General intelligence is an important human quantitative trait that accounts for much of the variation in diverse cognitive abilities. Individual differences in intelligence are strongly associated ...with many important life outcomes, including educational and occupational attainments, income, health and lifespan. Data from twin and family studies are consistent with a high heritability of intelligence, but this inference has been controversial. We conducted a genome-wide analysis of 3511 unrelated adults with data on 549,692 single nucleotide polymorphisms (SNPs) and detailed phenotypes on cognitive traits. We estimate that 40% of the variation in crystallized-type intelligence and 51% of the variation in fluid-type intelligence between individuals is accounted for by linkage disequilibrium between genotyped common SNP markers and unknown causal variants. These estimates provide lower bounds for the narrow-sense heritability of the traits. We partitioned genetic variation on individual chromosomes and found that, on average, longer chromosomes explain more variation. Finally, using just SNP data we predicted ∼1% of the variance of crystallized and fluid cognitive phenotypes in an independent sample (P=0.009 and 0.028, respectively). Our results unequivocally confirm that a substantial proportion of individual differences in human intelligence is due to genetic variation, and are consistent with many genes of small effects underlying the additive genetic influences on intelligence.
Background
Increased uptake of robotic surgery has led to interest in learning curves for robot‐assisted procedures. Learning curves, however, are often poorly defined. This systematic review was ...conducted to identify the available evidence investigating surgeon learning curves in robot‐assisted surgery.
Methods
MEDLINE, Embase and the Cochrane Library were searched in February 2018, in accordance with PRISMA guidelines, alongside hand searches of key congresses and existing reviews. Eligible articles were those assessing learning curves associated with robot‐assisted surgery in patients.
Results
Searches identified 2316 records, of which 68 met the eligibility criteria, reporting on 68 unique studies. Of these, 49 assessed learning curves based on patient data across ten surgical specialties. All 49 were observational, largely single‐arm (35 of 49, 71 per cent) and included few surgeons. Learning curves exhibited substantial heterogeneity, varying between procedures, studies and metrics. Standards of reporting were generally poor, with only 17 of 49 (35 per cent) quantifying previous experience. Methods used to assess the learning curve were heterogeneous, often lacking statistical validation and using ambiguous terminology.
Conclusion
Learning curve estimates were subject to considerable uncertainty. Robust evidence was lacking, owing to limitations in study design, frequent reporting gaps and substantial heterogeneity in the methods used to assess learning curves. The opportunity remains for the establishment of optimal quantitative methods for the assessment of learning curves, to inform surgical training programmes and improve patient outcomes.
Antecedentes
La aceptación creciente de la cirugía robótica ha generado interés en las curvas de aprendizaje para los procedimientos asistidos por robot. Sin embargo, las curvas de aprendizaje a menudo están mal definidas. Esta revisión sistemática se realizó para identificar la evidencia disponible en relación a las curvas de aprendizaje del cirujano en la cirugía asistida por robot.
Métodos
En Febrero de 2018, se realizaron búsquedas en MEDLINE, Embase y Cochrane Library, de acuerdo con las recomendaciones PRISMA, junto con búsquedas manuales de congresos clave y de revisiones ya existentes. Los artículos elegibles fueron aquellos que evaluaron las curvas de aprendizaje asociadas con la cirugía asistida por robot efectuada en pacientes.
Resultados
Las búsquedas bibliográficas identificaron 2.316 registros de los cuales 68 cumplían los criterios de elegibilidad y correspondían a 68 estudios primarios. De estos 68 estudios, 49 evaluaron las curvas de aprendizaje basadas en datos de pacientes de 10 especialidades quirúrgicas. Los 49 estudios eran todos estudios observacionales, en su mayoría de un solo brazo (35/49 (71%)) e incluían pocos cirujanos. Las curvas de aprendizaje mostraban una notable heterogeneidad, variando entre procedimientos, estudios y parámetros analizados. Los estándares de presentación de informes fueron generalmente deficientes, con solo 17/49 (35%) cuantificando la experiencia previa. Los métodos utilizados para evaluar la curva de aprendizaje fueron heterogéneos, a menudo carecían de validación estadística y usaban terminología ambigua.
Conclusión
Las estimaciones de la curva de aprendizaje estaban sujetas a una considerable incertidumbre, careciendo de evidencia robusta por las limitaciones en el diseño del estudio, lagunas de información en los artículos y heterogeneidad sustancial en los métodos utilizados para evaluar las curvas de aprendizaje. Queda pendiente establecer métodos cuantitativos óptimos para evaluar las curvas de aprendizaje, informar de los programas de formación quirúrgica y mejorar los resultados del paciente.
A broad systematic literature review was performed to characterize the current evidence base and appraise the methods used to measure and define learning curves for surgeons performing robot‐assisted surgery, taking a holistic, panspecialty view. The learning curve estimates identified are subject to considerable uncertainty, and robust evidence was often lacking due to limitations in study design and frequent reporting gaps. Thus, the opportunity remains for the establishment of optimal quantitative methods for the assessment of learning curves, which may inform surgical training programmes and improve patient outcomes.
Little consistency between studies
How I do it: 1st stage revision TKA Porteous, A.J.
The knee,
December 2020, 2020-Dec, 2020-12-00, 20201201, Letnik:
27, Številka:
6
Journal Article
Recenzirano
This article covers the key steps and decisions that we make when performing a 1st-stage revision Total Knee Arthroplasty (TKA) at the Avon Orthopaedic Centre and includes more detailed technique and ...tips regarding how we make our spacers.
The first stage of a two-stage protocol should be done in a stable patient with information about the organism, and with the option of plastic surgery flap coverage if required. It should ideally be performed in the unit that is going to perform the second stage, and the operation note should document the soft-tissues, bone loss and extensor mechanism issues that will influence planning for the second stage. Nothing will make up for a bad debridement, so we focus on this as the key step for infection clearance. Infection clearance is equivalent between mobile and static spacers, but patients generally prefer having the better mobility and function of a mobile spacer. We recommend a mobile spacer, unless there is compromise to ligaments or extensor mechanism, or if bone loss is large. Whichever spacer you use, it should aim to: deliver appropriate antibiotics; allow stability, pain relief and some function and weight-bearing prior to the second stage. Doing a good technical job with the spacer is important because you do not want complications with the spacer to cause harm or necessitate a return to theatre or re-operation sooner than planned. Ideally the second stage should be performed when the surgeon & MDT team deem it appropriate clinically and when the patient is fit and ready for further surgery.
Cognitive decline is a feared aspect of growing old. It is a major contributor to lower quality of life and loss of independence in old age. We investigated the genetic contribution to individual ...differences in nonpathological cognitive ageing in five cohorts of older adults. We undertook a genome-wide association analysis using 549 692 single-nucleotide polymorphisms (SNPs) in 3511 unrelated adults in the Cognitive Ageing Genetics in England and Scotland (CAGES) project. These individuals have detailed longitudinal cognitive data from which phenotypes measuring each individual's cognitive changes were constructed. One SNP--rs2075650, located in TOMM40 (translocase of the outer mitochondrial membrane 40 homolog)--had a genome-wide significant association with cognitive ageing (P=2.5 × 10(-8)). This result was replicated in a meta-analysis of three independent Swedish cohorts (P=2.41 × 10(-6)). An Apolipoprotein E (APOE) haplotype (adjacent to TOMM40), previously associated with cognitive ageing, had a significant effect on cognitive ageing in the CAGES sample (P=2.18 × 10(-8); females, P=1.66 × 10(-11); males, P=0.01). Fine SNP mapping of the TOMM40/APOE region identified both APOE (rs429358; P=3.66 × 10(-11)) and TOMM40 (rs11556505; P=2.45 × 10(-8)) as loci that were associated with cognitive ageing. Imputation and conditional analyses in the discovery and replication cohorts strongly suggest that this effect is due to APOE (rs429358). Functional genomic analysis indicated that SNPs in the TOMM40/APOE region have a functional, regulatory non-protein-coding effect. The APOE region is significantly associated with nonpathological cognitive ageing. The identity and mechanism of one or multiple causal variants remain unclear.
Mitochondrial oxidative damage contributes to a wide range of pathologies, including cardiovascular disorders and neurodegenerative diseases. Therefore, protecting mitochondria from oxidative damage ...should be an effective therapeutic strategy. However, conventional antioxidants have limited efficacy due to the difficulty of delivering them to mitochondria in situ. To overcome this problem, we developed mitochondria-targeted antioxidants, typified by MitoQ, which comprises a lipophilic triphenylphosphonium (TPP) cation covalently attached to a ubiquinol antioxidant. Driven by the large mitochondrial membrane potential, the TPP cation concentrates MitoQ several hundred-fold within mitochondria, selectively preventing mitochondrial oxidative damage. To test whether MitoQ was active in vivo, we chose a clinically relevant form of mitochondrial oxidative damage: cardiac ischemia-reperfusion injury. Feeding MitoQ to rats significantly decreased heart dysfunction, cell death, and mitochondrial damage after ischemia-reperfusion. This protection was due to the antioxidant activity of MitoQ within mitochondria, as an untargeted antioxidant was ineffective and accumulation of the TPP cation alone gave no protection. Therefore, targeting antioxidants to mitochondria in vivo is a promising new therapeutic strategy in the wide range of human diseases such as Parkinson's disease, diabetes, and Friedreich's ataxia where mitochondrial oxidative damage underlies the pathology.--Adlam, V. J., Harrison, J. C., Porteous, C. M., James, A. M., Smith, R. A. J., Murphy, M. P., Sammut, I. A. Targeting an antioxidant to mitochondria decreases cardiac ischemia-reperfusion injury.
Hydrogen peroxide (H2O2) is central to mitochondrial oxidative damage and redox signaling, but its roles are poorly understood due to the difficulty of measuring mitochondrial H2O2 in vivo. Here we ...report a ratiometric mass spectrometry probe approach to assess mitochondrial matrix H2O2 levels in vivo. The probe, MitoB, comprises a triphenylphosphonium (TPP) cation driving its accumulation within mitochondria, conjugated to an arylboronic acid that reacts with H2O2 to form a phenol, MitoP. Quantifying the MitoP/MitoB ratio by liquid chromatography-tandem mass spectrometry enabled measurement of a weighted average of mitochondrial H2O2 that predominantly reports on thoracic muscle mitochondria within living flies. There was an increase in mitochondrial H2O2 with age in flies, which was not coordinately altered by interventions that modulated life span. Our findings provide approaches to investigate mitochondrial ROS in vivo and suggest that while an increase in overall mitochondrial H2O2 correlates with aging, it may not be causative.
► A mitochondria-targeted mass spectrometry probe measures mitochondrial H2O2 in vivo ► Overall mitochondrial H2O2 increases with age but can be independent of life span ► Increased physical activity leads to a decrease in mitochondrial H2O2 ► Hypotheses dependent on overall mitochondrial ROS can now be assessed in vivo
Delivery of Bioactive Molecules to Mitochondria in vivo Robin A. J. Smith; Porteous, Carolyn M.; Gane, Alison M. ...
Proceedings of the National Academy of Sciences - PNAS,
04/2003, Letnik:
100, Številka:
9
Journal Article
Recenzirano
Odprti dostop
Mitochondrial dysfunction contributes to many human degenerative diseases but specific treatments are hampered by the difficulty of delivering bioactive molecules to mitochondria in vivo. To overcome ...this problem we developed a strategy to target bioactive molecules to mitochondria by attachment to the lipophilic triphenylphosphonium cation through an alkyl linker. These molecules rapidly permeate lipid bilayers and, because of the large mitochondrial membrane potential (negative inside), accumulate several hundredfold inside isolated mitochondria and within mitochondria in cultured cells. To determine whether this strategy could lead to the development of mitochondria-specific therapies, we investigated the administration and tissue distribution in mice of simple alkyltriphenylphosphonium cations and of mitochondria-targeted antioxidants comprising a triphenylphosphonium cation coupled to a coenzyme Q or vitamin E derivative. Significant doses of these compounds could be fed safely to mice over long periods, coming to steady-state distributions within the heart, brain, liver, and muscle. Therefore, mitochondria-targeted bioactive molecules can be administered orally, leading to their accumulation at potentially therapeutic concentrations in those tissues most affected by mitochondrial dysfunction. This finding opens the way to the testing of mitochondria-specific therapies in mouse models of human degenerative diseases.
Mitochondria-targeted molecules comprising the lipophilic TPP (triphenylphosphonium) cation covalently linked to a hydrophobic bioactive moiety are used to modify and probe mitochondria in cells and ...in vivo. However, it is unclear how hydrophobicity affects the rate and extent of their uptake into mitochondria within cells, making it difficult to interpret experiments because their intracellular concentration in different compartments is uncertain. To address this issue, we compared the uptake into both isolated mitochondria and mitochondria within cells of two hydrophobic TPP derivatives, 3HMitoQ (mitoquinone) and 3HDecylTPP, with the more hydrophilic TPP cation 3HTPMP (methyltriphenylphosphonium). Uptake of MitoQ by mitochondria and cells was described by the Nernst equation and was approximately 5-fold greater than that for TPMP, as a result of its greater binding within the mitochondrial matrix. DecylTPP was also taken up extensively by cells, indicating that increased hydrophobicity enhanced uptake. Both MitoQ and DecylTPP were taken up very rapidly into cells, reaching a steady state within 15 min, compared with approximately 8 h for TPMP. This far faster uptake was the result of the increased rate of passage of hydrophobic TPP molecules through the plasma membrane. Within cells MitoQ was predominantly located within mitochondria, where it was rapidly reduced to the ubiquinol form, consistent with its protective effects in cells and in vivo being due to the ubiquinol antioxidant. The strong influence of hydrophobicity on TPP cation uptake into mitochondria within cells facilitates the rational design of mitochondria-targeted compounds to report on and modify mitochondrial function in vivo.
The mitochondrial membrane potential (Δψm) is a major determinant and indicator of cell fate, but it is not possible to assess small changes in Δψm within cells or in vivo. To overcome this, we ...developed an approach that utilizes two mitochondria-targeted probes each containing a triphenylphosphonium (TPP) lipophilic cation that drives their accumulation in response to Δψm and the plasma membrane potential (Δψp). One probe contains an azido moiety and the other a cyclooctyne, which react together in a concentration-dependent manner by “click” chemistry to form MitoClick. As the mitochondrial accumulation of both probes depends exponentially on Δψm and Δψp, the rate of MitoClick formation is exquisitely sensitive to small changes in these potentials. MitoClick accumulation can then be quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS). This approach enables assessment of subtle changes in membrane potentials within cells and in the mouse heart in vivo.
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•Mass spectrometry and click chemistry can assess mitochondrial membrane potential•This approach can be applied to investigate membrane potential in cells and in vivo•Hypotheses dependent on small changes in membrane potential can be tested
The mitochondrial membrane potential is central to the organelle’s many functions. Combining mitochondria targeted probes, click chemistry, and mass spectrometry, Logan et al. develop a highly sensitive approach to assess small changes in membrane potential in cells and in vivo, and show its utility in proof-of-principle experiments.
Abstract Introduction The gold standard for measuring knee alignment is the lower limb mechanical axis (MA) using weight-bearing lower limb full-length x-ray (FLX). However, CT scanograms (CTS) are ...becoming increasingly popular in view of lower radiation exposure, speed of data acquisition and supine positioning. We compared the correlation and degree of agreement of knee joint coronal alignment using these two imaging modalities. Method From our series of complex primary and revision knee arthroplasty patients, we selected those with both FLX and CTS recorded onto digital PACS. The coronal alignments were assessed in 24 knees and the valgus/varus angles relative to the MA were measured. Results were analysed statistically using the paired samples t -test, Pearson's correlation coefficient, intra-class correlation coefficient, Cohen's kappa and Passing and Bablok regression to assess potential equality of methods. Results The mean MA was 180.5° (165°–200°) for the CTS and 181° (164°–202°) for the FLX. The CTS MA angle data between the assessors were highly correlated ( r = 0.971, p < 0.001) as were FLX MA angle measurements ( r = 0.988, p < 0.001). 41.7% of the CTS and 37.5% of the FLX were in varus alignment, while 50% of the CTS and 43.8% of the FLX were in valgus alignment. Malalignment > 5° was revealed by 18.8% of the CTS and 35.4% of the FLX. Conclusion Overall, good agreement was observed in MA angle data between the two imaging modalities, but reproducibility may be problematic. In the malaligned limb, weight-bearing FLX still remains a vital imaging modality. CTS should be used with caution in view of the under-detection of malalignment.
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