A targeted gene panel illuminates pathogenesis in young people with unexplained kidney failure.

BACKGROUND: Kidney failure in young people is often unexplained and a significant proportion will have an underlying genetic diagnosis. National Health Service England pioneered a comprehensive genomic testing service for such circumstances accessible to clinicians working outside of genetics. This is the first review of patients using this novel service since October 2021, following its introduction into clinical practice. METHODS: The 'Unexplained Young-Onset End-Stage Renal Disease' (test-code R257) gene panel uses targeted next generation sequencing to analyse 175 genes associated with renal disease in patients under 36 years of age. All tests undertaken between October 2021 and February 2022 were reviewed. Phenotypic data were extracted from request forms and referring clinicians contacted where additional details were required. RESULTS: Seventy-one patients underwent R257 testing over the study period. Among them, 23/71 patients (32%) were confirmed to have a genetic diagnosis and 2/71 (3%) had a genetically suggestive variant. Nephronophthisis and Alport syndrome were the most common conditions identified, (4/23 (17%) with pathogenic variants in NPHP1 and 4/23 (17%) with pathogenic variants in COL4A3/COL4A4). Positive predictors of a genetic diagnosis included a family history of renal disease (60% of positive cases) and extra-renal disease manifestations (48% of positive cases). CONCLUSION: This is the first study to evaluate the R257 gene panel in unexplained young-onset kidney failure, freely accessible to patients meeting testing criteria in England. A genetic diagnosis was identified in 32% of patients. This study highlights the essential and expanding role that genomic testing has for children and families affected by renal disease today.

Comparing nasal suction devices in children with bronchiolitis: A pilot randomized control trial.

BACKGROUND/OBJECTIVES: Bronchiolitis is the most common cause of lower respiratory tract infections that lead to hospitalizations in infants and young children. METHODS: In this randomized controlled pilot study, we compared two separate nasal suction devices, namely the over counter device by the brand name of NoseFrida and the standard hospital device NeoSucker, in hospitalized children with bronchiolitis to assess equivalence of length of stay within a ± 5-h equivalence margin and to compare readmission rates and associated complications. Additionally, parental satisfaction for the NoseFrida device was measured with a six question (5-point Likert scale) survey. RESULTS: There were 20 patients randomized to the NeoSucker group and 24 randomized to the NoseFrida group. The mean length of stay for the NoseFrida group was 33.5 ± 25.4 h compared to 31.0 ± 15.6 h in the NeoSucker group, which did not establish equivalence within the ±5-h equivalence margin (p = 0.352). Parents were generally satisfied with the NoseFrida. Patients treated with the two devices had similar frequencies of deep suctioning and readmission within 48 h. CONCLUSIONS: Although the mean length of stay was comparable for bronchiolitis patients treated with the NoseFrida and NeoSucker, the relatively small sample size and large amount of variability precluded demonstrating equivalence. Since this was a pilot, further studies are needed to evaluate the recommendation for the use of such devices in both the hospital setting and in the outpatient management of bronchiolitis.

Status 2 upgrade indication impacts posttransplant mortality in patients bridged with intraaortic balloon pump in the new heart allocation system.

To evaluate outcomes of patients undergoing heart transplants (HTs) using an intra-aortic balloon pump (IABP) under exception status. Adult patients supported by an IABP who underwent HT between November 18, 2018, and December 31, 2020, as documented in the United Network for Organ Sharing, were included. Patients were stratified according to requests for exception status. Kaplan-Meier methodology was used to look for differences in survival between groups. A total of 1284 patients were included; 492 (38.3%) were transplanted with an IABP under exception status. Exception status patients had higher body mass index, were more likely to be Black, and had longer waitlist times. Exception status patients received organs from younger donors, had a shorter ischemic time, and had a higher frequency of sex mismatch. The 1-year posttransplant survival was 93% for the nonexception and 88% for the exception IABP patients (hazard ratio: 1.85 [95% confidence interval: 1.12-2.86, P = .006]). The most common reason for requesting an exception status was inability to meet blood pressure criteria for extension (37% of patients). The most common reason for an extension request for an exception status was right ventricular dysfunction (24%). IABP patients transplanted under exception status have an increased 1-year mortality rate posttransplant compared with those without exception status.

Use of historical isoscapes to develop an estuarine nutrient baseline.

Coastal eutrophication is a prevalent threat to the healthy functioning of ecosystems globally. While degraded water quality can be detected by monitoring oxygen, nutrient concentrations, and algal abundance, establishing regulatory guidelines is complicated by a lack of baseline data (e.g., pre-Anthropocene). We use historical carbon and nitrogen isoscapes over ~300 years from sediment cores to reconstruct spatial and temporal changes in nutrient dynamics for a central California estuary, Elkhorn Slough, where development and agriculture dramatically enhanced nutrient inputs over the past century. We found strong contrasts between current sediment stable isotopes and those from the recent past, demonstrating shifts exceeding those in previously studied eutrophic estuaries and substantial increases in nutrient inputs. Comparisons of contemporary with historical isoscapes also revealed that nitrogen sources shifted from a historical marine-terrestrial gradient with higher δ15N near the inlet to amplified denitrification at the head and mouth of the modern estuary driven by increased N inputs. Geospatial analysis of historical data suggests that an increase in fertilizer application - rather than population growth or increases in the extent of cultivated land - is chiefly responsible for increasing nutrient loads during the 20th century. This study demonstrates the ability of isotopic and stoichiometric maps to provide important perspectives on long-term shifts and spatial patterns of nutrients that can be used to improve management of nutrient pollution.

Improved mapping of coastal salt marsh habitat change at Barnegat Bay (NJ, USA) using object-based image analysis of high-resolution aerial imagery.

Tidal wetlands are valued for the ecosystem services they provide yet are vulnerable to loss due to anthropogenic disturbances such as land conversion, hydrologic modifications, and the impacts of climate change, especially accelerating rates of sea level rise. To effectively manage tidal wetlands in face of multiple stressors, accurate studies of wetland extent and trends based on high-resolution imagery are needed. We provide salt marsh delineations for Barnegat Bay, New Jersey, by means of object-based image analysis of high-resolution aerial imagery and digital elevation models. We performed trends analyses of salt marsh extent from 1995 to 2015 and estimated drivers of marsh area change. We found that in 1995, 8830 ± 390 ha were covered with marsh vegetation, while in 2015 only 8180 ± 380 ha of salt marsh habitat remained. The resulting net loss rate of 0.37% yr-1 is equivalent to historic loss rates since the 1970s, indicating that despite regionally accelerating relative sea level rise and purported eutrophication, salt marsh loss rates at Barnegat Bay remain steady. The main drivers of salt marsh loss are excavations for mosquito control (409 ha), edge erosion (303 ha) and ponding (240 ha). Upland migration of salt marsh did not completely mitigate these losses but accounted for a gain of 147 ha of tidal marsh habitat. The methodology presented herein yielded accurate salt marsh delineations (>90%) and trend detection (85%), outperforming low-resolution wetland delineations used in coastal management. This study demonstrates the suitability of high-resolution imagery for the detection of open water features. For the purposes of salt marsh change detection and the identification of change drivers, management and conservation agencies should make use of high-resolution imagery whenever feasible.

Breast Imaging During a Cyberattack and Global Pandemic: What We Did to Pick Up the Pieces.

Cybersecurity in healthcare is a very real threat with the potential to severely disrupt patient care, place extra burden on an already strained system, and result in significant financial losses for a hospital or healthcare network. In October 2020, on the backdrop of the ongoing COVID-19 pandemic, our institution experienced one of the most significant cyberattacks on a healthcare system to date, lasting for nearly 40 days. By sharing our experience in radiology, and specifically in breast imaging, including the downtime procedures we relied upon and the lessons that we learned emerging from this cyberattack, we hope to help future victims of a healthcare cyberattack successfully weather such an experience.

Exploring the business skills, experiences and preparedness of UK-based private physiotherapists when establishing and developing a physiotherapy business: A hermeneutic phenomenological study.

AIM: To explore the business skills, experiences and preparedness of UK-based private physiotherapists when establishing and developing a physiotherapy business. DESIGN: A hermeneutic phenomenological approach. PARTICIPANTS: Six UK-based private physiotherapy practice owners were recruited via purposive and snowball sampling. METHODS: In-depth, semi-structured video interviews (n = 12) were audio-recorded and transcribed. Field notes, respondent validation and a reflexive diary were used. Data underwent line-by-line analysis, identifying codes and themes. Constant comparison of data, codes and themes occurred throughout. Peer review was utilised, and small sections of data and all emerging codes were independently reviewed. RESULTS: Knowledge acquisition: participants acquired business knowledge from training, external help, and trial-and-error approaches. Improved physiotherapy-related business training was requested. Business skills: Business plans were generally organic or lapsed with time. Success and timing of marketing strategies varied widely. The altruistic nature of many physiotherapists creates difficulties in requesting payments for services. Clinical policies: Lone working risks appeared more weighted towards protecting staff from physical abuse rather than allegations. CONCLUSIONS: Improved physiotherapy-related business support and guidance may be beneficial. Focusing on word-of-mouth, website marketing, and establishing support networks may benefit practice owners. Greater consideration of the potentially negative implications of lone working, particularly accusations of inappropriate sexual behaviour, is recommended.

Runnels mitigate marsh drowning in microtidal salt marshes.

As a symptom of accelerated sea level rise and historic impacts to tidal hydrology from agricultural and mosquito control activities, coastal marshes in the Northeastern U.S. are experiencing conversion to open water through edge loss, widening and headward erosion of tidal channels, and the formation and expansion of interior ponds. These interior ponds often form in high elevation marsh, confounding the notion applied in predictive modeling that salt marshes convert to open water when elevation falls below a critical surface inundation threshold. The installation of tidal channel extension features, or runnels, is a technique that has been implemented to reduce water levels and permit vegetation reestablishment in drowning coastal marshes, although there are limited data available to recommend its advisability. We report on 5 years of vegetation and hydrologic monitoring of two locations where a total of 600-m of shallow (0.15-0.30-m in diameter and depth) runnels were installed in 2015 and 2016 to enhance drainage, in the Pettaquamscutt River Estuary, in southern Rhode Island, United States. Results from this Before-After Control-Impact (BACI) designed study found that runnel installation successfully promoted plant recolonization, although runnels did not consistently promote increases in high marsh species presence or diversity. Runnels reduced the groundwater table (by 0.07-0.12 m), and at one location, the groundwater table experienced a 2-fold increase in the fraction of the in-channel tidal range that was observed in the marsh water table. We suggest that restoration of tidal hydrology through runnel installation holds promise as a tool to encourage revegetation and extend the lifespan of drowning coastal marshes where interior ponds are expanding. In addition, our study highlights the importance of considering the rising groundwater table as an important factor in marsh drowning due to expanding interior ponds found on the marsh platform.

High nutrient loads amplify carbon cycling across California and New York coastal wetlands but with ambiguous effects on marsh integrity and sustainability.

Eutrophic conditions in estuaries are a globally important stressor to coastal ecosystems and have been suggested as a driver of coastal salt marsh loss. Potential mechanisms in marshes include disturbance caused by macroalgae accumulations, enhanced soil sulfide levels linked to high labile carbon inputs, accelerated decomposition, and declines in belowground biomass that contribute to edge instability, erosion, and slumping. However, results of fertilization studies have been mixed, and it is unclear the extent to which local environmental conditions, such as soil composition and nutrient profiles, help shape the response of salt marshes to nutrient exposure. In this study, we characterized belowground productivity and decomposition, organic matter mineralization rates, soil respiration, microbial biomass, soil humification, carbon and nitrogen inventories, nitrogen isotope ratios, and porewater profiles at high and low marsh elevations across eight marshes in four estuaries in California and New York that have strong contrasts in nutrient inputs. The higher nutrient load marshes were characterized by faster carbon turnover, with higher belowground production and decomposition and greater carbon dioxide efflux than lower nutrient load marshes. These patterns were robust across marshes of the Atlantic and Pacific coasts that varied in plant species composition, soil flooding patterns, and soil texture. Although impacts of eutrophic conditions on carbon cycling appeared clear, it was ambiguous whether high nutrient loads are causing negative effects on long-term marsh sustainability in terms of studied metrics. While high nutrient exposure marshes had high rates of decomposition and soil respiration rates, high nutrient exposure was also associated with increased belowground production, and reduced levels of sulfides, which should lead to greater marsh sustainability. While this study does not resolve the extent to which nutrient loads are negatively affecting these salt marshes, we do highlight functional differences between Atlantic and Pacific wetlands which may be useful for understanding coastal marsh health and integrity.

Basement membrane defects in CD151-associated glomerular disease.

BACKGROUND: CD151 is a cell-surface molecule of the tetraspanin family. Its lateral interaction with laminin-binding integrin ɑ3ß1 is important for podocyte adhesion to the glomerular basement membrane (GBM). Deletion of Cd151 in mice induces glomerular dysfunction, with proteinuria and associated focal glomerulosclerosis, disorganisation of GBM and tubular cystic dilation. Despite this, CD151 is not routinely screened for in patients with nephrotic-range proteinuria. We aimed to better understand the relevance of CD151 in human kidney disease. METHODS: Next-generation sequencing (NGS) was used to detect the variant in CD151. Electron and light microscopy were used to visualise the filtration barrier in the patient kidney biopsy, and immunoreactivity of patient red blood cells to anti-CD151/MER2 antibodies was performed. Further validation of the CD151 variant as disease-causing was performed in zebrafish using CRISPR-Cas9. RESULTS: We report a young child with nail dystrophy and persistent urinary tract infections who was incidentally found to have nephrotic-range proteinuria. Through targeted NGS, a novel, homozygous truncating variant was identified in CD151, a gene rarely reported in patients with nephrotic syndrome. Electron microscopy imaging of patient kidney tissue showed thickening of GBM and podocyte effacement. Immunofluorescence of patient kidney tissue demonstrated that CD151 was significantly reduced, and we did not detect immunoreactivity to CD151/MER2 on patient red blood cells. CRISPR-Cas9 depletion of cd151 in zebrafish caused proteinuria, which was rescued by injection of wild-type CD151 mRNA, but not CD151 mRNA containing the variant sequence. CONCLUSIONS: Our results indicate that a novel variant in CD151 is associated with nephrotic-range proteinuria and microscopic haematuria and provides further evidence for a role of CD151 in glomerular disease. Our work highlights a functional testing pipeline for future analysis of patient genetic variants. A higher resolution version of the Graphical abstract is available as Supplementary information.

Relationships between ecosystem properties and sea-level rise vulnerability of tidal wetlands of the U.S. Mid-Atlantic.

Tidal wetlands in the Mid-Atlantic, USA, are experiencing high rates of relative sea level rise, and it is unclear whether they will be resilient in the face of future flooding increases. In a previous study, we found 80% of our study areas in tidal freshwater and salt marshes in the Delaware Estuary and Barnegat Bay had elevation change rates lower than the 19-year increase in mean sea level. Here, we examine relationships between marsh elevation dynamics and abiotic and biotic parameters in order to assess their utility as indicators of vulnerability to relative sea level rise. We further apply a range of marsh vulnerability indicators including elevation change rates to evaluate their ability to corroborate marsh habitat change over the last 30 years. Of the field measurements, soil bulk density and belowground plant biomass were among the strongest predictors of elevation change and accretion dynamics across all marsh types and settings. Both tidal freshwater and salt marshes tended to have higher rates of elevation increase and surface accretion in areas where soil bulk density and live belowground biomass were higher. Nine of the ten marshes experienced a net loss of area from the 1970s to 2015 ranging from 0.05 to 14%. Although tidal freshwater marshes were low in elevation and experienced variable elevation change rates, marsh area loss was low. Conversely, salt marshes closest to the coast and perched high in the tidal frame with a higher degree of human modification tended to experience the greatest marsh loss, which incorporated anthropogenic impacts and edge erosion. Thus, our regional assessment points to the need for a comprehensive understanding of factors that influence marsh resilience including human modifications and geomorphic settings.

Tidal Flushing Rather Than Non-Point Source Nitrogen Pollution Drives Nutrient Dynamics in A Putatively Eutrophic Estuary.

The effects of nonpoint source nutrients on estuaries can be difficult to pinpoint, with researchers often using indicator species, monitoring, and models to detect influence and change. Here, we made stable isotope measurements of nitrogen and carbon in sediment, water column particulates, primary producers, and consumers at 35 stations in the reportedly eutrophic Barnegat Bay (New Jersey) to assess N sources and processing pathways. Combined with water quality and hydrological data, our C and N isoscapes revealed four distinct geographic zones with diverging isotopic baselines, indicating variable nutrient sources and processing pathways. Overall, the carbon stable isotopes δ13C) reflected the terrestrial-marine gradient with the most depleted values in the urban and poorly flushed north of the estuary to the most enriched values in the salt marsh-dominated south. In contrast, the nitrogen stable isotope values δ15N) were most enriched near the oceanic inlets and were consistent with offshore δ15N values in particulate organic matter. Several biogeochemical processes likely alter δ15N, but the relatively lower δ15N values associated with the most urbanized area indicate that anthropogenic runoff is not a dominant N source to this area. Our findings stand in contrast to previous studies of similar estuaries, as δ15N signatures of biota in this system are inversely correlated to population density and nutrient concentrations. Further, our analyses of archival plant (Spartina sp., Phragmites australis) and shell (Geukensia demissa, Ilyanassa obsoleta) samples collected between 1880 and 2020 indicated that δ15N values have decreased over time, particularly in the consumers. Overall, we find that water quality issues appear to be most acute in the poorly flushed parts of Barnegat Bay and emphasize the important role that oceanic exchange plays in water quality and associated estuarine food webs in the lagoon.

The Forum, Society for Women Sports Medicine Orthopaedic Surgeons.

The Forum is a private, not-for-profit organization for board-certified, fellowship-trained, female orthopaedic surgeons. Founded in 1999, The Forum was conceived as a partnership with women in industry, designed to support women orthopaedic surgeons by providing a place to share research and practice ideas and to stimulate interest and research in arthroscopic surgery. Membership has grown from a handful of founding members to nearly 100 strong in 2021. An annual meeting is held over Martin Luther King, Jr., weekend each year, combining scientific and social programs and highlighted by the Sandy Kirkley Memorial Lecture. The Forum has recently gained notoriety through the work of some of its members in advocating for the protection of athletes from sexual abuse and the publication of the first position statement on the topic, subsequently endorsed by the American Academy of Orthopaedic Surgeons. A recent partnership with the American Orthopaedic Society for Sports Medicine and the Arthroscopy Association of North America to provide concurrent sessions at the 2021 combined annual meeting has increased the visibility of the society and its members.

Guidelines for Genetic Testing and Management of Alport Syndrome.

Genetic testing for pathogenic COL4A3-5 variants is usually undertaken to investigate the cause of persistent hematuria, especially with a family history of hematuria or kidney function impairment. Alport syndrome experts now advocate genetic testing for persistent hematuria, even when a heterozygous pathogenic COL4A3 or COL4A4 is suspected, and cascade testing of their first-degree family members because of their risk of impaired kidney function. The experts recommend too that COL4A3 or COL4A4 heterozygotes do not act as kidney donors. Testing for variants in the COL4A3-COL4A5 genes should also be performed for persistent proteinuria and steroid-resistant nephrotic syndrome due to suspected inherited FSGS and for familial IgA glomerulonephritis and kidney failure of unknown cause.

Consensus statement on standards and guidelines for the molecular diagnostics of Alport syndrome: refining the ACMG criteria.

The recent Chandos House meeting of the Alport Variant Collaborative extended the indications for screening for pathogenic variants in the COL4A5, COL4A3 and COL4A4 genes beyond the classical Alport phenotype (haematuria, renal failure; family history of haematuria or renal failure) to include persistent proteinuria, steroid-resistant nephrotic syndrome, focal and segmental glomerulosclerosis (FSGS), familial IgA glomerulonephritis and end-stage kidney failure without an obvious cause. The meeting refined the ACMG criteria for variant assessment for the Alport genes (COL4A3-5). It identified 'mutational hotspots' (PM1) in the collagen IV α5, α3 and α4 chains including position 1 Glycine residues in the Gly-X-Y repeats in the intermediate collagenous domains; and Cysteine residues in the carboxy non-collagenous domain (PP3). It considered that 'well-established' functional assays (PS3, BS3) were still mainly research tools but sequencing and minigene assays were commonly used to confirm splicing variants. It was not possible to define the Minor Allele Frequency (MAF) threshold above which variants were considered Benign (BA1, BS1), because of the different modes of inheritances of Alport syndrome, and the occurrence of hypomorphic variants (often Glycine adjacent to a non-collagenous interruption) and local founder effects. Heterozygous COL4A3 and COL4A4 variants were common 'incidental' findings also present in normal reference databases. The recognition and interpretation of hypomorphic variants in the COL4A3-COL4A5 genes remains a challenge.

Osseous lesions in the distal extremities of dogs with strangulating hair mats.

Strangulating hair mats in dogs are characterized as soft tissue injury secondary to chronically matted hair, which can encircle the extremities and constrict lymphatic tissue and local vasculature. As the tissue swells, the hair constriction tightens and may result in tissue necrosis and osseous changes secondary to ischemic necrosis. The objectives of this retrospective case series were to describe the radiographic characteristics of persistent hair mat strangulation in dogs, to identify clinical features that would distinguish between dogs with soft tissue lesions only and dogs with osseous changes and to describe the clinical outcome in these dogs. All dogs with clinically identified strangulating hair matting had radiographically identified soft tissues defects and over half of the limbs evaluated had osseous lesions including focal periostitis, bone remodeling, bone atrophy, lysis of bone, and occasionally subluxation of joints. Chronically matted hair and strangulating hair mats in dogs are recognized by veterinarians as a medical finding in animal neglect. The osseous features of strangulating hair mats have not been described in the veterinary medical literature. This study describes the clinical features and radiographic characteristics of strangulating hair mats.

Recent Carbon Storage and Burial Exceed Historic Rates in the San Juan Bay Estuary Peri-Urban Mangrove Forests (Puerto Rico, United States).

Mangroves sequester significant quantities of organic carbon (C) because of high rates of burial in the soil and storage in biomass. We estimated mangrove forest C storage and accumulation rates in aboveground and belowground components among five sites along an urbanization gradient in the San Juan Bay Estuary, Puerto Rico. Sites included the highly urbanized and clogged Caño Martin Peña in the western half of the estuary, a series of lagoons in the center of the estuary, and a tropical forest reserve (Piñones) in the easternmost part. Radiometrically dated cores were used to determine sediment accretion and soil C storage and burial rates. Measurements of tree dendrometers coupled with allometric equations were used to estimate aboveground biomass. Estuary-wide mangrove forest C storage and accumulation rates were estimated using interpolation methods and coastal vegetation cover data. In recent decades (1970-2016), the highly urbanized Martin Peña East (MPE) site with low flushing had the highest C storage and burial rates among sites. The MPE soil carbon burial rate was over twice as great as global estimates. Mangrove forest C burial rates in recent decades were significantly greater than historic decades (1930-1970) at Cañno Martin Peña and Piñones. Although MPE and Piñones had similarly low flushing, the landscape settings (clogged canal vs forest reserve) and urbanization (high vs low) were different. Apparently, not only urbanization, but site-specific flushing patterns, landscape setting, and soil fertility affected soil C storage and burial rates. There was no difference in C burial rates between historic and recent decades at the San José and La Torrecilla lagoons. Mangrove forests had soil C burial rates ranging from 88 g m-2 y-1 at the San José lagoon to 469 g m-2 y-1 at the MPE in recent decades. Watershed anthropogenic CO2 emissions (1.56 million Mg C y-1) far exceeded the annual mangrove forest C storage rates (aboveground biomass plus soils: 17,713 Mg C y-1). A combination of maintaining healthy mangrove forests and reducing anthropogenic emissions might be necessary to mitigate greenhouse gas emissions in urban, tropical areas.