Protective effect of ischaemic preconditioning on acute and chronic renal damage following ischaemia reperfusion injury: characterisation of fibrosis development after inflammation resolution.

OBJECTIVES: Acute Kidney Injury (AKI) and Chronic Kidney Disease (CKD) are increasingly recognised as one disease continuum, rather than distinct entities, and are associated with a huge burden to healthcare services. The leading cause of AKI worldwide is Ischaemia Reperfusion Injury (IRI), most commonly seen in clinical settings of sepsis-driven hypotension. Ischaemic Preconditioning (IPC) is a strategy aimed at reducing the deleterious effects of IRI. The objectives of this study were to demonstrate an efficacious in vivo model of Kidney IRI, and the protective influence of IPC in attenuating AKI and development of renal fibrosis. METHODS: A rat model of bilateral kidney IRI was used: Male Lewis rats (n=84) were assigned to IRI, sham or IPC. In IRI, renal pedicles were clamped for 45 minutes. IPC groups underwent pulsatile IPC prior to IRI. Kidneys were retrieved at 24 hours, 48 hours, 7 days, 14 days and 28 days, and assessed histologically. RESULTS: IRI led to marked AKI (24-48 h) and renal fibrosis development by 28 days. IPC attenuated this damage, with 66% less fibrosis. Interestingly, at 14-days, the histological appearance of both IRI and IPC kidneys was rather similar, potentially representing an important transitional point at which kidneys commit to either fibrosis or recovery. This may provide a suitable inflexion point for introduction of novel anti-fibrotic therapies. CONCLUSIONS: In conclusion, we have characterised a model of kidney injury from acute to chronic phases, allowing detailed mechanistic understanding and which can be manipulated by effective treatment strategies such as IPC.

Intravenous antibiotics for urinary tract infections in children with neurologic impairment.

BACKGROUND: Children with high-intensity neurologic impairment (HINI) have an increased risk of urinary tract infection (UTI) and prolonged intravenous (IV) antibiotic exposure. OBJECTIVE: To determine the association between short (≤3 days) and long (>3 days) IV antibiotic courses and UTI treatment failure in hospitalized children with HINI. METHODS: We performed a retrospective cohort study examining UTI hospitalizations at 49 hospitals in the Pediatric Health Information System from 2016 to 2021 for children (1-18 years) with HINI. The primary outcome was UTI readmission within 30 days. Our secondary outcome was the association of hospital-level variation in short IV antibiotic course use with readmission. Readmission rates were compared between short and long courses using multivariable regression. RESULTS: Of 5612 hospitalizations, 3840 (68.4%) had short IV antibiotic courses. In our adjusted model, children with short IV courses were less likely than with long courses to have a 30-day UTI readmission (4.0%, 95% CI [3.6%, 4.5%] vs. 6.3%, 95% CI [5.1%, 7.8%]). Despite marked hospital-level variation in short IV course use (50.0%-87.5% of hospitalizations), there was no correlation with readmissions. CONCLUSIONS: Children with HINI hospitalized with UTI had low UTI readmission rates, but those who received long IV antibiotic courses were more likely to experience UTI readmission versus those receiving short courses. While residual confounding may influence our results, we did not find that short IV courses impacted readmission at the hospital level despite variation in use across institutions. Long IV antibiotic courses are associated with risks and may not confer benefit in this population.

Energy poverty in the Energy Community region: Interrogating policy formulation and coverage.

The capacity of the state to develop and implement policy at the complex nexus of energy infrastructure, social inequality and housing is indicative of the political priorities of governing structures and, by extension, the nature of statecraft more generally. We compare and contrast the energy poverty amelioration policies of two former Yugoslav and two post-Soviet states located outside the European Union, but seeking to join its regulatory sphere - Serbia, Montenegro, Ukraine and Georgia - against the background of deep and persistent patterns of domestic energy hardship. We are particularly interested in uncovering the time horizons, socio-technical systems and target constituencies of different policy measures, as well as energy sector-specific responses to the COVID-19 pandemic. We find that most states in the region have done little to address some of the more substantive challenges around improving housing quality, energy efficiency and gender inequality. However, energy poverty is present in the policy lexicon of all case study countries, and Ukraine, in particular, has advanced a number of more sophisticated approaches and programmes.

Robust Rat and Mouse Models of Bilateral Renal Ischemia Reperfusion Injury.

BACKGROUND/AIM: Acute and chronic kidney diseases are a major contributor to morbidity and mortality worldwide, with no specific treatments currently available for these. To enable understanding the pathophysiology of and testing novel treatments for acute and chronic kidney disease, a suitable in vivo model of kidney disease is essential. In this article, we describe two reliable rodent models (rats and mice) of efficacious kidney injury displaying acute to chronic kidney injury progression, which is also reversible through novel therapeutic strategies such as ischemic preconditioning (IPC). MATERIALS AND METHODS: We utilized adult male Lewis rats and adult male wildtype (C57BL/6) mice, performed a midline laparotomy, and induced warm ischemia to both kidneys by bilateral clamping of both renal vascular pedicles for a set time, to mimic the hypoxic etiology of disease commonly found in kidney injury. RESULTS: Bilateral ischemia reperfusion injury caused marked structural and functional kidney injury as exemplified by histology damage scores, serum creatinine levels, and kidney injury biomarker levels in both rodents. Furthermore, this effect displayed a dose-dependent response in the mouse model. CONCLUSION: These rodent models of bilateral kidney IRI are reliable, reproducible, and enable detailed mechanistic study of the underlying pathophysiology of both acute and chronic kidney disease. They have been carefully optimised for single operator use with a strong track record of training both surgically trained and surgically naïve operators.

Plant networks are more connected by invasive brome and native shrub facilitation in Central California drylands.

Dominant vegetation in many ecosystems is an integral component of structure and habitat. In many drylands, native shrubs function as foundation species that benefit other plants and animals. However, invasive exotic plant species can comprise a significant proportion of the vegetation. In Central California drylands, the facilitative shrub Ephedra californica and the invasive Bromus rubens are widely dispersed and common. Using comprehensive survey data structured by shrub and open gaps for the region, we compared network structure with and without this native shrub canopy and with and without the invasive brome. The presence of the invasive brome profoundly shifted the network measure of centrality in the microsites structured by a shrub canopy (centrality scores increased from 4.3 under shrubs without brome to 6.3, i.e. a relative increase of 42%). This strongly suggests that plant species such as brome can undermine the positive and stabilizing effects of native foundation plant species provided by shrubs in drylands by changing the frequency that the remaining species connect to one another. The net proportion of positive and negative associations was consistent across all microsites (approximately 50% with a total of 14% non-random co-occurrences on average) suggesting that these plant-plant networks are rewired but not more negative. Maintaining resilience in biodiversity thus needs to capitalize on protecting native shrubs whilst also controlling invasive grass species particularly when associated with shrubs.

A new family of bacterial ribosome hibernation factors.

To conserve energy during starvation and stress, many organisms use hibernation factor proteins to inhibit protein synthesis and protect their ribosomes from damage1,2. In bacteria, two families of hibernation factors have been described, but the low conservation of these proteins and the huge diversity of species, habitats and environmental stressors have confounded their discovery3-6. Here, by combining cryogenic electron microscopy, genetics and biochemistry, we identify Balon, a new hibernation factor in the cold-adapted bacterium Psychrobacter urativorans. We show that Balon is a distant homologue of the archaeo-eukaryotic translation factor aeRF1 and is found in 20% of representative bacteria. During cold shock or stationary phase, Balon occupies the ribosomal A site in both vacant and actively translating ribosomes in complex with EF-Tu, highlighting an unexpected role for EF-Tu in the cellular stress response. Unlike typical A-site substrates, Balon binds to ribosomes in an mRNA-independent manner, initiating a new mode of ribosome hibernation that can commence while ribosomes are still engaged in protein synthesis. Our work suggests that Balon-EF-Tu-regulated ribosome hibernation is a ubiquitous bacterial stress-response mechanism, and we demonstrate that putative Balon homologues in Mycobacteria bind to ribosomes in a similar fashion. This finding calls for a revision of the current model of ribosome hibernation inferred from common model organisms and holds numerous implications for how we understand and study ribosome hibernation.

Longitudinal Position and Cancer Risk in the United States Revisited.

The debate over daylight saving time (DST) has surged, with interests in the effects of sunlight exposure on health. Prior studies simulated DST and standard time conditions by analyzing different locations within time zones and neighboring areas across time zone borders. We analyzed cancer incidence rates from various longitudinal positions within time zones and at time zone borders in the contiguous United States. Using data from State Cancer Profiles (2016-2020), we analyzed total cancer of 19 types and specific rates for eight cancers, adjusted for age and includes all demographics. log-linear regression is used to replicate a previous study, and spatial regression models are employed to explore discontinuities at borders. Cancer rate differences lack statistical significance within time zones and near borders for total cancer and most individual cancers. Exceptions included breast, prostate, and liver and bile duct cancers, which exhibited significant relationships with relative position at the 95% significance level. Breast and liver and bile duct cancers saw decreases, while prostate cancer incidence increased from west to east within time zones. Relative position does not have a significant impact on cancer incidence, hence cancer development in general. Isolated exceptions may warrant further investigation as more data become available. Our findings challenge prior research, revealing numerous inconsistencies. These disparities urge a reconsideration of the potential disparities in human health associated with DST and standard time. They offer insights contribute to the ongoing discussion surrounding the retention or abandonment of DST. SIGNIFICANCE: In this article, we investigate the relation between the epidemiology of cancer incidence in the United States and time zone-related longitudinal positions. Our results differ from previous research, which were based on a subset of our data, and show that the time zone effect on cancer incidence rate is not significant. Our research provides implications on the implementation of DST by suggesting that there is no cancer-risk associated reason to prefer one time over the other. Our study also uses regression discontinuity design using natural splines, a more advanced statistical method, to increase robustness of our result. Our findings challenge prior research, revealing numerous inconsistencies. These disparities urge a reconsideration of the potential disparities in human health associated with DST and standard time. They offer insights contribute to the ongoing discussion surrounding the retention or abandonment of DST.

Association of neighborhood opportunity and pediatric hospitalization rates in the United States.

We examined associations between a validated, multidimensional measure of social determinants of health and population-based hospitalization rates among children <18 years across 18 states from the 2017 Healthcare Cost and Utilization Project State Inpatient Databases and the US Census. The exposure was ZIP code-level Child Opportunity Index (COI), a composite measure of neighborhood resources and conditions that matter for children's health. The cohort included 614,823 hospitalizations among a population of 29,244,065 children (21.02 hospitalizations per 1000). Adjusted hospitalization rates decreased significantly and in a stepwise fashion as COI increased (p < .001 for each), from 26.56 per 1000 (95% confidence interval [CI] 26.41-26.71) in very low COI areas to 14.76 per 1000 (95% CI 14.66-14.87) in very high COI areas (incidence rate ratio 1.8; 95% CI 1.78-1.81). Decreasing neighborhood opportunity was associated with increasing hospitalization rates among children in 18 US states. These data underscore the importance of social context and community-engaged solutions for health systems aiming to eliminate care inequities.

A Conserved Ribosomal Protein Has Entirely Dissimilar Structures in Different Organisms.

Ribosomes from different species can markedly differ in their composition by including dozens of ribosomal proteins that are unique to specific lineages but absent in others. However, it remains unknown how ribosomes acquire new proteins throughout evolution. Here, to help answer this question, we describe the evolution of the ribosomal protein msL1/msL2 that was recently found in ribosomes from the parasitic microorganism clade, microsporidia. We show that this protein has a conserved location in the ribosome but entirely dissimilar structures in different organisms: in each of the analyzed species, msL1/msL2 exhibits an altered secondary structure, an inverted orientation of the N-termini and C-termini on the ribosomal binding surface, and a completely transformed 3D fold. We then show that this fold switching is likely caused by changes in the ribosomal msL1/msL2-binding site, specifically, by variations in rRNA. These observations allow us to infer an evolutionary scenario in which a small, positively charged, de novo-born unfolded protein was first captured by rRNA to become part of the ribosome and subsequently underwent complete fold switching to optimize its binding to its evolving ribosomal binding site. Overall, our work provides a striking example of how a protein can switch its fold in the context of a complex biological assembly, while retaining its specificity for its molecular partner. This finding will help us better understand the origin and evolution of new protein components of complex molecular assemblies-thereby enhancing our ability to engineer biological molecules, identify protein homologs, and peer into the history of life on Earth.

One hundred and six years of change in a Sonoran Desert plant community: Impact of climate anomalies and trends in species sensitivities.

A major restriction in predicting plant community response to future climate change is a lack of long-term data needed to properly assess species and community response to climate and identify a baseline to detect climate anomalies. Here, we use a 106-year dataset on a Sonoran Desert plant community to test the role of extreme temperature and precipitation anomalies on community dynamics at the decadal scale and over time. Additionally, we tested the climate sensitivity of 39 desert plant species and whether sensitivity was associated with growth form, longevity, geographic range, or local dominance. We found that desert plant communities had shifted directionally over the 106 years, but the climate had little influence on this directional change primarily due to nonlinear shifts in precipitation anomalies. Decadal-scale climate had the largest impact on species richness, species relative density, and total plant cover, explaining up to 26%, 45%, and 55% of the variance in each, respectively. Drought and the interaction between the frequency of freeze events and above-average summer precipitation were among the most influential climate factors. Increased drought frequency and wetter periods with frequent freeze events led to larger reductions in total plant cover, species richness, and the relative densities of dominant subshrubs Ambrosia deltoidea and Encelia farinosa. More than 80% of the tested species were sensitive to climate, but sensitivity was not associated with a species' local dominance, longevity, geographic range, or growth form. Some species appear to exhibit demographic buffering, where when they have a higher sensitivity to drought, they also tend to have a higher sensitivity to favorable (i.e., wetter and hotter) conditions. Overall, our results suggest that, while decadal-scale climate variation substantially impacts these desert plant communities, directional change in temperature over the last century has had little impact due to the relative importance of precipitation and drought. With projections of increased drought in this region, we may see reductions in total vegetation cover and species richness due to the loss of species, possibly through a breakdown in their ability to demographically buffer climatic variation, potentially changing community dynamics through a change in facilitative and competitive processes.

Consistent predictors of microbial community composition across spatial scales in grasslands reveal low context-dependency.

Environmental circumstances shaping soil microbial communities have been studied extensively. However, due to disparate study designs, it has been difficult to resolve whether a globally consistent set of predictors exists, or context-dependency prevails. Here, we used a network of 18 grassland sites (11 of those containing regional plant productivity gradients) to examine (i) if similar abiotic or biotic factors predict both large-scale (across sites) and regional-scale (within sites) patterns in bacterial and fungal community composition, and (ii) if microbial community composition differs consistently at two levels of regional plant productivity (low vs. high). Our results revealed that bacteria were associated with particular soil properties (such as base saturation) and both bacteria and fungi were associated with plant community composition across sites and within the majority of sites. Moreover, a discernible microbial community signal emerged, clearly distinguishing high and low-productivity soils across different grasslands independent of their location in the world. Hence, regional productivity differences may be typified by characteristic soil microbial communities across the grassland biome. These results could encourage future research aiming to predict the general effects of global changes on soil microbial community composition in grasslands and to discriminate fertile from infertile systems using generally applicable microbial indicators.

Ribosomal proteins can hold a more accurate record of bacterial thermal adaptation compared to rRNA.

Ribosomal genes are widely used as 'molecular clocks' to infer evolutionary relationships between species. However, their utility as 'molecular thermometers' for estimating optimal growth temperature of microorganisms remains uncertain. Previously, some estimations were made using the nucleotide composition of ribosomal RNA (rRNA), but the universal application of this approach was hindered by numerous outliers. In this study, we aimed to address this problem by identifying additional indicators of thermal adaptation within the sequences of ribosomal proteins. By comparing sequences from 2021 bacteria with known optimal growth temperature, we identified novel indicators among the metal-binding residues of ribosomal proteins. We found that these residues serve as conserved adaptive features for bacteria thriving above 40°C, but not at lower temperatures. Furthermore, the presence of these metal-binding residues exhibited a stronger correlation with the optimal growth temperature of bacteria compared to the commonly used correlation with the 16S rRNA GC content. And an even more accurate correlation was observed between the optimal growth temperature and the YVIWREL amino acid content within ribosomal proteins. Overall, our work suggests that ribosomal proteins contain a more accurate record of bacterial thermal adaptation compared to rRNA. This finding may simplify the analysis of unculturable and extinct species.

Changes in the Amount and Distribution of Soil Nutrients and Neighbours Have Differential Impacts on Root and Shoot Architecture in Wheat (Triticum aestivum).

Plants exhibit differential behaviours through changes in biomass development and distribution in response to environmental cues, which may impact crops uniquely. We conducted a mesocosm experiment in pots to determine the root and shoot behavioural responses of wheat, T. aestivum. Plants were grown in homogeneous or heterogeneous and heavily or lightly fertilized soil, and alone or with a neighbour of the same or different genetic identity (cultivars: CDC Titanium, Carberry, Glenn, Go Early, and Lillian). Contrary to predictions, wheat did not alter relative reproductive effort in the presence of neighbours, more nutrients, or homogenous soil. Above and below ground, the plants' tendency to use potentially shared space exhibited high levels of plasticity. Above ground, they generally avoided shared, central aerial space when grown with neighbours. Unexpectedly, nutrient amount and distribution also impacted shoots; plants that grew in fertile or homogenous environments increased shared space use. Below ground, plants grown with related neighbours indicated no difference in neighbour avoidance. Those in homogenous soil produced relatively even roots, and plants in heterogeneous treatments produced more roots in nutrient patches. Additionally, less fertile soil resulted in pot-level decreases in root foraging precision. Our findings illustrate that explicit coordination between above- and belowground biomass in wheat may not exist.

Incidence, aetiology and neurodisability associated with severe microcephaly: a national surveillance study.

OBJECTIVE: To determine the incidence, causes and neurodevelopmental impact of severe microcephaly (head circumference <-3SD) up to age 2 years. DESIGN: Binational active paediatric surveillance study undertaken in 2017-2018 to identify and characterise new diagnoses of severe microcephaly. SETTING: UK and Ireland. PARTICIPANTS: Infants aged under 12 months at diagnosis. INTERVENTIONS: Observational study. MAIN OUTCOME MEASURES: Incidence, aetiology and neurodevelopmental outcomes at age 2 years. RESULTS: Fifty-nine infants met the case definition, of whom 30 (51%) were girls; 24 (41%) were born preterm (<37 weeks' gestation); and 34 (58%) were of 'white' ethnicity. Eight (14%) children died before 12 months of age. Incidence of severe microcephaly was 5.5 per 100 000 infants (95% CI 4.0 to 7.3). Higher relative risk (RR) was associated with preterm birth (RR 7.7, 95% CI 3.8 to 15.1) and British Asian ethnicity (RR 3.6, 95% CI 1.6 to 7.8). Microcephaly was mainly due to genetic causes (59%), brain ischaemia/hypoxia (10%) and congenital infection (8%), and 19% remained undetermined. Each child was referred on average to eight specialists, and 75% had abnormal brain imaging. By 2 years of age, 55 children experienced neurodevelopmental abnormalities, including feeding problems (68%), motor delay (66%), visual impairment (37%), hearing loss (24%) and epilepsy (41%). CONCLUSIONS: Although severe microcephaly is uncommon, it is associated with high mortality, complex multimorbidity and neurodisability, thus representing a significant ongoing burden for families and healthcare services. Potentially preventable causes include preterm birth, hypoxic/ischaemic brain injury and congenital infections. Clinical guidelines are essential to standardise aetiological investigation and optimise multidisciplinary management.

Pharmacologic restraint use for children experiencing mental health crises in pediatric hospitals.

BACKGROUND: Children in mental health crises are increasingly admitted to children's hospitals awaiting inpatient psychiatric placement. During hospitalization, patients may exhibit acute agitation prompting pharmacologic restraint use. OBJECTIVE: To determine hospital-level incidence and variation of pharmacologic restraint use among children admitted for mental health conditions in children's hospitals. DESIGN, SETTING, AND PARTICIPANTS: We examined data for children (5 to ≤18 years) admitted to children's hospitals with a primary mental health condition from 2018 to 2020 using the Pediatric Health Information System database. Hospital rates of parenteral pharmacologic restraint use per 1000 mental health bed days were determined and compared after adjusting for patient-level and demographic factors. Cluster analysis (k-means) was used to group hospitals based on overall restraint use (rate quartiles) and drug class. Hospital-level factors for pharmacologic restraint use were compared. RESULTS: Of 29,834 included encounters, 3747 (12.6%) had pharmacologic restraint use. Adjusted hospital rates ranged from 35 to 389 pharmacologic restraint use days per 1000 mental health bed days with a mean of 175 (standard deviation: 72). Cluster analysis revealed three hospitals were high utilizers of all drug classes. No significant differences in pharmacologic restraint use were found in the hospital-level analysis. CONCLUSIONS: Children's hospitals demonstrate wide variation in pharmacologic restraint rates for mental health hospitalizations, with a 10-fold difference in adjusted rates between highest and lowest utilizers, and high overall utilizers order medications across all drug classes.

Protocol for the development of a multidisciplinary clinical practice guideline for the care of patients with chronic subdural haematoma.

Introduction: A common neurosurgical condition, chronic subdural haematoma (cSDH) typically affects older people with other underlying health conditions. The care of this potentially vulnerable cohort is often, however, fragmented and suboptimal. In other complex conditions, multidisciplinary guidelines have transformed patient experience and outcomes, but no such framework exists for cSDH. This paper outlines a protocol to develop the first comprehensive multidisciplinary guideline from diagnosis to long-term recovery with cSDH. Methods: The project will be guided by a steering group of key stakeholders and professional organisations and will feature patient and public involvement. Multidisciplinary thematic working groups will examine key aspects of care to formulate appropriate, patient-centered research questions, targeted with evidence review using the GRADE framework. The working groups will then formulate draft clinical recommendations to be used in a modified Delphi process to build consensus on guideline contents. Conclusions: We present a protocol for the development of a multidisciplinary guideline to inform the care of patients with a cSDH, developed by cross-disciplinary working groups and arrived at through a consensus-building process, including a modified online Delphi.

Business recovery from disasters: Lessons from natural hazards and the COVID-19 pandemic.

This paper compares economic recovery in the COVID-19 pandemic with other types of disasters, at the scale of businesses. As countries around the world struggle to emerge from the pandemic, studies of business impact and recovery have proliferated; however, pandemic research is often undertaken without the benefit of insights from long-standing research on past large-scale disruptive events, such as floods, storms, and earthquakes. This paper builds synergies between established knowledge on business recovery in disasters and emerging insights from the COVID-19 pandemic. It first proposes a disaster event taxonomy that allows the pandemic to be compared with natural hazard events from the perspective of economic disruption. The paper then identifies five key lessons on business recovery from disasters and compares them to empirical findings from the COVID-19 pandemic. For synthesis, a conceptual framework on business recovery is developed to support policy-makers to anticipate business recovery needs in economically disruptive events, including disasters. Findings from the pandemic largely resonate with those from disasters. Recovery tends to be more difficult for small businesses, those vulnerable to supply chain problems, those facing disrupted markets, and locally-oriented businesses in heavily impacted neighborhoods. Disaster assistance that is fast and less restrictive provides more effective support for business recovery. Some differences emerge, however: substantial business disruption in the pandemic derived from changes in demand due to regulatory measures as well as consumer behaviour; businesses in high-income neighborhoods and central business districts were especially affected; and traditional forms of financial assistance may need to be reconsidered.

Avoiding migration at open mesh plug inguinal hernioplasty.

The open repair of groin hernias is often augmented with prosthetic biomaterials (mesh) as this favours a lower recurrence rate. The use of such prostheses may be associated with various complications including migration the frequency of which is unclear. A 29-year review of this complication after mesh plug hernioplasty is undertaken and technical advice described to avoid this.