Pathogenesis and transmission of swine origin A(H3N2)v influenza viruses in ferrets

Recent isolation of a novel swine-origin influenza A H3N2 variant virus [A(H3N2)v] from humans in the United States has raised concern over the pandemic potential of these viruses. Here, we analyzed the virulence, transmissibility, and receptor-binding preference of four A(H3N2)v influenza viruses isolated from humans in 2009, 2010, and 2011. High titers of infectious virus were detected in nasal turbinates and nasal wash samples of A(H3N2)v-inoculated ferrets. All four A(H3N2)v viruses possessed the capacity to spread efficiently between cohoused ferrets, and the 2010 and 2011 A(H3N2)v isolates transmitted efficiently to naïve ferrets by respiratory droplets. A dose-dependent glycan array analysis of A(H3N2)v showed a predominant binding to α2-6–sialylated glycans, similar to human-adapted influenza A viruses. We further tested the viral replication efficiency of A(H3N2)v viruses in a relevant cell line, Calu-3, derived from human bronchial epithelium. The A(H3N2)v viruses replicated in Calu-3 cells to significantly higher titers compared with five common seasonal H3N2 influenza viruses. These findings suggest that A(H3N2)v viruses have the capacity for efficient replication and transmission in mammals and underscore the need for continued public health surveillance.Seasonal epidemics and periodic pandemics are an ever-present international public health burden. During seasonal epidemics, the risk for hospitalization and death are highest among persons at either end of the age spectrum as well as for individuals with underlying medical conditions (1, 2). Although the overall impact of the 2009 influenza pandemic, caused by an H1N1 virus [A(H1N1)pdm09] was more modest than those of prior pandemics, the disproportionate disease burden among children and younger adults distinguished this pandemic from seasonal influenza (3–5). The A(H1N1)pdm09 virus emerged from swine, with a unique constellation of genes from human, avian, and swine influenza viruses not previously observed in nature. Swine represent a unique host because of their ability to be infected by influenza viruses from multiple species and serve as a reservoir for specific subtypes of influenza capable of infecting humans (6–8). Triple-reassortant swine (TRS) H1N1 viruses, which share host gene-lineage origins with A(H1N1)pdm09 viruses, have been responsible for sporadic human cases since 2005 (9, 10). The emergence of the A(H1N1)pdm09 virus, to which the majority of children and younger adults had little preexisting immunity, highlights the public health threat posed by other swine-origin influenza virus subtypes.H3N2 viruses have circulated in humans since their pandemic emergence in 1968 and are generally associated with uncomplicated disease in young healthy adults. However, epidemics caused by H3N2 viruses have been more severe than those caused by seasonal H1N1 or influenza B viruses (11, 12). In 1997–1998, human H3N2 viruses infected swine and spread widely in North American swine (6–8). In particular, TRS H3N2 viruses with a human lineage polymerase subunit polymerase basic 1 (PB1) gene, avian lineage PB2 and polymerase acidic (PA) genes, and swine lineage nucleoprotein (NP), matrix (M), and nonstructural (NS) genes, referred to as the triple-reassortant internal gene (TRIG) constellation, have been isolated widely in pigs throughout the United States (6–8, 13). From the late 1990s to 2009, these novel variants of H3N2 viruses [A(H3N2)v] were limited to transmission among swine, with only occasional detections of transmission to humans (14). However, between September and November 2010, five cases of human infection with the novel swine-origin A(H3N2)v were reported (15). Although all five recovered fully from their illness, two of the five cases were hospitalized. In 2011, 12 additional human cases were documented in the United States, with limited human-to-human transmission in some cases (15–17). The 2011 A(H3N2)v viruses are similar to other A(H3N2)v viruses isolated from previous human infections over the past 2 y but are unique in that the M gene is derived from the A(H1N1)pdm09 virus. Antigenic characterization showed that the A(H3N2)v viruses are distinct from current seasonal H3N2 viruses but exhibit a low degree of serologic cross-reactivity with human H3N2 viruses that circulated in the early 1990s (6, 8, 13), suggesting that children born after this time period may be particularly susceptible to infection.The use of the ferret model has become indispensable for understanding the virulence and transmission of influenza viruses (18–20), partly because ferrets and humans share similar lung physiology as well as because human and avian influenza viruses exhibit similar patterns of binding to sialic acids, the receptor for influenza viruses distributed throughout the respiratory tract in both species (21, 22). In this study, we used glycan microarrays to determine the receptor-binding preference of the A(H3N2)v viruses isolated from humans. The culture model of bronchial epithelial Calu-3 cells was used to assess viral replication, and the ferret model was used to assess pathogenicity and transmissibility. Notably, the 2010 and 2011 swine-origin H3N2 viruses replicated even more efficiently than human seasonal influenza viruses in human airway Calu-3 cells and exhibited efficient respiratory-droplet (RD) transmission in ferrets. These findings suggest that swine-origin H3N2 viruses have the potential to cause additional human disease.     

The evolution of thyroid function with puberty

Objective This study was planned to describe thyroid functional status in different stages of puberty. Study design We collected data from five schools across different geographical zones of Delhi. All children who consented were evaluated for anthropometry, pubertal stage, goitre status, serum free T3 (FT3), free T4 (FT4), TSH, anti‐TPO (thyroid peroxidase) antibodies and thyroid ultrasound. From this sample, a disease‐ and risk‐free or ‘reference population’ was obtained by excluding those with history of thyroid disease or use of thyroid medications, family history of thyroid disease, goitre, hypoechogenicity or nodularity on ultrasound or positive antithyroid antibodies. Results The ‘total population’ comprised 3722 children; the ‘reference population’ comprised 2134 subjects. The mean, median, 3rd and 97th percentiles of serum FT3, FT4 and TSH for each stage of puberty were obtained. In both boys and girls, FT3 increased with entry into puberty and either stayed constant or declined marginally after stage 3 of puberty. In contrast, in both genders, FT4 decreased with entry into puberty and stayed relatively constant after stage 3 of puberty. TSH levels declined through puberty in boys, but remained largely unchanged in girls. An increased conversion of T4 to T3 is the possible explanation for this finding. Conclusions This large community‐based study in school‐age children using strict exclusion criteria provides data of thyroid function in the various stages of puberty. There is no evidence of ‘thyroidarche’ during or preceding puberty.     

Unintended Consequences of a Standard Admission Order Set on Venous Thromboembolism Prophylaxis and Patient Outcomes

BACKGROUND  

Standard order sets often increase the use of desirable interventions for patients likely to benefit from them. Whether such order sets also increase misuse of these interventions in patients potentially harmed by them is unknown. We measured the association between a paper-based standard admission order set with a venous thromboembolism pharmacoprophylaxis (VTEP) module and use of VTEP for patients likely to benefit from it as well as patients with unclear benefit or potential harm from it.     

Personalized Health Monitoring System for Managing Well-Being in Rural Areas

Rural India lacks easy access to health practitioners and medical centers, depending instead on community health workers. In these areas, common ailments that are easy to manage with medicines, often lead to medical escalations and even fatalities due to lack of awareness and delayed diagnosis. The introduction of wearable health devices has made it easier to monitor health conditions and to connect doctors and patients in urban areas. However, existing initiatives have not succeeded in providing adequate health monitoring to rural and low-literate patients, as current methods are expensive, require consistent connectivity and expect literate users. Our design considerations address these concerns by providing low-cost medical devices connected to a low-cost health platform, along with personalized guidance based on patient physiological parameters in local languages, and alerts to medical practitioners in case of emergencies. This patient-centric integrated healthcare system is designed to manage the overall health of villagers with real-time health monitoring of patients, to offer guidance on preventive care, and to increase health awareness and self-monitoring at an affordable price. This personalized health monitoring system addresses the health-related needs in remote and rural areas by (1) empowering health workers in monitoring of basic health conditions for rural patients in order to prevent escalations, (2) personalized feedback regarding nutrition, exercise, diet, preventive Ayurveda care and yoga postures based on vital parameters and (3) reporting of patient data to the patient’s health center with emergency alerts to doctor and patient. The system supports community health workers in the diagnostic procedure, management, and reporting of rural patients, and functions well even with only intermittent access to Internet.     

Insulin-like Growth Factor Messenger RNA-binding Protein 3 Expression Helps Prognostication in Patients with Upper Tract Urothelial Carcinoma

Background

Upper tract urothelial carcinoma (UTUC) is a clinically heterogeneous disease that lacks high-quality trials that provide definitive prognostic markers. Insulin-like growth factor messenger RNA binding protein 3 (IMP3) has been associated with outcomes in urothelial carcinoma of the bladder but was not yet studied in UTUC.

Objective

To evaluate the association of the oncofetal protein IMP3 with oncologic outcomes in patients with UTUC treated with radical nephroureterectomy (RNU).

Design, setting, and participants

We investigated the expression of IMP3 and its association with clinical outcomes using tissue microarrays constructed from 622 patients treated with RNU at seven international institutions between 1991 and 2008.

Intervention

All patients were diagnosed with UTUC and underwent RNU.

Outcome measurement and statistical analysis

Uni- and multivariable Cox regression analyses evaluated the association of IMP3 protein expression with disease recurrence, cancer-specific mortality, and all-cause mortality.

Results and limitations

IMP3 was expressed in 12.2% of patients with UTUC (n = 76). The expression was tumor specific and correlated with higher stages/grades. Within a median follow-up of 27 mo (interquartile range [IQR]: 12–53), 191 patients (25.4%) experienced disease recurrence, and 165 (21.9%) died of the disease. Patients with IMP3 demonstrated significantly worse recurrence-free survival (27.4% vs 75.1%; p < 0.01), cancer-specific survival (34.5% vs 78.9%; p < 0.01), and overall survival (15.6% vs 64.8%; p < 0.01) at 5 yr compared with those without IMP3. In multivariable Cox regression analyses, which adjusted for the effects of standard clinicopathologic features, IMP3expression was independently associated with disease recurrence (hazard ratio [HR]: 1.87; p < 0.01), cancer-specific mortality (HR: 2.15; p < 0.01), and all-cause mortality (HR: 2.07; p < 0.01). Major limitations include the retrospective design and relatively short follow-up time.

Conclusions

IMP3 expression is independently associated with disease recurrence, cancer-specific mortality, and all-cause mortality in UTUC. IMP3 may help improve risk stratification and prognostication of UTUC patients treated with RNU.