Decentralized clinical trials and rare diseases: a Drug Information Association Innovative Design Scientific Working Group (DIA-IDSWG) perspective.

BACKGROUND: Traditional clinical trials require tests and procedures that are administered in centralized clinical research sites, which are beyond the standard of care that patients receive for their rare and chronic diseases. The limited number of rare disease patients scattered around the world makes it particularly challenging to recruit participants and conduct these traditional clinical trials. MAIN BODY: Participating in clinical research can be burdensome, especially for children, the elderly, physically and cognitively impaired individuals who require transportation and caregiver assistance, or patients who live in remote locations or cannot afford transportation. In recent years, there is an increasing need to consider Decentralized Clinical Trials (DCT) as a participant-centric approach that uses new technologies and innovative procedures for interaction with participants in the comfort of their home. CONCLUSION: This paper discusses the planning and conduct of DCTs, which can increase the quality of trials with a specific focus on rare diseases.

Planning for the Next Pandemic: Ethics and Innovation Today for Improved Clinical Trials Tomorrow.

The coronavirus pandemic has brought public attention to the steps required to produce valid scientific clinical research in drug development. Traditional ethical principles that guide clinical research remain the guiding compass for physicians, patients, public health officials, investigators, drug developers and the public. Accelerating the process of delivering safe and effective treatments and vaccines against COVID-19 is a moral imperative. The apparent clash between the regulated system of phased randomized clinical trials and urgent public health need requires leveraging innovation with ethical scientific rigor. We reflect on the Belmont principles of autonomy, beneficence and justice as the pandemic unfolds, and illustrate the role of innovative clinical trial designs in alleviating pandemic challenges. Our discussion highlights selected types of innovative trial design and correlates them with ethical parameters and public health benefits. Details are provided for platform trials and other innovative designs such as basket and umbrella trials, designs leveraging external data sources, multi-stage seamless trials, preplanned control arm data sharing between larger trials, and higher order systems of linked trials coordinated more broadly between individual trials and phases of development, recently introduced conceptually as "PIPELINEs."

COVID-19-associated monocytic encephalitis (CAME): histological and proteomic evidence from autopsy.

Severe neurological symptoms are associated with Coronavirus disease 2019 (COVID-19). However, the morphologic features, pathological nature and their potential mechanisms in patient brains have not been revealed despite evidence of neurotropic infection. In this study, neuropathological damages and infiltrating inflammatory cells were quantitatively evaluated by immunohistochemical staining, ultrastructural examination under electron microscopy, and an image threshold method, in postmortem brains from nine critically ill COVID-19 patients and nine age-matched cadavers of healthy individuals. Differentially expressed proteins were identified by quantitative proteomic assays. Histopathological findings included neurophagocytosis, microglia nodules, satellite phenomena, extensive edema, focal hemorrhage, and infarction, as well as infiltrating mononuclear cells. Immunostaining of COVID-19 brains revealed extensive activation of both microglia and astrocytes, severe damage of the blood-brain barrier (BBB) and various degrees of perivascular infiltration by predominantly CD14+/CD16+/CD141+/CCR7+/CD11c+ monocytes and occasionally CD4+/CD8+ T lymphocytes. Quantitative proteomic assays combined with bioinformatics analysis identified upregulated proteins predominantly involved in immune responses, autophagy and cellular metabolism in COVID-19 patient brains compared with control brains. Proteins involved in brain development, neuroprotection, and extracellular matrix proteins of the basement membrane were downregulated, potentially caused by the activation of transforming growth factor ß receptor and vascular endothelial growth factor signaling pathways. Thus, our results define histopathological and molecular profiles of COVID-19-associated monocytic encephalitis (CAME) and suggest potential therapeutic targets.

Is negative e-WOM more powerful? Multimodal data analysis on air passengers’ perception of COVID-19 safety measures

During the normalization stage of the COVID-19 epidemic prevention and control, the safety threats caused by improper epidemic prevention measures of airlines have become the primary concern for air passengers. Negative e-WOM related to safety perception obtained based on online multimodal reviews of travel websites has become an important decision-making basis for potential air passengers when making airline choices. This study aims to examine the relationship between potential air passengers’ negative safety perception and the usefulness of online reviews, as well as to test the moderating effect of review modality and airline type. It also further explores the effectiveness and feasibility of applying big data sentiment analysis to e-WOM management. To this end, the theoretical model of negative safety perception, review modality, and airline type affecting review usefulness was constructed. Then we select 10 low-cost airlines and 10 full-service airlines, respectively, according to the number of reviews sorted by the TripAdvisor website, and use crawling techniques to obtain 10,485 reviews related to COVID-19 safety of the above companies from December 2019 to date, and conduct safety perception sentiment analysis based on Python’s Textblob library. Finally, to avoid data overdispersion, the model is empirically analyzed by negative binomial regression using R software. The results indicate that (1) Negative safety perception significantly and negatively affects review usefulness, that is, extreme negative safety perception can provide higher review usefulness for potential air passengers. (2) Review modality and airline type have a significant moderating effect on the relationship between negative safety perception and review usefulness, in which multimodal reviews and full-service airlines both weakened the negative impact of negative safety perception on review usefulness. The theoretical model in this paper is both an extension of the application of big data sentiment analysis techniques and a beneficial supplement to current research findings of e-WOM, providing an important reference for potential air passengers to identify useful reviews accurately and thus reduce safety risks in online decision-making.

Variations in Sulfur and Nitrogen Oxidation Rates in Summer Aerosols from 2014 to 2020 in Wuhan, China

To date, research regarding the changes of the sulfur and nitrogen rates in Wuhan during the summer is limited. In this study, we analyzed the air quality in Wuhan, China, using water-soluble ion, gaseous precursor, and weather data. A Spearman correlation analysis was then performed to investigate the temporal changes in air quality characteristics and their driving factors to provide a reference for air pollution control in Wuhan. The results indicate that SO2 in the atmosphere at Wuhan undergoes secondary conversion and photo-oxidation, and the conversion degree of SO2 is higher than that of NO2. During the summers of 2016 and 2017, secondary inorganic atmospheric pollution was more severe than during other years. The fewest oxidation days occurred in summer 2020 (11 days), followed by the summers of 2017 and 2014 (25 and 27 days, respectively). During the study period, ion neutralization was the strongest in summer 2015 and the weakest in August 2020. The aerosols in Wuhan were mostly acidic and NH4+ was an important neutralizing component. The neutralization factors of all cations showed little change in 2015. K+, Mg2+, and Ca2+ level changes were the highest in 2017 and 2020. At low temperature, high humidity, and low wind speed conditions, SO2 and NO2 were more easily converted into SO42− and NO3−.

Spatial region-resolved proteome map reveals mechanism of COVID-19-associated heart injury.

Direct myocardial and vascular injuries due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection-driven inflammation is the leading cause of acute cardiac injury associated with coronavirus disease 2019 (COVID-19). However, in-depth knowledge of the injury characteristics of the heart affected by inflammation is lacking. In this study, using a quantitative spatial proteomics strategy that combines comparative anatomy, laser-capture microdissection, and histological examination, we establish a region-resolved proteome map of the myocardia and microvessels with obvious inflammatory cells from hearts of patients with COVID-19. A series of molecular dysfunctions of myocardia and microvessels is observed in different cardiac regions. The myocardia and microvessels of the left atrial are the most susceptible to virus infection and inflammatory storm, suggesting more attention should be paid to the lesion and treatment of these two parts. These results can guide in improving clinical treatments for cardiovascular diseases associated with COVID-19.

Recommendations for the Management of Patients with Benign Prostatic Hyperplasia in the Context of the COVID-19 Pandemic: A Retrospective Study of 314 Cases.

Aim: Through investigation and analysis of the course management of 314 patients with benign prostatic hyperplasia (BPH) during the COVID-19 pandemic, we expected to offer effective recommendations for the management of patients with BPH against the background of the COVID-19 pandemic. Methods: We implemented telephone follow-ups of 314 patients with BPH who were diagnosed at the Urology Clinic of Xiangya Hospital of Central South University before January 24, 2020, and who were admitted to the hospital for reexamination after the epidemic was controlled in China, and we conducted research and analysis of their disease management during the COVID-19 pandemic. Results: In the follow-up, we found 245 patients (79.3%) over 60 years of age and 187 patients (60.5%) with underlying disease. There were 47 patients (15.2%) who returned for consultation during the COVID-19 pandemic, and of these, 18 were admitted to the hospital for follow-up consultation, and 29 patients underwent consultation via the internet or telephone. Eleven patients underwent surgery during the pandemic, and of these, three experienced emergency surgery. We encountered 65 patients (24.4%) who self-administered medications irregularly and 54 patients (20.3%) who self-medicated and adjusted the dosage and drug types themselves. There were 302 patients (97.7%) who wished to be reexamined during the COVID-19 pandemic. In terms of treatment, the proportion of patients "awaiting observation" declined from 13.9% to 4.4%, and the proportion of patients "awaiting surgery" increased from 4.9% to 16.4%. Using the International Prostate Symptom Score (IPSS) scale, the percentage of patients with moderate-to-severe symptoms increased from 79.9% to 90.1%, and the proportion with a quality of life (QOL) score ≥ 5 rose from 82.5% to 88.9%. The proportions of patients exhibiting storage, voiding, and postmicturition symptoms in lower urinary tract symptoms (LUTS) increased from 77.3%, 21.7%, and 18.8% to 91.9%, 27.5%, and 25.5%, respectively; those manifesting hematuria and urinary retention increased from 0.9% and 0.6% to 2.3% and 1.7%, respectively; those with a prostate specific antigen (PSA) > 4 ng/ml rose from 10.0% to 15.1%; patients with a maximum flow rate (Qmax) < 15 ml/s increased from 82.5% to 92.3%, and the proportion with a Qmax < 10 ml/s increased from 8.7% to 15.4%; the individuals with a prostate volume > 30 ml increased from 94.1% to 97.0%; the percentage of men with a bladder residual urine volume > 10 ml was augmented from 81.6% to 89.3%, and patients with prostate nodules on physical examination were elevated from 1.0% to 1.7%. We uncovered no prostate cancer in patients, and the proportion of patients administered the combination drug increased from 78.9% to 91.2%. Compared with patients receiving online or telephone consultations, patients undergoing reexamination at the hospital were better controlled. When we conducted a survey of whether patients chose to go to a public or private hospital for follow-up, we found that 46.6% of the patients chose to go to a private medical institution. Conclusions: COVID-19 greatly affected the treatment of patients with BPH. When conditions permit, we recommend that patients first consider going to the hospital for evaluation; however, when this is not possible, medical institutions should provide telephone or online consultation for patients with BPH. Surgical treatment should also be arranged for those in need as soon as possible to avoid delaying the patient's treatment.

High Sensitivity, Rapid Detection of Virus in High Traffic Environments.

The global pandemic caused by the SARS-CoV-2 virus has underscored the need for rapid, simple, scalable, and high-throughput multiplex diagnostics in non-laboratory settings. Here we demonstrate a multiplex reverse-transcription loop-mediated isothermal amplification (RT-LAMP) coupled with a gold nanoparticle-based lateral flow immunoassay (LFIA) capable of detecting up to three unique viral gene targets in 15 min. RT-LAMP primers associated with three separate gene targets from the SARS-CoV-2 virus (Orf1ab, Envelope, and Nucleocapsid) were added to a one-pot mix. A colorimetric change from red to yellow occurs in the presence of a positive sample. Positive samples are run through a LFIA to achieve specificity on a multiplex three-test line paper assay. Positive results are indicated by a characteristic crimson line. The device is almost fully automated and is deployable in any community setting with a power source.

Impact of COVID-19 pandemic on oncology clinical trial design, data collection and analysis.

BACKGROUND: To identify and assess via simulation the impact of COVID-19 pandemic on oncology trials and discuss potential mitigation strategies for study design, data collection, endpoints and analyses. METHODS: We simulated clinical trials to evaluate the COVID-19 impact on overall survival and progression-free survival. We evaluated survival in single-region trials with different proportions of impacted patients across treatment arms, and in multi-region randomized trials with different proportions of impacted patients across regions. We also assessed the impact on PFS when the missingness of disease assessment and censoring rules vary. Impact on the trial success and robustness of statistical inference was summarized. RESULTS: Without regional impact, the impact on OS analysis is minimal if proportions of impacted patients are similar across arms, however, if a larger proportion of treatment arm patients are impacted, trials may suffer substantial power loss and underestimate treatment effect size. For multi-region trials, if more treatment arm patients are enrolled from more severely impacted regions, trials also have poorer performance. For PFS analysis, the intent-to-treat rule performs well even when the treatment arm patients are more likely to miss disease assessments, while the consecutive-missing censoring rule may lead to poorer performance. CONCLUSION: COVID-19 affects oncology trials. Simulations would be highly informative to Data Monitoring Committee in understanding the impact and making appropriate recommendations, upon which the sponsor could start planning potential remedies. We also recommend a decision tree for choosing the appropriate methods for PFS evaluation in the presence of missing disease assessments due to COVID-19.

A single-cell transcriptomic landscape of the lungs of patients with COVID-19.

The lung is the primary organ targeted by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), making respiratory failure a leading coronavirus disease 2019 (COVID-19)-related mortality. However, our cellular and molecular understanding of how SARS-CoV-2 infection drives lung pathology is limited. Here we constructed multi-omics and single-nucleus transcriptomic atlases of the lungs of patients with COVID-19, which integrate histological, transcriptomic and proteomic analyses. Our work reveals the molecular basis of pathological hallmarks associated with SARS-CoV-2 infection in different lung and infiltrating immune cell populations. We report molecular fingerprints of hyperinflammation, alveolar epithelial cell exhaustion, vascular changes and fibrosis, and identify parenchymal lung senescence as a molecular state of COVID-19 pathology. Moreover, our data suggest that FOXO3A suppression is a potential mechanism underlying the fibroblast-to-myofibroblast transition associated with COVID-19 pulmonary fibrosis. Our work depicts a comprehensive cellular and molecular atlas of the lungs of patients with COVID-19 and provides insights into SARS-CoV-2-related pulmonary injury, facilitating the identification of biomarkers and development of symptomatic treatments.

Using airflow-driven, evaporative gradients to improve sensitivity and fluid control in colorimetric paper-based assays.

Microfluidic paper-based analytical devices (µPADs) are foundational devices for point-of-care testing, yet suffer from limitations in regards to their sensitivity and capability in handling complex assays. Here, we demonstrate an airflow-based, evaporative method that is capable of manipulating fluid flows within paper membranes to offer new functionalities for multistep delivery of reagents and improve the sensitivity of µPADs by 100-1000 times. This method applies an air-jet to a pre-wetted membrane, generating an evaporative gradient such that any solutes become enriched underneath the air-jet spot. By controlling the lateral position of this spot, the solutes in the paper strip are enriched and follow the air jet trajectory, driving the reactions and enhancing visualization for colorimetric readout in multistep assays. The technique has been successfully applied to drive the sequential delivery in multistep immunoassays as well as improve sensitivity for colorimetric detection assays for nucleic acids and proteins via loop-mediated isothermal amplification (LAMP) and ELISA. For colorimetric LAMP detection of the COVID-19 genome, enrichment of the solution on paper could enhance the contrast of the dye in order to more clearly distinguish between the positive and negative results to achieve a sensitivity of 3 copies of SARS-Cov-2 RNAs. For ELISA, enrichment of the oxidized TMB substrate yielded a sensitivity increase of two-to-three orders of magnitude when compared to non-enriched samples - having a limit of detection of around 200 fM for IgG. Therefore, this enrichment method represents a simple process that can be easily integrated into existing detection assays for controlling fluid flows and improving detection of biomarkers on paper.

A cohort autopsy study defines COVID-19 systemic pathogenesis.

Severe COVID-19 disease caused by SARS-CoV-2 is frequently accompanied by dysfunction of the lungs and extrapulmonary organs. However, the organotropism of SARS-CoV-2 and the port of virus entry for systemic dissemination remain largely unknown. We profiled 26 COVID-19 autopsy cases from four cohorts in Wuhan, China, and determined the systemic distribution of SARS-CoV-2. SARS-CoV-2 was detected in the lungs and multiple extrapulmonary organs of critically ill COVID-19 patients up to 67 days after symptom onset. Based on organotropism and pathological features of the patients, COVID-19 was divided into viral intrapulmonary and systemic subtypes. In patients with systemic viral distribution, SARS-CoV-2 was detected in monocytes, macrophages, and vascular endothelia at blood-air barrier, blood-testis barrier, and filtration barrier. Critically ill patients with long disease duration showed decreased pulmonary cell proliferation, reduced viral RNA, and marked fibrosis in the lungs. Permanent SARS-CoV-2 presence and tissue injuries in the lungs and extrapulmonary organs suggest direct viral invasion as a mechanism of pathogenicity in critically ill patients. SARS-CoV-2 may hijack monocytes, macrophages, and vascular endothelia at physiological barriers as the ports of entry for systemic dissemination. Our study thus delineates systemic pathological features of SARS-CoV-2 infection, which sheds light on the development of novel COVID-19 treatment.

Characteristics of Online Health Care Services From China's Largest Online Medical Platform: Cross-sectional Survey Study.

BACKGROUND: Internet hospitals in China are in great demand due to limited and unevenly distributed health care resources, lack of family doctors, increased burdens of chronic diseases, and rapid growth of the aged population. The COVID-19 epidemic catalyzed the expansion of online health care services. In recent years, internet hospitals have been rapidly developed. Ping An Good Doctor is the largest, national online medical entry point in China and is a widely used platform providing online health care services. OBJECTIVE: This study aims to give a comprehensive description of the characteristics of the online consultations and inquisitions in Ping An Good Doctor. The analyses tried to answer the following questions: (1) What are the characteristics of the consultations in Ping An Good Doctor in terms of department and disease profiles? (2) Who uses the online health services most frequently? and (3) How is the user experience of the online consultations of Ping An Good Doctor? METHODS: A total of 35.3 million consultations and inquisitions over the course of 1 year were analyzed with respect to the distributions of departments and diseases, user profiles, and consulting behaviors. RESULTS: The geographical distribution of the usage of Ping An Good Doctor showed that Shandong (18.4%), Yunnan (15.6%), Shaanxi (7.2%), and Guangdong (5.5%) were the provinces that used it the most; they accounted for 46.6% of the total consultations and inquisitions. In terms of department distribution, we found that gynecology and obstetrics (19.2%), dermatology (17.0%), and pediatrics (14.4%) were the top three departments in Ping An Good Doctor. The disease distribution analysis showed that, except for nondisease-specific consultations, acute upper respiratory infection (AURI) (4.1%), pregnancy (2.8%), and dermatitis (2.4%) were the most frequently consulted diseases. In terms of user profiles, females (60.4%) from 19 to 35 years of age were most likely to seek consultations online, in general. The user behavior analyses showed that the peak times of day for online consultations occurred at 10 AM, 3 PM, and 9 PM. Regarding user experience, 93.0% of users gave full marks following their consultations. For some disease-related health problems, such as AURI, dermatitis, and eczema, the feedback scores were above average. CONCLUSIONS: The prevalence of internet hospitals, such as Ping An Good Doctor, illustrated the great demand for online health care services that can go beyond geographical limitations. Our analyses showed that nondisease-specific issues and moderate health problems were much more frequently consulted about than severe clinical conditions. This indicated that internet hospitals played the role of the family doctor, which helped to relieve the stress placed on offline hospitals and facilitated people's lives. In addition, good user experiences, especially regarding disease-related inquisitions, suggested that online health services can help solve health problems. With support from the government and acceptance by the public, online health care services could develop at a fast pace and greatly benefit people's daily lives.

Pathological changes in the lungs and lymphatic organs of 12 COVID-19 autopsy cases.

Systematic autopsy and comprehensive pathological analyses of COVID-19 decedents should provide insights into the disease characteristics and facilitate the development of novel therapeutics. In this study, we report the autopsy findings from the lungs and lymphatic organs of 12 COVID-19 decedents-findings that evaluated histopathological changes, immune cell signature and inflammatory factor expression in the lungs, spleen and lymph nodes. Here we show that the major pulmonary alterations included diffuse alveolar damage, interstitial fibrosis and exudative inflammation featured with extensive serous and fibrin exudates, macrophage infiltration and abundant production of inflammatory factors (IL-6, IP-10, TNFα and IL-1ß). The spleen and hilar lymph nodes contained lesions with tissue structure disruption and immune cell dysregulation, including lymphopenia and macrophage accumulation. These findings provide pathological evidence that links injuries of the lungs and lymphatic organs with the fatal systematic respiratory and immune malfunction in critically ill COVID-19 patients.

Different characteristics of critical COVID-19 and thinking of treatment strategies in non-elderly and elderly severe adult patients.

BACKGROUND: The differences in the characteristics and main causes of critical COVID-19 infection in non-elderly and elderly severe patients remain unknown. METHODS: We included 273 adult patients with confirmed severe COVID-19 from Tongji Hospital, Wuhan, China from February 10 to March 8, 2020. Clinical characteristics and risk factors for outcomes were compared between the young and middle-aged and the elderly severe patients. RESULTS: Hemoglobin, neutrophil percentage, inflammatory markers, hepatic, renal, and cardiovascularparameters differed between the non-elderly and elderly severe patients. In young and middle-aged patients, critical patients showed higher high-sensitivity C-reactive protein (hsCRP) during hospitalization than severe patients. However, in the elderly patients, critical patients showed decreased hsCRP during hospitalization and higher proBNP values. The hsCRP fluctuation and proBNP were independent risk factors for intensive care unit (ICU) admission in young and middle-aged severe patients (OR=1.068) and elderly severe patients (OR=1.026), respectively. CONCLUSION: The study revealed different potential causes of disease and predictive factors for non-elderly and elderly critical patients and treatment recommendations. Deterioration of inflammatory state was the main cause of ICU admission in young and middle-aged severe COVID-19 patients, while a decline in hsCRP was not associated with better outcomes in elderly severe patients, indicating the need for different treatments for non-elderly and elderly severe patients. Anti-inflammatory therapy with corticosteroids should be considered in the early disease stage among non-elderly severe patients, but cardiovascular protection plays a more important role in elderly severe patients.

Assessing the Impact of COVID-19 on the Clinical Trial Objective and Analysis of Oncology Clinical Trials-Application of the Estimand Framework.

Abstract-Coronavirus disease 2019 (COVID-19) outbreak has rapidly evolved into a global pandemic. The impact of COVID-19 on patient journeys in oncology represents a new risk to interpretation of trial results and its broad applicability for future clinical practice. We identify key intercurrent events (ICEs) that may occur due to COVID-19 in oncology clinical trials with a focus on time-to-event endpoints and discuss considerations pertaining to the other estimand attributes introduced in the ICH E9 addendum. We propose strategies to handle COVID-19 related ICEs, depending on their relationship with malignancy and treatment and the interpretability of data after them. We argue that the clinical trial objective from a world without COVID-19 pandemic remains valid. The estimand framework provides a common language to discuss the impact of COVID-19 in a structured and transparent manner. This demonstrates that the applicability of the framework may even go beyond what it was initially intended for.