The study of de novo point mutations (new germline mutations arising from the gametes of the parents) remained largely static until the arrival of next-generation sequencing technologies, which made ...both whole-exome sequencing (WES) and whole-genome sequencing (WGS) feasible in practical terms. Single nucleotide polymorphism genotyping arrays have been used to identify de novo copy-number variants in a number of common neurodevelopmental conditions such as schizophrenia and autism. By contrast, as point mutations and microlesions occurring de novo are refractory to analysis by these microarray-based methods, little was known about either their frequency or impact upon neurodevelopmental disease, until the advent of WES. De novo point mutations have recently been implicated in schizophrenia, autism and mental retardation through the WES of case-parent trios. Taken together, these findings strengthen the hypothesis that the occurrence of de novo mutations could account for the high prevalence of such diseases that are associated with a marked reduction in fecundity. De novo point mutations are also known to be responsible for many sporadic cases of rare dominant mendelian disorders such as Kabuki syndrome, Schinzel-Giedion syndrome and Bohring-Opitz syndrome. These disorders share a common feature in that they are all characterized by intellectual disability. In summary, recent WES studies of neurodevelopmental and neuropsychiatric disease have provided new insights into the role of de novo mutations in these disorders. Our knowledge of de novo mutations is likely to be further accelerated by WGS. However, the collection of case-parent trios will be a prerequisite for such studies. This review aims to discuss recent developments in the study of de novo mutations made possible by technological advances in DNA sequencing.
This systematic review and meta-analysis aimed to determine the impact of presurgical waiting times on pre-/post-operative joint specific pain and function, health-related quality of life (HRQOL) and ...perspectives of patients awaiting primary elective total hip (THR) and knee (TKR) replacements. MEDLINE, EMBASE, PUBMED, and CENTRAL databases were searched from inception until 30th January 2023 (CRD42022288128). Secondary literature and unpublished datasets containing paediatric, non-elective, partial, or revision replacement populations were excluded. PRISMA 2020 reporting and GRADE certainty of evidence guidelines were followed. Residual maximum likelihood meta-analysis and linear meta-regression was performed to elucidate the influence of presurgical waiting time. Twenty-six studies were eligible for systematic review and sixteen for meta-analysis, capturing 89,996 patients (60.6% female, mean age 67.4 years) between 2001 and 2022. A significant deterioration in joint function (mean difference (MD):0.0575%; 95% CI 0.0064, 0.1086; p = 0.028(4d.p.); I2 = 73.1%) and HRQOL (MD: 0.05%; 95% CI - 0.0001.0009; p = 0.011(4 d.p.); I2 = 80.6%) was identified per additional day of waiting. Despite qualitative evidence, meta-analysis could not observe a relationship with postoperative outcome data. Patient responses to delayed THR and TKR surgery were unanimously negative. Immediate action should seek to reduce the increased patient anxiety and significant reductions in pre-operative joint functionality and HRQOL associated with prolonged pre-surgical waiting time, whilst mitigating any potential deleterious post-operative effects.
The Energetic Particle Detector (EPD) Investigation is one of 5 fields-and-particles investigations on the Magnetospheric Multiscale (MMS) mission. MMS comprises 4 spacecraft flying in close ...formation in highly elliptical, near-Earth-equatorial orbits targeting understanding of the fundamental physics of the important physical process called magnetic reconnection using Earth’s magnetosphere as a plasma laboratory. EPD comprises two sensor types, the Energetic Ion Spectrometer (EIS) with one instrument on each of the 4 spacecraft, and the Fly’s Eye Energetic Particle Spectrometer (FEEPS) with 2 instruments on each of the 4 spacecraft. EIS measures energetic ion energy, angle and elemental compositional distributions from a required low energy limit of 20 keV for protons and 45 keV for oxygen ions, up to >0.5 MeV (with capabilities to measure up to >1 MeV). FEEPS measures instantaneous all sky images of energetic electrons from 25 keV to >0.5 MeV, and also measures total ion energy distributions from 45 keV to >0.5 MeV to be used in conjunction with EIS to measure all sky ion distributions. In this report we describe the EPD investigation and the details of the EIS sensor. Specifically we describe EPD-level science objectives, the science and measurement requirements, and the challenges that the EPD team had in meeting these requirements. Here we also describe the design and operation of the EIS instruments, their calibrated performances, and the EIS in-flight and ground operations. Blake et al. (The Flys Eye Energetic Particle Spectrometer (FEEPS) contribution to the Energetic Particle Detector (EPD) investigation of the Magnetospheric Magnetoscale (MMS) Mission,
this issue
) describe the design and operation of the FEEPS instruments, their calibrated performances, and the FEEPS in-flight and ground operations. The MMS spacecraft will launch in early 2015, and over its 2-year mission will provide comprehensive measurements of magnetic reconnection at Earth’s magnetopause during the 18 months that comprise orbital phase 1, and magnetic reconnection within Earth’s magnetotail during the about 6 months that comprise orbital phase 2.
ABSTRACT
We report on results of spectropolarimetry of the afterglow of the long gamma-ray burst GRB 191221B, obtained with SALT/RSS and VLT/FORS2, as well as photometry from two telescopes in the ...MASTER Global Robotic Network, at the MASTER-SAAO (South Africa) and MASTER-OAFA (Argentina) stations. Prompt optical emission was detected by MASTER-SAAO 38 s after the alert, which dimmed from a magnitude (white-light) of ∼10–16.2 mag over a period of ∼10 ks, followed by a plateau phase lasting ∼10 ks and then a decline to ∼18 mag after 80 ks. The light curve shows complex structure, with four or five distinct breaks in the power-law decline rate. SALT/RSS linear spectropolarimetry of the afterglow began ∼2.9 h after the burst, during the early part of the plateau phase of the light curve. Absorption lines seen at ∼6010 and 5490 Å are identified with the Mg ii 2799 Å line from the host galaxy at z = 1.15 and an intervening system located at z = 0.96. The mean linear polarization measured over 3400–8000 Å was ∼1.5 per cent and the mean equatorial position angle (θ) was ∼65°. VLT/FORS2 spectropolarimetry was obtained ∼10 h post-burst, during a period of slow decline (α = −0.44), and the polarization was measured to be p = 1.2 per cent and θ = 60°. Two observations with the MeerKAT radio telescope, taken 30 and 444 d after the GRB trigger, detected radio emission from the host galaxy only. We interpret the light curve and polarization of this long GRB in terms of a slow-cooling forward shock.
Hedgehog (Hh) signaling regulates cell fate and self-renewal in development and cancer. Canonical Hh signaling is mediated by Hh ligand binding to the receptor Patched (Ptch), which in turn activates ...Gli-mediated transcription through Smoothened (Smo), the molecular target of the Hh pathway inhibitors used as cancer therapeutics. Small cell lung cancer (SCLC) is a common, aggressive malignancy with universally poor prognosis. Although preclinical studies have shown that Hh inhibitors block the self-renewal capacity of SCLC cells, the lack of activating pathway mutations have cast doubt over the significance of these observations. In particular, the existence of autocrine, ligand-dependent Hh signaling in SCLC has been disputed. In a conditional Tp53;Rb1 mutant mouse model of SCLC, we now demonstrate a requirement for the Hh ligand Sonic Hedgehog (Shh) for the progression of SCLC. Conversely, we show that conditional Shh overexpression activates canonical Hh signaling in SCLC cells, and markedly accelerates tumor progression. When compared to mouse SCLC tumors expressing an activating, ligand-independent Smo mutant, tumors overexpressing Shh exhibited marked chromosomal instability and Smoothened-independent upregulation of Cyclin B1, a putative non-canonical arm of the Hh pathway. In turn, we show that overexpression of Cyclin B1 induces chromosomal instability in mouse embryonic fibroblasts lacking both Tp53 and Rb1. These results provide strong support for an autocrine, ligand-dependent model of Hh signaling in SCLC pathogenesis, and reveal a novel role for non-canonical Hh signaling through the induction of chromosomal instability.
Chronic noncancer pain includes any painful condition that persists for at least three months and is not associated with malignant disease. According to seven national surveys conducted between ...1994-2008, 15%-19% of Canadian adults live with chronic noncancer pain. Chronic noncancer pain interferes with activities of daily living, has a major negative impact on quality of life and physical function, and is the leading cause of health resource utilization and disability among working-age adults. Here, Busse et al inform the prescribing of opioids for adults with chronic noncancer pain.
Recent research efforts have progressively shifted towards preventative psychiatry and prognostic identification of individuals before disease onset. We describe the development of a serum biomarker ...test for the identification of individuals at risk of developing schizophrenia based on multiplex immunoassay profiling analysis of 957 serum samples. First, we conducted a meta-analysis of five independent cohorts of 127 first-onset drug-naive schizophrenia patients and 204 controls. Using least absolute shrinkage and selection operator regression, we identified an optimal panel of 26 biomarkers that best discriminated patients and controls. Next, we successfully validated this biomarker panel using two independent validation cohorts of 93 patients and 88 controls, which yielded an area under the curve (AUC) of 0.97 (0.95-1.00) for schizophrenia detection. Finally, we tested its predictive performance for identifying patients before onset of psychosis using two cohorts of 445 pre-onset or at-risk individuals. The predictive performance achieved by the panel was excellent for identifying USA military personnel (AUC: 0.90 (0.86-0.95)) and help-seeking prodromal individuals (AUC: 0.82 (0.71-0.93)) who developed schizophrenia up to 2 years after baseline sampling. The performance increased further using the latter cohort following the incorporation of CAARMS (Comprehensive Assessment of At-Risk Mental State) positive subscale symptom scores into the model (AUC: 0.90 (0.82-0.98)). The current findings may represent the first successful step towards a test that could address the clinical need for early intervention in psychiatry. Further developments of a combined molecular/symptom-based test will aid clinicians in the identification of vulnerable patients early in the disease process, allowing more effective therapeutic intervention before overt disease onset.
Acetaminophen (paracetamol‐APAP) is the most common cause of drug‐induced liver injury in the Western world. Reactive metabolite production by cytochrome P450 enzymes (CYP‐metabolites) causes ...hepatotoxicity. We explored the toxicokinetics of human circulating APAP metabolites following overdose. Plasma from patients treated with acetylcysteine (NAC) for a single APAP overdose was analyzed from discovery (n = 116) and validation (n = 150) patient cohorts. In the discovery cohort, patients who developed acute liver injury (ALI) had higher CYP‐metabolites than those without ALI. Receiver operator curve (ROC) analysis demonstrated that at hospital presentation CYP‐metabolites were more sensitive/specific for ALI than alanine aminotransferase (ALT) activity and APAP concentration (optimal CYP‐metabolite receiver operating characteristic area under the curve (ROC‐AUC): 0.91 (95% confidence interval (CI) 0.83–0.98); ALT ROC‐AUC: 0.67 (0.50–0.84); APAP ROC‐AUC: 0.50 (0.33–0.67)). This enhanced sensitivity/specificity was replicated in the validation cohort. Circulating CYP‐metabolites stratify patients by risk of liver injury prior to starting NAC. With development, APAP metabolites have potential utility in stratified trials and for refinement of clinical decision‐making.
Background
Enhanced Recovery After Surgery (ERAS) protocols reduce length of stay, complications and costs for a large number of elective surgical procedures. A similar, structured approach appears ...to improve outcomes, including mortality, for patients undergoing high-risk emergency general surgery, and specifically emergency laparotomy. These are the first consensus guidelines for optimal care of these patients using an ERAS approach.
Methods
Experts in aspects of management of the high-risk and emergency general surgical patient were invited to contribute by the International ERAS® Society. Pubmed, Cochrane, Embase, and MEDLINE database searches on English language publications were performed for ERAS elements and relevant specific topics. Studies on each item were selected with particular attention to randomized controlled trials, systematic reviews, meta-analyses and large cohort studies, and reviewed and graded using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system. Recommendations were made on the best level of evidence, or extrapolation from studies on non-emergency patients when appropriate. The Delphi method was used to validate final recommendations. The guideline has been divided into two parts: Part 1—Preoperative Care and Part 2—Intraoperative and Postoperative management. This paper provides guidelines for Part 1.
Results
Twelve components of preoperative care were considered. Consensus was reached after three rounds.
Conclusions
These guidelines are based on the best available evidence for an ERAS approach to patients undergoing emergency laparotomy. Initial management is particularly important for patients with sepsis and physiological derangement. These guidelines should be used to improve outcomes for these high-risk patients.
Surface electromyography (sEMG) is the measurement of the electrical activity of the skeletal muscle tissue detected at the skin's surface. Typically, a bipolar electrode configuration is used. Most ...muscles have pennate and/or curved fibres, meaning it is not always feasible to align the bipolar electrodes along the fibres direction. Hence, there is a need to explore how different electrode designs can affect sEMG measurements.
A three layer finite element (skin, fat, muscle) muscle model was used to explore different electrode designs. The implemented model used as source signal an experimentally recorded intramuscular EMG taken from the biceps brachii muscle of one healthy male. A wavelet based intensity analysis of the simulated sEMG signal was performed to analyze the power of the signal in the time and frequency domain.
The model showed muscle tissue causing a bandwidth reduction (to 20-92- Hz). The inter-electrode distance (IED) and the electrode orientation relative to the fibres affected the total power but not the frequency filtering response. The effect of significant misalignment between the electrodes and the fibres (60°-90°) could be reduced by increasing the IED (25-30 mm), which attenuates signal cancellation. When modelling pennated fibres, the muscle tissue started to act as a low pass filter. The effect of different IED seems to be enhanced in the pennated model, while the filtering response is changed considerably only when the electrodes are close to the signal termination within the model. For pennation angle greater than 20°, more than 50% of the source signal was attenuated, which can be compensated by increasing the IED to 25 mm.
Differences in tissue filtering properties, shown in our model, indicates that different electrode designs should be considered for muscle with different geometric properties (i.e. pennated muscles).
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