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Mutation Research. Reviews in Mutation... 2023Mutations, the irreversible changes in an organism's DNA sequence, are present in tissues at a variant allele frequency (VAF) ranging from ∼10 per bp for a founder... (Review)
Review
Mutations, the irreversible changes in an organism's DNA sequence, are present in tissues at a variant allele frequency (VAF) ranging from ∼10 per bp for a founder mutation to ∼10 for a histologically normal tissue sample containing several independent clones - compared to 1%- 50% for a heterozygous tumor mutation or a polymorphism. The rarity of these events poses a challenge for accurate clinical diagnosis and prognosis, toxicology, and discovering new disease etiologies. Standard Next-Generation Sequencing (NGS) technologies report VAFs as low as 0.5% per nt, but reliably observing rarer precursor events requires additional sophistication to measure ultralow-frequency mutations. We detail the challenge; define terms used to characterize the results, which vary between laboratories and sometimes conflict between biologists and bioinformaticists; and describe recent innovations to improve standard NGS methodologies including: single-strand consensus sequence methods such as Safe-SeqS and SiMSen-Seq; tandem-strand consensus sequence methods such as o2n-Seq and SMM-Seq; and ultrasensitive parent-strand consensus sequence methods such as DuplexSeq, PacBio HiFi, SinoDuplex, OPUSeq, EcoSeq, BotSeqS, Hawk-Seq, NanoSeq, SaferSeq, and CODEC. Practical applications are also noted. Several methods quantify VAF down to 10 at a nt and mutation frequency (MF) in a target region down to 10 per nt. By expanding to > 1 Mb of sites never observed twice, thus forgoing VAF, other methods quantify MF < 10 per nt or < 15 errors per haploid genome. Clonal expansion cannot be directly distinguished from independent mutations by sequencing, so it is essential for a paper to report whether its MF counted only different mutations - the minimum independent-mutation frequency MF - or all mutations observed including recurrences - the larger maximum independent-mutation frequency MF which may reflect clonal expansion. Ultrasensitive methods reveal that, without their use, even mutations with VAF 0.5-1% are usually spurious.
Topics: Humans; Mutation; Neoplasms; Prognosis; High-Throughput Nucleotide Sequencing
PubMed: 37716438
DOI: 10.1016/j.mrrev.2023.108471 -
Current Opinion in Psychology Aug 2023Listening is a complex construct studied in various fields, including psychology, education, marketing, management, and medicine. Despite its importance, there is no... (Review)
Review
Listening is a complex construct studied in various fields, including psychology, education, marketing, management, and medicine. Despite its importance, there is no agreed definition of the construct. Therefore, we review existing definitions of listening, primarily recent, focusing on those that describe listening in interpersonal contexts. We identify 20 adjectives describing listening and found two underlying themes: unobservable versus observable behaviors and focusing on the speaker's or listener's interests. Focusing on the unobservable and the speaker's interest, we propose a novel, adjective-free listening definition: the degree of devotion to co-exploring the Other with and for the other. Adopting a dyadic view, we argue that either the listener or the speaker can generate such devotion and initiate the co-creation of a listening state. Our new definition can contribute to developing empirical measures with good discriminant validity.
Topics: Humans; Language; Marketing
PubMed: 37437381
DOI: 10.1016/j.copsyc.2023.101639 -
Journal of Nuclear Medicine : Official... Jul 2023Ga-fibroblast activation protein inhibitors (FAPIs) are promising radiotracers for cancer imaging, with emerging data in the recent years. Nonetheless, the interobserver...
Ga-fibroblast activation protein inhibitors (FAPIs) are promising radiotracers for cancer imaging, with emerging data in the recent years. Nonetheless, the interobserver agreement on Ga-FAPI PET/CT study interpretations in cancer patients remains poorly understood. Ga-FAPI PET/CT was performed on 50 patients with various tumor entities (sarcoma [ = 10], colorectal cancer [ = 10], pancreatic adenocarcinoma [ = 10], genitourinary cancer [ = 10], and other types of cancer [ = 10]). Fifteen masked observers reviewed and interpreted the images using a standardized approach for local, local nodal, and metastatic involvement. Observers were grouped by experience as having a low (<30 prior Ga-FAPI PET/CT studies; = 5), intermediate (30-300 studies; = 5), or high level of experience (>300 studies; = 5). Two independent readers with a high level of experience and unmasked to clinical information, histopathology, tumor markers, and follow-up imaging (CT/MRI or PET/CT) served as the standard of reference (SOR). Observer groups were compared by overall agreement (percentage of patients matching SOR) and Fleiss κ with mean and corresponding 95% CI. We defined acceptable agreement as a κ value of at least 0.6 (substantial or higher) and acceptable accuracy as at least 80%. Highly experienced observers agreed substantially on all categories (primary tumor: κ = 0.71; 95% CI, 0.71-0.71; local nodal involvement: κ = 0.62; 95% CI, 0.61-0.62; distant metastasis: κ = 0.75; 95% CI, 0.75-0.75), whereas observers with intermediate experience showed substantial agreement on primary tumor (κ = 0.73; 95% CI, 0.73-0.73) and distant metastasis (κ = 0.65; 95% CI, 0.65-0.65) but moderate agreement on local nodal stages (κ = 0.55; 95% CI, 0.55-0.55). Observers with low experience had moderate agreement on all categories (primary tumor: κ = 0.57; 95% CI, 0.57-0.58; local nodal involvement: κ = 0.51; 95% CI, 0.51-0.52; distant metastasis: κ = 0.54; 95% CI, 0.53-0.54). Compared with SOR, the accuracy for readers with high, intermediate, and low experience was 85%, 83%, and 78%, respectively. In summary, only highly experienced readers showed substantial agreement and a diagnostic accuracy of at least 80% in all categories. The interpretation of Ga-FAPI PET/CT for cancer imaging had substantial reproducibility and accuracy among highly experienced observers only, especially for local nodal and metastatic assessments. Therefore, for accurate interpretation of different tumor entities and pitfalls, we recommend training or experience with at least 300 representative scans for future clinical readers.
Topics: Humans; Positron Emission Tomography Computed Tomography; Gallium Radioisotopes; Prospective Studies; Adenocarcinoma; Observer Variation; Reproducibility of Results; Pancreatic Neoplasms; Fluorodeoxyglucose F18; Quinolines
PubMed: 37230530
DOI: 10.2967/jnumed.122.265245 -
Otology & Neurotology : Official... Sep 2023We reviewed a cohort of patients with untreated sporadic vestibular schwannoma (VS) and examined the relationship between high-frequency hearing loss (HFHL) in the... (Review)
Review
OBJECTIVE
We reviewed a cohort of patients with untreated sporadic vestibular schwannoma (VS) and examined the relationship between high-frequency hearing loss (HFHL) in the non-VS ear and long-term hearing outcomes in the VS-affected ear. We hypothesized that the progression of HFHL is associated with accelerated hearing decline in sporadic VS.
STUDY DESIGN
Retrospective cohort study.
SETTING
Tertiary center.
PATIENTS
We studied 102 patients with sporadic VS diagnosed from 1999 to 2015 with ≥5 years of observation (median, 6.92; interquartile range, 5.85-9.29). Sixty-six patients had AAO-HNS class A/B hearing at presentation and were included in analysis.
INTERVENTIONS
Audiometry, serial magnetic resonance imaging for observation of VS.
MAIN OUTCOME MEASURES
Four-frequency pure tone average (PTA) and word recognition scores (WRS) in the VS-affected ear. Decline in high-frequency PTA (average of thresholds at 4000, 6000, and 8,000 Hz) was defined as ≥10 dB during the study period. Decline in WRS was defined as ≥10%.
RESULTS
Compared with those without, patients with progressive HFHL in the non-VS ear were more likely to experience a decline in WRS in the VS ear (80% vs. 54%, p = 0.031). However, the same group showed no difference (52% vs. 41%, p = 0.40) in decline in PTA of the VS ear.
CONCLUSIONS
Patients with observed VS who experience progressive HFHL in the non-VS ear are more likely to experience significant declines in speech understanding in the VS-affected ear over time. Patients with a history of presbycusis may have an increased risk of losing serviceable hearing because of sporadic VS.
Topics: Humans; Neuroma, Acoustic; Presbycusis; Retrospective Studies; Treatment Outcome; Hearing; Audiometry, Pure-Tone
PubMed: 37442597
DOI: 10.1097/MAO.0000000000003947 -
Advances in Medical Education and... 2023The purpose of midwifery education is to produce clinically competent midwives. However, clinical training in Malawi faces multiple challenges, and the concept of... (Review)
Review
BACKGROUND
The purpose of midwifery education is to produce clinically competent midwives. However, clinical training in Malawi faces multiple challenges, and the concept of Clinical Competency (CC) has not been analysed in this context. This article analyses CC during undergraduate midwifery training in Malawi to elucidate its attributes, antecedents, consequences, and empirical referents.
METHODS
A literature search was performed on data bases, Google Scholar, PubMed, and CINAHL, using the following terms: clinical competency, midwifery competency, nursing competency, nursing and midwifery competency. Published articles were retrieved and clinical competency analysis was guided by Walker and Avant's strategy.
RESULTS
CC attributes were knowledge, skills, attitudes, performance level, professionalism, and entrustable professional activity. Antecedents included motivation, role models, learning environment and personal traits. The consequences of CC include confidence, client safety, and quality of care. CC can be measured through a combination of four strategies: observing a student practising it in clinical area, simulation or Objective Structured Clinical Examination (OSCE), application through written essays or case presentations, and knowledge-based assessment.
CONCLUSION
CC is a multidimensional concept and its definition and defining attributes are contextual. Similarly, clinical competencies are a major determinant of educational decisions such as curriculum nucleus, length of clinical placement, teaching strategies, and student assessment methods. However, CC and its attributes have not been fully utilised in Malawi, especially in clinical teaching and student clinical assessments. There is a need to adequately prepare midwifery educators, clinical staff, and students to deliver quality clinical competencies consistent with competency-based education. Adoption of different assessment strategies and development of valid and reliable tools is necessary to comprehensively measure CC among midwifery students in Malawi.
PubMed: 37789928
DOI: 10.2147/AMEP.S426347 -
BMC Public Health Dec 2023There is inconsistent evidence on the association of moderate alcohol consumption and stroke risk in the general population and is not well studied among U.S. Veterans....
BACKGROUND
There is inconsistent evidence on the association of moderate alcohol consumption and stroke risk in the general population and is not well studied among U.S. Veterans. Furthermore, it is unclear whether primarily drinking beer, wine, or liquor is associated with a difference in stroke risk.
METHODS
The study included 185,323 Million Veteran Program participants who self-reported alcohol consumption on the Lifestyle Survey. Moderate consumption was defined as 1-2 drinks/day and beverage preference of beer, wine or liquor was defined if ≥ 50% of total drinks consumed were from a single type of beverage. Strokes were defined using ICD-9 and ICD-10 codes from the participants' electronic health record.
RESULTS
The mean (sd) age of the sample was 64 (13) years and 11% were women. We observed 4,339 (94% ischemic; 6% hemorrhagic) strokes over a median follow-up of 5.2 years. In Cox models adjusted for age, sex, race, education, income, body mass index, smoking, exercise, diet, cholesterol, prevalent diabetes, prevalent hypertension, lipid-lowering medication, antihypertensive medication, and diabetes medication, moderate alcohol consumption (1-2 drinks/day) was associated with a 22% lower risk of total stroke compared with never drinking [Hazards ratio (HR) 95% confidence interval (CI): 0.78 (0.67, 0.92)]. When stratifying by stroke type, we observed a similar protective association with moderate consumption and ischemic stroke [HR (95% CI): 0.76 (0.65, 0.90)], but a non-statistically significant higher risk of hemorrhagic stroke [HR (95% CI): 1.29 (0.64, 2.61)]. We did not observe a difference in ischemic or hemorrhagic stroke risk among those who preferred beer, liquor or wine vs. no beverage preference. When stratifying by prior number of hospital visits (≤ 15, 16-33, 34-64, ≥ 65) as a proxy for health status, we observed attenuation of the protective association with greater number of visits [HR (95% CI): 0.87 (0.63, 1.19) for ≥ 65 visits vs. 0.80 (0.59, 1.08) for ≤ 15 visits].
CONCLUSIONS
We observed a lower risk of ischemic stroke, but not hemorrhagic stroke with moderate alcohol consumption and did not observe substantial differences in risk by beverage preference among a sample of U.S. Veterans. Healthy user bias of moderate alcohol consumption may be driving some of the observed protective association.
Topics: Humans; Female; Middle Aged; Male; Alcohol Drinking; Veterans; Risk Factors; Hemorrhagic Stroke; Alcoholic Beverages; Stroke; Surveys and Questionnaires; Diabetes Mellitus; Ischemic Stroke
PubMed: 38087273
DOI: 10.1186/s12889-023-17377-x -
Acta Neuropathologica Communications Jul 2023Oligodendrocyte (OL) injury and loss are central features of evolving lesions in multiple sclerosis. Potential causative mechanisms of OL loss include metabolic stress...
Oligodendrocyte (OL) injury and loss are central features of evolving lesions in multiple sclerosis. Potential causative mechanisms of OL loss include metabolic stress within the lesion microenvironment. Here we use the injury response of primary human OLs (hOLs) to metabolic stress (reduced glucose/nutrients) in vitro to help define the basis for the in situ features of OLs in cases of MS. Under metabolic stress in vitro, we detected reduction in ATP levels per cell that precede changes in survival. Autophagy was initially activated, although ATP levels were not altered by inhibitors (chloroquine) or activators (Torin-1). Prolonged stress resulted in autophagy failure, documented by non-fusion of autophagosomes and lysosomes. Consistent with our in vitro results, we detected higher expression of LC3, a marker of autophagosomes in OLs, in MS lesions compared to controls. Both in vitro and in situ, we observe a reduction in nuclear size of remaining OLs. Prolonged stress resulted in increased ROS and cleavage of spectrin, a target of Ca-dependent proteases. Cell death was however not prevented by inhibitors of ferroptosis or MPT-driven necrosis, the regulated cell death (RCD) pathways most likely to be activated by metabolic stress. hOLs have decreased expression of VDAC1, VDAC2, and of genes regulating iron accumulation and cyclophilin. RNA sequencing analyses did not identify activation of these RCD pathways in vitro or in MS cases. We conclude that this distinct response of hOLs, including resistance to RCD, reflects the combined impact of autophagy failure, increased ROS, and calcium influx, resulting in metabolic collapse and degeneration of cellular structural integrity. Defining the basis of OL injury and death provides guidance for development of neuro-protective strategies.
Topics: Humans; Multiple Sclerosis; Reactive Oxygen Species; Oligodendroglia; Cell Death; Multiple Sclerosis, Chronic Progressive; Adenosine Triphosphate
PubMed: 37408029
DOI: 10.1186/s40478-023-01601-1 -
Sante Publique (Vandoeuvre-les-Nancy,... Dec 2023It is time to consider the protection of our environment as a major public health issue in oral medicine. Evidence shows that activities related to dental practice, such...
It is time to consider the protection of our environment as a major public health issue in oral medicine. Evidence shows that activities related to dental practice, such as patient transportation, use of rare materials and chemicals, or energy consumption, affect our ecosystems and contribute to the global degradation we are increasingly observing. The degradation of our environment is considered the greatest threat to our health. Exposure of oral tissues to multiple environmental factors can lead to pathological conditions. In addition to these direct effects, there are more complex phenomena, leading to co-deficits in the health of populations. The example of the sugar industry illustrates the systemic failures resulting in the double degradation of the environment and the health of individuals. Face with these dynamically interacting phenomena, human communities must consider systemic responses such as those described in this article. The dental community will need to do its part and consider global oral health as a central issue. This conceptual work will help define the innovations and action needed to ensure equitable practice that respects planetary limits.
Topics: Humans; Ecosystem; Oral Health; Public Health; Global Health
PubMed: 38040640
DOI: 10.3917/spub.hs1.2023.0163 -
Philosophical Transactions. Series A,... Jul 2023General mathematical reasoning is computationally undecidable, but humans routinely solve new problems. Moreover, discoveries developed over centuries are taught to...
General mathematical reasoning is computationally undecidable, but humans routinely solve new problems. Moreover, discoveries developed over centuries are taught to subsequent generations quickly. What structure enables this, and how might that inform automated mathematical reasoning? We posit that central to both puzzles is the structure of procedural abstractions underlying mathematics. We explore this idea in a case study on five sections of beginning algebra on the Khan Academy platform. To define a computational foundation, we introduce Peano, a theorem-proving environment where the set of valid actions at any point is finite. We use Peano to formalize introductory algebra problems and axioms, obtaining well-defined search problems. We observe existing reinforcement learning methods for symbolic reasoning to be insufficient to solve harder problems. Adding the ability to induce reusable abstractions ('tactics') from its own solutions allows an agent to make steady progress, solving all problems. Furthermore, these abstractions induce an order to the problems, seen at random during training. The recovered order has significant agreement with the expert-designed Khan Academy curriculum, and second-generation agents trained on the recovered curriculum learn significantly faster. These results illustrate the synergistic role of abstractions and curricula in the cultural transmission of mathematics. This article is part of a discussion meeting issue 'Cognitive artificial intelligence'.
PubMed: 37271179
DOI: 10.1098/rsta.2022.0044 -
Journal of ISAKOS : Joint Disorders &... Aug 2023Ligament augmentation techniques (LATs) are surgical procedures, in which an anatomical ligament repair or reconstruction is strengthened with a synthetic material.... (Review)
Review
IMPORTANCE
Ligament augmentation techniques (LATs) are surgical procedures, in which an anatomical ligament repair or reconstruction is strengthened with a synthetic material. During the last decade, LATs have increased in prevalence in clinical practice and academic literature. Observing the trends in LAT publications can be used to identify clusters of strong evidence for clinical practice and to highlight areas of the literature which need further development.
OBJECTIVE
This article aims to define ligament augmentation as a technique category, observe anatomical, procedural, and temporal trends in LAT publication, and report on the state of current research in this field.
EVIDENCE REVIEW
Primary literature in the English language, which describes ligament augmentation and reports on human, cadaveric, or biomechanical models, and published prior to May 24th, 2022, was targeted for analysis. PubMed, Embase, and Cochrane CENTRAL databases were explored using a focused keyword search strategy, and the resulting publications were reviewed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Data were collected and analysed using descriptive statistics.
FINDINGS
Two hundred eighty-three publications reporting ligament augmentation techniques, published from May 1989 to May 2022, were included for final analysis. A wide technical and anatomical variety of procedures are reported. 36.8% of LAT publications describe knee ligaments, among which the anterior cruciate ligamenthas the highest focus in ligament augmentation publications (31.8% of articles). LAT literature has recently expanded in anatomical scope, with many contemporary articles describing the usage of a LAT in the ankle syndesmosis and coracoclavicular ligaments. 60.4% of LAT literature has been published since 2017. There has been an 11% average increase in the rate of LAT publication reports since 2015. Novel fixation devices-suture buttons and suture anchors-have gained wide popularity in the literature.
CONCLUSIONS AND RELEVANCE
In this review, we define LATs and quantitatively describe the expansion of LAT use reported in the literature. This data will provide physicians an overview of the history of these methods, as well as illustrate the broad range of applications available for the use of LATs.
Topics: Humans; Knee Joint; Ankle Joint; Ligaments, Articular; Suture Anchors
PubMed: 37105381
DOI: 10.1016/j.jisako.2023.04.003