BACKGROUND:Anterior cruciate ligament (ACL) graft failure and contralateral ACL tears are more frequent in children and adolescents than adults. The reasons for higher subsequent injury rates in this ...population are incompletely understood.
METHODS:We analyzed a continuous cohort of patients who were <18 years of age. Subjects underwent isolated, primary ACL reconstruction with autograft between 2006 and January 1, 2014, and had a minimum 2-year follow-up. Return-to-sport characteristics were described, and multivariable Cox regression modeling was used to identify predictors of a second ACL injury. Candidate variables included patient factors (age, sex, physeal status, tibial slope, notch width index), surgical characteristics (graft type, surgical technique), measures of recovery (time to return to sport, duration of physical therapy), and patients’ preoperative and postoperative sports involvement (primary and secondary sports, number of sports).
RESULTS:A total of 112 subjects met inclusion criteria; of these patients, 85 (76%) had complete follow-up data and were analyzed. The mean age (and standard deviation) was 13.9 ± 2.1 years (range, 6 to 17 years); 77% had open physes. The mean follow-up was 48.3 ± 15.3 months. Seventy-seven patients (91%) returned to sports, and 84% returned to the same sport. The mean Marx activity score at the time of the latest follow-up was 13.7 ± 3.5 points. Patients were involved in fewer sports after ACL reconstruction, 1.48 ± 0.92 compared with 1.83 ± 1.01 sports before reconstruction (p = 0.002). Sixteen patients (19%) sustained an ACL graft rupture, 11 patients (13%) sustained a contralateral ACL tear, and 1 of these patients (1%) sustained both. The overall prevalence of a second ACL injury was 32%. Time to return to sport was the only significant predictor of a second ACL injury, with a slower return being protective (hazard ratio per month, 0.87 95% confidence interval, 0.73 to 0.99; p = 0.04).
CONCLUSIONS:Pediatric athletes return to sports at a high rate (91%) after ACL reconstruction. Unfortunately, the prevalence of a second ACL injury is high at 32%. Within this population, an earlier return to sport is predictive of a second ACL injury.
LEVEL OF EVIDENCE:Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.
Specific forms of the lipid ceramide, synthesized by the ceramide synthase enzyme family, are believed to regulate metabolic physiology. Genetic mouse models have established C16 ceramide as a driver ...of insulin resistance in liver and adipose tissue. C18 ceramide, synthesized by ceramide synthase 1 (CerS1), is abundant in skeletal muscle and suggested to promote insulin resistance in humans. We herein describe the first isoform-specific ceramide synthase inhibitor, P053, which inhibits CerS1 with nanomolar potency. Lipidomic profiling shows that P053 is highly selective for CerS1. Daily P053 administration to mice fed a high-fat diet (HFD) increases fatty acid oxidation in skeletal muscle and impedes increases in muscle triglycerides and adiposity, but does not protect against HFD-induced insulin resistance. Our inhibitor therefore allowed us to define a role for CerS1 as an endogenous inhibitor of mitochondrial fatty acid oxidation in muscle and regulator of whole-body adiposity.
Spaceflight is known to impose changes on human physiology with unknown molecular etiologies. To reveal these causes, we used a multi-omics, systems biology analytical approach using biomedical ...profiles from fifty-nine astronauts and data from NASA’s GeneLab derived from hundreds of samples flown in space to determine transcriptomic, proteomic, metabolomic, and epigenetic responses to spaceflight. Overall pathway analyses on the multi-omics datasets showed significant enrichment for mitochondrial processes, as well as innate immunity, chronic inflammation, cell cycle, circadian rhythm, and olfactory functions. Importantly, NASA’s Twin Study provided a platform to confirm several of our principal findings. Evidence of altered mitochondrial function and DNA damage was also found in the urine and blood metabolic data compiled from the astronaut cohort and NASA Twin Study data, indicating mitochondrial stress as a consistent phenotype of spaceflight.
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•Multi-omics analysis and techniques with NASA’s GeneLab platform•The largest cohort of astronaut data to date utilized for analysis•Mitochondrial dysregulation driving spaceflight health risks•NASA Twin Study data validates mitochondrial dysfunction during space missions
A comprehensive multi-omics analysis from 59 astronauts and hundreds of samples flown in space provides insight into fundamental biological mechanisms affected by spaceflight and highlights mitochondrial dysregulation as a central hub for space biology.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Study objective We aim to determine the most efficacious of 3 common medication regimens for the sedation of acutely agitated emergency department (ED) patients. Methods We undertook a randomized, ...controlled, double-blind, triple-dummy, clinical trial in 2 metropolitan EDs between October 2014 and August 2015. Patients aged 18 to 65 years and requiring intravenous medication sedation for acute agitation were enrolled and randomized to an intravenous bolus of midazolam 5 mg–droperidol 5 mg, droperidol 10 mg, or olanzapine 10 mg. Two additional doses were administered, if required: midazolam 5 mg, droperidol 5 mg, or olanzapine 5 mg. The primary outcome was the proportion of patients adequately sedated at 10 minutes. Results Three hundred forty-nine patients were randomized to the 3 groups. Baseline characteristics were similar across the groups. Ten minutes after the first dose, significantly more patients in the midazolam-droperidol group were adequately sedated compared with the droperidol and olanzapine groups: differences in proportions 25.0% (95% confidence interval CI 12.0% to 38.1%) and 25.4% (95% CI 12.7% to 38.3%), respectively. For times to sedation, the differences in medians between the midazolam-droperidol group and the droperidol and olanzapine groups were 6 (95% CI 3 to 8) and 6 (95% CI 3 to 7) minutes, respectively. Patients in the midazolam-droperidol group required fewer additional doses or alternative drugs to achieve adequate sedation. The 3 groups’ adverse event rates and lengths of stay did not differ. Conclusion Midazolam-droperidol combination therapy is superior, in the doses studied, to either droperidol or olanzapine monotherapy for intravenous sedation of the acutely agitated ED patient.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Background Proximity to public open space, such as parks and other green spaces, has considerable health benefits, and people have been shown to be more likely to use such space for physical activity ...if it is of high quality. This paper describes a new remote-assessment approach that makes use of Google Earth Pro (the free version of this program is Google Earth) to provide rapid and inexpensive measurement of the quality of public open space. Purpose The aim of the study was to assess the correlation between assessments of the quality of public open space using (1) the remote method (making use of Google Earth Pro) and (2) direct observation with a well-established measure of quality, the Public Open Space Tool (POST). Methods Fifty parks selected from the southwest part of Sydney, Australia, were assessed in 2009 with the remote method (using Google Earth Pro), and scores were compared with those obtained from direct observation of the same parks using POST. The time taken to conduct the assessments using each method was also recorded. Raters for each method were blind to scores obtained from using the other method. Analyses were conducted in 2009. Results The Spearman correlation coefficient between the quality scores obtained for the 50 parks using the remote method and direct observation was 0.9 ( p <0.0001). The remote method took 4 hours, whereas direct observation took 42 hours, showing the remote method to be much faster and more resource efficient for the measurement of the quality of physical activity–related environments. Conclusions The remote-assessment method provides, for the first time, the capacity to assess the quality of large numbers of parks and other green spaces without the need for in-person visits, dramatically reducing the time required for environmental audits of public open space.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Defects in nucleocytoplasmic transport have been identified as a key pathogenic event in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) mediated by a GGGGCC hexanucleotide ...repeat expansion in C9ORF72, the most common genetic cause of ALS/FTD. Furthermore, nucleocytoplasmic transport disruption has also been implicated in other neurodegenerative diseases with protein aggregation, suggesting a shared mechanism by which protein stress disrupts nucleocytoplasmic transport. Here, we show that cellular stress disrupts nucleocytoplasmic transport by localizing critical nucleocytoplasmic transport factors into stress granules, RNA/protein complexes that play a crucial role in ALS pathogenesis. Importantly, inhibiting stress granule assembly, such as by knocking down Ataxin-2, suppresses nucleocytoplasmic transport defects as well as neurodegeneration in C9ORF72-mediated ALS/FTD. Our findings identify a link between stress granule assembly and nucleocytoplasmic transport, two fundamental cellular processes implicated in the pathogenesis of C9ORF72-mediated ALS/FTD and other neurodegenerative diseases.
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•Stress granule inducers disrupt nucleocytoplasmic transport•Nucleocytoplasmic transport factors localize to stress granules•Dipeptide repeat proteins disrupt nucleocytoplasmic transport via stress granules•Inhibiting stress granule assembly suppresses neurodegeneration in C9-ALS/FTD
Sequestration of key nucleocytoplasmic transport factors in stress granules exacerbates neurodegeneration, and blocking this aspect of the stress response ameliorates effects in a model of C9-ALS/FTD.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background and aims – Actinella species from Central Africa are only rarely reported. The acid waters from many stream and small rivers in the Congo Basin form a potential environment for species of ...this genus. We studied several samples from the region of Yangambi to confirm whether species belonging to this genus are present. Material and methods – Samples for diatom investigation were collected in several streams and small rivers (Moni, Ngima, and Libongo), in the tropical rainforest in the Yangambi Biosphere Reserve, Tshopo Province, Democratic Republic of the Congo. The samples were prepared to obtain permanent microscope slides for light microscopy studies using standard methods and cleaned material for scanning electron microscopy. Key results – A novel Actinella was observed in the studied samples. The taxon was compared to other species such as A. disjuncta , A. lange-bertalotii , A. modesta , A. pereunotioides , and A. pseudohantzschia , although the new species morphologically resembles most A. eunotioides , a species discovered in the Amazon basin in Brazil, and A. eunotioides var. minor, described in 1966 from the Central African Republic. The taxon observed in our material differs from A. eunotioides mainly in the valve dimensions, being much smaller, and the higher density of the marginal spines. Stria density also tends to be coarser. The valve length of A. eunotioides var. minor, on the other hand, corresponds with the smallest valves of our taxon but the valves are narrower, with a higher stria density. The ventral margin is slightly convex, while in the new taxon it is slightly concave. Moreover, in the original description of A. eunotioides var. minor, the absence of spines is mentioned, while they are present on the valves in the materials we investigated. Based on the observed morphological differences, we consider the taxon recorded in the streams and small rivers in the Yangambi Biosphere Reserve distinct from A. eunotioides and its var. minor and subsequently, we describe Actinella kufferathiana as a species new to science.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Indole-tethered ynones form an intramolecular electron donor-acceptor complex that can undergo visible-light-induced charge transfer to promote thiyl radical generation from thiols. This initiates a ...novel radical chain sequence, based on dearomatising spirocyclisation with concomitant C-S bond formation. Sulfur-containing spirocycles are formed in high yields using this simple and mild synthetic protocol, in which neither transition metal catalysts nor photocatalysts are required. The proposed mechanism is supported by various mechanistic studies, and the unusual radical initiation mode represents only the second report of the use of an intramolecular electron donor-acceptor complex in synthesis.
Indole-tethered ynones form an intramolecular electron donor-acceptor complex that can undergo visible-light-induced charge transfer to promote thiyl radical generation from thiols.
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IJS, KILJ, NUK, UL, UM, UPUK
We have employed a bespoke setup combining confocal Raman microscopy and an ultraviolet–visible (UV–Vis) spectroscopy flow cell to investigate the effect of excipients on the disproportionation ...kinetics of Pioglitazone HCl (PioHCl) in tablets during dissolution. Three binary formulations of PioHCl, containing citric acid monohydrate (CA), lactose monohydrate (LM), or magnesium stearate (MgSt), respectively, were used as models to study the influence of excipients’ physicochemical properties on the rate of salt disproportionation kinetics and dissolution performance in different aqueous pH environments. It was found that formulation excipients can induce or prevent salt disproportionation by modulating the microenvironmental pH regardless of the pH of the dissolution media. Incorporating CA in PioHCl tablets preserves the salt form and enhances the dissolution performance of the salt in the acidic medium (pH = 1.2). In contrast, LM and MgSt had a detrimental effect on in vitro drug performance by inducing salt disproportionation in the tablet during dissolution in the same acidic medium. Dissolution in the neutral medium (pH = 6.8) showed rapid formation of the free base upon contact with the dissolution medium. The Raman maps of the cross-sectioned tablets revealed the formation of a shell consisting of the free base around the edge of the tablet. This shell decreased the rate of penetration of the dissolution medium into the tablet, which had significant implications on the release of the API into the surrounding solution, as shown by the UV–vis absorption spectroscopy drug release data. Our findings highlight the utility of the Raman/UV–vis flow cell analytical platform as an advanced analytical technique to investigate the effect of excipients and dissolution media on salt disproportionation in real time. This methodology will be used to enhance our understanding of salt stability studies that may pave the way for more stable multicomponent formulations.
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IJS, KILJ, NUK, PNG, UL, UM
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