The state of integrated disease surveillance globally: synthesis report of a mixed methods study.

OBJECTIVES: Disease surveillance is an essential public health function needed to prevent, detect, monitor and respond to health threats. Integrated disease surveillance (IDS) enhances its utility and has been advocated for decades by the World Health Organization. This study sought to examine the state of IDS implementation worldwide. STUDY DESIGN: The study used a concurrent mixed methods approach consisting of a systematic scoping review of the literature on IDS, a survey of International Association of National Public Health Institutes (IANPHI) members and qualitative deep dive case studies in seven countries. METHODS: This report collates, analyses and synthesises the findings from the three components. The scoping review consisted of a review of summarised evidence on IDS. Eight reviews and five primary studies were included. The cross-sectional survey was conducted of 110 IANPHI members representing ninety-five countries. Qualitative case studies were conducted in Malawi, Mozambique, Uganda, Pakistan, Canada, Sweden, and England, which involved thirty-four focus group discussions and forty-eight key informant interviews. RESULTS: In the different countries, IDS is conceptualised differently and there are differing levels of maturity of IDS functions. Although the role of National Public Health Institutes has not been well defined in the IDS, they play a significant role in IDS in many countries. Fragmentation between sectors and resourcing (human and financial) issues were common. Good governance measures such as appropriate legislative and regulatory frameworks and roles and responsibilities for IDS were often unclear. The COVID-19 pandemic has strengthened some surveillance systems, often through leveraging existing respiratory surveillance systems. In some instances, improvements were seen only for COVID-19 related data but these changes were not sustained. Evaluation of IDS was also reported to be weak. CONCLUSIONS: Integration should be driven by a clear purpose and contextualised. Political commitment, clear governance, and resourcing are needed. Technology and the establishment of technical communities of practice may help. However, the complexity and cost of integration should not be under-estimated, and further economic and impact evaluations of IDS are needed.

Ukraine refugee crisis: evolving needs and challenges.

This case report examines the initial experience of Poland in responding to the refugee crisis triggered by the war in Ukraine. In the first 2 months of the crisis, more than 3 million Ukrainian refugees fled to Poland. The large influx of refugees rapidly overwhelmed local services and led to a complex humanitarian emergency. The initial priorities were to address basic human needs, such as shelter, infectious disease concerns and healthcare access, but evolved to include mental health, non-communicable diseases and protection needs. This necessitated a 'whole of society' response involving multiple agencies and civil society. Emerging lessons learned include the need for ongoing needs assessments, robust disease monitoring and surveillance, as well as flexible multisectoral responses that are culturally sensitive. Finally, Poland's efforts to integrate refugees may help mitigate some of the adverse consequences of the conflict-related migration.

Direct Observation of the Pressure-Induced Structural Variation in Gold Nanoclusters and the Correlated Optical Response.

The ability to gradually modify the atomic structures of nanomaterials and directly identify such structural variation is important in nanoscience research. Here, we present the first example of a high-pressure single-crystal X-ray diffraction analysis of atomically precise metal nanoclusters. The pressure-dependent, subangstrom structural evolution of an ultrasmall gold nanoparticle, Au25S18, has been directly identified. We found that a 0.1 Å decrease of the Au-Au bond length could induce a blue-shift of 30 nm in the photoluminescence spectra of gold nanoclusters. From theoretical calculations, the origins of the blue-shift and enhanced photoluminescence under pressure are investigated, which are ascribed to molecular orbital symmetry and conformational locking, respectively. The combination of the high-pressure in situ X-ray results with both theoretical and experimental optical spectra provides a direct and generalizable avenue to unveil the underlying structure-property relations for nanoclusters and nanoparticles which cannot be obtained through traditional physical chemistry measurements.

Corrigendum: Co-stimulation with TLR7 agonist imiquimod and inactivated Influenza virus particles promotes mouse B cell activation, differentiation, and accelerated antigen specific antibody production.

[This corrects the article DOI: 10.3389/fimmu.2018.02370.].

Evaluation of internal standards for inductively coupled plasma-mass spectrometric analysis of arsenic in soils.

Arsenic (As) is a common contaminant in soils, and analysis of soils by inductively coupled plasma-mass spectrometry (ICP-MS) is often used to detect As in soil extracts. Internal standards (ISs) are part of ICP-MS analyses to enhance precision and accuracy by compensating for instrument variability; however, an improper choice of IS can result in negative analytical bias. The goal of this study was to develop a protocol for evaluating ISs commonly used in ICP-MS. Three soils of varying clay content and total As were extracted with a dilute electrolyte [0.005 mol L-1 Mg(NO3 )2 ] and an acid digest. Arsenic concentrations were quantified by ICP-MS using typical ISs: 6 Li, 45 Sc, 69 Ga, 89 Y, 103 Rh, 115 In, 159  Tb, and 209 Bi. Standard addition was used as a benchmark for As quantification. The most consistent IS was 115 In. Elevated, naturally occurring concentrations were detected for several of the ISs, particularly in the total digests, emphasizing the necessity for screening soils prior to analysis.

Age-associated SARS-CoV-2 breakthrough infection and changes in immune response in a mouse model.

Older individuals are at higher risk of SARS-CoV-2 infection and severe outcomes, but the underlying mechanisms are incompletely understood. In addition, how age modulates SARS-CoV-2 re-infection and vaccine breakthrough infections remain largely unexplored. Here, we investigated age-associated SARS-CoV-2 pathogenesis, immune responses, and the occurrence of re-infection and vaccine breakthrough infection utilizing a wild-type C57BL/6N mouse model. We demonstrated that interferon and adaptive antibody response upon SARS-CoV-2 challenge are significantly impaired in aged mice compared to young mice, which results in more effective virus replications and severe disease manifestations in the respiratory tract. Aged mice also showed increased susceptibility to re-infection due to insufficient immune protection acquired during the primary infection. Importantly, two-dose COVID-19 mRNA vaccination conferred limited adaptive immune response among the aged mice, making them susceptible to SARS-CoV-2 infection. Collectively, our findings call for tailored and optimized treatments and prevention strategies against SARS-CoV-2 among older individuals.

Cross-linking peptide and repurposed drugs inhibit both entry pathways of SARS-CoV-2.

Up to date, effective antivirals have not been widely available for treating COVID-19. In this study, we identify a dual-functional cross-linking peptide 8P9R which can inhibit the two entry pathways (endocytic pathway and TMPRSS2-mediated surface pathway) of SARS-CoV-2 in cells. The endosomal acidification inhibitors (8P9R and chloroquine) can synergistically enhance the activity of arbidol, a spike-ACE2 fusion inhibitor, against SARS-CoV-2 and SARS-CoV in cells. In vivo studies indicate that 8P9R or the combination of repurposed drugs (umifenovir also known as arbidol, chloroquine and camostat which is a TMPRSS2 inhibitor), simultaneously interfering with the two entry pathways of coronaviruses, can significantly suppress SARS-CoV-2 replication in hamsters and SARS-CoV in mice. Here, we use drug combination (arbidol, chloroquine, and camostat) and a dual-functional 8P9R to demonstrate that blocking the two entry pathways of coronavirus can be a promising and achievable approach for inhibiting SARS-CoV-2 replication in vivo. Cocktail therapy of these drug combinations should be considered in treatment trials for COVID-19.

Long-Term Follow-Up of Retinal Detachment Repair in Patients With Stickler Syndrome.

BACKGROUND AND OBJECTIVE: To report the long-term anatomic and visual outcomes of patients with Stickler syndrome undergoing retinal detachment (RD) surgery. PATIENTS AND METHODS: Retrospective, interventional, consecutive case series of patients with Stickler syndrome undergoing RD repair from 1999 to 2017 at the Long Island Vitreoretinal Consultants, New York. Retinal attachment status and visual acuity (VA) at 1-year and last follow-up were assessed. RESULTS: Successful reattachment was achieved in 28 of 29 eyes (97%) with an average of 2.3 surgeries (including silicone oil removal surgeries). Redetachment after the first surgery occurred in 13 eyes (45%). Mean Snellen VA at initial presentation, 1-year follow-up, and last follow-up were 20/289, 20/118 (P = .012), and 20/103 (P = .022), respectively. CONCLUSIONS: Anatomic success can be achieved in most eyes. However, redetachments are common, and multiple surgeries are often required. Reasonable visual recovery is possible in many eyes. [Ophthalmic Surg Lasers Imaging Retina. 2020;51:612-616.].

H7N9 influenza A virus activation of necroptosis in human monocytes links innate and adaptive immune responses.

We previously demonstrated that avian influenza A H7N9 virus preferentially infected CD14+ monocyte in human peripheral blood mononuclear cells (PBMCs), which led to apoptosis. To better understand H7N9 pathogenesis in relation to monocyte cell death, we showed here that extensive phosphorylation of mixed lineage kinase domain-like (MLKL) protein occurred concurrently with the activation of caspases-8, -9 and -3 in H7N9-infected monocytes at 6 h post infection (hpi), indicating that apoptosis and necroptosis pathways were simultaneously activated. The apoptotic morphology was readily observed in H7N9-infected monocytes with transmission electron microscopy (TEM), while the pan-caspase inhibitor, IDN6556 (IDN), accelerated cell death through necroptosis as evidenced by the increased level of pMLKL accompanied with cell swelling and plasma membrane rupture. Most importantly, H7N9-induced cell death could only be stopped by the combined treatment of IDN and necrosulfonamide (NSA), a pMLKL membrane translocation inhibitor, but not by individual inhibition of caspase or RIPK3. Our data further showed that activation of apoptosis and necroptosis pathways in monocytes differentially contributed to the immune response of monocytes upon H7N9 infection. Specifically, caspase inhibition significantly enhanced, while RIPK3 inhibition reduced the early expression of type I interferons and cytokine/chemokines in H7N9-infected monocytes. Moreover, culture supernatants from IDN-treated H7N9-infected monocyte promoted the expression of co-stimulatory molecule CD80, CD83 and CD86 on freshly isolated monocytes and monocyte-derived dendritic cells (MDCs) and enhanced the capacity of MDCs to induce CD3+ T-cell proliferation in vitro. In contrast, these immune stimulatory effects were abrogated by using culture supernatants from H7N9-infected monocyte with RIPK3 inhibition. In conclusion, our findings indicated that H7N9 infection activated both apoptosis and necroptosis in monocytes. An intact RIPK3 activity is required for upregulation of innate immune responses, while caspase activation suppresses the immune response.

The use of bevacizumab in pediatric retinal and choroidal disease: A review.

The use of intravitreal bevacizumab in pediatric retinal and uveitic disease has become more widespread over the past decade. This article serves to outline the rationale underlying the use of intravitreal bevacizumab, and which disease entities it should be appropriately thought of as a primary or solo therapy, as opposed to an adjuvant one. Also presented is the relevant literature regarding each of these retinopathies.

Prostaglandin E2-Mediated Impairment of Innate Immune Response to A(H1N1)pdm09 Infection in Diet-Induced Obese Mice Could Be Restored by Paracetamol.

BACKGROUND: Obesity is associated with increased severity of influenza infection. However, the underlying mechanism is largely unknown. METHODS: We employed a mouse model with diet-induced obesity (DIO) to study the innate immune responses induced by influenza virus. RESULTS: The lungs of DIO mice were heavily affected by obesity-associated chronic systemic inflammation with a significant increase in inflammatory cytokines/chemokines. Concurrently, lipid immune mediator prostaglandin E2 (PGE2) was also significantly elevated in DIO mice. However, the DIO mice mounted a blunted and delayed upregulation of mRNA and protein concentrations of interferon-ß and inflammatory cytokines/chemokines upon A(H1N1)pdm09 virus (H1N1/415742Md) challenge compared with those of lean mice. PGE2 concentrations were significantly higher in the lungs of DIO mice compared to that of lean mice postchallenge. Treatment with paracetamol in challenged DIO mice significantly enhanced the expression of interferon-α/ß and cytokine genes at days 1 and 3 postinfection compared with that of untreated DIO mice. Furthermore, paracetamol treatment alone started 3 days before virus challenge and continued until 6 days postchallenge ameliorated the severity of a lethal H1N1/415742Md infection in DIO mice with improved survival. CONCLUSIONS: Impaired innate response to influenza in DIO mice is associated with elevated PGE2, which could be restored to some degree by paracetamol treatment.

A Framework to Assess the Quality of Non-traditional Articles in the Field of Disaster Response and Management.

OBJECTIVE: While carrying out a scoping review of earthquake response, we found that there is no universal standardized approach for assessing the quality of disaster evidence, much of which is variable or not peer reviewed. With the lack of a framework to ascertain the value and validity of this literature, there is a danger that valuable insights may be lost. We propose a theoretical framework that may, with further validation, address this gap. METHODS: Existing frameworks - quality of reporting of meta-analyses (QUORUM), meta-analysis of observational studies in epidemiology (MOOSE), the Cochrane assessment of bias, Critical Appraisal Skills Programme (CASP) checklists, strengthening the reporting of observation studies in epidemiology (STROBE), and consensus guidelines on reports of field interventions in disasters and emergencies (CONFIDE)-were analyzed to identify key domains of quality. Supporting statements, based on these existing frameworks were developed for each domain to form an overall theoretical framework of quality. This was piloted on a data set of publications from a separate scoping review. RESULTS: Four domains of quality were identified: robustness, generalizability, added value, and ethics with 11 scored, supporting statements. Although 73 out of 111 papers (66%) scored below 70%, a sizeable portion (34%) scored higher. CONCLUSION: Our theoretical framework presents, for debate and further validation, a method of assessing the quality of non-traditional studies and thus supporting the best available evidence approach to disaster response. (Disaster Med Public Health Preparedness. 2019;13:147-151).

Co-stimulation With TLR7 Agonist Imiquimod and Inactivated Influenza Virus Particles Promotes Mouse B Cell Activation, Differentiation, and Accelerated Antigen Specific Antibody Production.

Current influenza vaccines have relatively low effectiveness, especially against antigenically drifted strains, the effectiveness is even lower in the elderly and immunosuppressed individuals. We have previously shown in a randomized clinical trial that the topical application of a toll-like receptor 7 agonist, imiquimod, just before intradermal influenza vaccine could expedite and augment antibody response, including to antigenically-drifted strains. However, the mechanism of this vaccine and imiquimod combination approach is poorly understood. Here, we demonstrated that imiquimod alone directly activated purified mouse peritoneal B cells. When combined with inactivated H1N1/415742Md influenza virus particle (VP) as vaccine, co-stimulation of mouse peritoneal B cells in vitro induced stronger activation, proliferation, and production of virus-antigen specific IgM and IgG. Intraperitoneal injection of a combination of VP and imiquimod (VCI) was associated with an increased number of activated B cells with enhanced expression of CD86 in the mesenteric draining lymph nodes (mesLN) and the spleen at 18 h after injection. Three days after immunization with VCI, mouse spleen showed significantly more IgM and IgG secreting cells upon in vitro re-stimulation with inactivated virus, mouse sera were detected with viral neutralizing antibody. Transfer of these spleen B cells to naïve mice improved survival after lethal dose of H1N1/415742Md challenge. More importantly, the functional response of VCI-induced B cell activation was demonstrated by early challenge with a lethal dose of H1N1/415742Md influenza virus at 3 days after immunization. The spleen and mediastinal lymph nodes (mdLN) in mice immunized with VCI had germinal center formation, and significantly higher number of plasmablasts, plasma cells, and virus-antigen specific IgM and IgG secreting cells at only 3-4 days post virus challenge, compared with those of mice that have received imiquimod, inactivated virus alone or PBS. Serum virus-specific IgG2a, IgG2b, and IgG1 and bronchoalveolar lavage fluid (BALF) virus-specific IgA at 3 or 4 days post challenge were significantly higher in mice immunized with VCI, which had significantly reduced lung viral load and 100% survival. These findings suggested that imiquimod accelerates the vaccine-induced antibody production via inducing rapid differentiation of naïve B cells into antigen-specific antibody producing cells.

Bilateral Angle Closure Following the Infusion of a Monoclonal Antibody to Treat Relapsing Multiple Myeloma.

PURPOSE: We describe a case of bilateral angle closure glaucoma following the infusion of daratumumab, a monoclonal antibody used to treat relapsing multiple myeloma. METHODS: This is an interventional case report. RESULTS: A 59-year-old woman presented with bilateral angle closure glaucoma one day following her first infusion of daratumumab. B-scan echography showed ciliochoroidal effusions in both eyes. Cycloplegia was implemented given the suspicion for drug-induced angle closure, which resulted in prompt deepening of the anterior chambers and normalization of intraocular pressures. The ciliochoroidal effusions resolved 16 days following the cessation of daratumumab. CONCLUSIONS: Daratumumab may be associated with drug-induced secondary angle closure glaucoma.

Triple combination of FDA-approved drugs including flufenamic acid, clarithromycin and zanamivir improves survival of severe influenza in mice.

Seasonal influenza virus remains a common cause of mortality despite the use of neuraminidase inhibitors. This study evaluated the efficacy of a triple combination of zanamivir, clarithromycin and flufenamic acid (FFA) in the treatment of influenza virus A(H1N1) infection. An in vitro cell protection assay and a multiple-cycle growth assay showed that the antiviral activity of zanamivir was enhanced when combined with clarithromycin or FFA. A mouse challenge model was used here for the evaluation of the in vivo efficacy of the triple combination treatment. We found that mice receiving the triple combination of FFA, zanamivir, and clarithromycin had a significantly better survival rate than those receiving the double combination of zanamivir and clarithromycin (88% versus 44%, P = 0.0083) or zanamivir monotherapy (88% versus 26%, P = 0.0002). Mice in the FFA-zanamivir-clarithromycin triple combination group also exhibited significantly less body weight loss than those in the zanamivir-clarithromycin double combination group. There was no significant difference in the lung viral titers among the different groups from day 2 to day 6 postinfection. However, the levels of IL-1ß, TNF-α and RANTES in the FFA-zanamivir-clarithromycin triple combination group were significantly lower than those in the zanamivir-clarithromycin double combination group, zanamivir monotherapy group, or solvent group on day 2 postinfection. Our findings showed that the FFA-zanamivir-clarithromycin triple combination improved the inflammatory markers and survival of severe influenza A(H1N1) infection in mice.

Temporal trends and patterns in antimicrobial-resistant Gram-negative bacteria implicated in intensive care unit-acquired infections: A cohort-based surveillance study in Istanbul, Turkey.

OBJECTIVES: This study assessed trends and patterns in antimicrobial-resistant intensive care unit (ICU)-acquired infections caused by Gram-negative bacteria (GNB) in Istanbul, Turkey. METHODS: Bacterial culture and antimicrobial susceptibility data were collected for all GNB causing nosocomial infections in five adult ICUs of a large university hospital in 2012-2015. Multiresistance patterns were categorised as multidrug-resistant (MDR), extensively drug-resistant (XDR) and pandrug-resistant (PDR). Temporal patterns and trends were assessed using regression analyses. RESULTS: Of 991 pathogenic GNB recorded, the most frequent were Acinetobacter baumannii (35.3%), Klebsiella spp. (26.7%), Pseudomonas aeruginosa (18.1%) and Escherichia coli (6.7%). The overall infection rate decreased by 41% from 18.4 to 10.9 cases per 1000 patient-days in 2012 compared with 2015 (P<0.001), mostly representing decreases in bloodstream infections and pneumonias by A. baumannii and P. aeruginosa. The XDR proportion in A. baumannii increased from 52.4% in 2012 to 71.7% in 2015, but only one isolate was colistin-resistant. Multiresistance patterns remained stable in Klebsiella, with overall XDR and possible PDR proportions of 14.3% and 1.9%, respectively. A back-to-susceptibility trend was noted for P. aeruginosa in which the non-MDR proportion increased from 53.3% in 2012 to 70.6% in 2015. Moreover, 87.9% of E. coli and 39.5% of Enterobacter isolates were MDR, but none was XDR. CONCLUSIONS: Antimicrobial resistance patterns in pathogenic GNB continuously change over time and may not reflect single-agent resistance trends. The proportionate amount of antimicrobial-resistant GNB may persist despite overall decreasing infection rates. Timely regional surveillance data are thus imperative for optimal infection control.

Low population serum microneutralization antibody titer against the predominating influenza A(H3N2) N121K virus during the severe influenza summer peak of Hong Kong in 2017.

The 2017 Hong Kong influenza A(H3N2) summer season was unexpectedly severe. However, antigenic characterization of the 2017 circulating A(H3N2) viruses using ferret antisera did not show significant antigenic drift. We analyzed the hemagglutinin amino acid sequences of A(H3N2) virus circulating in Hong Kong in 2017, and found that viruses with hemagglutinin N121K substitution, which was rare before 2017, emerged rapidly and dominated in 2017 (52.4% of A[H3N2] virus in 2017 contains N121K substitution). Microneutralization assay using archived human sera collected from mid-2017 showed that the geometric mean microneutralization titer was 3.6-fold lower against a 2017 cell culture-grown circulating A(H3N2)-N121K virus (3391/2017 virus) than that against the cell culture-grown 2016-2017 A(H3N2) seasonal influenza vaccine-like vaccine virus (4801/2014 virus) (13.4 vs 41.8, P < 0.0001). Significantly fewer serum specimens had a microneutralization titer of 40 or above against 3391/2017 virus than that against 4801/2014 virus (26.4% vs 60.0%, P < 0.0001). Conversely, the geometric mean hemagglutination inhibition titer was slightly higher against 3391/2017 virus than that against the 4801/2014 virus (96.9 vs 55.4, P < 0.0001). Moreover, 59.1% of specimens had a significantly lower microneutralization antibody titer (≥4-fold) against 3391/2017 virus than that against 4801/2014 virus, but none for hemagglutination titer (P < 0.0001). Similar results of microneutralization and hemagglutination titers were observed for day 21-post-vaccination sera. Hence, the 2017 A(H3N2) summer peak in Hong Kong was associated with a low-microneutralization titer against the circulating virus. Our results support the use of microneutralization assay with human serum in assessing population susceptibility and antigenic changes of A(H3N2) virus. Novel and available immunization approach, such as topical imiquimod followed by intradermal vaccination, to broaden the neutralizing antibody response of influenza vaccine should be considered.

Prevalence of depressive symptoms and its associated factors in older adults: a cross-sectional study in Kathmandu, Nepal.

OBJECTIVE: Globally, depression is one of the most prevalent and burdensome conditions in older adults. However, there are few population-based studies of depression in older adults in developing countries. In this paper, we examine the prevalence of depressive symptoms and explore possible contributory risk factors in older adults living in Nepal. METHODS: A cross-sectional study was conducted in two semi-urban communities in Kathmandu, Nepal. Depression was assessed using the 15-item Geriatric Depression Scale in 303 participants, aged 60 years and over. Multivariate logistic regression was then used to assess associations between potential risk factors and depression. RESULTS: More than half of the participants (n = 175, 60.6%) had significant depressive symptomatology, with 27.7% having scores suggesting mild depression. Illiteracy (aOR = 2.01, 95% CI: 1.08-3.75), physical immobility (aOR = 5.62, 95% CI: 1.76-17.99), the presence of physical health problems (aOR = 1.97, 95% CI: 1.03-3.77), not having any time spent with family members (aOR = 3.55, 95% CI: 1.29-9.76) and not being considered in family decision-making (aOR = 4.02, 95% CI: 2.01-8.04) were significantly associated with depression in older adults. CONCLUSION: The prevalence of depression was significant in older adults. There are clear associations of depression with demographic, social support and physical well-being factors in this population. Strategies that increase awareness in the community along with the health and social care interventions are needed to address the likely drivers of depression in older adults.