MECHANISM AND RESISTANCE STUDIES OF SARS-CoV-2 MPRO INHIBITOR POMOTRELVIR (PBI-0451)

Background: The unprecedented scale of the COVID-19 pandemic and rapid evolution of SARS-CoV-2 variants underscores the need for broadly active inhibitors with a high barrier to resistance. The coronavirus main protease (Mpro) is an essential viral enzyme required for viral polyprotein processing and is highly conserved across human coronaviruses. Pomotrelvir (PBI-0451) is a novel Mpro inhibitor currently completing phase 2 clinical trial. Here we describe the mechanism of action, broad activity against SARS-CoV-2 clinical isolates, combination studies with other SARS-CoV-2 inhibitors and favorable resistance profile of pomotrelvir. Method(s): The kinetic parameters of pomotrelvir Mpro inhibition and its interaction with nirmaltrevir were determined in a kinetic protease assay. The IC50s of pomotrelvir on mutant Mpro proteins were measured in an endpoint Mpro assay. Combination studies of pomotrelvir with remdesivir and molnupiravir were carried out in A549-hACE2 cells infected with SARS-CoV-2 NLuc virus. Activity against SARS-CoV-2 clinical variants was assessed by infection of A549-ACE2-TMPRSS2 cells followed by immunostaining of the viral nucleocapsid protein. Result(s): Pomotrelvir is a potent competitive inhibitor of SARS-CoV-2 Mpro (Ki =2.7 nM). Binding of pomotrelvir and the Mpro inhibitor nirmatrelvir to the active site is mutually exclusive. In the SARS-CoV-2 NLuc assay, pomotrelvir is additive when combined with remdesivir or molnupiravir, two nucleoside analogs targeting viral RNA synthesis. When the effect of Mpro substitutions previously selected in a resistance study of pomotrelvir were analyzed in an enzyme assay, only Mpro-N133H showed a significant increase in IC50 (45-fold). The catalytic efficiency of Mpro-N133H is reduced by 10-fold and the recombinant virus SARSCoV-2 (WA1) -N133H is not viable, suggesting that N133H has lower replicative fitness. Lastly, pomotrelvir exhibits broad activity against all SARS-CoV-2 clinical isolates tested to date, including five omicron variants. Conclusion(s): PBI-0451 is a potent competitive inhibitor of SARS-CoV-2 Mpro and is broadly active against SARS-CoV-2 clinical isolates including omicron variants. Results from inhibitor interaction studies support the potential combination of pomotrelvir with remdesivir and molnupiravir but not nirmatrelvir. Enzymatic characterization of in vitro selected pomotrelvir resistant variants indicates they either confer no resistance or have reduced fitness.

Necessary adaptations of infection control measures in nursing homes and homes for the elderly - Results of an expert discussion in relation to the experience with the COVID 19 pandemic

The effects of the COVID-19 pandemic were particularly noticeable in the nursing homes. As part of an expert discussion, challenges and recommendations for future strategies in dealing with the pandemic in homes were discussed. Selected aspects are presented in this article. © 2022 mhp-Verlag GmbH. All rights reserved.

Opportunities to increase the attractiveness of the German Public Health Service as an employer : Laura Arnold

For decades, the public health service in Germany (PHS) experienced shortages of young professionals and challenges in recruiting qualified personnel. To sustainably counteract this challenge, it is necessary to understand the reasons of the perceived low attractiveness of PHS as a potential employer among students and young professionals. Two cross-sectional online surveys were conducted to assess the attitudes of medical, public health, and health science students towards the PHS as a potential employer. Wave 1, conducted from 2019-12 to 2020-04, focused on factors associated with high and with low interest in working for the PHS. Wave 2 was conducted from 2020-06 to 2020-09 to capture changes that may have resulted from the newfound attention of the PHS during the SARS-CoV-2 pandemic. Participants in both waves were asked about opportunities to increase the attractiveness of the PHS, which were analyzed using qualitative content analysis. In total 3040 students participated. Low interest in the PHS was associated with limited knowledge about public health, primary interest in clinical medicine, and a negative image of the public service. The qualitative analysis indicated as major obstacles: low visibility of and low awareness about the PHS, a perception of hierarchical and bureaucratic workplaces, and perceptions of repetitive occupations, among others. The participants suggested: improving awareness about the PHS in the population, including PHS in curriculum, and reducing entry barriers for non-medical students. The results of the largest survey of students on the attractiveness of the ÖGD in Germany provide valuable insights for ongoing reform processes. In addition to approaches to increase external visibility, existing processes and procedures within the ÖGD should be considered. Key messages • To counteract the shortage of skilled workers, the PHS must become more attractive to young professionals. This requires both, greater external visibility and modernization of internal structures. • Successful inclusion of the perspective of young professionals in the current modernization processes introduces opportunities to increase the attractiveness of the PHS in the long-term.

WICID 2.0: Integrating evidence and ethics in decisionmaking and guideline development on SARS-CoV-2 : Jan Stratil

Evidence-informed decision-making (EIDM) requires the balancing of numerous and often conflicting factors. During the SARS-CoV-2 pandemic, sound and fair EIDM procedures were challenged by time constraints and limited evidence. Beneficial effects had to be weight against public health impacts beyond COVID-19, broad societal consequences, or individual liberties. Evidence-to-decision (EtD) frameworks are neither able nor intended to replace stakeholder participation, but can serve as a tool to ensure the relevance and completeness of criteria to be considered for EIDM in public health and guideline development. Employing ‘best-fit’ framework synthesis, we used the WHO-INTEGRATE framework as a starting point to develop the WHO-INTEGRATE COVID-19 framework version 1.0. WICID 1.0 is based on a content analysis of comprehensive strategy documents to guide policy makers in implementing new or decrease existing measures to protect against COVID-19 in Germany. WICID 1.0 was validated by coding the framework against an updated set of the key strategy documents, and key strategy documents addressing non-pharmacological measures in long-term care facilities. In total, 12 key strategy documents were analysed to develop WICID 1.0, and 18 + 23 documents were analyzed for its refinement towards WICID 2.0. The revised framework consists of 11 + 1 criteria and includes implications for the health of individuals and populations due to and beyond COVID-19, infringement on liberties and fundamental human rights, acceptability and equity considerations, societal, environmental and economic implications, as well as implementation, resource and feasibility considerations. Validation found high consistency with minor revisions between WICID 1.0 and 2.0. WICID can be a tool to support researchers, practitioners, and policy makers to systematically integrate evidence and ethics and to balance of health, societal and other considerations when reflecting on PH interventions targeting COVID-19. Key messages • Due to the rapidly developing pandemic, decision-making process often did not include the views of all affected stakeholders and did not adequately include all criteria and considerations of relevance. • The WICID Framework can serve as a tool to support decision-makers in accounting for relevant considerations and criteria, even when not all stakeholders could be included.

How to improve the attractiveness of the German Public Health Service as a future employer - Results of two cross-sectional surveys among medical and public health students

Einleitung The Public Health Service in Germany (PHS, German: ÖGD) has been suffering from a significant shortage of young professionals for decades. An issue likely to intensify in the coming years due to demographic processes. This applies not only, but especially, to the municipal level. The reasons for the perceived low attractiveness of the PHS as a potential employer have been widely discussed, but so far, no empirical data is available. Therefore, the German Network of Young Professionals in Public Health (German: NOEG), has set up a study to analyze the attractiveness of the PHS as a potential employer for young professionals. Methoden We conducted two cross-sectional surveys to assess the requirements and expectations of students in PHSrelevant fields of study with regard to their future employers. The first survey (wave 1) was conducted from December 2019 to April 2020 and focused on wishes and expectations of medical, public health, and health science students regarding their prospective jobs and employers. It was postulated that the various roles and activities of the public health workforce within the PHS are of interest to many students but are not considered as potential fields of employment for a variety of reasons. The second survey (wave 2) was conducted from June to September 2020 to be able to address any changes that may have resulted from the newfound attention on the PHS during the coronavirus crisis, to identify changes in the evaluation of the PHS as a potential employer form a young professional perspective. Ergebnisse In the wave 1, 2456 students participated, with an additional 584 taking part in wave 2. Medical students were less likely to report interest in working for the PHS in comparison with public health students and students of other health sciences. The vast majority of those medical students that considered the PHS as a potential employer reported their main interest as working in primary health care. Public health students and other students have experienced barriers when seeking jobs in the PHS. The respondees reported on a number of domains contributing to a low attractiveness of the PHS as an employer, such as the PHS being perceived as antiquated, inefficient and slow, the occupations consisting of too much braucracy, and limited career opportunities. Suggestions for improvement included a stronger occupational focus on prevention, health promotion and public health impact, modernization and digitalization, as well as providing attractive job offers for candidates without a professional training in medicine. Schlussfolgerung The results of this largest survey regarding the attractivenss of the German PHS among students provide valuable insights for the reform of the German PHS. We synthesized a number of suggestions for reform, among others regarding training and education, occupation in the PHS, adminstrative processes, and career opportunities.

PBI-0451 AN ORALLY ADMINISTERED 3CL PROTEASE INHIBITOR of SARS-CoV-2 for COVID-19

Background: The 3CL protease (3CLpro) of coronaviruses (CoV) is responsible for essential & early steps of viral replication. Early treatment of SARS-CoV2 infection with a 3CLpro inhibitor has shown to substantially reduce the rate of hospitalization & death from COVID-19. There is a need for a protease inhibitor that can be used as a stand-alone agent to treat and prevent SARS-CoV-2 infection globally, in the setting of remote testing & healthcare delivery, and as unsupervised outpatient use by a significant number of people who take other medications. Methods: PBI-0451 was assessed in cultures of inducible pluripotent stem cell-derived alveolar type II (iPS-AT2) cells, in nonclinical PK and toxicity studies, and an ongoing randomized, double-blind first-in-human (FIH) study evaluating the tolerability, safety, and PK of single and multiple doses administered as an oral suspension to healthy adult subjects. The effect of food and the potential for a drug-drug interaction (DDI) with ritonavir were also explored. Results: PBI-0451 potently inhibited SARS-CoV-2 replication in iPS-AT2 cells with multi-log reductions in viral titer and mean (SD) IC50 & EC90 values of 32 (25) & 106 (90) nM, respectively. No clinically relevant adverse effects of PBI-0451 were observed in 14-day GLP toxicity studies in mice and dogs, including on the cardiovascular, CNS, or respiratory systems. PBI-0451 was not genotoxic in Ames and micronucleus tests. In the ongoing FIH study to date, study treatments were generally well tolerated with no study drug or study discontinuations. No Grade 2, 3, 4, or severe adverse events were reported. Preliminary single-dose concentration-time profile of PBI-0451 following administration with food demonstrated a 2-compartment PK profile with a median terminal elimination t1/2 ranging from 11-14 hours. PBI-0451 demonstrated good oral bioavailability and a linear increase in exposure over a 10-fold dose range when administered with food, achieving concentrations >1-, 3-& 10-fold the plasma protein binding-adjusted EC90 value (374 ng/mL) against SARS-CoV-2 at doses of 100, 300 & 1050 mg, respectively. The PK of PBI-0451 was unaffected by coadministration with ritonavir. Conclusion: PBI-0451 has shown favorable nonclinical properties and early clinical safety & PK that supports its continued evaluation as a stand-alone agent. Ongoing multiple-dose evaluation will further elucidate its clinical profile and inform the dose & dosing regimen selection for potential Phase II/III studies.

Exploring How COVID-19 Shapes the Professional Identities of South African Student Teachers

This article contributes to the literature on teacher identities by exploring how the pandemic affected the professional identities of final year student teachers at a South African university. The researchers collected journals and interviews from seven participants, and analysed the data through thematic analysis. The findings show that the participants' professional identities were enhanced or negatively affected by teaching in a pandemic. The participants whose professional identities were strengthened became more caring and hard working to support learners who had missed several months of school. Other participants, whose professional identities had been negatively affected by the lack of teaching practice, felt less confident and prepared to become teachers. While all the participants struggled with a heavy teaching load, one participant felt that the sheer amount of work prevented him from becoming a "relational" teacher. Schools and universities might strengthen pre-service teachers' professional identities development by discussing what support student teachers require to enact their preferred professional identities during the COVID-19 pandemic. © 2022 Society for Research and Knowledge Management. All right reserved.

Micronutrients for Attention-Deficit/Hyperactivity Disorder in Youths: A Placebo-Controlled Randomized Clinical Trial.

OBJECTIVE: To evaluate whether micronutrients (vitamins/minerals) benefit attention-deficit/hyperactivity disorder (ADHD) and irritability in a North American pediatric sample. METHOD: A 3-site, 8-week, placebo-controlled, randomized clinical trial of micronutrients was conducted in nonmedicated children aged 6 to 12 years with ADHD and at least 1 impairing irritability symptom by parent report on the Child and Adolescent Symptom Inventory-5 (CASI-5). A priori-defined primary outcomes were Clinical Global Impression-Improvement (CGI-I) (CGI-I of 1 or 2 = treatment responder) and parent-rated CASI-5 composite score of ADHD, oppositional defiant, disruptive mood dysregulation, and peer conflict symptoms, including impairment scores. RESULTS: Of 135 randomized (mean age 9.8 years), 126 youths (93%) comprised the modified intention-to-treat population. Blinding was maintained. For the CGI-I, 54% of the micronutrient and 18% of the placebo group were responders (risk ratio = 2.97, 97.5% CI = 1.50, 5.90, p < .001). CASI-5 composite scores improved significantly for both groups (p < .01), with a mean change of -0.31 (95% CI = -0.39, -0.23) in the micronutrient group and a mean change of -0.28 (95% CI = -0.38, -0.19) in the placebo group. However, the between-group difference was not significant (mean change = -0.02; 97.5% CI = -0.16, 0.12, effect size = 0.07, p = .70). The micronutrient group grew 6 mm more than the placebo group (p = .002). No serious adverse events or clinically significant changes from baseline in blood and urine tests occurred. CONCLUSION: Micronutrients showed global benefit over placebo by blinded clinician rating, but not by parent-report CASI-5 composite rating in a population with ADHD and irritability. Micronutrients showed greater height growth. Micronutrients were well tolerated, and the majority of participants adhered to the number of capsules prescribed. This randomized controlled trial replicates safety and efficacy reported for ADHD in 2 smaller trials of a similar formula containing all vitamins and known essential minerals in amounts between the Recommended Dietary Allowance and Upper Tolerable Intake Level. CLINICAL TRIAL REGISTRATION INFORMATION: Micronutrients for ADHD in Youth (MADDY) Study; https://clinicaltrials.gov; NCT03252522.

Incidence and Durability of SARS-CoV-2 Antibodies in Patients with Cancer and Health Care Workers following the First Wave of the Pandemic.

BACKGROUND: Patients with cancer and health care workers (HCW) are at higher risk for SARS-CoV-2 infection. There are limited data regarding the rate of symptomatic versus asymptomatic infection and subsequent seropositivity in both populations. METHODS: We performed a prospective study of patients and HCW across two institutions during the first wave of the pandemic to analyze the prevalence of SARS-CoV-2 antibodies, the extent of associated symptoms, and durability of serologic response. RESULTS: In 1,953 persons (733 patients and 1,220 HCW), overall seropositivity rates for 3.1% patients (95% CI 2.0-4.7) and 3.7% HCW (95% CI 2.7-4.9, p=0.520), were similar. Each institutions' seropositivity rates were numerically higher in HCW than patients. Non-Hispanic Whites and Asians had lower antibody rates (2.8%, 95% CI 2.0-3.8 and 3.3%, 95% CI 1.2-7.0) compared to Hispanics (6.9%, 95% CI 3.4-12.4) and non-Hispanic Blacks (5.9%, 95% CI 3.3-9.7), p < 0.001. Among persons with a positive SARS-CoV-2 antibody, 87% of patients and 56% of HCW did not recall having had a fever. Among HCW, administrative and technical personnel were most likely to be seropositive. The rate of persistent seropositivity at 3 months was similar between patients and HCW and was not influenced by the reporting of fever, cancer type, or therapy. CONCLUSION: These data suggest that patients are not at higher risk for febrile SARS-CoV-2 infections or more transient immunity than HCWs. Furthermore, racial differences and lack of association with the extent of HCW contact with COVID-19 patients suggest that community rather than hospital virus exposure was a source of many infections.

Impact of novel microbial secondary metabolites on the pharma industry.

Microorganisms are remarkable producers of a wide diversity of natural products that significantly improve human health and well-being. Currently, these natural products comprise half of all the pharmaceuticals on the market. After the discovery of penicillin by Alexander Fleming 85 years ago, the search for and study of antibiotics began to gain relevance as drugs. Since then, antibiotics have played a valuable role in treating infectious diseases and have saved many human lives. New molecules with anticancer, hypocholesterolemic, and immunosuppressive activity have now been introduced to treat other relevant diseases. Smaller biotechnology companies and academic laboratories generate novel antibiotics and other secondary metabolites that big pharmaceutical companies no longer develop. The purpose of this review is to illustrate some of the recent developments and to show the potential that some modern technologies like metagenomics and genome mining offer for the discovery and development of new molecules, with different functions like therapeutic alternatives needed to overcome current severe problems, such as the SARS-CoV-2 pandemic, antibiotic resistance, and other emerging diseases. KEY POINTS: • Novel alternatives for the treatment of infections caused by bacteria, fungi, and viruses. • Second wave of efforts of microbial origin against SARS-CoV-2 and related variants. • Microbial drugs used in clinical practice as hypocholesterolemic agents, immunosuppressants, and anticancer therapy.

Political reform process in the course of the COVID 19 pandemic: The pact for public health services

The German federal and state governments have agreed on a 4 billion euro pact for the Public Health Services (ÖGD) to strengthen the ÖGD in terms of personnel and infrastructure. The sustainable strengthening of the ÖGD plays a central role to ensure health protection measures for crisis management. In order for the ÖGD to be able to fulfil its complex task of providing high-quality health care on site in the long term, it will be necessary to optimize existing structures so that acute threat situations as well as more long-term and strategically oriented planning tasks can be mastered. © 2021 De Gruyter. All rights reserved.

Prevention policy - Not just a topic for the health department

Effective health promotion and prevention measures address overarching, structural risk factors for communicable and non-communicable diseases. These are mostly located outside the health sector and require a Health in All Policies approach. The worldwide spread of the SARS-CoV-2 virus illustrates the need for an intersectoral prevention policy with a clear HiAP perspective and political institutional manifestation.

Implementation of the German Prevention Act: Municipal Public Health Units as a Bottleneck?

Background The German Prevention Act (PrävG) came into force in 2015. As a federal law, it remains vague with regard to municipal structure. The municipalities, as those public health units that have direct access to the living environment, play a central role in the implementation of health promotion and prevention. The evaluation by the National Prevention Conference in 2019 showed that the involvement of the municipal public health services (ÖGD) has not yet been sufficiently achieved. A major problem is the heterogeneity of ÖGD units in Germany's federal structure, about which little information is available. Methods In order to fully capture this heterogeneity for the first time, a systematic online screening was carried out. For this purpose, the websites of all 358 ÖGD units were screened independently of two researchers according to structural conditions. Results 70% of all municipal ÖGD units are located at district level, 18% at city district level and 12% cumulatively. Population varies from 35,000 to about 1.5 million inhabitants. The allocation of the ÖGD units to youth service planning and social welfare varies in the federal states from 18.7% to 94.4%, within regulatory agency and veterinary office from 27.8% to 79.2%. Conclusions The heterogeneity makes the establishment of municipal standards difficult. Due to the diverse administrative allocation, different levels of policy-making must be considered on the way to health in all policies. The political classification reflects in roughly equal parts an ÖGD orientation towards health protection or social determinants of health, as recommended for the PrävG. A one-sided orientation towards health protection was shown by the temporary suspension of the use of financial resources for prevention in the course of the 2nd pandemic law to combat the COVID-19 pandemic. For the announced reform of the German ÖGD it is necessary to homogenize essential structural characteristics and to prevent a one-sided orientation. Key messages The heterogeneity of municipal health services makes it difficult to implement the German Prevention Act. In the course of the upcoming ÖGD reform, essential structural characteristics should be homogenized and a one-sided orientation of the municipal ÖGD units towards health protection should be avoided.

HIAP after CoviD-19: A perspective of the German network of young professionals in public health

In this article, members of the German Network of Young Professionals in Public Health, discuss the opportunities and challenges of the Health in All Policies (HiAP) approach, in view of the current COVID-19 pandemic. It outlines various perspectives, from the interaction and cooperation of different policy areas to the national Public Health Service.