Palliative Care in Advanced Liver Disease: Similar or Different Palliative Care Needs in Patients with a Prospect of Transplantation? Prospective Study from a Portuguese University Hospital and Transplantation Center

Background and Aims: End-stage liver disease (ESLD) is an important cause of morbidity and mortality, comparable to a large extent to other organ insufficiencies. The need for palliative care (PC) in patients with ESLD is high. In Portugal, in the only identified study, more than 80% of patients hospitalized with ESLD had criteria for PC. No results specified which needs they identified or their transplantation prospect status. Methods: Prospective observational study including 54 ESLD patients who presented to a university hospital and transplantation center, between November 2019 and September 2020. Assessment of their PC needs through the application of NECPAL CCOMS-ICO© and IPOS, considering their transplantation perspective status. Results: Of the 54 patients, 5 (9.3%) were on active waiting list for transplantation and 8 (14.8%) under evaluation. NECPAL CCOMS-ICO© identified 23 patients (n = 42.6%) that would benefit from PC. Assessment of PC needs by clinicians, functional markers and significant comorbidities were the most frequent criteria (47.8%, n = 11). IPOS also revealed a different sort of needs: on average, each patient identified about 9 needs (8.9 ±2.8). Among the symptoms identified, weakness (77.8%), reduced mobility (70.3%), and pain (48.1%) stood out, as well as the psychoemotional symptoms of depression (66.7%) and anxiety (77.8%). There were no significant differences between the subgroups of patients analyzed. Only 4 patients (7.4%) were followed by the PC team. Conclusion: All the ESLD patients included, independently of the group they belonged to, presented with PC needs. No significant differences between the subgroups of patients were identified, confirming that even patients with a transplantation prospect have important needs for PC

Genome-wide variant calling in reanalysis of exome sequencing data uncovered a pathogenic TUBB3 variant.

Almost half of all individuals affected by intellectual disability (ID) remain undiagnosed. In the Solve-RD project, exome sequencing (ES) datasets from unresolved individuals with (syndromic) ID (n = 1,472 probands) are systematically reanalyzed, starting from raw sequencing files, followed by genome-wide variant calling and new data interpretation. This strategy led to the identification of a disease-causing de novo missense variant in TUBB3 in a girl with severe developmental delay, secondary microcephaly, brain imaging abnormalities, high hypermetropia, strabismus and short stature. Interestingly, the TUBB3 variant could only be identified through reanalysis of ES data using a genome-wide variant calling approach, despite being located in protein coding sequence. More detailed analysis revealed that the position of the variant within exon 5 of TUBB3 was not targeted by the enrichment kit, although consistent high-quality coverage was obtained at this position, resulting from nearby targets that provide off-target coverage. In the initial analysis, variant calling was restricted to the exon targets ± 200 bases, allowing the variant to escape detection by the variant calling algorithm. This phenomenon may potentially occur more often, as we determined that 36 established ID genes have robust off-target coverage in coding sequence. Moreover, within these regions, for 17 genes (likely) pathogenic variants have been identified before. Therefore, this clinical report highlights that, although compute-intensive, performing genome-wide variant calling instead of target-based calling may lead to the detection of diagnostically relevant variants that would otherwise remain unnoticed

Water for small-scale biogas digesters in sub-Saharan Africa

Acknowledgements This work was part-funded by the UK Natural Environment Research Council funded ESPA project, NE/K010441/1 ‘ALTER – Alternative Carbon Investments in Ecosystems for Poverty Alleviation’. We are also grateful to the AUC for funding part of this work under the Afri-Flame project on ‘Adapta- tion of small-scale biogas digesters for use in rural households in sub-Saharan AfricaPeer reviewedPublisher PD

Solving patients with rare diseases through programmatic reanalysis of genome-phenome data

Publisher Copyright: © 2021, The Author(s).Reanalysis of inconclusive exome/genome sequencing data increases the diagnosis yield of patients with rare diseases. However, the cost and efforts required for reanalysis prevent its routine implementation in research and clinical environments. The Solve-RD project aims to reveal the molecular causes underlying undiagnosed rare diseases. One of the goals is to implement innovative approaches to reanalyse the exomes and genomes from thousands of well-studied undiagnosed cases. The raw genomic data is submitted to Solve-RD through the RD-Connect Genome-Phenome Analysis Platform (GPAP) together with standardised phenotypic and pedigree data. We have developed a programmatic workflow to reanalyse genome-phenome data. It uses the RD-Connect GPAP’s Application Programming Interface (API) and relies on the big-data technologies upon which the system is built. We have applied the workflow to prioritise rare known pathogenic variants from 4411 undiagnosed cases. The queries returned an average of 1.45 variants per case, which first were evaluated in bulk by a panel of disease experts and afterwards specifically by the submitter of each case. A total of 120 index cases (21.2% of prioritised cases, 2.7% of all exome/genome-negative samples) have already been solved, with others being under investigation. The implementation of solutions as the one described here provide the technical framework to enable periodic case-level data re-evaluation in clinical settings, as recommended by the American College of Medical Genetics.Peer reviewe

Community-Led Total Sanitation: A Mixed-Methods Systematic Review of Evidence and Its Quality

Background: Community-led total sanitation (CLTS) is a widely applied rural behavior change approach for ending open defecation. However, evidence of its impact is unclear. Objectives: We conducted a systematic review of journal-published and gray literature to a) assess evidence quality, b) summarize CLTS impacts, and c) identify factors affecting implementation and effectiveness. Methods: Eligible studies were systematically screened and selected for analysis from searches of seven databases and 16 websites. We developed a framework to appraise literature quality. We qualitatively analyzed factors enabling or constraining CLTS, and summarized results from quantitative evaluations. Discussion: We included 200 studies (14 quantitative evaluations, 29 qualitative studies, and 157 case studies). Journal-published literature was generally of higher quality than gray literature. Fourteen quantitative evaluations reported decreases in open defecation, but did not corroborate the widespread claims of open defecation–free (ODF) villages found in case studies. Over one-fourth of the literature overstated conclusions, attributing outcomes and impacts to interventions without an appropriate study design. We identified 43 implementation- and community-related factors reportedly affecting CLTS. This analysis revealed the importance of adaptability, structured posttriggering activities, appropriate community selection, and further research on combining and sequencing CLTS with other interventions. Conclusions: The evidence base on CLTS effectiveness available to practitioners, policy makers, and program managers to inform their actions is weak. Our results highlight the need for more rigorous research on CLTS impacts as well as applied research initiatives that bring researchers and practitioners together to address implementation challenges to improve rural sanitation efforts

A new multicompartmental reaction-diffusion modeling method links transient membrane attachment of E. coli MinE to E-ring formation

Many important cellular processes are regulated by reaction-diffusion (RD) of molecules that takes place both in the cytoplasm and on the membrane. To model and analyze such multicompartmental processes, we developed a lattice-based Monte Carlo method, Spatiocyte that supports RD in volume and surface compartments at single molecule resolution. Stochasticity in RD and the excluded volume effect brought by intracellular molecular crowding, both of which can significantly affect RD and thus, cellular processes, are also supported. We verified the method by comparing simulation results of diffusion, irreversible and reversible reactions with the predicted analytical and best available numerical solutions. Moreover, to directly compare the localization patterns of molecules in fluorescence microscopy images with simulation, we devised a visualization method that mimics the microphotography process by showing the trajectory of simulated molecules averaged according to the camera exposure time. In the rod-shaped bacterium _Escherichia coli_, the division site is suppressed at the cell poles by periodic pole-to-pole oscillations of the Min proteins (MinC, MinD and MinE) arising from carefully orchestrated RD in both cytoplasm and membrane compartments. Using Spatiocyte we could model and reproduce the _in vivo_ MinDE localization dynamics by accounting for the established properties of MinE. Our results suggest that the MinE ring, which is essential in preventing polar septation, is largely composed of MinE that is transiently attached to the membrane independently after recruited by MinD. Overall, Spatiocyte allows simulation and visualization of complex spatial and reaction-diffusion mediated cellular processes in volumes and surfaces. As we showed, it can potentially provide mechanistic insights otherwise difficult to obtain experimentally

Solving patients with rare diseases through programmatic reanalysis of genome-phenome data

Reanalysis of inconclusive exome/genome sequencing data increases the diagnosis yield of patients with rare diseases. However, the cost and efforts required for reanalysis prevent its routine implementation in research and clinical environments. The Solve-RD project aims to reveal the molecular causes underlying undiagnosed rare diseases. One of the goals is to implement innovative approaches to reanalyse the exomes and genomes from thousands of well-studied undiagnosed cases. The raw genomic data is submitted to Solve-RD through the RD-Connect Genome-Phenome Analysis Platform (GPAP) together with standardised phenotypic and pedigree data. We have developed a programmatic workflow to reanalyse genome-phenome data. It uses the RD-Connect GPAP’s Application Programming Interface (API) and relies on the big-data technologies upon which the system is built. We have applied the workflow to prioritise rare known pathogenic variants from 4411 undiagnosed cases. The queries returned an average of 1.45 variants per case, which first were evaluated in bulk by a panel of disease experts and afterwards specifically by the submitter of each case. A total of 120 index cases (21.2% of prioritised cases, 2.7% of all exome/genome-negative samples) have already been solved, with others being under investigation. The implementation of solutions as the one described here provide the technical framework to enable periodic case-level data re-evaluation in clinical settings, as recommended by the American College of Medical Genetics

The impact of a household biogas programme on energy use and expenditure in East Java

Biogas has been promoted as a renewable, cleaner and cheaper energy source. While there are several initiatives promoting the use of biogas, credible analyses of its effects on the use of alternative energy sources and energy related expenditure are limited. This study uses panel data from households engaged in dairy farming in rural East Java to assess the impact of a household level programme, which promotes the construction of digesters that produce biogas, on energy use and expenditures. Both a difference-in-difference analysis and a pipeline comparison show that the use of digesters leads to a sharp reduction in energy related expenditures and a reduction in the use of firewood and liquefied petroleum gas. However, without subsidies, the payback period of between 11 and 14 years, albeit based only on reductions in energy costs accruing from investing in a digester, is perhaps too long to justify the investment

Can 'functionlaity' save the community management model of rural water supply?

As attention increasingly turns to the sustainability of rural water supplies - and not simply overall levels of coverage or access - water point functionality has become a core concern for development practitioners and national governments, especially in Sub-Saharan Africa. Within the long-enduring Community-Based Management (CBM) model this has resulted in increased scrutiny of the “functionality” of the local water point committee (WPC) or similar community management organisation. This paper reviews the literature written from both practice-focused and critical-academic perspectives and identifies three areas that pose challenges to our understanding of water point functionality as it relates to CBM. These concern the relative neglect of (i) the local institutional and socio-economic landscape, (ii) broader governance processes and power dynamics, and (iii) the socio-technical interface. By examining these three areas, the paper engages with the specific issue of WPC functionality, whilst also considering broader issues relating to the framing of problems in development and the methodological and disciplinary ways that these are addressed. Furthermore, by focusing on community management of rural water points, the paper lays the ground for a more substantial critique of the continuing persistence of the CBM model as a central development strategy