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Abstract Background Pandemic influenza H1N1 (pdmH1N1) virus causes mild disease in humans but occasionally leads to severe complications and even death, especially in those who are pregnant or have underlying disease. Cytokine responses induced by pdmH1N1 viruses in vitro are comparable to other seasonal influenza viruses suggesting the cytokine dysregulation as seen in H5N1 infection is not a feature of the pdmH1N1 virus. However a comprehensive gene expression profile of pdmH1N1 in relevant primary human cells in vitro has not been reported. Type I alveolar epithelial cells are a key target cell in pdmH1N1 pneumonia. Methods We carried out a comprehensive gene expression profiling using the Affymetrix microarray platform to compare the transcriptomes of primary human alveolar type I-like alveolar epithelial cells infected with pdmH1N1 or seasonal H1N1 virus. Results Overall, we found that most of the genes that induced by the pdmH1N1 were similarly regulated in response to seasonal H1N1 infection with respect to both trend and extent of gene expression. These commonly responsive genes were largely related to the interferon (IFN) response. Expression of the type III IFN IL29 was more prominent than the type I IFN IFNβ and a similar pattern of expression of both IFN genes was seen in pdmH1N1 and seasonal H1N1 infection. Genes that were significantly down-regulated in response to seasonal H1N1 but not in response to pdmH1N1 included the zinc finger proteins and small nucleolar RNAs. Gene Ontology (GO) and pathway over-representation analysis suggested that these genes were associated with DNA binding and transcription/translation related functions. Conclusions Both seasonal H1N1 and pdmH1N1 trigger similar host responses including IFN-based antiviral responses and cytokine responses. Unlike the avian H5N1 virus, pdmH1N1 virus does not have an intrinsic capacity for cytokine dysregulation. The differences between pdmH1N1 and seasonal H1N1 viruses lay in the ability of seasonal H1N1 virus to down regulate zinc finger proteins and small nucleolar RNAs, which are possible viral transcriptional suppressors and eukaryotic translation initiation factors respectively. These differences may be biologically relevant and may represent better adaptation of seasonal H1N1 influenza virus to the host.

Objective To evaluate the survival and clinical performance of restorative materials used in the rehabilitation of generalised severe tooth wear within a UK NHS postgraduate teaching hospital.Methods The clinical performance of 527 restorations on 20 patients with generalised severe tooth wear was reviewed after a mean period of five years. Anterior teeth were restored with direct composite resin and posterior teeth with indirect restorations. The study used the modified United States Public Health Service criteria for restoration assessment. Survival of the restorations was analysed using Kaplan-Meier survival curves, the log-rank test and the Cox proportional hazards regression analysis.Results The sample included 20 participants: 13 men and 7 women, with a median age of 51.8 years (range: 33-73 years). The median survival time for all restorations was 11.3 years when major failures were considered and 5.9 years for restorations when all types of failure were considered. A median survival time of 5.9 years for composite resin restorations and over seven years for cast restorations was found when considering all failures. Composite resin restorations commonly failed as a result of fracture, wear and marginal discolouration. Factors significantly influencing restoration survival were the material used, aetiology, incisal relationship and tooth location. The biological complications associated with this treatment regime were rare. Patient satisfaction remained generally high, with greatest dissatisfaction related to treatment time.Conclusions The use of anterior composite resin with posterior indirect restorations to treat generalised severe tooth wear is a viable treatment modality with very few major complications., (© 2024. The Author(s).)

Terahertz (THz) imaging has been regarded as cutting-edge technology in a wide range of applications due to its ability to penetrate through opaque materials, non-invasive nature, and its increased bandwidth capacity. Recently, THz imaging has been extensively researched in security, driver assistance technology, non-destructive testing, and medical applications. The objective of this review is to summarize the selection criteria for current state-of-the-art THz image reconstruction algorithms developed for short-range imaging applications over the last two decades. Moreover, we summarize the selected algorithms' performance and their implementation process. This study provides an in-depth understanding of the fundamentals of image reconstruction algorithms related to THz short-range imaging and future aspects of algorithm processing and selection.

Objective: Describe trends in opioid plus high-risk medication coprescribing in the USA., Design: Analyses of serial, cross-sectional, nationally representative data of the National Ambulatory Medical Care Survey (NAMCS) over 2007-2016 and the National Hospital Ambulatory Medical Care Survey (NHAMCS) over 2007-2018., Setting: US ambulatory (NAMCS) and emergency department (ED, NHAMCS) settings., Participants: Patient visits in which the patient was 18 years and older with an opioid prescription in the NAMCS or NHAMCS databases., Primary and Secondary Outcome Measures: Frequency of opioid plus high-risk medication coprescribing., Results: From a combined sample of 700 499 visits over 2007-2018, there were 105 720 visits (15.1%) where opioids were prescribed. n=31 825 were from NAMCS and n=73 895 were from NHAMCS. The mean prevalence of coprescription of opioids and high-risk medications for the combined NAMCS and NHAMCS sample was 18.4% in 2007, peaked at 33.2% in 2014 and declined to 23.8% in 2016. Compared with adults receiving opioid prescriptions alone, those coprescribed opioids and high-risk medications were older, more likely female, white and using private or Medicare insurance (p<0.0001)., Conclusions: Coprescribing is more common in ambulatory than ED settings and has been declining, yet one in four patient visits where opioids were prescribed resulted in coprescribed, high-risk medications in 2016. Efforts and research to help lower the rates of high-risk prescribing are needed., Competing Interests: Competing interests: DK receives research and programmatic funding from the Cystic Fibrosis Foundation, the Fraser-Parker Foundation and the National Heart, Lung and Blood Institute (K01HL133466). MKA receives a grant (to Emory University) from Merck & Co., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The United Nations defines violence against women as "any act of gender-based violence that results in, or is likely to result in, physical, sexual or mental harm or suffering to women, including threats of such acts, coercion or arbitrary deprivation of liberty, whether occurring in public or in private life".[1] Violence can take many forms, including physical, sexual or emotional and varies in its severity. Gender discrimination, norms and practices mean that adolescent girls are likely to experience certain forms of violence, such as sexual violence, at much higher rates than boys., Methods: This cross-sectional study was conducted in a rural block of North India. A total of 500 adolescent girls in the age group of 13-19 years studying in class VIII to class XII in 10 government and private senior secondary schools of the Lakhanmajra block were included in the study. A pre-designed pre-tested semi-structured interview schedule was used., Results: In this study, we found the prevalence of physical, sexual and emotional violence among adolescent girls as 6.6, 5.4 and 5.2%, respectively. The most frequent perpetrator of physical violence was the parent and of sexual violence was the neighbour followed by friends or relatives. Higher emotional violence was experienced by adolescent girls from middle-class families ( P < 0.05). The prevalence of physical violence among adolescent girls was maximum in the younger age group 13-14 years (10.2%), followed by 15-17 years (4.0%). This association was found statistically significant ( P < 0.05)., Conclusions: There are several restrictions on free communication about violence-related topics in our highly conservative society. Blaming the victim is the rule rather than the exception and sexual abuse is usually linked to a loss of virginity and family honour in our patriarchal society. Hence, girls may be more reluctant to disclose their experience of violence., Competing Interests: There are no conflicts of interest., (Copyright: © 2022 Journal of Family Medicine and Primary Care.)

Importance: One of the main aims of research on nonmedical opioid use (NMOU) is to reduce the frequency of NMOU behaviors through interventions such as universal screening, reduced opioid exposure, and more intense follow-up of patients with elevated risk. The absence of data on the frequency of NMOU behavior is the major barrier to conducting research on NMOU., Objective: To determine the overall frequency of and the independent predictors for NMOU behavior., Design, Setting, and Participants: In this prognostic study, 3615 patients with cancer were referred to the supportive care center at MD Anderson Cancer Center from March 18, 2016, to June 6, 2018. Patients were eligible for inclusion if they had cancer and were taking opioids for cancer pain for at least 1 week. Patients were excluded if they had no follow-up within 3 months of initial consultation, did not complete the appropriate questionnaire, or did not have scheduled opioid treatments. After exclusion, a total of 1554 consecutive patients were assessed for NMOU behavior using established diagnostic criteria. All patients were assessed using the Edmonton Symptom Assessment Scale, the Screener and Opioid Assessment for Patients with Pain (SOAPP), and the Cut Down, Annoyed, Guilty, Eye Opener-Adapted to Include Drugs (CAGE-AID) survey. Data were analyzed from January 6 to September 25, 2020., Results: A total of 1554 patients (median [interquartile range (IQR)] age, 61 [IQR, 52-69] years; 816 women [52.5%]; 1124 White patients [72.3%]) were evaluable for the study, and 299 patients (19.2%) had 1 or more NMOU behaviors. The median (IQR) number of NMOU behaviors per patient was 1 (IQR, 1-3). A total of 576 of 745 NMOU behaviors (77%) occurred by the first 2 follow-up visits. The most frequent NMOU behavior was unscheduled clinic visits for inappropriate refills (218 of 745 [29%]). Eighty-eight of 299 patients (29.4%) scored 7 or higher on SOAPP, and 48 (16.6%) scored at least 2 out of 4 points on the CAGE-AID survey. Results from the multivariate model suggest that marital status (single, hazard ratio [HR], 1.58; 95% CI, 1.15-2.18; P = .005; divorced, HR, 1.43; 95% CI, 1.01-2.03; P = .04), SOAPP score (positive vs negative, HR, 1.35; 95% CI, 1.04-1.74; P = .02), morphine equivalent daily dose (MEDD) (HR, 1.003; 95% CI, 1.002-1.004; P < .001), and Edmonton Symptom Assessment Scale pain level (HR, 1.11; 95% CI, 1.06-1.16; P < .001) were independently associated with the presence of NMOU behavior. In recursive partition analysis, single marital status, MEDD greater than 50 mg, and SOAPP scores greater than 7 were associated with a higher risk (56%) for the presence of NMOU behavior., Conclusions and Relevance: This prognostic study of patients with cancer taking opioids for cancer pain found that 19% of patients developed NMOU behavior within a median duration of 8 weeks after initial supportive care clinic consultation. Marital status (single or divorced), SOAPP score greater than 7, higher levels of pain severity, and MEDD level were independently associated with NMOU behavior. This information will assist clinicians and investigators designing clinical and research programs in this important field.

Objective: Non-medical opioid use (NMOU) is a growing crisis. Cancer patients at elevated risk of NMOU (+risk) are frequently underdiagnosed. The aim of this paper was to develop a nomogram to predict the probability of +risk among cancer patients receiving outpatient supportive care consultation at a comprehensive cancer center., Method: 3,588 consecutive patients referred to a supportive care clinic were reviewed. All patients had a diagnosis of cancer and were on opioids for pain. All patients were assessed using the Edmonton Symptom Assessment Scale (ESAS), Screener and Opioid Assessment for Patients with Pain (SOAPP-14), and CAGE-AID (Cut Down-Annoyed-Guilty-Eye Opener) questionnaires. "+risk" was defined as an SOAPP-14 score of ≥7. A nomogram was devised based on the risk factors determined by the multivariate logistic regression model to estimate the probability of +risk., Results: 731/3,588 consults were +risk. +risk was significantly associated with gender, race, marital status, smoking status, depression, anxiety, financial distress, MEDD (morphine equivalent daily dose), and CAGE-AID score. The C-index was 0.8. A nomogram was developed and can be accessed at https://is.gd/soappnomogram. For example, for a male Hispanic patient, married, never smoked, with ESAS scores for depression = 3, anxiety = 3, financial distress = 7, a CAGE score of 0, and an MEDD score of 20, the total score is 9 + 9+0 + 0+6 + 10 + 23 + 0+1 = 58. A nomogram score of 58 indicates the probability of +risk of 0.1., Significance of Results: We established a practical nomogram to assess the +risk. The application of a nomogram based on routinely collected clinical data can help clinicians establish patients with +risk and positively impact care planning.

Background: Depression is more prevalent in women than in men. Among women's population sub-groups, there is paucity of research regarding occupational factors associated with depression in Pakistani nurses., Methods: This cross-sectional study was conducted on 250 female nurses working in a Federal Government tertiary care hospital in Islamabad. Pretested modified form of Agha Khan University Anxiety and Depression Scale was used to collect primary data. The questionnaires collected data on depressive symptoms, work experience, working hours, working environment, harassment by patients or attendants, job satisfaction and job stress. SPSS version 20 was used for data analysis. Chi-square test was used to see the association between different variables and depression., Results: This study indicated high level of depression in nurses who were having work experience of 5-7 years (p=0.000), who were working on rotating shifts (p=0.012), whose work hours were not flexible (p=0.032), who had experienced verbal abuse or harassment by patient or attendant (p=0.001), who thought that they had more responsibilities and less authorities at work (p=0.018), who suffered from injury at work (p=0.010), who thought that they had to work fast at job (p=0.004), who thought that they had to do extra physical work at job (p=0.003), who believed that they had insufficient time for patient care (p=0.006), who were not allowed to take decisions according to patient's requirements (p=0.005), who were neither appreciated nor received any feedback from their seniors (p=0.002), who did not enjoy their work (p=0.001), who did not enjoy relations with their colleagues (p=0.001), who were harassed by their administration (p=0.000), who were not satisfied from their job (p=0.012) and who believed that their job is stressful (p=0.000)., Conclusions: This study concluded that occupational factors play a very important role in determining depression in Pakistani nurses.

Introduction: Pregnancy and motherhood is a physiological phenomenon. However, approximately 830 women die from preventable causes related to pregnancy and childbirth every day. Birth preparedness and complication readiness (BPACR) improves preventive behavior and improves knowledge of mothers about danger signs., Objective: The objective of the study is to assess the status and sociodemographic determinants of BPACR among the women who have experienced motherhood recently., Materials and Methods: The study was carried out among 200 women in a rural block of Haryana over a period of 6 months. The tool used to collect data was adapted from survey tools of Johns Hopkins Program for International Education in Gynaecology and Obstetrics/Maternal and Neonatal Health Program., Results: BPACR index came out to be 66.93 and 58.5% women were well prepared for BPACR. Education and occupation of participants, education of participant's husband, socioeconomic status, and caste were found to be significantly associated with BPACR., Conclusion: BPACR is a comprehensive strategy to ensure safer pregnancy and motherhood. Providing educational and skill acquisition opportunities for rural women for their empowerment and increasing their role in decision-making are imperative in order to improve BPACR and promote utilization of skilled attendants at every delivery., Competing Interests: There are no conflicts of interest.

Background: Prevention of intimate partner violence is an important public health goal owing to its negative psychological and physical health consequence., Objectives: Estimate the prevalence of reciprocate and nonreciprocate violence, severity of injuries, and related risk factors., Materials and Methods: The present study was a community-based cross-sectional study using multistage random sampling in which a total of 880 currently married women in the age group 15-49 years were interviewed using modified conflict tactics scale. Logistic regression was used to identify factors associated with both the types of domestic violence., Results: Total prevalence for spousal violence was 33.2% (283), out of which 14.84% (42) were reciprocally violent. Alcoholic husband [Adjusted Odds Ratio (AOR): 3.262, P = 0.001], late year of marriage (>2 years) [AOR: 0.359, P = 0.001], low education of the participants [AOR: 1.443, P = 0.033], and low socioeconomic class [AOR: 0.562, P = 0.004] are the risk factors for nonreciprocate domestic violence. Alcoholic husband [AOR: 4.372, P = 0.001] and nuclear family [AOR: 3.115, P = 0.001] were found as significant risk factors for reciprocate domestic violence. Women indulging in reciprocate violence were associated with more severe injuries than nonreciprocate violence., Conclusion: This study depicts that every third female has experienced spousal violence and also highlights the existence of reciprocate violence in India. Alcoholism, low education of husbands, and living in nuclear family are the important determinants for reciprocate violence. Also, reciprocate violence is associated with severe injuries., Competing Interests: There are no conflicts of interest.

Background: Research across the globe highlights rights violations and abuses experienced by women and seldom are channeled toward any atrocities being experienced by men. Objectives: To find the prevalence, characteristics, and sociodemographic correlates of gender-based violence against men., Materials and Methods: It was a community-based, cross-sectional study using multistage random sampling in which a total of 1000 married men in the age group of 21-49 years were interviewed using modified conflict tactics scale., Results: In the present study, 52.4% of men experienced gender-based violence. Out of 1000, males 51.5% experienced violence at the hands of their wives/intimate partner at least once in their lifetime and 10.5% in the last 12 months. The most common spousal violence was emotional (51.6%) followed by physical violence (6%). Only in one-tenth cases, physical assaults were severe. In almost half of the cases, husband initiated physical and emotional violence. Gender symmetry does not exist in India for physical violence. Less family income, education up to middle class, nuclear family setup, and perpetrator under the influence of alcohol were identified as risk factors. Earning spouse with education up to graduation is the risk factor for bidirectional physical violence., Conclusion: Besides women, men are also the victims of gender-based violence. This demands the future investigation and necessary intervention on gender-based violence against men in India., Competing Interests: There are no conflicts of interest.

Cancer cachexia (CC) is one of the most distressing syndromes for both patients and their families. CC can have an impact on patient reported quality of life and overall survival. It is often associated with symptoms such as fatigue, depressed mood, early satiety, and anorexia. Prokinetic agents have been found to improve chronic nausea and early satiety associated with CC. Among the prokinetic agents, metoclopramide is one of the best studied medications. The role of the other prokinetic agents, such as domperidone, erythromycin, haloperidol, levosulpiride, tegaserod, cisapride, mosapride, renzapride, and prucalopride is unclear for use in cachectic cancer patients due to their side effect profile and limited efficacy studies in cancer patients. There has been an increased interest in the use of ghrelin-receptor agonists for the treatment of CC. Anamorelin HCl is a highly selective, novel ghrelin receptor agonist. A meta-analysis was conducted of the recent randomized trials using anamorelin (daily dose of 50 and 100 mg daily). Results show that both total body weight and lean body mass were significantly increased from baseline in the anamorelin group. Anamorelin did not improve overall survival or hand grip strength, and there were no significant differences between groups for frequency or severity of any adverse events. In this review, the authors discuss the available evidence for the use of prokinetics such as metoclopramide and ghrelin receptor agonists for the treatment of CC.

Objective: Perforations of the tympanic membrane are treated with various surgical techniques and materials. This study aimed to determine the efficacy of platelet-rich plasma during underlay myringoplasty., Methods: The study included 40 patients. Autologous platelet-rich plasma was applied in-between temporalis fascia graft and tympanic membrane remnant during underlay myringoplasty in group 1 (n = 20). The outcome was evaluated after three months and compared with group 2 (n = 20), a control group that underwent routine underlay tympanoplasty., Results: After three months' follow up, graft uptake was 95 per cent in group 1 and 85 per cent in group 2 (p < 0.03). Mean hearing threshold gain was 18.62 dB in group 1 and 13.15 dB in group 2. This difference was statistically significant (p < 0.01)., Conclusion: Platelet-rich plasma, with its ease of preparation technique, availability, low cost, autologous nature and good graft uptake rate, justifies its use in tympanoplasty type I procedures.

Background: No nation is untouched by domestic violence, and it is well-known that domestic violence has serious impact on women's health and well-being. The present study aimed to assess the prevalence and characteristics of domestic violence and injuries owing to domestic violence among currently married women., Materials and Methods: This was a community-based, cross-sectional study conducted in the rural and urban areas of Haryana. In total, 880 currently married females of the reproductive age group were interviewed using the Women's Questionnaire (used in National Family Health Survey-3) which is according to the Modified Conflict Tactics Scale., Results: Totally, 37% of the females had ever experienced domestic violence and 28.9% currently experienced domestic violence. All types of violence (except sexual violence) were significantly more common in the rural area than the urban area. Injuries owing to domestic violence were reported by more than half (55.4%) of the women. Among spousal violence, emotional violence was the most common type of violence followed by physical violence. Only 0.1% and 4.5% of females had ever initiated physical and emotional violence respectively, against their husbands, and in rest of the cases, it was the husband who initiated violence., Conclusion: Awareness regarding domestic violence needs to be made, and law enforcement regarding it needs to be made stringent. Rehabilitation of victims of domestic/spousal violence should also be considered on priority., Competing Interests: There are no conflicts of interest.

Background: Influenza virus infections are associated with a wide spectrum of disease. However, few studies have investigated in detail the epidemiological and virological characteristics of asymptomatic and mild illness with influenza virus infections., Methods: In a community-based study in Hong Kong from 2008 to 2014, we followed up initially healthy individuals who were household contacts of symptomatic persons with laboratory-confirmed influenza, to identify secondary infections. Information from daily symptom diaries was used to classify infections as symptomatic (≥2 signs/symptoms, including fever ≥37.8°C, headache, myalgia, cough, sore throat, runny nose and sputum), paucisymptomatic (1 symptom only), or asymptomatic (none of these symptoms). We compared the patterns of influenza viral shedding between these groups., Results: We identified 235 virologically confirmed secondary cases of influenza virus infection in the household setting, including 31 (13%) paucisymptomatic and 25 (11%) asymptomatic cases. The duration of viral RNA shedding was shorter and declined more rapidly in paucisymptomatic and asymptomatic than in symptomatic cases. The mean levels of influenza viral RNA shedding in asymptomatic and paucisymptomatic cases were approximately 1-2 log10 copies lower than in symptomatic cases., Conclusions: The presence of influenza viral shedding in patients with influenza who have very few or no symptoms reflects their potential for transmitting the virus to close contacts. These findings suggest that further research is needed to investigate the contribution of persons with asymptomatic or clinically mild influenza virus infections to influenza virus transmission in household, institutional, and community settings., (© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com)

Since their first isolation in 2013, influenza A/H5N6 viruses have spread amongst poultry across multiple provinces in China and to Laos, Vietnam and Myanmar. So far, there have been 14 human H5N6 infections with 10 fatalities.We investigated the tropism, replication competence and cytokine induction of one human and two avian H5N6 isolates in ex vivo and in vitro cultures derived from the human respiratory tract. Virus tropism and replication were studied in ex vivo cultures of human nasopharynx, bronchus and lung. Induction of cytokines and chemokines was measured in vitro in virus-infected primary human alveolar epithelial cells.Human H5N6 virus replicated more efficiently than highly pathogenic avian influenza (HPAI) H5N1 virus and as efficiently as H1N1pdm in ex vivo human bronchus and lung and was also able to replicate in ex vivo cultures of human nasopharynx. Avian H5N6 viruses replicated less efficiently than H1N1pdm in human bronchial tissues and to similar titres as HPAI H5N1 in the lung. While the human H5N6 virus had affinity for avian-like receptors, the two avian isolates had binding affinity for both avian- and human-like receptors. All three H5N6 viruses were less potent inducers of pro-inflammatory cytokines compared with H5N1 virus.Human H5N6 virus appears better adapted to infect the human airways than H5N1 virus and may pose a significant public health threat., (Copyright ©ERS 2017.)

Novel avian H7N9 virus emerged in China in 2013 resulting in a case fatality rate of around 39% and continues to pose zoonotic and pandemic risk. Amino acid substitutions in PB2 protein were shown to influence the pathogenicity and transmissibility of H7N9 following experimental infection of ferrets and mice. In this study, we evaluated the role of amino acid substitution PB2-627K or compensatory changes at PB2-591K and PB2-701N, on the tropism and replication competence of H7N9 viruses for human and swine respiratory tracts using ex vivo organ explant cultures. Recombinant viruses of A/Shanghai/2/2013 (rgH7N9) and its mutants with PB2-K627E, PB2-K627E + Q591K and PB2-K627E + D701N were generated by plasmid-based reverse genetics. PB2-E627K was essential for efficient replication of rgH7N9 in ex vivo cultures of human and swine respiratory tracts. Mutant rgPB2-K627E + D701N replicated better than rgPB2-K627E in human lung but not as well as rgH7N9 virus. The rgPB2-K627E mutant failed to replicate in human type I-like pneumocytes (ATI) and peripheral blood monocyte-derived macrophages (PMϕ) at 37 °C while the compensatory mutant rgPB2-K627E + Q591K and rgPB2-K627E + D701N had partly restored replication competence in PMϕ. Our results demonstrate that PB2-E627K was important for efficient replication of influenza H7N9 in both human and swine respiratory tracts.

Nearly 4 years after the first report of the emergence of Middle-East respiratory syndrome Coronavirus (MERS-CoV) and nearly 1800 human cases later, the ecology of MERS-CoV, its epidemiology, and more than risk factors of MERS-CoV transmission between camels are poorly understood. Knowledge about the pathways and mechanisms of transmission from animals to humans is limited; as of yet, transmission risks have not been quantified. Moreover the divergent sanitary situations and exposures to animals among populations in the Arabian Peninsula, where human primary cases appear to dominate, vs. other regions in the Middle East and Africa, with no reported human clinical cases and where the virus has been detected only in dromedaries, represents huge scientific and health challenges. Here, we have used expert-opinion elicitation in order to obtain ideas on relative importance of MERS-CoV risk factors and estimates of transmission risks from various types of contact between humans and dromedaries. Fourteen experts with diverse and extensive experience in MERS-CoV relevant fields were enrolled and completed an online questionnaire that examined pathways based on several scenarios, e.g., camels-camels, camels-human, bats/other species to camels/humans, and the role of diverse biological substances (milk, urine, etc.) and potential fomites. Experts believed that dromedary camels play the largest role in MERS-CoV infection of other dromedaries; however, they also indicated a significant influence of the season (i.e. calving or weaning periods) on transmission risk. All experts thought that MERS-CoV-infected dromedaries and asymptomatic humans play the most important role in infection of humans, with bats and other species presenting a possible, but yet undefined, risk. Direct and indirect contact of humans with dromedary camels were identified as the most risky types of contact, when compared to consumption of various camel products, with estimated "most likely" incidence risks of at least 22 and 13% for direct and indirect contact, respectively. The results of our study are consistent with available, yet very limited, published data regarding the potential pathways of transmission of MERS-CoV at the animal-human interface. These results identify key knowledge gaps and highlight the need for more comprehensive, yet focused research to be conducted to better understand transmission between dromedaries and humans.

Zoonotic infections by avian influenza viruses occur at the human-poultry interface, but the modes of transmission have not been fully investigated. We assessed the potential for airborne and fomite transmission at live poultry markets in Guangzhou city and in Hong Kong Special Administrative Region (SAR), China, during 2014 and 2015. Viral genome and infectious avian influenza A viruses of H5N6, H7N9, and H9N2 subtypes were detected predominantly from particles larger or equal to 1 μm in diameter in the air sampled with cyclone-based bioaerosol samplers at the live poultry markets in Guangzhou. Influenza A(H9N2) viruses were ubiquitously isolated every month during the study period from air and environmental swabs, and different lineages of H9N2 virus were isolated from markets where chickens and minor land-based poultry were sold. The use of de-feathering devices increased the quantity of virus-laden airborne particles while market closure reduced the amount of such particles. The results highlight the possibility of airborne transmission of avian influenza viruses among poultry or from poultry to humans within such settings. This may explain epidemiological observations in which some patients with H7N9 infection reported being in markets but no direct contact with live poultry or poultry stalls., Competing Interests: Conflicts of Interest: None declared., (This article is copyright of The Authors, 2016.)

Age-specific genetic and antigenic variations of influenza viruses have not been documented in tropical and subtropical regions. We implemented a systematic surveillance program in two tertiary hospitals in Hong Kong Island, to collect 112 A(H1N1)pdm09 and 254 A(H3N2) positive specimens from 2013 to 2014. Of these, 56 and 72 were identified as genetic variants of the WHO recommended vaccine composition strains, respectively. A subset of these genetic variants was selected for hemagglutination-inhibition (HI) tests, but none appeared to be antigenic variants of the vaccine composition strains. We also found that genetic and antigenicity variations were similar across sex and age groups of ≤18 yrs, 18 to 65 yrs, and ≥65 yrs. Our findings suggest that none of the age groups led other age groups in genetic evolution of influenza virus A strains. Future studies from different regions and longer study periods are needed to further investigate the age and sex heterogeneity of influenza viruses.

Highly pathogenic avian influenza (HPAI) H5N1 virus continues to pose pandemic threat, but there is a lack of understanding of its pathogenesis. We compared the apoptotic responses triggered by HPAI H5N1 and low pathogenic H1N1 viruses using physiologically relevant respiratory epithelial cells. We demonstrated that H5N1 viruses delayed apoptosis in primary human bronchial and alveolar epithelial cells (AECs) compared to H1N1 virus. Both caspase-8 and -9 were activated by H5N1 and H1N1 viruses in AECs, while H5N1 differentially up-regulated TRAIL. H5N1-induced apoptosis was reduced by TRAIL receptor silencing. More importantly, STAT3 knock-down increased apoptosis by H5N1 infection suggesting that H5N1 virus delays apoptosis through activation of STAT3. Taken together, we demonstrate that STAT3 is involved in H5N1-delayed apoptosis compared to H1N1. Since delay in apoptosis prolongs the duration of virus replication and production of pro-inflammatory cytokines and TRAIL from H5N1-infected cells, which contribute to orchestrate cytokine storm and tissue damage, our results suggest that STAT3 may play a previously unsuspected role in H5N1 pathogenesis.

Background: Identifying individual correlates of infectivity of influenza virus is important for disease control and prevention. Viral shedding is used as a proxy measure of infectivity in many studies. However, the evidence for this is limited., Methods: In a detailed study of influenza virus transmission within households in 2008-12, we recruited index cases with confirmed influenza infection from outpatient clinics, and followed up their household contacts for 7-10 days to identify secondary infections. We used individual-based hazard models to characterize the relationship between individual viral shedding and individual infectivity., Results: We analyzed 386 households with 1147 household contacts. Index cases were separated into 3 groups according to their estimated level of viral shedding at symptom onset. We did not find a statistically significant association of virus shedding with transmission. Index cases in medium and higher viral shedding groups were estimated to have 21% (95% CI: -29%, 113%) and 44% (CI: -16%, 167%) higher infectivity, compared with those in the lower viral shedding group., Conclusions: Individual viral load measured by RT-PCR in the nose and throat was at most weakly correlated with individual infectivity in households. Other correlates of infectivity should be examined in future studies.

Background: We estimated vaccine effectiveness (VE) against pediatric influenza B hospitalizations in Hong Kong year round between November 2001 and October 2014., Methods: We conducted a test-negative year-round study, enrolling children 6 months to 17 years of age admitted to two hospitals in Hong Kong with a febrile acute respiratory infection. Children were tested for influenza A and B. Conditional logistic regression was used to estimate overall and lineage-specific vaccine effectiveness comparing influenza vaccination history of the trivalent influenza vaccine (TIV) among patients testing positive for influenza B versus negative for influenza A and B, adjusting for age and sex and matching by calendar week of recruitment., Results: Of the 6013 children included in the analysis, 262 tested positive for influenza B. Vaccination coverage was low: 6.5% in the influenza B positive children when compared with 8.8% in children who tested negative for both influenza A and B (p=0.248). Overall, VE was 47.6% (95% CI: 10.0, 69.4%) against influenza B hospitalization despite variable co-circulation of both lineages in all years. VE for Victoria-like virus calculated from 3 years when the vaccine was lineage-matched was 59.1% (95% CI: 6.2, 82.2%). Lineage-matched VE for Yamagata-like virus was -8.8% (95% CI: -215.4, 62.5%) in a clade mismatch season. With wide confidence intervals, we were unable to demonstrate cross-lineage protection: VE against the mismatched B/Yamagata-like virus was 9.5% (95% CI: -240.4, 76.0%) in 2011/12 and against mismatched B/Victoria-like virus in 2013/14 was 42.7% (95% CI: -368.6, 93.0%)., Conclusions: TIV conferred an overall VE of 47.6% (95% CI: 10.0, 69.4%) against influenza B hospitalization in children despite variable co-circulation of both lineages in all years. Lineage-matched VE for Yamagata-like virus was poor and may be related to clade mismatch. Cross-lineage protection was not observed., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Influenza can cause acute lung injury. Because immune responses often play a role, antivirals may not ensure a successful outcome. To identify pathogenic mechanisms and potential adjunctive therapeutic options, we compared the extent to which avian influenza A/H5N1 virus and seasonal influenza A/H1N1 virus impair alveolar fluid clearance and protein permeability in an in vitro model of acute lung injury, defined the role of virus-induced soluble mediators in these injury effects, and demonstrated that the effects are prevented or reduced by bone marrow-derived multipotent mesenchymal stromal cells. We verified the in vivo relevance of these findings in mice experimentally infected with influenza A/H5N1. We found that, in vitro, the alveolar epithelium's protein permeability and fluid clearance were dysregulated by soluble immune mediators released upon infection with avian (A/Hong Kong/483/97, H5N1) but not seasonal (A/Hong Kong/54/98, H1N1) influenza virus. The reduced alveolar fluid transport associated with down-regulation of sodium and chloride transporters was prevented or reduced by coculture with mesenchymal stromal cells. In vivo, treatment of aged H5N1-infected mice with mesenchymal stromal cells increased their likelihood of survival. We conclude that mesenchymal stromal cells significantly reduce the impairment of alveolar fluid clearance induced by A/H5N1 infection in vitro and prevent or reduce A/H5N1-associated acute lung injury in vivo. This potential adjunctive therapy for severe influenza-induced lung disease warrants rapid clinical investigation.

Background: In early 2013, a novel avian-origin influenza A(H7N9) virus emerged in China, and has caused sporadic human infections. The incubation period is the delay from infection until onset of symptoms, and varies from person to person. Few previous studies have examined whether the duration of the incubation period correlates with subsequent disease severity., Methods and Findings: We analyzed data of period of exposure on 395 human cases of laboratory-confirmed influenza A(H7N9) virus infection in China in a Bayesian framework using a Weibull distribution. We found a longer incubation period for the 173 fatal cases with a mean of 3.7 days (95% credibility interval, CrI: 3.4-4.1), compared to a mean of 3.3 days (95% CrI: 2.9-3.6) for the 222 non-fatal cases, and the difference in means was marginally significant at 0.47 days (95% CrI: -0.04, 0.99). There was a statistically significant correlation between a longer incubation period and an increased risk of death after adjustment for age, sex, geographical location and underlying medical conditions (adjusted odds ratio 1.70 per day increase in incubation period; 95% credibility interval 1.47-1.97)., Conclusions: We found a significant association between a longer incubation period and a greater risk of death among human H7N9 cases. The underlying biological mechanisms leading to this association deserve further exploration.

Novel influenza viruses continue to emerge, posing zoonotic and potentially pandemic threats, such as with avian influenza A H7N9. Although closure of live poultry markets (LPMs) in mainland China stopped H7N9 outbreaks temporarily, closures are difficult to sustain, in view of poultry production and marketing systems in China. In this Personal View, we summarise interventions taken in mainland China, and provide evidence for other more sustainable but effective interventions in the live poultry market systems that reduce risk of zoonotic influenza including rest days, and banning live poultry in markets overnight. Separation of live ducks and geese from land-based (ie, non-aquatic) poultry in LPM systems can reduce the risk of emergence of zoonotic and epizootic viruses at source. In view of evidence that H7N9 is now endemic in over half of the provinces in mainland China and will continue to cause recurrent zoonotic disease in the winter months, such interventions should receive high priority in China and other Asian countries at risk of H7N9 through cross-border poultry movements. Such generic measures are likely to reduce known and future threats of zoonotic influenza., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Influenza A virus (IAV) poses global threats to human health. Acute respiratory distress syndrome and multi-organ dysfunction are major complications in patients with severe influenza infection. This may be explained by the recent studies which highlighted the role of the pulmonary endothelium as the center of innate immune cells recruitment and excessive pro-inflammatory cytokines production. In this report, we examined the potential immunomodulatory effects of two indirubin derivatives, indirubin-3'-(2,3-dihydroxypropyl)-oximether (E804) and indirubin-3'-oxime (E231), on IAV (H9N2) infected-human pulmonary microvascular endothelial cells (HPMECs). Infection of H9N2 on HPMECs induced a high level of chemokines and cytokines production including IP-10, RANTES, IL-6, IFN-β and IFN-γ1. Post-treatment of E804 or E231 could significantly suppress the production of these cytokines. H9N2 infection rapidly triggered the activation of innate immunity through phosphorylation of signaling molecules including mitogen-activated protein kinases (MAPKs) and signal transducer and activator of transcription (STAT) proteins. Using specific inhibitors or small-interfering RNA, we confirmed that indirubin derivatives can suppress H9N2-induced cytokines production through MAPKs and STAT3 signaling pathways. These results underscore the immunomodulatory effects of indirubin derivatives on pulmonary endothelium and its therapeutic potential on IAV-infection.

Background: In influenza epidemiology, analysis of paired sera collected from people before and after influenza seasons has been used for decades to study the cumulative incidence of influenza virus infections in populations. However, interpretation becomes challenging when sera are collected after the start or before the end of an epidemic, and do not neatly bracket the epidemic., Methods: Serum samples were collected longitudinally in a community-based study. Most participants provided their first serum after the start of circulation of influenza A(H1N1)pdm09 virus in 2009. We developed a Bayesian hierarchical model to correct for nonbracketing sera and estimate the cumulative incidence of infection from the serological data and surveillance data in Hong Kong., Results: We analyzed 4,843 sera from 2,097 unvaccinated participants in the study, collected from April 2009 to December 2010. After accounting for nonbracketing, we estimated that the cumulative incidence of H1N1pdm09 virus infection was 45% (95% credible interval [CI] = 40%, 49%), 17% (95% CI = 13%, 20%), and 11% (95% CI = 6%, 18%) for children ages 0-18 years, adults 19-50 years, and older adults >50 years, respectively. Including all available data substantially increased precision compared with a simpler analysis based only on sera collected at 6-month intervals in a subset of participants., Conclusions: We developed a framework for the analysis of antibody titers that accounted for the timing of sera collection with respect to influenza activity and permitted robust estimation of the cumulative incidence of infection during an epidemic.

Background: Viral shedding is often considered to correlate with the infectivity of influenza, but the evidence for this is limited., Methods: In a detailed study of influenza virus transmission within households in 2008-2012, index case patients with confirmed influenza were identified in outpatient clinics, and we collected nose and throat swab specimens for testing by reverse-transcription polymerase chain reaction from all household members regardless of illness. We used individual-based hazard models to characterize the relationship between viral load (V) and infectivity., Results: Assuming that infectivity was proportional to viral load V gave the worst fit, because it strongly overestimated the proportion of transmission occurring at symptom onset. Alternative models assuming that infectivity was proportional to a various functions of V provided better fits, although they all overestimated the proportion of transmission occurring >3 days after symptom onset. The best fitting model assumed that infectivity was proportion to V(γ), with estimates of γ = 0.136 and γ = 0.156 for seasonal influenza A(H1N1) and A(H3N2) respectively., Conclusions: All the models we considered that used viral loads to approximate infectivity of a case imperfectly explained the timing of influenza secondary infections in households. Identification of more accurate correlates of infectivity will be important to inform control policies and disease modeling., (© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Unlabelled: Seasonal influenza epidemics and occasional pandemics threaten public health worldwide. New alternative strategies for generating recombinant viruses with vaccine potential are needed. Interestingly, influenza viruses circulating in different hosts have been found to have distinct codon usage patterns, which may reflect host adaptation. We therefore hypothesized that it is possible to make a human seasonal influenza virus that is specifically attenuated in human cells but not in eggs by converting its codon usage so that it is similar to that observed from avian influenza viruses. This approach might help to generate human live attenuated viruses without affecting their yield in eggs. To test this hypothesis, over 300 silent mutations were introduced into the genome of a seasonal H1N1 influenza virus. The resultant mutant was significantly attenuated in mammalian cells and mice, yet it grew well in embryonated eggs. A single dose of intranasal vaccination induced potent innate, humoral, and cellular immune responses, and the mutant could protect mice against homologous and heterologous viral challenges. The attenuated mutant could also be used as a vaccine master donor strain by introducing hemagglutinin and neuraminidase genes derived from other strains. Thus, our approach is a successful strategy to generate attenuated viruses for future application as vaccines., Importance: Vaccination has been one of the best protective measures in combating influenza virus infection. Current licensed influenza vaccines and their production have various limitations. Our virus attenuation strategy makes use of the codon usage biases of human and avian influenza viruses to generate a human-derived influenza virus that is attenuated in mammalian hosts. This method, however, does not affect virus replication in eggs. This makes the resultant mutants highly compatible with existing egg-based vaccine production pipelines. The viral proteins generated from the codon bias mutants are identical to the wild-type viral proteins. In addition, our massive genome-wide mutational approach further minimizes the concern over reverse mutations. The potential use of this kind of codon bias mutant as a master donor strain to generate other live attenuated viruses is also demonstrated. These findings put forward a promising live attenuated influenza vaccine generation strategy to control influenza., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

Influenza B viruses split into 2 distinct lineages in the early 1980s, commonly named the Victoria and Yamagata lineages. There are few data on the comparative epidemiology of Victoria- and Yamagata-lineage viruses. In 2007-2011, we enrolled 75 and 34 households containing index patients with acute respiratory illness who tested positive for Yamagata- and Victoria-lineage viruses, respectively, from outpatient clinics in Hong Kong, China. These index patients and their household contacts were followed up for 7-10 days. We examined overall risk of polymerase chain reaction-confirmed infection among household contacts and the risk of secondary infection within households using an individual-based hazard model that accounted for tertiary transmission and infections occurring outside the household. We found that for Victoria-lineage viruses, the risk of within-household infection among household contacts aged ≤15 years was significantly higher (risk ratio = 12.9, 95% credibility interval: 4.2, 43.6) than that for older household contacts, while for Yamagata-lineage viruses, the risk of within-household infection for household contacts did not differ by age. Influenza B Yamagata- and Victoria-lineage viruses have similar characteristics in terms of viral shedding and clinical illness. The mechanisms underlying these epidemiologic differences deserve further investigation., (© The Author 2015. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Few previous studies have investigated the association between the severity of an infectious disease and the length of incubation period., Methods: We estimated the association between the length of the incubation period and the severity of infection with the severe acute respiratory syndrome coronavirus, using data from the epidemic in 2003 in Hong Kong., Results: We estimated the incubation period of severe acute respiratory syndrome based on a subset of patients with available data on exposure periods and a separate subset of patients in a putative common source outbreak, and we found associations between shorter incubation period and greater severity in both groups after adjusting for potential confounders., Conclusions: Our findings suggest that patients with a shorter incubation period went on to have more severe disease. Further studies are needed to investigate potential biological mechanisms for this association.

Few studies have explored age and sex differences in the disease burden of influenza, although men and women probably differ in their susceptibility to influenza infections. In this study, quasi-Poisson regression models were applied to weekly age- and sex-specific hospitalization numbers of pneumonia and influenza cases in the Hong Kong SAR, People's Republic of China, from 2004 to 2010. Age and sex differences were assessed by age- and sex-specific rates of excess hospitalization for influenza A subtypes A(H1N1), A(H3N2), and A(H1N1)pdm09 and influenza B, respectively. We found that, in children younger than 18 years, boys had a higher excess hospitalization rate than girls, with the male-to-female ratio of excess rate (MFR) ranging from 1.1 to 2.4. MFRs of hospitalization associated with different types/subtypes were less than 1.0 for adults younger than 40 years except for A(H3N2) (MFR = 1.6), while all the MFRs were equal to or higher than 1.0 in adults aged 40 years or more except for A(H1N1)pdm09 in elderly persons aged 65 years or more (MFR = 0.9). No MFR was found to be statistically significant (P < 0.05) for hospitalizations associated with influenza type/subtype. There is some limited evidence on age and sex differences in hospitalization associated with influenza in the subtropical city of Hong Kong., (© The Author 2015. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

In an observational study of 582 patients with laboratory-confirmed influenza virus infections and their household contacts, we found that the initiation of oseltamivir within 24 hours was associated with shorter duration of self-reported illness symptoms (56% reduction in duration; 95% confidence interval, 41%-67%). However, we did not find any association of oseltamivir treatment with duration of viral shedding by polymerase chain reaction or with the risk of household transmission., (© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)