The purpose of this review is to characterize and compare validated clinical rating scales and transducers that are used in the clinical assessment of tremor disorders. Tremor is an involuntary ...oscillatory movement of a body part. Tremor can be characterized in terms of amplitude and frequency of oscillation, and these kinematic properties vary randomly and with activities of daily living. Clinical rating scales are most useful when performing a comprehensive assessment of tremor severity (amplitude), anatomical distribution, activation conditions, and impact on activities of daily living and quality of life. Motion transducers are often used in conjunction with surface electromyography to discern properties of tremor that are important diagnostically. Motion transducers are needed for an accurate determination of tremor frequency and for precise quantification of changes in amplitude and frequency over time. The precision and accuracy of motion transducers exceed that of all clinical rating scales. However, these advantages of transducers are mitigated by the considerable within-subject random variability in tremor amplitude, such that the smallest detectable statistically significant change in tremor amplitude is comparable for scales and transducers. Comprehensive anatomical and behavioral assessment of tremor with transducers is not clinically feasible. Transducers and scales are presently viewed as complementary methods of quantifying tremor amplitude. Transducer measures are logarithmically related to clinical ratings, as predicted by the Weber-Fechner law of psychophysics. This relationship must be considered when interpreting change in clinical ratings, produced by disease or treatment. This article is part of the Special Issue "Tremor" edited by Daniel D. Truong, Mark Hallett, and Aasef Shaikh.
•Rating scales and motion transducers have comparable ability to detect statistically significant change in tremor severity.•Transducer measures of tremor amplitude are logarithmically related to clinical ratings.•There are no validated scales for tremor diagnosis.•Electrophysiology is useful in diagnosing primary orthostatic tremor, functional tremor, myorhythmia and cortical tremor.•Transducers and rating scales are complementary methods for assessing tremor severity.
A task force of the International Parkinson and Movement Disorder Society (MDS) recently published a tremor classification scheme that is based on the nosologic principle of two primary axes for ...classifying an illness: clinical manifestations (Axis 1) and etiology (Axis 2). An Axis 1 clinical syndrome is a recurring group of clinical symptoms, signs (physical findings), and possibly laboratory results that suggests the presence of at least one underlying Axis 2 etiology. Syndromes must be defined and used consistently to be of value in finding specific etiologies and effective treatments. The MDS task force concluded that essential tremor is a common neurological syndrome that has never been defined consistently by clinicians and researchers. The MDS task force defined essential tremor as a syndrome of bilateral upper limb action tremor of at least 3 years duration, with or without tremor in other locations (e.g., head, voice, or lower limbs), in the absence of other neurological signs (e.g., dystonia, parkinsonism, myoclonus, ataxia, peripheral neuropathy, and cognitive impairment). Deviations from this definition should not be labeled as essential tremor. Patients with additional questionably-abnormal signs or with signs of uncertain relevance to tremor are classified as essential tremor plus. The MDS classification scheme encourages a thorough unbiased phenotyping of patients with tremor, with no assumptions of etiology, pathology, pathophysiology, or relationship to other neurological disorders. The etiologies, pathology, and clinical course of essential tremor are too heterogeneous for this syndrome to be viewed as a disease or a family of diseases.
Methylation of DNA at CpG sites is the most common and stable of epigenetic changes in cancer. Hypermethylation acts to limit immune checkpoint blockade immunotherapy by inhibiting endogenous ...interferon responses needed for recognition of cancer cells. By contrast, global hypomethylation results in the expression of programmed death ligand 1 (PD-L1) and inhibitory cytokines, accompanied by epithelial-mesenchymal changes that can contribute to immunosuppression. The drivers of these contrasting methylation states are not well understood. DNA methylation also plays a key role in cytotoxic T cell ‘exhaustion’ associated with tumor progression. We present an updated exploratory analysis of how DNA methylation may define patient subgroups and can be targeted to develop tailored treatment combinations to help improve patient outcomes.
Genome-wide DNA methylation is a relatively stable epigenetic characteristic of cells, which can be dysregulated in cancer cells by oncogenic signals.
Hyper- or hypomethylation of DNA in melanoma cells underlies the categorization of melanoma patients into four groups according to PD-L1 expression and T cell infiltration.
Resistance of melanoma to immunotherapy by immune checkpoint inhibitors is associated with global hypermethylation and low PD-L1 expression whereas global hypomethylation is associated with constitutive PD-L1 expression and inhibitory cytokine production.
Hypermethylation of DNA in melanoma is associated with overexpression of DNA methyltransferases (DNMTs) and histone methyltransferase-EZH2 in the PRC2 repressive complex.
The T cell exhaustion state is associated with hypomethylation of PD1, LAG3, and TIM3 promoters. EZH2 can be activated by the YY1 transcription factor in human melanoma cells, downregulating the IL2 promoter by de novo methylation.
Essential tremor (ET) plus is a new tremor classification that was introduced in 2018 by a task force of the International Parkinson and Movement Disorder Society. Patients with ET plus meet the ...criteria for ET but have one or more additional systemic or neurologic signs of uncertain significance or relevance to tremor ("soft signs"). Soft signs are not sufficient to diagnose another tremor syndrome or movement disorder, and soft signs in ET plus are known to have poor interrater reliability and low diagnostic sensitivity and specificity. Therefore, the clinical significance of ET plus must be interpreted probabilistically when judging whether a patient is more likely to have ET or a combined tremor syndrome, such as dystonic tremor. Such a probabilistic interpretation is possible with Bayesian analysis. This review presents a Bayesian analysis of ET plus in patients suspected of having ET versus a dystonic tremor syndrome, which is the most common differential diagnosis in patients referred for ET. Bayesian analysis of soft signs provides an estimate of the probability that a patient with possible ET is more likely to have an alternative diagnosis. ET plus is a distinct tremor classification and should not be viewed as a subtype of ET. ET plus covers a more-comprehensive phenotyping of people with possible ET, and the clinical interpretation of ET plus is enhanced with Bayesian analysis of associated soft signs.
Electromagnetic ion cyclotron (EMIC) waves are potentially important drivers of the loss of energetic electrons from the radiation belts. Numerous theoretical calculations exist with conflicting ...predictions of one of the key parameters: the minimum resonance energy of electrons precipitated into the atmosphere by EMIC waves. In this study we initially analyze an EMIC electron precipitation event using data from two different spacecraft instruments to investigate the energies involved. Combining observations from these satellites, we find that the electron precipitation has a peak flux at ∼250 keV. Extending the analysis technique to a previously published database of similar scattering events, we find that the peak electron precipitation flux occurs predominantly around 300 keV, with only ∼11% of events peaking in the 1–4 MeV range. Such a significant population of low‐energy EMIC‐driven electron precipitation events highlights the possibility for EMIC waves to be significant drivers of radiation belt electron losses.
Key Points
EMIC waves are capable of scattering sub‐MeV electrons into the bounce loss cone
Only 11% of EMIC‐related electron precipitation events studied were strongly relativistic (i.e., 1–4 MeV)
We provide evidence to support recently published theoretical predictions of EMIC waves scattering nonresonant sub‐MeV energy electrons
Innovative strategies, such as HIV self-testing (HIVST), could increase HIV testing rates and diagnosis. Evidence to inform the design of an HIVST intervention in the UK is scarce with very little ...European data on this topic. This study aims to understand values and preferences for HIVST interventions targeting MSM in the UK. We explore the acceptability of HIVST among MSM in the context of known barriers and facilitators to testing for HIV; assess preferences for, and the concerns about, HIVST.
Six focus group discussions (FGD) were conducted with 47 MSM in London, Manchester and Plymouth. HIVST as a concept was discussed and participants were asked to construct their ideal HIVST intervention. OraQuickTM and BioSureTM kits were then demonstrated and participants commented on procedure, design and instructions. FGDs were recorded and transcribed verbatim, then analysed thematically.
Convenience and confidentiality of HIVST was seen to facilitate testing. Issues with domestic privacy problematised confidentiality. HIVST kits and instructions were thought to be unnecessarily complicated, and did not cater to the required range of abilities. The window period was the most important element of an HIVST, with strong preference for 4th generation testing. Kits which used a blood sample were more popular than those using saliva due to higher perceived accuracy although phobia of needles and/or blood meant some would only access HIVST if a saliva sample option was available. A range of access options was important to maintain convenience and privacy. HIVST kits were assumed to increase frequency of testing, with concerns related to the dislocation of HIVST from sexual health care pathways and services.
Utility of HIVST arises from relatively high levels of confidentiality and convenience. Until 4th generation assays are available HIVST will be seen as supplementary in a UK context.
We update a previous systematic review to inform new World Health Organization HIV self-testing (HIVST) recommendations. We compared the effects of HIVST to standard HIV testing services to ...understand which service delivery models are effective for key populations.
We did a systematic review of randomised controlled trials (RCTs) which compared HIVST to standard HIV testing in key populations, published from 1 January 2006 to 4 June 2019 in PubMed, Embase, Global Index Medicus, Social Policy and Practice, PsycINFO, Health Management Information Consortium, EBSCO CINAHL Plus, Cochrane Library and Web of Science. We extracted study characteristic and outcome data and conducted risk of bias assessments using the Cochrane ROB tool version 1. Random effects meta-analyses were conducted, and pooled effect estimates were assessed along with other evidence characteristics to determine the overall strength of the evidence using GRADE methodology.
After screening 5909 titles and abstracts, we identified 10 RCTs which reported on testing outcomes. These included 9679 participants, of whom 5486 were men who have sex with men (MSM), 72 were trans people and 4121 were female sex workers. Service delivery models included facility-based, online/mail and peer distribution. Support components were highly diverse and ranged from helplines to training and supervision. HIVST increased testing uptake by 1.45 times (RR=1.45 95% CI 1.20, 1.75). For MSM and small numbers of trans people, HIVST increased the mean number of HIV tests by 2.56 over follow-up (mean difference = 2.56; 95% CI 1.24, 3.88). There was no difference between HIVST and SoC in regard to positivity among tested overall (RR = 0.91; 95% CI 0.73, 1.15); in sensitivity analysis of positivity among randomised HIVST identified significantly more HIV infections among MSM and trans people (RR = 2.21; 95% CI 1.20, 4.08) and in online/mail distribution systems (RR = 2.21; 95% CI 1.14, 4.32). Yield of positive results in FSW was not significantly different between HIVST and SoC. HIVST reduced linkage to care by 17% compared to SoC overall (RR = 0.83; 95% CI 0.74, 0.92). Impacts on STI testing were mixed; two RCTs showed no decreases in STI testing while one showed significantly lower STI testing in the intervention arm. There were no negative impacts on condom use (RR = 0.95; 95% CI 0.83, 1.08), and social harm was very rare.
HIVST is safe and increases testing uptake and frequency as well as yield of positive results for MSM and trans people without negative effects on linkage to HIV care, STI testing, condom use or social harm. Testing uptake was increased for FSW, yield of positive results were not and linkage to HIV care was worse. Strategies to improve linkage to care outcomes for both groups are crucial for effective roll-out.
•This chapter provides an overview of clinical and electrophysiological tools for measuring and classifying tremor.•The distinguishing clinical and electrophysiologic features of the different forms ...of tremor are explained.•The pathophysiology of the different tremors is reviewed with an emphasis on electrophysiological methods.
The various forms of tremor are now classified in two axes: clinical characteristics (axis 1) and etiology (axis 2). Electrophysiology is an extension of the clinical exam. Electrophysiologic tests are diagnostic of physiologic tremor, primary orthostatic tremor, and functional tremor, but they are valuable in the clinical characterization of all forms of tremor. Electrophysiology will likely play an increasing role in axis 1 tremor classification because many features of tremor are not reliably assessed by clinical examination alone. In particular, electrophysiology may be needed to distinguish tremor from tremor mimics, assess tremor frequency, assess tremor rhythmicity or regularity, distinguish mechanical-reflex oscillation from central neurogenic oscillation, determine if tremors in different body parts, muscles, or brain regions are strongly correlated, document tremor suppression or entrainment by voluntary movements of contralateral body parts, and document the effects of voluntary movement on rest tremor. In addition, electrophysiologic brain mapping has been crucial in our understanding of tremor pathophysiology. The electrophysiologic methods of tremor analysis are reviewed in the context of physiologic tremor and pathologic tremors, with a focus on clinical characterization and pathophysiology. Electrophysiology is instrumental in elucidating tremor mechanisms, and the pathophysiology of the different forms of tremor is summarized in this review.
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