Vaccines for a sustainable planet.

The health of the planet is one objective of the United Nations' Sustainable Development Goals. Vaccines can affect not only human health but also planet health by reducing poverty, preserving microbial diversity, reducing antimicrobial resistance, and preventing an increase in pandemics that is fueled partly by climate change.

Global antibiotic use during the COVID-19 pandemic: analysis of pharmaceutical sales data from 71 countries, 2020–2022

Background Despite bacterial coinfection rates of less than 10%, antibiotics are prescribed to an estimated 75% of patients with COVID-19, potentially exacerbating antimicrobial resistance. We estimated the associations of COVID-19 cases and vaccinations with global antibiotic sales during the first two years of the COVID-19 pandemic. Methods We obtained monthly data on broad-spectrum antibiotic sales volumes (cephalosporins, penicillins, macrolides, and tetracyclines) in 71 countries during March 2020–May 2022 from the IQVIA MIDAS® database. These data were combined with country-month-level COVID-19 case and vaccination data from Our World in Data. We used least squares (pooled) and fixed-effects panel data regression models, accounting for country characteristics, to estimate the associations between antibiotic sales volumes and COVID-19 cases and vaccinations per 1000 people. Findings Sales of all four antibiotics fell sharply during April and May 2020, followed by a gradual rise to near pre-pandemic levels through May 2022. In fixed-effects regression models, a 10% increase in monthly COVID-19 cases was associated with 0.2%–0.3% higher sales of cephalosporins, 0.2%–0.3% higher sales of penicillins, 0.4%–0.6% higher sales of macrolides, and 0.3% higher sales of all four antibiotics combined per 1000 people. Across continents, a 10% increase in monthly COVID-19 cases was associated with 0.8%, 1.3%, and 1.5% higher macrolides sales in Europe, North America, and Africa respectively. Sales of other antibiotics across continent were also positively associated with COVID-19 cases, although the estimated associations were smaller in magnitude. No consistent associations were observed between antibiotic sales and COVID-19 vaccinations. Results from pooled regression analysis were similar to those from the fixed-effects models. Interpretation Antibiotic sales were positively associated with COVID-19 cases globally during 2020–2022. Our findings underline that antibiotic stewardship in the context of COVID-19 remains essential. Funding 10.13039/100000865Bill & Melinda Gates Foundation.

Global antibiotic use during the COVID-19 pandemic: analysis of pharmaceutical sales data from 71 countries, 2020-2022.

Background: Despite bacterial coinfection rates of less than 10%, antibiotics are prescribed to an estimated 75% of patients with COVID-19, potentially exacerbating antimicrobial resistance. We estimated the associations of COVID-19 cases and vaccinations with global antibiotic sales during the first two years of the COVID-19 pandemic. Methods: We obtained monthly data on broad-spectrum antibiotic sales volumes (cephalosporins, penicillins, macrolides, and tetracyclines) in 71 countries during March 2020-May 2022 from the IQVIA MIDAS® database. These data were combined with country-month-level COVID-19 case and vaccination data from Our World in Data. We used least squares (pooled) and fixed-effects panel data regression models, accounting for country characteristics, to estimate the associations between antibiotic sales volumes and COVID-19 cases and vaccinations per 1000 people. Findings: Sales of all four antibiotics fell sharply during April and May 2020, followed by a gradual rise to near pre-pandemic levels through May 2022. In fixed-effects regression models, a 10% increase in monthly COVID-19 cases was associated with 0.2%-0.3% higher sales of cephalosporins, 0.2%-0.3% higher sales of penicillins, 0.4%-0.6% higher sales of macrolides, and 0.3% higher sales of all four antibiotics combined per 1000 people. Across continents, a 10% increase in monthly COVID-19 cases was associated with 0.8%, 1.3%, and 1.5% higher macrolides sales in Europe, North America, and Africa respectively. Sales of other antibiotics across continent were also positively associated with COVID-19 cases, although the estimated associations were smaller in magnitude. No consistent associations were observed between antibiotic sales and COVID-19 vaccinations. Results from pooled regression analysis were similar to those from the fixed-effects models. Interpretation: Antibiotic sales were positively associated with COVID-19 cases globally during 2020-2022. Our findings underline that antibiotic stewardship in the context of COVID-19 remains essential. Funding: Bill & Melinda Gates Foundation.

Rapid Adoption of Telemedicine Increases Opioid Prescribing in Orthopedic Surgery.

Background: The COVID-19 pandemic led to health care practitioners utilizing new technologies to deliver health care, including telemedicine. The purpose of this study was to examine the effect of rapidly proliferative use of video visits on opioid prescribing to orthopedic patients at a large academic health system that had existing procedure-specific opioid prescribing guidelines. Methods: This IRB-exempt study examined 651 opioid prescriptions written to patients who had video (visual and audio), telephone (audio only), or in-person encounters at our institution from March 1 to June 1, 2020 and compared them with 963 prescriptions written during the same months in 2019. Prescriptions were converted into daily milligram morphine equivalents (MMEs) to facilitate direct comparison. Chi-square testing was used to compare categorical data, whereas analysis of variance and Mann-Whitney tests were used to compare numerical data between groups. Statistical significance was set at <0.05. Results: Six hundred fifty-one of 1,614 prescriptions analyzed (40.3%) occurred during the pandemic. Patients prescribed opioids during video visits were prescribed 53.3 ± 37 MME, significantly higher than in-person (p = 0.002) or audio visits (p < 0.001) before or during the pandemic. Prepandemic, significantly higher MME were prescribed for in-person versus audio only visits (41.6 ± 89 vs. 30.2 ± 28 MME; p = 0.026); during the pandemic, there was no difference between these groups (p = 0.91). Significantly higher MME were prescribed by Nurse Practitioners and Physician Associates versus MD or DO prescribers for both time periods (51.3 ± 109 vs. 27.9 ± 42 MME; p < 0.001; 42.9 ± 70 vs. 28.2 ± 42 MME; p < 0.001). Conclusion: During crisis and with new technology, we should be vigilant about prescribing of opioid analgesics. Despite well-established protocols, patients received significantly higher MME through video than for other encounter types, including in-person encounters. In addition, significantly higher MME were prescribed by mid-level prescribers compared with DOs or MDs. Institutions should ensure these prescribers are involved during creation of opioid prescribing protocols after orthopedic surgery.

Cohort Profile: Real-Time Insights of COVID-19 in India (RTI COVID-India).

BACKGROUND: The coronavirus disease (COVID) pandemic caused disruption globally and was particularly distressing in low- and middle-income countries such as India. This study aimed to provide population representative estimates of COVID-related outcomes in India over time and characterize how COVID-related changes and impacts differ by key socioeconomic groups across the life course. METHODS: The sample was leveraged from an existing nationally representative study on cognition and dementia in India: Harmonized Diagnostic Assessment of Dementia for the Longitudinal Aging Study in India (LASI-DAD). The wave-1 of LASI-DAD enrolled 4096 older adults aged 60 years and older in 3316 households from 18 states and union territories of India. Out of the 3316 LASI-DAD households, 2704 with valid phone numbers were contacted and invited to participate in the Real-Time Insights COVID-19 in India (RTI COVID-India) study. RTI COVID-India was a bi-monthly phone survey that provided insight into the individual's knowledge, attitudes, and behaviour towards COVID-19 and changes in the household's economic and health conditions throughout the pandemic. The survey was started in May 2020 and 9 rounds of data have been collected. FINDINGS TILL DATE: Out of the 2704 LASI-DAD households with valid phone numbers, 1766 households participated in the RTI COVID-India survey at least once. Participants were in the age range of 18-102 years, 49% were female, 66% resided in rural area. Across all rounds, there was a higher report of infection among respondents aged 60-69 years. There was a greater prevalence of COVID-19 diagnosis reported in urban (23.0%) compared to rural areas (9.8%). Respondents with higher education had a greater prevalence of COVID-19 diagnosis compared to those with lower or no formal education. Highest prevalence of COVID-19 diagnosis was reported from high economic status compared to middle and low economic status households. Comparing education gradients in experiencing COVID-19 symptoms and being diagnosed, we observe an opposite pattern: respondents with no formal schooling reported the highest level of experiencing COVID-19 symptoms, whereas the greatest proportion of the respondents with secondary school or higher education reported being diagnosed with COVID-19. FUTURE PLANS: The study group will analyse the data collected showing the real-time changes throughout the pandemic and will make the data widely available for researchers to conduct further studies.

Virology under the Microscope-a Call for Rational Discourse.

Viruses have brought humanity many challenges: respiratory infection, cancer, neurological impairment and immunosuppression to name a few. Virology research over the last 60+ years has responded to reduce this disease burden with vaccines and antivirals. Despite this long history, the COVID-19 pandemic has brought unprecedented attention to the field of virology. Some of this attention is focused on concern about the safe conduct of research with human pathogens. A small but vocal group of individuals has seized upon these concerns - conflating legitimate questions about safely conducting virus-related research with uncertainties over the origins of SARS-CoV-2. The result has fueled public confusion and, in many instances, ill-informed condemnation of virology. With this article, we seek to promote a return to rational discourse. We explain the use of gain-of-function approaches in science, discuss the possible origins of SARS-CoV-2 and outline current regulatory structures that provide oversight for virological research in the United States. By offering our expertise, we - a broad group of working virologists - seek to aid policy makers in navigating these controversial issues. Balanced, evidence-based discourse is essential to addressing public concern while maintaining and expanding much-needed research in virology.

Virology under the Microscope-a Call for Rational Discourse.

Viruses have brought humanity many challenges: respiratory infection, cancer, neurological impairment and immunosuppression to name a few. Virology research over the last 60+ years has responded to reduce this disease burden with vaccines and antivirals. Despite this long history, the COVID-19 pandemic has brought unprecedented attention to the field of virology. Some of this attention is focused on concern about the safe conduct of research with human pathogens. A small but vocal group of individuals has seized upon these concerns - conflating legitimate questions about safely conducting virus-related research with uncertainties over the origins of SARS-CoV-2. The result has fueled public confusion and, in many instances, ill-informed condemnation of virology. With this article, we seek to promote a return to rational discourse. We explain the use of gain-of-function approaches in science, discuss the possible origins of SARS-CoV-2 and outline current regulatory structures that provide oversight for virological research in the United States. By offering our expertise, we - a broad group of working virologists - seek to aid policy makers in navigating these controversial issues. Balanced, evidence-based discourse is essential to addressing public concern while maintaining and expanding much-needed research in virology.

Truncated ring-A amaryllidaceae alkaloid modulates the host cell integrated stress response, exhibiting antiviral activity to HSV-1 and SARSCoV-2.

The total synthesis of four novel mono-methoxy and hydroxyl substituted ring-A dihydronarciclasine derivatives enabled identification of the 7-hydroxyl derivative as a potent and selective antiviral agent targeting SARSCoV-2 and HSV-1. The concentration of this small molecule that inhibited HSV-1 infection by 50% (IC50), determined by using induced pluripotent stem cells (iPCS)-derived brain organ organoids generated from two iPCS lines, was estimated to be 0.504 µM and 0.209 µM. No significant reduction in organoid viability was observed at concentrations up to 50 mM. Genomic expression analyses revealed a significant effect on host-cell innate immunity, revealing activation of the integrated stress response via PERK kinase upregulation, phosphorylation of eukaryotic initiation factor 2α (eIF2α) and type I IFN, as factors potentiating multiple host-defense mechanisms against viral infection. Following infection of mouse eyes with HSV-1, treatment with the compound dramatically reduced HSV-1 shedding in vivo.

Virology under the Microscope-a Call for Rational Discourse.

Viruses have brought humanity many challenges: respiratory infection, cancer, neurological impairment and immunosuppression to name a few. Virology research over the last 60+ years has responded to reduce this disease burden with vaccines and antivirals. Despite this long history, the COVID-19 pandemic has brought unprecedented attention to the field of virology. Some of this attention is focused on concern about the safe conduct of research with human pathogens. A small but vocal group of individuals has seized upon these concerns - conflating legitimate questions about safely conducting virus-related research with uncertainties over the origins of SARS-CoV-2. The result has fueled public confusion and, in many instances, ill-informed condemnation of virology. With this article, we seek to promote a return to rational discourse. We explain the use of gain-of-function approaches in science, discuss the possible origins of SARS-CoV-2 and outline current regulatory structures that provide oversight for virological research in the United States. By offering our expertise, we - a broad group of working virologists - seek to aid policy makers in navigating these controversial issues. Balanced, evidence-based discourse is essential to addressing public concern while maintaining and expanding much-needed research in virology.

Treatment of infection and inflammation associated with COVID-19, multi-drug resistant pneumonia and fungal sinusitis by nebulizing a nanosilver solution.

Solutions containing Ag0 nanoclusters, Ag+1, and higher oxidation state silver, generated from nanocrystalline silver dressings, were anti-inflammatory against porcine skin inflammation. The dressings have clinically-demonstrated broad-spectrum antimicrobial activity, suggesting application of nanosilver solutions in treating pulmonary infection. Nanosilver solutions were tested for antimicrobial efficacy; against HSV-1 and SARS-CoV-2; and nebulized in rats with acute pneumonia. Patients with pneumonia (ventilated), fungal sinusitis, burns plus COVID-19, and two non-hospitalized patients with COVID-19 received nebulized nanosilver solution. Nanosilver solutions demonstrated pH-dependent antimicrobial efficacy; reduced infection and inflammation without evidence of lung toxicity in the rat model; and inactivated HSV-1 and SARS-CoV-2. Pneumonia patients had rapidly reduced pulmonary symptoms, recovering pre-illness respiratory function. Fungal sinusitis-related inflammation decreased immediately with infection clearance within 21 days. Non-hospitalized patients with COVID-19 experienced rapid symptom remission. Nanosilver solutions, due to anti-inflammatory, antiviral, and antimicrobial activity, may be effective for treating respiratory inflammation and infections caused by viruses and/or microbes.

The benefits and costs of U.S. employer COVID-19 vaccine mandates.

In 2021, the Biden Administration issued mandates requiring COVID-19 vaccinations for U.S. federal employees and contractors and for some healthcare and private sector workers. These mandates have been challenged in court; some have been halted or delayed. However, their costs and benefits have not been rigorously appraised. This study helps fill that gap. We estimate the direct costs and health-related benefits that would have accrued if these vaccination requirements had been implemented as intended. Compared with the January 2022 vaccination rates, we find that the mandates could have led to 15 million additional vaccinated individuals, increasing the overall proportion of the fully vaccinated U.S. population from 64% to 68%. The associated net benefits depend on the subsequent evolution of the pandemic-information unavailable ex ante to analysts or policymakers. In scenarios involving the emergence of a novel, more transmissible variant, against which vaccination and previous infection offer moderate protection, the estimated net benefits are potentially large. They reach almost $20,000 per additional vaccinated individual, with more than 20,000 total deaths averted over the 6-month period assessed. In scenarios involving a fading pandemic, existing vaccination-acquired or infection-acquired immunity provides sufficient protection, and the mandates' benefits are unlikely to exceed their costs. Thus, mandates may be most useful when the consequences of inaction are catastrophic. However, we do not compare the effects of mandates with alternative policies for increasing vaccination rates or for promoting other protective measures, which may receive stronger public support and be less likely to be overturned by litigation.

The Societal Value of Vaccines: Expert-Based Conceptual Framework and Methods Using COVID-19 Vaccines as a Case Study.

Health technology assessments (HTAs) of vaccines typically focus on the direct health benefits to individuals and healthcare systems. COVID-19 highlighted the widespread societal impact of infectious diseases and the value of vaccines in averting adverse clinical consequences and in maintaining or resuming social and economic activities. Using COVID-19 as a case study, this research work aimed to set forth a conceptual framework capturing the broader value elements of vaccines and to identify appropriate methods to quantify value elements not routinely considered in HTAs. A two-step approach was adopted, combining a targeted literature review and three rounds of expert elicitation based on a modified Delphi method, leading to a conceptual framework of 30 value elements related to broader health effects, societal and economic impact, public finances, and uncertainty value. When applying the framework to COVID-19 vaccines in post-pandemic settings, 13 value elements were consensually rated highly important by the experts for consideration in HTAs. The experts reviewed over 10 methods that could be leveraged to quantify broader value elements and provided technical forward-looking recommendations. Limitations of the framework and the identified methods were discussed. This study supplements ongoing efforts aimed towards a broader recognition of the full societal value of vaccines.

Female Gender Is Associated with Lower Satisfaction with Postoperative Telemedicine Visits in Sports Medicine.

Introduction: Telemedicine is a relatively new adjunct in orthopedic care but it has emerged from the periphery, driven in part by the COVID-19 pandemic. Although it has drastically increased in use, little is known of the factors that drive satisfaction with telemedicine. The purpose of the current study was to evaluate the patient's satisfaction with postoperative telemedicine visits in those undergoing knee or shoulder arthroscopy, and to analyze the factors associated with satisfaction with telemedicine. Methods: A prospective study was performed to evaluate satisfaction comparing postoperative telemedicine and in-office visits, in those undergoing shoulder and knee arthroscopy. Multiple factors were analyzed for correlation with satisfaction via multi-linear regression, including demographics such as gender, education, age, and race. Patients were also evaluated for preference for future visits with reference to the group in which they were placed. Results: Overall, 215 patients were included with a subgroup analysis of 93 patients receiving telemedicine visits. Patients reported overall similar satisfaction with telemedicine visits after shoulder and knee arthroscopy, with a high level of satisfaction seen in both. Female sex was found to be associated with decreasing satisfaction with telemedicine visits (p = 0.036). In addition, as a whole, the cohort was found to prefer future visits to be the same as the group they were placed in, but females statistically did not have this preference for their familiar group and were skewed toward the preference of in-person visits (p = 0.377). Conclusions: Our study found that female patients were less likely to be satisfied with postoperative telemedicine visits after knee or shoulder arthroscopy. Further, females were also less likely to indicate preference for future telemedicine visits. In contrast, education, history of prior surgery, age, and race were not associated with postoperative satisfaction.

Factors underlying COVID-19 vaccine and booster hesitancy and refusal, and incentivizing vaccine adoption.

The paper investigates the factors underlying COVID-19 vaccine and booster hesitancy in the United States, and the efficacy of various incentives or disincentives to expand uptake. We use cross-sectional, national survey data on 3,497 U.S. adults collected online from September 10, 2021 to October 20, 2021 through the Qualtrics platform. Results from a multinomial logistic regression reveal that hesitancy and refusal were greatest among those who expressed a lack of trust either in government or in the vaccine's efficacy (hesitancy relative risk ratio, or RRR: 2.86, 95% CI: 2.13-3.83, p<0.001). Hesitancy and refusal were lowest among those who typically get a flu vaccine (hesitancy RRR: 0.28, 95% CI: 0.21-0.36, p<0.001; refusal RRR: 0.08, 95% CI: 0.05-0.13, p<0.001). Similar results hold for the intention to get a booster shot among the fully vaccinated. Monetary rewards (i.e., lottery ticket and gift cards) fared poorly in moving people toward vaccination. In contrast, the prospect of job loss or increased health insurance premiums was found to significantly increase vaccine uptake, by 8.7 percentage points (p<0.001) and 9.4 percentage points (p<0.001), respectively. We also show that the motivations underlying individuals' hesitancy or refusal to get vaccinated vary, which, in turn, suggests that messaging must be refined and directed accordingly. Also, moving forward, it may be fruitful to more deeply study the intriguing possibility that expanding flu vaccine uptake may also enhance willingness to vaccinate in times of pandemics. Last, disincentives such as work-based vaccination mandates that would result in job loss or higher health insurance premiums for those who refuse vaccination should be strongly considered to improve vaccine uptake in the effort to address the common good.

Individual and Synergistic Anti-Coronavirus Activities of SOCS1/3 Antagonist and Interferon α1 Peptides.

Suppressors of Cytokine Signaling (SOCS) are intracellular proteins that negatively regulate the induction of cytokines. Amongst these, SOCS1 and SOCS3 are particularly involved in inhibition of various interferons. Several viruses have hijacked this regulatory pathway: by inducing SOCS1and 3 early in infection, they suppress the host immune response. Within the cell, SOCS1/3 binds and inhibits tyrosine kinases, such as JAK2 and TYK2. We have developed a cell penetrating peptide from the activation loop of the tyrosine kinase, JAK2 (residues 1001-1013), denoted as pJAK2 that acts as a decoy and suppresses SOCS1 and 3 activity. This peptide thereby protects against several viruses in cell culture and mouse models. Herein, we show that treatment with pJAK2 inhibited the replication and release of the beta coronavirus HuCoV-OC43 and reduced production of the viral RNA, as measured by RT-qPCR, Western blot and by immunohistochemistry. We confirmed induction of SOCS1 and 3 in rhabdomyosarcoma (RD) cells, and this induction was suppressed by pJAK2 peptide. A peptide derived from the C-terminus of IFNα (IFNα-C) also inhibited replication of OC43. Furthermore, IFNα-C plus pJAK2 provided more potent inhibition than either peptide alone. To extend this study to a pandemic beta-coronavirus, we determined that treatment of cells with pJAK2 inhibited replication and release of SARS-CoV-2 in Calu-3 cells. We propose that these peptides offer a new approach to therapy against the rapidly evolving strains of beta-coronaviruses.

The Approach to the COVID-19 Pandemic in Georgia-A Health Policy Analysis.

Objectives: This study aimed to analyze key COVID-19 pandemic-related policies and national strategic responses in light of Georgia's political, socioeconomic and cultural backgrounds. Methods: We applied a policy triangle framework for policy analysis, performed document and media content analysis, and described pandemic trends statistically. Results: Early introduction of stringent restrictive measures largely prevented a first wave in March-May 2020. This was communicated as a success story, prompting a public success perception. With unpopular restrictions lifted and hesitancy to embrace evidence-informed policymaking ahead of nationwide parliamentary elections, SARS-CoV-2 infection spread rapidly and was met with an insufficiently coordinated effort. Facing health system capacity saturation an almost complete lockdown was re-introduced in late 2020. Factors as delayed immunization campaign, insufficient coordination and, again, little evidence-informed policymaking eventually led to another devastating COVID-19 wave in summer of 2021. Conclusion: Georgia's pandemic health policy response was adversely impacted by a volatile political environment. National pandemic preparedness and response might benefit from an independent body with appointment procedures and operations shielded from political influences to effectively inform and communicate evidence-based pandemic policy.

Signaling Pathway Reporter Screen with SARS-CoV-2 Proteins Identifies nsp5 as a Repressor of p53 Activity.

The dysregulation of host signaling pathways plays a critical role in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and viral pathogenesis. While a number of viral proteins that can block type I IFN signaling have been identified, a comprehensive analysis of SARS-CoV-2 proteins in the regulation of other signaling pathways that can be critical for viral infection and its pathophysiology is still lacking. Here, we screened the effect of 21 SARS-CoV-2 proteins on 10 different host signaling pathways, namely, Wnt, p53, TGFß, c-Myc, Hypoxia, Hippo, AP-1, Notch, Oct4/Sox2, and NF-κB, using a luciferase reporter assay. As a result, we identified several SARS-CoV-2 proteins that could act as activators or inhibitors for distinct signaling pathways in the context of overexpression in HEK293T cells. We also provided evidence for p53 being an intrinsic host restriction factor of SARS-CoV-2. We found that the overexpression of p53 is capable of reducing virus production, while the main viral protease nsp5 can repress the transcriptional activity of p53, which depends on the protease function of nsp5. Taken together, our results provide a foundation for future studies, which can explore how the dysregulation of specific signaling pathways by SARS-CoV-2 proteins can control viral infection and pathogenesis.

Social Technology: An Interdisciplinary Approach to Improving Care for Older Adults.

Population aging is a defining demographic reality of our era. It is associated with an increase in the societal burden of delivering care to older adults with chronic conditions or frailty. How to integrate global population aging and technology development to help address the growing demands for care facing many aging societies is both a challenge and an opportunity for innovation. We propose a social technology approach that promotes use of technologies to assist individuals, families, and communities to cope more effectively with the disabilities of older adults who can no longer live independently due to dementia, serious mental illness, and multiple chronic health problems. The main contributions of the social technology approach include: (1) fostering multidisciplinary collaboration among social scientists, engineers, and healthcare experts; (2) including ethical and humanistic standards in creating and evaluating innovations; (3) improving social systems through working with those who deliver, manage, and design older adult care services; (4) promoting social justice through social policy research and innovation, particularly for disadvantaged groups; (5) fostering social integration by creating age-friendly and intergenerational programs; and (6) seeking global benefit by identifying and generalizing best practices. As an emergent, experimental approach, social technology requires systematic evaluation in an iterative process to refine its relevance and uses in different local settings. By linking technological interventions to the social and cultural systems of older people, we aim to help technological advances become an organic part of the complex social world that supports and sustains care delivery to older adults in need.