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BACKGROUND: In response to the dramatic emergence of resistant pneumococci, more judicious use of antibiotics has been advocated. Physician beliefs, their prescribing practices, and the attitudes of patients have been evaluated previously in separate studies. METHODS: This 3-part study included a statewide mailed survey, office chart reviews, and parent telephone interviews. We compared survey responses of 366 licensed pediatricians and family physicians in Georgia to recently published recommendations on diagnosis and treatment of upper respiratory infections (URIs). We further evaluated 25 randomly selected pediatricians from 119 surveyed in the Atlanta metropolitan area. For each, charts from the first 30 patients between the ages of 12 and 72 months seen on a randomly selected date were reviewed for encounters during the preceding year. A sample of parents from each practice were interviewed by telephone. RESULTS: In the survey, physicians agreed that overuse of antibiotics is a major factor contributing to the development of antibiotic resistance (97%), and that they should consider selective pressure for resistance in their decisions on providing antibiotic treatment for URIs in children in their practices (83%). However, many reported practices do not conform to the recently published principles for judicious antibiotic use. For example, 69% of physicians considered purulent rhinitis a diagnostic finding for sinusitis; 86% prescribed antibiotics for bronchitis regardless of the duration of cough; and 42% prescribed antibiotics for the common cold. Reported practices by family physicians were more often at odds with the published principles: they were significantly more likely than pediatricians to omit pneumatic otoscopy (46% vs 25%); to omit the requirement for prolonged symptoms to diagnose sinusitis (median 4 vs 10 days); and to omit laboratory testing for pharyngitis (27% vs 14%). Of the 7531 encounters analyzed in the chart review, 43% resulted in an antibiotic prescription, including 11% of checkups, 18% of telephone calls, and 72% of visits for URIs. There was wide variability in the overall antibiotic use rates among the 25 physicians (1-10 courses per child per year). There was an even wider variability in some diagnosis-specific rates; bronchitis and sinusitis in particular. Those with the highest antibiotic prescribing rates had up to 30% more return office visits. Physicians who prescribed antibiotics for purulent rhinitis were more likely to see parents who believed that their children should be evaluated for cold symptoms. CONCLUSIONS: Physicians recognize the problem of antibiotic resistance but their reported practices are not in line with recently published recommendations for most pediatric URIs. The actual prescribing practices of pediatricians are often considerably different from their close colleagues. Patient beliefs are correlated with their own physician's practices. [ABSTRACT FROM AUTHOR]

This article summarizes the principles of judicious antimicrobial therapy for three of the five conditions--cough, pharyngitis, the common cold--that account for most of the outpatient use of these drugs in the United States. The principles governing the other two conditions, otitis media and acute sinusitis, were presented in the previous issue. This article summarizes evidence against the use of antibiotic treatment for illness with cough or bronchitis in children, unless the cough is prolonged. Although empiric treatment may be started in patients with pharyngitis when streptococcal infection is suspected, the authors recommend withholding antibiotic treatment until antigen testing or culture is positive. There is never any indication for antibiotic treatment of the common cold; it is important to understand the natural history of colds, because symptoms such as mucopurulent rhinitis or cough, even when they persist for up to two weeks, do not necessarily indicate bacterial infection. [ABSTRACT FROM AUTHOR]

Five conditions--otitis media, acute sinusitis, cough, pharyngitis and the common cold--account for most of the outpatient use of antibiotics in the United States. The first part of this two-part article presents guidelines that encourage physicians to make an appropriate distinction between acute otitis media and otitis media with effusion, to use shorter courses of antibiotic therapy in uncomplicated cases of otitis media and to limit prophylaxis to recurrence as defined strictly by number of episodes. Sinusitis in younger children is difficult to distinguish from the common cold, and the criterion for use of antibiotics should be duration of symptoms. [ABSTRACT FROM AUTHOR]

Background: During 2004, a highly pathogenic avian influenza A (H5N1) virus caused poultry disease in eight Asian countries and infected at least 44 persons, killing 32; most of these persons had had close contact with poultry. No evidence of efficient person-to-person transmission has yet been reported. We investigated possible person-to-person transmission in a family cluster of the disease in Thailand. Methods: For each of the three involved patients, we reviewed the circumstances and timing of exposures to poultry and to other ill persons. Field teams isolated and treated the surviving patient, instituted active surveillance for disease and prophylaxis among exposed contacts, and culled the remaining poultry surrounding the affected village. Specimens from family members were tested by viral culture, microneutralization serologic analysis, immunohistochemical assay, reverse-transcriptase-polymerase-chain-reaction (RT-PCR) analysis, and genetic sequencing. Results: The index patient became ill three to four days after her last exposure to dying household chickens. Her mother came from a distant city to care for her in the hospital, had no recognized exposure to poultry, and died from pneumonia after providing 16 to 18 hours of unprotected nursing care. The aunt also provided unprotected nursing care; she had fever five days after the mother first had fever, followed by pneumonia seven days later. Autopsy tissue from the mother and nasopharyngeal and throat swabs from the aunt were positive for influenza A (H5N1) by RT-PCR. No additional chains of transmission were identified, and sequencing of the viral genes identified no change in the receptor-binding site of hemagglutinin or other key features of the virus. The sequences of all eight viral gene segments clustered closely with other H5N1 sequences from recent avian isolates in Thailand. Conclusions: Disease in the mother and aunt probably resulted from person-to-person transmission of this lethal avian influenzavirus during unprotected exposure to the critically ill index patient. [ABSTRACT FROM AUTHOR]

Objective To determine why health workers fail to follow integrated management of childhood illness (IMCI) guidelines for severely ill children at first-level outpatient health facilities in rural areas of the United Republic of Tanzania. Methods Retrospective and prospective case reviews of severely ill children aged < 5 years were conducted at health facilities in four districts. We ascertained treatment and examined the characteristics associated with referral, conducted follow-up interviews with parents of severely ill children, and gave health workers questionnaires and interviews. Findings In total, 502 cases were reviewed at 62 facilities. Treatment with antimalarials and antibiotics was consistent with the diagnosis given by health workers. However, of 240 children classified as having 'very severe febrile disease', none received all IMCI-recommended therapies, and only 25% of severely ill children were referred. Lethargy and anaemia diagnoses were independently associated with referral. Most (91%) health workers indicated that certain severe conditions can be managed without referral. Conclusion The health workers surveyed rarely adhered to IMCI treatment and referral guidelines for children with severe illness. They administered therapy based on narrow diagnoses rather than IMCI classifications, disagreed with referral guidelines and often considered referral unnecessary. To improve implementation of IMCI, attention should focus on the reasons for health worker non-adherence. Copyright © 2009 World Health Organization [ABSTRACT FROM AUTHOR]

Competing Interests: Competing interests: DLB is a current employee of the Bill & Melinda Gates Foundation, which partially funded the Global Health Security Index. Additionally, SFD and DLB are members of the international panel of experts that provides non-binding advice regarding the development of the Global Health Security Index. CI, GVE and JB are employees of NTI, which received prior grant funding from the BMGF, Open Philanthropy Foundation and the Rockefeller Foundation for the development of the 2021 Global Health Security Index. JBN contributed to the development of the 2021 Global Health Security Index, for which she received grant funding from NTI. The present analyses were conducted outside of the scope and without support of grant funding received for the Global Health Security Index.

Competing Interests: Competing interests: None declared.

Competing Interests: We all contributed to the collaborative surveillance concept paper(16) that is discussed in this Comment. We declare no other competing interests. This Comment represents the personal opinion of the authors and not that of the organisations for whom they work.

Background: Previous studies have observed that countries with the strongest levels of pandemic preparedness capacities experience the greatest levels of COVID-19 burden. However, these analyses have been limited by cross-country differentials in surveillance system quality and demographics. Here, we address limitations of previous comparisons by exploring country-level relationships between pandemic preparedness measures and comparative mortality ratios (CMRs), a form of indirect age standardisation, of excess COVID-19 mortality., Methods: We indirectly age standardised excess COVID-19 mortality, from the Institute for Health Metrics and Evaluation modelling database, by comparing observed total excess mortality to an expected age-specific COVID-19 mortality rate from a reference country to derive CMRs. We then linked CMRs with data on country-level measures of pandemic preparedness from the Global Health Security (GHS) Index. These data were used as input into multivariable linear regression analyses that included income as a covariate and adjusted for multiple comparisons. We conducted a sensitivity analysis using excess mortality estimates from WHO and The Economist., Results: The GHS Index was negatively associated with excess COVID-19 CMRs (table 2; β= -0.21, 95% CI= -0.35 to -0.08). Greater capacities related to prevention (β= -0.11, 95% CI= -0.22 to -0.00), detection (β= -0.09, 95% CI= -0.19 to -0.00), response (β = -0.19, 95% CI= -0.36 to -0.01), international commitments (β= -0.17, 95% CI= -0.33 to -0.01) and risk environments (β= -0.30, 95% CI= -0.46 to -0.15) were each associated with lower CMRs. Results were not replicated using excess mortality models that rely more heavily on reported COVID-19 deaths (eg, WHO and The Economist)., Conclusion: The first direct comparison of COVID-19 excess mortality rates across countries accounting for under-reporting and age structure confirms that greater levels of preparedness were associated with lower excess COVID-19 mortality. Additional research is needed to confirm these relationships as more robust national-level data on COVID-19 impact become available., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The aetiology of nodding syndrome remains unclear, and comprehensive genotyping and phenotyping data from patients remain sparse. Our objectives were to characterize the phenotype of patients with nodding syndrome, investigate potential contributors to disease aetiology, and evaluate response to immunotherapy. This cohort study investigated members of a single-family unit from Lamwo District, Uganda. The participants for this study were selected by the Ugandan Ministry of Health as representative for nodding syndrome and with a conducive family structure for genomic analyses. Of the eight family members who participated in the study at the National Institutes of Health (NIH) Clinical Center, three had nodding syndrome. The three affected patients were extensively evaluated with metagenomic sequencing for infectious pathogens, exome sequencing, spinal fluid immune analyses, neurometabolic and toxicology testing, continuous electroencephalography and neuroimaging. Five unaffected family members underwent a subset of testing for comparison. A distinctive interictal pattern of sleep-activated bursts of generalized and multifocal epileptiform discharges and slowing was observed in two patients. Brain imaging showed two patients had mild generalized cerebral atrophy, and both patients and unaffected family members had excessive metal deposition in the basal ganglia. Trace metal biochemical evaluation was normal. CSF was non-inflammatory and one patient had CSF-restricted oligoclonal bands. Onchocerca volvulus-specific antibodies were present in all patients and skin snips were negative for active onchocerciasis. Metagenomic sequencing of serum and CSF revealed hepatitis B virus in the serum of one patient. Vitamin B6 metabolites were borderline low in all family members and CSF pyridoxine metabolites were normal. Mitochondrial DNA testing was normal. Exome sequencing did not identify potentially causal candidate gene variants. Nodding syndrome is characterized by a distinctive pattern of sleep-activated epileptiform activity. The associated growth stunting may be due to hypothalamic dysfunction. Extensive testing years after disease onset did not clarify a causal aetiology. A trial of immunomodulation (plasmapheresis in two patients and intravenous immunoglobulin in one patient) was given without short-term effect, but longer-term follow-up was not possible to fully assess any benefit of this intervention., (Published by Oxford University Press on behalf of the Guarantors of Brain 2022.)

Competing Interests: We declare no competing interests.

Evidence-based approaches to preventing child death require evidence; without data on common causes of child mortality, taking effective action to prevent these deaths is difficult at best. Minimally invasive tissue sampling (MITS) is a potentially powerful, but nascent, technique to obtain gold standard information on causes of death. The Gates Foundation committed to further establishing the methodology and obtain the highest quality information on the major causes of death for children under 5 years. In 2018, the MITS Surveillance Alliance was launched to implement, refine, and enhance the use of MITS across high mortality settings. The Alliance and its members have contributed to some remarkable opportunities to improve mortality surveillance, and we have only just begun to understand the possibilities on larger scales. This supplement showcases studies conducted by MITS Surveillance Alliance members and represents a significant contribution to the cause-of-death literature from high mortality settings., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: Sub-Saharan Africa and south Asia contributed 81% of 5·9 million under-5 deaths and 77% of 2·6 million stillbirths worldwide in 2015. Vital registration and verbal autopsy data are mainstays for the estimation of leading causes of death, but both are non-specific and focus on a single underlying cause. We aimed to provide granular data on the contributory causes of death in stillborn fetuses and in deceased neonates and children younger than 5 years, to inform child mortality prevention efforts., Methods: The Child Health and Mortality Prevention Surveillance (CHAMPS) Network was established at sites in seven countries (Baliakandi, Bangladesh; Harar and Kersa, Ethiopia; Siaya and Kisumu, Kenya; Bamako, Mali; Manhiça, Mozambique; Bombali, Sierra Leone; and Soweto, South Africa) to collect standardised, population-based, longitudinal data on under-5 mortality and stillbirths in sub-Saharan Africa and south Asia, to improve the accuracy of determining causes of death. Here, we analysed data obtained in the first 2 years after the implementation of CHAMPS at the first five operational sites, during which surveillance and post-mortem diagnostics, including minimally invasive tissue sampling (MITS), were used. Data were abstracted from all available clinical records of deceased children, and relevant maternal health records were also extracted for stillbirths and neonatal deaths, to incorporate reported pregnancy or delivery complications. Expert panels followed standardised procedures to characterise causal chains leading to death, including underlying, intermediate (comorbid or antecedent causes), and immediate causes of death for stillbirths, neonatal deaths, and child (age 1-59 months) deaths., Findings: Between Dec 10, 2016, and Dec 31, 2018, MITS procedures were implemented at five sites in Mozambique, South Africa, Kenya, Mali, and Bangladesh. We screened 2385 death notifications for inclusion eligibility, following which 1295 families were approached for consent; consent was provided for MITS by 963 (74%) of 1295 eligible cases approached. At least one cause of death was identified in 912 (98%) of 933 cases (180 stillbirths, 449 neonatal deaths, and 304 child deaths); two or more conditions were identified in the causal chain for 585 (63%) of 933 cases. The most common underlying causes of stillbirth were perinatal asphyxia or hypoxia (130 [72%] of 180 stillbirths) and congenital infection or sepsis (27 [15%]). The most common underlying causes of neonatal death were preterm birth complications (187 [42%] of 449 neonatal deaths), perinatal asphyxia or hypoxia (98 [22%]), and neonatal sepsis (50 [11%]). The most common underlying causes of child deaths were congenital birth defects (39 [13%] of 304 deaths), lower respiratory infection (37 [12%]), and HIV (35 [12%]). In 503 (54%) of 933 cases, at least one contributory pathogen was identified. Cytomegalovirus, Escherichia coli, group B Streptococcus, and other infections contributed to 30 (17%) of 180 stillbirths. Among neonatal deaths with underlying prematurity, 60% were precipitated by other infectious causes. Of the 275 child deaths with infectious causes, the most common contributory pathogens were Klebsiella pneumoniae (86 [31%]), Streptococcus pneumoniae (54 [20%]), HIV (40 [15%]), and cytomegalovirus (34 [12%]), and multiple infections were common. Lower respiratory tract infection contributed to 174 (57%) of 304 child deaths., Interpretation: Cause of death determination using MITS enabled detailed characterisation of contributing conditions. Global estimates of child mortality aetiologies, which are currently based on a single syndromic cause for each death, will be strengthened by findings from CHAMPS. This approach adds specificity and provides a more complete overview of the chain of events leading to death, highlighting multiple potential interventions to prevent under-5 mortality and stillbirths., Funding: Bill & Melinda Gates Foundation., (Copyright © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

More than 85% of Covid-19 mortality in high income countries is among people 65 years of age or older. Recent disaggregated data from the UK and US show that minority communities have increased mortality among younger age groups and in South Africa initial data suggest that the majority of deaths from Covid-19 are under 65 years of age. These observations suggest significant potential for increased Covid-19 mortality among younger populations in Africa and South Asia and may impact age-based selection of high-risk groups eligible for a future vaccine., Competing Interests: No competing interests were disclosed., (Copyright: © 2020 Klugman KP et al.)

Recognizing the need for better primary data on the causes of global child mortality, the Bill & Melinda Gates Foundation made an unusually long funding commitment toward a surveillance system using pathology to identify opportunities to prevent child deaths and promote equity., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America.)

Little is known about the specific causes of neonatal and under-five childhood death in high-mortality geographic regions due to a lack of primary data and dependence on inaccurate tools, such as verbal autopsy. To meet the ambitious new Sustainable Development Goal 3.2 to eliminate preventable child mortality in every country, better approaches are needed to precisely determine specific causes of death so that prevention and treatment interventions can be strengthened and focused. Minimally invasive tissue sampling (MITS) is a technique that uses needle-based postmortem sampling, followed by advanced histopathology and microbiology to definitely determine cause of death. The Bill & Melinda Gates Foundation is supporting a new surveillance system called the Child Health and Mortality Prevention Surveillance network, which will determine cause of death using MITS in combination with other information, and yield cause-specific population-based mortality rates, eventually in up to 12-15 sites in sub-Saharan Africa and south Asia. However, the Gates Foundation funding alone is not enough. We call on governments, other funders, and international stakeholders to expand the use of pathology-based cause of death determination to provide the information needed to end preventable childhood mortality.

Nodding syndrome is an epileptic disorder of unknown etiology that occurs in children in East Africa. There is an epidemiological association with Onchocerca volvulus , the parasitic worm that causes onchocerciasis (river blindness), but there is limited evidence that the parasite itself is neuroinvasive. We hypothesized that nodding syndrome may be an autoimmune-mediated disease. Using protein chip methodology, we detected autoantibodies to leiomodin-1 more abundantly in patients with nodding syndrome compared to unaffected controls from the same village. Leiomodin-1 autoantibodies were found in both the sera and cerebrospinal fluid of patients with nodding syndrome. Leiomodin-1 was found to be expressed in mature and developing human neurons in vitro and was localized in mouse brain to the CA3 region of the hippocampus, Purkinje cells in the cerebellum, and cortical neurons, structures that also appear to be affected in patients with nodding syndrome. Antibodies targeting leiomodin-1 were neurotoxic in vitro, and leiomodin-1 antibodies purified from patients with nodding syndrome were cross-reactive with O. volvulus antigens. This study provides initial evidence supporting the hypothesis that nodding syndrome is an autoimmune epileptic disorder caused by molecular mimicry with O. volvulus antigens and suggests that patients may benefit from immunomodulatory therapies., (Copyright © 2017, American Association for the Advancement of Science.)

We estimated the seroprevalence and determined the frequency of acute infections with Neorickettsia sennetsu, spotted fever group rickettsiae, Rickettsia typhi, and Orientia tsutsugamushi among 2,225 febrile patients presenting to community hospitals in three rural Thailand provinces during 2002-2005. The seroprevalence was 0.2% for sennetsu neorickettsiosis (SN), 0.8% for spotted fever group (SFG) rickettsiae, 4.2% for murine typhus (MT), and 4.2% for scrub typhus (ST). The frequency of acute infections was 0.1% for SN, 0.6% for SFG, 2.2% for MT, and 1.5% for ST. Additional studies to confirm the distribution of these pathogens and to identify animal reservoirs and transmission cycles are needed to understand the risk of infection., (© The American Society of Tropical Medicine and Hygiene.)

Background: Increasing volumes of data and computational capacity afford unprecedented opportunities to scale up infectious disease (ID) mapping for public health uses. Whilst a large number of IDs show global spatial variation, comprehensive knowledge of these geographic patterns is poor. Here we use an objective method to prioritise mapping efforts to begin to address the large deficit in global disease maps currently available., Methodology/principal Findings: Automation of ID mapping requires bespoke methodological adjustments tailored to the epidemiological characteristics of different types of diseases. Diseases were therefore grouped into 33 clusters based upon taxonomic divisions and shared epidemiological characteristics. Disability-adjusted life years, derived from the Global Burden of Disease 2013 study, were used as a globally consistent metric of disease burden. A review of global health stakeholders, existing literature and national health priorities was undertaken to assess relative interest in the diseases. The clusters were ranked by combining both metrics, which identified 44 diseases of main concern within 15 principle clusters. Whilst malaria, HIV and tuberculosis were the highest priority due to their considerable burden, the high priority clusters were dominated by neglected tropical diseases and vector-borne parasites., Conclusions/significance: A quantitative, easily-updated and flexible framework for prioritising diseases is presented here. The study identifies a possible future strategy for those diseases where significant knowledge gaps remain, as well as recognising those where global mapping programs have already made significant progress. For many conditions, potential shared epidemiological information has yet to be exploited.

Acute encephalitis is a severe neurologic syndrome. Determining etiology from among ≈100 possible agents is difficult. To identify infectious etiologies of encephalitis in Thailand, we conducted surveillance in 7 hospitals during July 2003-August 2005 and selected patients with acute onset of brain dysfunction with fever or hypothermia and with abnormalities seen on neuroimages or electroencephalograms or with cerebrospinal fluid pleocytosis. Blood and cerebrospinal fluid were tested for >30 pathogens. Among 149 case-patients, median age was 12 (range 0-83) years, 84 (56%) were male, and 15 (10%) died. Etiology was confirmed or probable for 54 (36%) and possible or unknown for 95 (64%). Among confirmed or probable etiologies, the leading pathogens were Japanese encephalitis virus, enteroviruses, and Orientia tsutsugamushi. No samples were positive for chikungunya, Nipah, or West Nile viruses; Bartonella henselae; or malaria parasites. Although a broad range of infectious agents was identified, the etiology of most cases remains unknown.

Over the past decade, Vietnam has successfully responded to global health security (GHS) challenges, including domestic elimination of severe acute respiratory syndrome (SARS) and rapid public health responses to human infections with influenza A(H5N1) virus. However, new threats such as Middle East respiratory syndrome coronavirus (MERS-CoV) and influenza A(H7N9) present continued challenges, reinforcing the need to improve the global capacity to prevent, detect, and respond to public health threats. In June 2012, Vietnam, along with many other nations, obtained a 2-year extension for meeting core surveillance and response requirements of the 2005 International Health Regulations (IHR). During March-September 2013, CDC and the Vietnamese Ministry of Health (MoH) collaborated on a GHS demonstration project to improve public health emergency detection and response capacity. The project aimed to demonstrate, in a short period, that enhancements to Vietnam's health system in surveillance and early detection of and response to diseases and outbreaks could contribute to meeting the IHR core capacities, consistent with the Asia Pacific Strategy for Emerging Diseases. Work focused on enhancements to three interrelated priority areas and included achievements in 1) establishing an emergency operations center (EOC) at the General Department of Preventive Medicine with training of personnel for public health emergency management; 2) improving the nationwide laboratory system, including enhanced testing capability for several priority pathogens (i.e., those in Vietnam most likely to contribute to public health emergencies of international concern); and 3) creating an emergency response information systems platform, including a demonstration of real-time reporting capability. Lessons learned included awareness that integrated functions within the health system for GHS require careful planning, stakeholder buy-in, and intradepartmental and interdepartmental coordination and communication.

Increasingly, the need to strengthen global capacity to prevent, detect, and respond to public health threats around the globe is being recognized. CDC, in partnership with the World Health Organization (WHO), has committed to building capacity by assisting member states with strengthening their national capacity for integrated disease surveillance and response as required by International Health Regulations (IHR). CDC and other U.S. agencies have reinforced their pledge through creation of global health security (GHS) demonstration projects. One such project was conducted during March-September 2013, when the Uganda Ministry of Health (MoH) and CDC implemented upgrades in three areas: 1) strengthening the public health laboratory system by increasing the capacity of diagnostic and specimen referral networks, 2) enhancing the existing communications and information systems for outbreak response, and 3) developing a public health emergency operations center (EOC) (Figure 1). The GHS demonstration project outcomes included development of an outbreak response module that allowed reporting of suspected cases of illness caused by priority pathogens via short messaging service (SMS; i.e., text messaging) to the Uganda District Health Information System (DHIS-2) and expansion of the biologic specimen transport and laboratory reporting system supported by the President's Emergency Plan for AIDS Relief (PEPFAR). Other enhancements included strengthening laboratory management, establishing and equipping the EOC, and evaluating these enhancements during an outbreak exercise. In 6 months, the project demonstrated that targeted enhancements resulted in substantial improvements to the ability of Uganda's public health system to detect and respond to health threats.

Disease outbreaks of international public health importance continue to occur regularly; detecting and tracking significant new public health threats in countries that cannot or might not report such events to the global health community is a challenge. The Centers for Disease Control and Prevention's (CDC) Global Disease Detection (GDD) Operations Center, established in early 2007, monitors infectious and non-infectious public health events to identify new or unexplained global public health threats and better position CDC to respond, if public health assistance is requested or required. At any one time, the GDD Operations Center actively monitors approximately 30-40 such public health threats; here we provide our perspective on five of the top global infectious disease threats that we were watching in 2012: 1 avian influenza A (H5N1), 2 cholera, 3 wild poliovirus, 4 enterovirus-71, and 5 extensively drug-resistant tuberculosis11†Current address: Division of Integrated Biosurveillance, Armed Forces Health Surveillance Center, US Department of Defense, Silver Spring, MD, USA.

Introduction: Nodding Syndrome (NS), an unexplained illness characterized by spells of head bobbing, has been reported in Sudan and Tanzania, perhaps as early as 1962. Hypothesized causes include sorghum consumption, measles, and onchocerciasis infection. In 2009, a couple thousand cases were reportedly in Northern Uganda., Methods: In December 2009, we identified cases in Kitgum District. The case definition included persons who were previously developmentally normal who had nodding. Cases, further defined as 5- to 15-years-old with an additional neurological deficit, were matched to village controls to assess risk factors and test biological specimens. Logistic regression models were used to evaluate associations., Results: Surveillance identified 224 cases; most (95%) were 5-15-years-old (range = 2-27). Cases were reported in Uganda since 1997. The overall prevalence was 12 cases per 1,000 (range by parish = 0·6-46). The case-control investigation (n = 49 case/village control pairs) showed no association between NS and previously reported measles; sorghum was consumed by most subjects. Positive onchocerciasis serology [age-adjusted odds ratio (AOR1) = 14·4 (2·7, 78·3)], exposure to munitions [AOR1 = 13·9 (1·4, 135·3)], and consumption of crushed roots [AOR1 = 5·4 (1·3, 22·1)] were more likely in cases. Vitamin B6 deficiency was present in the majority of cases (84%) and controls (75%)., Conclusion: NS appears to be increasing in Uganda since 2000 with 2009 parish prevalence as high as 46 cases per 1,000 5- to 15-year old children. Our results found no supporting evidence for many proposed NS risk factors, revealed association with onchocerciasis, which for the first time was examined with serologic testing, and raised nutritional deficiencies and toxic exposures as possible etiologies.

Ten years have elapsed since the World Health Organization issued its first global alert for an unexplained illness named severe acute respiratory syndrome (SARS). The anniversary provides an opportunity to reflect on the international response to this new global microbial threat. While global surveillance and response capacity for public health threats have been strengthened, critical gaps remain. Of 194 World Health Organization member states that signed on to the International Health Regulations (2005), <20% had achieved compliance with the core capacities required by the deadline in June 2012. Lessons learned from the global SARS outbreak highlight the need to avoid complacency, strengthen efforts to improve global capacity to address the next pandemic using all available 21st century tools, and support research to develop new treatment options, countermeasures, and insights while striving to address the global inequities that are the root cause of many of these challenges.

Background: Nodding syndrome is an unexplained illness characterised by head-bobbing spells. The clinical and epidemiological features are incompletely described, and the explanation for the nodding and the underlying cause of nodding syndrome are unknown. We aimed to describe the clinical and neurological diagnostic features of this illness., Methods: In December, 2009, we did a multifaceted investigation to assess epidemiological and clinical illness features in 13 parishes in Kitgum District, Uganda. We defined a case as a previously healthy child aged 5-15 years with reported nodding and at least one other neurological deficit. Children from a systematic sample of a case-control investigation were enrolled in a clinical case series which included history, physical assessment, and neurological examinations; a subset had electroencephalography (EEG), electromyography, brain MRI, CSF analysis, or a combination of these analyses. We reassessed the available children 8 months later., Findings: We enrolled 23 children (median age 12 years, range 7-15 years) in the case-series investigation, all of whom reported at least daily head nodding. 14 children had reported seizures. Seven (30%) children had gross cognitive impairment, and children with nodding did worse on cognitive tasks than did age-matched controls, with significantly lower scores on tests of short-term recall and attention, semantic fluency and fund of knowledge, and motor praxis. We obtained CSF samples from 16 children, all of which had normal glucose and protein concentrations. EEG of 12 children with nodding syndrome showed disorganised, slow background (n=10), and interictal generalised 2·5-3·0 Hz spike and slow waves (n=10). Two children had nodding episodes during EEG, which showed generalised electrodecrement and paraspinal electromyography dropout consistent with atonic seizures. MRI in four of five children showed generalised cerebral and cerebellar atrophy. Reassessment of 12 children found that six worsened in their clinical condition between the first evaluation and the follow-up evaluation interval, as indicated by more frequent head nodding or seizure episodes, and none had cessation or decrease in frequency of these episodes., Interpretation: Nodding syndrome is an epidemic epilepsy associated with encephalopathy, with head nodding caused by atonic seizures. The natural history, cause, and management of the disorder remain to be determined., Funding: Division of Global Disease Detection and Emergency Response, US Centers for Disease Control and Prevention., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

An epidemic illness characterized by head nodding associated with onchocerciasis has been described in eastern Africa since the early 1960s; we summarize published reports and recent studies. Onset of nodding occurs in previously healthy 5-15-year-old children and is often triggered by eating or cold temperatures and accompanied by cognitive impairment. Its incidence has increased in Uganda and South Sudan over the past 10 years. Four case-control studies identified modest and inconsistent associations. There were nonspecific lesions seen by magnetic resonance imaging, no cerebrospinal fluid inflammation, and markedly abnormal electroencephalography results. Nodding episodes are atonic seizures. Testing has failed to demonstrate associations with trypanosomiasis, cysticercosis, loiasis, lymphatic filariasis, cerebral malaria, measles, prion disease, or novel pathogens; or deficiencies of folate, cobalamin, pyridoxine, retinol, or zinc; or toxicity from mercury, copper, or homocysteine. There is a consistent enigmatic association with onchocerciasis detected by skin snip or serologic analysis. Nodding syndrome is an unexplained epidemic epilepsy.

The global spread of severe acute respiratory syndrome highlighted the need to detect and control disease outbreaks at their source, as envisioned by the 2005 revised International Health Regulations (IHR). June 2012 marked the initial deadline by which all 194 World Health Organization (WHO) member states agreed to have IHR core capacities fully implemented for limiting the spread of public health emergencies of international concern. Many countries fell short of these implementation goals and requested a 2-year extension. The degree to which achieving IHR compliance will result in global health security is not clear, but what is clear is that progress against the threat of epidemic disease requires a focused approach that can be monitored and measured efficiently. We developed concrete goals and metrics for 4 of the 8 core capacities with other US government partners in consultation with WHO and national collaborators worldwide. The intent is to offer an example of an approach to implementing and monitoring IHR for consideration or adaptation by countries that complements other frameworks and goals of IHR. Without concrete metrics, IHR may waste its considerable promise as an instrument for global health security against public health emergencies.

With more than 250,000 cases and 4,000 deaths in the first 6 months, the cholera epidemic in Haiti has been one of the most explosive and deadly in recent history. It is also one of the best documented, with detailed surveillance information available from the beginning of the epidemic, which allowed its spread to all parts of the country to be traced. Piarroux et al. make good use of this information, along with their own careful field investigations, to trace the epidemic to its beginning and propose an explanation for its origins.

Objectives: Ebola hemorrhagic fever has killed over 1300 people, mostly in equatorial Africa. There is still uncertainty about the natural reservoir of the virus and about some of the factors involved in disease transmission. Until now, a maximum incubation period of 21 days has been assumed., Methods: We analyzed data collected during the Ebola outbreak (subtype Zaire) in Kikwit, Democratic Republic of the Congo, in 1995 using maximum likelihood inference and assuming a log-normally distributed incubation period., Results: The mean incubation period was estimated to be 12.7 days (standard deviation 4.31 days), indicating that about 4.1% of patients may have incubation periods longer than 21 days., Conclusion: If the risk of new cases is to be reduced to 1% then 25 days should be used when investigating the source of an outbreak, when determining the duration of surveillance for contacts, and when declaring the end of an outbreak.

We estimated the prevalence of anti-Bartonella antibodies among febrile and non-febrile patients presenting to community hospitals in rural Thailand from February 2002 through March 2003. Single serum specimens were tested for IgG titers to four Bartonella species, B. henselae, B. quintana, B. elizabethae and B. vinsonii subsp vinsonii using an indirect immunofluorescent assay. A titer 21:256 was considered positive. Forty-two febrile patients (9.9%) and 19 non-febrile patients (19%) had positive serology titers to at least one Bartonella species. Age-standardized Bartonella seroprevalence differed significantly between febrile (10%) and non-febrile patients (18%, p=0.047), but did not differ by gender. Among all 521 patients, IgG titers 21:256 to B. henselae were found in 20 participants (3.8%), while 17 (3.3%) had seropositivity to B. quintana, 51 (9.8%) to B. elizabethae, and 19 (3.6%) to B. vinsonii subsp vinsonii. These results suggest exposure to Bartonella species is more common in rural Thailand than previously suspected.