-
PloS One 2023We critically appraised the literature regarding in-flight transmission of a range of respiratory infections to provide an evidence base for public health policies for... (Meta-Analysis)
Meta-Analysis
We critically appraised the literature regarding in-flight transmission of a range of respiratory infections to provide an evidence base for public health policies for contact tracing passengers, given the limited pathogen-specific data for SARS-CoV-2 currently available. Using PubMed, Web of Science, and other databases including preprints, we systematically reviewed evidence of in-flight transmission of infectious respiratory illnesses. A meta-analysis was conducted where total numbers of persons on board a specific flight was known, to calculate a pooled Attack Rate (AR) for a range of pathogens. The quality of the evidence provided was assessed using a bias assessment tool developed for in-flight transmission investigations of influenza which was modelled on the PRISMA statement and the Newcastle-Ottawa scale. We identified 103 publications detailing 165 flight investigations. Overall, 43.7% (72/165) of investigations provided evidence for in-flight transmission. H1N1 influenza A virus had the highest reported pooled attack rate per 100 persons (AR = 1.17), followed by SARS-CoV-2 (AR = 0.54) and SARS-CoV (AR = 0.32), Mycobacterium tuberculosis (TB, AR = 0.25), and measles virus (AR = 0.09). There was high heterogeneity in estimates between studies, except for TB. Of the 72 investigations that provided evidence for in-flight transmission, 27 investigations were assessed as having a high level of evidence, 23 as medium, and 22 as low. One third of the investigations that reported on proximity of cases showed transmission occurring beyond the 2x2 seating area. We suggest that for emerging pathogens, in the absence of pathogen-specific evidence, the 2x2 system should not be used for contact tracing. Instead, alternate contact tracing protocols and close contact definitions for enclosed areas, such as the same cabin on an aircraft or other forms of transport, should be considered as part of a whole of journey approach.
Topics: Humans; Contact Tracing; SARS-CoV-2; COVID-19; Influenza A Virus, H1N1 Subtype; Communicable Diseases; Aircraft
PubMed: 36730309
DOI: 10.1371/journal.pone.0264294 -
Neurological Sciences : Official... Jun 2023Subacute sclerosing panencephalitis (SSPE) is a devastating brain disease caused by persistent infection by the measles virus. Several cases of SSPE in pregnant ladies... (Review)
Review
BACKGROUND
Subacute sclerosing panencephalitis (SSPE) is a devastating brain disease caused by persistent infection by the measles virus. Several cases of SSPE in pregnant ladies have been described. This systematic review is focused on maternal and foetal outcomes among pregnant women with SSPE.
METHODS
We searched four databases (PubMed, Embase, Scopus, and Google Scholar). We reviewed all relevant cases, published until 14 August 2022. The review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The protocol was registered with PROSPERO (CRD42022348630). The search items that we used were "((Pregnancy) OR (delivery)) AND (Subacute sclerosing panencephalitis (SSPE))". Dyken's criteria were used for the diagnosis of SSPE in pregnant women. The extracted data was recorded in an Excel sheet. The Joanna Briggs Institute Critical Appraisal tool for case reports was used to assess the quality of published cases.
RESULTS
We came across 19 reports describing details of 21 cases. The age of SSPE-affected women varied from 14 to 34 years (mean 23 years). In the majority (n=14), clinical manifestations were started in the antepartum period. Nine pregnant SSPE women presented with vision loss. After delivery, 13 SSPE-affected women died. On the contrary, 15 foetuses, though the majority were preterm, were alive. Five foetuses either died soon after birth or were still-born.
CONCLUSION
In conclusion, SSPE in pregnancy is often missed, as it mimics eclampsia. SSPE in pregnancy usually has a devastating course. Universal early childhood measles vaccination is the only way to fight this menace.
Topics: Infant, Newborn; Female; Humans; Child, Preschool; Pregnancy; Adolescent; Young Adult; Adult; Subacute Sclerosing Panencephalitis; Pregnant Women; Measles virus; Vision Disorders; Family; Measles
PubMed: 36729186
DOI: 10.1007/s10072-023-06650-x -
Nutrients Oct 2022Vitamin A (VA) deficiency is associated with increased host susceptibility to infections, but evidence on its role in the prevention and management of viral infections... (Review)
Review
Vitamin A (VA) deficiency is associated with increased host susceptibility to infections, but evidence on its role in the prevention and management of viral infections is still lacking. This review aimed at summarizing the effects of VA supplementation against viral infections to support clinicians in evaluating supplemental treatments. PubMed, Scopus, and Web of Science were searched. Randomized clinical trials comparing the direct effects of VA oral supplementation in any form vs. placebo or standard of care in the prevention and/or management of confirmed viral infections in people of any age were included. A narrative synthesis of the results was performed. The revised Cochrane Risk-Of-Bias tool was used to assess quality. Overall, 40 articles of heterogeneous quality were included. We found data on infections sustained by ( = 17), ( = 2), ( = 1), ( = 3), ( = 4), and ( = 13). Studies were published between 1987 and 2017 and mostly conducted in Africa. The findings were heterogeneous across and within viral families regarding virological, immunological, and biological response, and no meaningful results were found in the prevention of viral infections. For a few diseases, VA-supplemented individuals had a better prognosis and improved outcomes, including clearance of HPV lesions or reduction in some measles-related complications. The effects of VA oral supplementation seem encouraging in relation to the management of a few viral infections. Difference in populations considered, variety in recruitment and treatment protocols might explain the heterogeneity of the results. Further investigations are needed to better identify the benefits of VA administration.
Topics: Dietary Supplements; Humans; Randomized Controlled Trials as Topic; Virus Diseases; Vitamin A; Vitamin D
PubMed: 36235733
DOI: 10.3390/nu14194081 -
Frontiers in Pediatrics 2022In 2011, the first European League Against Rheumatism (EULAR) vaccination recommendations for pediatric patients with autoimmune inflammatory rheumatic diseases...
Efficacy, Immunogenicity and Safety of Vaccination in Pediatric Patients With Autoimmune Inflammatory Rheumatic Diseases (pedAIIRD): A Systematic Literature Review for the 2021 Update of the EULAR/PRES Recommendations.
BACKGROUND
In 2011, the first European League Against Rheumatism (EULAR) vaccination recommendations for pediatric patients with autoimmune inflammatory rheumatic diseases (pedAIIRD) were published. The past decade numerous new studies were performed to assess the safety, efficacy and immunogenicity of vaccinations in pedAIIRD. A systematic literature review (SLR) was therefore performed to serve as the basis for the updated 2021 EULAR/PRES recommendations.
METHODS
An SLR was performed according to the standard operating procedures for EULAR-endorsed recommendations. Primary outcomes were efficacy, immunogenicity and safety of vaccination in pedAIIRD. The search was performed in Medline, Embase and the Cochrane Library and included studies published from November 2010 until July 2020.
RESULTS
The SLR yielded 57 studies which were included for critical appraisal and data extraction. Only 8 studies described the occurrence of vaccine-preventable infections after vaccination (efficacy), none of these studies were powered to assess efficacy. The majority of studies assessed (humoral) immune responses as surrogate endpoint for vaccine efficacy. Studies on non-live vaccines showed that these were safe and in general immunogenic. Biologic disease-modifying antirheumatic drugs (bDMARDs) in general did not significantly reduce seroprotection rates, except for B-cell depleting therapies which severely hampered humoral responses. Four new studies on human papilloma virus vaccination showed that this vaccine was safe and immunogenic in pedAIIRD. Regarding live-attenuated vaccinations, level 1 evidence of the measles mumps rubella (MMR) booster vaccination became available which showed the safety of this booster for patients treated with methotrexate. In addition, level 3 evidence became available that suggested that the MMR and varicella zoster virus (VZV) vaccination for patients on low dose glucocorticosteroids and bDMARDs might be safe as well.
CONCLUSIONS
The past decade, knowledge on the safety and immunogenicity of (live-attenuated) vaccines in pedAIIRD significantly increased. Data on efficacy (infection prevention) remains scarce. The results from this SLR are the basis for the updated EULAR/PRES vaccination recommendations in pedAIIRD.
PubMed: 35874582
DOI: 10.3389/fped.2022.910026 -
Annals of the Rheumatic Diseases Jan 2023Recent insights supporting the safety of live-attenuated vaccines and novel studies on the immunogenicity of vaccinations in the era of biological disease-modifying...
OBJECTIVES
Recent insights supporting the safety of live-attenuated vaccines and novel studies on the immunogenicity of vaccinations in the era of biological disease-modifying antirheumatic drugs in paediatric patients with autoimmune/inflammatory rheumatic diseases (pedAIIRD) necessitated updating the EULAR recommendations.
METHODS
Recommendations were developed using the EULAR standard operating procedures. Two international expert committees were formed to update the vaccination recommendations for both paediatric and adult patients with AIIRD. After a systematic literature review, separate recommendations were formulated for paediatric and adult patients. For pedAIIRD, six overarching principles and seven recommendations were formulated and provided with the level of evidence, strength of recommendation and Task Force level of agreement.
RESULTS
In general, the National Immunisation Programmes (NIP) should be followed and assessed yearly by the treating specialist. If possible, vaccinations should be administered prior to immunosuppressive drugs, but necessary treatment should never be postponed. Non-live vaccines can be safely given to immunosuppressed pedAIIRD patients. Mainly, seroprotection is preserved in patients receiving vaccinations on immunosuppression, except for high-dose glucocorticoids and B-cell depleting therapies. Live-attenuated vaccines should be avoided in immunosuppressed patients. However, it is safe to administer the measles-mumps-rubella booster and varicella zoster virus vaccine to immunosuppressed patients under specific conditions. In addition to the NIP, the non-live seasonal influenza vaccination should be strongly considered for immunosuppressed pedAIIRD patients.
CONCLUSIONS
These recommendations are intended for paediatricians, paediatric rheumatologists, national immunisation agencies, general practitioners, patients and national rheumatology societies to attain safe and effective vaccination and optimal infection prevention in immunocompromised pedAIIRD patients.
Topics: Adult; Humans; Child; Vaccines, Attenuated; Rheumatic Diseases; Vaccination; Immunosuppressive Agents; Antirheumatic Agents; Autoimmune Diseases
PubMed: 35725297
DOI: 10.1136/annrheumdis-2022-222574 -
The Journal of Infectious Diseases Sep 2022We conducted a systematic review to assess whether measles humoral immunity wanes in previously infected or vaccinated populations in measles elimination settings. (Meta-Analysis)
Meta-Analysis
BACKGROUND
We conducted a systematic review to assess whether measles humoral immunity wanes in previously infected or vaccinated populations in measles elimination settings.
METHODS
After screening 16 822 citations, we identified 9 articles from populations exposed to wild-type measles and 16 articles from vaccinated populations that met our inclusion criteria.
RESULTS
Using linear regression, we found that geometric mean titers (GMTs) decreased significantly in individuals who received 2 doses of measles-containing vaccine (MCV) by 121.8 mIU/mL (95% confidence interval [CI], -212.4 to -31.1) per year since vaccination over 1 to 5 years, 53.7 mIU/mL (95% CI, -95.3 to -12.2) 5 to 10 years, 33.2 mIU/mL (95% CI, -62.6 to -3.9), 10 to 15 years, and 24.1 mIU/mL (95% CI, -51.5 to 3.3) 15 to 20 years since vaccination. Decreases in GMT over time were not significant after 1 dose of MCV or after infection. Decreases in the proportion of seropositive individuals over time were not significant after 1 or 2 doses of MCV or after infection.
CONCLUSIONS
Measles antibody waning in vaccinated populations should be considered in planning for measles elimination.
Topics: Antibodies, Viral; Humans; Measles; Measles Vaccine; Measles virus; Vaccination
PubMed: 35417025
DOI: 10.1093/infdis/jiac039 -
Vaccine Apr 2022Vaccinations are essential for preventing infectious diseases in children with chronic diseases as they have increased risk of infection from frequent use of biologics.... (Meta-Analysis)
Meta-Analysis Review
UNLABELLED
Vaccinations are essential for preventing infectious diseases in children with chronic diseases as they have increased risk of infection from frequent use of biologics. Response to immunizations in this group is not well known.
OBJECTIVE
A systematic review was performed to evaluate three primary outcomes: efficacy; immunogenicity; and safety of vaccines in children with chronic conditions treated with biologics.
METHODS
The protocol for our systematic review and meta-analysis was registered and published with PROSPERO. We searched electronic bibliographic databases for studies published from 2009 to 2019, focusing on vaccinations in children with chronic conditions treated with biologics.
RESULTS
We retrieved 532 records. Thirty-one full-text articles were selected, and 14 were included in the meta-analysis. No significant publication bias was found.
EFFICACY
limited data are available regarding the efficacy of vaccination, as most studies have focused on immunogenicity as surrogate outcome for efficacy. Immunogenicity: patients receiving anti-TNF-alpha therapy had a statistically significant risk of poor seroconversion (p = 0.028) and seroprotection by the serotype B influenza vaccine [inflammatory bowel disease (IBD) p = 0.013; juvenile idiopathic arthritis (JIA) p = 0.004]. We found adequate responses with H1N1 and H3N2 serotypes. Few studies existed for pneumococcal, hepatitis A virus, hepatitis B virus, varicella-zoster virus, Measles Mumps Rubella virus, and multiple vaccine administration.
SAFETY
vaccine administration was not associated with serious side effects, but JIA patients on anti-TNF alpha therapy had a statistically significant risk of presenting with myalgia or arthralgia postinfluenza vaccine (p = 0.014).
CONCLUSIONS
More evidence concerning efficacy, immunogenicity, and safety of vaccinations is needed to guide physicians in the vaccine decision process for this pediatric population.
Topics: Biological Products; Child; Humans; Immunogenicity, Vaccine; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H3N2 Subtype; Measles-Mumps-Rubella Vaccine; Pneumococcal Vaccines; Tumor Necrosis Factor Inhibitors
PubMed: 35370019
DOI: 10.1016/j.vaccine.2022.03.041 -
Frontiers in Pharmacology 2021Viruses cause various human diseases, some of which become pandemic outbreaks. This study synthesized evidence on antiviral medicinal plants in Africa which could... (Review)
Review
Viruses cause various human diseases, some of which become pandemic outbreaks. This study synthesized evidence on antiviral medicinal plants in Africa which could potentially be further studied for viral infections including Coronavirus disease 2019 (COVID-19) treatment. PUBMED, CINAHIL, Scopus, Google Scholar, and Google databases were searched through keywords; antiviral, plant, herb, and Africa were combined using "AND" and "OR". studies, studies, or clinical trials on botanical medicine used for the treatment of viruses in Africa were included. Thirty-six studies were included in the evidence synthesis. Three hundred and twenty-eight plants were screened for antiviral activities of which 127 showed noteworthy activities against 25 viral species. These, were Poliovirus (42 plants), HSV (34 plants), Coxsackievirus (16 plants), Rhinovirus (14plants), Influenza (12 plants), Astrovirus (11 plants), SARS-CoV-2 (10 plants), HIV (10 plants), Echovirus (8 plants), Parvovirus (6 plants), Semiliki forest virus (5 plants), Measles virus (5 plants), Hepatitis virus (3 plants), Canine distemper virus (3 plants), Zika virus (2 plants), Vesicular stomatitis virus T2 (2 plants). Feline herpesvirus (FHV-1), Enterovirus, Dengue virus, Ebola virus, Chikungunya virus, Yellow fever virus, Respiratory syncytial virus, Rift Valley fever virus, Human cytomegalovirus each showed sensitivities to one plant. The current study provided a list of African medicinal plants which demonstrated antiviral activities and could potentially be candidates for COVID-19 treatment. However, all studies were preliminary and screening. Further are required for plant-based management of viral diseases.
PubMed: 35002686
DOI: 10.3389/fphar.2021.682794 -
The Cochrane Database of Systematic... Nov 2021Measles, mumps, rubella, and varicella (chickenpox) are serious diseases that can lead to serious complications, disability, and death. However, public debate over the... (Review)
Review
BACKGROUND
Measles, mumps, rubella, and varicella (chickenpox) are serious diseases that can lead to serious complications, disability, and death. However, public debate over the safety of the trivalent MMR vaccine and the resultant drop in vaccination coverage in several countries persists, despite its almost universal use and accepted effectiveness. This is an update of a review published in 2005 and updated in 2012.
OBJECTIVES
To assess the effectiveness, safety, and long- and short-term adverse effects associated with the trivalent vaccine, containing measles, rubella, mumps strains (MMR), or concurrent administration of MMR vaccine and varicella vaccine (MMR+V), or tetravalent vaccine containing measles, rubella, mumps, and varicella strains (MMRV), given to children aged up to 15 years.
SEARCH METHODS
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library 2019, Issue 5), which includes the Cochrane Acute Respiratory Infections Group's Specialised Register, MEDLINE (1966 to 2 May 2019), Embase (1974 to 2 May 2019), the WHO International Clinical Trials Registry Platform (2 May 2019), and ClinicalTrials.gov (2 May 2019).
SELECTION CRITERIA
We included randomised controlled trials (RCTs), controlled clinical trials (CCTs), prospective and retrospective cohort studies (PCS/RCS), case-control studies (CCS), interrupted time-series (ITS) studies, case cross-over (CCO) studies, case-only ecological method (COEM) studies, self-controlled case series (SCCS) studies, person-time cohort (PTC) studies, and case-coverage design/screening methods (CCD/SM) studies, assessing any combined MMR or MMRV / MMR+V vaccine given in any dose, preparation or time schedule compared with no intervention or placebo, on healthy children up to 15 years of age.
DATA COLLECTION AND ANALYSIS
Two review authors independently extracted data and assessed the methodological quality of the included studies. We grouped studies for quantitative analysis according to study design, vaccine type (MMR, MMRV, MMR+V), virus strain, and study settings. Outcomes of interest were cases of measles, mumps, rubella, and varicella, and harms. Certainty of evidence of was rated using GRADE.
MAIN RESULTS
We included 138 studies (23,480,668 participants). Fifty-one studies (10,248,159 children) assessed vaccine effectiveness and 87 studies (13,232,509 children) assessed the association between vaccines and a variety of harms. We included 74 new studies to this 2019 version of the review. Effectiveness Vaccine effectiveness in preventing measles was 95% after one dose (relative risk (RR) 0.05, 95% CI 0.02 to 0.13; 7 cohort studies; 12,039 children; moderate certainty evidence) and 96% after two doses (RR 0.04, 95% CI 0.01 to 0.28; 5 cohort studies; 21,604 children; moderate certainty evidence). The effectiveness in preventing cases among household contacts or preventing transmission to others the children were in contact with after one dose was 81% (RR 0.19, 95% CI 0.04 to 0.89; 3 cohort studies; 151 children; low certainty evidence), after two doses 85% (RR 0.15, 95% CI 0.03 to 0.75; 3 cohort studies; 378 children; low certainty evidence), and after three doses was 96% (RR 0.04, 95% CI 0.01 to 0.23; 2 cohort studies; 151 children; low certainty evidence). The effectiveness (at least one dose) in preventing measles after exposure (post-exposure prophylaxis) was 74% (RR 0.26, 95% CI 0.14 to 0.50; 2 cohort studies; 283 children; low certainty evidence). The effectiveness of Jeryl Lynn containing MMR vaccine in preventing mumps was 72% after one dose (RR 0.24, 95% CI 0.08 to 0.76; 6 cohort studies; 9915 children; moderate certainty evidence), 86% after two doses (RR 0.12, 95% CI 0.04 to 0.35; 5 cohort studies; 7792 children; moderate certainty evidence). Effectiveness in preventing cases among household contacts was 74% (RR 0.26, 95% CI 0.13 to 0.49; 3 cohort studies; 1036 children; moderate certainty evidence). Vaccine effectiveness against rubella, using a vaccine with the BRD2 strain which is only used in China, is 89% (RR 0.11, 95% CI 0.03 to 0.42; 1 cohort study; 1621 children; moderate certainty evidence). Vaccine effectiveness against varicella (any severity) after two doses in children aged 11 to 22 months is 95% in a 10 years follow-up (rate ratio (rr) 0.05, 95% CI 0.03 to 0.08; 1 RCT; 2279 children; high certainty evidence). Safety There is evidence supporting an association between aseptic meningitis and MMR vaccines containing Urabe and Leningrad-Zagreb mumps strains, but no evidence supporting this association for MMR vaccines containing Jeryl Lynn mumps strains (rr 1.30, 95% CI 0.66 to 2.56; low certainty evidence). The analyses provide evidence supporting an association between MMR/MMR+V/MMRV vaccines (Jeryl Lynn strain) and febrile seizures. Febrile seizures normally occur in 2% to 4% of healthy children at least once before the age of 5. The attributable risk febrile seizures vaccine-induced is estimated to be from 1 per 1700 to 1 per 1150 administered doses. The analyses provide evidence supporting an association between MMR vaccination and idiopathic thrombocytopaenic purpura (ITP). However, the risk of ITP after vaccination is smaller than after natural infection with these viruses. Natural infection of ITP occur in 5 cases per 100,000 (1 case per 20,000) per year. The attributable risk is estimated about 1 case of ITP per 40,000 administered MMR doses. There is no evidence of an association between MMR immunisation and encephalitis or encephalopathy (rate ratio 0.90, 95% CI 0.50 to 1.61; 2 observational studies; 1,071,088 children; low certainty evidence), and autistic spectrum disorders (rate ratio 0.93, 95% CI 0.85 to 1.01; 2 observational studies; 1,194,764 children; moderate certainty). There is insufficient evidence to determine the association between MMR immunisation and inflammatory bowel disease (odds ratio 1.42, 95% CI 0.93 to 2.16; 3 observational studies; 409 cases and 1416 controls; moderate certainty evidence). Additionally, there is no evidence supporting an association between MMR immunisation and cognitive delay, type 1 diabetes, asthma, dermatitis/eczema, hay fever, leukaemia, multiple sclerosis, gait disturbance, and bacterial or viral infections. AUTHORS' CONCLUSIONS: Existing evidence on the safety and effectiveness of MMR/MMRV vaccines support their use for mass immunisation. Campaigns aimed at global eradication should assess epidemiological and socioeconomic situations of the countries as well as the capacity to achieve high vaccination coverage. More evidence is needed to assess whether the protective effect of MMR/MMRV could wane with time since immunisation.
Topics: Chickenpox; Child; Humans; Infant; Measles; Measles-Mumps-Rubella Vaccine; Mumps; Rubella
PubMed: 34806766
DOI: 10.1002/14651858.CD004407.pub5 -
The Pediatric Infectious Disease Journal Nov 2021The safety and immunogenicity of M-M-RII (measles, mumps and rubella virus vaccine live, Merck & Co., Inc., West Point, PA)-the only combined measles, mumps and rubella...
Evaluation of the Safety and Immunogenicity of M-M-RII (Combination Measles-mumps-rubella Vaccine): Clinical Trials of Healthy Children and Adults Published Between 2010 and 2019.
BACKGROUND
The safety and immunogenicity of M-M-RII (measles, mumps and rubella virus vaccine live, Merck & Co., Inc., West Point, PA)-the only combined measles, mumps and rubella vaccine licensed for use in the United States-were previously reported in pre- and postlicensure clinical trials conducted from 1988 to 2009. M-M-RII continues to be evaluated as a comparator in clinical trials of other vaccines. Here, we review safety and efficacy data from more recent clinical trials of M-M-RII.
METHODS
We performed a systematic literature review of trials using M-M-RII published from 2010 to 2019.
RESULTS
In the 15 studies that met the inclusion criteria, a total of 12,032 subjects were vaccinated: 7667 persons received a first dose only, 2137 participated in 2-dose studies (128 received 1 dose and 2009 received both) and 2063 received a single dose of M-M-RII as their second dose. Dose number was not specified for 165 participants, ≥6 years old, in 2 studies in which a single dose of M-M-RII was administered. Similar to previous reports, M-M-RII was well tolerated and immunogenic when administered alone or concomitantly with other routinely recommended vaccinations. The most common adverse events included transient injection site pain and fever. Serious adverse events were extremely rare, with only 4 probable or potential vaccine-related events reported among the 12,032 participating subjects.
CONCLUSIONS
In trials published from 2010 to 2019, M-M-RII continued to be safe and immunogenic in all age groups studied. These data, along with the results of earlier trials, indicate that the performance of the vaccine has been consistent across more than 30 years of postlicensure studies.
Topics: Antibodies, Viral; Clinical Trials as Topic; Humans; Immunization Schedule; Immunogenicity, Vaccine; Measles; Measles-Mumps-Rubella Vaccine; Mumps; Research Report; Rubella; Vaccination; Vaccines, Combined
PubMed: 34310506
DOI: 10.1097/INF.0000000000003273