 2005 to 2011, with the aims of predicting those donors more likely to be called for a second donation, assessing rates of serious adverse reactions and examining harvest yields. This was not a study of factors predictive of second allografts. During the study period 2591 donations were made, of which 120 (4.6%) were subsequent donations. The median time between donations was 179 days (range, 21–4016). Indications for a second allogeneic transplant included primary graft failure (11.7%), secondary graft failure (53.2%), relapse (30.6%) and others (1.8%). On multivariate analysis, bone marrow harvest at first donation was associated with subsequent donation requests (odds ratio 2.00, P=0.001). The rate of serious adverse reactions in donors making a subsequent donation appeared greater than the rate in those making a first donation (relative risk=3.29, P=0.005). Harvest yields per kilogram recipient body weight were equivalent between donations, although females appeared to have a lower yield at the subsequent donation. Knowledge of these factors will help unrelated donor registries to counsel their donors.

Background Many genetic factors play major roles in the outcome of hematopoietic stem cell transplants from unrelated donors. Transforming growth factor β1 is a member of a highly pleiotrophic family of growth factors involved in the regulation of numerous immunomodulatory processes.Design and Methods We investigated the impact of single nucleotide polymorphisms at codons 10 and 25 of TGFB1, the gene encoding for transforming growth factor β1, on outcomes in 427 mye-loablative-conditioned transplanted patients. In addition, transforming growth factor β1 plasma levels were measured in 263 patients and 327 donors.Results Patients homozygous for the single nucleotide polymorphism at codon 10 had increased non-relapse mortality (at 3 years: 46.8% versus 29.4%, P=0.014) and reduced overall survival (at 5 years 29.3% versus 42.2%, P=0.013); the differences remained statistically significant in multivariate analysis. Donor genotype alone had no impact, although multiple single nucleotide polymorphisms within the pair were significantly associated with higher non-relapse mortality (at 3 years: 44% versus 29%, P=0.021) and decreased overall survival (at 5 years: 33.8% versus 41.9%, P=0.033). In the 10/10 HLA matched transplants (n=280), recipients of non-wild type grafts tended to have a higher incidence of acute graft-versus-host disease grades II-IV (P=0.052). In multivariate analysis, when analyzed with patients’ genotype, the incidences of both overall and grades II-IV acute graft-versus-host disease were increased (P=0.025 and P=0.009, respectively) in non-wild-type pairs.Conclusions We conclude that increasing numbers of single nucleotide polymorphisms in codon 10 of TGFB1 in patients and donors are associated with a worse outcome following hematopoietic stem cell transplantation from unrelated donors.

Background A variety of immune pathways can lead to graft-versus-host disease. A better understanding of the type of immune response causing graft-versus-host disease in defined clinical hematopoietic stem cell transplant settings is required to inform development of methods for monitoring patients and providing them tailored care.Design and Methods Twenty-five patients were recruited presenting with myeloid malignancies and treated with a reduced intensity conditioning transplant regimen with graft-versus-host disease prophylaxis comprising in vivo lymphocyte depletion with alemtuzumab and cyclosporin. A prospective study was performed of lymphocyte subset reconstitution in peripheral blood in relation to the incidence of graft-versus-host disease.Results Acute graft-versus-host disease was associated with significantly higher numbers of natural killer cells and donor-derived effector CD4 T cells (CD45RO+ CD27−) early (day 30) after transplantation (p=0.04 and p=0.02, respectively). This association was evident before the emergence of clinical pathology in six out of seven patients. Although numbers of regulatory CD4 T cells (CD25high Foxp3+) were similar at day 30 in all patients, a significant deficit in those who developed acute graft-versus-host disease was apparent relative to effector CD4 T cells (median of 41 effectors per regulatory cell compared to 12 to 1 for patients without graft-versus-host disease) (p=0.03). By day 180, a functional regulatory CD4 T-cell population had expanded significantly in patients who developed chronic graft-versus-host disease, reversing the imbalance (median of 3 effectors per regulatory cell compared to 9.6 to 1 for patients without graft-versus-host disease) (p=0.018) suggesting no overt absence of immune regulation in the late onset form of the disease.Conclusions Imbalance of effector and regulatory CD4 T cells is a signature of graft-versus-host disease in this transplantation protocol.

Background A stored cord blood donation may be a valuable source of hemopoietic stem cells for allogeneic transplantation when a matched sibling donor is not available. We carried out a study to define the optimal size of a national cord blood bank for the UK.Design and Methods We calculated the actual numbers of possible donors and the chance of finding at least one donor for 2,000 unselected and for 722 non-North Western European patients for whom searches had been initiated as a function of three levels of HLA matching (4, 5 and 6 out of 6 alleles by HLA-A, -B low and -DRB1 high resolution HLA typing) according to various donor bank sizes.Results With a bank size of 50,000, 80% of patients will have at least one donor unit available at the 5 out of 6 HLA allele match level (median 9 donors per patient), and 98% will have at least one donor at the 4 out of 6 allele match level (median 261). Doubling the size of the bank yields at least one donor for only an additional 6% of patients at the 5 of 6 allele match level. Moreover, for non-North Western European patients a 50,000 unit bank provides a donor for 50% at the 5 allele match level, and for 96% at the 4 allele match level.Conclusions A bank containing 50,000 units is optimal for the UK and larger banks would only marginally increase the chance of finding suitable units.