Tumor-only sequencing, implemented for the identification of somatic variants, is oftentimes used for the detection of actionable germline variants. We sought to determine whether tumor-only ...sequencing assays are suitable for detection of actionable germline variants, given their importance for the delivery of targeted therapies and risk-reducing measures.
The detection of germline variants affecting moderate- and high-penetrance cancer susceptibility genes (CSGs) by tumor-only sequencing was compared to clinical germline testing in 21 333 cancer patients who underwent tumor and germline testing using the Food and Drug Administration (FDA)-authorized Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Targets (MSK-IMPACT) assay. Seven homologous recombination deficiency (HRD), two DNA damage response (DDR) and four mismatch repair (MMR) genes, as well as NF1, RB1 and TP53 were included in the analysis. FDA-authorized and New York State Department of Health-approved sequencing methods for germline, tumor/normal and tumor-only sequencing assays and analytical pipelines were employed.
In patients who underwent tumor and germline sequencing, as compared to clinical genetic testing, tumor-only sequencing failed to detect 10.5% of clinically actionable pathogenic germline variants in CSGs, including 18.8%, 12.8% and 7.3% of germline variants in MMR, DDR and HRD genes, respectively. The sensitivity for detection of pathogenic germline variants by tumor-only sequencing was 89.5%. Whilst the vast majority of pathogenic germline exonic single-nucleotide variants (SNVs) and small indels were detected by tumor-only sequencing, large percentages of germline copy number variants, intronic variants and repetitive element insertions were not detected.
Tumor-only sequencing is adequate for the detection of clinically actionable germline variants, particularly for SNVs and small indels; however, a small subset of alterations affecting HRD, DDR and MMR genes may not be detected optimally. Therefore, for high-risk patients with negative tumor-only sequencing results, clinical genetic testing could be considered given the impact of these variants on therapy and genetic counseling.
•In a cohort of >21 000 patients, tumor-only sequencing failed to detect 10.5% of pathogenic germline variants in 16 CSGs.•18.8%, 12.8% and 7.3% of pathogenic germline variants in MMR, DDR and HRD genes were not detected by tumor-only sequencing.•These undetected P/LP variants may affect the use of targeted therapies, preventative measures and familial surveillance.•For patients with negative tumor sequencing results, genetic testing is needed to guide therapy and genetic counseling.
Background Safe tissue removal is a challenge for minimally invasive procedures such as myomectomy, supracervical hysterectomy, or total hysterectomy of a large uterine specimen. There is concern ...regarding disruption or dissemination of tissue during this process, which may be of particular significance in cases of undetected malignancy. Contained tissue extraction techniques have been developed in an effort to mitigate morcellation-related risks. Objective The objective of the study was to quantify perioperative outcomes of contained tissue extraction using power morcellation, specifically evaluating parameters of tissue or fluid leakage from within the containment system. Study Design This was a study including a multicenter prospective cohort of adult women who underwent minimally invasive hysterectomy or myomectomy using a contained power morcellation technique. Blue dye was applied to the tissue specimen prior to removal to help identify cases of fluid or tissue leakage from within the containment system. Results A total of 76 patients successfully underwent the contained power morcellation protocol. Mean time for the contained morcellation procedure was 30.2 minutes (±22.4). The mean hysterectomy specimen weight was 480.1 g (±359.1), and mean myomectomy specimen weight was 239.1 g (±229.7). The vast majority of patients (73.7%) were discharged home the same day of surgery. Final pathological diagnosis was benign in all cases. Spillage of dye or tissue was noted in 7 cases (9.2%), although containment bags were intact in each of these instances. Conclusion Findings are consistent with prior work demonstrating the feasibility of contained tissue extraction; however, further refinement of this technique is warranted.
The aim of this prospective randomised controlled trial was to compare non-operative and operative management for acute isolated displaced fractures of the olecranon in patients aged ≥ 75 years.
...Patients were randomised to either non-operative management or operative management with either tension-band wiring or fixation with a plate. They were reviewed at six weeks, three and six months and one year after the injury. The primary outcome measure was the Disabilities of the Arm, Shoulder and Hand (DASH) score at one year.
A total of 19 patients were randomised to non-operative (n = 8) or operative (n = 11; tension-band wiring (n = 9), plate (n = 2)) management. The trial was stopped prematurely as the rate of complications (nine out of 11, 81.8%) in the operative group was considered to be unacceptable. There was, however, no difference in the mean DASH scores between the groups at all times. The mean score was 23 (0 to 59.6) in the non-operative group and 22 (2.5 to 57.8) in the operative group, one year after the injury (p = 0.763). There was no significant difference between groups in the secondary outcome measures of the Broberg and Morrey Score or the Mayo Elbow Score at any time during the one year following injury (all p ≥ 0.05).
These data further support the role of primary non-operative management of isolated displaced fractures of the olecranon in the elderly. However, the non-inferiority of non-operative management cannot be proved as the trial was stopped prematurely. Cite this article:
2017;99-B:964-72.
Aim
To examine the effects of a 16‐week resistance exercise training intervention on the speed of ankle and knee strength generation during stair ascent and descent, in people with neuropathy.
...Methods
A total of 43 people: nine with diabetic peripheral neuropathy, 13 with diabetes but no neuropathy and 21 healthy control subjects ascended and descended a custom‐built staircase. The speed at which ankle and knee strength were generated, and muscle activation patterns of the ankle and knee extensor muscles were analysed before and after a 16‐week intervention period.
Results
Ankle and knee strength generation during both stair ascent and descent were significantly higher after the intervention than before the intervention in the people with diabetes who undertook the resistance exercise intervention (P < 0.05). Although muscle activations were altered by the intervention, there were no observable patterns that underpinned the observed changes.
Conclusions
The increased speed of ankle and knee strength generation observed after the intervention would be expected to improve stability during the crucial weight acceptance phase of stair ascent and descent, and ultimately contribute towards reducing the risk of falling. Improvements in muscle strength as a result of the resistance exercise training intervention are likely to be the most influential factor for increasing the speed of strength generation. It is recommended that these exercises could be incorporated into a multi‐faceted exercise programme to improve safety in people with diabetes and neuropathy.
What's new?
We examined for the first time, the effects of a resistance exercise‐based intervention on speed of knee and ankle strength generation in people with diabetic peripheral neuropathy, during stair ascent and descent.
We observed that after a 16‐week intervention, people with diabetic peripheral neuropathy, and people with diabetes without neuropathy, increased the speed at which strength was developed at the ankle and knee during stair ascent and descent.
This would be expected to decrease the risk of falling during these movements; therefore, such exercises could be incorporated into a multi‐faceted exercise programme to improve safety in people with diabetes and diabetic peripheral neuropathy.
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The physical origin of charged interfaces involving electrolyte solutions is in the thermodynamic equilibrium between the surface reactive groups and certain dissolved ionic species ...in the bulk. This equilibrium is very strongly dependent on the precise local density of these species, also known as potential determining ions in the solution. The latter, however, is determined by the overall solution structure, which is dominated by the large number of solvent molecules relative to all solutes. Hence, the solvent contribution to the molecular structure is a crucial factor that determines the properties of electric double layers. Models that explicitly account for the solvent structure are often referred to as “civilized” as opposed to the “primitive” ones that consider the solvent as a structureless continuum. In the present paper, we demonstrate that for a physically correct description of charged interfaces that involve electrolyte solutions (electric double layers), the full solution structure needs to be taken into account in conjunction with the precise surface chemistry governed by the thermodynamic equilibrium. The analysis shows how the surface charge depends on various experimentally relevant parameters, many of which are outside the realm of simple electrostatics. We present results on the effects of solvent molecular dimensions, ionic solvation, surface chemistry, solvophilicity and solvophobicity.
Melt-spun NdFeB powders can be formed into a number of different types of permanent magnet for a variety of applications in electronics, automotive and clean technology industries. The melt-spinning ...process produces flake powder with a fine uniform array of nanoscale Nd2Fe14B grains. These powders can be net-shape formed into isotropic polymer-bonded magnets or hot formed into fully dense magnets. This paper discusses the influence of heavy rare earth elements and microstructure on the magnetic performance, thermal stability and material cost of NdFeB magnets. Evidence indicates that melt-spun nanocrystalline NdFeB magnets are less dependent on heavy rare earth elements for high-temperature performance than the alternative coarser-grained sintered NdFeB magnets. In particular, hot-pressed melt-spun magnets are an attractive low-cost solution for applications that require thermal stability up to 175-200 °C.
We present the first results from an optical reverberation mapping campaign executed in 2014 targeting the active galactic nuclei (AGNs) MCG+08-11-011, NGC 2617, NGC 4051, 3C 382, and Mrk 374. Our ...targets have diverse and interesting observational properties, including a "changing look" AGN and a broad-line radio galaxy. Based on continuum-Hβ lags, we measure black hole masses for all five targets. We also obtain Hγ and He ii λ4686 lags for all objects except 3C 382. The He ii λ4686 lags indicate radial stratification of the BLR, and the masses derived from different emission lines are in general agreement. The relative responsivities of these lines are also in qualitative agreement with photoionization models. These spectra have extremely high signal-to-noise ratios (100-300 per pixel) and there are excellent prospects for obtaining velocity-resolved reverberation signatures.
We present a synthesis of 0–5 Ma paleomagnetic directional data collected from 17 different locations under the collaborative Time Averaged geomagnetic Field Initiative (TAFI). When combined with ...regional compilations from the northwest United States, the southwest United States, Japan, New Zealand, Hawaii, Mexico, South Pacific, and the Indian Ocean, a data set of over 2000 sites with high quality, stable polarity, and declination and inclination measurements is obtained. This is a more than sevenfold increase over similar quality data in the existing Paleosecular Variation of Recent Lavas (PSVRL) data set, and has greatly improved spatial sampling. The new data set spans 78°S to 53°N, and has sufficient temporal and spatial sampling to allow characterization of latitudinal variations in the time‐averaged field (TAF) and paleosecular variation (PSV) for the Brunhes and Matuyama chrons, and for the 0–5 Ma interval combined. The Brunhes and Matuyama chrons exhibit different TAF geometries, notably smaller departures from a geocentric axial dipole field during the Brunhes, consistent with higher dipole strength observed from paleointensity data. Geographical variations in PSV are also different for the Brunhes and Matuyama. Given the high quality of our data set, polarity asymmetries in PSV and the TAF cannot be attributed to viscous overprints, but suggest different underlying field behavior, perhaps related to the influence of long‐lived core‐mantle boundary conditions on core flow. PSV, as measured by dispersion of virtual geomagnetic poles, shows less latitudinal variation than predicted by current statistical PSV models, or by previous data sets. In particular, the Brunhes data reported here are compatible with a wide range of models, from those that predict constant dispersion as a function of latitude to those that predict an increase in dispersion with latitude. Discriminating among such models could be helped by increased numbers of low‐latitude data and new high northern latitude sites. Tests with other data sets, and with simulations, indicate that some of the latitudinal signature previously observed in VGP dispersion can be attributed to the inclusion of low‐quality, insufficiently cleaned data with too few samples per site. Our Matuyama data show a stronger dependence of dispersion on latitude than the Brunhes data. The TAF is examined using the variation of inclination anomaly with latitude. Best fit two‐parameter models have axial quadrupole contributions of 2–4% of the axial dipole term, and axial octupole contributions of 1–5%. Approximately 2% of the octupole signature is likely the result of bias incurred by averaging unit vectors.
Molecular dynamics (MD) simulations have been used to examine the structure and dynamics of a system containing an inorganic nanoparticle embedded in a polymer matrix. This paper represents a ...preliminary investigation into the feasibility of examining such relatively large systems using atomistic modeling techniques. No attempt is made here to model any specific system. A generic linear polymer “united-atom” model is first created in an amorphous phase before the insertion of an atomistically detailed silica nanoparticle of diameter ∼4.4 nm. A novel method to insert a nanoparticle into a polymer matrix is given. The entire system is contained in a standard periodic simulation cell of side length ∼10 nm. The volume fraction of silica corresponded to ∼4.5%. The composite system was subsequently relaxed at 300 K and at two different pressures using standard MD techniques, the gmq suite of programs being used for this purpose. Results are presented regarding the variation of the structure and dynamics of the system with respect to the distance from the polymer−nanoparticle interface and as a function of pressure. A clear structuring of the polymer chains around the nanoparticle is seen with prominent first and second peaks in the radial density function and a concurrent development of preferred chain orientation. The probability of trans conformers is also higher close to the interface and shows a distinct gradient. In contrast, evidence for chain immobilization is less obvious overall although dynamic properties are more sensitive to changes in the pressure. Comparisons are also made between the bulk moduli of the pure polymer and composite systems.
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