Green treasures: Investigating the biodiversity potential of equine yards through the presence and quality of landscape features in the Netherlands.

At a time of mounting ecological crises and biodiversity loss, there is an urgent need for nature-based solutions. Equestrian properties cover a considerable proportion of the European rural and peri-urban landscape and provide much potential for integrating ecosystem services, such as the inclusion of small landscape features. The aim of this study was to investigate the presence and quality of landscape features (LF) to help determine how the equine sector can contribute to the agro-ecological transition. Using a citizen science approach, 87 commercial and 420 private yard owners reported the type, frequency and geometric dimension of LFs and additional biodiversity enhancing features. A hierarchical multivariate regression was used to determine how equine property characteristics explain variation in the Percentage Property Coverage (PPC) of LFs. The model explained 47% of the variation of PPC. The variables that explained significant variation in PPC included Yard size, Number of LFs, Tree rows, Fruit orchard, Wild hedges, Flowering strips, Buffer strips, Embankments and Cluttered corners. Commercial yards are significantly larger with significantly more horses and on average only 9% (±13.87%) of the property was covered by LFs whilst private yards had significantly more coverage of LFs with on average 12% (±14.77%). These findings highlight the substantial yet untapped potential of equine yards in fostering biodiversity, suggesting that the equine sector could play an important role in the agro-ecological transition. To encourage more biodiverse-inclusive yard designs, tailored strategies should consider the diverse factors influencing equine yard design, including existing knowledge, client demands, financial considerations, and equine health and welfare.

Iron limitation of heterotrophic bacteria in the California Current System tracks relative availability of organic carbon and iron.

Iron is an essential nutrient for all microorganisms of the marine environment. Iron limitation of primary production has been well documented across a significant portion of the global surface ocean, but much less is known regarding the potential for iron limitation of the marine heterotrophic microbial community. In this work, we characterize the transcriptomic response of the heterotrophic bacterial community to iron additions in the California Current System, an eastern boundary upwelling system, to detect in situ iron stress of heterotrophic bacteria. Changes in gene expression in response to iron availability by heterotrophic bacteria were detected under conditions of high productivity when carbon limitation was relieved but when iron availability remained low. The ratio of particulate organic carbon to dissolved iron emerged as a biogeochemical proxy for iron limitation of heterotrophic bacteria in this system. Iron stress was characterized by high expression levels of iron transport pathways and decreased expression of iron-containing enzymes involved in carbon metabolism, where a majority of the heterotrophic bacterial iron requirement resides. Expression of iron stress biomarkers, as identified in the iron-addition experiments, was also detected insitu. These results suggest iron availability will impact the processing of organic matter by heterotrophic bacteria with potential consequences for the marine biological carbon pump.

CHF6297: a novel potent and selective p38 MAPK inhibitor with robust anti-inflammatory activity and suitable for inhaled pulmonary administration as dry powder.

Inhibition of p38 mitogen-activated protein kinase (MAPKs) is a potential therapeutic approach for the treatment of acute and chronic pulmonary inflammatory conditions. Here, we report the in vitro and in vivo characterization of the anti-inflammatory effects of CHF6297, a novel potent and selective p38α inhibitor designed for inhalation delivery as a dry powder formulation. CHF6297 has been proven to inhibit p38α enzymatic activity with sub-nanomolar potency (IC50 = 0.14 ± 0.06 nM), with >1,000-fold selectivity against p38γ and p38δ. In human peripheral blood mononuclear cells (PBMCs) stimulated with lipopolysaccharides (LPS), as well as in human bronchial epithelial cells (BEAS2B) stimulated with TNF-α or cigarette smoke extract (CSE), CHF6297 inhibited interleukin (IL)-8 release with low nanomolar potency. CHF6297 administered to rats by using a nose-only inhalation device as a micronized dry powder formulation blended with lactose dose-dependently inhibited the LPS-induced neutrophil influx in the bronchoalveolar lavage fluid (BALF). CHF6297 administered intratracheally to rats dose-dependently counteracted the IL-1ß (0.3 mg/kg)-induced neutrophil influx (ED50 = 0.22 mg/kg) and increase in IL-6 levels (ED50 = 0.82 mg/kg) in the BALF. In mice exposed to tobacco smoke (TS), CHF6297, administered intranasally (i.n.) for 4 days at 0.03 or 0.3 mg/kg, dose-dependently inhibited the corticosteroid-resistant TS-induced neutrophil influx in the BALF. In a murine house dust mite (HDM) model of asthma exacerbated by influenza virus A (IAV) (H3N3), CHF6297 (0.1 mg/kg, i.n.) significantly decreased airway neutrophilia compared to vehicle-treated IAV/HDM-challenged mice. When CHF6297, at a dose ineffective per se (0.03 mg/kg), was added to budesonide, it augmented the anti-inflammatory effects of the steroid. Overall, CHF6297 effectively counteracted lung inflammation in experimental models where corticosteroids exhibit limited anti-inflammatory activity, suggesting a potential for the treatment of acute exacerbations associated with chronic obstructive pulmonary disease (COPD) and asthma, acute lung injury (ALI), and viral-induced hyperinflammation.

A Comparison of Patient Characteristics and Outcomes Between Patients Receiving Flexor Digitorum Superficialis Slip Excision or Isolated A1 Pulley Release for Trigger Finger.

PURPOSE: Resection of the radial or ulnar slip of the flexor digitorum superficialis (FDS) tendon is a known treatment option for persistent trigger finger. Risk factors for undergoing FDS slip excision are unclear. We hypothesized that patients who underwent A1 pulley release with FDS slip excision secondary to persistent triggering would have a higher comorbidity burden compared to those receiving A1 pulley release alone. METHODS: We identified all adult patients who underwent A1 pulley release with FDS slip excision because of persistent triggering either intraoperatively or postoperatively from 2018 to 2023. We selected a 3:1 age- and sex-matched control group who underwent isolated A1 pulley release. Charts were retrospectively reviewed for demographics, selected comorbidities, trigger finger history, and postoperative course. We performed multivariable logistic regression to assess the probability of FDS slip excision after adjusting for several variables that were significant in bivariate comparisons. RESULTS: We identified 48 patients who underwent A1 pulley release with FDS slip excision and 144 controls. Our multivariable model showed that patients with additional trigger fingers and a preoperative proximal interphalangeal (PIP) joint contracture were significantly more likely to undergo FDS slip excision. CONCLUSIONS: Patients who underwent A1 pulley release with FDS slip excision were significantly more likely to have multiple trigger fingers or a preoperative PIP joint contracture. Clinicians should counsel patients with these risk factors regarding the potential for FDS slip excision in addition to A1 pulley release to alleviate triggering of the affected digit. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic III.

Four-week inhibition of the renin-angiotensin system in spontaneously hypertensive rats results in persistently lower blood pressure with reduced kidney renin and changes in expression of relevant gene networks.

AIMS: Prevention of human hypertension is an important challenge and has been achieved in experimental models. Brief treatment with renin-angiotensin system (RAS) inhibitors permanently reduces the genetic hypertension of the spontaneously hypertensive rat (SHR). The kidney is involved in this fascinating phenomenon, but relevant changes in gene expression are unknown. METHODS: In SHR, we studied the effect of treatment between 10 and 14 weeks of age with the angiotensin receptor blocker, losartan, or the angiotensin-converting enzyme (ACE) inhibitor, perindopril (with controls for non-specific effects of lowering BP) on differential RNA expression, DNA methylation and renin immunolabelling in the kidney at 20 weeks of age. RESULTS: RNA sequencing revealed a 6-fold increase in renin gene (Ren) expression during losartan treatment (P < 0.0001). Six weeks after losartan, arterial pressure remained lower (P = 0.006), yet kidney Ren showed reduced expression by 23% after losartan (P = 0.03) and by 43% after perindopril (P = 1.4 x 10-6) associated with increased DNA methylation (P = 0.04). Immunolabelling confirmed reduced cortical renin after earlier RAS blockade (P = 0.002). RNA sequencing identified differential expression of mRNAs, miRNAs and lncRNAs with evidence of networking and co-regulation. These included 13 candidate genes (Grhl1, Ammecr1l, Hs6st1, Nfil3, Fam221a, Lmo4, Adamts1, Cish, Hif3a, Bcl6, Rad54l2, Adap1, Dok4), the miRNA miR-145-3p and the lncRNA AC115371. Gene ontogeny analyses revealed that these networks were enriched with genes relevant to BP, RAS and the kidneys. CONCLUSIONS: Early RAS inhibition in SHR resets genetic pathways and networks resulting in a legacy of reduced Ren expression and BP persisting for a minimum of 6 weeks.

A shared neoantigen vaccine combined with immune checkpoint blockade for advanced metastatic solid tumors: phase 1 trial interim results.

Therapeutic vaccines that elicit cytotoxic T cell responses targeting tumor-specific neoantigens hold promise for providing long-term clinical benefit to patients with cancer. Here we evaluated safety and tolerability of a therapeutic vaccine encoding 20 shared neoantigens derived from selected common oncogenic driver mutations as primary endpoints in an ongoing phase 1/2 study in patients with advanced/metastatic solid tumors. Secondary endpoints included immunogenicity, overall response rate, progression-free survival and overall survival. Eligible patients were selected if their tumors expressed one of the human leukocyte antigen-matched tumor mutations included in the vaccine, with the majority of patients (18/19) harboring a mutation in KRAS. The vaccine regimen, consisting of a chimp adenovirus (ChAd68) and self-amplifying mRNA (samRNA) in combination with the immune checkpoint inhibitors ipilimumab and nivolumab, was shown to be well tolerated, with observed treatment-related adverse events consistent with acute inflammation expected with viral vector-based vaccines and immune checkpoint blockade, the majority grade 1/2. Two patients experienced grade 3/4 serious treatment-related adverse events that were also dose-limiting toxicities. The overall response rate was 0%, and median progression-free survival and overall survival were 1.9 months and 7.9 months, respectively. T cell responses were biased toward human leukocyte antigen-matched TP53 neoantigens encoded in the vaccine relative to KRAS neoantigens expressed by the patients' tumors, indicating a previously unknown hierarchy of neoantigen immunodominance that may impact the therapeutic efficacy of multiepitope shared neoantigen vaccines. These data led to the development of an optimized vaccine exclusively targeting KRAS-derived neoantigens that is being evaluated in a subset of patients in phase 2 of the clinical study. ClinicalTrials.gov registration: NCT03953235 .

Flexible B12 ecophysiology of Phaeocystis antarctica due to a fusion B12-independent methionine synthase with widespread homologues.

Coastal Antarctic marine ecosystems are significant in carbon cycling because of their intense seasonal phytoplankton blooms. Southern Ocean algae are primarily limited by light and iron (Fe) and can be co-limited by cobalamin (vitamin B12). Micronutrient limitation controls productivity and shapes the composition of blooms which are typically dominated by either diatoms or the haptophyte Phaeocystis antarctica. However, the vitamin requirements and ecophysiology of the keystone species P. antarctica remain poorly characterized. Using cultures, physiological analysis, and comparative omics, we examined the response of P. antarctica to a matrix of Fe-B12 conditions. We show that P. antarctica is not auxotrophic for B12, as previously suggested, and identify mechanisms underlying its B12 response in cultures of predominantly solitary and colonial cells. A combination of proteomics and proteogenomics reveals a B12-independent methionine synthase fusion protein (MetE-fusion) that is expressed under vitamin limitation and interreplaced with the B12-dependent isoform under replete conditions. Database searches return homologues of the MetE-fusion protein in multiple Phaeocystis species and in a wide range of marine microbes, including other photosynthetic eukaryotes with polymorphic life cycles as well as bacterioplankton. Furthermore, we find MetE-fusion homologues expressed in metaproteomic and metatranscriptomic field samples in polar and more geographically widespread regions. As climate change impacts micronutrient availability in the coastal Southern Ocean, our finding that P. antarctica has a flexible B12 metabolism has implications for its relative fitness compared to B12-auxotrophic diatoms and for the detection of B12-stress in a more diverse set of marine microbes.

Disproportionate Rates of COVID-19 Among Black Canadian Communities: Lessons from a Cross-Sectional Study in the First Year of the Pandemic.

BACKGROUND: Racialized communities, including Black Canadians, have disproportionately higher COVID-19 cases. We examined the extent to which SARS-CoV-2 infection has affected the Black Canadian community and the factors associated with the infection. METHODS: We conducted a cross-sectional survey in an area of Ontario (northwest Toronto/Peel Region) with a high proportion of Black residents along with 2 areas that have lower proportions of Black residents (Oakville and London, Ontario). SARS-CoV-2 IgG antibodies were determined using the EUROIMMUN assay. The study was conducted between August 15, 2020, and December 15, 2020. RESULTS: Among 387 evaluable subjects, the majority, 273 (70.5%), were enrolled from northwest Toronto and adjoining suburban areas of Peel, Ontario. The seropositivity values for Oakville and London were comparable (3.3% (2/60; 95% CI 0.4-11.5) and 3.9% (2/51; 95% CI 0.5-13.5), respectively). Relative to these areas, the seropositivity was higher for the northwest Toronto/Peel area at 12.1% (33/273), relative risk (RR) 3.35 (1.22-9.25). Persons 19 years of age or less had the highest seropositivity (10/50; 20.0%, 95% CI 10.3-33.7%), RR 2.27 (1.23-3.59). There was a trend for an interaction effect between race and location of residence as this relates to the relative risk of seropositivity. INTERPRETATION: During the early phases of the pandemic, the seropositivity within a COVID-19 high-prevalence zone was threefold greater than lower prevalence areas of Ontario. Black individuals were among those with the highest seroprevalence of SARS-CoV-2.

Two plastidial lysophosphatidic acid acyltransferases differentially mediate the biosynthesis of membrane lipids and triacylglycerols in Phaeodactylum tricornutum.

Lysophosphatidic acid acyltransferases (LPAATs) catalyze the formation of phosphatidic acid (PA), a central metabolite in both prokaryotic and eukaryotic organisms for glycerolipid biosynthesis. Phaeodactylum tricornutum contains at least two plastid-localized LPAATs (ptATS2a and ptATS2b), but their roles in lipid synthesis remain unknown. Both ptATS2a and ptATS2b could complement the high temperature sensitivity of the bacterial plsC mutant deficient in LPAAT. In vitro enzyme assays showed that they prefer lysophosphatidic acid over other lysophospholipids. ptATS2a is localized in the plastid inner envelope membrane and CRISPR/Cas9-generated ptATS2a mutants showed compromised cell growth, significantly changed plastid and extra-plastidial membrane lipids at nitrogen-replete condition and reduced triacylglycerols (TAGs) under nitrogen-depleted condition. ptATS2b is localized in thylakoid membranes and its knockout led to reduced growth rate and TAG content but slightly altered molecular composition of membrane lipids. The changes in glycerolipid profiles are consistent with the role of both LPAATs in the sn-2 acylation of sn-1-acyl-glycerol-3-phosphate substrates harboring 20:5 at the sn-1 position. Our findings suggest that both LPAATs are important for membrane lipids and TAG biosynthesis in P. tricornutum and further highlight that 20:5-Lyso-PA is likely involved in the massive import of 20:5 back to the plastid to feed plastid glycerolipid syntheses.

Autobiographical Cerebral Network Activation in Older Adults Before and After Reminiscence Therapy: A Preliminary Report.

INTRODUCTION: Reminiscence therapy (RT), which engages individuals to evoke positive memories, has been shown to be effective in improving psychological well-being in older adults suffering from PTSD, depression, and anxiety. However, its impact on brain function has yet to be determined. This paper presents functional magnetic resonance imaging (fMRI) data to describe changes in autobiographical memory networks (AMN) in community-dwelling older adults. METHODS: This pilot study used a within-subject design to measure changes in AMN activation in 11 older adults who underwent 6 weeks of RT. In the scanner, participants retrieved autobiographical memories which were either recent or remote, rehearsed or unrehearsed. Participants also underwent a clinical interview to assess changes in memory, quality of life, mental health, and affect. FINDINGS: Compared to pretreatment, anxiety decreased (z = -2.014, p = .040) and activated significant areas within the AMN, including bilateral medial prefrontal cortex, left precuneus, right occipital cortex, and left anterior hippocampus. CONCLUSION: Although RT had subtle effects on psychological function in this sample with no evidence of impairments, including depression at baseline, the fMRI data support current thinking of the effect RT has on the AMN. Increased activation of right posterior hippocampus following RT is compatible with the Multiple Trace Theory Theory (Nadel & Moscovitch, 1997).

DYNATE: Localizing rare-variant association regions via multiple testing embedded in an aggregation tree.

Rare-variants (RVs) genetic association studies enable researchers to uncover the variation in phenotypic traits left unexplained by common variation. Traditional single-variant analysis lacks power; thus, researchers have developed various methods to aggregate the effects of RVs across genomic regions to study their collective impact. Some existing methods utilize a static delineation of genomic regions, often resulting in suboptimal effect aggregation, as neutral subregions within the test region will result in an attenuation of signal. Other methods use varying windows to search for signals but often result in long regions containing many neutral RVs. To pinpoint short genomic regions enriched for disease-associated RVs, we developed a novel method, DYNamic Aggregation TEsting (DYNATE). DYNATE dynamically and hierarchically aggregates smaller genomic regions into larger ones and performs multiple testing for disease associations with a controlled weighted false discovery rate. DYNATE's main advantage lies in its strong ability to identify short genomic regions highly enriched for disease-associated RVs. Extensive numerical simulations demonstrate the superior performance of DYNATE under various scenarios compared with existing methods. We applied DYNATE to an amyotrophic lateral sclerosis study and identified a new gene, EPG5, harboring possibly pathogenic mutations.

Ultra-rare genetic variation in relapsing polychondritis: a whole-exome sequencing study.

OBJECTIVE: Relapsing polychondritis (RP) is a systemic inflammatory disease of unknown aetiology. The objective of this study was to examine the contribution of rare genetic variations to RP. METHODS: We performed a case-control exome-wide rare variant association analysis that included 66 unrelated European American cases with RP and 2923 healthy controls (HC). Gene-level collapsing analysis was performed using Firth's logistics regression. Exploratory pathway analysis was performed using three different methods: Gene Set Enrichment Analysis, sequence kernel association test and higher criticism test. Plasma DCBLD2 levels were measured in patients with RP and HC using ELISA. RESULTS: In the collapsing analysis, RP was associated with a significantly higher burden of ultra-rare damaging variants in the DCBLD2 gene (7.6% vs 0.1%, unadjusted OR=79.8, p=2.93×10-7). Plasma DCBLD2 protein levels were significantly higher in RP than in HC (median 4.06 ng/µL vs 0.05 ng/µL, p<0.001). The pathway analysis revealed a statistically significant enrichment of genes in the tumour necrosis factor signalling pathway driven by rare damaging variants in RELB, RELA and REL using higher criticism test weighted by eigenvector centrality. CONCLUSIONS: This study identified specific rare variants in the DCBLD2 gene as a putative genetic risk factor for RP. These findings should be validated in additional patients with RP and supported by future functional experiments.

Short-term acidification promotes diverse iron acquisition and conservation mechanisms in upwelling-associated phytoplankton.

Coastal upwelling regions are among the most productive marine ecosystems but may be threatened by amplified ocean acidification. Increased acidification is hypothesized to reduce iron bioavailability for phytoplankton thereby expanding iron limitation and impacting primary production. Here we show from community to molecular levels that phytoplankton in an upwelling region respond to short-term acidification exposure with iron uptake pathways and strategies that reduce cellular iron demand. A combined physiological and multi-omics approach was applied to trace metal clean incubations that introduced 1200 ppm CO2 for up to four days. Although variable, molecular-level responses indicate a prioritization of iron uptake pathways that are less hindered by acidification and reductions in iron utilization. Growth, nutrient uptake, and community compositions remained largely unaffected suggesting that these mechanisms may confer short-term resistance to acidification; however, we speculate that cellular iron demand is only temporarily satisfied, and longer-term acidification exposure without increased iron inputs may result in increased iron stress.

Transcriptional and epigenetic regulators of human CD8+ T cell function identified through orthogonal CRISPR screens.

Clinical response to adoptive T cell therapies is associated with the transcriptional and epigenetic state of the cell product. Thus, discovery of regulators of T cell gene networks and their corresponding phenotypes has potential to improve T cell therapies. Here we developed pooled, epigenetic CRISPR screening approaches to systematically profile the effects of activating or repressing 120 transcriptional and epigenetic regulators on human CD8+ T cell state. We found that BATF3 overexpression promoted specific features of memory T cells and attenuated gene programs associated with cytotoxicity, regulatory T cell function, and exhaustion. Upon chronic antigen stimulation, BATF3 overexpression countered phenotypic and epigenetic signatures of T cell exhaustion. Moreover, BATF3 enhanced the potency of CAR T cells in both in vitro and in vivo tumor models and programmed a transcriptional profile that correlates with positive clinical response to adoptive T cell therapy. Finally, we performed CRISPR knockout screens that defined cofactors and downstream mediators of the BATF3 gene network.

Molecular Forecasting of Domoic Acid during a Pervasive Toxic Diatom Bloom.

In 2015, the largest recorded harmful algal bloom (HAB) occurred in the Northeast Pacific, causing nearly 100 million dollars in damages to fisheries and killing many protected marine mammals. Dominated by the toxic diatom Pseudo-nitzschia australis , this bloom produced high levels of the neurotoxin domoic acid (DA). Through molecular and transcriptional characterization of 52 near-weekly phytoplankton net-tow samples collected at a bloom hotspot in Monterey Bay, California, we identified active transcription of known DA biosynthesis ( dab ) genes from the three identified toxigenic species, including P. australis as the primary origin of toxicity. Elevated expression of silicon transporters ( sit1 ) during the bloom supports the previously hypothesized role of dissolved silica (Si) exhaustion in contributing to bloom physiology and toxicity. We find that co-expression of the dabA and sit1 genes serves as a robust predictor of DA one week in advance, potentially enabling the forecasting of DA-producing HABs. We additionally present evidence that low levels of iron could have co-limited the diatom population along with low Si. Iron limitation represents a previously unrecognized driver of both toxin production and ecological success of the low iron adapted Pseudo-nitzschia genus during the 2015 bloom, and increasing pervasiveness of iron limitation may fuel the escalating magnitude and frequency of toxic Pseudo-nitzschia blooms globally. Our results advance understanding of bloom physiology underlying toxin production, bloom prediction, and the impact of global change on toxic blooms. Significance: Pseudo-nitzschia diatoms form oceanic harmful algal blooms that threaten human health through production of the neurotoxin domoic acid (DA). DA biosynthetic gene expression is hypothesized to control DA production in the environment, yet what regulates expression of these genes is yet to be discovered. In this study, we uncovered expression of DA biosynthesis genes by multiple toxigenic Pseudo-nitzschia species during an economically impactful bloom along the North American West Coast, and identified genes that predict DA in advance of its production. We discovered that iron and silica co-limitation restrained the bloom and likely promoted toxin production. This work suggests that increasing iron limitation due to global change may play a previously unrecognized role in driving bloom frequency and toxicity.

Zinc stimulation of coastal productivity in low carbon dioxide environments.

Zinc (Zn) is a key micronutrient used by phytoplankton for carbon (C) acquisition, yet there have been few observations of its influence on natural oceanic phytoplankton populations. In this study, we observed Zn limitation of growth in the natural phytoplankton community of Terra Nova Bay, Antarctica, due to low (~220 µatm) pCO2 conditions, in addition to primary iron (Fe) limitation. Shipboard incubation experiments amended with Zn and Fe resulted in significantly higher chlorophyll a content and dissolved inorganic carbon drawdown compared to Fe addition alone. Zn and Fe response proteins detected in incubation and environmental biomass provided independent verification of algal co-stress for these micronutrients. These observations of Zn limitation under low pCO2 conditions demonstrate Zn can influence coastal primary productivity. Yet, as surface ocean pCO2 rises with continued anthropogenic emissions, the occurrence of Zn/C co-limitation will become rarer, impacting the biogeochemical cycling of Zn and other trace metal micronutrients.

Single-nucleus DNA sequencing reveals hidden somatic loss-of-heterozygosity in Cerebral Cavernous Malformations.

Cerebral Cavernous Malformations (CCMs) are vascular malformations of the central nervous system which can lead to moderate to severe neurological phenotypes in patients. A majority of CCM lesions are driven by a cancer-like three-hit mutational mechanism, including a somatic, activating mutation in the oncogene PIK3CA, as well as biallelic loss-of-function mutations in a CCM gene. However, standard sequencing approaches often fail to yield a full complement of pathogenic mutations in many CCMs. We suggest this reality reflects the limited sensitivity to identify low-frequency variants and the presence of mutations undetectable with bulk short-read sequencing. Here we report a single-nucleus DNA-sequencing approach that leverages the underlying biology of CCMs to identify lesions with somatic loss-of-heterozygosity, a class of such hidden mutations. We identify an alternative genetic mechanism for CCM pathogenesis and establish a method that can be repurposed to investigate the genetic underpinning of other disorders with multiple somatic mutations.

Progress and challenges in exploring aquatic microbial communities using non-targeted metabolomics.

Advances in bioanalytical technologies are constantly expanding our insights into complex ecosystems. Here, we highlight strategies and applications that make use of non-targeted metabolomics methods in aquatic chemical ecology research and discuss opportunities and remaining challenges of mass spectrometry-based methods to broaden our understanding of environmental systems.

Techniques and Fixation of Olecranon Osteotomy: A Systematic Review.

Purpose: We aimed to characterize the incidence of complications regarding olecranon osteotomy, looking more specifically at the type of osteotomy and the fixation construct used to repair the osteotomy. Methods: In accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, a comprehensive search was performed. A study was included if it was an adult clinical study, a transverse or chevron olecranon osteotomy was performed, and the study explicitly states the fixation construct used to repair the osteotomy. A quality assessment was performed in each study prior to data extraction. Results: We included 39 studies with a total of 1,445 patients. Most studies included patients who were being treated primarily for a distal humerus fracture. The overall incidence of delayed union was 27/643 (4.2%), with a higher rate in transverse osteotomy than in chevron osteotomy (5/49 (10.2%) vs 22/595 (3.7%)). Nonunion occurred in 43/811 (5.4%) of patients, with a higher rate in transverse osteotomy (6/73 (8.2%) vs. 37/712 (5.2%)). Implant failure or loss of reduction occurred in 44/746 (5.9%) of patients, with a higher rate in transverse osteotomy (11/49 (22.4%) vs 33/688 (4.8%)). The removal of implants occurred in 236/1078 (21.9%) of all patients, with the highest rate in those studies that used plate fixation 44/99 (44.4%). Conclusions: Compared with chevron osteotomy, patients who underwent transverse osteotomy had a higher incidence of delayed union, nonunion, and implant failure or loss of reduction requiring revision surgery. The incidence of implant removal indicates that patients should be informed that nearly half of the osteotomy fixed with a plate was removed after implantation. Type of study/level of evidence: Therapeutic III.