A Coadunation of Biological and Mathematical Perspectives on the Pandemic COVID-19: A Review

Background: Coronavirus disease 2019 (COVID-19) outbreak has created an emergency globally, and social distancing and isolation are the only solution to prevent its spread. Several countries have announced a full lockdown to tackle this pandemic. The coronavirus family is inclu-sive of pathogens of both-animal species and humans, encapsulating the isolated severe acute respiratory syndrome coronavirus (SARS-CoV). Researchers around the globe have been dexterously working to decode this lethal virus. Many mathematical frameworks have also been depicted, which have helped to understand the dynamics of the COVID-19. Method(s): This systematic review highlights the virus genomic composition, preliminary phylogenetic analysis, pathogenesis, symptomatology, diagnosis, and prognosis along with mathematical models of disease transmission and dynamics. Result(s): Our preliminary phylogenetic analysis of the novel coronavirus sequence discerns that al-though shares its lineage with SARS, BAT-CoV, Beta-BAT-SARS, however, this protein is highly dissimilar to its ancestors. The widely prominent amino acid residues found in the protein are ala-nine (ALA), aspartic acid (ASP), phenylalanine (PHE), leucine (LEU), aspartic acid (ASP), threo-nine (THR), valine (VAL), tyrosine (TYR) and asparagine (ASN) that are responsible for its replication process. Conclusion(s): Research on coronaviruses continues towards developing a strong understanding of the rapidly evolving viral replication and its transmission between individuals.Copyright © 2021 Bentham Science Publishers.

The effect of the COVID-19 pandemic on newborn hyperphenylalaninemia screening program

Phenylketonuria is an inherited metabolic disease that can be treated if detected early and can easily be screened with phenylalanine as a biomarker. Phenylketonuria is included in the National Neonatal Screening Program. We aimed to investigate the possible effects of the pandemic on phenylketonuria screening in our country during coronavirus disease 2019 (COVID-19) era. We retrospectively evaluated patients who were referred to our center due to elevated blood phenylalanine levels detected by national screening program retrospective- and prospectively within one-year as of 11 March 2020, the date when first COVID-19 case was detected in our country. Multivariate analysis showed birth region and phenylalanine levels to be independently associated with the time period until the first admission to hospital, but none of the parameters were significantly associated with the pandemic. There was no evidence that the COVID-19 pandemic affected the screening of newborn phenylketonuria, however since the data was limited to our center and to draw generalized conclusions larger scaled multicentric studies are needed.

Interferon-gamma Mediated Metabolic Pathways in Hospitalized Patients During Acute and Reconvalescent COVID-19.

Background: Fatigue, sleep disturbance, and neurological symptoms during and after COVID-19 are common and might be associated with inflammation-induced changes in tryptophan (Trp) and phenylalanine (Phe) metabolism. Aim: This pilot study investigated interferon gamma inducible biochemical pathways (namely Trp catabolism, neopterin, tyrosine [Tyr], and nitrite formation) during acute COVID-19 and reconvalescence. Patients and methods: Thirty one patients with moderate to severe COVID-19 admitted to the University Hospital of Innsbruck in early 2020 (March-May) were followed up. Neurotransmitter precursors Trp, Phe, Tyr as well as kynurenine (Kyn), neopterin, nitrite, and routine laboratory parameters were analyzed during acute infection and at a follow-up (FU) 60 days thereafter. Clinical symptoms of patients (neurological symptoms, fatigue, sleep disturbance) were recorded and associations with concentrations of laboratory parameters investigated. Results and conclusion: Almost half of the patients suffered from neurological symptoms (48.4%), the majority of patients experienced sleep difficulties (56.7%) during acute COVID-19. Fatigue was present in nearly all patients. C-reactive protein (CRP), interleukin-6 (IL-6), neopterin, Kyn, Phe concentrations were significantly increased, and Trp levels depleted during acute COVID-19. Patients with sleep impairment and neurological symptoms during acute illness presented with increased CRP and IL-6 concentrations, Trp levels were lower in patients with sleep disturbance. In general, inflammatory markers declined during reconvalescence. A high percentage of patients suffered from persistent symptoms at FU (neurological symptoms: 17.2%, fatigue: 51.7%, sleeping disturbance: 34.5%) and had higher CRP concentrations. Nitrite and Phe levels were lower in patients with sleeping difficulties at FU and Kyn/Trp ratio, as indicator of IDO activity, was significantly lower in patients with neurological symptoms compared to patients without them at FU. In summary, inflammation induced alterations of amino acid metabolism might be related to acute and persisting symptoms of COVID-19.

Phenylalanine metabolism and tetrahydrobiopterin bio-availability in COVID-19 and HIV.

Various metabolomics studies have reported increased phenylalanine serum concentrations in SARS-CoV-2 positive cases and have correlated increased phenylalanine with COVID-19 severity. In this study, we report similar results based upon metabolomics analysis of serum collected from a South African cohort of adults with confirmed COVID-19. The novelty of this study is the inclusion of HIV positive cases in the African context. We found that pre-existing HIV co-infection exacerbates the disruption of phenylalanine metabolism in COVID-19. What is lacking in literature is biological context and deeper understanding of perturbed phenylalanine metabolism in COVID-19. We delve deep into the metabolism of phenylalanine in COVID-19 and posit new insights for COVID-19 cases co-infected with HIV; namely, HIV-COVID-19 co-infected individuals do not have sufficient bioavailability of tetrahydrobiopterin (BH4). Hence, we identify BH4 as a potential supplement to alleviate/lessen COVID-19 symptoms.

Starting the conversation on gene therapy for phenylketonuria: Current perspectives of patients, caregivers, and advocates.

Phenylketonuria (PKU) is a rare genetic condition caused by inborn error(s) in the gene for the enzyme phenylalanine hydroxylase. Resulting loss of phenylalanine (Phe) metabolism requires strict dietary therapy and/or medication to prevent toxic accumulation of Phe. Novel investigational therapies, including gene therapies that aim to address underlying causes of PKU, are now entering clinical trials. However, perceptions of this technology in the PKU community have not been assessed. We conducted a qualitative survey recruiting adult patients, caregivers, and patient advocates from the US and 3 EU countries to assess the impact of living with PKU and the perceptions of gene therapy. Telephone interviews were conducted for up to 60 min following a standardized discussion guide. Interviewers classified each participant by their level of knowledge regarding gene therapy as either: low (little or no prior awareness); moderate (awareness of gene therapy as a concept in PKU); or high (working knowledge of gene therapy, e.g., vectors). In total, 33 participants were recruited (patients, n = 24; caregivers, n = 5; advocates, n = 4). The patient sample was well balanced among age groups, sex, and US/EU geographies. The participants' experiences and burden of living with PKU were largely negative, characterized by frustrations with current management consistent with prior reports. Most participants (n = 18/33) were identified as displaying moderate gene-therapy knowledge, 10/33 as displaying high knowledge, and 5/33 as displaying low knowledge. Both positive and negative perceptions were observed; positive perceptions were often linked to "hope" that gene therapy may represent a cure, whereas negative perceptions were linked to the "uncertainty" of outcomes. High knowledge of gene therapy appeared to trend with negative perceptions; 7/10 participants from this group reported high levels of concern over gene therapy. In contrast, participants who displayed low knowledge reported low (n = 3/5) or moderate (n = 2/5) concern, with predominantly positive perceptions. These data highlight the need for education around the theoretical risk:benefit profile of gene therapy. Despite current unknowns around gene therapy, our study demonstrates the important role of healthcare providers as educators who can use available data to provide balanced information to patients and caregivers.

Anti-inflammatory and antiviral activities of flavone C-glycosides of Lophatherum gracile for COVID-19.

Lophatherum gracile (L. gracile) has long been used as a functional food and herbal medicine. Previous studies have demonstrated that extracts of L. gracile attenuate inflammatory response and inhibit SARS-CoV-2 replication; however, the underlying active constituents have yet to be identified. This study investigated the bioactive components of L. gracile. Flavone C-glycosides of L. gracile were found to dominate both anti-inflammatory and antiviral effects. A simple chromatography-based method was developed to obtain flavone C-glycoside-enriched extract (FlavoLG) from L. gracile. FlavoLG and its major flavone C-glycoside isoorientin were shown to restrict respiratory bursts and the formation of neutrophil extracellular traps in activated human neutrophils. FlavoLG and isoorientin were also shown to inhibit SARS-CoV-2 pseudovirus infection by interfering with the binding of the SARS-CoV-2 spike on ACE2. These results provide scientific evidence indicating the efficacy of L. gracile as a potential supplement for treating neutrophil-associated COVID-19.

Ivermectin Affects Neutrophil-Induced Inflammation through Inhibition of Hydroxylysine but Stimulation of Cathepsin G and Phenylalanine Secretion.

The invasion and integrin-dependent adhesion of neutrophils to lung tissues and their secretion lead to the development of pneumonia in various pulmonary pathologies, including acute respiratory distress syndrome in coronavirus disease. We studied the effect of ivermectin, a possible therapeutic agent for inflammation and cancer, on integrin-dependent neutrophil adhesion to fibronectin and the concomitant secretion. Ivermectin did not affect the attachment of neutrophils to the substrate and the reactive oxygen species production but sharply inhibited the adhesion-induced release of hydroxylysine and stimulated the release of phenylalanine and cathepsin G. Hydroxylysine is a product of lysyl hydroxylase, which is overexpressed in tumor cells with an increased ability to invade and metastasize. The inhibition of hydroxylysine release by ivermectin, by analogy, may indicate the suppression of neutrophil invasion into tissue. The increase in the release of phenylalanine in our experiments coincided with the secretion of cathepsin G, which indicates the possible role of this enzyme in the cleavage of phenylalanine. What is the substrate in such a reaction is unknown. We demonstrated that exogenously added angiotensin II (1-8) can serve as a substrate for phenylalanine cleavage. Mass spectrometry revealed the formation of angiotensin II (1-7) in the secretion of neutrophils, which attached to fibronectin in the presence of ivermectin and exogenous angiotensin II (1-8), indicating a possible involvement of ivermectin in the inactivation of angiotensin II.

Metabolic Reprogramming in SARS-CoV-2 Infection Impacts the Outcome of COVID-19 Patients.

Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection triggers inflammatory clinical stages that affect the outcome of patients with coronavirus disease 2019 (COVID-19). Disease severity may be associated with a metabolic imbalance related to amino acids, lipids, and energy-generating pathways. The aim of this study was to characterize the profile of amino acids and acylcarnitines in COVID-19 patients. A multicenter, cross-sectional study was carried out. A total of 453 individuals were classified by disease severity. Levels of 11 amino acids, 31 acylcarnitines, and succinylacetone in serum samples were analyzed by electrospray ionization-triple quadrupole tandem mass spectrometry. Different clusters were observed in partial least squares discriminant analysis, with phenylalanine, alanine, citrulline, proline, and succinylacetone providing the major contribution to the variability in each cluster (variable importance in the projection >1.5). In logistic models adjusted by age, sex, type 2 diabetes mellitus, hypertension, and nutritional status, phenylalanine was associated with critical outcomes (odds ratio=5.3 (95% CI 3.16-9.2) in the severe vs. critical model, with an area under the curve of 0.84 (95% CI 0.77-0.90). In conclusion the metabolic imbalance in COVID-19 patients might affect disease progression. This work shows an association of phenylalanine with critical outcomes in COVID-19 patients, highlighting phenylalanine as a potential metabolic biomarker of disease severity.

Antimicrobial activity of quaternary ammonium salts: structure-activity relationship

Compounds with antimicrobial activity have gained much attention in research due to the outbreak of coronavirus disease 2019 (COVID-19). Quaternary ammonium salts (QASs) are an emerging group of antibacterial agents that are used as disinfectants. Many studies have been carried out involving the applications of QASs as antifouling agents for the inhibition of biofilm growth on medical implants and antibacterials on surfaces and in an aquatic environment. In investigating the antibacterial activity of QASs, we addressed the structure-activity relationship and the physicochemical factors. This review is focused on the fine-tuning of the chemical structures of QASs for their applications as wide antibacterial agents. [GRAPHICS] .

eP276: Development of an overdue outreach program to improve adherence to phenylketonuria management

Introduction: Phenylketonuria (PKU) is an inherited autosomal recessive disorder caused by variants in the PAH gene which encodes for phenylalanine hydroxylase (PAH). PAH deficiency leads to phenylalanine (Phe) accumulation, which untreated can cause intellectual disability, microcephaly, delayed speech, seizures, psychiatric symptoms, and behavioral abnormalities. Early detection of elevated Phe through newborn screening allows for rapid initiation of a Phe-restricted diet to prevent severe neurological outcomes;however, suboptimal Phe control throughout the lifespan is associated with increased rates of psychiatric illness and deficits in executive function even in early treated patients. Lifelong management of PKU is challenging, and it is well documented that many adult patients become lost to follow-up, despite the American College of Medical Genetics recommendation for lifelong management. Here we describe and evaluate efforts to improve follow-up care for patients with PKU of all ages at one center through formalization of clinic guidelines and creation of an overdue outreach program. Methods: The PKU clinic team is a multidisciplinary team consisting of an APN Director, physician, dieticians, diet tech, genetic counselor, registered nurse, and social worker. Regular meetings were scheduled with all clinic staff members to review PKU treatment guidelines, recommended lab monitoring, and visit frequency. After establishing formal guidelines, algorithms were created to determine thresholds for initiating patient outreach based on both age and type of PKU treatment. EMR-based data collection is used to track adherence to both clinic visits and consistent submission of Phe levels. Data was collected and analyzed for Lurie Children’s PKU program, which consists of roughly 250 patients. Baseline levels for adherence to clinic visits and filter card submission were collected at time of implementation. Data was then collected and analyzed initially after 18 months, and has been further analyzed for a second 18 months (which correlates with the start of the COVID-19 pandemic). Results: Overall baseline adherence across the PKU patient population for annual clinic visits was 72% (144/200). Clinic visit adherence increased to 88% at 18 months, and then was essentially unchanged at 86% through COVID-19 pandemic. In the pediatric patient population, annual clinic follow-up adherence was 92% (79/86) at baseline, which increased to 98% with implementation and maintained 98% during the pandemic. In the adult patient population, 54% (57/106) were adherent at baseline with clinic follow-up. With implementation compliance increased to 80% initially and was then reported to be 74% during the pandemic. Baseline for all PKU patients showed 81% (161/200) filter card submission within the last 12 months. Submission increased to 91% after 18 months of overdue outreach, and as of October 2021, 85% of all patients had submitted a filter card within the last calendar year. Adult patients specifically showed an increase, with 53% at baseline to 69% after implementation. Hyperphenylalaninemia (hyperphe) patients over the age of 2 showed an 18% (5/28) submission at baseline. With the overdue outreach program, this increased to 31% of patients initially and has further increased to 39%. Clinic visits for patients greater than 7 years old rose from 13% (3/24) initially to 57% and has further increased to 67%. Conclusion: Implementation of a coordinated overdue outreach program is successful in re-engaging patients with the PKU clinic and improving adherence to treatment recommendations. We have seen increased patient adherence across all domains, and have maintained this improved adherence despite the global COVID-19 pandemic. We believe that integrating overdue outreach guidelines into clinical practice is a replicable model for PKU clinics.

From PKU Online Lessons for Dietetics Students to the PKU Sandwiches Album

The purpose of the manuscript is to present to academic teachers, doctors and nutritionists how practical online classes with dietetics students can be used to develop ready-made tools at work and for the education of phenylketonuria (PKU) patients and their caregivers/parents. During online classes in 2020, as part of the subject—diet therapy of metabolic blocks, 53 students prepared PKU sandwiches at home. Each PKU sandwich has a calculated nutritional value, and phenylalanine exchanger content, but does not include low-protein bread. The selection of a particular type of PKU bread depends solely on the PKU patient, hence it was deliberately not included in the calculations. The sandwiches, made by students and assessed by academic teachers, will be published with the following title “The PKU Sandwiches Album”. The Album with more than 400 colorful pictures of PKU sandwiches, will be expected to inspire patients and help them add appeal to their diet, enriching it with new tastes, at the same time facilitating the memorizing process of ingredients, thanks to visualization and presented calculations, and motivating them to comply with strict dietary recommendation. The same nutritional calculations and ideas for sandwiches, with the use of different bread, e.g., gluten-free, may be useful in other diseases, such as celiac disease.

A Review of Sensors and Biosensors Modified with Conducting Polymers and Molecularly Imprinted Polymers Used in Electrochemical Detection of Amino Acids: Phenylalanine, Tyrosine, and Tryptophan.

Recently, the studies on developing sensors and biosensors-with an obvious interdisciplinary character-have drawn the attention of many researchers specializing in various fundamental, but also complex domains such as chemistry, biochemistry, physics, biophysics, biology, bio-pharma-medicine, and bioengineering. Along these lines, the present paper is structured into three parts, and is aimed at synthesizing the most relevant studies on the construction and functioning of versatile devices, of electrochemical sensors and biosensors, respectively. The first part presents examples of the most representative scientific research focusing on the role and the importance of the phenylalanine, tyrosine, and tryptophan amino acids, selected depending on their chemical structure and their impact on the central nervous system. The second part is dedicated to presenting and exemplifying conductor polymers and molecularly imprinted polymers used as sensitive materials in achieving electrochemical sensors and biosensors. The last part of the review analyzes the sensors and biosensors developed so far to detect amino acids with the aid of conductor polymers and molecularly imprinted polymers from the point of view of the performances obtained, with emphasis on the detection methods, on the electrochemical reactions that take place upon detection, and on the electroanalytical performances. The present study was carried out with a view to highlighting, for the benefit of specialists in medicine and pharmacy, the possibility of achieving and purchasing efficient devices that might be used in the quality control of medicines, as well as in studying and monitoring diseases associated with these amino acids.

PAWG Pilot Study on Quantification of SARS-CoV-2 Monoclonal Antibody - Part 1

Under the auspices of the Protein Analysis Working Group (PAWG) of the Comité Consultatif pour la Quantité de Matière (CCQM) a pilot study, CCQM-P216, was coordinated by the Chinese National Institute of Metrology (NIM), National Research Council of Canada (NRC) and the Bureau International des Poids et Mesures (BIPM). Eleven Metrology Institutes or Designated Institutes and the BIPM participated in the first phase of the pilot study (Part 1). The purpose of this pilot study was to develop measurement capabilities for larger proteins using a recombinant humanized IgG monoclonal antibody against Spike glycoprotein of SARS-CoV-2 (Anti-S IgG mAb) in solution. The first phase of the study was designed to employ established methods that had been previously studies by the CCQM Protein Analysis Working Group, involving the digestion of protein down to the peptide or amino acid level.The global coronavirus pandemic has also led to increased focus on antibody quantitation methods. IgG are among the immunoglobulins produced by the immune system to provide protection against SARS-CoV-2. Anti-SARS-CoV-2 IgG can therefore be detected in samples from affected patients. Antibody tests can show whether a person has been exposed to the SARS-CoV-2, and whether or not they potentially show lasting immunity to the disease. With the constant spread of the virus and the high pressure of re-opening economies, antibody testing plays a critical role in the fight against COVID-19 by helping healthcare professionals to identify individuals who have developed an immune response, either via vaccination or exposure to the virus. Many countries have launched large-scale antibody testing for COVID-19. The development of measurement standards for the antibody detection of SARS-CoV-2 is critically important to deal with the challenges of the COVID-19 pandemic. In this study, the SARS-CoV-2 monoclonal antibody is being used as a model system to build capacity in methods that can be used in antibody quantification. Amino acid reference values with corresponding expanded uncertainty of 36.10 ± 1.55 mg/kg, 38.75 ± 1.45 mg/kg, 18.46 ± 0.78 mg/kg, 16.20 ± 0.67 mg/kg and 30.61 ± 1.30 mg/kg have been established for leucine, valine, phenylalanine, isoleucine and proline, respectively. Agreement between nearly all laboratories was achieved for the amino acid analysis within 2 to 2.5 %, with one participant achieving markedly higher results due to a technical issue found in their procedure;this result was thus excluded from the reference value calculations. The relatively good agreement within a laboratory between different amino acids was not dissimilar to previous results for peptides or small proteins, indicating that factors such as hydrolysis conditions and calibration procedures could be the largest sources of variability.Peptide reference values with corresponding expanded uncertainty of 4.99 ± 0.28 mg/kg and 6.83 ± 0.65 mg/kg have been established for ALPAPIEK and GPSVFPLAPSSK, respectively. Not surprisingly due to prior knowledge from previous studies on peptide quantitation, agreement between laboratories for the peptide-based analysis was slightly poorer at 3 to 5 %, with one laboratory's result excluded for the peptide GPSVFPLAPSSK. Again, this level of agreement was not significantly poorer than that achieved in previous studies with smaller or less complex proteins.To reach the main text of this paper, click on Final Report.

Phenylalanine and COVID-19: Tracking disease severity markers.

BACKGROUND: Although there are several severity predictors for COVID-19, none are specific. Serum levels of phenylalanine were recently associated with increased inflammation, higher SOFA scores, ICU admission, and mortality rates among non-COVID-19 patients. Here, we investigated the relationship between phenylalanine and inflammatory markers in adults with COVID-19. METHODS: We assessed adults with COVID-19 at hospital admission for clinical and laboratory data. Nuclear magnetic resonance spectroscopy measured serum levels of phenylalanine and other amino acids of its metabolomic pathway. Flow Cytometry measured serum levels of IL-2, IL-4, IL-6, Il-10, TNF-α, and IFN-γ. Linear regression models adjusted for potential confounders assessed the relationship between serum levels of phenylalanine and inflammatory cytokines. RESULTS: Phenylalanine and tyrosine were significantly lower in mild disease as compared to moderate and severe groups. Linear regression models showed that phenylalanine is independently and positively associated with disease severity regardless of the cytokine analyzed and after adjustment for potential confounders. In addition, mild cases showed consistently lower serum phenylalanine levels within the first ten days from disease onset to hospital admission. CONCLUSIONS: Phenylalanine is a marker of disease severity. This association is independent of the time between the onset of symptoms and the magnitude of the inflammatory state.

The serum amino acid profile in COVID-19.

The pandemic of the coronavirus disease (COVID-19) caused by SARS-CoV-2 affects millions of people worldwide. There are still many unknown aspects to this infection which affects the whole world. In addition, the potential impacts caused by this infection are still unclear. Amino acid metabolism, in particular, contains significant clues in terms of the development and prevention of many diseases. Therefore, this study aimed to compare amino acid profile of COVID-19 and healthy subject. In this study, the amino acid profiles of patients with asymptomatic, mild, moderate, and severe/critical SARS-CoV-2 infection were scanned with LC-MS/MS. The amino acid profile encompassing 30 amino acids in 142 people including 30 control and 112 COVID-19 patients was examined. 20 amino acids showed significant differences when compared to the control group in COVID-19 patient groups with different levels of severity in the statistical analyses conducted. It was detected that the branched-chain amino acids (BCAAs) changed in correlation with one another, and L-2-aminobutyric acid and L-phenylalanine had biomarker potential for COVID-19. Moreover, it was concluded that L-2-aminobutyric acid could provide prognostic information about the course of the disease. We believe that a new viewpoint will develop regarding the diagnosis, treatment, and prognosis as a result of the evaluation of the serum amino acid profiles of COVID-19 patients. Determining L-phenylalanine and L-2-aminobutyric levels can be used in laboratories as a COVID-19-biomarker. Also, supplementing COVID patients with taurine and BCAAs can be beneficial for treatment protocols.

Phytoconstituents from ten natural herbs as potent inhibitors of main protease enzyme of SARS-COV-2: In silico study.

Background: Lack of treatment of novel Coronavirus disease led to the search of specific antivirals that are capable to inhibit the replication of the virus. The plant kingdom has demonstrated to be an important source of new molecules with antiviral potential. Purpose: The present study aims to utilize various computational tools to identify the most eligible drug candidate that have capabilities to halt the replication of SARS-COV-2 virus by inhibiting Main protease (Mpro) enzyme. Methods: We have selected plants whose extracts have inhibitory potential against previously discovered coronaviruses. Their phytoconstituents were surveyed and a library of 100 molecules was prepared. Then, computational tools such as molecular docking, ADMET and molecular dynamic simulations were utilized to screen the compounds and evaluate them against Mpro enzyme. Results: All the phytoconstituents showed good binding affinities towards Mpro enzyme. Among them laurolitsine possesses the highest binding affinity i.e. -294.1533 kcal/mol. On ADMET analysis of best three ligands were simulated for 1.2 ns, then the stable ligand among them was further simulated for 20 ns. Results revealed that no conformational changes were observed in the laurolitsine w.r.t. protein residues and low RMSD value suggested that the Laurolitsine-protein complex was stable for 20 ns. Conclusion: Laurolitsine, an active constituent of roots of Lindera aggregata, was found to be having good ADMET profile and have capabilities to halt the activity of the enzyme. Therefore, this makes laurolitsine a good drug candidate for the treatment of COVID-19.

PKU and COVID19: How the pandemic changed metabolic control.

BACKGROUND: COVID19 pandemic urged the need to take severe measures for reducing the epidemic spread. Lockdowns were imposed throughout countries and even Inborn errors of metabolism (IEMs) affected patients had to face it and adapt, with management strategies changes coming along. Phenylketonuria (PKU) is an inborn error of phenylalanine (Phe) metabolism causing, when not treated, blood Phe increases and consequent central nervous system (CNS) damage. Dietary intervention is the main recognized treatment and must be maintained long-life, however adherence is often suboptimal in adulthood. Aim of this study was to evaluate whether and how the pandemic had impacted PKUs metabolic control and what factors may have played a role as potential modifiers. METHODS: Patients ≥4 yo and in follow-up at our Metabolic Clinic were enrolled in this study, divided into subgroups according to age (GROUP A < 12 yo; GROUP B ≥ 12 yo). Videoconsults were conducted on a minimum monthly basis and collected DBS were studied and compared to previous year same time-period in order to evaluate possible changes. RESULTS: 39% of patients (n = 121) increased the number of performed DBS. "Non-compliant" patients were reduced (11-3%) with a - 14% of patients with mean Phe levels >600 umol/l and a - 8% of patients with 100% DBS above same level. GROUP A maintained substantially unchanged metabolic control among two analyzed time-periods. On the contrary, GROUP B demonstrated significant reductions in mean blood Phe concentrations (p < 0.0001) during the pandemic (mean 454 umol/l, SD ± 252, vs. 556.4 umol/l, SD ± 301). DISCUSSION: COVID19 pandemic strongly impacted people's life with lifestyle habits changing consistently. PKU patients had to adapt their dietary restrictions to the new environment they were exposed to and, if younger patients could have been less exposed (meals strictly according to diet plan independently from setting), adolescent and adults strongly reflected the obligation to stay home by showing better metabolic control. Multiple factors could have played a role in that and the availability of teleconsultancy may have contributed allowing easier connections, but our data demonstrate how the pandemic and the environment can strongly impact PKUs adherence to treatment and how removing distance barriers can ameliorate and optimize metabolic compliance.