Prior effective sample size in phase II clinical trials with mixed binary and continuous responses

The problem of finding Effective Sample Size (ESS) in Phase II clinical trials where toxicity and efficacy are the two components of the treatment response vector is considered. In particular, one of the components is assumed to be binary and the other is assumed to be continuous. The case of binary safety and continuous efficacy is studied for different prior distributions under different set up. Theoretical expressions are obtained in various situations. The methods are evaluated and compared by simulation studies. The proposed method is then illustrated by using some real life data on a phase II vaccine trial for Covid‐19.

Gastrointestinal, Respiratory, and Olfactory Neurotropism of Sars-Cov2 as a Possible Trigger of Parkinson's Disease: Is a Multi-Hit Multi-Step Process on the Cards.

Since the first emergence of COVID-19 on the global stage, there has been a wealth of evidence to suggest that SARS-Cov2 is not merely a pulmonary pathogen. This virus is unique in its ability to disrupt cellular pathways related to protein homeostasis, mitochondrial function, stress response, and aging. Such effects raise concerns about the long-term fate of survivors of COVID-19 infection, particularly regarding neurodegenerative diseases. The concept of interaction between environmental factors and alpha-synuclein formation in the olfactory bulb and vagal autonomic terminals with subsequent caudo-cranial migration has received much attention in the context of PD pathogenesis. Anosmia and gastrointestinal symptoms are two well-known symptoms of COVID-19, with evidence of an olfactory bulb and vagal infiltration by SARS-CoV2. This raises the possibility of the spread of the viral particles to the brain along multiple cranial nerve routes. Neurotropism, coupled with the ability of the SARS-Cov2 virion to induce abnormal protein folding and stress responses in the central nervous system, in presence of an inflammatory milieu, reinforced by hypoxia, coagulopathy, and endothelial dysfunction, reverberates the intriguing possibility of activation of a neurodegenerative cascade leading to the development of pathological alpha-synuclein aggregates and thus, triggering the development of PD in survivors of COVID19. This review attempts to summarize and critically appraise existing evidence from basic science research and clinical reports of links between COVID-19 and PD and explores the prospect of a multi-hit pathophysiological process, induced by SARS-Cov2 infection, ultimately converging on perturbed cellular protein homeostasis, which although is intriguing, presently lacks robust evidence for confirmation.

Quality of life and Concerns of Parkinson's Disease Patients and their Caregivers during COVID-19 Pandemic: An Indian Study.

Objectives: Parkinson's disease (PD) patients have suffered during the coronavirus disease 2019 pandemic, with worsening of both motor and nonmotor symptoms. We conducted this study to evaluate the quality of life (QoL) and concerns of PD patients and their caregivers. Methods: The study was conducted in mixed method, where the baseline data was taken by face-to-face interview during the unlock phase of December 2020 to March 2021, when there was no lockdown. This included demography, Hoehn and Yahr (HY) stage, Parkinson's Disease Questionnaire-8 (PDQ-8), and Parkinson's Disease Questionnaire for Carer (PDQ-Carer). During the second wave of COVID-19 (April-June 2021), telephonic interview was conducted using Depression, Anxiety Stress Scale- 21 Items (DASS-21), PDQ-8, PDQ-Carer, and open-ended questions regarding their concerns. Results: Compared with the baseline data, PDQ-8 and PDQ-Carer scores showed significant worsening during the second wave. DASS-21 scores had significant correlation with PDQ-Carer and PDQ-8 scores. Female patients reported poorer QoL. Caregivers of non-vaccinated patients had worse PDQ-Carer Strain scores. There was no significant association between worsening of motor symptoms and PDQ-8 and PDQ-Carer scores. More than 80% patients and 70% caregivers reported anxiety and depression. Their concerns were regarding difficulties due to social isolation, restriction of activity, and financial constraints. Additionally, there were worries about patient care, vaccination, and recurrence of the wave. Conclusions: The QoL of both patients and their caregivers were affected by the pandemic. A significant proportion had anxiety and depression, and this correlated with QoL. There were some important concerns on various aspects of the pandemic.

A study of the impact of policy interventions on daily COVID scenario in India using interrupted time series analysis

The rapid increase both in daily cases and daily deaths made the second wave of COVID-19 pandemic in India more lethal than the first wave. Record number of infections and casualties were reported all over India during this period. Delhi and Maharashtra are the two most affected places in India during the second wave. So in response to this, the Indian government implemented strict intervention policies ("lockdowns”, "social distancing” and "vaccination drive”) in every state during this period to prohibit the spread of this virus. The objective of this article is to conduct an interrupted time series (ITS) analysis to study the impact of the interventions on the daily cases and deaths.We collect daily data for Delhi and Maharashtra before and after the intervention points with a 14-day (incubation period of COVID-19) observation window. A segmented linear regression analysis is done to study the post-intervention slopes as well as whether there were any immediate changes after the interventions or not. We also add the counterfactuals and delayed time effects in the analysis to investigate the significance of our ITS design.Here, we observe the post-intervention trends to be statistically significant and negative for both the daily cases and the daily deaths. We also find that there is no immediate change in trend after the start of intervention, and hence we study some delayed time effects which display how changes in the trends happened over time. And from the Counterfactuals in our study, we can have an idea what would have happened to the COVID scenario had the interventions not been implemented.We statistically try to figure out different circumstances of COVID scenario for both Delhi and Maharashtra by exploring all possible ingredients of ITS design in our analysis in order to present a feasible design to show the importance of implementation of proper intervention policies for tackling this type of pandemic which can have various highly contagious variants.

Health status of persons with dementia and caregivers' burden during the second wave of COVID-19 pandemic: an Indian study ESTADO DE SAÚDE DE PESSOAS COM DEMÊNCIA E SOBRECARGA DOS CUIDADORES DURANTE A 2ª ONDA DA PANDEMIA DE COVID-19: UM ESTUDO INDIANO

. Due to the disruption of normal flow of treatment during the restrictions related to the coronavirus disease 2019 (COVID-19) pandemic, the health status of persons with dementia (PwD) and their caregivers' burden might worsen. Objective: The article aims to find out the health status of PwD and caregivers' burden during the peak of second wave of COVID-19 and make a comparison with the preceding trough phase. Methods: The study was conducted with 53 PwD and their caregivers in two phases. On their visit to the hospital during the unlock phase (phase 1), data were collected for CDR from PwD, and NPI-Q and ZBI from their caregivers. During the peak of second wave (phase 2), data were collected for NPI-Q, ZBI, and DASS-21 through telephonic communication, and statistical analyses were performed on the collected data. Results: Significantly higher caregiver burden (p=0.001) and neuropsychiatric symptoms (NPSs) [both in severity (p=0.019) and distress (p=0.013)] were observed among the respondents during the peak of second wave of the pandemic as compared to the preceding trough phase. Positive correlations were observed between the caregiver burden and depression, anxiety, and stress of the caregivers (p<0.001) and between the severity of dementia in PwD and caregiver burden (p<0.001) for both the first and second phases. Positive correlation was also observed between the severity of dementia in PwD and depression (p=0.042) and stress (p=0.023) of caregivers. Conclusions: Significant increase in the burden and distress was observed among caregivers due to increased NPSs of PwD during the second wave of COVID-19 pandemic.

Health status of persons with dementia and caregivers' burden during the second wave of COVID-19 pandemic: an Indian study.

Due to the disruption of normal flow of treatment during the restrictions related to the coronavirus disease 2019 (COVID-19) pandemic, the health status of persons with dementia (PwD) and their caregivers' burden might worsen. Objective: The article aims to find out the health status of PwD and caregivers' burden during the peak of second wave of COVID-19 and make a comparison with the preceding trough phase. Methods: The study was conducted with 53 PwD and their caregivers in two phases. On their visit to the hospital during the unlock phase (phase 1), data were collected for CDR from PwD, and NPI-Q and ZBI from their caregivers. During the peak of second wave (phase 2), data were collected for NPI-Q, ZBI, and DASS-21 through telephonic communication, and statistical analyses were performed on the collected data. Results: Significantly higher caregiver burden (p=0.001) and neuropsychiatric symptoms (NPSs) [both in severity (p=0.019) and distress (p=0.013)] were observed among the respondents during the peak of second wave of the pandemic as compared to the preceding trough phase. Positive correlations were observed between the caregiver burden and depression, anxiety, and stress of the caregivers (p<0.001) and between the severity of dementia in PwD and caregiver burden (p<0.001) for both the first and second phases. Positive correlation was also observed between the severity of dementia in PwD and depression (p=0.042) and stress (p=0.023) of caregivers. Conclusions: Significant increase in the burden and distress was observed among caregivers due to increased NPSs of PwD during the second wave of COVID-19 pandemic.

Devido à interrupção do fluxo normal de tratamento durante as restrições relacionadas à pandemia de COVID-19, o estado de saúde das pessoas com demência (PcD) e a sobrecarga de seus cuidadores podem piorar. Objetivo: O artigo teve como objetivo conhecer o estado de saúde da PcD e a sobrecarga dos cuidadores durante o pico da 2ª onda de COVID-19 e fazer uma comparação com a fase anterior. Métodos: O estudo foi realizado com 53 PcD e seus cuidadores em duas fases. Em sua visita ao hospital durante a fase de desbloqueio (Fase 1), CDR, NPI-Q e ZBI foram administrados às PcD e seus cuidadores. Durante o pico da segunda onda (Fase 2), NPI-Q, ZBI e DASS-21 foram administrados por telefone e foram realizadas análises estatísticas dos dados coletados. Resultados: Foram observados sobrecarga do cuidador significativamente maior (p=0,001) e sintomas neuropsiquiátricos [tanto em gravidade (p=0,019) quanto angústia (p=0,013)] entre os entrevistados durante o pico da 2ª onda da pandemia em comparação com a fase anterior de passagem. Foram observadas correlações positivas entre sobrecarga do cuidador e depressão, ansiedade e estresse dos cuidadores (p<0,001) e entre gravidade da demência em PcD e sobrecarga do cuidador (p<0,001) tanto para a 1ª quanto para a 2ª fase. Também foi observada correlação positiva entre a gravidade da demência em PcD e depressão (p=0,042) e estresse (p=0,023) dos cuidadores. Conclusões: Foi observado um aumento significativo na sobrecarga e angústia entre os cuidadores devido ao aumento dos sintomas neuropsiquiátricos de PcD durante a 2ª onda da pandemia de COVID-19.

Prior effective sample size in phase II clinical trials with mixed binary and continuous responses

The problem of finding Effective Sample Size (ESS) in Phase II clinical trials where toxicity and efficacy are the two components of the treatment response vector is considered. In particular, one of the components is assumed to be binary and the other is assumed to be continuous. The case of binary safety and continuous efficacy is studied for different prior distributions under different set up. Theoretical expressions are obtained in various situations. The methods are evaluated and compared by simulation studies. The proposed method is then illustrated by using some real life data on a phase II vaccine trial for Covid‐19. [ FROM AUTHOR]

Exploring Caregiver Burden and Health Condition of Dementia Patients during Lockdown due to COVID-19 Pandemic.

Background: To combat the COVID-19 pandemic, several countries imposed strict lockdown to ensure social distancing to limit the spread of the virus. This caused difficulties in the management and care of patients with various chronic disorders including dementia. Objectives: The objective of the study was to explore the health condition of patients with dementia and assess their caregivers' burden during the lockdown. Methods: A total of 57 caregivers of patients with dementia who had attended the cognitive clinic of the institute for a follow-up within 1 year preceding the lockdown were assessed through telephonic interviews. Caregivers' details were noted following an interview related to the patients' health condition during lockdown and caregiver concerns. Results: Findings showed a deterioration in memory in 66.7% of patients with dementia and an increase in symptoms like agitation, sleeplessness, low mood, restlessness, aggression, etc., Caregivers felt helpless and had to manage new concerns and they were not sure as to how to deal with the situation. Conclusion: The lockdown situation disrupted the health conditions of dementia patients and caregivers faced novel challenges while managing them.

Change-point analysis through integer-valued autoregressive process with application to some COVID-19 data.

In this article, we consider the problem of change-point analysis for the count time series data through an integer-valued autoregressive process of order 1 (INAR(1)) with time-varying covariates. These types of features we observe in many real-life scenarios especially in the COVID-19 data sets, where the number of active cases over time starts falling and then again increases. In order to capture those features, we use Poisson INAR(1) process with a time-varying smoothing covariate. By using such model, we can model both the components in the active cases at time-point t namely, (i) number of nonrecovery cases from the previous time-point and (ii) number of new cases at time-point t. We study some theoretical properties of the proposed model along with forecasting. Some simulation studies are performed to study the effectiveness of the proposed method. Finally, we analyze two COVID-19 data sets and compare our proposed model with another PINAR(1) process which has time-varying covariate but no change-point, to demonstrate the overall performance of our proposed model.