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this has now become the dominant strain producing an illness that is transmitted in the same way as seasonal influen

this is an openaccess article distributed under the terms of the creative commons attribution noncommercial license httpcreativecommonsorglicensesbync30 which permits unrestricted noncommercial use distribution and reproduction in any medium provided the original work is properly cited za which in most cases is mild which can be effectively treated with antiviral drugs and for which a vaccine is now available by the end of 2009 many countries were still reporting disease activity and an impact on healthcare services [2]

in the early days of the h1n1 pandemic when there was uncertainty about the infectivity and virulence of the new virus a more precautionary approach to management was advocated this included laboratory testing of suspected cases contact tracing isolation of cases and contacts antiviral medication for treatment and prophylaxis and clinical surveillance and followup

in this short case report we describe the personal experience and management of the first case of h1n1 reported in the united arab emirates uae

the patient was a 48 yearold male academic public health physician who had just returned to the middle east after

wwweshaworg spending a week with his family in saskatoon in canada his journey to the uae was via calgary and heathrow airport in london uk he started feeling lethargic and developed a sore throat with cough and high fever for around 10 hours since the night of his arrival in dubai uae this led him to consult the onduty infectious disease consultant at the emergency department of a local hospital at around 800 am the following day

the consultation included a discussion of any possible exposure to h1n1 since canada was recognized then as experiencing a large number of cases of the infection a combined influenza ab antigen screen on a nasopharyngeal swab was positive and an additional swab and a blood sample were then sent for further confirmatory testing he was prescribed oseltamivir 75 mg orally twice daily for five days azithromycin 500 mg daily and paracetamol 500 mg three times daily for three days and advised to remain at home until the confirmatory test results were available

by the next morning the patients fever and sore throat had subsided and he was feeling better despite the very low but nevertheless real risk of having swine flu the patient had to make some important difficult decisions regarding his state of health and his work deadlines his work place was a university campus and as he had no lectures that day he had no need to be in contact with any students all scheduled appointments on his calendar for the day were cancelled but he decided to proceed with a tenminute scheduled presentation to six of his peers regarding a large research grant proposal a mask was not worn during the presentation and he returned home immediately after the event the patient was alone at home but one of his relatives came to visit him unannounced accompanied by his wife and a ten year old child from a neighboring town they stayed at his home for that night as the distance for return travel was considerable

on the next day the patient received a call from the health authority confirming influenza a h1n1 infection and he was therefore in the unenviable although historical position of being the first reported case of h1n1 infection in the uae the patient was admitted to hospital with airborne and contact isolation where he completed the rest of the maximum recommended 10 days quarantine period the visiting couple and child also had to stay at the patients home for 10 days of quarantine and all also received prophylactic medicine oseltamivir no lab tests were advised

as a public health physician the index case had considered the h1n1 situation before commencing his travels to canada at that time may 8 2009 the world health organization who did not recommend restricting travel although some individual national authorities were advising against nonessential travel the advice on the various websites seemed very pragmatic observe basic hygiene handwashing and cough etiquette do not travel when ill and seek medical advice if you become ill after your return the patients route to canada took him through london 34 cases reported in the uk at that time and toronto 15 cases in ontario to saskatoon 2 cases by the time he was due to return to the uae from saskatoon via calgary the number of cases in canada had increased from 242 to 496 with 19 in saskatchewan and 67 in alberta during his stay in saskatoon he did not recall meeting anyone with respiratory symptoms and he was quite well on his journey back to dubai he was therefore not certain where and from whom he caught the infection

this case raised several issues related to workplace and general public health measures taken by the uae government to prevent an influenza epidemic include the installation of thermal scanners at dubai sharjah and abu dhabi airports three major international airports in the united arab emirates the individual was afebrile and symptomfree on arrival at the airport and so was not detained for further enquiry the thermal scanners will detect individuals with fever from whatever cause but will not necessarily detect those with early h1n1 infection especially if they are afebrile [3]

effective and timely communication is essential to allay unwarranted concerns from the public and at the workplace queries from the media were channeled to a senior member of the administration from the office of the dean to ensure consistency in the information provided he was briefed by public health physicians occupational health physicians and hospital clinicians dealing directly with the case a central news release was provided to staff and students on h1n1 reiterating the importance of hygiene in regards to limitation of transmission the workplace was a university campus this case did not have any lectures or meetings with students contact with a few coworkers was transient not more than 15 minutes in the same area these contacts were counselled on the low likelihood of acquiring the infection they were informed about seeking medical advice if they had any other reasons for concern or if they developed h1n1 symptoms doctors nurses and ancillary healthcare workers looking after the case while in hospital were briefed on hygiene and infection control procedures n95 masks gloves and gowns were provided to healthcare staff

the health department took prompt action family members with close contact were quarantined at home they were given a prophylactic course of oseltamivir adequate supplies of food and provisions and maintenance of phone communiwwweshaworg cation was confirmed the public health department dealt with general queries from the public official release of information and contact with the who was through the federal ministry of health the airline that transported the case from canada to the uae sought to contact passengers in the rows adjacent to the passengers allocated seat none of those who were traced developed any flulike illness within the incubation period following the timing of the flight

where new epidemics of infectious diseases appear history has shown that the cases have often included healthcare workers and their family members [4] the index case for ebola infection was a hospital laboratory worker and secondary cases occurred in other healthcare workers and within the family twothirds of the deaths from the early outbreaks of ebola infection occurred in healthcare staff the early cases of sars and h5n1 infection included doctors and nurses [5] [6] [7] the likelihood of healthcare staff being affected in such infections is high especially in the absence of adequate preventive measures or if there is poor compliance with recommended precautions in this particular first reported case of h1n1 infection in the uae prompt and appropriate action resulted in the individual being treated the risk of transmission being reduced and the provision of information being timely and adequate none of the known contacts developed signs and symptoms of the disease it was not possible to contact the taxi driver who shared the same vehicle with the case during the hour long journey from the airport home but there were no reports of infection in any dubai taxi driver in the 2 weeks following the journey

we now believe that even if they are infectious clinicians who practice good respiratory and hand hygiene will limit the risk of transmission to others standard and droplet precautions should be in place [8] standard precautions minimize exposure to potentially infected blood and body fluids and include hand hygiene and the use of appropriate personal protective equipment droplet precautions require that a medical mask is worn when working within one meter of the patient and that when performing aerosolgenerating procedures further measures are taken including the use of eye protection n95 masks or other equivalent or more effective respirators and other personal protective equipment in addition respiratory or cough etiquette should be observed so that all persons cover their mouth and nose with a disposable tissue when coughing or sneezing and then disposing the used tissue promptly within the healthcare setting administrative environmental and engineering controls such as frequent cleaning of work areas should also be in place

generally it will not be appropriate to conduct contact tracing of patients or to provide antiviral prophylaxis however if there has been a particular type of contact between a healthcare worker and a patient for example intubation or a patient is at high risk of severe or complicated infection then further risk assessment is indicated with a view to offering prophylaxis an alternative approach if practical is to monitor exposed persons and administer antiviral treatment when symptoms develop when a vaccine becomes available the first priority should be to immunize healthcare staff

when pandemic influenza is widespread in a community it will inevitably have consequences for the workplace not least because that is a setting where transmission can occur in these circumstances occupational health practitioners should be prepared to lead a consistent and proportionate response staff with influenza will be diagnosed on the basis of symptoms the clinical diagnostic criteria are fever 38 o c or a history of fever and two or more symptoms of an influenzalike illness ie cough sore throat headache etc those who satisfy this case definition should be sent home and advised not to work until fully recovered a risk assessment should be carried out and the risk of transmission to other staff members should be considered in terms of the excess risk compared to acquiring the infection from other community sources

stories about the new h1n1 case in town appeared daily and reflected public anxiety the media can play an important role in allaying the fears of the community by providing adequate and accurate information the installation of thermal scanners at points of entry has their limitations and is not recommended by the who studies indicate many of its drawbacks including a low positive predictive value of 35 [2]

an unpublished population study carried out in the uae during october 2009 by medical students investigated the impact of the recent h1n1 pandemic on the parents of primary school children they found that while the majority of parents had good knowledge of h1n1 and its mode of transmission many had mistaken beliefs about the origin of the virus for example thinking that it had been genetically engineered parents reported changing their behaviour because of h1n1 taking measures such as cancelling travel plans and restricting socializing also while most had confidence in the way in which the authorities had managed the pandemic they continued to worry that their families were at risk of infection and were not persuaded of the safety of available vaccines

b09fe466052873919115ea1da6510a01704c6c3a background chronic cough in children is a diagnostic challenge objective to discover the utility of nasal dipsticks and polymerase chain reaction pcrdna analysis in differentiating bacterial sinusitis from other causes of chronic cough and identifying pathogens from the nasal cavity method we recruited 22 patients under 15 years of age with cough lasting longer than 4 weeks group 1 7 controls with allergic rhinitis group 2 and 10 controls without respiratory symptoms group 3 based on symptoms the results of nasal secretion assays and nasal endoscopy a diagnosis of clinical bacterial sinusitis was made we identified potential pathogens by quantitative pcr of nasal secretions results group 1a cough with clinical bacterial sinusitis n 10 eight 80 patients had bacterial sinusitis associated with dominant potential pathogenic bacteria ppb streptococcus pneumoniae haemophilus influenzae and moraxella catarrhalis group 1b cough without clinical bacterial sinusitis n 12 none had dominant ppb group 2 allergic rhinitis n 7 none had dominant ppb group 3 asymptomatic n 10 none had dominant ppb twenty to 57 of all groups were colonized with staphylococcus aureus fifty to 70 were colonized with staphylococcus epidermidis corynebacterium pseudodiphtheriticum and dolosigranulum pigrum conclusion in children with chronic cough clinicians can utilize a simple and inexpensive nasal secretion dipstick assay for rapid diagnosis of sinusitis and identify ppb by dnapcr test for specific antibiotic treatment "chronic cough is defined as daily cough lasting 4 weeks or longer 1 in children under 15 years of age the causes of chronic cough include congenital defects asthma foreign body aspiration infections allergic diseases gastroesophageal reflux tumors and other rare causes 2 among these the most common etiologies include asthma upper airway cough syndrome protracted bacterial bronchitis and nonspecific cough 3 4 the diagnosis of asthma or cough variant asthma can be made on the basis of naepp epr3 criteria and response to a bronchodilator 5 upper airway cough syndrome is a common entity 3 4 most likely triggered by postnasal drip due to either allergic and nonallergic rhinitis or bacterial and nonbacterial sinusitis protracted bacterial bronchitis is now recognized as one of the most common causes of chronic wet cough especially in young children under 5 years of age 6 7 once asthma and other conditions listed above are ruled out upper airway cough syndrome or protracted bacterial bronchitis need to be considered as the most likely diagnoses in approaching these clinical entities our goal was to promptly detect the patients with bacterial sinusitis and the involved pathogens and to treat them with appropriate antibiotics to this end we decided to employ a novel method described by huang and small 8 who reported that nasal secretion dipstick assay was highly correlated with sinus imaging studies and could be utilized for the diagnosis of sinusitis we employed this simple approach for obvious reasons speed costeffectiveness and avoidance of radiation risk associated with sinus imaging studies we also sought an equally simple and rapid method for identification of the pathogens for the suspected sinusitis positive findings in imaging studies of sinuses such as opacities and thickened lining indicate the presence of inflammation possibly infection but may have poor correlation with clinical disease 910 and do not reveal any information on etiologies although sinus puncture would yield such information 11 this cannot be performed in most nonsurgical office settings studies have documented that nasal culture is a poor reflection of the microbes in the sinus cavity 12 therefore we analyzed the microbes from the osteomeatal area utilizing a quantitative pcr method in an attempt to detect the pathogens that may cohabit both sinus and nasal cavities

this prospective study was conducted between 2017 and 2018 with the approval of the institutional review board and human subject committee at la biomedharborucla medical center informed consent was obtained from all patients

we recruited 39 children from 1 to 14 years of age composed of 3 groups

patients with chronic cough group 1a and 1b we studied 22 children who had cough for longer than 4 weeks among these 10 patients who met the clinical diagnostic criteria of bacterial sinusitis listed below were subclassified as group 1a cough with clinical bacterial sinusitis and the other 12 as group 1b cough without clinical bacterial sinusitis

patients with allergic rhinitis group 2 we studied 7 patients with rhinitis and positive skin tests for respiratory allergens but without cough and lower respiratory symptoms

subjects without respiratory symptoms group 3 we studied 10 children without current or past respiratory complaints who were seen for routine physical checkups

all patients were interviewed for pertinent history and had nasal secretion assays and quantitative pcr analysis of nasal secretions the patients with chronic cough group 1 and allergic rhinitis group 2 had additional procedures nasal endoscopy and allergy skin testing

the clinical diagnosis of bacterial sinusitis was made when a patient met 2 out of 3 criteria consisting of positive clinical history of sinusitis nasal endoscopy and nasal secretion score as explained below

clinical history the complaint of facial pain sinus pressure or purulent nasal drainage was considered as positive history

nasal endoscopy jedmed flexible fiberoptic nasopharyngoscope st louis mo was used after the application of oxymetazoline nasal spray and 2 lidocaine spray to each nostril 3 times the presence of purulent discharge in the middle meatus or in the nasopharynx was considered to be a strong indicator for bacterial sinusitis

nasal secretion assay nasal discharge was obtained by swabbing with a wet cotton applicator 1 to 2 cm into the nasal antrum laterally and aiming at the middle meatus the applicator tip was then smeared over a urine dip strip the strip was scored in 4 components protein nitrite ph at 60 s and leukocytes at 120 s the scoring was done according to the protocol published by huang et al 8 as follows

the total score was the sum of individual scores of protein ph leukocyte esterase and nitrite a score above 3 was considered as an indicator of bacterial sinusitis

nasal secretion samples were collected by inserting the swab into the nostrils and rubbing while rotating the swab from a depth of 2 to 3 cm and sent to microgen diagnostics lubbock tx for dna analysis of nasal microbes for rapid identification of ppb potential pathogenic bacteria and ppv potential pathogenic virus

this report generated within 24 hours of sample collection utilized the rapid quantitative pcr method using a roche lightcycler 480 ii instrument that detects 7 types of bacteria and the bacterial load 1 fungus 19 resistance genes for the following antibiotics were included vancomycin methicillins betalactams carbapenems macrolides aminoglycosides tetracyclines and quinolones once the presence of bacteria was identified relative quantity abundance of these was reported in percentage of total bacterial load subsequently by using ngs nextgeneration sequencing machine the method utilized universal 16s and internal transcribed space amplicon sequencing on the ion torrant personal genome machine a bacterium with abundance greater than 50 was considered to be a dominant species

streptococcus pneumonia sp hi and moraxella catarrhalis mc were classified as ppb and staphylococcus epidermidis se corynebacterium pseudodiphtheriticum cp and dolosigranulum pigrum dp were classified as pnpb sa was classified separately rhinovirus and parainfluenza virus were classified as potentially pathogenic viruses ppv these classifications will be elaborated in the discussion section

allergy skin tests were employed to identify patients with allergic rhinitis group 2 tests were performed according to a standard procedure using 16 to 40 inhalant allergens stallergenes greer london uk applied to the skin by multitest applicator lincoln diagnostics decatur il the allergens included dust mites cat dog molds and pollens of grass trees and weeds specific to southern california

means or medians and standard deviations or interquartile ranges were computed for continuous variables frequencies and percentages were compared for categorical variables analysis of variance was used if the outcome followed a normal distribution the kruskalwallis test was used for nonnormal continuous outcomes chisquare or fisher exact tests were used to compare differences in proportions among groups sas 94 software cary nc was used for all data analyses

as stated in the methods section subjects who met 2 out of 3 sinusitis criteria were classified as group 1a nasal endoscopic findings p 04 and nasal secretion scores p 0001 were highly sensitive and could have been used as the selection criteria by themselves as shown in table 1 tables 2 and 3 and figure 1

the group with clinical diagnosis of bacterial sinusitis group 1a carried ppb in their nasal cavity in higher percentage nppb sa and ppv were present in various degrees in all 3 groups but there were no statistically significant patterns discernible group 1b twelve patients were classified into a nonbacterial cough group since they did not meet the above bacterial sinusitis criteria two patients 17 demonstrated the presence of ppb but none of which were dominant three 25 patients demonstrated the presence of ppv antigens and 1 8 had concomitant ppb and ppv group 2 among 7 patients with allergic rhinitis 1 patient had nondominant ppb one 14 patient carried ppv

all patients in group 1a reported improvement of cough after 2 to 8 weeks of antibiotic treatment nasal secretion assay score also decreased below 4 in all patients in group 1b were symptomatically managed with varying success without the use of antibiotics

all patients in group 1a 1b and 2 were tested for the sensitization to aeroallergens allergic sensitization was present in 5 out of 10 patients 50 in group 1a and 11 out of 12 patients 91 in group 1b

in children acute sinusitis is usually defined as symptoms lasting less than 30 days chronic sinusitis longer than 90 days and subacute sinusitis in between these 2 ranges 13 acute sinusitis is associated with sinus pressure purulent nasal drainage cough and the presence of ppb 13 14 in chronic and subacute sinusitis protracted cough may play a more prominent role than nasal symptoms 13 15 the pathology of subacute sinusitis may resemble acute sinusitis 14 while chronic sinusitis may involve inflammatory processes in association with various microbes including sa especially in patients with nasal polyposis 1416 among group 1 patients 9 patients had chronic and 13 patients subacute symptoms data not shown once we made the clinical diagnosis of bacterial sinusitis based on the previously mentioned criteria group 1a we sought to identify the predominant bacteria associated with the condition although asymptomatic children may be colonized by ppb in the middle meatus 17 the presence of these ppb in the nasal cavity of patients diagnosed with clinical sinusitis may reveal the pathogens lee et al reported a study of 31 adults with acute sinusitis in which 61 of nasopharyngeal and 48 of middle meatal samples grew ppb and that the concordance rate between the 2 sites was 84 18 we wanted to increase the sensitivity of microbial identification by employing dnabased molecular diagnostics recent studies indicate that molecular diagnostic approaches yield much more accurate results with regard to diversity and quantities of microbes present in the sinus and nasal cavities [19] [20] [21] [22] [23] once the pcr results were reported we classified these bacteria into different categories depending on their pathogenic potential sp hi and mc were classified as ppb since these have been established as predominant pathogens for acute and subacute sinusitis by previous studies 12 24 se is reported to be a commensal bacterium in the nasal cavity 25 although cp was characterized as pathogenic in some studies 26 it was reported to be part of natural microbiota of the nares and throat 27 dp has not been reported to cause sinusitis 28 sa was classified separately because of its presence in the nasal and sinus cavities of asymptomatic subjects [29] [30] [31] and patient with sinusitis 32 33 rhinovirus and parainfluenza virus were the only viruses identified and classified as potentially pathogenic viruses ppv since it is well known to cause upper respiratory symptoms as seen in tables 2 and 3 the presence of ppb as a dominant species in the nasal cavities correlated with the clinical diagnosis of bacterial sinusitis p 002 indicating that dominance of microbes over others is an important element of pathogenesis 34 the presence of a ppb in group 1b 2 and 3 is not surprising because it is known to inhabit the nasal cavities of asymptomatic subjects 17 the nondominance of these ppb along with other clinical features should enable the clinicians to separate these groups from the ones with bacterial sinusitis 1a group 1a may represent a combination of recurrent acute subacute and chronic sinusitis with bacterial infections these ppb are also reported to be the most common pathogens associated with acute otitis media 33 and protracted bacterial bronchitis 6 7 it is possible that these patients may indeed have simultaneous sinusitis and protracted bacterial bronchitis since antibiotic treatment stops coughing in both entities such coexistence via one airway needs to be explored in the future in group 1b chronic cough was most likely due to postnasal drip resulting from nonbacterial pathologies such as allergy 91 of the patients had allergen sensitization as shown in table 1 viral infection or chronic irritation although sa was present as dominant species in 2 patients in this group its pathogenic role is doubtful due to their presence in control groups 2 and 3 staphylococci were present in the sinus aspirates of acute 29 chronic sinusitis 14 20 21 and in the nasal cavities of those with crs with nasal polyps 16 and may play a role in the pathogenesis of sinusitis especially in adults 32 33 but they were also shown to be present in the nasal cavities of 25 to 30 of asymptomatic subjects 30 in a competing relationship with pnpb 22 and their presence may be a transient colonization rather than infection 36 the presence of pnpb in all groups table 2 and figure 1 is consistent with the recent studies revealing asymptomatic cohorts also carry diverse commensal bacteria in the nasal cavities including sa se dp and cp and they maintain competing relationship among themselves 20 22 an intriguing finding was the presence of rhinovirus in all groups including asymptomatic controls indicating that its colonization was not necessarily associated with clinical symptoms in group 1a 60 of the patients carried ppv and 40 carried both ppb and ppv indicating that both viruses and bacteria were coexistent rhinovirus the most common viral pathogen in our study was shown to increase adhesion of ppb to nasal epithelial cells at least 2fold compared to uninfected controls 37 38 conclusion we demonstrated as others have in children with chronic cough with sinusitis microbial balance of the sinus cavity is disturbed and ppb takes the dominance this can be detected by simple methods dipstick assay and quantitative dnapcr test of the nasal secretion therefore we recommend that clinicians utilize these methods as an alternative to imaging studies to make a diagnosis of bacterial sinusitis and offer a specific therapy for the pathogens in a rapid and accurate manner further studies are indicated to replicate these findings and refine the potential diagnostic capabilities of dnabased methods for bacterial sinusitis and bronchitis

the editors gratefully acknowledge the assistance of margaret keller md lynn smith md and joaquin madrenas md phd who reviewed the manuscript

the authors declared no potential conflicts of interest with respect to the research authorship andor publication of this article

this study was approved by los angeles biomed clinical trial registration httpsimedrislabiomedorgdatabase3090701

the authors disclosed receipt of the following financial support for the research authorship andor publication of this article dnabased analysis was provided to the authors free of charge by microgen diagnostics lubbock tx

approved by institutional review board

informed consents were obtained from all subjects who participated in this project

this article does not contain any studies with animal subjects" "Song

165792449dc650fba4a923f3a94a851754a7bcb7 "the international health regulations ihr 2005 as the overarching instrument for global health security are designed to prevent and cope with major international public health threats but poor implementation in countries hampers their effectiveness in the wake of a number of major international health crises such as the 2014 ebola and 2016 zika outbreaks and the findings of a number of highlevel assessments of the global response to these crises it has become clear that there is a need for more joinedup thinking between health system strengthening activities and health security efforts for prevention alert and response who is working directly with its member states to promote this approach more specifically around how to better embed the ihr 2005 core capacities into the main health system functions this paper looks at how and where the intersections between the ihr and the health system can be best leveraged towards developing greater health system resilience this merging of approaches is a key component in pursuit of universal health coverage and strengthened global health security as two mutually reinforcing agendas

background in todays increasingly interconnected and interdependent world where people goods and services move easily across borders it is more important than ever to ensure that countries are able to respond in timely and effective fashion to contain and indeed prevent threats to public health [1] [2] [3] recent global health crises including h1n1 influenza 2009 ebola 2014 and zika 2016 have resulted in pointed criticisms of the international health communitys ability to deal with such threats but crises also offer opportunities for learning and improvement an important result of such criticism has been an incremental strengthening of international resolve and knowhow to promote and improve global health security covering both individual and collective health security at globalinternational level 4

as the leading global organisation with responsibility for health governance who has bore the brunt of the criticism [5] [6] [7] depending on the crisis accusations have ranged from responding too slowly or in ad hoc fashion to overreacting and fearmongering as well as not learning lessons and not making necessary structural and organisational reforms proposals for taking the health security agenda forward have thus included reaffirming and strengthening whos central role and the need to better resource the organisation to removing emergency response from whos purview and even setting up a new body entirely 8 9 against the backdrop of such debate who continues to implement a wider reform process which since ebola includes emergency capacities and work in promoting global health security i

central to these discussions are the international health regulations ihr which have been at the heart of the global health security agenda since 1969 preceded by the international sanitary regulations from 1951 the ihr aim to prevent protect against control and provide a response to public health threats through improved surveillance reporting and international cooperation and to do so in ways which avoid unnecessary interference with international traffic and trade 10

enforceability has long been seen as a concern 11 who works directly with countries to make the ihr 2005 obligations easier to implement and maintain moreover a concerted effort is underway to ensure that the ihr requirements are an integral part of essential public health operations and to better embed them into whos health systems strengthening work this is to ensure that the ihr 2005 core capacity requirements are integral to national health systems rather than seen as a topdown set of externally imposed stipulations

in making the case for better embedding the ihr into national health systems in pursuit of universal health coverage uhc this paper outlines the need for more joinedup thinking between the ihr core capacities and health system functions it provides a brief outline of the ihr before focusing on a number of important intersections with health systems and showing where they can be built on in closing we touch on actions that who is taking to increase its effectiveness in this area and stress the importance of strong health systems for delivering ihr commitments the aim is to identify a number of key issues in order to prompt discussion about health systems and global health security in general as well as whos role and the ihr

the international health regulations working for global health security following the severe acute respiratory syndrome crisis of 2003 the international community agreed to improve the detection reporting and response to potential public health emergencies worldwide this required reevaluating the existing ihr 1969 which was a framework for reporting only three infectious diseases cholera plague and yellow fever smallpox was removed in 1981 following its official eradication in 1980 the result was a new articulation of the ihr in 2005 that widened the scope of coverage to include all events including chemical and nuclear hazards that could lead to public health emergencies of international concern pheic the revised ihr 2005 came into force in 2007

in 2009 in the aftermath of the h1n1 influenza pandemic whos executive board convened an independent review of the effectiveness of the ihr 2005 12 the review highlighted a number of positives but concluded that more was required for the world to respond adequately to sustained public health emergencies and delivered a series of recommendations including lessons for future pheics what are the new findings that health system strengthening and health security efforts for prevention alert and response need to be pursued in tandem as part of the same mutually reinforcing approach to developing resilient health systems is a new understanding there is now a demonstrated need to embed the ihr 2005 core capacities into health systems across the six health system functions where the leadership and governance function is probably the most important to improving ihr implementation and pursuing universal health coverage uhc uhc supports health security eg preventing outbreaks through high immunisation coverage providing early alert by rapid access of all patients to healthcare better response thanks to reliable infrastructure and healthcare workforce for case management etc while health security investment supports uhc by avoiding health crises that prevent patients accessing healthcare eg a health workforce diverted from regular care to focus on crisis response or is itself victim of the crisis as seen during severe acute respiratory syndrome influenza pandemics ebola etc or patients fear of contamination sees them avoid regular care seeking understanding this mutual reinforcement and the urgent need for joint work and synergy between health system strengthening and health security efforts is a new concept

recommendations for policy close coordination between the health system and health security is a new approach which is gaining momentum as major donors as well as the g7 and g20 want to see systematic coordination between uhc and global health security things are already changing for instance through the joint external evaluations jee for country health emergency preparedness and the subsequently developed national action plans which embed health security functions within the national health system strategy and budget in future it is expected that the bridge between health systems and global health security will become stronger given their shared objective of creating resilient health systems

the ability to detect and assess events ensure that surveillance systems and laboratories can detect potential threats and understand the nature and potential severity and impact of the event in order to be able to make decisions in public health emergencies notify and report events report specific diseases plus any potential public health emergencies to who through a network of national ihr focal points verify and respond countries are expected to be able to implement preliminary control measures immediately and respond appropriately to public health risks and emergencies 10 the ihr 2005 also require some core capacity for designated airports ports and ground crossingspoints of entryat all times as well as responding to pheics in order to limit the international spread of public health risks and to prevent unwarranted travel and trade restrictions there are further expectations around countries capacity for coordination multisectoral action eg between health transport food agriculture the environment etc and ability to mutually support each other in the event of a public health emergency

once an event is reported who reviews the situation declaring the event a pheic if it is thought to constitute a public health risk to other countries through the international spread of disease and if it potentially requires a coordinated international response to date despite increasing numbers of potential events being reported and hundreds of updates and announcements posted on the ihr event information site for national ihr focal points who has declared just four pheics influenza a h1n1 pandemic 2009 intersections with health systems who supports assessments of countries ihr 2005 core capacities to date these have been selfreported and involve states parties returning annually a completed questionnaire to who implementation and reporting has not been consistent across countries 11 13 and the information does not necessarily indicate how the ihr 2005 capacity requirements are actually implemented in the country ii to improve the quality of reporting countries have been recommended to move from exclusive selfevaluation to approaches that combine selfevaluation peer review and voluntary external evaluations involving a combination of domestic and independent experts this has been addressed by the newly proposed ihr monitoring and evaluation framework which includes in addition to the selfevaluation voluntary joint external evaluation jee simulation exercises and afteraction ii the commission on creating a global health risk framework for the future ghrf noted in its report that only a third of countries had so far complied with the ihr 2005 requirements reviews the jee and the other assessment instruments help assess gaps to develop a national action plan to strengthen country ihr capacity including through multisectoral action iii

much of the data and feedback can also be related to how well the health system itself is functioning as the ihr 2005 address a subset of health systems strengthening and coordination challenges 14 a countrys ability to detect report and respond to health threats requires strong relationships between for example clinical laboratories and health information systems and medical technologies and between numbers of emergency personnel and training of the public health workforce moreover emergency responses to health threats involve coordination financing incident management systems public awareness and community engagement underpinned by strong government commitment and resources 15 these are all system issues and are reflected in the who health systems framework iv which comprises six independent but interrelated building blocks working in tandem

1 service delivery 2 health workforce 3 health information systems 4 medical products vaccines and health technologies 5 health financing and 6 leadership and governance 16 a recent systematic review of the building blocks relevance to the ebola outbreak underlines their importance in practice and as an evaluative framework 17 while all of these components are necessary for organising a systemwide response this paper focuses primarily on two areas at the backbone of any response to a public health emergency and where the ihrhealth system intersections can be particularly strengthened and better institutionalised in countries leadershipgovernance and health information systems these blocks are broader functional domains requiring more crosscutting policy responses and longterm strategic planning

of all of the health system building blocks leadership and governance is probably the most important in improving ihr implementation and in countering outbreaks in general it underpins the other health system components and constitutes the cornerstone of any effort to strengthen health security this is true at both national and global level

at national level where compliance with ihr 2005 remains patchy despite a whoissued series of guidance for implementation in national legislation v a stronger legal basis to overcome the lack of a formal enforcement mechanism and to ensure coordinated and rapid action through the health system could help to address iii see httpappswhointirishandle10665204368 iv who defines a health system as consisting of all organisations people and actions whose primary intent is to promote restore or maintain health its goals are improved health and health equity towards universal health coverage uhc v see httpwwwwhointihrlegal_issueslegislationen

some of the implementation gaps and failings already identified for instance the usa employs a public health legal preparedness phlp framework which represents a legal imperative for multisectoral action in emergencies 18 while the us framework was borne of the need to serve a federal structure there is a need for something similar in countries in order to formally mandate obligatory multisectoral responses in support of health system emergency preparedness and the ihr 2005 and while this cannot necessarily eliminate the potential for domestic political factors to impede ihr 2005 complianceas was the case with both the h1n1 pandemic and ebola outbreaksuch a mesolevel bottomup approach can help to ensure an adequate response and make the case for greater compliance this is in line with calls from civil society for a socialisation of the ihr 2005 19 the need for strong intervention at and with community level 20 and the need to confer national ownership to countries a stronger implementation of the ihr 2005 both in terms of its embedding into the fabric of health systems and into national law potentially supported via an external funding source 21 could facilitate improved and timely detection and response to health threats and governance more widely

regarding the global level whos strengthening of the ihr 2005 is not just normative but constructive in a global health environment characterised by an increasing number of actors and agencies who is the de facto steward facilitating action and collaboration within the global health system at large 22 this involves priority setting at global level and ensuring that ihr 2005 and health system strengthening activities are part of wider international frameworks and directions such as the move towards uhc and the sustainable development agenda 2030 strong health systems resilient to health crises and with robust emergency policies are central to uhc and research has highlighted that a resilient health system is indeed one that is moving towards uhc 23 24 who can help to ensure that countries work towards meeting the sustainable development goals in line with global emergency preparedness activities eg in health financing and human resources for health collaboration with relevant international initiatives such as the global health security agenda vi support global health security as an international priority and global public good requiring full implementation of the ihr 2005

additionally there are longstanding calls for who to work more closely with nonstate actors such as the private sector and civil society vii such engagement is necessary to institutionalise the ihr 2005 requirements and build up health systems emergency response capacity 20 as animal health transport education finance civil defence and security towards such an objective article 44 of the ihr 2005 on collaboration and assistance requires who to the extent possible to work with other international bodies and networks and this could be further leveraged in a more proactive manner

finally messaging is crucial in a global health climate characterised by the need to demonstrate outcomes it is difficult to sell prevention and preparedness governments should acknowledge that health security has a cost with no immediate apparent outcome but that such investment is irreplaceable in the face of an imminent health emergency when the health system is capable of preventing detecting or effectively addressing a public health threat the greatest beneficiary is society at large at the same time many actors of the national economy eg transport tourism and trade and the private sector also benefit thus the messaging around investing in health security needs to be less on the tools and procedures and more on the destination for example a safer world such that public health emergencies do not spread globally and have limited if any impact on international travel trade and the economy

surveillance and monitoring is another central pillar of the ihr 2005 yet many countries continue to lack the required capabilities 13 25 from a health systems perspective this is a concern but perhaps not surprising a recent review of a number of leading health system frameworks found that surveillance capacity was in general insufficiently integrated and in some cases even nonexistent as a dedicated function who unpublished report 2015 where surveillance was included it was indicatorbased in turn highlighting the need for more eventbased surveillance for quicker risk and event detection as called for under the ihr 2005

national health information systems need to have the ability to detect verify and track events as soon as possible and to ensure the flow of health data among a variety of national and international stakeholders including who moreover they need to be able to rapidly transform such data into information for realtime decisionmaking all of this implies a good integration of data sources and systems involving surveillance clinical and laboratory services alert functions evidence synthesis and communication activities census results observational data and health system resources data continuing improvement of incident management systems requires the integration and standardisation of information and reporting requirements so that they are in place during emergency responses most countries already have some type of public health surveillance system that measures disease burden and mortalitymorbidity trends in order to guide programmes and resources along with an early warning and response system for public health threats integrating the ihr 2005 requirements into such bmj global health systems and creating or strengthening them where they are weak or nonexistent is a necessity

but the ihr 2005 also have more specific surveillance requirements such those as relating to points of entry in these jurisdictions for example customs immigration shipping and conveyance authorities etc collecting public health data is rarely seen as a priority addressing this is complex it would require changing protocols to ensure that more and relevant data are collected by such systems and services on an ongoing basis as well as training officials and including public health medical personnel in such settings this is equally the case for veterinary public health and agriculture as per the ihr 2005 given the potential threats stemming from the movement of animals and livestock and food production and distribution national health information systems need to be able to speak to and have interoperability with other sectors in terms of data exchange this includes being able to capture local specificities and connect with affected communities and actors an aspect of core capacitybuilding that is not explicitly covered in the ihr 2005 and which was clearly lacking in the countries affected by the ebola outbreak in west africa 26 mobilising other health system components for health emergency preparedness and response while leadership and health information systems require longterm strategic thinking the ability to quickly activate other health system building blocks are priorities both during emergencies and for securing the health system itself fulfilment of the ihr 2005 requires contributions from all parts of the health system encompassing service delivery as well as human financial and technological resources

with regard to services how these are organised managed and delivered is the most visible demonstration of the overall functioning and efficiency of the health systemespecially during a crisisand a core component of the uhc agenda the provision and maintenance of safe healthcare services ie with infection isolation procedures in place together with other infection control services that health professionals provide is the frontline of outbreak response with respect to the ihr 2005 there is a need to improve the coordination of delivery systems for public health and clinical care around emergenciessystems need to be flexible with plans developed and functions articulated collaboration with other stakeholders most notably the private sector for improved logistics in emergencies is also needed local healthcare service providers and local communities along with civil society must be involved as well indeed community awareness can boost surveillance 13 and all can play a crucial role in the rapid delivery of key services

a related health system building block is medical products vaccines and health technologies which are central to delivering emergency response under the ihr 2005 plans for their bulk purchase stockpiling and distribution need to be in place moreover stockpiles need to be real rather than simply pledged close relations with the private sector to help with drug development and vaccine delivery in emergency situations are also required

another crucial issue for emergency preparedness and response is human resources for healthin terms of numbers and availability relevant expertise and training and deployment for ihr 2005 purposes there is a raft of profiles required from the health workforce this includes epidemiologists clinicians public health specialists laboratory personnel health information experts and biostatisticians risk communication professionals sociologists and anthropologists as well as doctors nurses and veterinarians close collaboration with the health system can help to understand the optimal size skillmix and distribution of the health workforce required and can help in the design of appropriate training curricula for instance given the centrality of laboratory systems and services to the ihr 2005 designing field epidemiology and laboratory training programmes for staff are essential as is linking them to the health system

finally the importance of financing cannot be understated in estimating the economic cost of the ebola crisis on the economies of guinea liberia and sierra leone the world bank stresses how important investment in surveillance detection and treatment capacity is would have been 27 countries need to invest in their public health institutions and infrastructure such as local laboratory and diagnostic services to identify the hazards and events which can lead to emergencies and potential pheics as well as in specialist personnel and supplies additionally being able to mobilise health system finances in an emergency situation is key a health financing component should therefore be a central element of a countrys ihr 2005 planning

in terms of more concrete actions who is further supporting ihr 2005 training and capacity development in countries promoting the effectiveness of surveillance systems and supporting timely communication and informationsharing through the global network of national ihr focal points to complement the voluntary jee under the ihr monitoring and evaluation framework who is promoting and supporting public health threat simulation exercises and afteraction review whose results reflect the actual operational capacity of the alert and response system

additionally the organisation is heeding calls for housekeeping 28 the implementation of the ihr 2005 is often done in a vertical manner outside the health system strengthening effort at national level this situation traditionally reflects a similar issue within who where the ihr programme is seen as a vertical one even though it overlaps with other frameworks eg uhc the sustainable development goals essential public health functionsoperations with individual departments bmj global health and with other programmes responsible for delivering in ihrrelated areas eg the antimicrobial resistance and vaccine preventable diseases programmes the imperative for improving internal coherence and joint working has led to the creation of the new who health emergencies programme whe designed to build up whos effective operational role in emergency preparedness and during health crises its establishment reflects a key recommendation of the ebola interim assessment panel report 8 the new programme has one workforce one budget one line of accountability one set of processes systems and one set of benchmarks and maintains a standing interdepartmental task force at headquarters and regional office levels

changes are also required in terms of more immediate programmatic and daytoday activities one proposal is for the establishment of a who crosscutting task force comprising staff from health systems whe including ihr and other relevant programmes for it is clear that there are a number of very practical questions in relation to embedding the ihr capacity requirements within health systems viii such a who crosscutting task force and interdisciplinary group would provide guidance where technical and operational details need to be developed the group is already looking to develop a matrix crossreferencing ihr 2005 capacitiesspecifically coordination surveillance response preparedness and laboratory capabilitieswith the six health system building blocks in order to draw out areas of synergy promoting a systems approach as well as for the jee areas of work moreover there are key interlays with public health functionsall who regions have their own frameworks 29 which need to be developed such a group through its interregional composition would minimise silos and will introduce the ihr 2005 at all levels of who

stronger and more resilient health systems to improve global health security this paper has made an initial case for better embedding the ihr 2005 into health systems also highlighting whos crucial role in supporting this but what the discussion has also underlinedfor the ihr 2005 and for global health security more widelyis the importance of investing in health systems and activities to strengthen them both as an end of their own and so that they become resilient to health emergencies and can deliver health services in times when they are most needed this is also key in the pursuit of uhc the message from the us institute of medicine is that as health threats require the deployment of the same skills and infrastructure that support routine healthcare investing in strong viii this proposal developed out of an interregional meeting hosted by the who european regional office in copenhagen in april 2016 httpwwweurowhointenhealthtopicshealthsystemspages newsnews201604whotoembedinternationalhealthregulationsinhealthsystemsstrengtheningprocess and resilient health systems facilitates their emergency response capacity 30 likewise the ghrf commission stresses the need to invest in national health systems to ensure a robust global health risk framework 13 and civil society too has pressed home this point 20 additionally it should not be forgotten that public health crises also carry economic development and social consequences that could be mitigated by better health system investment upfront the world bank estimated the economic impact of ebola in guinea liberia and sierra leone through 2015 at us22 billion ix the majority of which were economic impacts that disproportionately affected the poor who itself has consistently stated that health systems are at the heart of how countries respond to new disease threats and sustained investment to keep them strong is required 16 ultimately investing in stronger and more resilient health systems is investing in health security and towards uhc 31 32 this is not a new message and while its reiteration is important given recent public health emergencies it needs to be more nuanced and mindful of different national settings simply calling on countries such as those in west africa to invest more in order to contribute to global health security through the ihr is not helpful as a way forward strategies and policies at regional and global level to help lowerincome countries strengthen their systems will be crucial in respect of future preparedness in this regard the need for a global strategy for local investment in core capacity to detect report and respond rapidly to outbreaks is the first recommendation of the harvardlshtm independent panel on the global response to ebola 7 and others have further noted the need for a new funding source entirely 21 equally clear is that governments need to see the ihr as theirs and as part of the national health system such that investment can be sustained and activities institutionalised as ebola and other global crises have shown health systems and global health security are only as strong as their weakest linkthis points to the most fragile and unprepared states and our collective need to work together to strengthen not just their ihr 2005 capacities but more fundamentally their health systems insofar as the military provides an appropriate metaphor it is important to plan build and test our health systems capacities and responsiveness during peacetime remaining attentive to the potential for war through the sudden emergence of health threats when war erupts it is too late to begin planning for it working towards a closer embedded relationship between the ihr 2005 and national health systems is an important step in this direction and who will need to play a leading role

contributors hk provided strategic guidance gp developed the concept and undertook the purposive literature review and gp and hk drafted the manuscript ix httpsreliefwebintsitesreliefwebintfilesresources958040wp0ouo900e0april150box385458bpdf" "Kluge

d2c536058f4f78ea00836ff72187c4c1b43e47da "the 19771978 influenza epidemic was probably not a natural event as the genetic sequence of the virus was nearly identical to the sequences of decadesold strains while there are several hypotheses that could explain its origin the possibility that the 1977 epidemic resulted from a laboratory accident has recently gained popularity in discussions about the biosafety risks of gainoffunction gof influenza virus research as an argument for why this research should not be performed there is now a moratorium in the united states on funding gof research while the benefits and risks including the potential for accident are analyzed given the importance of this historical epidemic to ongoing policy debates we revisit the evidence that the 1977 epidemic was not natural and examine three potential origins a laboratory accident a livevaccine trial escape or deliberate release as a biological weapon based on available evidence the 1977 strain was indeed too closely matched to decadesold strains to likely be a natural occurrence while the origin of the outbreak cannot be conclusively determined without additional evidence there are very plausible alternatives to the laboratory accident hypothesis diminishing the relevance of the 1977 experience to the modern gof debate

citation rozo m gronvall gk 2015 the reemergent 1977 h1n1 strain and the gainoffunction debate mbio 64e0101315" "i n 1977 an h1n1 influenza virus appeared and circled the globe

colloquially referred to as the russian flu as the ussr was the first to report the outbreak to the world health organization who the 1977 strain was actually isolated in tientsin liaoning and jilin china almost simultaneously in may of that year 1 it was atypically mild for a new epidemic strain the influenza mortality rate imr of the 1977 flu was calculated to be 5 out of 100000 less than typical seasonal influenza infections imr of 6100000 people 2 in addition the 1977 strain appeared to affect only those 26 years of age and younger 3 these odd characteristics turned out to have a simple scientific explanation the virus was not novel the 1977 strain was virtually identical to an h1n1 influenza strain that was prevalent in the 1950s but had since dropped out of circulation 4

the first researchers to point out the unusual characteristics of the 1977 strain suggested multiple theories to explain the remarkable preservation of the genetic information in the resurgent strain these possibilities included sequential passage in an animal reservoir in which influenza viruses replicate without rapid genetic change or perhaps a frozen [reservoir] in nature or elsewhere 4 however given the extensive experience with typical influenza strain evolution a natural origin for the 1977 strain is not likely

there are multiple potential explanations that may explain the viral resurgence but the possibility that the epidemic was the result of a laboratory accident has recently gained currency in discussions about the biosafety risks of gainoffunction gof influenza virus research and has been used as an argument for why this research should not be performed gof studies aim to better understand disease pathways but they have been controversial because they involve enhancing viral traits such as pathogenicity or transmissibility prompting biosafety concerns there is now a moratorium in the united states on funding gof research while the risks and benefits are being analyzed and the possibility that a laboratory escape could lead to an epidemic will be considered and quantified 5 given the importance of this historical epidemic to modern policy debates we compared the sequences of 1977 strains to earlier strains and examined available evidence that could explain the 1977 h1n1 resurgence we summarize these possible hypotheses discuss informal evidence and examine the trends of how the most popular explanation has changed over time in relation to political and world events explanations for the 1977 h1n1 reemergence include the deliberate release of the virus a vaccine trial or challenge mishap or a laboratory accident

confirmation that the 1977 strain was derived from a 1950s strain in 1978 researchers demonstrated that an h1n1 influenza virus strain from 1950 and another strain from 1977 fort warren [fw] and ussr90 respectively were unusually closely related although they were isolated 27 years apart 4 6 7 using the ncbi influenza virus resource database we analyzed the hemagglutinin ha sequences of all the late 1950s h1n1 strains 1947 to 1957 and compared them to the ha sequences of the 1977 isolates table 1 we found that the 1977 cluster has the closest degree of genetic similarity to strains isolated in albany ny in 1948 and 1950 strains isolated in rome italy in 1949 and strains isolated in fort leonard wood mo in 1951 instead of the fw 1950 strain examined previously fig 1 these strains are 984 identical table 2 containing only four differences among the 566 amino acids that make up the protein evidence that the 1977 h1n1 epidemic strain is derived from a 1950s virus

possible origin i deliberate release there are historical and epidemiological aspects of the 1977 influenza epidemic that can be considered suspicious during that time the soviet union employed tens of thousands of scientists to make biological weapons and as the 1979 release of aerosolized anthrax in sverdlovsk soviet union demonstrated the safety record for the weapons program was not perfect 8 in addition influenza was considered to be an incapacitating agent especially to those without previous exposure to a specific virus strain the lack of immunity to the resurgent strain was clearly evident by the affected population individuals who were 26 years of age or younger were especially vulnerable to infection as this is the predominant age range of the activeduty military population influenza virus could have been used as a biological weapon to target this group

indeed outbreaks of aussr9077h1n1 in military academies were described in official memos as explosive 9 10 the royal air force in upper heyford england was first affected in january 1978 followed by the us air force academy usafa in colorado in february the outbreak at the usafa was so severeover the course of 9 days 76 or 3280 cadets became illthat all academic and military training was suspended this was the first such interruption in training due to influenza illness in the cadet population 9 an epidemiological investigation at usafa revealed no link to other outbreaks nor a temporal association between the onset of cases and athletic competitions with other institutions with influenza cases it should be noted however that the investigations of illness at military academies were likely better investigated and documented than similar outbreaks at other universities and colleges

while it is possible that the 1977 influenza was caused by deliberate release of the virus the soviet bioweapons program biopreparat tended to use influenza preparedness as a cover story for some of the more nefarious work that was being performed 11 for example the omutninsk chemical factory manufactured large amounts of influenza vaccine and crop production bacteria aboveground while plague and tularemia were researched in heavily guarded underground facilities the omutninsk chemical factorys capacity to mass produce viruses and bacteria allowed the production of 100 tons of each weapon annually 11 while biopreparat has not been judged by experts to have seriously investigated influenza as a bioweapon there were documented attempts to find the 1918 pandemic h1n1 strain in old icehouses where victims were buried and studies were performed attempting to create radiationresistant and aerosolized influenza virus 11 thus the likelihood of a biological weapons explanation for the 1977 epidemic cannot be completely ruled out though it may not be considered likely

ii vaccine trial or challenge there are two factors that point to the 1977 epidemic as resulting from vaccine challenge or trials i live attenuated influenza virus laiv research was extensive at the time and ii a 1976 h1n1 swine flu outbreak was feared to have pandemic potential and led to a resurgent interest in h1n1 protection and research 12

between 1962 and 1973 almost 40000 children participated in eight laiv trials in the ussr 13 scientists at the peking vaccine and serum institute in china also carried out clinical trials using live vaccines during the same time period 1 additionally there are records of the mass production of a live h1n1 vaccine in odessa ussr in 1977 14 15 in the early days of research in the 1940s laivs were often able to regain virulence upon administration to humans and cause disease 16 in addition many strains isolated from the 1977 outbreak for example the atientsin7877 isolate were temperature sensitive ts meaning that the virus could not replicate at higher temperatures temperature sensitivity generally occurs only after a series of laboratory manipulations typical in generation of laivs and is used as a biological marker of attenuation while not all of the 19771978 strains were temperature sensitive a comparison of all 1977 strains shows a higher prevalence of the ts phenotype than in 1950 strains supporting the claim that the outbreak may have resulted from attempts at attenuation for vaccine purposes 1 17 the possibility that the 19771978 strain could have resulted from a laiv trial was also mentioned in a personal communication from c m chu renowned virologist and the former director of the chinese academy of medical sciences to peter palese who described the introduction of this 1977 virus [as] the result of vaccine trials in the far east involving the challenge of several thousand military recruits with live h1n1 virus 18 whether this involved an ineffectively attenuated vaccine or a laboratorycultivated challenge strain the deliberate infection of several thousand people with h1n1 would be a plausible spark for the outbreak

the timing is probably not coincidental in 1976 the swine h1n1 epizootic influenza virus infected 230 soldiers at fort dix nj causing severe respiratory illness in 13 and one death 12 edwin kilbourne and others led a campaign that resulted in president gerald ford announcing a program to inoculate everyone in the united states against swine flu and the concomitant production of 150 million doses of influenza vaccine however the program was halted soon after as it became clear that anew jersey 1976 was not spreading outside the basic training group it is possible that an archival h1n1 strain from the early 1950s was used as a challenge virus to evaluate the efficacy of the h1n1 vaccines prepared in response to the 1976 swine flu outbreak if this virus were not attenuated properly it may have been able to spread and cause a global epidemic iii laboratory accident a biosafety lapse in a research laboratory is now most often cited as the cause of the 19771978 reemergence of the h1n1 influenza virus strain fig 2 the evidence in favor of this possibility is the clear unnatural origin of the virus and its temperature sensitivity suggesting laboratory manipulations at the time of the epidemic however the world health organization excluded the lab accident possibility after discussions with influenza virus laboratory researchers in the soviet union and china finding that the laboratories concerned either had never kept h1n1 virus or had not worked with it for a long time 1 it is likely that the swine flu scare the previous year prompted the international community to reexamine their stocks of the latest previously circulating h1n1 strains to attempt to develop a vaccine however the tripartite origin of the outbreak in northeast china that produced almost identical isolates is not supportive of the conclusion that this was a single laboratory accident

it is more likely that either the vaccines produced from these stocks or the viruses themselves used in tests of vaccine development were virulent enough to spark the 1977 epidemic the bulk of the evidence rests with this possibility the unnatural origin mildness of presentation of the virus widespread dissemination of cases in a short amount of time temperature sensitivity of the samples contemporary observations and existence of livevirus vaccine trials which were occurring at that time

explanations been influenced by political considerations fig 2 in 1991 in the last days of the soviet union researchers suggested that the virus was potentially frozen in nature until its reemergence an unsatisfying explanation that places no blame on china or russia for the incident see reference 13 in the appendix in 2008 it was suggested that the epidemic was probably the result of an influenza vaccine trial 19 20 the 2009 h1n1 flu pandemic h1n109 virus brought the 1977 epidemic back to the forefront as there were soondiscredited rumors that it was the result of a lab accident 21 22 this reenergized the discussion on the origin of the epidemic with explanations now assum[ing] that the virus was kept frozen in a yet unidentified laboratory although how it was released was left in doubt 23 24 however morerecent publications focusing on the gof debate have strengthened this stance concluding that it was almost certainly due to an escape from a virology lab 25 26 also see references 34 to 41 in the appendix additionally proponents against gof research continue to use the potential reemergence from a laboratory accident in their slides and presentations at debates and public forums as a cautionary tale some examples include the risks and benefits of gof studies are performed with the aim to better understand disease pathways but have been controversial because they involve enhancing viral traits such as pathogenicity or transmissibility prompting biosafety concerns coupled with recent laboratory accidents at the us centers for disease control and prevention cdc the controversy over the potential risks of gof research led to the recent decision by the us government to pause federal funding for gof influenza research and severe acute respiratory syndrome sars research until an assessment can be made of its risks and benefits 30 the moratorium for mers and other coronavirus research was lifted but the evaluation of gof influenza research risks and benefits is expected to take nearly a year 31 32

while the use of the 1977 influenza epidemic as a cautionary tale for potential laboratory accidents is expedient the relevance to gof research is greatly diminished if the 1977 epidemic was the result of a vaccine trial or vaccine development gone awry these are both more plausible explanations than a single laboratory accident in addition in 1977 influenza research was performed without modern biosafety regulations and protective equipment making the lab accident hypothesis much less relevant to the modern gof debate while the events that led to the 1977 influenza epidemic cannot preclude a future consequential accident stemming from the laboratory it remains likely that to this date there has been no realworld example of a laboratory accident that has led to a global epidemic 29 " "Rozo

a7dea443868b1327fef754465f3792ea33a224ca "being sessile organisms plants are constantly challenged by their environment and their situation is compounded by biotic stresses a number of plant pathogens such as fungi oomycetes bacteria viruses nematodes etc pose serious threats to the plant wellbeing nonetheless over the course of evolution plants have acquired a refined twolayered immune system to respond to pathogen attack 1 the first line of plant immunity thought to be the most ancient relies on the recognition of evolutionarilyconserved pathogen molecules known as pamps pathogenassociated molecular patterns and is therefore referred to as pamptriggered immunity pti [2] [3] [4] pattern recognition receptors prrs are plant components responsible for the detection of pamps 5 and for activating the immune machinery of plants one of the best characterized prrs in plants is flagellin sensitive 2 fls2 a receptor kinase that activates pti upon perception of flagellin a conserved protein found in bacterial flagellum 6 7 to gain greater access to plant resources for subsequent colonization plant pathogens just like their animal equivalents deploy an arsenal of highlysophisticated molecules known as effectors these molecules greatly augment the pathogens capacity to propagate on its host by interfering with various cellular processes including pti fortunately plants monitor the presence of some effectors through their resistance rproteins which constitutes the second line of defense also known as effectortriggered immunity eti 1 eti typically results in a strong hypersensitive response characterized by cell death which shows some mechanistical similarities with apoptosis in animals 8 it is regulated by direct physical interaction between a rprotein and its corresponding effector ligandreceptor model or between a rprotein and a hostprotein modified by an effector guard model resistance thus depends on the presence of both the rprotein and its corresponding effector a situation depicted by flors geneforgene model 9 10 for pathogens to succeed proper delivery of these effectors is as crucial as the molecule itself the bacterial type three secretion system t3ss one of many secretion systems deployed by pseudomonas syringae is wellcharacterized and has been studied in great detail the syringelike t3ss provides bacteria with a robust mechanical structure which enables it to inject key molecules involved in pathogenicity directly into host cells 11 obligate biotrophic filamentous pathogens such as many fungi and oomycetes are devoid of such secretion systems instead they invaginate within host cells to form particular infection structures called haustoria 12 13 to accommodate haustoria host cells are forced to greatly expand their plasma membrane and it is plausible that pathogens drive this process for their own benefit

filamentous pathogens have a large suite of predicted secreted proteins which could act early during infection to suppress pti as the pathogens are establishing themselves and at later stages to rewire host cellular activities to meet the pathogens metabolic needs it has been proposed that protein trafficking from haustoria allows pathogens to hijack host cells for their own purposes however the precise mechanism governing effector translocation from the extrahaustorial space to host cells has eluded scientists thus far 14 for the purpose of this review we have classified effectors into three types based on the subcellular compartment they target apoplastic effectors cytoplasmic effectors and nuclear effectors apoplastic effectors can be secreted by appressoria and or hyphae invading the intercellular space where they remain outside the cells this class of effectors includes proteins with inhibitory functions interfering with plant proteases and peroxidases for example the avr2 effector from the biotrophic fungal pathogen cladosporium fulvum suppresses basal defense through inhibition of specific host proteases [15] [16] [17] on the other side cytoplasmic and nuclear effectors affect host defense mechanisms by several obligate biotrophic phytopathogens namely oomycetes and fungi invade and feed on living plant cells through specialized structures known as haustoria deploying an arsenal of secreted proteins called effectors these pathogens balance their parasitic propagation by subverting plant immunity without sacrificing host cells such secreted proteins which are thought to be delivered by haustoria conceivably reprogram host cells and instigate structural modifications in addition to the modulation of various cellular processes as effectors represent tools to assist disease resistance breeding this short review provides a birds eye view on the relationship between the virulence function of effectors and their subcellular localization in host cells

targeting proteins involved in plant immune signaling cascades moreover they also manipulate various plant processes further predisposing the host cellular machinery to act in a pathogenconducive manner 18 19 as their names suggest cytoplasmic effectors target cytosolic components or are redirected to other organelles while nuclear effectors transit via the cytosol but have a different purpose than the other two effector types described in subsequent sections the biology of infection of obligate biotrophic pathogens is rather unique due to the establishment of haustoria the different strategies deployed by intracellular biotrophic hyphae produced by various pathogens to secrete their effectors are beautifully illustrated by giraldo and valent 13 in this minireview we offer a retrospective of the molecular interactions between obligate biotrophic pathogens and their hosts speculating on this rather intimate relationship at the molecular level and focusing on cellular components representing potential effector targets

it is pertinent to demystify the terminological ambiguity around effectors since until recently their nomenclature was contingent upon host reactions when a molecule from a particular pathogen modulates the hosts defensive cover to increase the pathogens fitness it is called a virulence factor however when the same molecule is recognized by host immunoreceptors thereby failing to augment pathogenicity and instead triggering a defense response it is referred to as an avirulence factor this variation in pathogenicity is a commonlyoccurring phenomenon a particular effector may be a virulence factor on one host and an avirulence factor on another a situation observed even within a single plant species where interactions are racespecific because of this inconsistency terms such as virulence and avirulence have their limitations since they are dependent on the specific host system in which they have been observed the above discussed terminology in plant pathology is thus rather different from that employed in the medical field in plant immunity the terms virulence and avirulence are mainly related to the plants ability to resist or succumb to the pathogen thus depending on plant genotype 9 in the medical field avirulence refers to the loss of a virulence component belonging to the pathogen consequently an inclusive and neutral term such as effector is preferred 20 as it accounts for all the molecules secreted by a pathogen during infection that alter host cell structure or function 21 as mentioned earlier flors work was instrumental in establishing the geneforgene concept 9 10 flor was quite foresighted when he noted that for each gene conditioning a reaction in the host there is a corresponding gene that conditions pathogenicity in the pathogen 9 his deduction came from studies on the inheritance of pathogenicity in flax rust melampsora lini and on the inheritance of resistance in flax linum usitatissimum 10 many years later the flaxflax rust pathosystem remains instrumental in our understanding of the molecular aspects of geneforgene interactions this pathosystem enabled inroads to be made in the molecular interaction between rand avrprotein mainly through studies of l and m resistance genes and their corresponding avr loci flax rust avrl567 genes whose products are recognized by the l5 l6 and l7 rproteins of flax are highly diverse and under diversifying selection pressure with 12 sequence variants identified from six rust strains 22 ravensdale et al 23 studied direct molecular interactions between l5 and l6 two alleles of l and their avirulence targets in detail sitedirected mutagenesis in avrl567 and the construction of chimeric lproteins revealed that the recognition specificities of l5 and l6 are conditioned by their leucinerich repeat regions their study indicated that mutations in the tir or nbarc domain also affect recognition which prompted the authors to suggest that interaction with the avr ligand directly competes with intramolecular interactions causing rprotein activation 23 the avrm effector from flax rust also interacts directly with the flax rprotein m and this interaction can also be observed in yeast twohybrid assays catanzariti et al showed that the cterminal domain of avrm is required for mdependent celldeath consistent with the fact that it interacts with mprotein in yeast 24 furthermore these authors demonstrated that cterminal 34 amino acids formed a structured domain unlike the nterminal part of the protein and gel filtration revealed that avrma can dimerize 22 recently ve et al resolved the structure of avrm and avrma and showed that both possess an lshaped fold and form a dimer with an unusual nonglobular shape 25 the avirulence properties of avrm and avrl have been described but yield no clues with regard to their targets and their potential virulence functions few rust effectors have been shown to be expressed during infection and translocated to host cells one of these effectors is rusttransferred protein 1 rtp1 which belongs to a family of effector proteins specific to the order pucciniales 26 rtp1 from uromyces fabae was the first rust effector demonstrated to localize in host cells and it was also observed that the transfer of the protein was dependent on the developmental stage of haustoria 27 rtp1 translocates from the extrahaustorial matrix where it first accumulates transits through the cytoplasm then further moves to the nucleus 27 unlike most localization studies cited herein which are mainly based on green fluorescent protein gfp fusion and transient expression rtp1 localization was assessed by immunolocalization during uromyces fabae infection using four independentlyraised polyclonal antibodies 27 rtp1 sequence analyses indicated that the cterminal domain exhibited similarities to cysteine protease inhibitors and rtp1 was indeed shown to inhibit proteolytic activity 26

when dealing with a subject as broad as effectors it is worthwhile to classify them to the extent that current knowledge in this domain will allow therefore in an attempt to draw clear lines they can be largely divided into three major groups based on their localization and site of activity apoplastic cytoplasmic and nuclearnucleolar effectors