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Introduction: Indicators that assess relationships among leukocytes may inform more and/or earlier than those measured in isolation. Method(s): Blood leukocyte differential counts collected from 101 Mayo Clinic COVID-19 patients were related to later outcomes following two approaches: (i) as unstructured data (e.g., lymphocyte percentages) and (ii) as data structures that assess intercellular interactions. Analyzing the same primary data, it was asked whether information contents differed among methods and/or when two sets of structured indicators are used. Result(s): While unstructured data did not distinguish survivors from non-survivors (Fig. 1, rectangle A), one data structure (here identified with letters expressed in italics) exhibited one perpendicular inflection that differentiated two patient groups (B). Two survivor-related observations were also distinguished from the remaining data points (B). A second data structure also revealed a single line of observations and a perpendicular data inflection (C), while more (four) patient groups were identified (D). Four validations were conducted: (i) increasing mortality levels among contiguous data subsets (0, 7.1, 16.2, or 44.4%) suggested construct validity (D);(ii) internal validity was indicated because 22 of the 45 survivors detected by the first data structure were also captured by the second one;(iii) the analysis of patients that differed in address, co-morbidities and other aspects supported external validity;and (iv) quasi non-overlapping data intervals predicted statistical validity (E, F). The structured approach also uncovered new and/ or dissimilar information: different leukocyte-related ratios explained the clusters identified in these analyses (E, F). Conclusion(s): Structured data may yield more information than methods that do not assess multicellular interactions. Possible applications include daily, longitudinal, and personalized analysis of hospital data.
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Over the course of a clinical trial, changes in the practice environment have the potential to reduce internal and external validity and impact change in patient outcomes. Such ''history effects''1 can take the form of changes in standard of care, clinical guidelines and recommendations, new drug/device availability in the marketplace, testing and screening procedures, and, as recently experienced, a global pandemic. Clinical trials conducted over many years are particularly susceptible to history effects. Such effects can impact foundational ability to continue a trial, including clinician equipoise and ability to implement trial interventions, necessitating awareness and action planning. For example, Curtis et al.2 acknowledged challenges with clinical guideline history effects and issued recommendations for addressing them such as consideration of participant wellbeing, stakeholder engagement, safety monitoring, review of guideline and policy changes, and development of rules for protocol changes. This session will explore how four multisite clinical trials conducted with VA Cooperative Studies Program sponsorship and coordination have weathered history effects during prolonged periods of enrollment. Topics to be covered include the implementation of pragmatic designs, monitoring of clinical guidelines, assessing control group treatment conditions, modifying protocols, adjusting quality assurance procedures, refining recruitment pathways, and training site investigators. The speakers, Study Chairs, will describe best practices and provide recommendations for navigating history effects in prolonged multisite clinical trials that can ensure outcomes remain relevant and compelling to inform public health at trial commencement. The CSP 2008/PTXRx study is a pragmatic, randomized, double-blind, placebo-controlled, multicenter clinical trial of Veteran patients with diabetic kidney disease (DKD) examining whether pentoxifylline (PTX), when added to usual care, can delay time to end-stage renal disease or death. Enrollment for the study began in 2019, and it is anticipated that 9 years of follow-up will be required to observe the required number of primary events. Given the long duration of the study, changes in clinical guidelines were anticipated and have occurred, including the approval of new DKD therapies and introduction of a new formula for estimated glomerular filtration rate (eGFR) calculation. In anticipation of these changes, the study design allows for whatever standard of care is extant at any time during the course of the study. PTXR's pragmatic trial design and protocol leverage the VA's research infrastructure and remote platforms allowing the study to be responsive to external changes and to safely continue during a global pandemic. The CSP 596/OPTION study is a randomized, double- blind, multicenter trial of Veteran patients with a first or second recurrent Clostridium difficile infection (CDI) comparing (1) fidaxomicin and (2) vancomycin, followed by a taper and pulse to (3) a standard vancomycin regimen. Since enrollment began in 2016, significant changes in CDI epidemiology and clinical management have impacted the study. The COVID-19 pandemic also resulted in an administrative hold on all trial activity followed by staggered reopening of sites due to variable COVID-19 activity and clinical priorities. Many clinical laboratories switched to algorithms that included free toxin assays in addition to polymerase chain reaction (PCR) tests out of concern for overdiagnosis based on PCR testing alone, reducing the number of potentially enrollable cases. There has been increased empirical vancomycin treatment for recurrent CDI without confirmation by stool testing, a requirement for enrollment, and a recruitment strategy for identifying potential cases. Finally, conflicting clinical guidelines for recurrent CDI has created potential equipoise when considering enrollment. Ongoing educational efforts have been made to clarify the protocol and emphasize the validity of the research question as well as protoco changes to allow safe enrollment and follow-up of participants in the face of the ongoing COVID-19 pandemic. The CSP 2005/VALOR is a phase III randomized, open label, multicenter clinical trial of Veteran patients with operable stage I non-small cell lung cancer that compares stereotactic radiotherapy and anatomic pulmonary resection with a primary outcome measure of overall survival. The study was activated in 2017 and recruitment to the trial has been affected by ongoing changes in public and clinician perceptions about stereotactic radiotherapy and surgery that have interfered with equipoise and willingness of participants to enroll. The study team perpetually addresses this challenge through group conversations with local site investigators, study coordinators, and other research personnel to preserve group equipoise across the study. Since the study's activation, new safety information about stereotactic radiotherapy has emerged necessitating protocol modifications while aiming to preserve internal and external validity. The includes modifying standard operating procedures for the study's centralized quality assurance program that has had to adapt its process to remain contemporary. STARPORT, funded by VA CSRD with CSP collaboration, is a randomized, open label, multicenter clinical trial of Veteran patients with oligorecurrent prostate cancer comparing the effects of standard systemic therapy (SST) alone or with PET-directed local therapy using surgery or radiation. Although enrollment was initiated in 2021, changes are already evident in clinical practice guidelines regarding the use of imaging in workup in this patient population. Shortly before the start of accrual, 18F-DCFPyL PSMA PET/CT received FDA-approval. Consequently, it is being rapidly adopted at the STARPORT VA medical centers and the use of conventional imaging using CT or bone scan prior to PET/CT imaging-part of the original eligibility criteria-quickly is falling out of favor. Furthermore, shortly after the start of enrollment, NCCN guidelines adopted the stance that conventional imaging was no longer required in the setting of PSMA PET/CT imaging, solidifying the transition away from conventional imaging. Thus, the protocol is being amended to remove the requirement for conventional imaging as part of workup for oligorecurrence. In addition, to be generalizable, the study is designed to integrate future PSMA radiotracers that are incorporated into practice as well as changes in SST regimens over the time of the study.
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Background: During COVID-19 pneumonia management, CT scan is highly contributive. It represents the gold standard examination for both positive and severity diagnosis. Objective(s): We aimed to compare 2 methods of evaluation of CT scan involvement. Method(s): We conducted a prospective cohort study in the ICU of Abderrahmen Mami hospital between January and December 2021. We included critically-ill patients COVID-19 who had a CT scan. We considered two ways to evaluate severity of lung damage: 1/Percentage of lung damage extent (< 50%, 50 to 75% and >= 75%), 2/ CT score (assimilated to Lung Ultrasound Score): Subdivision of each hemithorax into 6 regions: antero-superior and inferior, latero-superior and inferior, postero-superior and inferior. A score was attributed according to the patterns: 0 if normal parenchyma, 1 if few ground-glass lesions, 2 if extensive ground-glass lesions, and 3 if condensations. CT score was the sum of the scores of the 12 regions, thus varying between 0 and 36 Results: We included 158 patients with mean age of 56 +/- 13 years and gender ratio of 1.6. Mean values of SAPS II and APACHE II were respectively 25.4+/-7.7 and 8.7+/-5. Mean initial PaO2/FiO2 was 127.4 +/- 59.7mmHg and ARDS was diagnosed in 153 (98%) patients. The CT extent was distributed as <50 % (27.3 %), [50% - 75 %] (37.8 %) and > 75 % (34.9 %). Mean CT score was 19.4+/-5.8 [5 - 34]. The comparison of the 2 methods, showed a statistically significant result between the CT score and a damage < 50% (p = 0.002), and also between CT score and a damage >= 75% (p = 0.003). Conclusion(s): In COVID-19 pneumonia, lung damage extent seems to be appreciated with percentages as well as CT score. An external validity is mandatory for CT-scan score.
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Objective: Excessive use of corticosteroids therapy along with gross immunocompromised conditions in the Coronavirus Disease 2019 (COVID-19) pandemic has raised the risks of contracting opportunistic fungal infections. Here, we describe our experience with the implementation of a surgical protocol to treat and reconstruct Rhino-orbitalcerebral mucormycosis. Material(s) and Method(s): We conducted a prospective, single institution study utilizing our Mucormycosis Management Protocol. All patients included in this study underwent reconstruction after recovering from COVID-19. Wide local excision was performed in all cases removing all suspected and edematous tissue. Reconstruction was done primarily after clear margins were achieved on clinical assessment under a cover of injectable liposomal amphotericin B. Result(s): Fourteen patients were included. The average age was 43.6 years and follow up was 24.3 months. Thirteen patients had been admitted for inpatient care of COVID-19. Steroid therapy was implemented for 2 weeks in eleven patients and for 3 weeks in 3 patients. Eight patients (57.1%) had a maxillectomy and mucosal lining resection with/without skin excision, and six patients (42.8%) underwent maxillectomy and wide tissue excision: (Maxillectomy and partial zygomatic resection, orbital exenteration, orbital floor resection, nose debridement, or skull base debridement). Anterolateral thigh flaps were used to cover defects in all patients. All flaps survived. No major or minor complications occurred. No recurrence of mucormycosis was noted. Conclusion(s): The approach presented in this study indicates immediate reconstruction is safe and reliable in cases when appropriate tissue resection is accomplished. Further studies are required to verify the external validity of these findings.
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The Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV2) initially was perceived as a lower respiratory tract infection. However, with time coronavirus disease (COVID-19) presented with a wide variability of symptoms, including gastrointestinal and hepatic. This because the viral tropism to the angiotensin-converting enzyme 2 (ACE2) receptor found in liver and bile-duct epithelial cells. The ACE2 expression is mainly in cholangiocytes (60% of cells), minimally expressed in hepatocytes (3% of cells) and absent in Kupffer cells. Hepatic involvement can be evidenced with elevation of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH), these alterations have been evidenced in up to 43% of patients. The aim of this study is to evaluate liver damage in pediatric patients with COVID-19. Material(s) and Method(s): A retrospective cohort was carried out between March 2020 to October 2021 at the Instituto Nacional de Pediatria in Mexico City. We include all patients between 0 to 18 years with positive COVID-19 PCR test or antigen rapid test. Result(s): We had a total population of 161 subjects of which 83 had liver function tests (inflammation, excretion, or synthesis) during SARS-CoV2 infection;82 had ALT value. Mean age was 5.3 years and 56% were men (n: 47). Fifty-four patients (65%) had previous comorbidity, with oncological diseases being the most frequent (33%). Of the 54 patients with previous comorbidity, 3 had liver disease (Graft-versus-host disease, nonalcoholic fatty liver disease and autoimmune hepatitis). Regarding treatment, 32 patients did not require oxygen support, 32 patients had non-invasive devices and 19 patients required mechanical ventilation. Fifty-four percent (n = 45) were using steroid management. In relation to the outcome of the patients, 11 die and the rest were discharged. Liver function tests were submitted 2 days after admission, 51 patients (62%) presented elevation of ALT (according to age and sex). Second liver function tests were taken around day 23 53 patients. Table 1 shows the average of each of the parameters. It has been documented that severe COVID-19 is associated with higher levels of inflammatory mediators like C-reactive protein (CRP) and ferritin. Therefore, levels of this inflammatory mediators were evaluated, the average of this parameters was 1601 ng/mL and 8.19 mg/L respectively in the first test. Analysis: We evaluated the difference that existed in liver function tests by comparing the first and second determination. Regarding AST, INR and PT, a significant difference was found (p = <0.05) with improvement compared to baseline. While the ALT did not show a significant difference, there was an improvement compared to baseline. Secondary to the association described between elevation of inflammatory mediators and severity of the disease, a Pearson Correlation test was performed between liver inflammatory tests and ferritin/prealbumin. A significant correlation was obtained when comparing ALT with ferritin (r = 0.301, p = 0.033) and AST with ferritin (r = 0.311, p= 0.028), which demonstrate a weak correlation probably associated with the amount of population. The correlation between ALT/AST and prealbumin was carried out without being significant. In search of associated factors, it was found that the alteration of liver function tests is a risk factor for needing support with supplemental oxygen with an Odds Ratio of 2.007 (CI: 0.77-5.31). From 19 patients who required mechanical ventilation, 73.7% had altered liver function tests. Conclusion(s): SARS-CoV2 is a virus that has been shown to have liver involvement which can be demonstrated with elevation of liver function test. In our series, 62% had elevated ALT, being the most sensitive parameter of liver inflammation. With respect to factors associated with liver impairment, we found that higher ferritin levels are associated with greater liver involvement, as well as that having hepatic impairment is a risk factor for the use of supplemental oxygen. Therefore, it is important to consider in patients with COVID-19 liver function tests and thus make a timely detection of alterations at this level. Studies with more population are required to have external validity.
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Background/aims Although an increasing volume of research is emerging, rehabilitative treatment of patients with COVID-19 still continues to be a matter of great importance that must be explored further. The purpose of the present study was to describe the effects of inpatient rehabilitation in acute patients treated in a sub-intensive hospital setting during the COVID-19 pandemic. Methods A retrospective analysis was conducted based on the prospectively collected data of 192 patients with COVID-19 undergoing a physiotherapeutic regimen during their hospitalisation. Patients were admitted because of COVID-19-related pneumonia from the periods of 25 March-12 June 2020 and 2 November 2020-9 June 2021. This study investigated dyspnoea intensity using the modified Borg scale, motor function through the 1-minute sit-to-stand test, and daily walked distance. In a subset of 57 patients, handgrip strength and respiratory muscle function was also evaluated. Measurements were taken at baseline and discharge. Results Patients were classified according to the severity of their ratio of arterial oxygen partial pressure to fractional inspired oxygen (mean 225 +/- 82 mmHg). At discharge to home or to another hospital facility, patients performed a mean of 12 repetitions (1-minute sit-to-stand test);dyspnoea intensity was 1.4 (modified Borg scale), and they were able to walk a mean distance of 266.7 metres. The mean handgrip strength of the dominant hand was 29.3 kg, the maximal inspiratory pressure was 43.5 cmH(2)O, and the maximal expiratory pressure was 59.1 cmH(2)O. Overall, significant differences before and after treatment were detected for all clinical variables. Dyspnoea improved by 0.7 points;walked distance by 200 metres;the number of repetitions at the 1-minute sit-to-stand test by 5.6;the handgrip strength by 1.2 kg (right hand) and 1.7 kg (left hand);maximal inspiratory pressure by 7.7 cmH(2)O;and maximal expiratory pressure by 9.5 cmH(2)O. Conclusions Patients obtained significant improvements in functional capacity, dyspnoea perception, handgrip strength and respiratory muscle function. In addition, the treatment was feasible and well tolerated by patients, and no adverse related events were observed in a sub-intensive care setting.
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We test whether laboratory measures of individual preferences for risk and guilt relate to risk-connected behaviors in a pandemic, such as socializing, dining in at restaurants, and hand washing. We utilize a survey administrated to a nationally representative subject pool in the United States in April, 2020 - the month following the declaration of a national state of emergency in response to the global outbreak of COVID-19. We find that higher levels of risk aversion are associated with risk-reducing behaviors during the COVID-19 pandemic. Meanwhile, we do not find strong evidence that guilt relates to the same behavior.
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Introduction: In 2020, the COVID-19 pandemic required the UA RKKCOP Self-Care Therapeutics course, taught traditionally as an oncampus flipped classroom design, to be offered as an online course. Research Question or Hypothesis: Student performance on exams will be similar regardless of students attending a flipped classroom on campus versus online, via web-conferencing. Study Design: Retrospective comparison between an on-campus and online flipped classroom Self Care Therapeutics course. Methods: Exam performance was compared for the 2019 in-person attending cohort and the 2020 online attending cohort. Course design was similar between the two cohorts, with each completing assigned pre-reading, an associated quiz, in-class small group discussions and inclass large group faculty-led debrief. For small group discussions, the oncampus cohort selected their own group members while the online cohort was randomly placed into different groups for each class. Three examinations were administered consisting of 33 multiple choice questions. Descriptive statistics and a two tailed Mann-Whitney U test was used to compare student performance between the on-campus and online attendance cohorts. A significance level of 0.05 was used. Results: There were 243 students included in the analysis (58% female, 42% male). Minimal differences between the exam averages were observed for all 3 exams with statistically significant differences observed in performance for exam 1 only (exam 1 = 0.04±0.11, p=0.02;exam 2 = 0.03±0.09, p=0.11;exam 3 = 0±0.09, p=0.95). The correlation in scores between different exams appeared the same for both years. There was a moderate positive correlation between scores on exams 1, 2, and 3. Conclusion: Based on examination results, content in a flipped classroom design may have been as effectively delivered online as it was in person. Further research using data from multiple courses or from the same cohort, randomized, is needed to improve the external validity of these findings.
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Introduction. As defined by the Food and Drug Administration, real-world data (RWD) is data related to a patient's health and/or health care delivery, usually collected from various sources as part of real-world clinical practice research. Objective: to describe the feasible and the most sought-after designs of non-interventional real-world clinical practice trials that provide evidence for the efficacy and safety of drug administration in the therapy of novel coronavirus infection. Material and methods. A search strategy for the terms “COVID-19 AND real-life”, “COVID-19 AND real-data”, “COVID-19 AND real-world” was developed to extract articles published between December 1, 2020 and March 12, 2021 from the databases: PubMed/MEDLINE, the Cochrane Database of Systematic Reviews, and the ClinicalTrials.gov database. Results. The search yielded 137 non-repetitive articles, 32 of them were included in the review. All randomized clinical trials (pragmatic and simplified large ones), studies of the effectiveness of laboratory diagnostic methods, medical triage, social distancing and other sanitary and epidemiological measures to cope with the epidemic were excluded. Conclusion. High-quality, non-randomized RWD studies can enhance the external validity of registration randomized clinical trials by complementing them with a broader range of indicators, which is essential in supporting medical and public health decision-making in the COVID-19 pandemic.
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Objectives: To describe the feasible and the most sought-after designs of non-interventional real-world clinical practice trials that provide evidence for the efficacy and safety of drug administration in the therapy of novel coronavirus infection. Methods: A search strategy for the terms "covid-19" AND "real-life", "covid-19" AND "real-data", "covid-19" AND "real-world" was developed to extract articles published between December 1, 2020, and March 12, 2021, in the literature review databases: MEDLINE/PubMed, the Cochrane Database of Systematic Reviews, and the database. Results: The search yielded 137 non-repetitive articles, of which 32 were included in the review. All randomized clinical trials (pragmatic and simplified large ones), studies of the effectiveness of laboratory diagnostic methods, medical triage, social distancing and other sanitary and epidemiological measures to contain the epidemic were excluded from the review. Conclusions: The inconsistency of the results suggests some concerns about the reliability of the data obtained in the framework of RWD. There is a need to analyze RWD with evidence-based medicine tools to obtain a more valid RWD or RWE (Real - world evidence). High-quality, non-randomized RWD studies can enhance the external validity of registration RCTs by complementing them with a broader range of indicators, which is essential in supporting medical and public health decision-making in the COVID-19 pandemic.
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Initial results from various phase-III trials on vaccines against SARS-CoV-2 are promising. For proper translation of these results to clinical guidelines, it is essential to determine how well the general population is reflected in the study populations of these trials. This study was conducted among 7162 participants (age-range: 51-106 years; 58% women) from the Rotterdam Study. We quantified the proportion of participants that would be eligible for the nine ongoing phase-III trials. We further quantified the eligibility among participants at high risk to develop severe COVID-19. Since many trials were not explicit in their exclusion criterion with respect to 'acute' or 'unstable preexisting' diseases, we performed two analyses. First, we included all participants irrespective of this criterion. Second, we excluded persons with acute or 'unstable preexisting' diseases. 97% of 7162 participants was eligible for any trial with eligibility for separate trials ranging between 11-97%. For high-risk individuals the corresponding numbers were 96% for any trial with separate trials ranging from 5-96%. Importantly, considering persons ineligible due to 'acute' or 'unstable pre-existing' disease drastically dropped the eligibilities for all trials below 43% for the total population and below 36% for high-risk individuals. The eligibility for ongoing vaccine trials against SARS-CoV-2 can reduce by half depending on interpretation and application of a single unspecified exclusion criterion. This exclusion criterion in our study would especially affect the elderly and those with pre-existing morbidities. These findings thus indicate the difficulty as well as importance of developing clinical recommendations for vaccination and applying these to the appropriate target populations. This becomes especially paramount considering the fact that many countries worldwide have initiated their vaccination programs by first targeting the elderly and most vulnerable persons.
Subject(s)
COVID-19 Vaccines , COVID-19/prevention & control , Research Design/statistics & numerical data , Aged , Aged, 80 and over , Comorbidity , Europe/epidemiology , Female , Humans , Male , Middle Aged , Reproducibility of Results , SARS-CoV-2ABSTRACT
The randomized clinical trial (RCT) has long been recognized as the 'gold standard' for developing evidence for clinical treatments and vaccines; however, the successful implementation and translation of these findings is predicated upon external validity. The generalization of RCT findings are jeopardized by the lack of participation of at-risk groups such as African Americans, with long-recognized disproportional representation. Distinct factors that deter participation in RCTs include distrust, access, recruitment strategies, perceptions of research, and socioeconomic factors. While strategies have been implemented to improve external validity with greater participation among all segments of the population in RCTs, the coronavirus disease 2019 (COVID-19) pandemic may exacerbate disparities in RCT participation with the potential impact of delaying treatment development and vaccine interventions that are applicable and generalizable. Thus, it is essential to include diverse populations in such strategies and RCTs. This Perspective aims to direct attention to the additional harm from the pandemic as well as a refocus on the unresolved lack of inclusion of diverse populations in conducting RCTs.