Prevalence and clinical impact of mono- and co-infections with endemic coronaviruses 229E, OC43, NL63, and HKU-1 during the COVID-19 pandemic.

Introduction: Endemic human coronaviruses (eHCoVs) are found worldwide and usually result in mild to moderate upper respiratory tract infections. They can lead to more severe illnesses such as croup, bronchiolitis, and pneumonia in vulnerable populations. During the coronavirus disease 2019 (COVID-19) pandemic, information on HCoV prevalence and incidence and clinical impact of co-infections of HCoV with SARS-CoV-2 was lacking. Objectives: Thus, this study aimed to determine the prevalence and clinical significance of infections caused by eHCoVs during the COVID-19 pandemic in Bulgaria. Methods: From January 2021 to December 2022, nasopharyngeal swabs of patients with acute upper or lower respiratory tract infections were tested for 17 respiratory viruses using multiplex real-time polymerase chain reaction assays. The clinical data and laboratory parameters of patients infected with respiratory viruses were analysed. Results: Of the 1375 patients screened, 24 (1.7 %) were positive for HCoVs, and 197 (14.3 %) were positive for eight other seasonal respiratory viruses. Five (0.7 %) of 740 patients positive for SARS-CoV-2 were co-infected with eHCoVs. Co-infected patients had a mean C-reactive protein level of 198.5 ± 2.12 mg/mL and a mean oxygen saturation of 82 ± 2.8 mmHg, while those in patients co-infected with SARS-CoV-2 and other respiratory viruses were 61.8 mg/mL and 92.8 ± 4.6 mmHg, respectively (p < 0.05). Pneumonia was diagnosed in 63.3 % of patients with HCoV infection and 6 % of patients positive for other seasonal respiratory viruses (p < 0.05). Patients with SARS-CoV-2 mono-infection stayed in hospital for an average of 5.8 ± 3.7 days, whereas the average hospital stay of patients with eHCoV and SARS-CoV-2 co-infection was 9 ± 1.4 days (p < 0.05). Conclusion: These findings indicate the low prevalence of eHCoVs and low co-infection rate between eHCoVs and SARS-CoV-2 during the COVID-19 pandemic in Bulgaria. Despite their low incidence, such mixed infections can cause severe signs that require oxygen therapy and longer hospital stays, underlining the need for targeted testing of severe COVID-19 cases to identify potential co-infections.

The contribution of SARS-CoV-2 to the burden of acute respiratory infections in winter season 2022/2023: Results from the DigiHero study.

OBJECTIVES: In winter 2022/23 SARS-CoV-2 had developed into one of many seasonal respiratory pathogens, causing an additional burden of acute respiratory infections (ARI). While testing was still widely used, many positive tests were not reported for the official statistics. Using data from a population-based cohort, we aimed to investigate the contribution of SARS-CoV-2 to the burden of ARI. METHODS: Over 70,000 participants of the German population-based DigiHero study were invited to a questionnaire about the number and time point of ARI, and SARS-CoV-2 test results in winter 2022/23. We calculated the incidence of non-SARS ARI, the additional contribution of SARS-CoV-2, and extrapolated the age-specific estimates to obtain the total burden of SARS-CoV-2 in Germany. RESULTS: For the winter 2022/23, 37,708 participants reported 54,813 ARI, including 9,358 SARS-CoV-2 infections. This translated into a cumulative incidence of 145 infections/100 persons for all ARI, 120 infections/100 persons for non-SARS ARI and 25 infections/100 persons for SARS ARI (+21%). CONCLUSIONS: Our estimate for ARI related to SARS-CoV-2 is consistent with the difference in all ARI between pre-pandemic years and 2022/23. This additional burden should be considered, particularly with respect to the implications for the work force.

Antibiotics Not Associated with Shorter Duration or Reduced Severity of Acute Lower Respiratory Tract Infection.

BACKGROUND: Antibiotic use remains common for the treatment of lower respiratory tract infections. The objective of this study was to evaluate the impact of antibiotic use on the duration and severity of acute lower respiratory tract infection (LRTI). PARTICIPANTS: Adult patients presenting to US primary or urgent care sites with a chief complaint of cough and symptoms consistent with LRTI. MAIN MEASURES: Collected data included demographics, comorbidities, symptoms, and 48 viral and bacterial respiratory pathogens by PCR. Severity of signs/symptoms was reported for up to 28 days using diaries and text messages. Interpolation was used where data were missing. KEY RESULTS: Of 718 patients with baseline data, 29% had an antibiotic prescribed at baseline. The most common antibiotics were amoxicillin-clavulanate, azithromycin, doxycycline, and amoxicillin in 85% of patients. Provision of an antibiotic had no effect on the duration or overall severity of cough, including in patients with viral, bacterial, and mixed infections. Receipt of an antibiotic did reduce the likelihood of a follow-up visit (14.1% vs 8.2%, aOR 0.47, 95% CI 0.26-0.84), perhaps by removing the motivation of getting an antibiotic at a follow-up visit. However, they were also more likely to receive a systemic corticosteroid (31.9% vs 4.5%, p < 0.001) and were also more likely to receive an albuterol inhaler (22.7% vs 7.6%, p < 0.001). Patients believed that receiving an antibiotic would reduce the duration of their illness by nearly 4 days. CONCLUSIONS: In this large prospective study in the US primary and urgent care setting, antibiotics had no measurable impact on the severity or duration of cough due to acute LRTI. Patients had unrealistic expectations regarding the duration of LRTI and the effect of antibiotics which should be the target of antibiotic stewardship efforts.

Pre-COVID-19-pandemic RSV epidemiology and clinical burden in pediatric primary care in Italy: a comparative analysis across two regions for the 2019/2020 season.

BACKGROUND: Respiratory syncytial virus (RSV) infection in children under 5 years have a significant clinical burden, also in primary care settings. This study investigates the epidemiology and burden of RSV in Italian children during the 2019/20 pre-pandemic winter season. METHODS: A prospective cohort study was conducted in two Italian regions. Children with Acute Respiratory Infection (ARI) visiting pediatricians were eligible. Nasopharyngeal swabs were collected and analyzed via multiplex PCR for RSV detection. A follow-up questionnaire after 14 days assessed disease burden, encompassing healthcare utilization and illness duration. Statistical analyses, including regression models, explored associations between variables such as RSV subtype and regional variations. RESULTS: Of 293 children with ARI, 41% (119) tested positive for RSV. Median illness duration for RSV-positive cases was 7 days; 6% required hospitalization (median stay: 7 days). Medication was prescribed to 95% (110/116) of RSV cases, with 31% (34/116) receiving antibiotics. RSV subtype B and regional factors predicted increased healthcare utilization. Children with shortness of breath experienced a 36% longer illness duration. CONCLUSIONS: This study highlights a significant clinical burden and healthcare utilization associated with RSV in pre-pandemic Italian primary care settings. Identified predictors, including RSV subtype and symptomatology, indicate the need for targeted interventions and resource allocation strategies. RSV epidemiology can guide public health strategies for the implementation of preventive measures.

Excess mortality in Europe coincides with peaks of COVID-19, influenza and respiratory syncytial virus (RSV), November 2023 to February 2024.

Since the end of November 2023, the European Mortality Monitoring Network (EuroMOMO) has observed excess mortality in Europe. During weeks 48 2023-6 2024, preliminary results show a substantially increased rate of 95.3 (95% CI:  91.7-98.9) excess all-cause deaths per 100,000 person-years for all ages. This excess mortality is seen in adults aged 45 years and older, and coincides with widespread presence of COVID-19, influenza and respiratory syncytial virus (RSV) observed in many European countries during the 2023/24 winter season.

Lessons Learned from COVID-19 Response in Correctional and Detention Facilities.

The COVID-19 pandemic disproportionately affected persons held in and working in correctional and detention facilities, causing facilities' traditional priorities to shift when healthcare and public health needs temporarily drove many aspects of operations. During July-August 2022, we interviewed members of health departments and criminal justice organizations to document lessons learned from the COVID-19 response in correctional settings. Participants valued enhanced partnerships, flexibility, and innovation, as well as real-time data and corrections-specific public health guidance. Challenges included cross-sector collaborations, population density, scarcity of equipment and supplies, and mental health. Most participants reported improved relationships between criminal justice and public health organizations during the pandemic. Lessons from COVID-19 can be applied to everyday public health preparedness and emergency response in correctional facilities by ensuring representation of correctional health in public health strategy and practice and providing timely, data-driven, and partner-informed guidance tailored to correctional environments when public health needs arise.

Lessons Learned from Cross-Systems Approach to COVID-19 Pandemic Response in Juvenile Justice System, Colorado, USA.

The global COVID-19 pandemic illustrates the importance of a close partnership between public health and juvenile justice systems when responding to communicable diseases. Many setting-specific obstacles must be navigated to respond effectively to limit disease transmission and negative health outcomes while maintaining necessary services for youth in confinement facilities. The response requires multidisciplinary expertise and collaboration to address unique considerations. Public health mitigation strategies must balance the risk for disease against the negative effects of restrictions. Key aspects of the COVID-19 response in the juvenile justice system of Colorado, USA, involved establishing robust communication and data reporting infrastructures, building a multidisciplinary response team, adapting existing infection prevention guidelines, and focusing on a whole-person health approach to infection prevention. We examine lessons learned and offer recommendations on pandemic emergency response planning and managing a statewide public health emergency in youth confinement settings that ensure ongoing readiness.

Correlation of SARS-CoV-2 in Wastewater and Individual Testing Results in a Jail, Atlanta, Georgia, USA.

Institution-level wastewater-based surveillance was implemented during the COVID-19 pandemic, including in carceral facilities. We examined the relationship between COVID-19 diagnostic test results of residents in a jail in Atlanta, Georgia, USA (average population ≈2,700), and quantitative reverse transcription PCR signal for SARS-CoV-2 in weekly wastewater samples collected during October 2021‒May 2022. The jail offered residents rapid antigen testing at entry and periodic mass screenings by reverse transcription PCR of self-collected nasal swab specimens. We aggregated individual test data, calculated the Spearman correlation coefficient, and performed logistic regression to examine the relationship between strength of SARS-CoV-2 PCR signal (cycle threshold value) in wastewater and percentage of jail population that tested positive for COVID-19. Of 13,745 nasal specimens collected, 3.9% were COVID-positive (range 0%-29.5% per week). We observed a strong inverse correlation between diagnostic test positivity and cycle threshold value (r = -0.67; p<0.01). Wastewater-based surveillance represents an effective strategy for jailwide surveillance of COVID-19.

Development and Evaluation of Surveillance System for Identifying Jail-Associated COVID-19 Cases in Minnesota, USA, 2022.

Confinement facilities are high-risk settings for the spread of infectious disease, necessitating timely surveillance to inform public health action. To identify jail-associated COVID-19 cases from electronic laboratory reports maintained in the Minnesota Electronic Disease Surveillance System (MEDSS), Minnesota, USA, the Minnesota Department of Health developed a surveillance system that used keyword and address matching (KAM). The KAM system used a SAS program (SAS Institute Inc., https://www.sas.com) and an automated program within MEDSS to identify confinement keywords and addresses. To evaluate KAM, we matched jail booking data from the Minnesota Statewide Supervision System by full name and birthdate to the MEDSS records of adults with COVID-19 for 2022. The KAM system identified 2,212 cases in persons detained in jail; sensitivity was 92.40% and specificity was 99.95%. The success of KAM demonstrates its potential to be applied to other diseases and congregate-living settings for real-time surveillance without added reporting burden.

Lessons Learned from Public Health and State Prison Collaborations during COVID-19 Pandemic and Multifacility Tuberculosis Outbreak, Washington, USA.

The large COVID-19 outbreaks in prisons in the Washington (USA) State Department of Corrections (WADOC) system during 2020 highlighted the need for a new public health approach to prevent and control COVID-19 transmission in the system's 12 facilities. WADOC and the Washington State Department of Health (WADOH) responded by strengthening partnerships through dedicated corrections-focused public health staff, improving cross-agency outbreak response coordination, implementing and developing corrections-specific public health guidance, and establishing collaborative data systems. The preexisting partnerships and trust between WADOC and WADOH, strengthened during the COVID-19 response, laid the foundation for a collaborative response during late 2021 to the largest tuberculosis outbreak in Washington State in the past 20 years. We describe challenges of a multiagency collaboration during 2 outbreak responses, as well as approaches to address those challenges, and share lessons learned for future communicable disease outbreak responses in correctional settings.

A case report of unusual recurrent bronchopneumonia infections in Mounier-Kuhn syndrome.

Mounier-Kuhn syndrome is a rare airway disease characterized by tracheal and bronchial dilatation, primarily affecting middle-aged men. We present a case of Mounier-Kuhn syndrome in a 40-year-old man with a history of recurrent respiratory infections since adolescence. The diagnostic journey involved a multidisciplinary approach incorporating clinical evaluation, radiological imaging, and bronchoscopy. Computed tomography findings, including maximum intensity projection reconstructions and 3D rendering, facilitated the diagnosis by revealing significant airway dilation and associated abnormalities. Treatment primarily focused on supportive measures, including antibiotic therapy and respiratory physiotherapy. This case underscores the importance of considering Mounier-Kuhn syndrome in patients with recurrent respiratory infections and highlights the role of advanced imaging techniques in diagnosis.

Informing the pandemic response: the role of the WHO's COVID-19 Weekly Epidemiological Update.

On 31 December 2019, the Municipal Health Commission of Wuhan, China, reported a cluster of atypical pneumonia cases. On 5 January 2020, the WHO publicly released a Disease Outbreak News (DON) report, providing information about the pneumonia cases, implemented response interventions, and WHO's risk assessment and advice on public health and social measures. Following 9 additional DON reports and 209 daily situation reports, on 17 August 2020, WHO published the first edition of the COVID-19 Weekly Epidemiological Update (WEU). On 1 September 2023, the 158th edition of the WEU was published on WHO's website, marking its final issue. Since then, the WEU has been replaced by comprehensive global epidemiological updates on COVID-19 released every 4 weeks. During the span of its publication, the webpage that hosts the WEU and the COVID-19 Operational Updates was accessed annually over 1.4 million times on average, with visits originating from more than 100 countries. This article provides an in-depth analysis of the WEU process, from data collection to publication, focusing on the scope, technical details, main features, underlying methods, impact and limitations. We also discuss WHO's experience in disseminating epidemiological information on the COVID-19 pandemic at the global level and provide recommendations for enhancing collaboration and information sharing to support future health emergency responses.

Non-tuberculous mycobacterial pulmonary infection presenting in a patient with unilateral pulmonary artery agenesis.

People who have structural or developmental lung disease are more likely to develop non-tuberculous mycobacterial infections. We present the case of a young man in his 30s who had unilateral pulmonary artery agenesis on the right side and presented with a 6-month history of productive cough and fever. His CT scan showed nodular and cavitating lesions on the right side, and sputum analysis confirmed infection with Mycobacterium chimaera He had to undergo modifications in his treatment, including a change from rifampicin to rifabutin due to drug interactions and his amikacin had to be stopped due to signs of vestibular toxicity. Using a multidisciplinary approach, we were able to formulate an appropriate drug regimen for him, and he is now under regular follow-up with infectious diseases and respiratory medicine.

Seasonal extreme temperatures and short-term fine particulate matter increases pediatric respiratory healthcare encounters in a sparsely populated region of the intermountain western United States.

BACKGROUND: Western Montana, USA, experiences complex air pollution patterns with predominant exposure sources from summer wildfire smoke and winter wood smoke. In addition, climate change related temperatures events are becoming more extreme and expected to contribute to increases in hospital admissions for a range of health outcomes. Evaluating while accounting for these exposures (air pollution and temperature) that often occur simultaneously and may act synergistically on health is becoming more important. METHODS: We explored short-term exposure to air pollution on children's respiratory health outcomes and how extreme temperature or seasonal period modify the risk of air pollution-associated healthcare events. The main outcome measure included individual-based address located respiratory-related healthcare visits for three categories: asthma, lower respiratory tract infections (LRTI), and upper respiratory tract infections (URTI) across western Montana for ages 0-17 from 2017-2020. We used a time-stratified, case-crossover analysis with distributed lag models to identify sensitive exposure windows of fine particulate matter (PM2.5) lagged from 0 (same-day) to 14 prior-days modified by temperature or season. RESULTS: For asthma, increases of 1 µg/m3 in PM2.5 exposure 7-13 days prior a healthcare visit date was associated with increased odds that were magnified during median to colder temperatures and winter periods. For LRTIs, 1 µg/m3 increases during 12 days of cumulative PM2.5 with peak exposure periods between 6-12 days before healthcare visit date was associated with elevated LRTI events, also heightened in median to colder temperatures but no seasonal effect was observed. For URTIs, 1 unit increases during 13 days of cumulative PM2.5 with peak exposure periods between 4-10 days prior event date was associated with greater risk for URTIs visits that were intensified during median to hotter temperatures and spring to summer periods. CONCLUSIONS: Delayed, short-term exposure increases of PM2.5 were associated with elevated odds of all three pediatric respiratory healthcare visit categories in a sparsely population area of the inter-Rocky Mountains, USA. PM2.5 in colder temperatures tended to increase instances of asthma and LRTIs, while PM2.5 during hotter periods increased URTIs.

RSV Disease Burden in Primary Care in Italy: A Multi-Region Pediatric Study, Winter Season 2022-2023.

INTRODUCTION: Human respiratory syncytial virus (RSV) is one of the most frequent causes of respiratory infections in children under 5 years of age, but its socioeconomic impact and burden in primary care settings is still little studied. METHODS: During the 2022/2023 winter season, 55 pediatricians from five Italian regions participated in our community-based study. They collected a nasal swab for RSV molecular test from 650 patients under the age of 5 with acute respiratory infections (ARIs) and performed a baseline questionnaire. The clinical and socioeconomic burden of RSV disease in primary care was evaluated by two follow-up questionnaires completed by the parents of positive children on Days 14 and 30. RESULTS: RSV laboratory-confirmed cases were 37.8% of the total recruited ARI cases, with RSV subtype B accounting for the majority (65.4%) of RSV-positive swabs. RSV-positive children were younger than RSV-negative ones (median 12.5 vs. 16.5 months). The mean duration of symptoms for all children infected by RSV was 11.47 ± 6.27 days. We did not observe substantial differences in clinical severity between the two RSV subtypes, but RSV-A positive patients required more additional pediatric examinations than RSV-B cases. The socioeconomic impact of RSV infection was considerable, causing 53% of children to be absent from school, 46% of parents to lose working days, and 25% of families to incur extra costs. CONCLUSIONS: Our findings describe a baseline of the RSV disease burden in primary care in Italy before the introduction of upcoming immunization strategies.

Cost of SARS-CoV-2 self-test distribution programmes by different modalities: a micro-costing study in five countries (Brazil, Georgia, Malaysia, Ethiopia and the Philippines).

OBJECTIVE: Diagnostic testing is an important tool to combat the COVID-19 pandemic, yet access to and uptake of testing vary widely 3 years into the pandemic. The WHO recommends the use of COVID-19 self-testing as an option to help expand testing access. We aimed to calculate the cost of providing COVID-19 self-testing across countries and distribution modalities. DESIGN: We estimated economic costs from the provider perspective to calculate the total cost and the cost per self-test kit distributed for three scenarios that differed by costing period (pilot, annual), the number of tests distributed (actual, planned, scaled assuming an epidemic peak) and self-test kit costs (pilot purchase price, 50% reduction). SETTING: We used data collected between August and December 2022 in Brazil, Georgia, Malaysia, Ethiopia and the Philippines from pilot implementation studies designed to provide COVID-19 self-tests in a variety of settings-namely, workplace and healthcare facilities. RESULTS: Across all five countries, 173 000 kits were distributed during pilot implementation with the cost/test distributed ranging from $2.44 to $12.78. The cost/self-test kit distributed was lowest in the scenario that assumed implementation over a longer period (year), with higher test demand (peak) and a test kit price reduction of 50% ($1.04-3.07). Across all countries and scenarios, test procurement occupied the greatest proportion of costs: 58-87% for countries with off-site self-testing (outside the workplace, for example, home) and 15-50% for countries with on-site self-testing (at the workplace). Staffing was the next key cost driver, particularly for distribution modalities that had on-site self-testing (29-35%) versus off-site self-testing (7-27%). CONCLUSIONS: Our results indicate that it is likely to cost between $2.44 and $12.78 per test to distribute COVID-19 self-tests across common settings in five heterogeneous countries. Cost-effectiveness analyses using these results will allow policymakers to make informed decisions on optimally scaling up COVID-19 self-test distribution programmes across diverse settings and evolving needs.

Bronchiectasis-associated infections and outcomes in a large, geographically diverse electronic health record cohort in the United States.

BACKGROUND: Bronchiectasis is a pulmonary disease characterized by irreversible dilation of the bronchi and recurring respiratory infections. Few studies have described the microbiology and prevalence of infections in large patient populations outside of specialized tertiary care centers. METHODS: We used the Cerner HealthFacts Electronic Health Record database to characterize the nature, burden, and frequency of pulmonary infections among persons with bronchiectasis. Chronic infections were defined based on organism-specific guidelines. RESULTS: We identified 7,749 patients who met our incident bronchiectasis case definition. In this study population, the organisms with the highest rates of isolate prevalence were Pseudomonas aeruginosa with 937 (12%) individuals, Staphylococcus aureus with 502 (6%), Mycobacterium avium complex (MAC) with 336 (4%), and Aspergillus sp. with 288 (4%). Among persons with at least one isolate of each respective pathogen, 219 (23%) met criteria for chronic P. aeruginosa colonization, 74 (15%) met criteria for S. aureus chronic colonization, 101 (30%) met criteria for MAC chronic infection, and 50 (17%) met criteria for Aspergillus sp. chronic infection. Of 5,795 persons with at least two years of observation, 1,860 (32%) had a bronchiectasis exacerbation and 3,462 (60%) were hospitalized within two years of bronchiectasis diagnoses. Among patients with chronic respiratory infections, the two-year occurrence of exacerbations was 53% and for hospitalizations was 82%. CONCLUSIONS: Patients with bronchiectasis experiencing chronic respiratory infections have high rates of hospitalization.

Post-pandemic trends: Epidemiological and etiological insights into acute respiratory infections in southern China.

Data on people suspected with acute respiratory infections (ARIs) from August 2022 to December 2023 in southern China were analyzed. Following the COVID-19 pandemic, the positive detection rates of respiratory pathogens increased to 56.9%. Influenza A virus (IAV) emerged as the predominant prevalence pathogen (52.1%), followed by Mycoplasma pneumoniae (Mp: 21.2%), and SARS-CoV-2 (11.6%). Mp, IAV, and Human rhinovirus (HRV) infection were the primary etiologies of ARIs patients under age 18, accounting for 49.4%, 48.6%, and 21.7%, respectively. Mp, HRV, Respiratory syncytial virus (RSV), and Adenovirus (ADV) contributed to ARIs cases in virtually every month in this group, with Mp being particularly notable for its consistent presence and high co-infection rate (31.0%). IAV was predominant in the 19 to 59 age group (88.6%), SARS-CoV-2 was responsible for most of ARIs in the elderly group (82.5%). This study provides valuable insights into the dynamic nature of respiratory pathogens post COVID-19 era.

Epidemiological Characteristics of Human Parainfluenza Viruses Infections - China, 2019-2023.

Introduction: A retrospective study based on sentinel surveillance was conducted in 10 provincial-level administrative divisions (PLADs) in China to enhance the understanding of the epidemiological characteristics of human parainfluenza viruses (HPIVs). Methods: From January 2019 to June 2023, respiratory specimens were collected from individuals with acute respiratory infections (ARIs) and screened for four HPIVs serotypes and other common respiratory viruses using multiplex real-time polymerase chain reaction (PCR). This study analyzed the association of HPIVs infections with seasonal patterns, geographical distribution, demographic profiles, clinical features, and co-infection status. Results: During the study period, a total of 12,866 ARIs were included. The overall detection rate of HPIVs was 6.15%, varying from 5.04% in 2022 to 9.70% in 2020. The median age of HPIVs-infected patients was 3 years. HPIV2 was more prevalent among individuals aged 5-17 years (42.57%), while HPIV4 was more common in those over 65 years (12.24%). HPIV3 (54.16%) and HPIV1 (27.18%) were the predominant serotypes, and their prevalence exhibited significant seasonal fluctuations post- coronavirus disease 2019 (COVID-19) pandemic. The peak of HPIV3 shifted three months later in 2020 compared to 2019 and returned to a summer peak thereafter. Two peaks of HPIV1 were observed in 2021 following the peak of HPIV3. Additionally, co-infections were frequent in HPIVs cases (overall rate: 22.12%), with human rhinovirus being the most common co-infecting virus. Conclusions: The prevalence of HPIVs in China was predominantly due to HPIV3 and HPIV1, and their seasonal patterns were altered by pandemic restrictions. Hence, continuous surveillance of HPIVs is essential.