The Burden of Narcolepsy in Adults: A Population Sampling Study Using Personal Media.

OBJECTIVE: To obtain insight in the spectrum of narcolepsy symptoms and associated burden in a large cohort of patients. METHODS: We used the Narcolepsy Monitor, a mobile app, to easily rate the presence and burden of 20 narcolepsy symptoms. Baseline measures were obtained and analyzed from 746 users aged between 18 and 75 years with a reported diagnosis of narcolepsy. RESULTS: Median age was 33.0 years (IQR 25.0-43.0), median Ullanlinna Narcolepsy Scale 19 (IQR 14.0-26.0), 78% reported using narcolepsy pharmacotherapy. Excessive daytime sleepiness (97.2%) and lack of energy were most often present (95.0%) and most often caused a high burden (79.7% and 76.1% respectively). Cognitive symptoms (concentration 93.0%, memory 91.4%) and psychiatric symptoms (mood 76.8%, anxiety/panic 76.4%) were relatively often reported to be present and burdensome. Conversely, sleep paralysis and cataplexy were least often reported as highly bothersome. Females experienced a higher burden for anxiety/panic, memory, and lack of energy. CONCLUSIONS: This study supports the notion of an elaborate narcolepsy symptom spectrum. Each symptom's contribution to the experienced burden varied, but lesser-known symptoms did significantly add to this as well. This emphasizes the need to not only focus treatment on the classical core symptoms of narcolepsy.

The impact of healthy pregnancy on features of heart rate variability and pulse wave morphology derived from wrist-worn photoplethysmography.

Due to the association between dysfunctional maternal autonomic regulation and pregnancy complications, tracking non-invasive features of autonomic regulation derived from wrist-worn photoplethysmography (PPG) measurements may allow for the early detection of deteriorations in maternal health. However, even though a plethora of these features-specifically, features describing heart rate variability (HRV) and the morphology of the PPG waveform (morphological features)-exist in the literature, it is unclear which of these may be valuable for tracking maternal health. As an initial step towards clarity, we compute comprehensive sets of HRV and morphological features from nighttime PPG measurements. From these, using logistic regression and stepwise forward feature elimination, we identify the features that best differentiate healthy pregnant women from non-pregnant women, since these likely capture physiological adaptations necessary for sustaining healthy pregnancy. Overall, morphological features were more valuable for discriminating between pregnant and non-pregnant women than HRV features (area under the receiver operating characteristics curve of 0.825 and 0.74, respectively), with the systolic pulse wave deterioration being the most valuable single feature, followed by mean heart rate (HR). Additionally, we stratified the analysis by sleep stages and found that using features calculated only from periods of deep sleep enhanced the differences between the two groups. In conclusion, we postulate that in addition to HRV features, morphological features may also be useful in tracking maternal health and suggest specific features to be included in future research concerning maternal health.

Automated sleep staging in people with intellectual disabilities using heart rate and respiration variability.

BACKGROUND: People with intellectual disabilities (ID) have a higher risk of sleep disorders. Polysomnography (PSG) remains the diagnostic gold standard in sleep medicine. However, PSG in people with ID can be challenging, as sensors can be burdensome and have a negative influence on sleep. Alternative methods of assessing sleep have been proposed that could potentially transfer to less obtrusive monitoring devices. The goal of this study was to investigate whether analysis of heart rate variability and respiration variability is suitable for the automatic scoring of sleep stages in sleep-disordered people with ID. METHODS: Manually scored sleep stages in PSGs of 73 people with ID (borderline to profound) were compared with the scoring of sleep stages by the CardioRespiratory Sleep Staging (CReSS) algorithm. CReSS uses cardiac and/or respiratory input to score the different sleep stages. Performance of the algorithm was analysed using input from electrocardiogram (ECG), respiratory effort and a combination of both. Agreement was determined by means of epoch-per-epoch Cohen's kappa coefficient. The influence of demographics, comorbidities and potential manual scoring difficulties (based on comments in the PSG report) was explored. RESULTS: The use of CReSS with combination of both ECG and respiratory effort provided the best agreement in scoring sleep and wake when compared with manually scored PSG (PSG versus ECG = kappa 0.56, PSG versus respiratory effort = kappa 0.53 and PSG versus both = kappa 0.62). Presence of epilepsy or difficulties in manually scoring sleep stages negatively influenced agreement significantly, but nevertheless, performance remained acceptable. In people with ID without epilepsy, the average kappa approximated that of the general population with sleep disorders. CONCLUSIONS: Using analysis of heart rate and respiration variability, sleep stages can be estimated in people with ID. This could in the future lead to less obtrusive measurements of sleep using, for example, wearables, more suitable to this population.

Direct application of an ECG-based sleep staging algorithm on reflective photoplethysmography data decreases performance.

OBJECTIVE: The maturation of neural network-based techniques in combination with the availability of large sleep datasets has increased the interest in alternative methods of sleep monitoring. For unobtrusive sleep staging, the most promising algorithms are based on heart rate variability computed from inter-beat intervals (IBIs) derived from ECG-data. The practical application of these algorithms is even more promising when alternative ways of obtaining IBIs, such as wrist-worn photoplethysmography (PPG) can be used. However, studies validating sleep staging algorithms directly on PPG-based data are limited. RESULTS: We applied an automatic sleep staging algorithm trained and validated on ECG-data directly on inter-beat intervals derived from a wrist-worn PPG sensor, in 389 polysomnographic recordings of patients with a variety of sleep disorders. While the algorithm reached moderate agreement with gold standard polysomnography, the performance was significantly lower when applied on PPG- versus ECG-derived heart rate variability data (kappa 0.56 versus 0.60, p < 0.001; accuracy 73.0% versus 75.9% p < 0.001). These results show that direct application of an algorithm on a different source of data may negatively affect performance. Algorithms need to be validated using each data source and re-training should be considered whenever possible.

Exploring the Parkinson patients' perspective on home-based video recording for movement analysis: a qualitative study.

BACKGROUND: Parkinson's disease is a complex neurological disorder characterized by a variety of motor- as well as non-motor symptoms. Video-based technology (using continuous home monitoring) may bridge the gap between the fragmented in-clinic observations and the need for a comprehensive understanding of the progression and fluctuation of disease symptoms. However, continuous monitoring can be intrusive, raising questions about feasibility as well as potential privacy violation. METHODS: We used a grounded theory approach in which we performed semi-structured interviews to explore the opinion of Parkinson's patients on home-based video recording used for vision-based movement analysis. RESULTS: Saturation was reached after sixteen interviews. Three first-level themes were identified that specify the conditions required to perform continuous video monitoring: Camera recording (e.g. being able to turn off the camera), privacy protection (e.g. patient's behaviour, patient's consent, camera location) and perceived motivation (e.g. contributing to science or clinical practice). CONCLUSION: Our findings show that Parkinson patients' perception of continuous, home-based video recording is positive, when a number of requirements are taken into account. This knowledge will enable us to start using this technology in future research and clinical practice in order to better understand the disease and to objectify outcomes in the patients' own homes.

Complexes of N antitermination protein of phage lambda with specific and nonspecific RNA target sites on the nascent transcript.

The mechanisms that control N protein dependent antitermination in phage lambda have counterparts in many eukaryotic systems, including specific regulatory interactions of the antitermination protein with the nascent RNA transcript. Here we describe the specific and nonspecific RNA binding modes of antitermination protein N. These modes differ markedly in RNA binding affinity and in structure. N protein, either free in solution or as a complex with nonspecific RNA, lacks observable secondary and tertiary structure and binds RNA sequences indiscriminately with a dissociation constant (Kd) of approximately 10(-6) M. In contrast N becomes partially folded with at least 16-18 amino acids of ordered alpha-helical structure and binds much more tightly (Kd approximately 10(-9) M) on forming a highly specific 1:1 complex with its cognate boxB RNA hairpin. These observations and others are used to help define a bipartite model of N-dependent antitermination in which these specific and nonspecific interactions control the binding of N to the nascent transcript. Finally the role of RNA looping in delivering the bound N to the transcription complex and determining the stability (and thus the terminator specificity) of the resulting antitermination interaction of N with the RNA polymerase is considered in quantitative terms.

Assembly of the N-dependent antitermination complex of phage lambda: NusA and RNA bind independently to different unfolded domains of the N protein.

The N protein of bacteriophage lambda activates expression of the delayed early genes of this phage by modifying RNA polymerase (RNAP) into a form that is resistant to termination signals. N binds to the boxB hairpin that forms in the nascent RNA transcript upon transcription of the nut regulatory element, and then interacts with RNAP by RNA looping. The binding of the N-boxB subassembly to the transcription complex is further stabilized by interaction with the Escherichia coli NusA protein. N, free in solution, exists as an unfolded protein that becomes partially structured upon binding specifically to boxB RNA. Because NusA does not assist in antitermination unless N is specifically bound to boxB, we have asked whether the structural change induced by binding to boxB affects the interaction of N with NusA. Using fluorescence spectroscopy, we have measured the affinity of N for NusA in the presence and absence of boxB RNA. We find that NusA binds to the unfolded N protein with a dissociation constant (Kd) of approximately 70 nM, and although N undergoes a significant structural change upon binding to boxB, the binding affinity of NusA for a N protein complexed with boxB is not altered. We have also shown that the boxA element of nut does not affect NusA binding to N-boxB. These results demonstrate that the interaction of N with NusA is independent of RNA binding, arguing that NusA must interact with an unfolded region of the polypeptide that remains unstructured even when N binds to boxB RNA. To further establish this point we isolated a truncated peptide containing the amino-terminal 36 residues of the N protein. Binding of boxB RNA to this peptide showed that all of the structural change in N that occurs upon binding to boxB RNA is localized within the amino-terminal 36 residues of N, therefore the C terminus of N, including the regions necessary for NusA binding and RNAP activation, remains unfolded when the full length N binds to boxB RNA. Thus it appears that N can be described as an unfolded multi-domain protein that becomes ordered in a modular fashion as it encounters its various binding partners within the N-dependent antitermination complex.

Histidine-tryptophan interactions in T4 lysozyme: 'anomalous' pH dependence of fluorescence.

A variant of T4 lysozyme which contains only a single tryptophan residue (at position 138) has been prepared (W126Y/W158Y designated 'YWY'). Two additional mutations to YWY have been prepared involving replacement of glutamine 105, which hydrogen bonds to the indole N-H of trp 138 in wild type, with either a histidine (YWY/Q105H) or an alanine (YWY/Q105A). The fluorescence properties of these two species are investigated as a function of pH. YWY/Q105A exhibits essentially a single exponential fluorescence decay (5% tau = 0.35 ns 95% tau = 5 ns) and almost no pH dependence in steady state or time resolved fluorescence behavior. In contrast, YWY/Q105H exhibits complex fluorescence decay over the entire pH range used in these experiments. As the pH is lowered from 8 to 4, there is an increase in the quantum yield and a change in the average lifetime (from 2.0 to 3.1 ns). Using this data, the pKa of histidine 105 has been determined to be 5.9. These results are contrasted to those from other proteins which show a pH dependent tryptophan fluorescence associated with a neighboring histidine or other residue. Quenching behavior in terms of the stereochemistry of the tryptophan-histidine interaction and implications of these results for current models of complex fluorescence behavior of single tryptophan proteins are also discussed.

Structural and thermodynamic characteristics of the binding of the lambda N protein to a RNA hairpin.

The specific binding of the lambda N protein to a 15 nucleotide RNA oligomer that forms a hairpin structure has been investigated by biophysical methods. Using fluorescence spectroscopy and equilibrium ultra-centrifugation, it was found that the N protein binds specifically to this RNA hairpin as a monomer. Circular dichroism experiments show that both the N protein and the RNA hairpin undergo structural change upon association of the complex.

Quenching interactions and nonexponential decay: tryptophan 138 of bacteriophage T4 lysozyme.

Site-directed mutagenesis has been used to prepare variants of bacteriophage T4 lysozyme that contain only one tryptophan residue at position 138 and to change the residues in the immediate environment of this buried residue. Replacement of glutamine-105 by alanine results in a 2.7-fold increase in fluoresence quantum yield and converts the fluorescence decay from a highly nonexponential form to a single-exponential decay. This is atributed to electron transfer quenching of tryptophan-138 fluorescence by glutamine-105. Replacemeent of alanine-146 by threonine results in a 1.6-fold decrease in fluorescence intensity, indicating enhanced quenching by glutamine-105; replacement of glutamine-105 by alanine in this species results in a 5-fold in crease in fluorescence intensity. The interpretation of the nonexponential decay of the glutamine-105-containing species is discussed in terms of reversibility of the quenching process.