Projecting the SARS-CoV-2 transition from pandemicity to endemicity: Epidemiological and immunological considerations.

In this review, we discuss the epidemiological dynamics of different viral infections to project how the transition from a pandemic to endemic Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) might take shape. Drawing from theories of disease invasion and transmission dynamics, waning immunity in the face of viral evolution and antigenic drift, and empirical data from influenza, dengue, and seasonal coronaviruses, we discuss the putative periodicity, severity, and age dynamics of SARS-CoV-2 as it becomes endemic. We review recent studies on SARS-CoV-2 epidemiology, immunology, and evolution that are particularly useful in projecting the transition to endemicity and highlight gaps that warrant further research.

Sequential viral introductions and spread of BA.1 across Pakistan provinces during the Omicron wave.

BACKGROUND: COVID-19 waves caused by specific SARS-CoV-2 variants have occurred globally at different times. We focused on Omicron variants to understand the genomic diversity and phylogenetic relatedness of SARS-CoV-2 strains in various regions of Pakistan. METHODS: We studied 276,525 COVID-19 cases and 1,031 genomes sequenced from December 2021 to August 2022. Sequences were analyzed and visualized using phylogenetic trees. RESULTS: The highest case numbers and deaths were recorded in Sindh and Punjab, the most populous provinces in Pakistan. Omicron variants comprised 93% of all genomes, with BA.2 (32.6%) and BA.5 (38.4%) predominating. The first Omicron wave was associated with the sequential identification of BA.1 in Sindh, then Islamabad Capital Territory, Punjab, Khyber Pakhtunkhwa (KP), Azad Jammu Kashmir (AJK), Gilgit-Baltistan (GB) and Balochistan. Phylogenetic analysis revealed Sindh to be the source of BA.1 and BA.2 introductions into Punjab and Balochistan during early 2022. BA.4 was first introduced in AJK and BA.5 in Punjab. Most recent common ancestor (MRCA) analysis revealed relatedness between the earliest BA.1 genome from Sindh with Balochistan, AJK, Punjab and ICT, and that of first BA.1 from Punjab with strains from KPK and GB. CONCLUSIONS: Phylogenetic analysis provides insights into the introduction and transmission dynamics of the Omicron variant in Pakistan, identifying Sindh as a hotspot for viral dissemination. Such data linked with public health efforts can help limit surges of new infections.

Beyond clinical trials: Evolutionary and epidemiological considerations for development of a universal influenza vaccine.

The prospect of universal influenza vaccines is generating much interest and research at the intersection of immunology, epidemiology, and viral evolution. While the current focus is on developing a vaccine that elicits a broadly cross-reactive immune response in clinical trials, there are important downstream questions about global deployment of a universal influenza vaccine that should be explored to minimize unintended consequences and maximize benefits. Here, we review and synthesize the questions most relevant to predicting the population benefits of universal influenza vaccines and discuss how existing information could be mined to begin to address these questions. We review three research topics where computational modeling could bring valuable evidence: immune imprinting, viral evolution, and transmission. We address the positive and negative consequences of imprinting, in which early childhood exposure to influenza shapes and limits immune responses to future infections via memory of conserved influenza antigens. However, the mechanisms at play, their effectiveness, breadth of protection, and the ability to "reprogram" already imprinted individuals, remains heavily debated. We describe instances of rapid influenza evolution that illustrate the plasticity of the influenza virus in the face of drug pressure and discuss how novel vaccines could introduce new selective pressures on the evolution of the virus. We examine the possible unintended consequences of broadly protective (but infection-permissive) vaccines on the dynamics of epidemic and pandemic influenza, compared to conventional vaccines that have been shown to provide herd immunity benefits. In conclusion, computational modeling offers a valuable tool to anticipate the benefits of ambitious universal influenza vaccine programs, while balancing the risks from endemic influenza strains and unpredictable pandemic viruses. Moving forward, it will be important to mine the vast amount of data generated in clinical studies of universal influenza vaccines to ensure that the benefits and consequences of these vaccine programs have been carefully modeled and explored.

Population-level mathematical modeling of antimicrobial resistance: a systematic review.

BACKGROUND: Mathematical transmission models are increasingly used to guide public health interventions for infectious diseases, particularly in the context of emerging pathogens; however, the contribution of modeling to the growing issue of antimicrobial resistance (AMR) remains unclear. Here, we systematically evaluate publications on population-level transmission models of AMR over a recent period (2006-2016) to gauge the state of research and identify gaps warranting further work. METHODS: We performed a systematic literature search of relevant databases to identify transmission studies of AMR in viral, bacterial, and parasitic disease systems. We analyzed the temporal, geographic, and subject matter trends, described the predominant medical and behavioral interventions studied, and identified central findings relating to key pathogens. RESULTS: We identified 273 modeling studies; the majority of which (> 70%) focused on 5 infectious diseases (human immunodeficiency virus (HIV), influenza virus, Plasmodium falciparum (malaria), Mycobacterium tuberculosis (TB), and methicillin-resistant Staphylococcus aureus (MRSA)). AMR studies of influenza and nosocomial pathogens were mainly set in industrialized nations, while HIV, TB, and malaria studies were heavily skewed towards developing countries. The majority of articles focused on AMR exclusively in humans (89%), either in community (58%) or healthcare (27%) settings. Model systems were largely compartmental (76%) and deterministic (66%). Only 43% of models were calibrated against epidemiological data, and few were validated against out-of-sample datasets (14%). The interventions considered were primarily the impact of different drug regimens, hygiene and infection control measures, screening, and diagnostics, while few studies addressed de novo resistance, vaccination strategies, economic, or behavioral changes to reduce antibiotic use in humans and animals. CONCLUSIONS: The AMR modeling literature concentrates on disease systems where resistance has been long-established, while few studies pro-actively address recent rise in resistance in new pathogens or explore upstream strategies to reduce overall antibiotic consumption. Notable gaps include research on emerging resistance in Enterobacteriaceae and Neisseria gonorrhoeae; AMR transmission at the animal-human interface, particularly in agricultural and veterinary settings; transmission between hospitals and the community; the role of environmental factors in AMR transmission; and the potential of vaccines to combat AMR.

Pediatric Minor Traumatic Brain Injury With Intracranial Hemorrhage: Identifying Low-Risk Patients Who May Not Benefit From ICU Admission.

BACKGROUND: Pediatric patients with any severity of traumatic intracranial hemorrhage (tICH) are often admitted to intensive care units (ICUs) for early detection of secondary injury. We hypothesize that there is a subset of these patients with mild injury and tICH for whom ICU care is unnecessary. OBJECTIVES: To quantify tICH frequency and describe disposition and to identify patients at low risk of inpatient critical care intervention (CCI). METHODS: We retrospectively reviewed patients aged 0 to 17 years with tICH at a single level I trauma center from 2008 to 2013. The CCI included mechanical ventilation, invasive monitoring, blood product transfusion, hyperosmolar therapy, and neurosurgery. Binary recursive partitioning analysis led to a clinical decision instrument classifying patients as low risk for CCI. RESULTS: Of 296 tICH admissions without prior CCI in the field or emergency department, 29 had an inpatient CCI. The decision instrument classified patients as low risk for CCI when patients had absence of the following: midline shift, depressed skull fracture, unwitnessed/unknown mechanism, and other nonextremity injuries. This clinical decision instrument produced a high likelihood of excluding patients with CCI (sensitivity, 96.6%; 95% confidence interval, 82.2%-99.9%) from the low-risk group, with a negative likelihood ratio of 0.056 (95% confidence interval, -0.053-0.166). The decision instrument misclassified 1 patient with CCI into the low-risk group, but would have impacted disposition of 164 pediatric ICU admissions through 5 years (55% of the sample). CONCLUSIONS: A subset of low-risk patients may not require ICU admission. The proposed decision rule identified low-risk children with tICH who may be observable outside an ICU, although this rule requires external validation before implementation.

A Commitment to Making Health Care Personal.

In this narrative medicine essay, an emergency medicine pediatrician describes the care his mother received in her last days and calls on the health care profession to aim for providing a personal touch when caring for patients.

Performance characteristics of magnetic resonance imaging without contrast agents or sedation in pediatric appendicitis.

BACKGROUND: Magnetic resonance imaging (MRI) has emerged as a promising modality for evaluating pediatric appendicitis. However optimal imaging protocols, including roles of contrast agents and sedation, have not been established and diagnostic criteria have not been fully evaluated. OBJECTIVE: To investigate performance characteristics of rapid MRI without contrast agents or sedation in the diagnosis of pediatric appendicitis. MATERIALS AND METHODS: We included patients ages 4-18 years with suspicion of appendicitis who underwent rapid MRI between October 2013 and March 2015 without contrast agent or sedation. After two-radiologist review, we determined performance characteristics of individual diagnostic criteria and aggregate diagnostic criteria by comparing MRI results to clinical outcomes. We used receiver operating characteristic (ROC) curves to determine cut-points for appendiceal diameter and wall thickness for optimization of predictive power, and we calculated area under the curve (AUC) as a measure of test accuracy. RESULTS: Ninety-eight MRI examinations were performed in 97 subjects. Overall, MRI had a 94% sensitivity, 95% specificity, 91% positive predictive value and 97% negative predictive value. Optimal cut-points for appendiceal diameter and wall thickness were ≥7 mm and ≥2 mm, respectively. Independently, those cut-points produced sensitivities of 91% and 84% and specificities of 84% and 43%. Presence of intraluminal fluid (30/33) or localized periappendiceal fluid (32/33) showed a significant association with acute appendicitis (P<0.01), with sensitivities of 91% and 97% and specificities of 60% and 50%. For examinations in which the appendix was not identified by one or both reviewers (23/98), the clinical outcome was negative. CONCLUSION: Rapid MRI without contrast agents or sedation is accurate for diagnosis of pediatric appendicitis when multiple diagnostic criteria are considered in aggregate. Individual diagnostic criteria including optimized cut-points of ≥7 mm for diameter and ≥2 mm for wall thickness demonstrate high sensitivities but relatively low specificities. Nonvisualization of the appendix favors a negative diagnosis.

Impact of an Inpatient Psychiatric Unit on Pediatric Emergency Mental Health Care.

OBJECTIVES: Mental health complaints are a frequent presentation to the pediatric emergency department (PED). It is unclear if having an on-site inpatient pediatric psychiatric unit impacts pediatric mental health care in the acute setting. The objective of this study was to compare PED mental health care between a pediatric tertiary care center with an associated inpatient child psychiatric unit (PAPED) and one that does not (NOPED) with the hypothesis that children have longer lengths of stay (LOS) at the PED without an inpatient unit. METHODS: This was a retrospective, observational study of all mental health presentations aged 1 to 18 years to 2 tertiary care PEDs from March 2012 to June 2013 with a final mental health diagnosis International Classification of Diseases, Ninth Revision code. RESULTS: A total of 1409 patient encounters comprised the study group. The PAPED had a significantly higher rate of admission 41.3% versus 18.8% (P < 0.0001). The LOS was significantly longer at the NOPED compared with the PAPED with a visit of 15.6 versus 6.3, respectively (P < 0.0001). When LOS was stratified for disposition, patients requiring admission from the NOPED had a significantly longer LOS of 33.4 compared with an emergency department LOS of 8.1 at the PAPED (P < 0.0001). CONCLUSIONS: Mental health care in the PED seems to be affected by having an associated inpatient child psychiatric unit. Further research needs to address this growing problem and ways to utilize community resources to develop safe outpatient plans and divert admission if possible.

A randomized trial of Plasma-Lyte A and 0.9 % sodium chloride in acute pediatric gastroenteritis.

BACKGROUND: Compare the efficacy and safety of Plasma-Lyte A (PLA) versus 0.9 % sodium chloride (NaCl) intravenous (IV) fluid replacement in children with moderate to severe dehydration secondary to acute gastroenteritis (AGE). METHODS: Prospective, randomized, double-blind study conducted at eight pediatric emergency departments (EDs) in the US and Canada (NCT#01234883). The primary outcome measure was serum bicarbonate level at 4 h. Secondary outcomes included safety and tolerability. The hypothesis was that PLA would be superior to 0.9 % NaCl in improvement of 4-h bicarbonate. Patients (n = 100) aged ≥6 months to <11 years with AGE-induced moderate-to-severe dehydration were enrolled. Patients with a baseline bicarbonate level ≤22 mEq/L formed the modified intent to treat (mITT) group. RESULTS: At baseline, the treatment groups were comparable except that the PLA group was older. At hour 4, the PLA group had greater increases in serum bicarbonate from baseline than did the 0.9 % NaCl group (mean ± SD at 4 h: 18 ± 3.74 vs 18.0 ± 3.67; change from baseline of 1.6 and 0.0, respectively; P = .004). Both treatment groups received similar fluid volumes. The PLA group had less abdominal pain and better dehydration scores at hour 2 (both P = .03) but not at hour 4 (P = 0.15 and 0.08, respectively). No patient experienced clinically relevant worsening of laboratory findings or physical examination, and hospital admission rates were similar. One patient in each treatment group developed hyponatremia. Four patients developed hyperkalemia (PLA:1, 0.9 % NaCl:3). CONCLUSION: In comparison with 0.9 % NaCl, PLA for rehydration in children with AGE was well tolerated and led to more rapid improvement in serum bicarbonate and dehydration score. TRIAL REGISTRATION: NCT#01234883 (Registration Date: November 3, 2010).

Mental Health Utilization in a Pediatric Emergency Department.

OBJECTIVE: Mental health complaints are frequent in the pediatric emergency department (PED). The objective of this study was to describe trends over time in PED utilization for mental health care at in a single pediatric tertiary care hospital. It is our hypothesis that the resources used by this patient population are high and that mental health-related visits have increased over the most recent decade. METHODS: This was a retrospective study of all pediatric mental health presentations to the PED from January 2009 to July 2013 at a single pediatric hospital. All patients aged 1 to 19 years with an International Classification of Diseases, Ninth Revision code of 291, 292, 295 to 309, and 311 to 314 were included. Data collected included demographic data, medications received, restraint use, suicidality, length of stay (LOS), charges incurred, final disposition, and daily PED operation variables. Trends over time in presentation, charges, and LOS were analyzed using multiple mixed effects regression models after adjusting for potential patient and PED level confounding variables and clustering of multiple visits within patients. RESULTS: A total of 732 PED visits from 2009 to 2013 were identified representing 646 unique patients. The average age was 13.8 years, and 53% were male. Approximately 25% of the patients expressed suicidal ideation, and 44% of those had attempted suicide before arrival. Behavioral or chemical restraints were used in 33% of patients during their PED visit. There were statistically significant increases in annual visits, LOS, and charges over this period (P < 0.05). Increased charges were significantly associated with longer LOS (P = 0.0062). Charges (P = 0.46) and LOS (P = 0.62) were not significantly different between suicidal and nonsuicidal patients. Approximately 21% of patients were admitted or transferred to another facility. CONCLUSIONS: In this single-center study, we found evidence that the resources required to care for pediatric patients with mental health complaints have increased significantly over time both by increased number of annual visits and an increasing LOS. Further research is necessary to determine if our data are consistent with national trends to further our understanding of the problem and improve resource allocation.

Adding multiple micronutrient powders to a homestead food production programme yields marginally significant benefit on anaemia reduction among young children in Nepal.

Anaemia affects 46% of preschool-aged children in Nepal. A cluster-randomised study was conducted in rural Nepal to test whether providing micronutrient powders (MNP) in addition to enhanced homestead food production (EHFP) programme, consisting of home gardens, poultry and nutrition education, could lead to a higher reduction in anaemia compared with providing only EHFP. This sub-study enrolled 335 children aged 6-9 months into one of three groups: (1) EHFP + MNP; (2) EHFP; or (3) control. The EHFP + MNP group received 60 sachets of MNP for flexible consumption at the start and 6 months later for a total supplementation period of 11 months. The MNP contained 15 micronutrients including iron (10 mg encapsulated ferrous fumarate). Haemoglobin and anthropometry were measured at baseline and post-MNP supplementation. Mean ± SE haemoglobin concentration increased significantly in all groups, with a slightly higher but non-significant increase in the EHFP + MNP and EHFP compared with control (difference-in-differences: 4.1 g L(-1) for EHFP + MNP vs. control; 3.6 g L(-1) for EHFP vs. control; 0.5 g L(-1) for EHFP + MNP vs. EHFP). Anaemia decreased at a slightly higher magnitude in the EHFP + MNP [51.5 percentage points (PP)] than the EHFP (48.6 PP) and control (39.6 PP), with adjusted odds ratios (95% CI) at post-supplementation of 0.52 (0.25-1.12) for EHFP + MNP and 0.69 (0.35-1.36) for EHFP, compared with control. There was no impact on child growth. Combining EHFP and MNP programmes yielded a marginally significant reduction in anaemia among children.

Using formative research to design a context-specific behaviour change strategy to improve infant and young child feeding practices and nutrition in Nepal.

Global recommendations on strategies to improve infant feeding, care and nutrition are clear; however, there is limited literature that explains methods for tailoring these recommendations to the local context where programmes are implemented. This paper aims to: (1) highlight the individual, cultural and environmental factors revealed by formative research to affect infant and young child feeding and care practices in Baitadi district of Far Western Nepal; and (2) outline how both quantitative and qualitative research methods were used to design a context-specific behaviour change strategy to improve child nutrition. Quantitative data on 750 children aged 12-23 months and their families were collected via surveys administered to mothers. The participants were selected using a multistage cluster sampling technique. The survey asked about knowledge, attitude and behaviours relating to infant and young child feeding. Qualitative data on breastfeeding and complementary feeding beliefs and practices were also collected from a separate sample via focus group discussions with mothers, and key informant interviews with mothers-in-law and husbands. Key findings revealed gaps in knowledge among many informants resulting in suboptimal infant and young child feeding practices - particularly with relation to duration of exclusive breastfeeding and dietary diversity of complementary foods. The findings from this research were then incorporated into a context-specific nutrition behaviour change communication strategy.

Pediatric migraine: abortive management in the emergency department.

Studies suggest that headache accounts for approximately 1% of pediatric emergency department (ED) visits. ED physicians must distinguish between primary headaches, such as a tension or migraine, and secondary headaches caused by systemic disease including neoplasm, infection, or intracranial hemorrhage. A recent study found that 40% of children presenting to the ED with headache were diagnosed with a primary headache, and 75% of these were migraine. Once the diagnosis of migraine has been made, the ED physician is faced with the challenge of determining appropriate abortive treatment. This review summarizes the most recent literature on pediatric migraine with an emphasis on diagnosis and abortive treatment in the ED.

Diagnostic testing and treatment of pediatric headache in the emergency department.

OBJECTIVE: To describe the variability in diagnostic testing and treatment of headaches in children presenting to the emergency department (ED) with use of a nationally representative sample. STUDY DESIGN: This was a retrospective cohort study using the National Hospital Ambulatory Medical Care Survey during 2005-2009. To assess the use of evidence-based treatment, we analyzed all patients <18 years old in 2 groups: (1) primary discharge diagnosis of headache and (2) discharge diagnosis of migraine. RESULTS: Four hundred forty-eight sampled ED visits from 2005-2009 represented a national estimate of 1.7 million visits with a discharge diagnosis of headache. A total of 95 visits represented a national estimate of 340 000 visits with a discharge diagnosis of migraine. Median age was 13.1 years and 60% were female with a primary diagnosis of headache. In this group, neuroimaging was performed in 37% of patients and 39% underwent blood tests. Nonsteroidal anti-inflammatory drugs and opioids were most commonly used for treatment. For children with a discharge diagnosis of migraine, approximately 40% of patients received non-evidence-based treatment, most commonly with opioid medications, and >20% of patients underwent computed tomography scanning. CONCLUSIONS: There is significant variability in the evaluation and treatment of pediatric headache in the ED. Despite evidence-based clinical guidelines for migraine headache, a large number of children continue to receive opioids and ionizing radiation in the ED.

A novel biomarker panel to rule out acute appendicitis in pediatric patients with abdominal pain.

OBJECTIVES: To identify a biomarker panel with sufficient sensitivity and negative predictive value to identify children with abdominal pain at low risk for acute appendicitis in order to avoid unnecessary imaging. METHODS: We prospectively enrolled 503 subjects aged two to 20 years with <72 hours of abdominal pain consistent with appendicitis. Blood samples from each patient were analyzed for CBC, differential, and 5 candidate proteins. Biomarker values were evaluated using principal component, recursive partitioning and logistic regression to select the combination that best discriminated between those subjects with and without disease. RESULTS: The prevalence of acute appendicitis was 28.6%. A mathematical combination of three inflammation-related markers in a panel comprised of white blood cell count (WBC), C-reactive protein (CRP), and myeloid-related protein 8/14 complex (MRP 8/14) provided the best discrimination. This panel exhibited a sensitivity of 96.5% (95% CI, 92-99%), a negative predictive value of 96.9% (95% CI, 93-99%), a negative likelihood ratio of 0.08 (95% CI, 0.03- 0.19), and a specificity of 43.2% (95% CI, 38-48%) for acute appendicitis. Sixty of 185 CT scans (32.4%) were done for patients with negative biomarker panel results which, if deferred, would have reduced CT utilization at initial presentation by one third at the cost of missing five of 144 (3.5%) patients with appendicitis. CONCLUSION: This panel may be useful in identifying pediatric patients with signs and symptoms suggestive of acute appendicitis who are at low risk and can be followed clinically, potentially sparing them exposure to the ionizing radiation of CT.

Bedside optic nerve sheath diameter ultrasound for the evaluation of suspected pediatric ventriculoperitoneal shunt failure in the emergency department.

OBJECTIVE: To determine the feasibility and test characteristics of optic nerve sheath diameter (ONSD) measured by ocular ultrasound as a screening tool for ventriculoperitoneal shunt (VPS) failure. METHODS: Prospective observational study using a convenience sample of children 6 months to 18 years of age, presenting to an academic pediatric emergency department for evaluation of possible VPS failure between September 2008 and March 2009. ONSD was measured by anterior transbulbar and lateral transbulbar techniques. Mean ONSD was compared between subjects with and without shunt failure, as determined by neurosurgical decision to operate. RESULTS: A total of 39 encounters were completed, including 20 VPS failures. The mean ONSD was 4.5 ± 0.9 and 5.0 ± 0.6 mm among encounters with and without shunt failure (p = 0.03), respectively. The mean ONSD was not statistically different when obtained by the anterior transbulbar vs. the lateral transbulbar approach (4.8 ± 1.0 vs. 4.7 ± 0.8 mm, p = 0.12). ONSD ultrasound had a sensitivity of 61.1 % (95 % CI 35.7-82.7) and specificity of 22.2 % (95 % CI 6.4-47.6 %) for detecting shunt failure in this sample. CONCLUSIONS: ONSD ultrasound does not appear to be a useful primary screening tool in emergency department evaluation of VPS failure. There was no difference between the anterior transbulbar approach and the lateral transbulbar approach. Children with VPS in our sample have larger ONSD measurements than in previously reported studies.

Evaluation of a novel pediatric appendicitis pathway using high- and low-risk scoring systems.

OBJECTIVES: This study aimed to determine the test characteristics of a pathway for pediatric appendicitis and its effects on emergency department (ED) length of stay, imaging, and admissions. METHODS: Children age 3 to 18 years with suspicion for appendicitis at 1 tertiary care ED were prospectively enrolled, using validated low- and high-risk scoring systems incorporating history, physical examination, and white blood cell count. Low-risk patients were discharged or observed in the ED. High-risk patients were admitted. Those meeting neither low-risk nor high-risk criteria were evaluated by surgery, with imaging at their discretion. Chart review or telephone follow-up was conducted 2 weeks after the visit. A retrospective study before and after was also performed. Charts of a random sample of patients evaluated for appendicitis in the 8 months before and after the pathway implementation were reviewed. RESULTS: Appendicitis was diagnosed in 65 of 178 patients. Of those with appendicitis, 63 were not low-risk (sensitivity, 96.9%; specificity, 40.7%). The high-risk criteria had a sensitivity of 75.3% and specificity of 75.2%. We reviewed 292 visits before and 290 after the pathway implementation. Emergency department length of stay was similar (253 minutes before vs 257 minutes after, P = 0.77). Computed tomography was used in 12.7% of visits before and 6.9% of visits after (P = 0.02). Use of ultrasound was not significantly different (47.3% vs 53.7%). Admission rates were not significantly different (45.5% vs 42.7%). CONCLUSIONS: The low-risk criteria had good sensitivity in ruling out appendicitis. The high-risk criteria could be used to guide referral or admission. Neither outperformed the a priori judgment of experienced providers.

Migratory flyway and geographical distance are barriers to the gene flow of influenza virus among North American birds.

Despite the importance of migratory birds in the ecology and evolution of avian influenza virus (AIV), there is a lack of information on the patterns of AIV spread at the intra-continental scale. We applied a variety of statistical phylogeographic techniques to a plethora of viral genome sequence data to determine the strength, pattern and determinants of gene flow in AIV sampled from wild birds in North America. These analyses revealed a clear isolation-by-distance of AIV among sampling localities. In addition, we show that phylogeographic models incorporating information on the avian flyway of sampling proved a better fit to the observed sequence data than those specifying homogeneous or random rates of gene flow among localities. In sum, these data strongly suggest that the intra-continental spread of AIV by migratory birds is subject to major ecological barriers, including spatial distance and avian flyway.