Exploring Symptom Fluctuations and Triggers in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Using Novel Patient-Centred N-of-1 Observational Designs: A Protocol for a Feasibility and Acceptability Study.

BACKGROUND: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic condition of unknown aetiology associated with a range of disabling symptoms, including post-exertional malaise, chronic fatigue, musculoskeletal pain, orthostatic intolerance, unrefreshing sleep, and cognitive dysfunction. ME/CFS is a heterogeneous disorder, with significant variation in symptom type and severity between individuals, as well as within individuals over time. The diversity of ME/CFS symptom presentation makes management challenging; treatments supported by data from randomised controlled trials may not work for all individuals due to the variability in experienced symptoms. Studies using quantitative N-of-1 observational designs involve repeated outcome measurements in an individual over time and can generate rigorous individual-specific conclusions about symptom patterns and triggers in individuals with ME/CFS. This study aims to explore the feasibility and acceptability of using novel patient-centred N-of-1 observational designs to explore symptom fluctuations and triggers in ME/CFS at the individual level. METHODS AND ANALYSIS: Individuals with a medical diagnosis of ME/CFS will be recruited through ME/CFS patient organisations to participate in a series of patient-centred N-of-1 observational studies. Using a wrist-worn electronic diary, participants will complete ecological momentary assessments of fatigue, stress, mood, and cognitive demand, three times per day for a period of 6-12 weeks. Personally relevant symptoms and triggers will also be incorporated into the questionnaire design. Physical activity will be objectively measured via an integrated accelerometer. Feasibility and acceptability outcomes will be assessed including the percentage of diary entries completed, as well as recruitment and retention rate, feasibility of analysing and interpreting the data collected, and participant views about participation elicited via a post-study semi-structured interview. DISCUSSION: This study will assess the feasibility and acceptability of patient-centred N-of-1 observational studies to assess diseases with complex presentations such as ME/CFS, as well as provide individual-level evidence about fluctuations and triggers of ME/CFS symptoms that may aid self-management. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry: ACTRN12618001898246. Registered on 22 November 2018.

Low thymine content in PINK1 mRNAs and insights into Parkinson's disease.

Thymine is the only nucleotide base which is changed to uracil upon transcription, leaving mRNA less hydrophobic compared to its DNA counterpart. All the 16 codons that contain uracil (or thymine in gene) as the second nucleotide code for the five large hydrophobic residues (LHRs), namely phenylalanine,v isoleucine, leucine, methionine and valine. Thymine content (i.e. the fraction of XTX codons, where X = A, C, G, or T) in PINK1 mRNA sequences and its relationship with protein stability and function are the focus of this work. This analysis will shed light on PINK1's stability, thus a clue can be provided to understand the mitochondrial dysfunction and the failure of oxidative stress control frequently observed in Parkinson's disease. We obtained the complete PINK1 mRNA sequences of 8 different species. The distributions of XTX codons in different frames are calculated. We observed that the thymine content reached the highest level in the coding frame 1 of the PINK1 mRNA sequence of Bos Taurus (Bt), that is peaked at 27%. Coding frame 1 containing low thymine leads to the reduction in LHRs in the corresponding proteins. Therefore, we conjecture that proteins from the other organisms, including Homo sapiens, lost some of their hydrophobicity and became susceptible to dysfunction. Genes such as PINK1 have reduced thymine in the evolutionary process thereby making their protein products potentially being susceptible to instability and causing disease. Adding more hydrophobic residues (thymine) at appropriate places might help conserve important biological functions.