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Microemulsions are thermodynamically stable, transparent, isotropic mixtures of oil, water and surfactant (and sometimes a co-surfactant), which have shown potential for widespread application in disinfection and self-preservation. This is thought to be due to an innate antimicrobial effect. It is suggested that the antimicrobial nature of microemulsions is the result of a combination of their inherent kinetic energy and their containing surfactants, which are known to aid the disruption of bacterial membranes. This review examines the contemporary evidence in support of this theory.

Transcription factor (TF)-induced reprogramming of somatic cells across lineages and to induced pluripotent stem cells (iPSCs) has revealed a remarkable plasticity of differentiated cells and presents great opportunities for generating clinically relevant cell types for disease modeling and regenerative medicine. The understanding of iPSC reprogramming provides insights into the mechanisms that safeguard somatic cell identity, drive epigenetic reprogramming, and underlie cell fate specification in vivo. The combinatorial action of TFs has emerged as the key mechanism for the direct and indirect effects of reprogramming factors that induce the remodelling of the enhancer landscape. The interplay of TFs in iPSC reprogramming also yields trophectoderm- and extraembryonic endoderm-like cell populations, uncovering an intriguing plasticity of cell states and opening new avenues for exploring cell fate decisions during early embryogenesis.

ObjectivesCOVIDTrach is a UK multicentre prospective cohort study project that aims to evaluate the outcomes of tracheostomy in patients with COVID-19 receiving mechanical ventilation and record the incidence of SARS-CoV-2 infection among healthcare workers involved in the procedure.DesignData on patient demographic, clinical history and outcomes were entered prospectively and updated over time via an online database (REDCap). Clinical variables were compared with outcomes, with logistic regression used to develop a model for mortality. Participants recorded whether any operators tested positive for SARS-CoV-2 within 2 weeks of the procedure.SettingUK National Health Service departments involved in treating patients with COVID-19 receiving mechanical ventilation.ParticipantsThe cohort comprised 1605 tracheostomy cases from 126 UK hospitals collected between 6 April and 26 August 2020.Main outcome measuresMortality following tracheostomy, successful wean from mechanical ventilation and length of time from tracheostomy to wean, discharge from hospital, complications from tracheostomy, reported SARS-CoV-2 infection among operators.ResultsThe median time from intubation to tracheostomy was 15 days (IQR 11, 21). 285 (18%) patients died following the procedure. 1229 (93%) of the survivors had been successfully weaned from mechanical ventilation at censoring and 1049 (81%) had been discharged from hospital. Age, inspired oxygen concentration, positive end-expiratory pressure setting, fever, number of days of ventilation before tracheostomy, C reactive protein and the use of anticoagulation and inotropic support independently predicted mortality. Six reports were received of operators testing positive for SARS-CoV-2 within 2 weeks of the procedure.ConclusionsTracheostomy appears to be safe in mechanically ventilated patients with COVID-19 and to operators performing the procedure and we identified clinical parameters that are predictive of mortality.Trial registration numberThe study is registered with ClinicalTrials.Gov (NCT04572438).

Tent fires are a growing issue in regions with large homeless populations given the rise in homelessness within the United States and existing data that suggest worse outcomes in this population. The aim of this study was to describe the characteristics and outcomes of tent fire burn injuries in the homeless population. A retrospective review was conducted involving two verified regional burn centers with patients admitted for tent fire burns between January 2015 and December 2020. Variables recorded include demographics, injury characteristics, hospital course, and patient outcomes. Sixty-nine patients met the study inclusion criteria. The most common mechanisms of injury were by portable stove accident, assault, and tobacco or methamphetamine related. Median percent total body surface area (%TBSA) burned was 6% (interquartile range [IQR] 9%). Maximum depth of injury was partial thickness in 65% (n = 45) and full thickness in 35% (n = 24) of patients. Burns to the upper and lower extremities were present in 87% and 54% of patients, respectively. Median hospital length of stay (LOS) was 10 days (IQR = 10.5) and median ICU LOS was 1 day (IQR = 5). Inhalation injury was present in 14% (n = 10) of patients. Surgical intervention was required in 43% (n = 30) of patients, which included excision, debridement, skin grafting, and escharotomy. In-hospital mortality occurred in 4% (n = 3) of patients. Tent fire burns are severe enough to require inpatient and ICU level of care. A high proportion of injuries involved the extremities and pose significant barriers to functional recovery in this vulnerable population. Strategies to prevent these injuries are paramount.

This special issue of the New Zealand Journal of Marine and Freshwater Research is a tribute to one of New Zealand’s eminent freshwater scientists, Dr John Quinn, who sadly passed away in November ...

Larvae (glochidia) of the freshwater mussel order Unionida undergo a brief parasitic phase by attaching to and metamorphosing on suitable host fish. Here, novel observations of complex glochidia release strategies and glochidia morphometry are reported and compared in two sympatric New Zealand hyriid species, Echyridella menziesii (Gray, 1843) and Echyridella aucklandica (Gray, 1843). Echyridella menziesii produced glochidia averaging 277 ± 0.7 (SE) µm in diameter which were broadcast individually and bound to mucus threads into the water column. In contrast, the sympatric E. aucklandica produced miniature glochidia (99 ± 0.3 µm SE) embedded in functional conglutinates, thought to facilitate host fish attraction. To our knowledge, this is the first Unionida species, outside of North America, reported to be using functional conglutinates to mimic host diet as an infection strategy. The production of miniature glochidia that were morphologically distinguishable from those of E. menziesii, coupled with contrasting release strategies, highlights the potential for partitioning of host resources through contrasting attachment strategies and infection times. Additionally, these findings provide the basis for distinguishing glochidia of the two Echyridella species in field studies of host fish infection and highlight the need to develop novel methods for captive propagation of E. aucklandica to support restoration of declining populations.

Island nations such as New Zealand provide valuable insights into conservation challenges posed by strongly connected and recently developed or exploited freshwater and marine ecosystems. The narrow land mass, high rainfall, and steep terrain of New Zealand, like many other island nations, mean that land‐based stressors are rapidly transferred to freshwater habitats and propagated downstream to coastal environments via short, fast‐flowing river systems. Freshwater and marine environments are linked through faunal life histories; for example, diadromous fishes, many of which are considered threatened or at risk of extinction, and require cross‐ecosystem conservation to ensure survival of critical life stages and persistence of source populations. Recent invasions of marine and freshwater environments by non‐indigenous species reveal rapid impacts on a naive biota and highlight conservation conundrums caused by management aimed at enhancing native biodiversity by improving habitat connectivity. Understanding and managing interconnected freshwater and marine ecosystems is a key concept for local indigenous communities, and highlights socio‐cultural connectivity and sustainable local harvesting of traditional resources as key elements of contemporary marine and freshwater conservation planning in New Zealand.

Mitochondrial disease is hugely diverse with respect to associated clinical presentations and underlying genetic causes, with pathogenic variants in over 300 disease genes currently described. Approximately half of these have been discovered in the last decade due to the increasingly widespread application of next generation sequencing technologies, in particular unbiased, whole exome—and latterly, whole genome sequencing. These technologies allow more genetic data to be collected from patients with mitochondrial disorders, continually improving the diagnostic success rate in a clinical setting. Despite these significant advances, some patients still remain without a definitive genetic diagnosis. Large datasets containing many variants of unknown significance have become a major challenge with next generation sequencing strategies and these require significant functional validation to confirm pathogenicity. This interface between diagnostics and research is critical in continuing to expand the list of known pathogenic variants and concomitantly enhance our knowledge of mitochondrial biology. The increasing use of whole exome sequencing, whole genome sequencing and other “omics” techniques such as transcriptomics and proteomics will generate even more data and allow further interrogation and validation of genetic causes, including those outside of coding regions. This will improve diagnostic yields still further and emphasizes the integral role that functional assessment of variant causality plays in this process—the overarching focus of this review.

Global biodiversity loss is accelerating at an alarming rate. While considerable effort and resources have gone into conservation management for many threatened species in New Zealand (NZ),...

BACKGROUND: Right heart failure (RHF) is a well-known consequence of left ventricular assist device (LVAD) placement, and has been linked to negative surgical outcomes. However, little is known regarding risk factors associated with RHF. This article delineates pre- and intra-operative risk factors for RHF following LVAD implantation and demonstrates the effect of RHF severity on key surgical outcomes. METHODS: We performed a retrospective analysis of consecutive LVAD patients treated at our center between 2008 and 2016. RHF was categorized using the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) definition of none/mild, moderate, severe, and acute-severe. We constructed a predictive model using multivariable logistic regression and performed a competing risks analysis for survival stratified by RHF severity. RESULTS: Of 202 subjects, 52 (25.7%) developed moderate or worse RHF. Cardiopulmonary bypass (CPB) time and nadir hematocrit contributed jointly to the model of RHF severity (moderate or worse vs. none/mild; area under the curve =0.77). Postoperative length of stay (LOS) was shortest in the non/mild group and longest in the acute-severe group (median 13 vs. 29.5 days; P

Understanding the multiple agents of decline is important for the conservation of globally threatened Unionida (Class Bivalvia), but threats from non‐native species have received limited attention. To address this gap, a global meta‐analysis was conducted aimed at identifying known interactions and mechanisms of impact and informing potential effect pathways for the New Zealand unionid fauna. The main non‐native groups identified as interacting with unionids were fish (38% of published studies), macrophytes (33%), and vertebrate predators (30%), with ~70% of interactions leading to adverse impacts on mussels. Most studies used field surveys (~50%) and were conducted in rivers (~50%). Impacts occurred across the unionid life cycle (adult, glochidia, host, and juvenile), and primarily affected processes that determine the transitions between life‐cycle stages (fertilization, infestation, settlement, and maturation). The impacts of non‐native macrophytes and fish were predicted to be greater for transitional stages than the impact of vertebrate predators, which mostly affected adult mussels. New Zealand Unionida are most likely to be affected by interactions with non‐native species in lowland lakes and waterways, where connectivity for diadromous native fish hosts and high bioinvasion potential intersect.

Unbiased estimates of the current state of target ecosystems and identification of potential causal factors are key to managing stressors over large scales, and for guiding policy and decision makers to set realistic targets and expectations in light of economic pressures. A probability survey design for 176 target wadeable, perennial streams mapped on developed land in the Waikato Region, New Zealand, sampled over three austral summers (2013 to 2015), was used to i) estimate the extent to which “Poor” stressor and biological condition states occur, ii) determine the co-occurrence likelihood of “Poor” biological and environmental condition, and iii) identify and estimate the relative importance of key environmental stressors. The probability survey design also allowed the quantification of uncertainty around mean estimates of extent and risk. These analyses reveal that between 25 and 50% of mapped target stream length can be considered to be in “Poor” condition based on biological indices derived from macroinvertebrate and fish community data. For assessed stressors, Poor condition was estimated for 10 to 50% of the target stream network depending on the stressor. Poor biological condition was likely to co-occur with Poor stressor condition for 10 of the 12 assessed stressors for macroinvertebrate indices, and 5 of the 12 stressors for the fish index. These analyses identify that management actions targeted at improving instream habitat quality, particularly reducing fine sediment deposition, when applied across the entire stream network are likely to yield the most widespread improvement in biological condition indices. Our findings also highlight the importance of extending policy development beyond a singular focus on water quality if ecosystem health objectives are to be met.

Resilience in river ecosystems requires that organisms must persist in the face of highly dynamic hydrological and geomorphological variations. Disturbance events such as floods and droughts are postulated to shape life history traits that support resilience, but river management and conservation would benefit from greater understanding of the emergent effects in communities of river organisms. We unify current knowledge of taxonomic‐, phylogenetic‐, and trait‐based aspects of river communities that might aid the identification and quantification of resilience mechanisms. Temporal variations in river productivity, physical connectivity, and environmental heterogeneity resulting from floods and droughts are highlighted as key characteristics that promote resilience in these dynamic ecosystems. Three community‐wide mechanisms that underlie resilience are (a) partitioning (competition/facilitation) of dynamically varying resources, (b) dispersal, recolonization, and recruitment promoted by connectivity, and (c) functional redundancy in communities promoted by resource heterogeneity and refugia. Along with taxonomic and phylogenetic identity, biological traits related to feeding specialization, dispersal ability, and habitat specialization mediate organism responses to disturbance. Measures of these factors might also enable assessment of the relative contributions of different mechanisms to community resilience. Interactions between abiotic drivers and biotic aspects of resource use, dispersal, and persistence have clear implications for river conservation and management. To support these management needs, we propose a set of taxonomic, phylogenetic, and life‐history trait metrics that might be used to measure resilience mechanisms. By identifying such indicators, our proposed framework can enable targeted management strategies to adapt river ecosystems to global change.

Objective “NPO at midnight” is a standard preoperative practice intended to reduce aspiration risk but can result in prolonged feeding interruptions in critically ill burn patients. Postoperative hyperalimentation in the form of a “catch-up” tube feeding protocol is routine. A retrospective review of our perioperative fasting practices and “catch-up” enteral feeding protocols was performed. Methods Patients admitted to the Burn ICU from July 1st, 2015 to August 31st, 2016 were reviewed. Patients who had a protected airway in place, prescribed enteral nutrition, and underwent surgery were included. The time from NPO to surgical start (NPO-SS), NPO to feeding restart (NPO-FR), and calories received/prescribed were quantified. The efficacy of a postoperative catch-up feeding protocol was analyzed. Results There were 41 patients that fit inclusion criteria with some undergoing multiple surgeries, yielding 109 surgeries/discrete perioperative events. The average total body surface area burn (38.1 ± 23.6%), age (38.8 ± 20.1 years), ICU days (45.0 ± 37.3 days), and ventilator days (35.1 ± 33.8 days) were calculated. Average fasting durations of NPO-SS and NPO-FR were 9.3 ± 3.1 and 14.2 ± 4.1 h, respectively. The average caloric deficit to prescribed calories ratio during the NPO-SS and NPO-FR periods were 1154 ± 629/3534 ± 851 kcal and 1765 ± 928/3534 ± 851 kcal, respectively. A post-operative catch-up protocol completely compensated for perioperative caloric deficits 68.8% (22/32) of the time. Conclusions In critically ill burn patients, a preoperative fast resulted in an average loss of greater than 50% of prescribed calories on the day of surgery. Clinicians should re-evaluate the standard practice of making preoperative patients “NPO at midnight”. An effective catch-up protocol can adequately reduce caloric deficits.

Mutations in OPA1 cause autosomal dominant optic atrophy (DOA) as well as DOA+, a phenotype characterized by more severe neurological deficits. OPA1 deficiency causes mitochondrial fragmentation and also disrupts cristae, respiration, mitochondrial DNA (mtDNA) maintenance, and cell viability. It has not yet been established whether phenotypic severity can be modulated by genetic modifiers of OPA1. We screened the entire known mitochondrial proteome (1,531 genes) to identify genes that control mitochondrial morphology using a first‐in‐kind imaging pipeline. We identified 145 known and novel candidate genes whose depletion promoted elongation or fragmentation of the mitochondrial network in control fibroblasts and 91 in DOA+ patient fibroblasts that prevented mitochondrial fragmentation, including phosphatidyl glycerophosphate synthase (PGS1). PGS1 depletion reduces CL content in mitochondria and rebalances mitochondrial dynamics in OPA1‐deficient fibroblasts by inhibiting mitochondrial fission, which improves defective respiration, but does not rescue mtDNA depletion, cristae dysmorphology, or apoptotic sensitivity. Our data reveal that the multifaceted roles of OPA1 in mitochondria can be functionally uncoupled by modulating mitochondrial lipid metabolism, providing novel insights into the cellular relevance of mitochondrial fragmentation., Phenotypic screening of OPA1 patient fibroblasts identifies multiple genetic suppressors of mitochondrial fragmentation including PGS1, a key enzyme in cardiolipin biosynthesis. PGS1 depletion reduces mitochondrial fission and restores normal mitochondrial morphology to OPA1‐deficient fibroblasts.

The transition from naive to primed pluripotency is accompanied by an extensive reorganisation of transcriptional and epigenetic programmes. However, the role of transcriptional enhancers and three-dimensional chromatin organisation in coordinating these developmental programmes remains incompletely understood. Here, we generate a high-resolution atlas of gene regulatory interactions, chromatin profiles and transcription factor occupancy in naive and primed human pluripotent stem cells, and develop a network-graph approach to examine the atlas at multiple spatial scales. We uncover highly connected promoter hubs that change substantially in interaction frequency and in transcriptional co-regulation between pluripotent states. Small hubs frequently merge to form larger networks in primed cells, often linked by newly-formed Polycomb-associated interactions. We identify widespread state-specific differences in enhancer activity and interactivity that correspond with an extensive reconfiguration of OCT4, SOX2 and NANOG binding and target gene expression. These findings provide multilayered insights into the chromatin-based gene regulatory control of human pluripotent states., The role of transcriptional enhancers and 3D chromatin organisation in coordinating the transition from naive to primed pluripotency remains poorly understood. Here the authors generate a high-resolution atlas of gene regulatory interactions, chromatin profiles and transcription factor occupancy in naive and primed human pluripotent stem cells to provide insights into these developmental processes.

Consensus as to best practices for the selection, reporting, and interpretation of primary and secondary outcomes of randomized controlled trials is lacking. We reviewed the strategies adopted in publications of randomized controlled trials (RCTs) for the analysis, presentation, and interpretation of efficacy outcomes from a survey of all cardiovascular RCTs published in the New England Journal of Medicine, Lancet, and the Journal of the American Medical Association during 2019. We focus on the choice of primary outcomes, the variety of approaches to selecting secondary outcomes, the options sometimes used to control type I error, and the common practice to not correct for multiple testing in reporting secondary outcomes. We comment on current practice across journals in the reporting of P values and also how conclusions in trial reports frequently adhere to an undue reliance on P 0.05 as a basis for positive claims of treatment efficacy. We conclude with recommendations for how future RCT reports could best select, report, and interpret their findings on primary and secondary outcomes.

Although next-generation sequencing technologies have accelerated the discovery of novel gene-to-disease associations, many patients with suspected Mendelian diseases still leave the clinic without a genetic diagnosis. An estimated one third of these patients will have disorders caused by mutations impacting splicing. RNA-sequencing has been shown to be a promising diagnostic tool, however few methods have been developed to integrate RNA-sequencing data into the diagnostic pipeline. Here, we introduce dasper, an R/Bioconductor package that improves upon existing tools for detecting aberrant splicing by using machine learning to incorporate disruptions in exon-exon junction counts as well as coverage. dasper is designed for diagnostics, providing a rank-based report of how aberrant each splicing event looks, as well as including visualization functionality to facilitate interpretation. We validate dasper using 16 patient-derived fibroblast cell lines harbouring pathogenic variants known to impact splicing. We find that dasper is able to detect pathogenic splicing events with greater accuracy than existing LeafCutterMD or z-score approaches. Furthermore, by only applying a broad OMIM gene filter (without any variant-level filters), dasper is able to detect pathogenic splicing events within the top 10 most aberrant identified for each patient. Since using publicly available control data minimises costs associated with incorporating RNA-sequencing into diagnostic pipelines, we also investigate the use of 504 GTEx fibroblast samples as controls. We find that dasper leverages publicly available data effectively, ranking pathogenic splicing events in the top 25. Thus, we believe dasper can increase diagnostic yield for a pathogenic splicing variants and enable the efficient implementation of RNA-sequencing for diagnostics in clinical laboratories.

Hypoglycemic episodes are associated with worse hospital outcomes. All adult patients admitted to our burn center from 2015 to 2019 were retrospectively reviewed. Patient demographics and burn characteristics were recorded. The primary outcome was mortality, and secondary outcomes were total length-of-stay and intensive care unit length-of-stay. All patients experiencing at least one hypoglycemic episode were compared to patients who did not experience hypoglycemia. There were 914 patients with acute burns admitted during the study period, 33 of which (4%) experienced hypoglycemic episodes. Of these, 17 patients (52%) experienced a single hypoglycemic episode, while the remainder experienced multiple hypoglycemic episodes. Patients with one or more hypoglycemic events were matched to non-hypoglycemic controls using propensity matching. Patients that experienced hypoglycemia had significantly less TBSA involvement (5% vs. 13%,median, p < 0.0002), higher prevalence of diabetes (48% vs. 18%, p < 0.0001), higher mortality (18% vs. 7%, p = 0.01), longer total length-of-stay (22 vs. 8 days, median, p < 0.0001), and longer ICU length-of-stay (12 vs. 0 days, median, p < 0.0001). A single hypoglycemic episode was associated with prolonged total (IRR = 1.91, p < 0.0001) and ICU length-of-stay (IRR = 3.86, p < 0.0001). Hypoglycemia was not associated with higher mortality in the survival analysis (p = 0.46).

Parkinson’s disease (PD) is a prevalent neurodegenerative disease with no approved disease-modifying therapies. Multiplications, mutations, and single nucleotide polymorphisms in the SNCA gene, encoding α-synuclein (aSyn) protein, either cause or increase risk for PD. Intracellular accumulations of aSyn are pathological hallmarks of PD. Taken together, reduction of aSyn production may provide a disease-modifying therapy for PD. We show that antisense oligonucleotides (ASOs) reduce production of aSyn in rodent preformed fibril (PFF) models of PD. Reduced aSyn production leads to prevention and removal of established aSyn pathology and prevents dopaminergic cell dysfunction. In addition, we address the translational potential of the approach through characterization of human SNCA-targeting ASOs that efficiently suppress the human SNCA transcript in vivo. We demonstrate broad activity and distribution of the human SNCA ASOs throughout the nonhuman primate brain and a corresponding decrease in aSyn cerebral spinal fluid (CSF) levels. Taken together, these data suggest that, by inhibiting production of aSyn, it may be possible to reverse established pathology; thus, these data support the development of SNCA ASOs as a potential disease-modifying therapy for PD and related synucleinopathies.

This Festschrift presents essays from a symposium organized in honor of Paul Rabinow. Our hope is that, collectively, the essays offer a sense of the evolution and range of the topics and problems Rabinow investigated, and the diverse projects of anthropological inquiry that have been built in conversation with Rabinow and his work. But most importantly, they bring into focus an audacious proposal, formulated over a remarkable career, for an anthropology of the contemporary world.

The signalling pathways that maintain primed human pluripotent stem cells (hPSCs) have been well characterised, revealing a critical role for TGFβ/Activin/Nodal signalling. In contrast, the signalling requirements of naïve human pluripotency have not been fully established. Here, we demonstrate that TGFβ signalling is required to maintain naïve hPSCs. The downstream effector proteins – SMAD2/3 – bind common sites in naïve and primed hPSCs, including shared pluripotency genes. In naïve hPSCs, SMAD2/3 additionally bind to active regulatory regions near to naïve pluripotency genes. Inhibiting TGFβ signalling in naïve hPSCs causes the downregulation of SMAD2/3-target genes and pluripotency exit. Single-cell analyses reveal that naïve and primed hPSCs follow different transcriptional trajectories after inhibition of TGFβ signalling. Primed hPSCs differentiate into neuroectoderm cells, whereas naïve hPSCs transition into trophectoderm. These results establish that there is a continuum for TGFβ pathway function in human pluripotency spanning a developmental window from naïve to primed states.

Postdischarge services, such as outpatient wound care, may affect long-term health outcomes and postrecovery quality-of-life. Access to these services may vary according to insurance status and ability to cover out-of-pocket expenses. Our objective was to compare discharge location between burn patients who were uninsured, publicly insured, and privately insured at the time of their burn unit admissions. A retrospective review from July 1, 2015 to November 1, 2019 was performed at an American Burn Association-verified burn center. All admitted burn patients 18 years and older were identified and categorized according to insurance payer type. The primary outcome was discharge location, and secondary outcomes included readmission and outpatient burn care attendance. In total, 284 uninsured, 565 publicly insured, and 293 privately insured patients were identified. There were no significant differences in TBSA (P = .3), inhalation injury (P = .3), intensive care unit days (P = .09), or need for skin grafting (P = .1) between the three groups. For primary outcome, uninsured patients were more likely to be discharged without ancillary services (P < .0001) compared to both publicly and privately insured. Publicly insured patients were more likely to receive skilled nursing care (P = .0007). Privately insured patients were more likely to receive homecare (P = .0005) or transfer for ongoing inpatient care (P < .0001). There was no difference in burn unit readmission rates (P = .5). The uninsured were more likely to follow up with outpatient burn clinic after discharge (P = .004). Uninsured patients were less likely to receive postdischarge resources. Uninsured patients received fewer postdischarge wound care resources which could result in suboptimal long-term results, and diminished return to preinjury functional status. Given the impact of insurance status on discharge location and resources, efforts to increase access for uninsured patients to postdischarge resources will ensure greater healthcare equity and improve quality of comprehensive care regardless of insurance status.

Catchment impacts on downstream ecosystems are difficult to quantify, but important for setting management targets. Here we compared 12 years of monitoring data of seagrass area and biomass in Cleveland Bay, northeast Australia, with discharge and associated sediment loads from nearby rivers. Seagrass biomass and area exhibited different trajectories in response to river inputs. River discharge was a slightly better predictor of seagrass indicators than total suspended solid (TSS) loads, indicating that catchment effects on seagrass are not restricted to sediment. Linear relationships between Burdekin River TSS loads delivered over 1–4 years and seagrass condition in Cleveland Bay generated Ecologically Relevant Targets (ERT) for catchment sediment inputs. Our predicted ERTs were comparable to those previously estimated using mechanistic models. This study highlights the challenges of linking catchment inputs to condition of downstream ecosystems, and the importance of integrating a variety of metrics and approaches to increase confidence in ERTs.

This chapter centers on Limn, a scholarly magazine that focuses on tensions arising at the intersection of politics, expertise, and collective life. It describes Limn as an experiment in scholarly publishing in the interpretive human sciences that aims to make possible new kinds of communication and collective work. It also mentions Martin Høyem, who custom designed Limn with a range of imagery and graphic material related to the contributions, including a featured graphic that links diverse contributions in a common conceptual problem-space. The chapter discusses Limn as a vehicle for exploring new forms of collaboration in the interpretive human sciences. It recounts the changing field of American anthropology during the 1990s and 2000s in which discipline encouraged individualized work and valorized virtuosic interpretation and writing, with little space for collaborative inquiry.

This special collection examines insurance as an increasingly central mechanism in shaping how the effects of climate change are transforming local economies and ways of life. The papers study a range of exemplary cases, ranging from agricultural micro-insurance in development policy and regional sovereign risk facilities in the Caribbean to public and private insurance in the United States. This framing essay situates these papers in a longer tradition of scholarship on the government of risk and security. It also describes three themes that run through the papers: the economization of climate change; the moral economy of risk and responsibility; and the plasticity of insurance as an abstract technology that may be taken up in various governmental assemblages, in the name of various political projects.

Autophagy is the major intracellular degradation route in mammalian cells. Systemic ablation of core autophagy-related (ATG) genes in mice leads to embryonic or perinatal lethality, and conditional models show neurodegeneration. Impaired autophagy has been associated with a range of complex human diseases, yet congenital autophagy disorders are rare.We performed a genetic, clinical, and neuroimaging analysis involving five families. Mechanistic investigations were conducted with the use of patient-derived fibroblasts, skeletal muscle-biopsy specimens, mouse embryonic fibroblasts, and yeast.We found deleterious, recessive variants in human ATG7, a core autophagy-related gene encoding a protein that is indispensable to classical degradative autophagy. Twelve patients from five families with distinct ATG7 variants had complex neurodevelopmental disorders with brain, muscle, and endocrine involvement. Patients had abnormalities of the cerebellum and corpus callosum and various degrees of facial dysmorphism. These patients have survived with impaired autophagic flux arising from a diminishment or absence of ATG7 protein. Although autophagic sequestration was markedly reduced, evidence of basal autophagy was readily identified in fibroblasts and skeletal muscle with loss of ATG7. Complementation of different model systems by deleterious ATG7 variants resulted in poor or absent autophagic function as compared with the reintroduction of wild-type ATG7.We identified several patients with a neurodevelopmental disorder who have survived with a severe loss or complete absence of ATG7, an essential effector enzyme for autophagy without a known functional paralogue. (Funded by the Wellcome Centre for Mitochondrial Research and others.).

SUMMARYX chromosome inactivation (XCI) is a developmental regulatory process that initiates with remarkable diversity in various mammalian species. Here we addressed the contribution of XCI regulators, most of which are lncRNA genes characterized in the mouse, to this mechanistic diversity. By combining analysis of single-cell RNA-seq data from early human embryogenesis with various functional assays in naïve and primed pluripotent stem cells and in differentiated cells, we demonstrate that JPX is a major regulator of XIST expression in human and in mouse. However, the underlying mechanisms differ radically between species and require Jpx RNA in the mouse and the act of transcription of JPX locus in the human. Moreover, biogenesis of XIST is affected at different regulatory steps between these species. This study illustrates how diversification of LRGs modes of action during evolution provide opportunities for innovations within constrained gene regulatory networks.Graphical abstract

SUMMARY Generating mammalian cells with desired mitochondrial DNA (mtDNA) sequences is enabling for studies of mitochondria, disease modeling, and potential regenerative therapies. MitoPunch, a high-throughput mitochondrial transfer device, produces cells with specific mtDNA-nuclear DNA (nDNA) combinations by transferring isolated mitochondria from mouse or human cells into primary or immortal mtDNA-deficient (ρ0) cells. Stable isolated mitochondrial recipient (SIMR) cells isolated in restrictive media permanently retain donor mtDNA and reacquire respiration. However, SIMR fibroblasts maintain a ρ0-like cell metabolome and transcriptome despite growth in restrictive media. We reprogrammed non-immortal SIMR fibroblasts into induced pluripotent stem cells (iPSCs) with subsequent differentiation into diverse functional cell types, including mesenchymal stem cells (MSCs), adipocytes, osteoblasts, and chondrocytes. Remarkably, after reprogramming and differentiation, SIMR fibroblasts molecularly and phenotypically resemble unmanipulated control fibroblasts carried through the same protocol. Thus, our MitoPunch “pipeline” enables the production of SIMR cells with unique mtDNA-nDNA combinations for additional studies and applications in multiple cell types., Graphical Abstract, In Brief Patananan and colleagues demonstrate a pipeline for transferring isolated mitochondria into mtDNA-deficient recipient cells. mtDNA-depleted fibroblasts permanently retain acquired non-native mtDNA through cell fate transitions. Initially, mitochondrial recipients show mtDNA-deficient cell transcriptome and metabolome profiles, with improvement to control profiles by reprogramming to pluripotency and subsequent differentiation.

Introduction Patients with diabetes are prone to foot injuries and burns. Managing burned feet in patients with diabetes can be difficult due to multiple concomitant patient comorbidities that delay wound healing. Burn surgeons tasked with treating these complex foot burns understand that these patients are at risk of developing significant complications, such as infections and non-healing diabetic foot ulcers, which may ultimately lead to amputation. Although there are many studies that examine the causes and outcomes of diabetic foot ulcers and their management, there is a lack of consensus on how to best manage lower extremity burns in patients with diabetes. Methods A systematic review was performed according to PRISMA criteria and identified 18 articles addressing the management of burned feet in patients with diabetes. Means and standard deviations of scale variables and frequencies derived from nominal and ordinal variables abstracted from the literature were compared between each group. A meta-analysis was attempted but existing data was not of sufficient quality for meaningful analysis, and data aggregation was done where applicable. Results The three-database search identified 726 articles, which yielded 18 full text articles that met inclusion criteria. mean age of patients was 54 years (SD 7), and 80% (n=203) were male. Most (90%, n=179) had type II diabetes, and 10% (n=20) had Type I diabetes. Mean duration of diabetic disease was 11 years (SD 4), and mean A1c at admission was 9% (SD 1). Peripheral neuropathy (64%, n=123) was the most common comorbidity. Median TBSA burned was 2% (IQR 2), and scald (56%, n=155) was the most common mechanism of injury. Full thickness burns (70%, n=102) were most common, followed by partial thickness (28%, n=41), and superficial thickness (2%, n=2). A majority (55%, n=88) had burn wound infection identified at admission. Patients had a median delay in presentation from time of injury to hospital admission of 4 days (IQR 4.5). Sixty percent of patients received surgical treatment via excision and grafting, had a median length-of-stay of 20.5 days despite a median total body surface area involvement of 2%, and experienced sequelae of impaired wound healing such as infections, graft loss, and need for further surgery. Ultimately, 23% of patients had significant wound healing issues that resulted in amputation. Conclusions Excision and grafting may not be the optimal approach for managing foot burns in patients with diabetes, many of whom are at high risk of amputation. Non-operative management of foot burns in patients with diabetes should be explored as a method to decrease amputations in patients with foot burns.

Supplemental Digital Content is available in the text., Background: In the WRAP-IT trial (Worldwide Randomized Antibiotic Envelope Infection Prevention), adjunctive use of an absorbable antibacterial envelope resulted in a 40% reduction of major cardiac implantable electronic device infection without increased risk of complication in 6983 patients undergoing cardiac implantable electronic device revision, replacement, upgrade, or initial cardiac resynchronization therapy defibrillator implant. There is limited information on the cost-effectiveness of this strategy. As a prespecified objective, we evaluated antibacterial envelope cost-effectiveness compared with standard-of-care infection prevention strategies in the US healthcare system. Methods: A decision tree model was used to compare costs and outcomes of antibacterial envelope (TYRX) use adjunctive to standard-of-care infection prevention versus standard-of-care alone over a lifelong time horizon. The analysis was performed from an integrated payer-provider network perspective. Infection rates, antibacterial envelope effectiveness, infection treatment costs and patterns, infection-related mortality, and utility estimates were obtained from the WRAP-IT trial. Life expectancy and long-term costs associated with device replacement, follow-up, and healthcare utilization were sourced from the literature. Costs and quality-adjusted life years were discounted at 3%. An upper willingness-to-pay threshold of $150 000 per quality-adjusted life year was used to determine cost-effectiveness, in alignment with the American College of Cardiology/American Heart Association practice guidelines and as supported by the World Health Organization and contemporary literature. Results: The base case incremental cost-effectiveness ratio of the antibacterial envelope compared with standard-of-care was $112 603/quality-adjusted life year. The incremental cost-effectiveness ratio remained lower than the willingness-to-pay threshold in 74% of iterations in the probabilistic sensitivity analysis and was most sensitive to the following model inputs: infection-related mortality, life expectancy, and infection cost. Conclusions: The absorbable antibacterial envelope was associated with a cost-effectiveness ratio below contemporary benchmarks in the WRAP-IT patient population, suggesting that the envelope provides value for the US healthcare system by reducing the incidence of cardiac implantable electronic device infection. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02277990.

Burn injury can cause abnormal healing and pathologic scar formation that significantly impairs patients' ability to return to baseline levels of functioning. Quality of life can be significantly diminished due to pain, stiffness, contracture, and the psychological burden of disfigurement. Traditional scar therapies such as silicone sheeting and compression garments are highly reliant on patient compliance, and have not demonstrated satisfactory efficacy. Even more invasive therapies such as intralesional medication delivery or surgical contracture release have high recurrence rates. Recently, fractional CO

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We present a high‐resolution 2‐D P‐wave velocity model from a 225‐km‐long active seismic profile, collected over ~60–75 Ma central Atlantic crust. The profile crosses five ridge segments separated by a transform and three nontransform offsets. All ridge discontinuities share similar primary characteristics, independent of the offset. We identify two types of crustal segment. The first displays a classic two‐layer velocity structure with a high gradient Layer 2 (~0.9 s$^{−1}$) above a lower gradient Layer 3 (0.2 s$^{−1}$). Here, PmP coincides with the 7.5 km s$^{−1}$ contour, and velocity increases to >7.8 km s$^{−1}$ within 1 km below. We interpret these segments as magmatically robust, with PmP representing a petrological boundary between crust and mantle. The second has a reduced contrast in velocity gradient between the upper and lower crust and PmP shallower than the 7.5 km s$^{−1}$ contour. We interpret these segments as tectonically dominated, with PmP representing a serpentinized (alteration) front. While velocity‐depth profiles fit within previous envelopes for slow‐spreading crust, our results suggest that such generalizations give a misleading impression of uniformity. We estimate that the two crustal styles are present in equal proportions on the floor of the Atlantic. Within two tectonically dominated segments, we make the first wide‐angle seismic identifications of buried oceanic core complexes in mature (>20 Ma) Atlantic Ocean crust. They have a ~20‐km‐wide “domal” morphology with shallow basement and increased upper crustal velocities. We interpret their midcrustal seismic velocity inversions as alteration and rock‐type assemblage contrasts across crustal‐scale detachment faults.

COVIDTrach is a UK multidisciplinary collaborative project that aims to evaluate the outcomes of tracheostomy in COVID-19 patients. It also examines the implementation of national guidance in COVID-19 tracheostomies and the incidence of COVID-19 infections amongst those health care workers involved in the procedure. An invitation to participate in an online survey tool (REDCap) was disseminated to all UK NHS departments involved in tracheostomy in mechanically ventilated COVID-19 patients via the Federation of Surgical Specialty Associations, it’s subsidiary organisations and the Intensive Care Society. To date 78 hospitals have submitted 564 COVID-19 tracheostomy cases. Fifty-two percent (n=219/465) of patients who had undergone tracheostomy and were still alive had been successfully weaned from mechanical ventilation at the point of completing the survey. The all cause in-hospital mortality following tracheostomy was 12% (n=62/530), with 3% of these (n=2/62) due to tracheostomy related complications and the remaining deaths due to COVID-19 related complications. Amongst 400 cases submitting data two weeks after the tracheostomy, no instance of COVID-19 infection amongst operators was recorded. FFP3 masks or Powered Air Purifying Respirators were used by operators in 100% of tracheostomies and a face visor or hood with face shield was available in 99% of cases. This interim report highlights early outcomes following tracheostomy in mechanically ventilated COVID-19 patients. Future reporting from COVIDTrach will include more detailed analysis at later timepoints using comparator groups in order to provide a more comprehensive assessment of tracheostomy in COVID-19.

This chapter follows a series of important moments in the twentieth-century history of system-vulnerability thinking: the interwar articulation of strategic bombing theory in Europe and the US, which focused on the 'vital targets' of an enemy's industrial system and the development of defence mobilization and emergency preparedness in the US during the Cold War as a means of defending the industrial system against a targeted nuclear attack. The moments also include the emergence of all-hazards planning and 'total preparedness' as paradigms for response to disruptions of vital systems; and the widespread diffusion of formal models for assessing the vulnerability of vital systems. The chapter describes the process through which a new way of defining and intervening in collective security problems emerged over the course of the twentieth century. Critical infrastructure protection is only one such response, and one whose actualization in bureaucratic arrangements, resource flows, and established regimes of security is just beginning to emerge.

During development, human primordial germ cells (hPGCs) transition through a transcriptional and epigenetic state similar to pre-implantation naive ground state epiblast cells. In hPGCs, this state is called naive-like ground state pluripotency. Diagnostic transcription factors that define this state include TFAP2C, KLF4, and TFCP2L1, with TFAP2C necessary for both establishment of the naive-like ground state in hPGC-like cells (hPGCLCs) and establishment of naive ground state human embryonic stem cells (hESCs). Here, we show that KLF4 and TFCP2L1 are not required for hPGC specification or establishment of the naive-like ground state in hPGCLCs. Instead, KLF4 and TFCP2L1 are each required for reversion of primed hESCs to the self-renewing naive ground state. Additionally, TFCP2L1 but not KLF4 function after hPGC specification in the proliferation and survival of hPGCLCs.

Ponds are increasingly being constructed to enhance amenity values in human-dominated lowland landscapes, but little is known of design features that influence macroinvertebrates which can provide important food resources for fish and waterbirds. We quantified pond characteristics, sampled benthic and water-column macroinvertebrates in winter, and related abundance, biomass and community composition to characteristics of 34 ponds on the lower Waikato River floodplain, northern New Zealand. Compositionally different macroinvertebrate communities occupied water-column and benthic habitats. Landscape setting had a significant effect on benthic composition in terms of biomass, while the independent effects of frequency of pond drying or flooding, respectively, influenced benthic (abundance, biomass) or water-column (abundance) communities. Distance-based linear models highlighted physicochemical conditions, water depth regimes and riparian vegetation composition as key variables accounting for dissimilarity in total macroinvertebrate biomass between ponds. Our results indicate that managing hydrological stability of ponds in terms of permanence and flooding influences the composition and biomass of invertebrate communities. Within this hydrological template, design of appropriate depth regimes and riparian conditions can enhance accrual of macroinvertebrate biomass, thereby increasing food resources for fish and waterbirds.