Remote Prescription During Pandemic: Challenges and Solutions.

The current COVID-19 pandemic has created an awareness and at the same time provides an impetus to transform digitalisation of healthcare delivery. Remote prescription is one key component of telemedicine, but it is the easiest and already practised in most places during the current pandemic even without the framework of virtual medicine in place. However, remote prescription, with its antecedent problems cannot be properly and safely executed in isolation. To ensure patients' safety and health outcomes, specific guidelines will need to be developed to cater for specific medical conditions to address individual drug prescriptions and concerns. There is a need for a robust governance to ensure that patient's safety is the foremost priority, and provisions should be made for requirements of remote prescription in the different medical subspecialities. The pandemic provides an enormous opportunity for stakeholders and policymakers to come together to create a seamless and user friendly and yet innovative healthcare ecosystem to transform clinical healthcare delivery with patient safety as the core driver in the implementation.

Association of NOTCH2NLC Repeat Expansions With Parkinson Disease.

Importance: The presence of Notch homolog 2 N-terminal-like C (NOTCH2NLC) repeat expansions are associated with neuronal intranuclear inclusion body disease (NIID), with varied neurological signs, including neuropathy, ataxia, parkinsonism, and tremor. To date, genetic screening of NOTCH2NLC GGC repeats in a cohort with typical Parkinson disease (PD) appears not to have been reported. Objective: To investigate if NOTCH2NLC GGC expansions are present in a cohort of patients with PD and controls. Design, Setting, and Participants: This case-control study was conducted in 2 tertiary movement disorder centers in Singapore. Participants were recruited and followed up from January 2005 to January 2020. The presence of NOTCH2NLC GGC expansion repeats was screened using polymerase chain reaction tests, and representative samples were verified with long-read genome sequencing. Main Outcomes and Measures: Qualitative and quantitative comparisons between participants with sporadic PD, healthy control participants, and individuals with NIID. Results: A total of 2076 participants, including 1000 with sporadic PD (600 men [60.0%]; mean age at onset, 62.6 [7.7] years) and 1076 healthy controls (581 men [54.0%]; mean age at study recruitment, 54.9 [9.4] years) were recruited. A total of 13 patients with PD and no healthy control participants were identified as carrying NOTCH2NLC GGC repeat expansions of more than 40 units; the frequency of more than 40 repeat expansions was higher in participants with PD than controls (P < .001). None of the patients with PD were carriers of known PD-associated genes. Ten patients with PD carried a GGC expansion of between 41 and 64 repeats (1% of patients with sporadic PD; mean [SD], 49.4 [9.2] repeats). The other 3 patients carried GGC repeats of 79 or more units, 2 with 122 and 79 repeats, respectively, exhibited typical parkinsonism and were responsive to small dosages of levodopa over many years, with no clinical or imaging features of NIID. The other patient with PD, who had 130 repeats, only developed cognitive impairment before death. Within the GGC expansions, there was no GGA interruptions (mean [SD] GGA percentage in the 3 patients with PD vs patients with NIID, 0% vs 12% [9%]), and the frequency of AGC interruptions was 3 times higher in these patients with PD than patients with NIID (mean [SD], 25% [12%] vs 8% [8%]). Conclusions and Relevance: This study demonstrated that individuals with sporadic PD who carried pathogenic NOTCH2NLC GGC repeat expansions can present with typical parkinsonism, requiring only low dosages of levodopa, without displaying other clinical or imaging features of NIID even after several years of follow-up. None of the patients with PD had GGA interruptions within their GGC expansions, and the frequency of AGC interruptions was much higher than that of patients with NIID. The functional significance of a higher moderate repeat expansion in patients with PD compared with healthy controls needs to be further investigated.

The impact of levodopa therapy-induced complications on quality of life in Parkinson's disease patients in Singapore.

The objective of this study was to investigate the impact of levodopa therapy-induced complications on the quality of life (QoL) of Parkinson's disease (PD) patients in Singapore over a 1-year follow-up period. 274 PD patients were prospectively recruited, of which 78 patients completed the follow-up. Patients were evaluated on: (1) motor symptoms, (2) non-motor symptoms, (3) levodopa therapy-induced complications and (4) QoL. Levodopa-induced complications including dyskinesia and OFF symptoms occurred in 13.5% and 55.9% of the study population, respectively. In patients who completed the 1-year follow-up, there was a trend suggestive of increasing dyskinesia duration, more disabling dyskinesia as well as longer, more sudden and unpredictable OFF periods. There was a significant decline in the overall QoL at follow-up, in particular, activities of daily living, emotional well-being, cognition and communication domains were the most affected. The multivariable analysis demonstrated that worsening of UPDRS IV total score over 1-year interval was associated with worsening in PDQ-Summary Index score (d = 0.671, p = 0.014). In conclusion, levodopa-induced complications had significant adverse impacts on QoL. This study substantiates the importance for clinicians to closely monitor and promptly manage levodopa therapy-induced complications that may arise in patients.

The Characteristics of Patients Associated With High Caregiver Burden in Parkinson's Disease in Singapore.

Introduction: Given the complex multitude of Parkinson's disease (PD) symptoms, caregiving for PD patients can be highly demanding. Our study was aimed to investigate the characteristics of PD patients related to different levels of caregiver burden. Methods: This cross-sectional study recruited 104 idiopathic PD patient-caregiver pairs. Patients were evaluated on motor, non-motor symptoms, and quality of life (QoL). Caregiver burden was quantified using Zarit Burden Inventory and subsequently stratified into 3 subgroups. Statistical analysis was performed to identify differences in the no-or little, mild-moderate, and high caregiver burden subgroups. Results: The mean disease duration was significantly longer in the high caregiver burden group compared to no-or little group (9.63 vs. 5.17 years; p-value 0.003). The mean levodopa equivalent daily dose (LEDD) and mean total UPDRS Part IV scores (UPDRS4) were significantly higher in the high caregiver burden group compared to no-or little group (p-value 0.011 and 0.004, respectively). The high caregiver burden group had significantly higher median QoL scores (PDQ-39) for PD patients for domain 2 (ADL, p-value 0.005), domain 4 (stigma, p-value 0.005), and domain 6 (cognition, p-value 0.002) compared to no-or little group. Conclusion: Greater caregiver burden was observed in PD patients with more prolonged disease duration, higher LEDD to control motor symptoms as well as greater levodopa related motor complications. Further studies on potential interventions to mitigate or delay levodopa related motor complications may reduce caregiver burden. Marked worsening in patient's QoL, specifically ADL, stigma and cognition in the high compared to no-or little caregiver burden group suggests the possible utility of monitoring these factors for early identification of increasing caregiver stress and burden.

Regulation of the NRF2 transcription factor by andrographolide and organic extracts from plant endophytes.

The transcription factor NF-E2 Related Factor-2 (NRF2) is an important drug target. Activation of NRF2 has chemopreventive effects in cancer and exerts beneficial effects in a number of diseases, including neurodegenerative diseases, inflammatory diseases, hepatosteatosis, obesity and insulin resistance. Hence, there have been great efforts to discover and characterize novel NRF2 activators. One reported NRF2 activator is the labdane diterpenoid andrographolide. In this study, we identified the mechanism through which andrographolide activates NRF2. We showed that andrographolide inhibits the function of KEAP1, a protein that together with CUL3 and RBX1 forms an E3 ubiquitin ligase that polyubiquitinates NRF2. Andrographolide partially inhibits the interaction of KEAP1 with CUL3 in a manner dependent on Cys151 in KEAP1. This suggests that andrographolide forms Michael acceptor dependent adducts with Cys151 in KEAP1 in vivo, leading to inhibition of NRF2 ubiquitination and consequently accumulation of the transcription factor. Interestingly, we also showed that at higher concentrations andrographolide increases NRF2 protein expression in a Cys151 independent, but likely KEAP1 dependent manner, possibly through modification of other Cys residues in KEAP1. In this study we also screened secondary metabolites produced by endophytes isolated from non-flowering plants for NRF2-inducing properties. One of the extracts, ORX 41, increased both NRF2 protein expression and transcriptional activity markedly. These results suggest that endophytes isolated from non-flowering or other plants may be a good source of novel NRF2 inducing compounds.