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SARS-CoV-2 can infect wildlife, and SARS-CoV-2 variants of concern might expand into novel animal reservoirs, potentially by reverse zoonosis. White-tailed deer and mule deer of North America are the only deer species in which SARS-CoV-2 has been documented, raising the question of whether other reservoir species exist. We report cases of SARS-CoV-2 seropositivity in a fallow deer population located in Dublin, Ireland. Sampled deer were seronegative in 2020 when the Alpha variant was circulating in humans, 1 deer was seropositive for the Delta variant in 2021, and 12/21 (57%) sampled deer were seropositive for the Omicron variant in 2022, suggesting host tropism expansion as new variants emerged in humans. Omicron BA.1 was capable of infecting fallow deer lung type-2 pneumocytes and type-1–like pneumocytes or endothelial cells ex vivo. Ongoing surveillance to identify novel SARS-CoV-2 reservoirs is needed to prevent public health risks during human–animal interactions in periurban settings.

Nairobi Sheep Disease (NSD) is a typical tick-borne syndrome characterized by severe hemorrhagic gastroenteritis, spontaneous abortion, and a high case fatality rate in small ruminants. The pathogenic agent, Nairobi sheep disease virus (NSDV), has also been associated with human infections, indicating its possible zoonotic potential. Prior to this study, NSDV has been detected from ticks collected in Jilin, Hubei, and Liaoning provinces in China. In the present study, a total of 343 ticks (Haemaphysalis longicornis) were collected in Shandong province, China in 2020, and pooled into 16 libraries. Analysis of the meta-transcriptomic sequencing data identified NSDV strains SDWL07, SDWL08, and SDWL16 from three pools. The SDWL07 and SDWL16 strains were detected from unfed ticks, while SDWL08 was detected from cattle-feeding ticks. Phylogenetic analyses showed higher sequence identities between the three strains and other Chinese NSDV strains than those from India and Kenya. Phylogenetic analyses also revealed that they clustered together and fell within the China lineage, suggesting no potential genetic reassortment among them. In summary, this is the first report of the identification of NSDV in Shandong province, highlighting the continually expanding endemic regions of this pathogen. Surveillance of NSDV should be intensified in China, especially in areas where H. longicornis is endemic.

Human enteroviruses (EVs) represent a global public health concern due to their association with a range of serious pediatric illnesses. Despite the high morbidity and mortality exerted by EVs, no broad-spectrum antivirals are currently available. Herein, we presented evidence that doxycycline can inhibit in vitro replication of various neurotropic EVs, including enterovirus A71 (EV-A71), enterovirus D68 (EV-D68), and coxsackievirus (CV)-A6, in a dose-dependent manner. Further investigations indicated that the drug primarily acted at the post-entry stage of virus infection in vitro, with inhibitory effects reaching up to 89 % for EV-A71 when administered two hours post-infection. These findings provide valuable insights for the development of antiviral drugs against EV infections.

Background: The Cardiac Arrest Registry to Enhance Survival (CARES) was created in 2004 in collaboration with the Centers for Disease Control and Prevention (CDC) and Emory University School of Medicine’s Department of Emergency Medicine. The registry allows local communities to benchmark their performance, enhance the quality of care, and increase survival rates for out-of-hospital cardiac arrest (OHCA). Methods/design: CARES enrolls patients who experience a non-traumatic, EMS-treated OHCA. For each case, data is collected from three sources: 911 call center data, EMS data, and hospital data. CARES data is de-identified and stored in a secured web-based cloud platform and maintains confidentiality throughout the process. CARES data is subjected to an internal auditing system that oversees both local and regional levels. The variables in CARES adhere with the Utstein style reporting system and the National EMS Information System (NEMSIS) standard. Discussion: As of 2023, CARES captures data from a population base of over 178 million people which accounts for 53% of the total U.S. population. Over the past two decades, CARES has consistently been a part of public health surveillance for OHCA and serves as a quality improvement tool to improve cardiac arrest outcomes. Moreover, CARES commits to facilitate observational research on OHCA, continues to modernize its software platform, and comprehensively expands its coverage for the entire U.S.

During April–July 2022, outbreaks of severe acute hepatitis of unknown etiology (SAHUE) were reported in 35 countries. Five percent of cases required liver transplantation, and 22 patients died. Viral metagenomic studies of clinical samples from SAHUE cases showed a correlation with human adenovirus F type 41 (HAdV-F41) and adeno-associated virus type 2 (AAV2). To explore the association between those DNA viruses and SAHUE in children in Ireland, we quantified HAdV-F41 and AAV2 in samples collected from a wastewater treatment plant serving 40% of Ireland’s population. We noted a high correlation between HAdV-F41 and AAV2 circulation in the community and SAHUE clinical cases. Next-generation sequencing of the adenovirus hexon in wastewater demonstrated HAdV-F41 was the predominant HAdV type circulating. Our environmental analysis showed increased HAdV-F41 and AAV2 prevalence in the community during the SAHUE outbreak. Our findings highlight how wastewater sampling could aid in surveillance for respiratory adenovirus species.

Background and Objectives Primary cutaneous leiomyosarcoma (cLMS), a rare, typically intradermal tumor, has previously been reported to exhibit an indolent course of disease with zero-to-low risk of local recurrence or distant metastasis. This study seeks to evaluate recurrence and survival of cLMS patients through study of its clinicopathologic and treatment characteristics. Methods All patients included underwent resection of primary cLMS at this institution between 2006 and 2019. A retrospective cohort study analysis of clinicopathologic characteristics, treatment, recurrence, and overall survival was performed. Data was assessed through descriptive statistics and outcome measures assessed by Cox proportional models and log-rank tests. Results Eighty-eight patients with cLMS were evaluated. The majority were men (n = 68, 77%) and Caucasian (n = 85, 97%), with median age at diagnosis of 66 years (range 20–96). 65% of tumors were located on the extremities, with a median size of 1.3 cm (range .3–15). Assessment revealed low (n = 41, 47%), intermediate (n = 29, 33%), and high (n = 18, 20%) grade tumors, demonstrating extension into subcutaneous tissue in 38/60 (60%), with 3 patients exhibiting extension into muscle (3%). All underwent resection as primary treatment with median 1 cm margins (range .5–2). With median follow-up of 27.5 months (IQR 8–51; range 1–131), no low-grade cases had recurrence or death while there was a recurrence rate of 19.1% (9/47) and death rate of 8.5% (4/47) in intermediate- to high-grade cases. Conclusions Primary tumor resection of cLMS provides excellent local control for low-grade tumors as no low-grade cases experienced recurrence. For patients with intermediate- to high-grade tumors, there is potential for local recurrence, distant metastasis, and death, and therefore surveillance following treatment is encouraged.

In 2021, twenty children exhibiting influenza-like illnesses were reported from a kindergarten in Shandong Province, China. Eleven genomes of Coxsackievirus A4 (CV-A4) were obtained from the pediatric cases, sharing

Genitourinary (GU) melanoma is a rare presentation of melanoma accounting for approximately 0.5% of all melanomas. GU melanomas include primary melanomas of the vulva, vagina, uterine cervix, ovary, penis, scrotum, urethra, bladder, ureter, and kidney. These melanomas are often diagnosed in advanced stages and stigma is thought to contribute to delays in presentation. As the likely diagnosing provider, it is imperative that dermatologists, urologists, and gynecologists are aware of these uncommon sites of presentation. While there have been major advances in the treatment of melanomas as a whole in the last 10 years, their applications to GU melanomas have often been overlooked. GU melanomas have not been included in many of the major phase III clinical trials which brought contemporary advanced treatments to market and the prognoses for GU melanomas remain poor. Due to the rarity of GU melanomas, much of the literature provides generalized recommendations across multiple different organs affected by GU melanomas or omits certain topics, making it difficult to appreciate the fundamentals of the individual presentations. This review aimed to provide background information on the pathogenesis and epidemiology of the different sites of GU melanomas and categorize data specific to the presentation, staging, treatment, and prognosis of each type of GU melanoma to guide the clinician. It was also meant to encourage a multidisciplinary approach to the management of these patients as it spans the expertise of surgical oncologists, medical oncologists, radiation oncologist, dermatologists, urologists, and gynecologists.

Summary: The impairment of antibody-mediated immunity is a major factor associated with fatal cases of severe fever with thrombocytopenia syndrome (SFTS). By collating the clinical diagnosis reports of 30 SFTS cases, we discovered the overproliferation of monoclonal plasma cells (MCP cells, CD38+cLambda+cKappa−) in bone marrow, which has only been reported previously in multiple myeloma. The ratio of CD38+cLambda+ versus CD38+cKappa+ in SFTS cases with MCP cells was significantly higher than that in normal cases. MCP cells presented transient expression in the bone marrow, which was distinctly different from multiple myeloma. Moreover, the SFTS patients with MCP cells had higher clinical severity. Further, the overproliferation of MCP cells was also observed in SFTS virus (SFTSV)-infected mice with lethal infectious doses. Together, SFTSV infection induces transient overproliferation of monoclonal lambda-type plasma cells, which have important implications for the study of SFTSV pathogenesis, prognosis, and the rational development of therapeutics.

BackgroundDysregulated immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are thought to underlie the progression of coronavirus disease 2019 (COVID-19) to severe disease. We sought to determine whether early host immune-related gene expression could predict clinical progression to severe disease.MethodsWe analysed the expression of 579 immunological genes in peripheral blood mononuclear cells taken early after symptom onset using the NanoString nCounter and compared SARS-CoV-2 negative controls with SARS-CoV-2 positive subjects with mild (SARS+ Mild) and Moderate/Severe disease to evaluate disease outcomes. Biobanked plasma samples were also assessed for type I (IFN-α2a and IFN-β), type II (IFN-γ) and type III (IFN-λ1) interferons (IFNs) as well as 10 additional cytokines using multiplex immunoassays.ResultsWe identified 19 significantly deregulated genes in 62 SARS-CoV-2 positive subject samples within 5 days of symptom onset and 58 SARS-CoV-2 negative controls and found that type I interferon (IFN) signalling (MX1, IRF7, IFITM1, IFI35, STAT2, IRF4, PML, BST2, STAT1) and genes encoding proinflammatory cytokines (TNF, TNFSF4, PTGS2 and IL1B) were upregulated in both SARS+ groups. Moreover, we found that FCER1, involved in mast cell activation, was upregulated in the SARS+ Mild group but significantly downregulated in the SARS+ Moderate/Severe group. In both SARS+ groups we discovered elevated interferon type I IFN-α2a, type II IFN and type III IFN λ1 plasma levels together with higher IL-10 and IL-6. These results indicate that those with moderate or severe disease are characterised by deficiencies in a mast cell response together with IFN hyper-responsiveness, suggesting that early host antiviral immune responses could be a cause and not a consequence of severe COVID-19.ConclusionsThis study suggests that early host immune responses linking defects in mast cell activation with host interferon responses correlates with more severe outcomes in COVID-19. Further characterisation of this pathway could help inform better treatment for vulnerable individuals.

Background Technetium-99m-labeled Tilmanocept, a multivalent mannose, is readily internalized by the CD206 surface receptor on macrophages and dendritic cells which are abundantly present in lymph nodes. We want to examine the drainage patterns of Technetium-99m-labeled Tilmanocept to sentinel lymph nodes (SLNs) in melanoma patients following the 10% rule. Methods Multi-center retrospective review of patients with cutaneous melanoma undergoing SLN biopsy using Technetium-99m-labeled Tilmanocept between 2008 and 2014 was conducted. Statistical methods were used for data analyses. Results Of the 564 patients (mean age of 60.3 and 62% male) with preoperative lymphoscintigraphy showing at least one SLN, several primary tumor sites were included: 27% head/neck, 33% trunk, 21% upper extremity and 19% lower extremity. For the head/neck primary site, 36.5% of patients had multiple draining basins; for the trunk site, 36.4% of patients; for the upper extremity site, 13% of patients; and for the lower extremity, 27.4% of patients. A median of 3 (range 1-18) SLNs were identified and resected. Overall, 78% of patients had >1 SLN identified by Technetium-99m-labeled Tilmanocept. In a multivariate model, patients with >1 SLN were significantly associated with age, Breslow depth, tumor location and higher AJCC tumor stage. A total of 17.7% of patients (100/564) had a positive SLN identified. A total of 145 positive SLNs were identified out of 1,812 SLNs with a positive SLN rate of 8%. Positive SLN status was significantly associated with younger age, greater Breslow depth, mitosis rate, higher AJCC tumor stage, presence of ulceration and angiolymphatic invasion. Conclusions Using the 10% rule, Technetium-99m-labeled Tilmanocept detects multiple SLNs in most melanoma patients.

PurposeChlamydia psittaci (C. psittaci) has caused sporadic, but recurring, fatal community-acquired pneumonia outbreaks worldwide, posing a serious threat to public health. Our understanding of host inflammatory responses to C. psittaci is limited, and many bronchitis cases of psittaci have rapidly progressed to pneumonia with deterioration.MethodsTo clarify the host inflammatory response in psittacosis, we analyzed clinical parameters, and compared transcriptomic data, concentrations of plasma cytokines/chemokines, and changes of immune cell populations in 17 laboratory-confirmed psittacosis cases, namely, 8 pneumonia and 9 bronchitis individuals, in order to assess transcriptomic profiles and pro-inflammatory responses.ResultsPsittacosis cases with pneumonia were found to have abnormal routine blood indices, liver damage, and unilateral pulmonary high-attenuation consolidation. Transcriptome sequencing revealed markedly elevated expression of several pro-inflammatory genes, especially interleukins and chemokines. A multiplex-biometric immunoassay showed that pneumonia cases had higher levels of serum cytokines (G-CSF, IL-2, IL-6, IL-10, IL-18, IP-10, MCP-3, and TNF-α) than bronchitis cases. Increases in activated neutrophils and decreases in the number of lymphocytes were also observed in pneumonia cases.ConclusionWe identified a number of plasma biomarkers distinct to C. psittaci pneumonia and a variety of cytokines elevated with immunopathogenic potential likely inducing an inflammatory milieu and acceleration of the disease progression of psittaci pneumonia. This enhances our understanding of inflammatory responses and changes in vascular endothelial markers in psittacosis with heterogeneous symptoms and should prove helpful for developing both preventative and therapeutic strategies.

Objective: The SARS-CoV-2 pathogen has established endemicity in humans. This necessitates the development of rapid genetic surveillance methodologies to serve as an adjunct to existing comprehensive, albeit though slower, genome sequencing-driven approaches. Methods: A total of 21,789 complete genomes were downloaded from GISAID on May 28, 2020, for analyses. We have defined the major clades and subclades of circulating SARS-CoV-2 genomes. A rapid sequencing-based genotyping protocol was developed and tested on SARS-CoV-2-positive RNA samples by next-generation sequencing. Results: We describe eleven major mutation events that defined five major clades (G614, S84, V251, I378, and D392) of globally-circulating viral populations. The clades can be specifically identified using an 11-nucleotide genetic barcode. An analysis of amino acid variation in SARS-CoV-2 proteins provided evidence of substitution events in the viral proteins involved in both host entry and genome replication. Conclusion: Globally-circulating SARS-CoV-2 genomes could be classified into five major clades based on mutational profiles defined by an 11-nucleotide barcode. We have successfully developed a multiplexed sequencing-based, rapid genotyping protocol for high-throughput classification of major clade types of SARS-CoV-2 in clinical samples. This barcoding strategy will be required to monitor genetic diversity decrease as treatment and vaccine approaches become widely available.

Abstract Background The objectives of this study were to investigate the relationships between polymorphisms at the interferon lambda (IFNL) locus and CD4+:CD8+ ratio normalisation in people living with HIV (PLWH) on effective antiretroviral therapy (ART); and to examine whether these polymorphisms influence the composition of T lymphocyte compartments in long-term treated HIV-1 infection. Methods A cross-sectional study in PLWH enrolled into the Mater Immunology study. We performed IFNL genotyping on stored samples and evaluated the association of IFNL single-nucleotide polymorphisms (rs368234815 and rs12979860) with CD4+:CD8+ ratio normalization (> 1) and expanded CD4+ and CD8+ T-cell subsets; CD45RO+CD62L+ (central-memory), CD45RO+ CD62L−(effector-memory) and CD45RO−CD62L+ (naïve), using logistic and linear regression models, respectively. Results 190 ambulatory PLWH recruited to the main study, 143 were included in the analysis (38 had no stored DNA and 9 no T-lymphocyte subpopulation). Of 143 included, the median age (IQR) was 45(39–48) years, 64% were male and 66% were of Caucasian ethnicity. Heterosexual-contact (36%), injecting drug-use (33%) and men who have sex with men (24%) were the most presented HIV-transmission risk groups. The majority of subjects (90.2%) were on ART with 79% of the cohort having an undetectable HIV-RNA (

ABSTRACTHaemorrhagic fever with renal syndrome (HFRS) following Hantaan virus (HTNV) infection displays variable clinical signs. Humoral responses elicited during HTNV infections are considered important, however, this process remains poorly understood. Herein, we have investigated the phenotype, temporal dynamics, and characteristics of B-cell receptor (BCR) repertoire in an HFRS cohort. The serological profiles were characterized by a lowered expression level of nucleoprotein (NP)-specific antibody in severe cases. Importantly, B-cell subsets were activated and proliferated within the first two weeks of symptom onset and moderate cases reacted more rapidly. BCR analysis in the recovery phase revealed a dramatic increase in the immunoglobulin gene diversity which was more significantly progressed in moderate infections. In severe cases, B-cell-related transcription was lower with inflammatory sets overactivated. Taken together, these data suggest the clinical signs and disease recovery in HFRS patients were positively impacted by rapid and efficacious humoral responses.

Abstract Immune thrombocytopenic purpura (ITP) is a rare complication associated with vaccines targeting various diseases, including influenza, measles‐mumps‐rubella, hepatitis B, and diphtheria‐tetanus‐pertussis. We report 2 cases of ITP in healthy 20‐year‐old and 21‐year‐old women presenting to Emory University in Atlanta, GA, 2 days after the second dose and 11 days after the first dose (respectively) of the Pfizer‐BioNTech messenger RNA severe acute respiratory syndrome coronavirus 2 vaccine. Both patients recovered quickly. With more than a billion doses of coronavirus disease 2019 vaccines safely administered worldwide as of May 2021, discussions with patients should put into perspective the low risks of vaccination against the enormous societal benefit of the coronavirus disease 2019 vaccine.

ABSTRACTCoxsackievirus A4 (CVA4) infection can cause hand, foot and mouth disease (HFMD), an epidemic illness affecting neonatal and paediatric cohorts, which can develop to severe neurological disease with high mortality. In this study, we established the first ICR mouse model of CVA4 infection for the evaluation of inactivated vaccines and antiviral drug screening. The CVA4 YT226R strain was selected to infect the neonatal mice and three infectious factors were optimized to establish the infection model. The 3-day-old neonatal mice exhibited clinical symptoms such as hind limb paralysis and death. The severe inflammatory reactions were closely related to the abnormal expression of the acute phase response proinflammatory cytokine IL-6 and an imbalance in the IFN-γ/IL-4 ratio. Importantly, the inactivated CVA4 whole-virus vaccine induced humoral immune responses in adult females and the maternal antibodies afforded mice complete protection against lethal dose challenges of homologous or heterologous CVA4 strains. Both IFN-α2a and antiserum inhibited the replication of CVA4 and increased the survival rates of neonatal mice during the early stages of infection. This neonatal murine model of CVA4 infection will be useful for the development of prophylactic and therapeutic vaccines and for screening of antiviral drugs targeting CVA4 to decrease morbidity and mortality.

Patients with unresectable hepatic metastases, from uveal or ocular melanoma, are challenging to treat with an overall poor prognosis. Although over the past decade significant advances in systemic therapies have been made, metastatic disease to the liver, especially from uveal melanoma, continues to be a poor prognosis. Percutaneous hepatic perfusion (PHP) is a safe, viable treatment option for these patients. PHP utilizes high dose chemotherapy delivered directly to the liver while minimizing systemic exposure and can be repeated up to 6 times. Isolation of the hepatic vasculature with a double-balloon catheter allows for high concentration cytotoxic therapy to be administered with minimal systemic adverse effects. A detailed description of the multidisciplinary treatment protocol used at an institution with over 12 years of experience is discussed and recommendations are given. A dedicated team of a surgical or medical oncology, interventional radiology, anesthesiology and a perfusionist allows PHP to be repeatedly performed as a safe treatment strategy for unresectable hepatic metastases.

Alteplase, or tissue plasminogen activator (tPA), lyses clots by enhancing activation of plasminogen to plasmin. Conversely, tranexamic acid (TXA) functions by inhibiting the conversion of plasminogen to plasmin, which inhibits fibrinolysis. TXA has proven safe and effective in major bleeding with various etiologies. A 76-year-old male developed acute ischemic stroke symptoms. Systemic alteplase was administered and he showed clinical improvement. Shortly thereafter, the patient became hypotensive and lost pulses. Point-of-care ultrasound revealed cardiac tamponade. TXA was immediately given to inhibit fibrinolysis since cryoprecipitate and blood products were not immediately available. Pericardiocentesis was performed and successfully removed 200 milliliters of blood with return of pulses. Clinicians must consider TXA as a rapidly accessible antagonist of tPA’s fibrinolytic effects.

We isolated Tamdy virus (TAMV; strain XJ01/TAMV/China/2018) from Hyalomma asiaticum ticks infesting Bactrian camels in Xinjiang, China, in 2018. The genome of the strain showed high nucleotide similarity with previously described TAMV strains from Asia. Our study highlights the potential threat of TAMV to public health in China.

Abstract In the past decade, hand, foot, and mouth disease (HFMD) has posed a serious threat to childhood health in China; however, no epidemiological data from large HFMD epidemics have been described since 2013. In the present study, we described the epidemiological patterns of HFMD in Shandong province during 2009–2016 from a large number of symptomatic cases (n = 839,483), including >370,000 HFMD cases since 2013. Our results revealed that HFMD activity has remained at a high level and continued to cause annual epidemics in Shandong province from 2013 onwards. Although the incidence rate was significantly higher in urban areas than in rural areas, no significantly higher case-severity and case-fatality rates were found in urban areas. Furthermore, the seventeen cities of Shandong province could be classified into three distinct epidemiological groups according to the different peak times from southwest (inland) to northeast (coastal) regions. Notably, a replacement of the predominant HFMD circulating agent was seen and non-EVA71/Coxsackievirus A16 enteroviruses became dominant in 2013 and 2015, causing approximately 30% of the severe cases. Our study sheds light on the latest epidemiological characteristics of HFMD in Shandong province and should prove helpful for the prevention and control of the disease in Shandong and elsewhere.

Coxsackievirus A4 (CVA4) is one of the most prevalent pathogens associated with hand, foot and mouth disease (HFMD), an acute febrile illness in children, and is also associated with acute localized exanthema, myocarditis, hepatitis and pancreatitis. Despite this, limited CVA4 genome sequences are currently available. Herein, complete genome sequences from CVA4 strains (n = 21), isolated from patients with HFMD in Shandong province, China between 2014 and 2016, were determined and phylogenetically characterized. Phylogenetic analysis of the VP1 gene from a larger CVA4 collection (n = 175) showed that CVA4 has evolved into four separable genotypes: A, B, C, and D; and genotype D could be further classified in to two sub-genotypes: D1 and D2. Each of the 21 newly described genomes derived from isolates that segregated with sub-genotype D2. The CVA4 genomes displayed significant intra-genotypic genetic diversity with frequent synonymous substitutions occurring at the third codon positions, particularly within the P2 region. However, VP1 was relatively stable and therefore represents a potential target for molecular diagnostics assays and also for the rational design of vaccine epitopes. The substitution rate of VP1 was estimated to be 5.12 × 10-3 substitutions/site/year, indicative of ongoing CVA4 evolution. Mutations at amino acid residue 169 in VP1 gene may be responsible for differing virulence of CVA4 strains. Bayesian skyline plot analysis showed that the population size of CVA4 has experienced several dynamic fluctuations since 1948. In summary, we describe the phylogenetic and molecular characterization of 21 complete genomes from CVA4 isolates which greatly enriches the known genomic diversity of CVA4 and underscores the need for further surveillance of CVA4 in China.

For decades, isolated limb infusion (ILI) and hyperthermic isolated limb perfusion (HILP) have been used to treat melanoma in-transit metastases and unresectable sarcoma confined to the limb utilizing the effect of loco-regional high-dose chemotherapy to the isolated limb. Both procedures are able to provide high response rates in patients with numerous or bulky lesions in whom other loco-regional treatments are becoming ineffective. In comparison to systemic therapies, on the other hand, ILI and HILP have the advantage of not being associated with systemic side-effects. Although in principle ILI and HILP are similar procedures, ILI is technically simpler to perform and differs from HILP in that it takes advantage of the hypoxic and acidotic environment that develops in the isolated limb, potentiating anti-tumour activity of the cytotoxic agents melphalan +/− actinomycin-D. Due to its simplicity, ILI can be used in both preclinical and clinical studies to test new cytotoxic regimens and combinations with the aim to overcome tumour resistance. In the future, administration of cytotoxic agents by ILI, in combination with systemic treatments such as BRAF/MEK/KIT inhibitors, immunotherapy (CTLA-4 blockade), and/or programmed death (PD-1) pathway inhibitors, has the potential to improve responses further by inducing increased tumour cell death while limiting the ability of the tumour to suppress the immune response.

Bluetongue (BT) is an arthropod-borne viral disease of ruminants with serious trade and socio-economic implications. Although the disease has been reported in a number of countries in sub-Saharan Africa, there is currently no information on circulating serotypes and disease distribution in Zambia. Following surveillance for BT in domestic and wild ruminants in Zambia, BT virus (BTV) nucleic acid and antibodies were detected in eight of the 10 provinces of the country. About 40% (87/215) of pooled blood samples from cattle and goats were positive for BTV nucleic acid, while one hartebeest pool (1/43) was positive among wildlife samples. Sequence analysis of segment 2 revealed presence of serotypes 3, 5, 7, 12 and 15, with five nucleotypes (B, E, F, G and J) being identified. Segment 10 phylogeny showed Zambian BTV sequences clustering with Western topotype strains from South Africa, intimating likely transboundary spread of BTV in Southern Africa. Interestingly, two Zambian viruses and one isolate from Israel formed a novel clade, which we designated as Western topotype 4. The high seroprevalence (96.2%) in cattle from Lusaka and Central provinces and co-circulation of multiple serotypes showed that BT is widespread, underscoring the need for prevention and control strategies.

An understanding of the global migration dynamics of highly pathogenic avian influenza A(H5N1) virus is helpful for surveillance and disease prevention. To characterize the migration network of this virus, we used genetic analysis, which supported a global persistence model in which each of 9 regions acts to some extent as a source. Siberia is the major hub for the dispersal of the virus. Southeast Asia and Africa are major sources of genetically and antigenically novel strains. We found evidence of local persistence of the virus in Southeast Asia and Africa, which is rare for human influenza A viruses. The differences in migration dynamics between avian and human influenza viruses might help with the design of region-specific surveillance efforts and the selection of vaccine candidates.

New geochemical analyses of volcanic rocks in El Salvador add to existing data from Nicaragua and Costa Rica to create a comprehensive set of geochemical data for Central American volcanics. These data coupled with previously published 40Ar/39Ar ages covering the past 30 Ma show that Costa Rica and Nicaragua had similar U/Th and Ba/La values until 10 Ma when the region developed the distinctive along arc variations that made this margin famous. U/Th values increased in Nicaragua since the Miocene, while remaining unchanged along the rest of the volcanic front. This coincides temporally with the Carbonate Crash, which caused a transition in Cocos plate sediments from low‐U carbonates to high‐U, organic rich hemipelagic muds. Increases in uranium are not observed in Costa Rica because its lower slab dip produces a more diffuse zone of partial melting and because of the contribution from Galapagos‐derived tracks dilutes this signal. Ba/La has been used as a geochemical proxy for contributions from the subducting slab; however, our analyses indicate that the Ba concentrations do not vary significantly along strike either in the subducting sediment or the volcanic front. Along‐arc variation is controlled by changes in La, an indicator of the degree of partial melting or source enrichment. Trace element models of five segments of the volcanic front suggest that a subducting sediment component is more important to magmas produced in El Salvador and Nicaragua than in Costa Rica, where the geochemistry is controlled by recent (

Human adenovirus (HAdV) serotype 14 is rarely identified. However, an emerging variant, termed HAdV-14p1, recently has been described in the United States in association with outbreaks of acute respiratory disease with high rates of illness and death. We retrospectively analyzed specimens confirmed positive for HAdV by immunofluorescence, virus culture, or real-time PCR during July 1, 2009–July 31, 2010, and describe 9 cases of HAdV-14p1 infection with characteristic mutations in the fiber and E1A genes that are phylogenetically indistinguishable from the viruses previously detected in the United States. Three patients died; 2 were immunocompromised, and 1 was an immunocompetent adult. We propose that surveillance should be increased for HAdV-14p1 and recommend that this virus be considered in the differential diagnosis of sudden-onset acute respiratory disease, particularly fatal infections, for which an etiology is not clear.

JC and BK polyomaviruses were discovered over 40 years ago and have become increasingly prevalent causes of morbidity and mortality in a variety of distinct, immunocompromised patient cohorts. The recent discoveries of eight new members of the Polyomaviridae family that are capable of infecting humans suggest that there are more to be discovered and raise the possibility that they may play a more significant role in human disease than previously understood. In spite of this, there remains a dearth of specific therapeutic options for human polyomavirus infections and an incomplete understanding of the relationship between the virus and the host immune system. This review summarises the human polyomaviruses with particular emphasis on pathogenesis in those directly implicated in disease aetiology and the therapeutic options available for treatment in the immunocompromised host.