Repurposing of Drug: Utility of Animal Models

Drug repurposing is an up-and-coming concept in the world of medicine. It is an efficient way to use already existing drug formulations in the treatment of diseases besides the ones which were initially intended for. This circumvents the tedious process of drug development and approval and helps to conserve resources. While multiple drugs have already been repurposed, their utility and reintroduction into the market is still a new concept. Even though it optimizes the use of resources, lab testing and animal model trials form a crucial aspect of determining the efficacy of these drugs in different diseases. This review encompasses the methods and trends in the repurposing of drugs while highlighting the use of animal models and the benefits of repurposing drugs during the COVID-19 pandemic. © Springer Nature Singapore Pte Ltd. 2023.

METFORMIN REDUCED SARS-CoV-2 VIRAL LOAD IN A PHASE 3 RANDOMIZED CLINICAL TRIAL

Background: Metformin has in vitro activity against SARS-CoV-2. In a published phase 3, quadruple-blinded, placebo-controlled randomized trial of outpatient COVID-19 therapy, metformin resulted in a 42% reduction in ER visits/hospitalizations/deaths by day 14, 58% reduction in hospitalizations/ death by day 28, and 42% reduction in Long Covid through 10 months. This analysis presents the results of viral load sampling performed during that clinical trial. Method(s): Covid-Out trial (NCT04510194) enrolled adults aged 30 to 85 within 3 days of a documented SARS-CoV-2 infection and < 7 days after symptom onset. The trial randomized 1323 participants to metformin (1000mg/day days 2-5;1500mg/day days 6 to 14), ivermectin, fluvoxamine, and/or exact-matching placebo in a 2x3 factorial trial design. Nasal swabs for viral load were an optional component, self-collected from the anterior nares on day 1, 5, and 10. Viral loads were measured via RT-qPCR using N1 and N2 targets in the SARSCoV- 2 nucleocapsid protein, with relative Ct values converted to absolute copy number via calibration to droplet digital PCR. A linear Tobit regression model was used to assess change over time while accounting for left censoring due to the viral load limit of detection. Results were adjusted for other treatment allocations within the factorial design, vaccination status, and baseline viral load. Repeated measures were accounted for using clustered standard errors within participants. Result(s): Samples were available from n = 945, 871, and 775 participants on days 1, 5, and 10, respectively. The mean change from baseline to followup was -0.64 log10 copies/mL (95%CI, -1.16 to -0.13) for metformin versus placebo, which equates to a 4.4-fold greater decrease. The mean change in SARS-CoV-2 from baseline to day 5 was -0.48 log10 copies/mL, and was -0.81 log10 copies/mL from baseline to day 10. The anti-viral effect increased with increased metformin dosing days 6-14. The antiviral effect was larger in those unvaccinated (mean -0.95 log copies/mL) than vaccinated (mean -0.39 log copies/mL). There was no change in viral load vs. placebo for ivermectin or fluvoxamine. Conclusion(s): Metformin lowered SARS-CoV-2 viral load in this quadrupleblinded, randomized clinical trial. The temporal relationship to dose titration suggests a dose-dependent effect. The magnitude of antiviral effect was similar to nirmatrelvir at day 5, greater than nirmatrelvir at day 10. Metformin is safe, widely available, and has few contraindications.

Rehabilitation of children and adolescents with diabetes during Coronavirus Pandemic in comparison to the year before the pandemic

Background during the pandemic a decrease of more than 30% of pediatric rehabilitations was seen in the year 2020. These data are are provided by the German Rentenversicherung (DRV). DRV is not the only provider of pediatric rehabilitations. DPV database can analyse data independent of the funding provider and a comparison of the prepandemic year with the pandemic years 2020/21 can be performed. Methods Comparison of inpatient rehabilitation of 11 pediatric rehabilitation clinics in the years 2019 (pre pandemic) and 2020/21. Monthly analysis of number of admissions, duration of stay, HbA1c, and BMI development. Comparison of rehabilitation in east and west German clinics and subanalysis of age below and above 12 years. Results In 2019 in total 2237 children and adolescents with type 1 diabetes were admitted, in 2020 a reduction to 1455 (-35%) and no improvement in 2021 (n=1447) was seen. A dramatic decrease was evident in April and May 2020 during the first lockdown. During the first lockdown the duration of stay in the clinic was siginificantly reduced. The eastern German clinics remained with more stable admissions in this period. HbA1c showed a significant increase during the first lockdown (April 2019: 8.19% (7.94, 8.44);April 2020: 8.68% (8.25, 9.11);April 2021 7.94% (7.63, 8.24)). The age stratified analysis showed a higher HbAc1 level in the adolescents compared to the children. BMI-SDS was 0.29 (0.24, 0.33) in 2019, increased to 0.35 (0.29;0.41) in 2020 and further increased to 0.41 (0.35;0.46) in 2021. Conclusion We saw a significant reduction of the number of pediatric diabetes rehabilitations in the Coronavirus Pandemic and no improvment of this decrease during 2021.

Severe Pulmonary Hemorrhage in a 3 Weeks Old Neonate with Covid-19 Infection

Aims To describe a case of 3 weeks old neonate presenting with severe pulmonary hemorrhage due to COVID-19 infection and its outcome. Methods We report an interesting case of pulmonary hemorrhage presenting at a young age of 3 weeks, in a previously healthy neonate who was infected with COVID-19 virus;Literature review and investigation results are included. This is a 3-week-old female, a product of full-term pregnancy and an uneventful perinatal course. She was admitted from the emergency department initially as a case of late neonatal sepsis, where a full septic workup was done. Her presenting complaints were low-grade fever and a blocked nose for one day. She was hemodynamically stable in the emergency department except for tachycardia secondary to fever, which improved once the fever was controlled. Her initial blood workup, including blood gas and CSF study, was reassuring (table 1a). Her COVID PCR was positive with a CT value of 17.77. She was treated with IV antibiotics and supportive management. Later that day, the patient developed cardiopulmonary arrest, CPR was initiated, and the patient was intubated. The patient was found to have pulmonary hemorrhage as evident by the fresh blood coming out of the endotracheal tube and the chest X-Ray findings of ground-glass opacities and dense consolidation (figure 1). After initial brief stabilization, the patient started deteriorating requiring escalation of respiratory support to HFOV. The patient continued to deteriorate and developed bilateral pneumothorax requiring bilateral chest tube insertion. After chest tube insertion, there was a mild transient improvement in oxygenation. The patient was put on the maximum ventilatory settings, but she kept having frequent desaturation, requiring frequent manual bag to tube ventilation. Later, she started developing progressive hypotension, that required support with maximum doses of inotropes. Her urine output started decreasing, for which frusemide were started with no response. Blood investigations showed severe DIC picture (table 1b and 1c). She was empirically covered with Meropenem and Vancomycin along with Remdesivir and Dexamethasone for COVID 19 pneumonia. Eventually, the child developed progressive desaturation, hypotension, and poor perfusion. Shortly after that, she developed cardiac arrest and was declared dead. Results The clinical picture of COVID 19 infection is more indistinct in children than in adults, with the most common symptoms being fever, cough, dyspnea, and malaise. In the few published cases of COVID-19 in the neonate, the presentation was that of late neonatal sepsis;interestingly, the lung involvement was not described as frequently as in older age groups. Pulmonary hemorrhage has been reported in adults but rarely in children. Some reports in adults suggested that patients with COVID infection had an increased inflammatory state that led to the development of vasculitis and pulmonary hemorrhage. Up to our knowledge, this is the youngest age at which a patient with COVID-19 infection developed pulmonary hemorrhage with no other underlying cause of it. Conclusion While many of the cases of COVID infection in children are mild, fatal complications like pulmonary hemorrhage can be present. Adding new challenges to the management of this viral infection.

COLONOSCOPY COMPLETION RATES AND PATIENT TOLERANCE AFTER COMPLICATED DIVERTICULITIS;IS CT COLONOSCOPY A BETTER OPTION?

Introduction ACPGBI and ESCP guidelines suggest colonic examination after acute complicated diverticulitis due to a higher prevalence of colorectal cancer (CRC), but colonoscopy in this cohort can be challenging. We examined completion rates, pain scores and analgesic use in endoscopic follow-up of complicated diverticulitis in a district general hospital. Methods Patients were identified from hospital records with a coded diagnosis of acute diverticulitis from 01/01/2021 - 01/ 07/2021. Electronic records were examined to identify those with complicated diverticulitis on CT who had not had surgery. The endoscopy system was interrogated from 01/01/2021 - 01/01/2022 for these patients. Information was collected on: whether colonoscopy was requested and performed, site reached, quality of mucosal views, pain scores (average of physician and nurse), analgesia and sedation use, and reason for incomplete colonoscopy. We gathered the same data for the preceding and/or succeeding patients on the endoscopy list for comparison. Results From 01/01/2021 - 01/07/2021 there were 49 cases of acute complicated diverticulitis;4 had emergency surgery. of the remaining 45 cases, 28 had a colonoscopy requested. By 01/01/2022, 17 had an colonoscopy (group 1), and the mean time from discharge to endoscopy was 108 days. These were compared to the 26 colonoscopies immediately preceding or succeeding the group 1 colonoscopies (group 2). Colonoscopy completion rates were lower in group 1, and reasons for incomplete examination were: patient discomfort x2, tight angulation x1, muscular hypertrophy x1. Reasons for incomplete examination in group 2 were: poor bowel prep x2. In group 1 the mean pain scores were higher, as was use of fentanyl and midazolam. Entonox use was about equivalent. Conclusions Endoscopic follow-up of complicated diverticulitis was not universal. There was a delay beyond the recommended follow-up at 6 weeks which corresponds with delays in endoscopy for other indications since the COVID-19 pandemic. Completion rates were lower for the complicated diverticulitis group and the procedure was more poorly tolerated. Colonoscopy completion rates have not been looked at specifically for complicated diverticulitis follow-up elsewhere. The completion rates in this sample are lower than those for the endoscopic follow-up of all diverticulitis in other studies. If these rates are found in a larger sample then alternative methods for examining the colon, such as CT colonoscopy, may be a more attractive option.

Multi-institutional perspective on screening mammography and breast cancer stage at diagnosis during the COVID-19 pandemic

Background: During the SARS-CoV-2 pandemic in 2020, the use of routine screening mammography (SM) and diagnostic mammography (DM) was limited for several months in order to reduce patient exposure and redeploy medical personnel. Previous studies suggest such delays result in more late-stage breast cancer diagnoses. We hypothesized that this impact would vary between institutions depending on regional variations in shutdown periods and the ability and willingness of patients to resume screening. Methods: Patients diagnosed with invasive breast cancers from 2016-2020 were identified using the Beth Israel Deaconess Medical Center (BIDMC) and the Duke University Medical Center (DUMC) cancer registries. Rates of mammography were ascertained from billing data. Baseline patient characteristics, demographics, and clinical information were gathered and cross-referenced with the electronic medical record. Late-stage was defined as Anatomic Stage III-IV disease (AJCC 8th edition). Chi-squared analysis was used to examine monthly distributions in stage at presentation for diagnosis in 2016-2019 compared to in 2020 at each institution. Results: There were 5907 patients diagnosed with invasive breast cancer between 2016-2019 (1597 at BIDMC and 4310 at DUMC) and 1075 in 2020 (333 and 742, respectively). Mammography was limited from 3/16/20-6/8/20 at BIDMC and from 3/16/20-4/20/20 Sa t DUMC. There were fewer SM at each institution during their respective shutdown periods in 2020 than in the same months in 2019: BIDMC 1713 versus 8566 (80% reduction) and at DUMC 1649 versus 5698 (71% reduction). Following the pandemic shutdown, SM volume increased in July-December 2020 compared to July-December 2019 (108% at BIDMC and 116% at DUMC). The proportion of patients diagnosed with late-stage disease at BIDMC was greater in 2020 than in 2016-2019, at 12.6% and 6.6%, respectively (p < 0.001);86% of late-stage diagnoses and 68% of all diagnoses in 2020 at BIDMC occurred from July-December following the initial shutdown period. The proportion of patients diagnosed with late-stage disease at DUMC in these two cohorts were 14.3% in 2020 and 16.2%% in 2016-2019 (p = 0.1);50% of late-stage diagnoses and 51% of all diagnoses in 2020 at DUMC occurred in the period following the initial shutdown from July-December. Conclusion: We identified variation between two large academic medical centers in the impact of the SARS-CoV-2 pandemic shutdown on the proportion of late-stage breast cancer diagnoses. These dissimilar outcomes may be the result of differences in referral patterns as well as regional differences in the approach to SM during the pandemic. In particular, a shorter closure time and substantial increase in SM volume following the initial shutdown period in the Southeast region may have prevented an increase in late-stage diagnoses. Further information and analysis may help suggest additional strategies to minimize adverse effects of reduced cancer screening in future public-health emergencies.

Pericarditis as a Secondary Complication of COVID-19 in a Renal Transplant Patient

INTRODUCTION: A wide range of complications from COVID-19 are being reported, including cardiac complications. CASE PRESENTATION: A 71-year-old woman with systemic lupus erythematosus complicated by focal segmental glomerular sclerosis status post kidney transplant presented with worsening left-sided chest pain after receiving treatment for COVID-19 pneumonia at an outside hospital. She was subsequently diagnosed with acute pericarditis, likely secondary to viral infection with COVID-19, and was successfully treated with aspirin and colchicine for 90 days without complications. DISCUSSION: NSAIDs and colchicine are mainstays in acute pericarditis treatment. Though treatment presented a potential challenge given this patient's prior kidney transplant, aspirin and colchicine proved to be effective in treating her case of COVID-19-associated pericarditis. CONCLUSION: This report has implications for future treatment of renal transplant patients with COVID-19-related pericarditis and emphasizes the need for research into the pathophysiology of pericarditis in the context of COVID-19, including risk factors and treatment.

Weight loss approaches in rural and urban u.s. adults in the international weight control registry

Background: Individuals living in rural areas have higher obesity and obesity related co-morbidities than their urban counterparts. Understanding rural-urban differences associated with weight management may inform the development of effective weight management interventions for adults living in rural areas. Methods: The International Weight Control Registry (IWCR) is an online registry designed to assess factors contributing to successes and challenges with weight loss and weight loss maintenance across the world. We examined demographics, weight history and weight management strategies in a sample of urban and rural residents in the Midwestern U.S. (IA, IL, IN, KS, MI, MN, MO, ND, NE, OH, SD, WI). Participants were classified as rural or urban by the Rural-Urban Commuting Area Code. Analyses included Chi-square tests for proportions and independent t-test and Wilcoxon rank sum test for continuous variables. Results: The sample was 45% rural (n = 78 of a total N = 174) with a mean age of 50.3 years. Rural residents were more likely to be white, non-college graduates, and have lower family income compared with urban areas (p < 0.05). Rural and urban residents reported similar weight histories and strategies for weight management. Work-related physical activity was higher and weekday sitting time was lower in rural compared to urban residents (p < 0.01). These data could potentially be impacted by the relative number of residents working from home during COVID-19 (Urban: 59% vs. Rural: 37%, p < 0.05). Rural residents were more likely to report a lack of neighborhood walkability (p < 0.01) and healthy food availability (p < 0.05) compared with urban residents. Conclusions: These data suggest rural-urban differences in demographic characteristics, opportunity for leisure time physical activity, and the availability of heathy foods should be considered in the development of weight management interventions. The consistency of the observed findings will be evaluated at the regional, national and international levels as the size of the available sample in the IWCR increases.

Classification of X-ray images into COVID-19, pneumonia, and TB using cGAN and fine-tuned deep transfer learning models

Purpose: The rapid increase in the spread of the coronavirus disease of 2019 (COVID-19) has led to a need for reliable, effective, and readily available testing on a large scale. While diagnostic testing has been a support to public health, newer technology can be used to provide low-cost and convenient test options for patients. X-ray scanning can be performed to resolve this issue and produce quicker and more precise results. Currently, a radiologist is required to examine these X-ray images. However, deep convolutional neural networks can also be used to perform X-ray examinations and employed for the detection of COVID-19. We propose a Conditional Generative Adversarial Network (cGAN) with a fine-tuned deep transfer learning model to classify chest X-rays into six categories: COVID-Mild, COVID-Medium, COVID-Severe, Normal, Pneumonia, and Tuberculosis. Methods: A total of 1229 images were taken to form a dataset containing six classes corresponding to the six categories. A cGAN was used to increase the number of images. Generative Adversarial Networks (GAN) are used to train a model for generating new images. cGAN is an extension of GAN consisting of a generator and discriminator network that are trained simultaneously to optimize the model. The generated images were then trained using deep transfer learning models such as ResNet50, Xception, and DenseNet-169 to achieve the classification into six classes. Results: The proposed model helped achieve a training and validation accuracy of up to 98.20 % and 94.21 % respectively. The model was able to achieve a test accuracy of 93.67 %. The use of cGAN not only helped to increase the size of the training dataset but it also helped to reduce the problem of over-fitting. Conclusion: The proposed approach will help to diagnose COVID-19 quickly at an early stage. © 2021, Sociedade Brasileira de Engenharia Biomedica.

The impact of COVID-19 on breast cancer stage at diagnosis

Background: During the SARS-CoV-2 pandemic, routine screening mammography (SM) was stopped and diagnostic mammography (DM) was limited for several months across the United States in order to reduce patient exposure and redeploy medical personnel. We hypothesized that this delay would result in patients presenting with later-stage disease following the initial shutdown. Methods: Patients diagnosed with invasive breast cancers from 2016-2020 were identified using the Beth Israel Deaconess Medical Center Cancer Registry. Baseline patient characteristics, demographics, and clinical information were gathered and cross-referenced with our electronic medical record. Late-stage disease was defined as initial anatomic stage III-IV disease in the AJCC 8th edition staging system. The control cohort consisted of patients diagnosed from 2016-2019;patients diagnosed in 2020 were the test cohort. Chi-squared analysis was used to compare monthly distributions in stage at diagnosis between the control and test cohorts. Multivariate analysis was performed using a logistic regression model. Results: There were 1597 patients diagnosed with invasive breast cancer between 2016-2019 and 333 in 2020. Median age at diagnosis was 60 years;99% were female, and 69.1% were white. Mammography was limited from 3/16/20-6/8/20, with 90% reduction in volume during this time. The number of screening studies performed in March, April, May, and June of 2020 were 987, 1, 4, and 721 compared to 2042, 2141, 2241, and 2142 in 2019. The volume of new diagnoses per month decreased substantially during the shutdown (see table). The proportion of patients diagnosed with late-stage disease was 6.6% in the control cohort compared to 12.6% in the 2020 test cohort (p < 0.001);92.9% of late-stage diagnoses in 2020 occurred from June to December following the shutdown period. On multivariate analysis, year of diagnosis (2020 vs 2016-2019;OR = 4.25 95% CI 0.035-0.095, p < 0.001), lower income (<200% of the federal poverty level;OR = 2.73 95% CI 0.016-0.099, p = 0.006) and increased Charlson Comorbidity Index (OR = 12.01 95% CI 0.037-0.052, p < 0.001) were associated with later stage at diagnosis. Conclusions: Patients were more likely to be diagnosed with late-stage breast cancer following the global shutdown due to the SARSCoV-2 pandemic. Patients with lower income and medical comorbidities were disproportionately affected. These data raise significant concerns regarding the impact of SARS-CoV-2 on cancer diagnoses and long-term outcomes, especially in vulnerable patient populations. (Table Presented).

Psychological impact of the COVID-19 pandemic on frontline health care physicians

The Coronavirus Disease 2019 (COVID-19) pandemic began in December 2019 in Wuhan, China. Such sudden infectious outbreaks take a toll on the psychological health of our brave frontline health care physicians. Frontline health care physicians become vulnerable to psychological problems like depression, anxiety, stress, and insomnia. Long working hours, increased patient load, and risk of spread of contagion to family members are a few of the major contributing factors. Such factors, coupled with chronic stress and emotional exhaustion predispose doctors to experience burnout which has also been reported to increase the risk of mental morbidities. Early counselling, pandemic preparedness, self-care efforts, and stress management can help to cope in these adverse times. Various online portals have also been developed as an intervention strategy in mitigating the negative impact of this pandemic. The purpose of this viewpoint is to highlight the need to address such issues in physicians, find possible root causes, and suggest relevant measures to curb the incidence of these problems.