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Earthquakes are catastrophic natural disasters that cause extensive damage to infrastructure and disrupt the lives of millions worldwide. Beyond the immediate physical and psychological damage caused by earthquakes, these events can significantly impact respiratory health. The inhalation of dust, smoke, particulates, toxic gases, and asbestos exposure can lead to various respiratory health pathologies. These include respiratory infections, exacerbations of pre-existing respiratory diseases, chest traumas, and pulmonary and venous thromboembolism. Longitudinal studies are necessary to assess the long-term respiratory health effects in affected populations. By addressing these knowledge gaps, future mitigation strategies and preparedness measures can be developed to minimize the respiratory health impacts of earthquakes and improve the well-being of affected communities. Robust building infrastructure and comprehensive earthquake preparedness are emerging as the most important determinants for not only mitigating building collapse but also significantly reducing the potential health impacts that follow. This comprehensive review aims to provide a systematic overview of the lung health impacts of earthquakes. It highlights the need for further research to identify specific pollutants, air contaminants, and environmental factors contributing to respiratory health issues following earthquakes.

Urban agriculture encompasses all agricultural activities within or near urban areas. Due to its complex interactions within environmental, social, and economic contexts, urban agriculture faces various challenges. Therefore, various stakeholders are involved in the process of developing urban agriculture. This study aims to determine the place and importance of urban agriculture in the eyes of stakeholders in Iğdır City and its surrounding areas. This will provide an understanding of what can be done in the region within the scope of urban agriculture. Semi-structured interview forms were used in the study. Five questions were asked to the stakeholders, and descriptive analysis, one of the qualitative data analysis methods, was used to analyze the data. According to the findings, it was concluded that Iğdır city holds significant potential in terms of urban agricultural activities. Based on the stakeholder opinions, opportunities for urban agriculture in Iğdır City were discussed.

PURPOSEIn this study, we aimed to reveal the relationship between initial lung parenchymal involvement patterns and the subsequent need for hospitalization and/or intensive care unit admission in coronavirus disease 2019 (COVID-19) positive cases.METHODSOverall, 231 patients diagnosed with COVID-19 as proven by PCR were included in this study. Based on the duration of hospitalization, patients were divided into three groups as follows: Group 1, patients receiving outpatient treatment or requiring hospitalization

Take Home Message: Capsaicin modified inflammatory response and caused toxicity in bronchial epithelial cultures from patients with COPD. More importantly, capsaicin decreased ciliary beat frequency and induced epithelial permeability and these effects were partially prevented by formoterol and roflumilast.Tear gas is widely used to halt mass demonstrations. Studies have reported its adverse effects on multiple organ systems; however, its effect on individuals with chronic respiratory diseases and the underlying mechanisms of these effects are unclear. For the first time in the literature, we investigated the effects of capsaicin, the active ingredient of tear gas, on bronchial epithelial cell (BEC) cultures obtained from well-characterized groups of nonsmokers, smokers, and patients with chronic obstructive pulmonary disease (COPD). BEC cultures were incubated with 50-500 μM capsaicin in the absence and presence of formoterol (1μM) and roflumilast (0.1 μM) for 24 h. Ciliary beat frequency (CBF) and transepithelial electrical resistance (TEER) were assessed at T1/4, T1/2, T1, T2, T4, T6, and T24 h, whereas the release of granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-8, and lactate dehydrogenase (LDH) was measured at T24 h. Capsaicin (250 µM) significantly decreased CBF of all BEC cultures from T1/4 h to T24 h (p

One of the important elements in the public open and green lands and used extensively by the people of the city is urban parks. Urban parks are usually located in the city center or close to the city center. Urban parks are shaped by cultural values, political and socio-economic structure. Urban parks offer many opportunities for urban, social, psychological, functional and recreational aspects and contribute to urban identity and urban ecology. The aim of this study is to reveal the contributions of the people in the vicinity of Amasya Courthouse Urban Park in line with the functions of the buildings, the reasons and density of the city's use of the park. There are various public institutions and organizations, educational institutions, business centers, eating and drinking places, and residential areas etc. placed near by the urban park. Within the scope of the study, a survey was conducted with 100 people face to face. As a result of the study, it was determined that the Amasya Courthouse Urban Park has the characteristic of being a meeting point and it is not used for all age groups in terms of recreational activities.

Background and objectivesAlthough several repurposed antiviral drugs have been used for the treatment of COVID-19, only a few such as remdesivir and molnupiravir have shown promising effects. The objectives of our study were to investigate the association of repurposed antiviral drugs with COVID-19 morbidity.MethodsPatients admitted to 26 different hospitals located in 16 different provinces between March 11–July 18, 2020, were enrolled. Case definition was based on WHO criteria. Patients were managed according to the guidelines by Scientific Board of Ministry of Health of Turkey. Primary outcomes were length of hospitalization, intensive care unit (ICU) requirement, and intubation.ResultsWe retrospectively evaluated 1,472 COVID-19 adult patients; 57.1% were men (mean age = 51.9 ± 17.7years). A total of 210 (14.3%) had severe pneumonia, 115 (7.8%) were admitted to ICUs, and 69 (4.7%) were intubated during hospitalization. The median (interquartile range) of duration of hospitalization, including ICU admission, was 7 (5–12) days. Favipiravir (n = 328), lopinavir/ritonavir (n = 55), and oseltamivir (n = 761) were administered as antiviral agents, and hydroxychloroquine (HCQ, n = 1,382) and azithromycin (n = 738) were used for their immunomodulatory activity. Lopinavir/ritonavir (β [95% CI]: 4.71 [2.31–7.11]; p = 0.001), favipiravir (β [95% CI]: 3.55 [2.56–4.55]; p = 0.001) and HCQ (β [95% CI]: 0.84 [0.02–1.67]; p = 0.046) were associated with increased risk of lengthy hospital stays. Furthermore, favipiravir was associated with increased risks of ICU admission (OR [95% CI]: 3.02 [1.70–5.35]; p = 0.001) and invasive mechanical ventilation requirement (OR [95% CI]: 2.94 [1.28–6.75]; p = 0.011).ConclusionOur findings demonstrated that antiviral drugs including lopinavir, ritonavir, and favipiravir were associated with negative clinical outcomes such as increased risks for lengthy hospital stay, ICU admission, and invasive mechanical ventilation requirement. Therefore, repurposing such agents without proven clinical evidence might not be the best approach for COVID-19 treatment.

Objective: Angiotensin II promotes growth and angiogenesis via type 1 receptors (AGTR1) in certain tumors. In this study, we examine the bone marrow AGTR1 expression in multiple myeloma (MM) and its relationship with the regulation of angiogenesis and prognostic factors. Materials and Methods: Bone marrow AGTR1 mRNA levels of 39 MM patients and 15 healthy controls were analyzed with quantitative RT-PCR. Immunohistochemical staining of the tissue vascular endothelial growth factor (VEGF), CD34, and factor VIIIrAg (fVIIIrAg) was used to assess bone marrow angiogenesis. Results: Bone marrow samples of the patients showed increased VEGF, fVIIIrAg, and CD34 staining and higher AGTR1 expression levels when compared to controls. Patients with severe-diffuse bone marrow infiltration showed higher bone marrow VEGF, fVIIIrAg, CD34, and AGTR1 mRNA levels when compared to other patients. Conclusion: AGTR1 expression was found positively correlated with plasma β2-microglobulin level and patients with increased AGTR1 expression showed increased bone marrow CD34 levels.

Myasthenia gravis (MG) is an autoimmune disease mediated by autoantibodies predominantly against the acetylcholine receptor (AChR). Specific T cell subsets are required for long-term antibody responses, and cytokines secreted mainly from CD4+ T cells regulate B cell antibody production. The aim of this study was to assess the differences in the cytokine expressions of CD4+ T cells in MG patients with AChR antibodies (AChR-MG) and the effect of immunosuppressive (IS) therapy on cytokine activity and to test these findings also in MG patients without detectable antibodies (SN-MG). Clinically diagnosed AChR-MG and SN-MG patients were included. The AChR-MG patients were grouped as IS-positive and -negative and compared with age- and sex-matched healthy controls. Peripheral blood mononuclear cells were used for ex vivo intracellular cytokine production, and subsets of CD4+ T cells and circulating follicular helper T (cTfh) cells were detected phenotypically by the expression of the chemokine and the costimulatory receptors. Thymocytes obtained from patients who had thymectomy were also analyzed. IL-21, IL-4, IL-10, and IL-17A productions in CD4+ T cells were increased in AChR-MG compared to those in healthy controls. IS treatment enhanced IL-10 and reduced IFN-γ production in AChR-MG patients compared to those in IS-negative patients. Increased IL-21 and IL-4 productions were also demonstrated in SN-MG patients. Among CD4+ T cells, Th17 cells were increased in both disease subgroups. Treatment induced higher proportions of Th2 cells in AChR-MG patients. Both CXCR5+ and CXCR5− CD4+ T cells expressed higher programmed cell death protein 1 (PD-1) and inducible costimulatory (ICOS) in AChR-MG and SN-MG groups, mostly irrespective of the treatment. Based on chemokine receptors on CXCR5+PD-1+ in CD4+ T (cTfh) cells, in AChR-MG patients without treatment, the proportions of Tfh17 cells were higher than those in the treated group, whereas the Tfh1 cells were decreased compared with those in the controls. The relevance of CXCR5 and PD-1 in the pathogenesis of AChR-MG was also suggested by the increased presence of these molecules on mature CD4 single-positive thymocytes from the thymic samples. The study provides further evidence for the importance of IL-21, IL-17A, IL-4, and IL-10 in AChR-MG. Disease-related CD4+T cells are identified mainly as PD-1+ or ICOS+ with or without CXCR5, resembling cTfh cells in the circulation or probably in the thymus. AChR-MG and SN-MG seem to have some similar characteristics. IS treatment has distinctive effects on cytokine expression.

Çalışma alanı olarak seçilen Amasya kenti, doğal ve kültürel değerlere sahip önemli bir ilimizdir. Yeşilırmak Nehri, Yeşilırmak Vadisi, Geleneksel Osmanlı Evi örnekleri, Helenistik döneme ait Kaya Mezarlıkları kent peyzajının önemli unsurları durumundadır. Kent formu üzerinde etkili olan Yeşilırmak Nehri ve Vadisi, kentin ulaşım sistemi üzerinde önemli rol oynamaktadır. Çalışma kapsamında; “Amasya Kenti İçin Yeşilırmak Koridorunu İçine Alan Bir Kentsel Yeşilyol Önerisi” isimli yüksek lisans tezinde oluşturulan yeşilyol güzergâhlarının Analitik Hiyerarşi Süreci (AHS) yöntemi kullanılarak öncelikli işlevleri belirlenmiştir. Her bir güzergâhın baskın fonksiyonunun belirlenmesi için 10 kişiden oluşan uzman gruba anket çalışması yapılmıştır. ‘Alternatif ulaşım’, ‘Süreklilik’ ve ‘Diğer İşlevsel Katkılar’ yeşilyol güzergâhları için belirlenen ana fonksiyonlardır. Ana fonksiyonlar açısından değerlendirildiğinde; Amasya-Erzincan Karayolu Koridoru’nda ‘Süreklilik’, Yeşilırmak Nehri Koridoru’nda ‘Alternatif Ulaşım’, Amasya Kalesi Koridoru’nda ise ‘Diğer İşlevsel Katkılar (turizm ve ekonomik katkı, rekreasyon, görüntü kontrolü vb.)’ fonksiyonu en yüksek değeri almıştır. Ayrıca belirlenen 3 güzergâha ek olarak, farklı işlevlere ve alternatif ulaşıma sahip 2 tane yeni güzergâh önerilmiştir. ______________________________________________________________________________A Study on the Determination of Priority Functions of Greenway Routes Using AHP in Amasya City ExampleAbstractAmasya city, which has been chosen as the study site is an important city with its natural and cultural values. The important elements of the urban landscape are Yeşilırmak River, Yeşilırmak Valley, Traditional Ottoman Houses and Rock Tombs (Sepulchres) belonging to the Hellenistic Era. Yeşilırmak River which is influential on the form of the city also acts as an important determiner of the transportation system. The scope of work “An Urban Greenway Proposal For Amasya City Including Yeşilırmak Corridor” is created greenway routes of Analytic Hierarchy Process (AHP) the primary functions were determined using the method. To determine each route’s dominant function is carried out survey work group of experts consisting of 10 people. ‘Alternative transportation’, ‘Continuity’ and ‘Other Functional Contribution’ main functions are set for the greenway routes. In terms of the main functions Amasya-Erzincan Highway Corridor ‘Continuity’, Yeşilırmak River Corridor ‘Alternative Transportation’, while in Amasya Castle Corridor ‘Other Functional Contribution (tourism and economic contribution, recreation, view control etc.)’ function has the highest value. In addition to these three designated routes, new routes have been proposed 2 units with different functions and alternative transportation.

Dünya üzerindeki yaşamın kalitesi çevrenin kalitesi ile ayrılmaz bir bütündür. Günümüzde organik ve inorganik kirlenme çevre ve insan sağlığı üzerinde önemli sorunlar meydana getirmektedir. Kentleşmenin artması ve sanayinin gelişmesi ile insan odaklı ağır metal kullanımı giderek artmıştır. Ağır metaller toprak ve suya karışarak besin zincirini üzerinde olumsuz etkilere sahiptir. Son yıllarda kirlenmiş toprak ve suyun iyileştirilmesi için güçlü ve etkili teknikler geliştirilmiştir. Ayrıca bu tekniklerin yerinde, etkili, ekonomik ve çevre dostu olması önemlidir. Bu nedenle fitoremediasyon ve biyoremediasyon teknikleri ile yapılan çalışmalar ve literatürlerde önemli yer tutmuştur. Bu çalışma ile su, toprak ve çevre üzerinde ağır metallerin uzaklaştırılması faaliyeti olarak kullanılan fitoremediasyon ve biyoremediasyon konuları hakkında bilgi verilecektir. Ayrıca dünyaca bilinen ve fitoremediasyon bitkisi olan Vetiver çimi (Vetiveria zizanioides (Linn.) Nash) ağır metal kirlenmesini gidermesi için kullanımından ve biyoremediasyon organizması olan bazı solucanların ağır metal kirleniminin temizlenmesinde kullanılabilirliği tartışılmıştır. _______________________________________________________Remediation Contaminated Soil by Heavy Metal: Vetiver Grass (Vetiveria zizanioides (Linn.) Nash) and EarthwormsAbstractQuality of life and environment of the world are inseparable. Nowadays, organic and inorganic contamination produces major problems on the environment and human health. People-oriented heavy metal usage has increased due to urbanization and industrial development. Heavy metals have negative impacts on the soil and water, blending into the food chain. Powerful and effective techniques for treating contaminated soil and water have been developed in recent years. It is important that these techniques are appropriate, effective and eco-friendly. Therefore phytoremediation and bioremediation techniques in the studies and literatures take an important place. With this study, phytoremediation and bioremediation will be informed about topics that used as removal of heavy metals activities on water, soil and environment. In addition, worldwide known and phytoremediation plants Vetiver grass (Vetiveria zizanioides (Linn.) Nash) were discussed to use for removal of heavy metal contamination. Then bioremediation organisms earthworms were discussed to use for purified of heavy metal contamination.

Yoğun kentleşme ile birlikte çocukların oyun alanları kentler arasında sıkıştırılmıştır. Çocuklar için tasarlanmış çocuk oyun alanları engelli çocukların ihtiyaç ve gereksinimlerine yönelik tasarlanmalıdır. Çünkü engelli çocukların sosyal hayata katılımları ve diğer çocuklarla sosyalleşme imkânları ancak oyun alanlarında gerçekleşir. Bu sebeple çocuk oyun alanları tüm çocuklara hizmet verecek biçimde doğa ile uyumlu tasarlanmalıdır. Bu çalışmanın amacı; açık yeşil alan tasarımlarından çocuk oyun alanları ve uygulamalarında fiziksel engelli çocuklara yönelik tasarım ilkelerini tespit etmektir. Çalışma “bedensel engelli bireyler için ulaşılabilir ve kullanılabilir olmak” düşüncesi ile öncelikle çocuklara yönelik olarak hazırlanmıştır. Çocuk oyun olanaklarının engelli çocuklar açısından tasarım ilkeleri belirlenerek araştırma sonuçları ortaya konulmuştur. Engelli çocuk oyun alanlarında doğal elemanlarla (topoğrafya, hayvanlar, bitkiler, su, toprak ve kum) düzenlenen oyun aktivitelerinin çocuklar üzerinde ruhsal açıdan olumlu etkileri olduğu sonucuna varılmıştır._________________________________________________________________________Disabled Children's Play Areas Compatible with NatureAbstractWith intensive urbanization children's play areas have become compressed playgrounds across the city. Children’s playground which design for children should be designed according to disabled children's needs and requirements. Because it just takes place in the playgrounds, disabled children's participation in social life and it is opportunity to socialize with other children too. For this reason, children's playgrounds should be designed in harmony with nature and they will serve all children. The purpose of this study, to identify design principles of children's play areas and open green space under consideration orthopedic disabled children. This study also considers that "be available and accessible for the physically disabled individual" with the thought that is intended primarily for children. . With determining the design principles of children's playground for disabled children has revealed in the results of this research. Playing activities that regulated with natural elements (topography, animals, plants, water, soil and sand) in the children’s playground have positive psychological effects on disabled children.

Savaşların ve terör saldırılarının sanat ve kültür üzerinde önemli etkisi olduğu ve özellikle birinci ve ikinci dünya savaşları dünya mimarisini ve kent kimliğini olumsuz yönde etkilediği görülmüştür. Son zamanlarda gerçekleşen terör saldırıları toplumda bazı sosyal ve kültürel değerlerin ortaya çıkmasına neden olmuş ve bu değerlerin vurgulanmasına yönelik olarak da anı bahçeleri tasarlanmaya başlanmıştır. Anı bahçeleri savaş ya da saldırılarda ölenlerin hatıralarını canlı tutmak, arda kalan savaş ve saldırı izi taşıyan yapıları ve eserleri korumak, kayıp verme duygusundan kaçınarak yaşananları kayıt altına tutmak ve barışı yaymayı amaçlamaktadır. Bu bağlamda ele alınan bu çalışmada savaşların ve saldırıların etkisi ile ortaya çıkan dünyada bilinen anı bahçeleri örnekleri ile bunların tasarım ilkeleri incelenmiştir. Analysis of Some Memorial Gardens in Terms of Landscape Design PrinciplesAbstract Wars and terrorist attacks always have affected cultures and arts of the nations. Especially the first and second world war has been a negative impact on the world of architecture and urban identity. Terrorist attacks happened the last decades have triggered some values in the society and consequently attempt at keeping those values caused the memorials gardens are created. In this article, it is tried to take a total look at global art formed by war effects. Furthermore, there are evaluated some well-known universal memorial gardens to put forward some instructions and concepts available to the planner and designers of the memorial gardens. In this context, this study dealt with the effects of wars and attacks occurring in the world well-known example memories of gardens and their design principles have been examined.

The size of the areal use in planning allows for increase in recreational diversity. When considered that recreational needs are the times that people spend to make use of their spare time, it is obvious that the decisions taken based on the user will lead the planner to more accurate planning targets. While determining the recreational planning decisions, decisions should be evaluated in an integrated approach and in accordance with the requests and demands of users. This study aimed at taking planning decisions required for the recreational connections which are on the coast and for the improvement of people's social life between the coastal city and coastal users. Within the study, the diversity of Trabzon coastal area in terms of recreational activity based on measurement and observation was revealed. In the study, subclasses determined for Trabzon coast were formed by sticking to CORINE classification system, and the coast was divided into 9 sections considering the size and clarity of the area. In CBS environment, each section was digitized according to separate layers and areas with ArcCIS program in terms of recreational area usages. As a result of the study, it was revealed that the diversity of activity was more intense in sections where areal use was more intense depending on the size of the area.

Objective: It is widely known that myocardial damage is not immediately terminated after the elimination of epicardial occlusion in cases of myocardial infarction. In situ thrombosis during epicardial occlusion might contribute to poor myocardial perfusion after reperfusion of an occluded epicardial artery. In the current study, we sought to determine the effects of ischemia and reperfusion on microvascular thrombotic occlusion. Methods: Thirty male Wistar rats were included in the study. After the rats had been anesthetized and thoracotomized, the left coronary artery was occluded for 30 minutes in the first group, and it was occluded for 30 minutes and reperfused for an additional 20 minutes in the second group. Ten rats were used as a sham-operated control group. After completion of the study protocol, excised heart preparations were analyzed by immunohistochemistry and electron microscopy. Results: A significant difference was found between the infarction plus reperfusion group and the other 2 groups, with respect to microvascular fibrin and thrombocyte deposition in immunohistochemistry analysis. These results were confirmed by morphological examination with electron microscopy. Conclusion: In situ fibrin formation accompanies microvascular obstruction in acute myocardial infarction. Our results indicate that additional therapeutic approaches are needed in order to achieve better tissue perfusion in contemporary treatment of acute myocardial infarction after successful reopening of the infarct-related artery.

OBJECTIVE: Osteoporosis, osteosclerosis, and lytic bone lesions have been observed in patients with systemic mastocytosis (SM). We examined bone mineral density (BMD) biochemical turnover markers and serum tryptase levels in SM, which is considered a rare disease. METHODS: Seventeen adult patients (5 females, 12 males; median age: 33 years, range: 20-64) with mastocytosis were included in this study. We investigated the value of quantitative ultrasound (QUS) of the calcaneus in the assessment of BMD in SM patients, as well as BMD of the lumbar spine (L1-L4), femoral neck, and distal radius using dual energy x-ray absorptiometry (DXA) and plasma tryptase levels, biochemical markers of bone turnover. RESULTS: At lumbar spine L1-L4, the femoral neck, and the distal radius or as calcaneus stiffness, 12 of 17 patients had T-scores of less than -1 at least at 1 site, reflecting osteopenia. Three of 17 patients had T-scores showing osteoporosis (T-score

Overexpression of DEK oncogene is associated with increased proliferation of carcinoma cells and it is observed in several solid tumors due to the amplification of the 6p22.3 chromosomal region where DEK locates. Although the same chromosomal amplification occurs in multiple myeloma (MM), a plasma cell neoplasm, whether the expression and the copy number of the DEK gene are affected in MM remains elusive. We show that despite the increased copy number in CD138positive MM cells (4 out of 41 MM samples), DEK mRNA expression was down-regulated compared with that in CD138negative bone marrow (BM) cells of the same patients (P

Primary pancreatic lymphoma (PPL) is a rare tumor that usually presents with the clinical picture of advanced adenocarcinoma but has a much better prognosis. A 38-year-old man was referred after percutaneous transhepatic external biliary drainage for obstructive jaundice. Abdominal magnetic resonance imaging (MRI) and magnetic resonance cholangiopancreatography had revealed a 5-cm pancreatic head mass that caused biliary tract dilation. Computed tomography angiography showed that the mass encased the celiac trunk as well as the common hepatic and splenic arteries. MRI also revealed a metastatic lesion at the third lumbar vertebra. Serum carcinoembryonic antigen and carbohydrate antigen 19-9 levels were within normal range. The initial diagnosis was inoperable pancreatic adenocarcinoma; however, Tru-Cut pancreatic biopsy showed a large B cell lymphoma. After 6 sessions of chemotherapy and 21 sessions of radiotherapy, both the pancreatic mass and the vertebral metastasis had disappeared. However, he had persistent distal common bile duct stricture that could not be negotiated by either the endoscopic or percutaneous route. A Roux-en-Y hepaticojejunostomy was performed. The patient stayed alive without recurrence for 52 months after the initial diagnosis and 45 months after completion of oncologic treatment. In conclusion, a large pancreatic mass with grossly involved peripancreatic lymph nodes, without ascites, liver or splenic metastasis, should alert the clinician to the possibility of PPL. Cure is possible by chemoradiotherapy even in the presence of vertebral metastasis. Persistent stricture in the distal common bile duct may require a biliodigestive anastomosis.

Kikuchi-Fujimoto disease (KFD) is a disease which goes with fever, leucopenia and cervical lymphadenopaty; and generally self-limited in several weeks to months. Recurrences are seen in 3% of the cases. It is also called histiocytic necrotizing lymphadenopaty. The patients suffer from this disease can be misdiagnosed such as tuberculosis, systemic lupus erythematosus, lymphoma. Therefore, the diagnosis of this disease which have usually benign prognosis but rarely fatal, gains importance. We want to discuss this rare, hard to diagnose and as much important disease, while presenting our two patients with KFD who are 32- and 39-year-old.

Patients with primary biliary cirrhosis (PBC) are at increased risk for various malignancies including lymphoproliferative diseases. In this report, we describe a 52-year-old man with the simultaneous diagnosis of PBC and IgG-kappa multiple myeloma (MM). Serum cholestatic enzyme (alkaline phosphatase and gamma-glutamyltransferase) levels decreased after three courses of vincristine, adriamycin and dexamethasone treatment followed by six courses of melphalan and methylprednisolone, given for MM. Pruritus also disappeared. He did not show any progression during the next 24 months of clinical follow-up. The coexistence of PBC and MM is rare and the pathogenetic mechanism under this association remains unclear. Clinical improvement of both diseases in this patient after chemotherapy may indicate an association; however, absence of concurrency in previous large series increases the possibility of coincidence in this case. When compared with the previous single case reports, this case provided long-term results about response after chemotherapy.

Respiratory syncytial virus (RSV) is a common cause of severe respiratory tract infection at the extremes of age and in vulnerable populations. However, it is difficult to predict the clinical course and most infants who develop severe disease have no pre-existing risk factors. With the recent licencing of RSV vaccines and monoclonal antibodies, it is important to identify high-risk individuals in order to prioritise those who will most benefit from prophylaxis. The immune response to RSV and the mechanisms by which the virus prevents the establishment of immunological memory have been extensively investigated but remain incompletely characterised. In animal models, beneficial and harmful immune responses have both been demonstrated. While only chimpanzees are fully permissive for human RSV replication, most research has been conducted in rodents, or in calves infected with bovine RSV. Based on these studies, components of innate and adaptive immune systems, cytokines, chemokines and metabolites, and specific genetic and transcriptomic signatures are identified as potential predictive indicators of RSV disease severity. These findings may inform the development of future human studies and contribute to the early identification of patients at high risk of severe infection. This narrative review summarises the factors involved in the immune response to RSV infection in these models and highlights the relationship between potential biomarkers and disease severity., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jeroen Aerssens reports a relationship with Janssen Pharmaceutica NV that includes: employment. Jeroen Aerssens reports a relationship with Johnson and Johnson Ltd that includes: equity or stocks. Deniz Oner reports a relationship with Janssen Pharmaceutica NV that includes: employment. SBD has previously received honoraria from Sanofi for taking part in RSV advisory boards and has provided consultancy and/or investigator roles in relation to product development for Janssen, AstraZeneca, Pfizer, Moderna, Valneva, MSD, iLiAD, MundiPharma and Sanofi with fees paid to my institution. SBD is a member of the UK Department of Health and Social Care's (DHSC) Joint Committee on Vaccination and Immunisation (JCVI) RSV subcommittee and Medicines and Healthcare products Regulatory Agency's (MHRA) Paediatric Medicine Expert Advisory Group (PMEAG), but the reviews expressed herein do not necessarily represent those of DHSC, JCVI, MHRA or PMEAG. AJP is chair of DHSC's Joint Committee on Vaccination and Immunisation and has been funded on RSV vaccines by the EC IMI programme. RST has received honoraria for internal presentations at AstraZeneca, GSK and Sanofi. PJMO has consulted for GSK, Moderna, Janssen, Seqirus, Pfizer, AstraZeneca, Shionogi, BioNet Asia and Sanofi. DO was an employee of Janssen Pharmaceutica NV JA was an employee of Janssen Pharmaceutica NV and is a shareholder of Johnson & Johnson. DT, JP, CM, JM have no conflicts to declare. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction: Respiratory syncytial virus (RSV) causes acute respiratory tract infection (ARTI) and reinfects adults throughout life, posing a risk for hospitalization in older adults (>60 years) with frailty and comorbidities., Methods: To investigate serum and mucosal antibodies for protection against RSV infections, baseline serum samples were compared for RSV-pre- and -post-fusion (F) binding, and RSV-A2 neutralizing IgG antibodies between symptomatic RSV-ARTI ( N = 30), non-RSV (RSV negative) ARTI ( N = 386), and no ARTI ( N = 338). Mucosal RSV-pre-F IgA and IgG levels, as well as serum RSV-G IgG antibodies, were analyzed to determine their association with protection from symptomatic RSV-ARTI in a subset study., Results: Using a receiver operating characteristic (ROC) analysis, we established thresholds of 1.4- to 1.6-fold change (FC) for RSV-pre-F and -post-F, and RSV-A2 neutralizing IgG antibodies, respectively, enabling the identification of asymptomatic RSV cases with high sensitivity and specificity (>80% and >90%, respectively). As a result, serum RSV-pre-F, RSV-G IgG, and mucosal pre-F binding IgA antibodies showed correlations with protection against symptomatic RSV infection. RSV-pre-F IgG antibodies were correlated with protection from RSV infections irrespective of the symptoms., Discussion: This study provides insights into antibody-mediated protection for symptomatic RSV infection in a community-dwelling older-adult population and establishes a threshold to identify asymptomatic RSV infection using a data-driven approach., Competing Interests: DÖ, SB-J, MC, AB, KT, SO, and JA were employed at the time the work was performed by Janssen Pharmaceuticals, a Johnson & Johnson company, and may be Johnson & Johnson stockholders. CV and AM were employed by Sanofi at the time the work was performed and may be Sanofi stockholder. CV is now employed by Vaccines Europe, Brussels, Belgium. BS and JD are employed by GlaxoSmithKline and may be GlaxoSmithKline stockholders. CB has participated in two virtual Advisory Boards for Moderna relevant to RSV vaccination on 30 March 2023 and 18 May 2023 and received payments. TV has received grant from Innovative Medicines Initiative European Commission, in which Biomerieux, Abbott, BD, BioRad, Janssen contributed ValueDx project, NIHR for project on cellulitis, and NHS UK regional funding for project on respiratory tract infections. He have been on the Advisory Board of a US study on lower respiratory tract infections in primary care EAST-PC funded by the Agency for Healthcare Research and Quality. He is a member of the Dutch Health Council. SD has provided consultancy and/or investigator roles in relation to product development for Janssen, AstraZeneca, Pfizer, Moderna, Valneva, MSD, iLiAD and Sanofi with fees paid to St George’s, University of London. SD has been on the RSV advisory board Sanofi Pasteur and received fees. SD also received support for travel for chairing a conference session, fees paid to his institution SGUL. SD is a member of the UK Department of Health and Social Care’s DHSC Joint Committee on Vaccination and Immunisation JCVI RSV subcommittee and Medicines and Healthcare products Regulatory Agency’s MHRA Paediatric Medicine Expert Advisory Group PMEAG. JW is investigator for clinical trials funded by pharmaceutical companies including AstraZeneca, Merck, Pfizer, Sanofi, and Janssen and investigator for clinical trials funded by IMI/Horizon2020 and ZonMw, with payments paid to her institution. She was a speaker at Sanofi sponsored symposium ESPID, payments paid to her institution. JW participated in the advisory board of Janssen RSV older adults and Sanofi advisory board with fees paid to UMCU. AP is part of EC IMI Programme RESCEU, payments paid to his institution. He has received grants from Gates, Wellcome, CEPI, MRC, NIHR, Serum Institute of India, AstraZeneca, and EC, with payments paid to his institution. Oxford University has entered into a partnership with AZ for development of COVID-19 vaccines. AP is a contributor to intellectual property licensed by Oxford University Innovation to AstraZeneca. AP is chair of the UK Department of Health and Social Care’s DHSC Joint Committee on Vaccination and Immunisation JCVI, NIHR Senior Investigator, member of the Academy of Medical Sciences AMS and was a member of WHO’s SAGE until January 2022. AP’s institution received funding from the European Commission’s IMI programme for the conduct of this study. Oxford University has entered a partnership with AstraZeneca for the development of COVID-19 vaccines. PO received honoraria GSK, Pfizer Inc, Sanofi Pasteur, Seqirus, Moderna and Janssen for participation in advisory boards and expert meetings and for acting as a speaker in congresses outside the scope of the submitted work. PO is also a principal investigator in the INFLAMMAGE trial co-funded by the Medical Research Council UK and GSK as part of the EMINENT consortium to promote inflammation research. He received grants from UKRI-MRC/DHSC NIHR Grant award MR/V027859/1, and UKRI-BEIS for human infection challenge with SARS-CoV-2 and had roles as school governor Sidcot, Somerset. LB has regular interaction with pharmaceutical and other industrial partners. He has not received personal fees or other personal benefits. UMCU has received major funding >€100,000 per industrial partner for investigator-initiated studies from AbbVie, MedImmune, AstraZeneca, Sanofi, Janssen, Pfizer, MSD and MeMed Diagnostics. UMCU has received major funding for the RSV GOLD study from the Bill and Melinda Gates Foundation. UMCU has received major funding as part of the public private partnership IMI-funded RESCEU and PROMISE projects with partners GSK, Novavax, Janssen, AstraZeneca, Pfizer and Sanofi. UMCU has received major funding from Julius Clinical for participating in clinical studies sponsored by MedImmune and Pfizer. UMCU received minor funding €1,000-25,000 per industrial partner for consultation and invited lectures by AbbVie, MedImmune, Ablynx, Bavaria Nordic, MabXience, GSK, Novavax, Pfizer, Moderna, AstraZeneca, MSD, Sanofi, Genzyme, Janssen. LB is the founding chairman of the ReSViNET Foundation. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Öner, Vernhes, Balla-Jhagjhoorsingh, Moureau, Crabbe, Salaun, Bastian, Thys, De Smedt, Ooft, Korsten, Adriaenssens, Coenen, Butler, Verheij, Drysdale, Wildenbeest, Pollard, Openshaw, Bont and Aerssens.)

Rationale: Respiratory syncytial virus (RSV) is a common global respiratory virus that is increasingly recognized as a major pathogen in frail older adults and as a cause of chronic obstructive pulmonary disease (COPD) exacerbations. There is no single test for RSV in adults that has acceptable diagnostic accuracy. Trials of RSV vaccines have recently shown excellent safety and efficacy against RSV in older adults; defining the frequency of RSV-related community infections and COPD exacerbations is important for vaccine deployment decisions. Objectives: This prospective study aimed to establish the frequency of outpatient-managed RSV-related exacerbations of COPD in two well-characterized patient cohorts using a combination of diagnostic methods. Methods: Participants were recruited at specialist clinics in London, United Kingdom, and Groningen, the Netherlands, beginning in 2017 and observed for three consecutive RSV seasons, during exacerbations, and at least twice yearly. RSV infections were detected by RT-PCR and serologic testing. Measurements and Main Results: A total of 377 patients with COPD attended 1,999 clinic visits and reported 310 exacerbations. There were 27 RSV-related exacerbations (8.7% of the total); of these, seven were detected only by PCR, 16 only by serology, and four by both methods. Increases in RSV-specific Nucleoprotein antibody were as sensitive as those in the antibody to Pre-Fusion or Post-Fusion for serodiagnosis of RSV-related exacerbations. Conclusions: RSV is associated with 8.7% of outpatient-managed COPD exacerbations in this study. Antibodies to RSV Nucleoprotein may have diagnostic value and are potentially important in a vaccinated population. The introduction of vaccines that prevent RSV is expected to benefit patients with COPD.

Background: There is no consensus on how to best quantify disease severity in infants with respiratory syncytial virus (RSV) and/or bronchiolitis; this lack of a sufficiently validated score complicates the provision of clinical care and, the evaluation of trials of therapeutics and vaccines. The ReSVinet score appears to be one of the most promising; however, it is too time consuming to be incorporated into routine clinical care. We aimed to develop and externally validate simplified versions of this score., Methods: Data from a multinational (the Netherlands, Spain, and United Kingdom) multicenter case-control study of infants with RSV were used to develop simplified versions of the ReSVinet score by conducting a grid search to determine the best combination of equally weighted parameters to maximize for the discriminative ability (measured by area under the receiver operating characteristic curve [AUROC]) across a range of outcomes (hospitalization, intensive care unit admission, ventilation requirement). Subsequently discriminative validity of the score for a range of secondary care outcomes was externally validated by secondary analysis of datasets from Rwanda and Colombia., Results: Three candidate simplified scores were identified using the development dataset; they were excellent (AUROC >0.9) at discriminating for a range of outcomes, and their performance was not significantly different from the original ReSVinet score despite having fewer parameters. In the external validation datasets, the simplified scores were moderate to excellent (AUROC, 0.7-1) across a range of outcomes. In all outcomes, except in a single dataset for predicting admission to the high-dependency unit, they performed at least as well as the original ReSVinet score., Conclusions: The candidate simplified scores developed require further external validation in larger datasets, ideally from resource-limited settings before any recommendation regarding their use., Competing Interests: Potential conflicts of interest . Y. L. has received funding from Wellcome Trust and GSK, outside the submitted work, and has received personal fees from Pfizer. S. B. D. has received honoraria from MSD and Sanofi for taking part in respiratory syncytial virus advisory boards and has provided consultancy and/or investigator roles in relation to product development for Janssen, AstraZeneca, Pfizer, Valneva, MSD, iLiAD, and Sanofi, with fees paid to St George's, University of London. J. G. W. participated in an advisory board for Janssen, with fees paid to the University Medical Center Utrecht. D. O. and J. A. are employees of Janssen Pharmaceutica. F. M. T. reports grants from Janssen, MSD, GSK, and AstraZeneca; personal fees from Ablynx, GSK, Pfizer, MSD, Moderna, AstraZeneca, Sanofi-Pasteur, Novavax, Seqirus, and Biofabri; nonfinancial support from GSK, Pfizer, MSD, and Seqirus; and trial fees paid to his institution from all these companies, except Biofabri. A. J. P. is chair of the UK Department of Health and Social Care's Joint Committee on Vaccination and Immunisation. The University of Oxford has entered into a partnership with AstraZeneca for the development of a coronavirus disease 2019 vaccine. L. B. has received funding through the University Medical Center Utrecht from AbbVie, Janssen, the Bill & Melinda Gates Foundation, Nutricia Danon, MeMed Diagnostics, GSK, AstraZeneca, Sanofi, Ablynx, Bavaria Nordic, MabXience, Novavax, and Pfizer. H. N. has received funding from Innovative Medicines Initiative, the National Institute for Health and Care Research, Icosavax and Pfizer and has received fees from GSK, AbbVie, AstraZeneca, Pfizer, Novavax, Sanofi, Merck, Icosavax and ReViral all paid to the insitution. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed, (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Respiratory syncytial virus (RSV) is a significant cause of infant morbidity and mortality worldwide. Most children experience at least one 1 RSV infection by the age of two 2 years, but not all develop severe disease. However, the understanding of genetic risk factors for severe RSV is incomplete. Consequently, we conducted a genome-wide association study of RSV severity., Methods: Disease severity was assessed by the ReSVinet scale, in a cohort of 251 infants aged 1 week to 1 year. Genotyping data were collected from multiple European study sites as part of the RESCEU Consortium. Linear regression models were used to assess the impact of genotype on RSV severity and gene expression as measured by microarray., Results: While no SNPs reached the genome-wide statistical significance threshold (P < 5 × 10-8), we identified 816 candidate SNPs with a P-value of <1 × 10-4. Functional annotation of candidate SNPs highlighted genes relevant to neutrophil trafficking and cytoskeletal functions, including LSP1 and RAB27A. Moreover, SNPs within the RAB27A locus significantly altered gene expression (false discovery rate, FDR P < .05)., Conclusions: These findings may provide insights into genetic mechanisms driving severe RSV infection, offering biologically relevant information for future investigations., Competing Interests: Potential conflicts of interest. F. M.-T. and P. J. M. O. have received honoraria from the GSK group of companies, Pfizer, Sanofi Pasteur, MSD, Seqirus, AstraZeneca, Moderna, and Janssen for taking part in advisory boards and expert meetings and for acting as a speaker in congresses outside the scope of the submitted work. F. M.-T. has also acted as principal investigator in randomized controlled trials of the aforementioned companies as well as Ablynx, Gilead, Regeneron, Roche, Abbott, Novavax, and MedImmune, with honoraria paid to his institution. S. B. D. has received honoraria from MSD and Sanofi for taking part in RSV advisory boards and has provided consultancy and/or investigator roles in relation to product development for Janssen, AstraZeneca, Pfizer, Moderna, Valneva, MSD, iLiAD, and Sanofi with fees paid to St George's, University of London. S. B. D. is a member of the UK Department of Health and Social Care's Joint Committee on Vaccination and Immunisation RSV subcommittee and Medicines and Healthcare Products Regulatory Agency's Paediatric Medicine Expert Advisory Group, but the reviews expressed herein do not necessarily represent any of those groups. A. J. P. is chair of the Department of Health and Social Care's Joint Committee on Vaccination and Immunisation. J. W. participated in the advisory board of Janssen and Sanofi with fees paid to University Medical Centre Utrecht and has been an investigator for clinical trials sponsored by pharmaceutical companies including AstraZeneca, Merck, Pfizer, Sanofi, and Janssen. All funds have been paid to University Medical Centre Utrecht. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Whereas most infants infected with respiratory syncytial virus (RSV) show no or only mild symptoms, an estimated 3 million children under five are hospitalized annually due to RSV disease. This study aimed to investigate biological mechanisms and associated biomarkers underlying RSV disease heterogeneity in young infants, enabling the potential to objectively categorize RSV-infected infants according to their medical needs. Immunophenotypic and functional profiling demonstrated the emergence of immature and progenitor-like neutrophils, proliferative monocytes (HLA-DR Low , Ki67+), impaired antigen-presenting function, downregulation of T cell response and low abundance of HLA-DR Low B cells in severe RSV disease. HLA-DR Low monocytes were found as a hallmark of RSV-infected infants requiring hospitalization. Complementary transcriptomics identified genes associated with disease severity and pointed to the emergency myelopoiesis response. These results shed new light on mechanisms underlying the pathogenesis and development of severe RSV disease and identified potential new candidate biomarkers for patient stratification., (© 2023 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

Introduction: The immune mechanisms supporting partial protection from reinfection and disease by the respiratory syncytial virus (RSV) have not been fully characterized. In older adults, symptoms are typically mild but can be serious in patients with comorbidities when the infection extends to the lower respiratory tract., Methods: This study formed part of the RESCEU older-adults prospective-cohort study in Northern Europe (2017-2019; NCT03621930) in which a thousand participants were followed over an RSV season. Peripheral-blood samples (taken pre-season, post-season, during illness and convalescence) were analyzed from participants who (i) had a symptomatic acute respiratory tract infection by RSV (RSV-ARTI; N=35) or (ii) asymptomatic RSV infection (RSV-Asymptomatic; N=16). These analyses included evaluations of antibody (Fc-mediated-) functional features and cell-mediated immunity, in which univariate and machine-learning (ML) models were used to explore differences between groups., Results: Pre-RSV-season peripheral-blood biomarkers were predictive of symptomatic RSV infection. T-cell data were more predictive than functional antibody data (area under receiver operating characteristic curve [AUROC] for the models were 99% and 76%, respectively). The pre-RSV season T-cell phenotypes which were selected by the ML modelling and which were more frequent in RSV-Asymptomatic group than in the RSV-ARTI group, coincided with prominent phenotypes identified during convalescence from RSV-ARTI (e.g., IFN-γ+, TNF-α+ and CD40L+ for CD4+, and IFN-γ+ and 4-1BB+ for CD8+)., Conclusion: The evaluation and statistical modelling of numerous immunological parameters over the RSV season suggests a primary role of cellular immunity in preventing symptomatic RSV infections in older adults., Competing Interests: Authors CV and AM were employed by the company Sanofi during the development of the study and own stock options in the company. Authors SB-J, AB, JA and DÖ were employed by the company Janssen Pharmaceutica NV. Authors SB-J, AB and JA own stocks from Johnson & Johnson. Authors MJ, BS, CL, and JD were employed by the company GSK, and BS and CL own stocks from the company. Author CL had submitted a patent application for COMPOSITIONS AND METHODS FOR IMPROVING THE IMMUNE RESPONSE TO SARS-COV2. During this time, he was a GSK representative as a co-leader for a subgroup in the Adventitious Virus Detection Technologies Interest Groups AVDTIG. Author SD has been an investigator for clinical trials of vaccines and antimicrobials for pharmaceutical companies including AstraZeneca, Merck, Pfizer, Valneva, Iliad, Sanofi, and Janssen, and previously sat on RSV advisory boards for Sanofi and Merck. Author JW was a member of Janssen and Sanofi advisory boards. She also worked closely together with author LB on many projects and clinical studies for which LB received grants. Author AP received grants from: Gates, Wellcome, MRC, NIHR and European Commission IMI RESCEU. During this time the laboratory assays were provided by GSK. Author AP is a contributor to intellectual property licensed by Oxford University Innovation to AstraZeneca. He also received consulting fees from Shionogi. He was chair of DHSC’s Joint Committee on Vaccination and Immunisation and also a member of WHOs SAGE until 2022. Author PO received the RESCEU EU IMI award and consulting fees from: GSK, Moderna, Janssen, Seqirus and Pfizer. He also received payments or honoraria from Moderna, Medscape and support for attending meetings for Moderna. During this project he was also a school governor for Sidcot, Somerset. He received grants from UKRI and MRC EMINENT. Author LB has regular interaction with pharmaceutical and other industrial partners. UMCU has received funding for investigator-initiated studies from AbbVie, MedImmune, AstraZeneca, Sanofi, Janssen, Pfizer, MSD and MeMed Diagnostics. UMCU has received funding for the RSV GOLD study from the Bill and Melinda Gates Foundation. UMCU has received funding as part of the public private partnership IMI funded RESCEU and PROMISE projects with partners GSK, Novavax, Janssen, AstraZeneca, Pfizer and Sanofi. UMCU has received funding by Julius Clinical for participating in clinical studies sponsored by MedImmune and Pfizer. UMCU received funding for consultation and invited lectures by AbbVie, MedImmune, Ablynx, Bavaria Nordic, MabXience, GSK, Novavax, Pfizer, Moderna, Astrazeneca, MSD, Sanofi, Genzyme, Janssen. Author LB is the founding chairman of the ReSViNET Foundation. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Salaun, De Smedt, Vernhes, Moureau, Öner, Bastian, Janssens, Balla-Jhagjhoorsingh, Aerssens, Lambert, Coenen, Butler, Drysdale, Wildenbeest, Pollard, Openshaw and Bont.)

Background: Respiratory syncytial virus (RSV) infections occur in human populations around the globe, causing disease of variable severity, disproportionately affecting infants and older adults (>65 years of age). Immune responses can be protective but also contribute to disease. Experimental studies in animals enable detailed investigation of immune responses, provide insights into clinical questions, and accelerate the development of passive and active vaccination. We aimed to review the role of antibody and T-cell responses in relation to RSV disease severity in animals., Methods: Systematic review and meta-analysis of animal studies examining the association between T-cell responses/phenotype or antibody titers and severity of RSV disease. The PubMed, Zoological Record, and Embase databases were screened from January 1980 to May 2018 to identify animal studies of RSV infection that assessed serum antibody titer or T lymphocytes with disease severity as an outcome. Sixty-three studies were included in the final review., Results: RSV-specific antibody appears to protect from disease in mice, but such an effect was less evident in bovine RSV. Strong T-cell, Th1, Th2, Th17, CD4/CD8 responses, and weak Treg responses accompany severe disease in mice., Conclusions: Murine studies suggest that measures of T-lymphocyte activity (particularly CD4 and CD8 T cells) may be predictive biomarkers of severity. Further inquiry is merited to validate these results and assess relevance as biomarkers for human disease., Competing Interests: Potential conflicts of interest. S. D. acts on behalf of St George’s, University of London as an investigator on studies sponsored and/or funded by vaccine manufacturers including Janssen and MedImmune. He receives no personal financial benefit for this work. A. J. P. is Chair of the United Kingdom DHSC JCVI and the European Medicines Agency (EMA) Scientific Advisory Group on Vaccines and is a member of the WHO’s Strategic Advisory Group of Experts on Immunization. P. O. is the president of the International RSV Society and has been a member of scientific advisory panels for Janssen (J&J), Bavarian Nordic, Pfizer, and Cepheid. He holds a grant award with co-funding from the Medical Research Council UK and GSK (the EMINENT consortium). A. J. P. and P. O. are NIHR Senior Investigators. J. A. and D. Ö. are employees of Janssen Pharmaceutica NV. All other authors report no potential conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Respiratory syncytial virus (RSV) causes substantial morbidity and mortality in infants and young children worldwide. Here we evaluated host demographic and viral factors associated with RSV disease severity in 325 RSV-infected infants under 1 year of age from 3 European countries during 2017-2020. Younger infants had a higher clinical severity (ReSViNET) score and were more likely to require hospitalization, intensive care, respiratory support, and/or mechanical ventilation than older infants (<3 months vs 3 to <6 months and 3 to <6 months vs ≥6 months). Older age (≥6 months vs <3 months), higher viral load, and RSV-A were associated with a greater probability of fever. RSV-A and RSV-B caused similar disease severity and had similar viral dynamics. Infants with a more severe RSV infection, demonstrated by having a higher ReSViNET score, fever, and requiring hospitalization and intensive care, were more likely to have developed subsequent wheezing at 1 year of age., Clinical Trials Registration: NCT03756766., Competing Interests: Potential conflicts of interest. D. Ö. and J. A. are employees of Janssen Pharmaceutica NV. O. G. is an employee of the GSK group of companies. H. N. has received funding from Sanofi and Pfizer; and honoraria from Sanofi, Abbvie, Janssen, ReViral, and Novavax. F. M.-T. has received honoraria from GSK, Pfizer Inc, Sanofi Pasteur, MSD, Seqirus, and Janssen for taking part in advisory boards and expert meetings and for acting as a speaker in congresses outside the scope of the submitted work; has acted as principal investigator in randomized controlled trials of GSK, Pfizer Inc, Sanofi Pasteur, MSD, Seqirus, Janssen, Ablynx, Regeneron, Roche, Abbott, Novavax, and MedImmune, with honoraria paid to his institution; and receives support for his research activities from the Instituto de Salud Carlos III (Proyecto de Investigación en Salud, Acción Estratégica en Salud): Fondo de Investigación Sanitaria (FIS; PI1601569/PI1901090) del Plan Nacional de I + D + I and Fondos FEDER. S. B. D. has been an investigator for clinical trials of vaccines and antimicrobials for pharmaceutical companies including AstraZeneca, Merck, and Janssen; and sits on an RSV advisory board for Sanofi Pasteur. A. J. P. is a NIHR Senior Investigator with funding from the British Research Council. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Human respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infection in young children globally, but little is known about within-host RSV diversity. Here, we characterised within-host RSV populations using deep-sequencing data from 319 nasopharyngeal swabs collected during 2017-2020. RSV-B had lower consensus diversity than RSV-A at the population level, while exhibiting greater within-host diversity. Two RSV-B consensus sequences had an amino acid alteration (K68N) in the fusion (F) protein, which has been associated with reduced susceptibility to nirsevimab (MEDI8897), a novel RSV monoclonal antibody under development. In addition, several minor variants were identified in the antigenic sites of the F protein, one of which may confer resistance to palivizumab, the only licensed RSV monoclonal antibody. The differences in within-host virus populations emphasise the importance of monitoring for vaccine efficacy and may help to explain the different prevalences of monoclonal antibody-escape mutants between the two subgroups., (© 2021. The Author(s).)

In some cases of sexual assault that are not reported to judicial authorities within a certain time, it is important to detect and identify seminal stains on laundered fabrics. In this study, we aimed to reveal the effect of the time from staining to laundering on the detectability and identification of seminal stains on laundered clothes. A total of 180 pieces of fabric (four different colours and five different types) were stained with seminal fluids, and three different lag times (12 hours, 1 week and 1 month) from staining to laundering were used. Three different laundering protocols were applied to these fabrics after staining. The built-in camera of the Mobile Multispectral UV-VIS-IR Imaging System® was used to take photos (1260 in total) of the stains with seven different wavelength and filter options, and the obtained images were evaluated. The Seratec® PSA Semiquant test was used to analyse the presence of prostate-specific antigen (PSA) in the seminal stains laundered after different lag times. We observed that in examining with the forensic light source (FLS) system, the time from staining to laundering affected the detectability of seminal stains on pieces of cloth. The best fluorescence was obtained in the examination of semen-stained fabric with FLS, particularly when the fabric was not laundered for one month after staining. On the other hand, the time from staining to laundering had a more limited effect on PSA test positivity than on the results of the examination with FLS.

Background: Respiratory syncytial virus (RSV) infection in older adults is recognised as an important health issue. We aimed to assess the community burden of RSV in Europe in older adults aged ≥60 years., Methods: This international, prospective, observational cohort study is part of work by the REspiratory Syncytial virus Consortium in EUrope (RESCEU). Participants were recruited through general practitioners' (GPs) offices before two independent RSV seasons. Participants reported weekly about symptoms of acute respiratory tract infection (ARTI) during one RSV season. ARTI patients were tested for RSV during home visits and completed a daily symptom diary. RSV illness included PCR-confirmed ARTI and those showing seroconversion over the season. RSV ARTI was based on PCR alone (ClinicalTrials.gov, NCT03621930)., Results: We recruited 1040 participants (527 in season 2017-2018 and 513 in season 2018-2019) with a median age of 75 years (range 60-100 years). Of these, 1023 (99%) lived independently at home at baseline. RSV illness incidence was 22 out of 527 (4.2%) and 37 out of 513 (7.2%) in the respective seasons. RSV illness did not affect frailty or cardiopulmonary status during the course of the study. No patients were hospitalised or died from RSV illness. In the 36 patients with PCR confirmed RSV ARTI, symptom duration averaged 19 days, while a doctor's visit took place in 11 out of 36 cases (31%). RSV ARTI could not be differentiated clinically from all other ARTIs based on symptoms., Conclusion: This European study showed that RSV is prevalent in community-dwelling older adults and rarely causes severe disease. This suggests that watchful waiting, using a continuity of care approach to identify those who do need more intensive care, is often justified when RSV is suspected in family practice., Competing Interests: Conflict of interest: K. Korsten has nothing to disclose. Conflict of interest: N. Adriaenssens has nothing to disclose. Conflict of interest: S. Coenen reports grants and non-financial support from European Union (EU) Horizon 2020 research and innovation programme and the European Federation of Pharmaceutical Industries and Associations (EFPIA) Innovative Medicines Initiative 2 (IMI-2) Joint Undertaking (grant: 116019), during the conduct of the study. Conflict of interest: C. Butler reports grants from the National Institute for Health Research (NIHR) (as NIHR Senior Investigator), grants from the EU Horizon 2020 programme to support the study, grants from the NIHR Health Protection Research Unit on Health Care Associated Infections and Antimicrobial Resistance, grants from the NIHR Health for the MedTech and In Vitro Diagnostics Cooperative for innovative diagnostics and monitoring technology to enhance community healthcare, during the conduct of the study; personal fees for advisory board work from Pfizer and Roche Molecular Systems; and grants from Roche Molecular Diagnostics. Conflict of interest: B. Ravanfar has nothing to disclose. Conflict of interest: H. Rutter has nothing to disclose. Conflict of interest: J. Allen has nothing to disclose. Conflict of interest: A. Falsey reports grants from Janssen, Merck, Sharpe and Dohme, and Pfizer, as well as non-financial support for meeting attendance from Sanofi Pasteur, outside the submitted work. Conflict of interest: J-Y. Pirçon is an employee of GlaxoSmithKline Vaccines. Conflict of interest: O. Gruselle is an employee of GlaxoSmithKline. Conflict of interest: V. Pavot is an employee of Sanofi Pasteur. Conflict of interest: C. Vernhes is an employee of Sanofi Pasteur. Conflict of interest: S. Balla-Jhagjhoorsingh is an employee of Janssen Vaccines & Prevention. Conflict of interest: D. Öner is an employee of Janssen Pharmaceutica NV and reports grants from the IMI-2 Joint Undertaking (grant: 116019), during the conduct of the study. Conflict of interest: G. Ispas is an employee of Janssen Pharmaceutica NV. Conflict of interest: J. Aerssens is an employee of Janssen Pharmaceutica NV. Conflict of interest: V. Shinde has nothing to disclose. Conflict of interest: T. Verheij reports grants from Janssen Pharmaceuticals, Becton Dickinson, Abbott and Biomerieux, outside the submitted work. Conflict of interest: L. Bont has regular interaction with pharmaceutical and other industrial partners. He has not received personal fees or other personal benefits; however, University Medical Center Utrecht has received major funding for investigator-initiated studies from AbbVie, MedImmune, Janssen, the Bill and Melinda Gates Foundation, Nutricia (Danone) and MeMed Diagnostics; has received major cash or in kind funding as part of the public–private partnership, IMI-2 funded REspiratory Syncytial virus Consortium in EUrope (RESCEU) project from GlaxoSmithKline, Novavax, Janssen, AstraZeneca, Pfizer and Sanofi; has received major funding from Julius Clinical for participating in the INFORM study sponsored by MedImmune; has received minor funding for participation in trials by Regeneron and Janssen from 2015–2017; and has received minor funding for consultation and invited lectures by AbbVie, MedImmune, Ablynx, Bavaria Nordic, MabXience, Novavax, Pfizer and Janssen. L. Bont is also the founding chairman of the ReSViNET Foundation. Conflict of interest: J. Wildenbeest has nothing to disclose., (Copyright © ERS 2021.)

Background: Clinical manifestations of respiratory syncytial virus (RSV) infection vary widely from mild, self-limiting illness to severe life-threatening disease. There are gaps in knowledge of biomarkers to objectively define severe disease and predict clinical outcomes., Methods: A systematic search was performed, 1945-March 2019 in databases Ovid Medline, Embase, Global health, Scopus, and Web of Science. Risk of bias was assessed using the Cochrane tool., Results: A total of 25 132 abstracts were screened and studies were assessed for quality, risk of bias, and extracted data; 111 studies met the inclusion criteria. RSV severity was correlated with antibody titers, reduced T and B cells, dysregulated innate immunity, neutrophil mobilization to the lungs and blood, decreased Th1 response, and Th2 weighted shift. Microbial exposures in respiratory tract may contribute to neutrophil mobilization to the lungs of the infants with severe RSV compared with mild RSV disease., Conclusions: Although a wide range of biomarkers have been associated with RSV disease severity, robust validated biomarkers are lacking. This review illustrates the broad heterogeneity of study designs and high variability in the definition of severe RSV disease. Prospective studies are required to validate biomarkers. Additional research investigating epigenetics, metabolomics, and microbiome holds promise for novel biomarkers., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Respiratory syncytial virus (RSV) is the leading viral pathogen associated with acute lower respiratory tract infection and hospitalization in children < 5 years of age worldwide. While there are known clinical risk factors for severe RSV infection, the majority of those hospitalized are previously healthy infants. There is consequently an unmet need to identify biomarkers that predict host response, disease severity, and sequelae. The primary objective is to identify biomarkers of severe RSV acute respiratory tract infection (ARTI) in infants. Secondary objectives include establishing biomarkers associated with respiratory sequelae following RSV infection and characterizing the viral load, RSV whole-genome sequencing, host immune response, and transcriptomic, proteomic, metabolomic and epigenetic signatures associated with RSV disease severity. Six hundred thirty infants will be recruited across 3 European countries: the Netherlands, Spain, and the United Kingdom. Participants will be recruited into 2 groups: (1) infants with confirmed RSV ARTI (includes upper and lower respiratory tract infections), 500 without and 50 with comorbidities; and (2) 80 healthy controls. At baseline, participants will have nasopharyngeal, blood, buccal, stool, and urine samples collected, plus complete a questionnaire and 14-day symptom diary. At convalescence (7 weeks ± 1 week post-ARTI), specimen collection will be repeated. Laboratory measures will be correlated with symptom severity scores to identify corresponding biomarkers of disease severity., Clinical Trials Registration: NCT03756766., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Carbon nanotubes (CNTs) except MWCNT-7 have been classified as Group 3 ["Not classifiable as to its carcinogenicity to humans"] by the IARC. Despite considerable mechanistic evidence in vitro/in vivo, the classification highlights a general lack of data, especially among humans. In our previous study, we reported epigenetic changes in the MWCNT exposed workers. Here, we evaluated whether MWCNT can also cause alterations in aging related features including relative telomere length (TL) and/or mitochondrial copy number (mtDNAcn). Relative TL and mtDNAcn were measured on extracted DNA from peripheral blood from MWCNT exposed workers (N = 24) and non-exposed controls (N = 43) using a qPCR method. A higher mtDNAcn and longer TL were observed in MWCNT exposed workers when compared to controls. Independent of age, sex, smoking behavior, alcohol consumption and BMI, MWCNT-exposure was associated with an 18.30 % increase in blood TL (95 % CI: 7.15-30.62 %; p = 0.001) and 35.21 % increase in mtDNAcn (95 % CI: 19.12-53.46 %). Our results suggest that exposure to MWCNT can induce an increase in the mtDNAcn and TL; however, the mechanistic basis or consequence of such change requires further experimental studies., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Introduction: Inhalation of asbestos induces lung cancer via different cellular mechanisms. Together with the increased production of carbon nanotubes (CNTs) grows the concern about adverse effects on the lungs given the similarities with asbestos. While it has been established that CNT and asbestos induce epigenetic alterations, it is currently not known whether alterations at epigenetic level remain stable after withdrawal of the exposure. Identification of DNA methylation changes after a low dose of CNT and asbestos exposure and recovery can be useful to determine the fibre/particle toxicity and adverse outcome., Methods: Human bronchial epithelial cells (16HBE) were treated with a low and non-cytotoxic dose (0.25 µg/ml) of multi-walled carbon nanotubes (MWCNTs-NM400) or single-walled carbon nanotubes (SWCNTs-SRM2483) and 0.05 µg/ml amosite (brown) asbestos for the course of four weeks (sub-chronic exposure). After this treatment, the cells were further incubated (without particle/fibre) for two weeks, allowing recovery from the exposure (recovery period). Nuclear depositions of the CNTs were assessed using femtosecond pulsed laser microscopy in a label-free manner. DNA methylation alterations were analysed using microarrays that assess more than 850 thousand CpG sites in the whole genome., Results: At non-cytotoxic doses, CNTs were noted to be incorporated with in the nucleus after a four weeks period. Exposure to MWCNTs induced a single hypomethylation at a CpG site and gene promoter region. No change in DNA methylation was observed after the recovery period for MWCNTs. Exposure to SWCNTs or amosite induced hypermethylation at CpG sites after sub-chronic exposure which may involve in 'transcription factor activity' and 'sequence-specific DNA binding' gene ontologies. After the recovery period, hypermethylation and hypomethylation were noted for both SWCNTs and amosite. Hippocalcinlike 1 (HPCAL1), protease serine 3 (PRSS3), kallikrein-related peptidase 3 (KLK3), kruppel like factor 3 (KLF3) genes were hypermethylated at different time points in either SWCNT-exposed or amosite-exposed cells., Conclusion: These results suggest that the specific SWCNT (SRM2483) and amosite fibres studied induce hypo- or hypermethylation on CpG sites in DNA after very low-dose exposure and recovery period. This effect was not seen for the studied MWCNT (NM400)., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Carbon nanotubes (CNTs) are nanoscale tube-shaped carbon materials used in many industrial areas. Their fiber shape has caused concerns about their toxicity given their structural similarity with asbestos. The aim here was to elucidate the effect of CNTs and asbestos exposure on global DNA and RNA methylation and the methylation of genes associated with cell cycle, inflammation, and DNA damage processes in human lung cells. Human bronchial epithelial cells (16HBE14o-) were exposed for 24 h to 25 and 100 μg/mL CNTs (single-walled CNTs [SWCNTs] and multiwalled CNTs [MWCNTs]) and 2.5 μg/mL asbestos (chrysotile, amosite, and crocidolite). Global DNA and RNA (hydroxy)methylation to cytosines was measured by a validated liquid chromatography tandem-mass spectrometry method. Global RNA methylation to adenines was measured by a colorimetric ELISA-like assay. Gene-specific DNA methylation status at certain cytosine-phosphate-guanine (CpG) sites of cyclin-dependent kinase inhibitor 1A ( CDKN1A), serine/threonine kinase ( ATM), and TNF receptor-associated factor 2 ( TRAF2) were analyzed by using bisulfite pyrosequencing technology. Only MWCNT-exposed cells showed significant global DNA hypomethylation of cytosine and global RNA hypomethylation of adenosine. SWCNT, MWCNT, and amosite exposure decreased DNA methylation of CDKN1A. ATM methylation was affected by chrysotile, SWCNT, and MWCNT. However, SWCNT exposure led to DNA hypermethylation of TRAF2. These findings contribute to further understanding of the effect of CNTs on different carcinogenic pathways.

Inhalation exposure to asbestos is associated with lung and pleural diseases in humans and remains a major public health issue worldwide. Human bronchial epithelial cells (16HBE) were exposed to UICC amosite, crocidolite and chrysotile. Cytotoxicity, genotoxicity, global DNA methylation on cytosine residues (using LC-MS/MS) were investigated at different doses (2.5-100 μg/ml). Gene-specific DNA methylation alterations at the whole genome were investigated using a microarray that interrogates >450 thousand CpG sites. Subsequently, gene functional analyses (KEGG pathway, Gene Ontology and functional classification) were performed on genes with differentially methylated gene promoters. At non-cytotoxic doses, global DNA methylation was altered after 24 h exposure to amosite and crocidolite (>2.5 μg/ml). Exposure to amosite and crocidolite (amphibole type asbestos) induced both hypomethylation and hypermethylation at single CpG site and gene promoter levels whereas exposure to chrysotile (serpentine type asbestos) induced hypomethylation at the gene promoter level. Gene functional classification analyses revealed that all types of asbestos fibres induce alterations on GO-clusters i.e. on regulation of Rho-protein signal transduction, nucleus, (e.g. homeobox genes), ATP-binding function and extracellular region (e.g. WNT-group of genes). These differentially methylated genes might contribute to asbestos-related diseases in bronchial cells., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Recent studies have identified carbon nanotube (CNT)-induced epigenetic changes as one of the key players in patho-physiological response. In the present study, we investigated whether CNT exposure is associated with epigenetic changes in human bronchial epithelial cells (16 HBE), in vitro . We focused on global DNA methylation, methylation of LINE-1 elements and promoter sequence of twelve functionally important genes ( SKI, DNMT1, HDAC4 , NPAT, ATM, BCL2L11, MAP3K10, PIK3R2, MYO1C, TCF3, FGFR 1 and AGRN ). Additionally, we studied the influence of CNT exposure on miRNA expression. Using a LC-MS/MS method and pyrosequencing for LINE-1 , we observed no significant changes in global DNA methylation (%) between the concentrations of multi-walled and single-walled CNT (MWCNT and SWCNT, respectively). Significant changes in sequence-specific methylation was observed in at least one CpG site for DNMT1 (SWCNT), HDAC4 (MWCNT), NPAT/ATM (MWCNT and SWCNT), MAP3K10 (MWCNT), PIK3R2 (MWCNT and SWCNT) and MYO1C (SWCNT). While changes in DNA methylation of the genes were relatively small, these changes were associated with changes in RNA expression, especially for MWCNT. However, the study did not reveal any significant alteration in the miRNA expression, associated with MWCNT and SWCNT exposure. Based on our results, mainly MWCNT influence DNA methylation and expression of the studied genes and could have significant impact on several critical cellular processes., Competing Interests: CONFLICTS OF INTEREST The authors do not have any conflicts of interest.

Background: Subtle DNA methylation alterations mediated by carbon nanotubes (CNTs) exposure might contribute to pathogenesis and disease susceptibility. It is known that both multi-walled carbon nanotubes (MWCNTs) and single-walled carbon nanotubes (SWCNTs) interact with nucleus. Such, nuclear-CNT interaction may affect the DNA methylation effects. In order to understand the epigenetic toxicity, in particular DNA methylation alterations, of SWCNTs and short MWCNTs, we performed global/genome-wide, gene-specific DNA methylation and RNA-expression analyses after exposing human bronchial epithelial cells (16HBE14o- cell line). In addition, the presence of CNTs on/in the cell nucleus was evaluated in a label-free way using femtosecond pulsed laser microscopy., Results: Generally, a higher number of SWCNTs, compared to MWCNTs, was deposited at both the cellular and nuclear level after exposure. Nonetheless, both CNT types were in physical contact with the nuclei. While particle type dependency was noticed for the identified genome-wide and gene-specific alterations, no global DNA methylation alteration on 5-methylcytosine (5-mC) sites was observed for both CNTs. After exposure to MWCNTs, 2398 genes were hypomethylated (at gene promoters), and after exposure to SWCNTs, 589 CpG sites (located on 501 genes) were either hypo- (N = 493 CpG sites) or hypermethylated (N = 96 CpG sites). Cells exposed to MWCNTs exhibited a better correlation between gene promoter methylation and gene expression alterations. Differentially methylated and expressed genes induced changes (MWCNTs > SWCNTs) at different cellular pathways, such as p53 signalling, DNA damage repair and cell cycle. On the other hand, SWCNT exposure showed hypermethylation on functionally important genes, such as SKI proto-oncogene (SKI), glutathione S-transferase pi 1 (GTSP1) and shroom family member 2 (SHROOM2) and neurofibromatosis type I (NF1), which the latter is both hypermethylated and downregulated., Conclusion: After exposure to both types of CNTs, epigenetic alterations may contribute to toxic or repair response. Moreover, our results suggest that the observed differences in the epigenetic response depend on particle type and differential CNT-nucleus interactions.

Akın DF, Aşlar-Öner D, Kürekçi E, Akar N. Frequency of thiopurine S-methyltransferase gene variations in Turkish children with acute leukemia. Turk J Pediatr 2018; 60: 147-152. In this study we aim to determine the genotype distribution and allele frequencies of common TPMT (*2, *3A, *3B and *3C) polymorphisms in Turkish children with acute leukemia. The study population consisted of 169 patients aged between 1 and 15 years who were admitted to Losante Pediatric Hematology and Children`s Hospital with the diagnosis of acute leukemia. Genotyping of TPMT polymorphisms was screened with real-time PCR using fluorescence melting curve detection analysis. We found that the frequencies of four allelic variants of TPMT are *2 (238 G > C) (0,0%), *3A (460G > A and 719A > G) (1.7%), *3B (460G > A) (1,7%) and *3C (719A > G) (2.4%). Frequency of TPMT alleles increases the efficacy of leukemia treatment. Thus, TPMT genotyping can be useful for optimizing 6-MP therapy.