title: Elective bone marrow transplantation in a child with X-linked hyper-IgM syndrome presenting with acute respiratory distress syndrome

text: We describe a 10-month-old boy diagnosed with X-linked hyper-IgM syndrome (XHIM) after suffering from life-threatening acute respiratory distress syndrome (ARDS) caused by Pneumocystis carinii pneumonia (PCP), although his previous clinical history and first level laboratory tests investigating immunological function did not indicate immunodeficiency. When the patient's overall condition was good, elective bone marrow transplantation from an HLA-matched older brother was performed successfully. We describe how correct diagnosis and successful treatment were made possible thanks to the involvement of a network of specialists.


title: What to do when your technology is good but a licence is terminated

text: One of the biggest challenges in the biotech industry is to secure sufficient funding to support product or technology development. Partnering with companies that have cash and expertise – which, for the most part are larger biotech or pharmaceutical industries – may for many small biotech companies be more appealing than dealing with the financial community – venture capitalists and the like. The risk to the small biotech, however, is enormous because the partner may decide to return the rights to the product. This event usually leaves the product in limbo and the technology used to develop it tainted because of uncertainty regarding the real reasons for the return and the assumption in the world at large that there is something wrong with the product/technology. Thus, the licensor is left in the dark and is faced with ‘what's next?’ Here our company's strategy to overcome the terminated licence disaster or alternatively to take advantage of the terminated licence opportunity is described.


title: Encephalopathy in pediatric patients after allogeneic hematopoietic stem cell transplantation is associated with a poor prognosis

text: Encephalopathy is a poorly characterized complication of hematopoietic stem cell transplantation (HSCT). No comprehensive report of encephalopathy exists for children, and the literature contains only a few for adults. We analyzed a large cohort of 405 pediatric patients who underwent allogeneic HSCT during a 10-year period and identified 26 patients (6.4%) who experienced encephalopathy. Identifiable causes of encephalopathy included infection (n=5), single or multiorgan failure (n=4), medication-related complications (n=3), nonconvulsive seizures (n=4), acute disseminated encephalomyelitis (n=2), thrombotic thrombocytopenic purpura (n=2), and stroke (n=1). We were unable to identify the etiology of encephalopathy in five (19%) patients. The prognosis for pediatric patients with encephalopathy was poor: only four (15%) experienced complete neurologic recovery, and 10 (38%) patients experienced partial recovery with residual neurologic deficits. Nine (35%) patients with complete or partial recovery survive long term. A total of 17 patients died; one died of progressive encephalopathy, and 16 died of either relapse of primary disease or toxicity. MRI, CSF analysis including molecular testing for infectious pathogens, and brain biopsy were helpful in obtaining a diagnosis in most of our patients. However, a standardized approach to accurate and timely diagnosis and treatment is needed to improve outcome in these patients.


title: Low molecular weight heparin for the prevention of hepatic veno-occlusive disease (VOD) after hematopoietic stem cell transplantation: a prospective phase II study

text: We evaluated 40 patients undergoing high-dose chemo/radiotherapy (HDCT) and hematopoietic stem cell transplantation (HSCT) (allogeneic (22), autologous (18)) to determine the safety and feasibility of administering low molecular weight heparin (LMWH) as hepatic veno-occlusive disease (VOD) prophylaxis. Patients received a once daily subcutaneous injection of dalteparin 2500 anti-Xa i.u. commencing the day prior to starting HDCT, and continuing until day +30 post HSCT or hospital discharge, whichever came first. Dosage adjustments were made for patients developing renal failure. All bleeding episodes were recorded and graded and VOD was diagnosed and graded according to Seattle criteria. At 100 days of follow-up, the overall survival and probability of regimen-related mortality were 85 and 15%, respectively. Nine patients developed VOD. The probability of developing VOD post allogeneic and autologous HSCT was 28% (95% CI, 6–45) and 17% (95% CI, 0–32), respectively. VOD was graded as moderate (n=8) and severe (n=1). VOD resolved in all cases except for one patient who died secondary to severe VOD and multiorgan failure. Clinically significant bleeding episodes occurred in three patients; 24 patients developed minor bleeding not requiring specific therapy. All bleeding episodes resolved. These results suggest that LMWH for VOD prophylaxis is safe with a low incidence of serious bleeding events. Whether it is superior to unfractionated heparin, however, is unknown and should be addressed within the context of a randomized controlled trial.


title: Allogeneic bone marrow transplantation for active Epstein–Barr virus-related lymphoproliferative disease and hemophagocytic lymphohistiocytosis in an infant with severe combined immunodeficiency syndrome

text: A 5-month-old male presented with fever, hepatosplenomegaly, leukocytosis with atypical lymphoblasts, anemia and thrombocytopenia. Severe combined imunodeficiency syndrome (T−, B+, NK+), B lymphoproliferative disease and hemophagocytic lymphohistiocytosis triggered by Epstein–Barr virus (EBV) were diagnosed. As his clinical situation deteriorated rapidly, BMT was performed with unmanipulated marrow stem cells from his EBV-positive HLA-identical sister after conditioning with dexamethasone (1.75 mg/kg/day), cyclophosphamide (114 mg/kg) and etoposide (10 mg/kg), with no immunosuppression given post transplant. Engraftment occurred on day 6 with explosive proliferation of donor CD8(+) T cells. The patient died 3 days later from acute respiratory distress syndrome. Autopsy revealed full donor engraftment and no signs of hemophagocytic lymphohistiocytosis or B lymphoproliferative disease. Thus, transplanted T cells can expand very rapidly within days after BMT and clear EBV lymphoproliferative disease and hemophagocytic lymphohistiocytosis. Bone Marrow Transplantation (2002) 29, 519–521. doi:10.1038/sj.bmt.1703396


title: CD34(+) cell dose and establishment of full donor chimerism at day +100 are important factors for survival with reduced-intensity conditioning with fludarabine and melphalan before allogeneic hematopoietic SCT for hematologic malignancies

text: The combination of fludarabine and melphalan as a reduced-intensity conditioning (RIC) regimen extends allogeneic hematopoietic SCT (HSCT) as a therapeutic option for elderly or frail patients with relapsed, refractory or other high-risk hematologic malignancies. Whether any modifiable factors exist that could improve survival before or immediately after HSCT is unknown. We reviewed the medical records of the first 50 patients at our institution to undergo fludarabine/melphalan RIC from September 2000 to September 2007 to determine factors associated with survival. A total of 25 (50%) patients had undergone prior HSCT and as such was a high-risk group of patients. On multivariate analysis, CD34(+) cell dose greater than 5.5 × 10(6) per kg (risk ratio (RR) 0.44, 95% CI 0.19–0.98, P=0.02) and full donor chimerism at day +100 (RR 0.17, 95% CI 0.06–0.64, P=0.002) remained independent prognostic factors. In our series, achievement of full donor chimerism at day +100 was associated with an approximately 70% 2-year survival, a favorable outcome in this high-risk group of patients. Although the infused CD34(+) cell dose is a modifiable variable, whether donor lymphocyte infusions or other immunologic interventions should be performed to promote the establishment of full chimerism early post transplant remains unknown.


title: Toxicity associated with high-dose cytosine arabinoside and total body irradiation as conditioning for allogeneic bone marrow transplantation

text: Seventy-three patients with hematological cancers undergoing allogeneic bone marrow transplantation (BMT) were evaluated for event-free survival (EFS) and toxicity. All received 36 g/m(2) cytosine arabinoside (HDA) and 1200 cGy fractionated total body irradiation (TBI). We assessed the association of EFS and toxicities with the following risk factors: age, gender, diagnosis, initial relapse risk and patient–donor histocompatibility. The EFS probability is 33% at 800 days post-BMT. Twenty-six patients (36%) died of toxicity within 100 days and 14 (19%) have relapsed. EFS was inversely associated with age (P < 0.0001) and initial relapse risk (P = 0.007). The risk of pulmonary (P = 0.023) and hepatic toxicity (P = 0.011) increased with age. Diagnosis other than acute lymphoblastic leukemia (ALL) was a risk factor (P = 0.015) for graft-versus-host disease (GVHD); and fewer ALL patients died from toxicity (P = 0.014). The probability of sepsis within 100 days post-BMT correlated (P = 0.007) with initial relapse risk. We conclude: (1) the lower EFS and greater pulmonary and hepatic toxicity associated with increasing age indicate a need for less toxic regimens that maintain high antileukemic efficacy for older patients; (2) the high GVHD and sepsis rates seen in certain categories of patients indicate a need for careful definition of eligibility criteria for this still highly toxic treatment.


An editorial overview: HIV/AIDS in China


Face mask stockpile uncovered


title: Successful non-invasive ventilatory support in a patient with regimen-related toxicity during allogeneic bone marrow transplantation

text: A 13-year-old patient with transfusion-dependent β thalassemia major developed acute regimen-related lung toxicity after the conditioning regimen but before allogeneic bone marrow transplantation. He was successfully managed on non-invasive ventilatory support. Advances in non-invasive ventilatory support may drastically improve the outlook of this subset of patients who otherwise have a grim prognosis


The 45th Annual Meeting of the European Society for Blood and Marrow Transplantation: Physicians – Poster Session


Inhibition of IRF3-dependent antiviral responses by cellular and viral proteins


title: Activation of human tonsil and skin mast cells by agonists of proteinase activated receptor‐2

text: Aim: To investigate the effects of the agonists of proteinase activated receptor (PAR)‐2, and histamine on degranulation of human mast cells. Methods: Human mast cells were enzymatically dispersed from tonsil and skin tissues. The dispersed cells were then cultured with various stimuli, and tryptase and histamine levels in cell supernatants collected from challenge tubes were measured. Results: PAR‐2 agonist peptide SLIGKV provoked a dose‐dependent release of histamine from skin mast cells. It also induced tryptase release from tonsil mast cells. tc‐LIGRLO appeared less potent than SLIGKV in induction of release of histamine and tryptase. Trypsin was able to induce a “bell” shape increase in tryptase release from tonsil mast cells. It was also able to induce a dose‐dependent release of histamine from both tonsil and skin mast cells. The actions of trypsin on mast cells were inhibited by soy bean trypsin inhibitor (SBTI) or α(1)‐antitrypsin (α(1)‐AT). Time course study revealed that both stimulated tryptase or histamine release initiated within 10 s and reached their peak release between 4 and 6 min. Pretreatment of cells with metabolic inhibitors or pertussis toxin reduced the ability of mast cells to release tryptase or histamine. Conclusion: It was demonstrated that the in vitro tryptase release properties of human tonsil and skin mast cells suggested a novel type of mast cell heterogeneity. The activation of mast cells by PAR‐2 agonists indicated a self‐amplification mechanism of mast cell degranulation.


title: Natural product juglone targets three key enzymes from Helicobacter pylori: inhibition assay with crystal structure characterization

text: AIM: To investigate the inhibition features of the natural product juglone (5-hydroxy-1,4-naphthoquinone) against the three key enzymes from Helicobacter pylori (cystathionine γ-synthase [HpCGS], malonyl-CoA:acyl carrier protein transacylase [HpFabD], and β-hydroxyacyl-ACP dehydratase [HpFabZ]). METHODS: An enzyme inhibition assay against HpCGS was carried out by using a continuous coupled spectrophotometric assay approach. The inhibition assay of HpFabD was performed based on the α-ketoglutarate dehydrogenase-coupled system, while the inhibition assay for HpFabZ was monitored by detecting the decrease in absorbance at 260 nm with crotonoyl-CoA conversion to β-hydroxybutyryl-CoA. The juglone/FabZ complex crystal was obtained by soaking juglone into the HpFabZ crystal, and the X-ray crystal structure of the complex was analyzed by molecular replacement approach. RESULTS: Juglone was shown to potently inhibit HpCGS, HpFabD, and HpFabZ with the half maximal inhibitory concentration IC(50) values of 7.0±0.7, 20±1, and 30±4 μmol/L, respectively. An inhibition-type study indicated that juglone was a non-competitive inhibitor of HpCGS against O-succinyl-L-homoserine (K(i)=αK(i)=24 μmol/L), an uncompetitive inhibitor of HpFabD against malonyl-CoA (αK(i)=7.4 μmol/L), and a competitive inhibitor of HpFabZ against crotonoyl-CoA (K(i)=6.8 μmol/L). Moreover, the crystal structure of the HpFabZ/juglone complex further revealed the essential binding pattern of juglone against HpFabZ at the atomic level. CONCLUSION: HpCGS, HpFabD, and HpFabZ are potential targets of juglone.


title: Acute respiratory failure and the kinetics of neutrophil recovery in pediatric hematopoietic cell transplantation: a multicenter study

text: In this multicenter study, we investigated the kinetics of neutrophil recovery in relation to acuity and survival among 125 children undergoing allogeneic hematopoietic cell transplantation (allo-HCT) who required invasive mechanical ventilation (IMV). Recovery of neutrophils, whether prior to or after initiation of IMV, was associated with a significantly decreased risk of death relative to never achieving neutrophil recovery. A transient increase in acuity (by oxygenation index and vasopressor requirements) occurred among a subset of the patients who achieved neutrophil recovery after initiation of IMV; 61.5% of these patients survived to discharge from the intensive care unit (ICU). Improved survival among patients who subsequently achieved neutrophil recovery on IMV was not limited to those with peri-engraftment respiratory distress syndrome. The presence of a respiratory pathogen did not affect the risk of death while on IMV but was associated with an increased length of IMV (p < 0.01). Among patients undergoing HCT who develop respiratory failure and require advanced therapeutic support, neutrophil recovery at time of IMV and/or presence of a respiratory pathogen should not be used as determining factors when counseling families about survival.


title: Effect of iron overload and iron-chelating therapy on allogeneic hematopoietic SCT in children

text: Iron overload is known to increase complications of hematopoietic SCT (HSCT). We investigated the association of pre-transplant ferritin level with complications and survival after allogeneic HSCT, and evaluated the efficacy of iron-chelating therapy before HSCT. We retrospectively reviewed 101 patients who underwent allogeneic HSCT and divided these patients into three groups: F>1000, patients with ferritin level above 1000 ng/ml at the time of HSCT; F<1000, patients whose ferritin levels were maintained below 1000 ng/ml before HSCT without iron-chelating therapy; IC, patients with ferritin level decreased to less than 1000 ng/ml after iron-chelating therapy before HSCT. In the comparison between the F>1000 group and the F<1000 group, hyperbilirubinemia and treatment-related mortality (TRM) were significantly higher in the F>1000 group. The F>1000 group also showed decreased OS and EFS. In the comparison of the F<1000 and IC groups, there was no significant difference in complications and survival. When compared with the F>1000 group, the IC group showed lower TRM and higher survival. Elevated serum ferritin level was associated with increased TRM and decreased survival, and the analysis of the IC group suggested the benefit of iron-chelating therapy to improve the outcome of HSCT.


title: Clinical features and outcome of 2009-influenza A (H1N1) after allogeneic hematopoietic SCT

text: The impact of the 2009 H1N1-Influenza A (H1N1) pandemic in allogeneic hematopoietic SCT recipients (allo-HSCT) is not yet well defined. Between May 2009 and May 2010, all allo-HSCTs who presented with respiratory symptoms were screened for the presence of the H1N1 virus. Oseltamivir resistance was assessed and chart reviews were performed for all cases. In all, 51 of 248 (20%) allo-HSCT recipients followed at our outpatient clinic were screened. We identified 10 patients with H1N1 infection. Close contact with children was the most commonly suspected mode of transmission. Upper and lower respiratory tract infections were present in eight and five patients, respectively. Lymphopenia (<1 G/L) was the most frequent biological abnormality. High immunosuppression was responsible for severe infection requiring mechanical ventilation associated with prolonged viral shedding in three patients who had significant comorbidities and GvHD. Two of them developed an oseltamivir-resistant strain and both patients died subsequently despite intensive therapy, resulting in a case fatality rate of 20%. In conclusion, although most allo-HSCTs had mild symptoms from H1N1 infection, severe immunosuppression and emergence of oseltamivir resistance were likely responsible for a substantial morbidity, further supporting the need for vaccination and monitoring of close contacts, especially children.


Physicians – Poster Session


title: Angiotensin-converting enzyme 2 protects from lethal avian influenza A H5N1 infections

text: The potential for avian influenza H5N1 outbreaks has increased in recent years. Thus, it is paramount to develop novel strategies to alleviate death rates. Here we show that avian influenza A H5N1-infected patients exhibit markedly increased serum levels of angiotensin II. High serum levels of angiotensin II appear to be linked to the severity and lethality of infection, at least in some patients. In experimental mouse models, infection with highly pathogenic avian influenza A H5N1 virus results in downregulation of angiotensin-converting enzyme 2 (ACE2) expression in the lung and increased serum angiotensin II levels. Genetic inactivation of ACE2 causes severe lung injury in H5N1-challenged mice, confirming a role of ACE2 in H5N1-induced lung pathologies. Administration of recombinant human ACE2 ameliorates avian influenza H5N1 virus-induced lung injury in mice. Our data link H5N1 virus-induced acute lung failure to ACE2 and provide a potential treatment strategy to address future flu pandemics. SUPPLEMENTARY INFORMATION: The online version of this article (doi:10.1038/ncomms4594) contains supplementary material, which is available to authorized users.


The impact of COVID-19 on the provision of donor hematopoietic stem cell products worldwide: collateral damage


title: PKC promotes proliferation of airway smooth muscle cells by regulating cyclinD1 expression in asthmatic rats

text: AIM: To determine whether protein kinase C (PKC) has any effect on the expression of cyclinD1, a key regulator of growth control and G(1)/S transition, and to investigate the underlying molecular mechanisms of PKC involving the remodeling of the asthmatic airway smooth muscle (ASM). METHODS: The treatment of synchronized ASM cells from asthmatic rats with PKC-specific agonist phorbol 12-myristate 13-acetate (PMA) and antagonist 2-{1-[3-(amidinothio) propyl]-1H-indol-3-yl}-3-(1-methylindol-3-yl) maleimide methanesulfonate salt (Ro31-8220) was followed by the proliferation assay. PKCα and cyclinD1 expressions in ASM cells (ASMC) were detected by RT-PCR and Western blotting. The relation between PKCα and cyclinD1 was assessed by linear regression analysis. The effect of the construct recombinant plasmid pcDNA3.1-antisense cyclinD1 (pcDNA3.1-ascyclinD1) on the proliferation of ASMC was found to be induced by PMA. RESULTS: The data showed phorbol ester-dependent PKCα promoted the proliferation of ASMC. The closely-positive correlation existed between the expression of PKCα and cyclinD1 at the transcriptional (r=0.821, P<0.01) and transla-tional (r=0.940, P<0.01) levels. pcDNA3.1-ascyclinD1 could inhibit the proliferation of ASMC. pcDNA3.1-ascyclinD1 almost completely attenuated the PMA-induced proliferation effect as Ro31-8220+pcDNA3.1. CONCLUSION: The proliferation of ASMC by PKC might by regulated by the cyclinD1 expression in asthmatic rats.


Physicians Oral Abstracts: EBMT 2012


title: Summary of: A pilot study of bioaerosol reduction using an air cleaning system during dental procedures

text: Background Bioaerosols are defined as airborne particles of liquid or volatile compounds that contain living organisms or have been released from living organisms. The creation of bioaerosols is a recognized consequence of certain types of dental treatment and represents a potential mechanism for the spread of infection. Objectives The aims of the present study were to assess the bioaerosols generated by certain dental procedures and to evaluate the efficiency of a commercially available Air Cleaning System (ACS) designed to reduce bioaerosol levels. Methods Bioaerosol sampling was undertaken in the absence of clinical activity (baseline) and also during treatment procedures (cavity preparation using an air rotor, history and oral examination, ultrasonic scaling and tooth extraction under local anaesthesia). For each treatment, bioaerosols were measured for two patient episodes (with and without ACS operation) and between five and nine bioaerosol samples were collected. For baseline measurements, 15 bioaerosol samples were obtained. For bioaerosol sampling, environmental air was drawn on to blood agar plates using a bioaerosol sampling pump placed in a standard position 20 cm from the dental chair. Plates were incubated aerobically at 37°C for 48 hours and resulting growth quantified as colony forming units (cfu/m(3)). Distinct colony types were identified using standard methods. Results were analysed statistically using SPSS 12 and Wilcoxon signed rank tests. Results The ACS resulted in a significant reduction (p = 0.001) in the mean bioaerosols (cfu/m(3)) of all three clinics compared with baseline measurements. The mean level of bioaerosols recorded during the procedures, with or without the ACS activated respectively, was 23.9 cfu/m(3) and 105.1 cfu/m(3) (p = 0.02) for cavity preparation, 23.9 cfu/m(3) and 62.2 cfu/m(3) (p = 0.04) for history and oral examination; 41.9 cfu/m(3) and 70.9 cfu/m(3) (p = 0.01) for ultrasonic scaling and 9.1 cfu/m(3) and 66.1 cfu/m(3) (p = 0.01) for extraction. The predominant microorganisms isolated were Staphylococcus species and Micrococcus species. Conclusion These findings indicate potentially hazardous bioaerosols created during dental procedures can be significantly reduced using an air cleaning system.


title: Influenza A (H1N1) virus infection and TNF-308, IL6, and IL8 polymorphisms in Egyptian population: a case–control study

text: BACKGROUND: The importance of influenza is increasing mainly because of the appearance of novel pandemic strains such as swine and avian. Each year, influenza has spread around the world causing about 250,000–500,000 deaths and more than 5 million cases of severe illness. The objective is as follows: evaluating the outcomes of patients with influenza A (H1N1) virus in relation to certain TNF-308, IL6, and IL8 polymorphisms and identifying the associated factors with the severe outcome. SUBJECT AND METHODS: This is a case–control study. The cases were patients confirmed by real-time polymerase chain reaction (RT-PCR) to be influenza A (H1N1) virus infected. The controls were healthy individuals. Medical history and outcome of the disease was registered. In all study participants, polymorphisms of TNF rs1800629, IL6 rs18138879, and IL8 rs4073; odds ratio (OR); and the 95% confidence interval (95% CI) were calculated. RESULTS: Infection with influenza A (H1N1) virus was associated more with the following genotypes: TNF-308 AA (OR = 4.041; 95% CI = 1.215–13.4) and IL8 AA (OR = 3.273; 95% CI = 1.372–7.805). According to our study results, HCV (OR = 3.2, 95% CI 1.2–8.5), renal disease (OR = 3.4, 95% CI 0.9–13.6), cancer (OR = 3.1, 95% CI 0.3–31.1), TB (OR = 8.4, 95% CI 1.8–39.7), ICU (OR = 2.9, 95%1.2–7.1), and mortality (OR = 7.9, 95% CI 0.9–67.4) are considered as risk factors for influenza A (H1N1)-infected patients. CONCLUSIONS: Our findings concluded that TNF-308 (AA) and IL8 (AA) polymorphisms may increase the susceptibility to be infected with H1N1influenza virus.


Disinfectants in Laboratory Animal Science: What Are They and Who Says They Work?


title: T- and B-cell responses to multivalent prime-boost DNA and viral vectored vaccine combinations against hepatitis C virus in non-human primates

text: Immune responses against multiple epitopes are required for the prevention of hepatitis C virus (HCV) infection, and the progression to phase I trials of candidates may be guided by comparative immunogenicity studies in non-human primates. Four vectors, DNA, SFV, human serotype 5 adenovirus (HuAd5) and Modified Vaccinia Ankara (MVA) poxvirus, all expressing hepatitis C virus Core, E1, E2 and NS3, were combined in three prime-boost regimen, and their ability to elicit immune responses against HCV antigens in rhesus macaques was explored and compared. All combinations induced specific T-cell immune responses, including high IFN-γ production. The group immunized with the SFV+MVA regimen elicited higher E2-specific responses as compared with the two other modalities, while animals receiving HuAd5 injections elicited lower IL-4 responses as compared with those receiving MVA. The IFN-γ responses to NS3 were remarkably similar between groups. Only the adenovirus induced envelope-specific antibody responses, but these failed to show neutralizing activity. Therefore, the two novel regimens failed to induce superior responses as compared with already existing HCV vaccine candidates. Differences were found in response to envelope proteins, but the relevance of these remain uncertain given the surprisingly poor correlation with immunogenicity data in chimpanzees, underlining the difficulty to predict efficacy from immunology studies. SUPPLEMENTARY INFORMATION: The online version of this article (doi:10.1038/gt.2016.55) contains supplementary material, which is available to authorized users.


title: Adjuvant effect of HER-2/neu-specific adenoviral vector stimulating CD8(+) T and natural killer cell responses on anti-HER-2/neu antibody therapy for well-established breast tumors in HER-2/neu transgenic mice

text: Approximately one third of patients with advanced human epidermal growth factor receptor 2 (HER-2)/neu-positive breast cancer respond to trastuzumab monotherapy, a humanized anti-HER-2/neu antibody. However, de novo and acquired antibody resistance is one of the major limitations of trastuzumab therapy warranting the search for other therapeutic strategies. One of the most remarkable features of adenovirus (AdV)-based vaccine is its ability to induce exceptionally high and sustained frequencies of transgene product-specific CD8(+) T-cell responses. In this study, we constructed two recombinant AdVs (AdV(OVA) and AdV(HER-2)) expressing ovalbumin (OVA) and HER-2/neu, and assessed AdV-induced antigen-specific cellular immune responses and preventive/therapeutic antitumor immunity. We demonstrate that AdV(OVA) stimulates efficient OVA-specific CD8(+) cytotoxic T lymphocyte (CTL) and natural killer responses, leading to preventive long-term immunity against OVA-expressing BL6-10ova melanoma in wild-type C56BL/6 mice. We further demonstrate that AdV(HER-2) stimulates HER-2/neu-specific CD8(+) CTL responses, leading to a significant reduction in breast carcinogenesis in transgenic FVBneuN mice (P<0.05), but has little therapeutic effect on pre-existing Tg1-1 tumor even at early stage (15 mm(3)). In contrast, the anti-HER-2/neu antibody therapy is capable of completely inhibiting Tg1-1 tumor growth at early stage, but fails to eradicate well-established Tg1-1 breast tumor (100 mm(3)). Interestingly, a combinatorial immunotherapy of anti-HER-2/neu antibody with AdV(HER-2) vaccine was capable of curing 4 of 10 studied mice bearing well-established Tg1-1 breast tumors and significantly delaying in death of the remaining six tumor-bearing mice (P<0.05). Taken together, our results suggest an adjuvant effect of AdV(HER-2) on anti-HER-2/neu antibody therapy for well-established breast tumor in transgenic FVBneuN mice, and this combinatorial immunotherapy of trastuzumab with AdV(HER-2) vaccine may be used as a new therapeutic strategy for treatment of advanced HER-2/neu-positive breast cancer.


Fatal H1N1 influenza infection in an allo-SCT recipient


Host immunity dictates influenza A(H1N1)pdm09 infection outcome in hematology–oncology patients


title: An unexpectedly high incidence of Epstein–Barr virus lymphoproliferative disease after CD34+ selected autologous peripheral blood stem cell transplant in neuroblastoma

text: The risk of Epstein–Barr virus lymphoproliferative disease (EBV-LPD) increases with the use of highly immunosuppressive therapies. Allogeneic BMT, especially supported by T-cell-depleted stem cell products, is a risk factor for EBV-LPD. Although the risk of EBV-LPD after autologous transplantation is low, case reports of this complication in the autologous setting exist. We report a higher incidence than previously described of EBV-LPD in children undergoing sequential high-dose chemotherapy supported with CD34 selected peripheral blood stem cells (CD34+ PBSC). The median time to LPD after tandem transplant was 3 months (range 1–5 months). Five patients out of 156 (3.5%) developed EBV-LPD while enrolled on two trials of tandem autologous SCT in high-risk pediatric malignancies. Both studies employed five cycles of induction therapy, followed by tandem autologous PBSC transplants. In all, 108 out of 156 patients received CD34+ PBSC; 48 received unselected PBSC. All patients contracting LPD were from the CD34 selected group. Treatment of EBV-LPD included rituximab in four out of five patients, IVIg in two out of five patients, and gancyclovir in two out of five patients. EBV-LPD resolved in four out of five patients. We conclude that the combination of tandem SCT and CD34 selection may have increased immunosuppression in these patients to a point where there is an elevated risk of EBV-LPD.


title: What is CD4+CD56+ malignancy and how should it be treated?

text: CD4+CD56+ malignancy is a rare neoplasm with a typical clinical pattern, an aggressive course and high early relapse rate despite good initial response to chemotherapy. In this review, the impact of different therapeutic approaches on clinical outcome has been studied. We evaluated 91 published cases and our own six patients in terms of clinical features, immunophenotype/cytogenetics and treatment outcome. Treatment was divided into four groups: (A) chemotherapy less intensive than CHOP; (B) CHOP and CHOP-like regimens; (C) therapy for acute leukemia; (D) allogeneic/autologous stem cell transplantation. The median overall survival was only 13 months for all patients. Patients with skin-restricted disease showed no difference in the overall survival from patients with advanced disease (17 and 12 months, respectively). Age ⩾60 years was a negative prognostic factor. Age-adjusted analysis revealed improved survival after high-dose chemo/radiotherapy followed by allogeneic stem cell transplantation when performed in first complete remission. This therapeutic approach should be recommended for eligible patients with CD4+CD56+ malignancy. For older patients the best treatment option is still unknown.


Keyword index to Volume 23


title: Pulmonary enterovirus infections in stem cell transplant recipients

text: In recent years, it has been recognised that the community respiratory viruses are a frequent cause of upper and lower respiratory tract infections in immunocompromised hosts such as bone marrow transplant recipients. By contrast, infections by non-polio enteroviruses have rarely been reported after stem cell transplantation. We present four cases of acute respiratory illness with enterovirus isolated as the sole pathogen from bronchoalveolar lavage. All four patients developed pneumonia and three died of progressive pneumonia, which reflects the severity of this complication. We conclude that enteroviral pulmonary infections may be a cause of severe pneumonia in immunocompromised hosts.


title: Gene therapy for cystic fibrosis: an example for lung gene therapy

text: Gene therapy is currently being evaluated for a wide range of acute and chronic lung diseases. The requirement of gene transfer into the individual cell types of the complex lung structure will very much depend on the target disease. Over the last decade, the gene therapy community has recognized that there is not even one vector that is good for all applications, but that the gene transfer agent has to be carefully chosen. Gene therapy is particularly attractive for diseases that currently do not have satisfactory treatment options and probably easier for monogenic disorders than for complex diseases. Cystic fibrosis (CF) fulfills these criteria and is therefore a good candidate for gene therapy-based treatment. This review will focus on CF as an example for lung gene therapy and discuss the progress made in this field over the last couple of years.


title: Solid organ transplantation following allogeneic haematopoietic cell transplantation: experience from a referral organ transplantation center and systematic review of literature

text: Solid organ transplantation (SOT) following haematopoietic cell transplantation (HCT) is a rare event. Uncertainty exists whether such recipients are at higher risk of relapse of underlying haematological disease or at increased risk of developing infectious or immunological complications and malignancies following SOT. The experience at our referral organ transplantation center and the present literature of SOT (n = 198) in recipients following previous HCT was systematically reviewed. Outcome analysis of 206 SOT recipients following HCT challenges the validity of the frequently stated comparable outcome with recipients without prior HCT. SOT recipients after HCT are younger and have a higher mortality and morbidity in comparison with “standard” recipients. Rejection rates for SOT recipients following HCT appear to be lower for all organs, except for liver transplantation. In the setting of liver transplantation following HCT, mortality for recipients of deceased donor grafts appears to be exceptionally high, although experience with grafts of living donors are favourable. Morbidity was mostly associated with infectious and malignant complications. Of note some SOT recipients who received solid organ donation from the same HCT donor were able to achieve successful withdrawal of immune suppression. Despite limited follow-up, recipients with prior HCT show a different course after SOT, necessitating attention and closer follow-up.


The 45th Annual Meeting of the European Society for Blood and Marrow Transplantation: Physicians – Oral Session


title: Respiratory status deterioration during G-CSF-induced neutropenia recovery

text: Exacerbation of prior pulmonary involvement may occur during neutropenia recovery. Granulocyte colony-stimulating factor (G-CSF)-related pulmonary toxicity has been documented in cancer patients, and experimental models suggest a role for G-CSF in acute lung injury during neutropenia recovery. We reviewed 20 cases of noncardiac acute respiratory failure during G-CSF-induced neutropenia recovery. Half the patients had received hematopoietic stem cell transplants. All patients experienced pulmonary infiltrates during neutropenia followed by respiratory status deterioration coinciding with neutropenia recovery. Neutropenia duration was 10 (4–22) days, and time between respiratory symptoms and the first day with more than 1000 leukocytes/mm(3) was 1 (−0.5 to 2) day. Of the 20 patients, 16 received invasive or noninvasive mechanical ventilation, including 14 patients with acute respiratory distress syndrome (ARDS). Five patients died, with refractory ARDS. In patients with pulmonary infiltrates during neutropenia, G-CSF-induced neutropenia recovery carries a risk of respiratory status deterioration with acute lung injury or ARDS. Clinicians must maintain a high index of suspicion for this diagnosis, which requires eliminating another cause of acute respiratory failure, G-CSF discontinuation and ICU transfer for early supportive management including diagnostic confirmation and noninvasive mechanical ventilation.


Oral Sessions and Working Party


title: Intra-arterial administration of a replication-selective adenovirus (dl1520) in patients with colorectal carcinoma metastatic to the liver: a phase I trial

text: Both replication-incompetent and replication-selective adenoviruses are being developed for the treatment of cancer and other diseases. Concerns have been raised about the safety of intra-vascular adenovirus administration following a patient death on a clinical trial with a replication-defective adenovirus. In addition, the feasibility of vascular delivery to distant tumors has been questioned. dl1520 (ONYX-015) is a replication-selective adenovirus that has previously shown safety and antitumoral activity following intratumoral injection. This is the first report of intra-vascular administration with a genetically engineered, replication-selective virus. A phase I dose-escalation trial was performed in patients with liver-predominant gastrointestinal carcinoma (n = 11 total; primarily colorectal). dl1520 was infused into the hepatic artery at doses of 2 × 10(8)–2 × 10(12) particles for two cycles (days 1 and 8). Subsequent cycles of dl1520 were administered in combination with intravenous 5-fluorouracil (5-FU) and leucovorin. No dose-limiting toxicity, maximally tolerated dose or treatment-emergent clinical hepatotoxicity were identified following dl1520 infusion. Mild to moderate fever, rigors and fatigue were the most common adverse events. Antibody titers increased significantly in all patients. Viral replication was detectable in patients receiving the highest two doses. An objective response was demonstrated in combination with chemotherapy in a patient who was refractory to both 5-FU and dl1520 as single agents. Therefore, hepatic artery infusion of the attenuated adenovirus dl1520 was well-tolerated at doses resulting in infection, replication and chemotherapy-associated antitumoral activity.


Publication Only


Physicians Abstracts


title: Interleukin-2 after autologous stem cell transplantation for hematologic malignancy: a phase I/II study

text: The success of autologous stem cell transplantation (ASCT) for hematologic malignancy is limited largely by a high relapse rate. It is postulated that IL-2 administered after ASCT may eliminate minimal residual disease and thereby reduce relapses. A phase I/II study was performed to identify a regimen of IL-2 (Chiron) that could be given early after ASCT in phase III trials. In the phase I study, beginning a median of 46 days after ASCT for hematologic malignancy, cohorts of three to four patients received escalating doses of ‘induction’ IL-2 of 9, 10, or 12 × 10(6) IU/m(2)/day for 4 or 5 days by continuous i.v. infusion (CIV), followed by a 4-day rest period, and then 1.6 × 10(6) IU/m(2)/day of maintenance IL-2 by CIV for 10 days. The maximum tolerated dose (MTD) of induction IL-2 was 9 × 10(6) IU/m(2)/day × 4. In the phase II study, 52 patients received the MTD. Eighty percent of patients completed induction IL-2. Most patients exhibited some degree of capillary leak. One patient died of CMV pneumonia and one died of ARDS. Maintenance IL-2 was well tolerated. In the phase I/II study, 16 of 31 patients with non-Hodgkin lymphoma (NHL), 3/8 with Hodgkin disease (HD), 4/17 with AML, and 4/5 with ALL remain in CR. Two of six multiple myeloma (MM) patients remain in PR. Although the regimen of IL-2 identified had significant side-effects in some patients, it was well tolerated in the majority of patients. Phase III prospectively randomized clinical trials are in progress to determine if this IL-2 regimen will decrease the relapse rate after ASCT for AML and NHL.


Pandemic influenza A H1N1/09 virus infection in hematopoietic SCT recipient


Physicians – Oral Sessions


Physicians Abstracts: EBMT 2010


title: Importance of AT1 and AT2 receptors in the nucleus of the solitary tract in cardiovascular responses induced by a high-fat diet

text: A high-fat diet (HFD) induces an increase in arterial pressure and a decrease in baroreflex function, which may be associated with increased expression of angiotensin type 1 receptor (AT1R) and pro-inflammatory cytokine genes and reduced expression of the angiotensin type 2 receptor (AT2R) gene within the nucleus of the solitary tract (NTS), a key area of the brainstem involved in cardiovascular control. Thus, in the present study, we evaluated the changes in arterial pressure and gene expression of components of the renin–angiotensin system (RAS) and neuroinflammatory markers in the NTS of rats fed a HFD and treated with either an AT1R blocker or with virus-mediated AT2R overexpression in the NTS. Male Holtzman rats (300–320 g) were fed either a standard rat chow diet (SD) or HFD for 6 weeks before commencing the tests. AT1R blockade in the NTS of HFD-fed rats attenuated the increase in arterial pressure and the impairment of reflex bradycardia, whereas AT2R overexpression in the NTS only improved the baroreflex function. The HFD also increased the hypertensive and decreased the protective axis of the RAS and was associated with neuroinflammation within the NTS. The expression of angiotensin-converting enzyme and neuroinflammatory components, but not AT1R, in the NTS was reduced by AT2R overexpression in this site. Based on these data, AT1R and AT2R in the NTS are differentially involved in the cardiovascular changes induced by a HFD. Chronic inflammation and changes in the RAS in the NTS may also account for the cardiovascular responses observed in HFD-fed rats.


title: Long-term outcome in acute myelogenous leukemia autografted with mafosfamide-purged marrow in a single institution: adverse events and incidence of secondary myelodysplasia

text: We have analyzed the long-term outcome and toxicities in 98 patients with high-risk acute myelogenous leukemia (AML) who were treated with autologous bone marrow transplantation (ABMT) and monitored for a median observation period of 11.67 years. Between 1983 and 1994, 98 patients in our institution in first or second and higher complete remission (CR) underwent total body irradiation and high-dose cyclophosphamide prior to ABMT purged with mafosfamide. Twenty-seven out of the 90 evaluable patients (30%) were alive and in continuous CR for a median of 11.67 years (range, 6.39–15.53) after ABMT and could be considered as ‘cured’. Among the 90 patients, 39 were transplanted at first CR and had a significantly higher survival rate than those transplanted at ⩾2 CR. Younger patients (<40 years) had a better prognosis and patients with FAB M1–4 had a more favorable outcome than those with M5. Long-term complications included four patients with cardiac complications, two with renal insufficiency. Five developed HCV infections, four myelodysplastic syndrome. The incidence of cataract among the long-term survivors was 44.4%. Therefore, a significant number of adult patients with AML in first CR derived long-term benefit from ABMT, despite the risks of a few long-term complications and of MDS (4.4%).


Vitamin D Receptor Signaling and Cancer


title: Exacerbation of Chronic Obstructive Pulmonary Disease

text: Chronic obstructive pulmonary disease (COPD) is a disease with high prevalence and substantial associated economical burden. A significant determinant of quality of life, long-term survival, and health care costs is an acute exacerbation of COPD. Acute exacerbations are provoked by respiratory viruses, altered airway microbiome, and environmental factors. The current treatment options are limited. In order to develop specific therapeutic measures, it is important to understand how acute exacerbations evolve. This review focuses on pathophysiology of stable and exacerbated COPD.


title: ARDS Subphenotypes: Understanding a Heterogeneous Syndrome

text: This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency Medicine 2020. Other selected articles can be found online at https://www.biomedcentral.com/collections/annualupdate2020. Further information about the Annual Update in Intensive Care and Emergency Medicine is available from http://www.springer.com/series/8901.


title: Renal replacement therapy is independently associated with a lower risk of death in patients with severe acute kidney injury treated with targeted temperature management after out-of-hospital cardiac arrest

text: BACKGROUND: The effect of renal replacement therapy (RRT) on the outcomes of severe acute kidney injury (AKI) after out-of-hospital cardiac arrest (OHCA) is uncertain. This study aimed to evaluate the association of RRT with 6-month mortality in patients with severe AKI treated with targeted temperature management (TTM) after OHCA. METHODS: This was a retrospective analysis of a prospectively collected multicentre observational cohort study that included adult OHCA patients treated with TTM across 22 hospitals in South Korea between October 2015 and December 2018. AKI was diagnosed using the Kidney Disease: Improving Global Outcomes criteria. The primary outcome was 6-month mortality and the secondary outcome was cerebral performance category (CPC) at 6 months. Multivariate Cox regression analysis was performed to define the role of RRT in stage 3 AKI. RESULTS: Among 10,426 patients with OHCA, 1373 were treated with TTM. After excluding those who died within 48 h of return of spontaneous circulation (ROSC) and those with pre-arrest chronic kidney disease, our study cohort comprised 1063 patients. AKI developed in 590 (55.5%) patients and 223 (21.0%) had stage 3 AKI. Among them, 115 (51.6%) were treated with RRT. The most common treatment modality among RRT patients was continuous renal replacement therapy (111 [96.5%]), followed by intermittent haemodialysis (4 [3.5%]). The distributions of CPC (1–5) at 6 months for the non-RRT vs. the RRT group were 3/108 (2.8%) vs. 12/115 (10.4%) for CPC 1, 0/108 (0.0%) vs. 1/115 (0.9%) for CPC 2, 1/108 (0.9%) vs. 3/115 (2.6%) for CPC 3, 6/108 (5.6%) vs. 6/115 (5.2%) for CPC 4, and 98/108 (90.7%) vs. 93/115 (80.9%) for CPC 5, respectively (P = 0.01). The RRT group had significantly lower 6-month mortality than the non-RRT group (93/115 [81%] vs. 98/108 [91%], P = 0.04). Multivariate Cox regression analyses showed that RRT was independently associated with a lower risk of death in patients with stage 3 AKI (hazard ratio, 0.569 [95% confidence interval, 0.377–0.857, P = 0.01]). CONCLUSION: Dialysis interventions were independently associated with a lower risk of death in patients with stage 3 AKI treated with TTM after OHCA.


title: Therapeutic Potential of the Gut Microbiota in the Management of Sepsis


title: Diagnostic performance of nucleic acid tests in tuberculous pleurisy

text: BACKGROUND: Tuberculous pleurisy (TBP) is the most common form of extrapulmonary tuberculosis (TB). However, rapid diagnostic methods with high accuracy for tuberculous pleurisy are urgently needed. In the present study, we evaluated the diagnostic accuracy of Xpert MTB/RIF, LAMP and SAT-TB assay with pleural fluids from culture-positive TBP patients. METHODS: We prospectively enrolled 300 patients with exudative pleural effusions used as the samples for Xpert MTB/RIF, LAMP and SAT-TB assay. Of these, 265 including 223 patients diagnosed with TBP and 42 non-TBP patients used as controls were analyzed. RESULTS: The sensitivities of Xpert MTB/RIF (27.4%), LAMP (26.5%) and SAT-TB assay (32.3%) were significantly higher than that of pleural effusion smear (14.3%, X(2) = 20.65, P < 0.001), whereas they were much lower than expected for the analysis of pleural effusion samples. Both SAT-TB assay and Xpert MTB/RIF demonstrated high specificities (100%) and PPVs (100%), but the NPVs of all of the tests were < 22%. The area under ROC curve of pleural effusion smear, LAMP, Xpert MTB/RIF and SAT-TB assays was 0.524 (95% CI 0.431–0.617), 0.632 (95% CI 0.553–0.71), 0.637 (95% CI 0.56–0.714) and 0.673 (95% CI 0.6–0.745). SAT-TB assays had the highest AUC. CONCLUSION: Nucleic acid amplification tests are not the first choice in the diagnosis of tuberculous pleurisy. In this type of test, SAT-TB is recommended because of its low cost, relatively more accurate compared with the other two tests. This prospective study was approved by The Ethics Committee of the Shanghai Pulmonary Hospital (approval number: K19–148). TRIAL REGISTRATION: ClinicalTrials.gov identifier: ChiCTR1900026234 (Retrospectively registered). The registration date is September 28, 2019.


title: A Clinician’s Guide to Management of Intra-abdominal Hypertension and Abdominal Compartment Syndrome in Critically Ill Patients


title: Artificial Intelligence in the Intensive Care Unit


40th International Symposium on Intensive Care & Emergency Medicine: Brussels, Belgium. 24-27 March 2020


title: Respiratory Muscle Rehabilitation in Patients with Prolonged Mechanical Ventilation: A Targeted Approach


title: Physiology of the Respiratory Drive in ICU Patients: Implications for Diagnosis and Treatment


title: Genetic and virulence characterisation of Vibrio parahaemolyticus isolated from Indian coast

text: BACKGROUND: V. parahaemolyticus is autochthonous to the marine environment and causes seafood-borne gastroenteritis in humans. Generally, V. parahaemolyticus recovered from the environment and/or seafood is thought to be non-pathogenic and the relationship between environmental isolates and acute diarrhoeal disease is poorly understood. In this study, we explored the virulence potential of environmental V. parahaemolyticus isolated from water, plankton and assorted seafood samples collected from the Indian coast. RESULTS: Twenty-two V. parahaemolyticus isolates from seafood harboured virulence associated genes encoding the thermostable-direct haemolysin (TDH), TDH-related haemolysin (TRH), and Type 3 secretion systems (T3SS) and 95.5% of the toxigenic isolates had pandemic strain attributes (toxRS/new(+)). Nine serovars, with pandemic strain traits were newly identified and an O4:K36 tdh(−)trh(+)V. parahaemolyticus bearing pandemic marker gene was recognised for the first time. Results obtained by reverse transcription PCR showed trh, T3SS1 and T3SS2β to be functional in the seafood isolates. Moreover, the environmental strains were cytotoxic and could invade Caco-2 cells upon infection as well as induce changes to the tight junction protein, ZO-1 and the actin cytoskeleton. CONCLUSION: Our study provides evidence that environmental isolates of V. parahaemolyticus are potentially invasive and capable of eliciting pathogenic characteristics typical of clinical strains and present a potential health risk. We also demonstrate that virulence of this pathogen is highly complex and hence draws attention for the need to investigate more reliable virulence markers in order to distinguish the environmental and clinical isolates, which will be crucial for the pathogenomics and control of this pathogen.


title: Changes in shunt, ventilation/perfusion mismatch, and lung aeration with PEEP in patients with ARDS: a prospective single-arm interventional study

text: BACKGROUND: Several studies have found only a weak to moderate correlation between oxygenation and lung aeration in response to changes in PEEP. This study aimed to investigate the association between changes in shunt, low and high ventilation/perfusion (V/Q) mismatch, and computed tomography-measured lung aeration following an increase in PEEP in patients with ARDS. METHODS: In this preliminary study, 12 ARDS patients were subjected to recruitment maneuvers followed by setting PEEP at 5 and then either 15 or 20 cmH(2)O. Lung aeration was measured by computed tomography. Values of pulmonary shunt and low and high V/Q mismatch were calculated by a model-based method from measurements of oxygenation, ventilation, and metabolism taken at different inspired oxygen levels and an arterial blood gas sample. RESULTS: Increasing PEEP resulted in reduced values of pulmonary shunt and the percentage of non-aerated tissue, and an increased percentage of normally aerated tissue (p < 0.05). Changes in shunt and normally aerated tissue were significantly correlated (r = − 0.665, p = 0.018). Three distinct responses to increase in PEEP were observed in values of shunt and V/Q mismatch: a beneficial response in seven patients, where shunt decreased without increasing high V/Q; a detrimental response in four patients where both shunt and high V/Q increased; and a detrimental response in a patient with reduced shunt but increased high V/Q mismatch. Non-aerated tissue decreased with increased PEEP in all patients, and hyperinflated tissue increased only in patients with a detrimental response in shunt and V/Q mismatch. CONCLUSIONS: The results show that improved lung aeration following an increase in PEEP is not always consistent with reduced shunt and V/Q mismatch. Poorly matched redistribution of ventilation and perfusion, between dependent and non-dependent regions of the lung, may explain why patients showed detrimental changes in shunt and V/Q mismatch on increase in PEEP, despite improved aeration. TRIAL REGISTRATION: ClinicalTrails.gov, NCT04067154. Retrospectively registered on August 26, 2019.


title: Burnout and Joy in the Profession of Critical Care Medicine


title: Essential Noninvasive Multimodality Neuromonitoring for the Critically Ill Patient


title: Monitoring Patient Respiratory Effort During Mechanical Ventilation: Lung and Diaphragm-Protective Ventilation


title: Small interference RNA-mediated knockdown of sperm associated antigen 9 having structural homology with c-Jun N-terminal kinase-interacting protein

text: Recently, we reported a novel testis-specific sperm associated antigen 9 (SPAG9) protein, a new member of the JNK-interacting protein family, having a functional role in sperm–egg fusion [N. Jagadish, R. Rana, R. Selvi, D. Mishra, M. Garg, S. Yadav, J.C. Herr, K. Okumura, A. Hasegawa, K. Koyama, A. Suri, Biochem. J. 389 (2005) 73–82]. NCBI Blast searches revealed SPAG9 nucleotide sequence similarities with ESTs of various cancerous tissues. In the present study, we compared the efficiency of two independent SPAG9 specific small interfering RNA (siRNA) constructs, BS/U6/spag9 and BS/U6/spag9-I, to ablate the SPAG9 expression in mammalian cells. A positive correlation between the ratio of target gene versus siRNA and the suppression of SPAG9 expression was observed. Further, the cotransfection of BS/U6/spag9 with pcDNA-SPAG9 and pFlag-CMV2-JNK-3 resulted in specific suppression of SPAG9 without affecting JNK-3 expression. The present investigation will eventually extend the application of SPAG9 siRNA in in vivo targeting experiments that aim to define the SPAG9 functional genomics in tumor and reproductive biology.


title: Policy processes sans frontières: interactions in transnational governance of global health

text: National policy on global health (NPGH) arenas are multisectoral governing arrangements for cooperation between health, development, and foreign affairs sectors in government policy for global health governance. To explore the relationship between national and global processes for governing global health, this paper asks: in what forms of interaction between NPGH arenas and global health governance are learning and networking processes present? In a multiple case study of Norwegian and Swiss NPGH arenas, we collected data on intersectoral policy processes from semi-structured interviews with 33 informants in 2014-2015. Adapting Real-Dato’s framework, we analyzed each case separately, producing monographs for comparing NPGH arenas. Analyzing both NPGH arenas for relational structures linking external resources to internal policy arena processes, we found five zones of interactions - including institutions, transgovernmental clubs, and connective forms. These interactions circulate ideas and soften arenas’ boundaries. We argue that NPGH is characteristic of transnational governance of global health. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s11077-020-09375-2) contains supplementary material, which is available to authorized users.


title: Antibody epitope repertoire analysis enables rapid antigen discovery and multiplex serology

text: The detection of pathogen-specific antibodies remains a cornerstone of clinical diagnostics. Yet, many test exhibit undesirable performance or are completely lacking. Given this, we developed serum epitope repertoire analysis (SERA), a method to rapidly discover conserved, pathogen-specific antigens and their epitopes, and applied it to develop an assay for Chagas disease caused by the protozoan parasite Trypanosoma cruzi. Antibody binding peptide motifs were identified from 28 Chagas repertoires using a bacterial display random 12-mer peptide library and next-generation sequencing (NGS). Thirty-three motifs were selected and mapped to candidate Chagas antigens. In a blinded validation set (n = 72), 30/30 Chagas were positive, 30/30 non-Chagas were negative, and 1/12 Leishmania sp. was positive. After unblinding, a Leishmania cross-reactive epitope was identified and removed from the panel. The Chagas assay exhibited 100% sensitivity (30/30) and specificity (90/90) in a second blinded validation set including individuals with other parasitic infections. Amongst additional epitope repertoires with unknown Chagas serostatus, assay specificity was 99.8% (998/1000). Thus, the Chagas assay achieved a combined sensitivity and specificity equivalent or superior to diagnostic algorithms that rely on three separate tests to achieve high specificity. NGS-based serology via SERA provides an effective approach to discover antigenic epitopes and develop high performance multiplex serological assays.


title: The data set development for the National Spinal Cord Injury Registry of Iran (NSCIR-IR): progress toward improving the quality of care

text: STUDY DESIGN: Descriptive study. OBJECTIVES: The aim of this manuscript is to describe the development process of the data set for the National Spinal Cord Injury Registry of Iran (NSCIR-IR). SETTING: SCI community in Iran. METHODS: The NSCIR-IR data set was developed in 8 months, from March 2015 to October 2015. An expert panel of 14 members was formed. After a review of data sets of similar registries in developed countries, the selection and modification of the basic framework were performed over 16 meetings, based on the objectives and feasibility of the registry. RESULTS: The final version of the data set was composed of 376 data elements including sociodemographic, hospital admission, injury incidence, prehospital procedures, emergency department visit, medical history, vertebral injury, spinal cord injury details, interventions, complications, and discharge data. It also includes 163 components of the International Standards for the Neurologic Classification of Spinal Cord Injury (ISNCSCI) and 65 data elements related to quality of life, pressure ulcers, pain, and spasticity. CONCLUSION: The NSCIR-IR data set was developed in order to meet the quality improvement objectives of the registry. The process was centered around choosing the data elements assessing care provided to individuals in the acute and chronic phases of SCI in hospital settings. The International Spinal Cord Injury Data Set was selected as a basic framework, helped by comparison with data from other countries. Expert panel modifications facilitated the implementation of the registry process with the current clinical workflow in hospitals.


title: In-depth characterization of a novel live-attenuated Mayaro virus vaccine candidate using an immunocompetent mouse model of Mayaro disease

text: Mayaro virus (MAYV) is endemic in South American countries where it is responsible for sporadic outbreaks of acute febrile illness. The hallmark of MAYV infection is a highly debilitating and chronic arthralgia. Although MAYV emergence is a potential threat, there are no specific therapies or licensed vaccine. In this study, we developed a murine model of MAYV infection that emulates many of the most relevant clinical features of the infection in humans and tested a live-attenuated MAYV vaccine candidate (MAYV/IRES). Intraplantar inoculation of a WT strain of MAYV into immunocompetent mice induced persistent hypernociception, transient viral replication in target organs, systemic production of inflammatory cytokines, chemokines and specific humoral IgM and IgG responses. Inoculation of MAYV/IRES in BALB/c mice induced strong specific cellular and humoral responses. Moreover, MAYV/IRES vaccination of immunocompetent and interferon receptor-defective mice resulted in protection from disease induced by the virulent wt MAYV strain. Thus, this study describes a novel model of MAYV infection in immunocompetent mice and highlights the potential role of a live-attenuated MAYV vaccine candidate in host’s protection from disease induced by a virulent MAYV strain.


title: A Novel Mutation in ACAT1 Causing Beta-Ketothiolase Deficiency in a 4-Year-Old Sri Lankan Boy with Metabolic Ketoacidosis

text: Beta-ketothiolase (mitochondrial acetoacetyl-CoA thiolase, T2) deficiency is a rare genetic disorder of ketone utilization and isoleucine catabolism caused by mutations in the ACAT1 gene. Here we report the first Sri Lankan case of T2 deficiency confirmed by genetic analysis. A 4-year-old boy presented with the first episode of severe metabolic ketoacidosis after a febrile illness. On admission, the child was drowsy and had circulatory collapse needing intubation. Initial investigations were not detective of a cause and symptomatic management did not improve the condition. During the acute episode, his urine organic acid profile revealed elevations in 3-OH-2-methyl-butyric acid and tiglylglycine whilst 2-methylacetoacetic acid was not detected. The differential diagnoses for the urine organic acid profile included deficiency in T2 or 2-methyl-3-OH-butyryl-CoA dehydrogenase enzymes. Genetic analysis using polymerase chain reaction and DNA sequencing of ACAT1 gene revealed that the proband is homozygous for the novel missense likely pathogenic variant c.152C > T p.(Pro51Leu) confirming the diagnosis of T2 deficiency. This case highlights the importance of suspecting T2 deficiency in the differential diagnosis of pediatric metabolic ketoacidosis in preventing life threatening consequences of an otherwise benign disorder.


title: Microcirculatory dysfunction and dead-space ventilation in early ARDS: a hypothesis-generating observational study

text: BACKGROUND: Ventilation/perfusion inequalities impair gas exchange in acute respiratory distress syndrome (ARDS). Although increased dead-space ventilation (V(D)/V(T)) has been described in ARDS, its mechanism is not clearly understood. We sought to evaluate the relationships between dynamic variations in V(D)/V(T) and extra-pulmonary microcirculatory blood flow detected at sublingual mucosa hypothesizing that an altered microcirculation, which is a generalized phenomenon during severe inflammatory conditions, could influence ventilation/perfusion mismatching manifested by increases in V(D)/V(T) fraction during early stages of ARDS. METHODS: Forty-two consecutive patients with early moderate and severe ARDS were included. PEEP was set targeting the best respiratory-system compliance after a PEEP-decremental recruitment maneuver. After 60 min of stabilization, hemodynamics and respiratory mechanics were recorded and blood gases collected. V(D)/V(T) was calculated from the CO(2) production ([Formula: see text] ) and CO(2) exhaled fraction ([Formula: see text] ) measurements by volumetric capnography. Sublingual microcirculatory images were simultaneously acquired using a sidestream dark-field device for an ulterior blinded semi-quantitative analysis. All measurements were repeated 24 h after. RESULTS: Percentage of small vessels perfused (PPV) and microcirculatory flow index (MFI) were inverse and significantly related to V(D)/V(T) at baseline (Spearman’s rho = − 0.76 and − 0.63, p < 0.001; R(2) = 0.63, and 0.48, p < 0.001, respectively) and 24 h after (Spearman’s rho = − 0.71, and − 0.65; p < 0.001; R(2) = 0.66 and 0.60, p < 0.001, respectively). Other respiratory, macro-hemodynamic and oxygenation parameters did not correlate with V(D)/V(T). Variations in PPV between baseline and 24 h were inverse and significantly related to simultaneous changes in V(D)/V(T) (Spearman’s rho = − 0.66, p < 0.001; R(2) = 0.67, p < 0.001). CONCLUSION: Increased heterogeneity of microcirculatory blood flow evaluated at sublingual mucosa seems to be related to increases in V(D)/V(T), while respiratory mechanics and oxygenation parameters do not. Whether there is a cause–effect relationship between microcirculatory dysfunction and dead-space ventilation in ARDS should be addressed in future research.


title: Predicting the Speed of Epidemics Spreading in Networks

text: Global transport and communication networks enable information, ideas, and infectious diseases to now spread at speeds far beyond what has historically been possible. To effectively monitor, design, or intervene in such epidemic-like processes, there is a need to predict the speed of a particular contagion in a particular network, and to distinguish between nodes that are more likely to become infected sooner or later during an outbreak. Here, we study these quantities using a message-passing approach to derive simple and effective predictions that are validated against epidemic simulations on a variety of real-world networks with good agreement. In addition to individualized predictions for different nodes, we find an overall sudden transition from low density to almost full network saturation as the contagion progresses in time. Our theory is developed and explained in the setting of simple contagions on treelike networks, but we are also able to show how the method extends remarkably well to complex contagions and highly clustered networks.


A Disappearing Lung Mass: Round Pneumonia


title: Transmission Electron Microscopy Improves the Diagnostic Sensitivity in Nonbacterial Etiology of Severe Pneumonia: A Retrospective Study

text: BACKGROUND: Severe pneumonia is responsible for great mortality and morbidity worldwide, and early-applied effective anti-infective therapy can improve the prognosis of patients. However, identification of infectious agents in severe pneumonia remains a major challenge so far. In this study, the potential utility of transmission electron microscopy (TEM) in detecting nonbacterial pathogens in patients with severe pneumonia was retrospectively evaluated. MATERIALS AND METHODS: A total of 106 patients diagnosed with severe pneumonia at our hospital from September 2015 to December 2017 were included, and their baseline clinical characteristics were collected. Nonbacterial infectious agents detected by TEM in bronchoalveolar lavage fluid (BALF) and serological tests were summarized. The detection rates were further compared between TEM and serological tests. RESULTS: BALF examination under the transmission electron microscope revealed 24 viruses, 16 mycoplasmas, 18 chlamydia, 2 fungi and 74 bacteria in 99 samples, among which 61 samples were mixed infections. The combined use of serological tests and TEM significantly improved the detection rate of nonbacterial infectious agents in patients with severe pneumonia. CONCLUSIONS: Our data support that implementation of TEM could improve the sensitivity for detecting viruses, atypical pathogens and mixed infections in BALF from patient of severe pneumonia. Therefore, TEM may be used as an auxiliary diagnostic method of other microbiological tests in severe pneumonia.


Global health research for America's vital interest


title: Standard and Transmission-Based Precautions: An Update for Dentistry

text: BACKGROUND: Standard Precautions are the foundation of all infection control programs and include infection control practices that apply to all patients and situations regardless of whether the infection status is suspected, confirmed or unknown. METHODS: The author reviewed Standard Precautions, including two new elements introduced by the Centers for Disease Control and Prevention in 2007: safe injection practices and respiratory hygiene and cough etiquette. Standard Precautions sometimes are referred to as the first tier of precautions because for some diseases and circumstances, transmission cannot be interrupted completely with Standard Precautions alone and it is necessary to use second-tier Transmission-Based Precautions. The author reviewed the three categories of Transmission-Based Precautions—Airborne, Droplet and Contact—with an emphasis on their use in dental health care outpatient settings. CONCLUSIONS AND CLINICAL IMPLICATIONS: Dental health care personnel (DHCP) should update their infection control programs to ensure that safe injection practices and respiratory hygiene and cough etiquette measures are used routinely. In addition, with the emergence of new pathogens, re-emergence of variant organisms and more patients seeking care in ambulatory care facilities, DHCP need to be aware of additional measures to take when treating patients in their offices who are actively infected with certain organisms to protect fully other patients, their staff members and themselves.


Presidential address: awakening the hero within


Disaster Preparedness


title: Multiday maintenance of extracorporeal lungs using cross-circulation with conscious swine

text: OBJECTIVES: Lung remains the least-utilized solid organ for transplantation. Efforts to recover donor lungs with reversible injuries using ex vivo perfusion systems are limited to <24 hours of support. Here, we demonstrate the feasibility of extending normothermic extracorporeal lung support to 4 days using cross-circulation with conscious swine. METHODS: A swine behavioral training program and custom enclosure were developed to enable multiday cross-circulation between extracorporeal lungs and recipient swine. Lungs were ventilated and perfused in a normothermic chamber for 4 days. Longitudinal analyses of extracorporeal lungs (ie, functional assessments, multiscale imaging, cytokine quantification, and cellular assays) and recipient swine (eg, vital signs and blood and tissue analyses) were performed. RESULTS: Throughout 4 days of normothermic support, extracorporeal lung function was maintained (arterial oxygen tension/inspired oxygen fraction >400 mm Hg; compliance >20 mL/cm H(2)O), and recipient swine were hemodynamically stable (lactate <3 mmol/L; pH, 7.42 ± 0.05). Radiography revealed well-aerated lower lobes and consolidation in upper lobes of extracorporeal lungs, and bronchoscopy showed healthy airways without edema or secretions. In bronchoalveolar lavage fluid, granulocyte-macrophage colony-stimulating factor, interleukin (IL) 4, IL-6, and IL-10 levels increased less than 6-fold, whereas interferon gamma, IL-1α, IL-1β, IL-1ra, IL-2, IL-8, IL-12, IL-18, and tumor necrosis factor alpha levels decreased from baseline to day 4. Histologic evaluations confirmed an intact blood–gas barrier and outstanding preservation of airway and alveolar architecture. Cellular viability and metabolism in extracorporeal lungs were confirmed after 4 days. CONCLUSIONS: We demonstrate feasibility of normothermic maintenance of extracorporeal lungs for 4 days by cross-circulation with conscious swine. Cross-circulation approaches could support the recovery of damaged lungs and enable organ bioengineering to improve transplant outcomes.


title: Emergency Preparedness and the Development of Health Care Coalitions: A Dynamic Process

text: Health care emergency preparedness has undergone significant changes since the first widespread distribution of federal funds occurred in 2002. Prior to the development of the Health Resources and Service Administration Bioterrorism Preparedness grant, support to hospitals and public health was limited to smaller regional preparedness programs such as the Chemical Stockpile Emergency Preparedness Program. Measurable progress with both the hospital preparedness program and public health emergency preparedness requires development of partnerships, establishment of coalitions, development of measurable objectives, and a community willingness to work together to solve complex preparedness problems.


Global Infections—Avian Influenza and Other Significant Emerging Pathogens: An Overview


Avian Influenza: The Next Pandemic?


title: Multifunctional nanoparticles: Analytical prospects

text: Multifunctional nanoparticles are among the most exciting nanomaterials with promising applications in analytical chemistry. These applications include (bio)sensing, (bio)assays, catalysis and separations. Although most of these applications are based on the magnetic, optical and electrochemical properties of multifunctional nanoparticles, other aspects such as the synergistic effect of the functional groups and the amplification effect associated with the nanoscale dimension have also been observed. Considering not only the nature of the raw material but also the shape, there is a huge variety of nanoparticles. In this review only magnetic, quantum dots, gold nanoparticles, carbon and inorganic nanotubes as well as silica, titania and gadolinium oxide nanoparticles are addressed. This review presents a narrative summary on the use of multifuncional nanoparticles for analytical applications, along with a discussion on some critical challenges existing in the field and possible solutions that have been or are being developed to overcome these challenges.


title: Special Features of Asthma in Children

text: Asthma in children has many special features which deserve consideration. This disease is probably underdiagnosed and is often undertreated. Vague, persistent respiratory symptoms, especially chronic cough, may often be due to asthma. Chronic bronchitis is extremely rare in the pediatric patient and is a manifestation of reactive airway disease or cystic fibrosis. The absolute severity, the extent of the disease, responses to treatment, and long-term course should be evaluated by repeated pulmonary function tests. Fortunately, asthma responds well to pharmacologic and supportive therapy, and it is important to approach its management as that of a chronic rather than episodic illness. Therapy should include comprehensive, closely supervised drug therapy, health education, and a program of selfmanagement. Asthma usually starts before youngsters enter school, and the majority get better as they get older. Nevertheless, many children with moderate or severe asthma will continue to be troubled by intermittent or chronic airway obstruction into adulthood, and they require long-term, anticipatory treatment programs. Comprehensive care will optimize the quality of life for the affected children and their families, and it will minimize the discomfort and restrictions to which some of them have been subjected unnecessarily. Asthma in childhood, especially when not well controlled, may constitute a risk factor for the development of chronic obstructive pulmonary disease in adulthood; however, this is as yet only suspected and not proved.(47)


title: The Incidence of Respiratory Tract Infection in Adults Requiring Hospitalization for Asthma

text: Acute respiratory tract infections (RTI) are known to worsen asthma particularly in children. There are few studies in adults assessing the incidence of RTI in patients hospitalized with acute asthma. AIM: To document the incidence of RTI in adults hospitalized with acute asthma. METHODS: A prospective study of patients with acute asthma admitted to the Department of Respiratory Medicine, Western Hospital Footscray, over a 12-month period. A control group was studied from elective surgical inpatients. Patients were investigated with serologic tests for Chlamydia, Mycoplasma, Legionella, and influenza A and R. Nasopharyngeal aspirate (NPA) samples were cultured for influenza, respiratory syncytial virus (RSV), adenovirus, parainfluenza, rhinovirus, and herpes simplex virus. If sputum was available, it was assessed with microscopy and culture. Rlood cultures were taken if patients were febrile and all patients had a chest radiograph. Control subjects completed serologic tests and NPA. RESULTS: Seventy-nine patients (33 male and 46 female) and 54 control subjects (26 male and 28 female) were studied. Two patients were enrolled twice. Mean (±SD) age of patients was 35 ±15 years (range, 16 to 66 years), and mean age of control subjects was 37±15 years (range, 18 to 69 years). In the patient group, 29 (37%) had evidence of recent RTI of which 23 were viral. Five of the control subjects (9%) had evidence of recent RTI (p<0.001). Twenty-four patients were positive on serologic and/or NPA culture. Five patients had positive serologic test results and/or NPA culture to two or more agents. Two patients tested positive on sputum, radiograph, and temperature criteria. Three patients tested positive on the basis of radiographic evidence of consolidation, blood neutrophilia, and temperature. Influenza A (13) and rhinovirus (9) were the most common infectious agents. Other agents identified were RSV (one), influenza R (two), adenovirus (one), and Mycoplasma (one). Influenza and rhinovirus infections occurred predominantly in late and early winter, respectively. Summer hospitalization did not relate to RTI. CONCLUSION: Thirty-seven percent of adult patients with acute asthma admitted to the Department of Respiratory Medicine over a 12-month period had evidence of recent RTI.


title: COPD in Asia: Where East Meets West

text: COPD is a global health concern, and is a major cause of chronic morbidity and mortality worldwide. According to the World Health Organization, it is currently the sixth leading cause of death in the world, and further increases in the prevalence and mortality of the disease is predicted for the coming decades. These increases are mainly linked to the epidemic of tobacco exposure and indoor and outdoor air pollution in Asian countries. The burden of COPD in Asia is currently greater than that in developed Western countries, both in terms of the total number of deaths and the burden of disease, as measured in years of life lost and years spent living with disability. The types of health-care policies and the practice of medicine vary considerably among the regions of Asia and have an impact on the burden of disease. Treatment aims in Asian countries are based on evidence-based management guidelines. Barriers to the implementation of disease management guidelines are related to issues of resource conflict and lack of organizational support rather than cultural differences in medical practice. To reduce this burden of COPD in Asian countries, there is a need for a multifaceted approach in improving awareness of prevalence and disease burden, in facilitating accurate diagnosis of COPD among chronic respiratory diseases, in championing health policies that reduce the burden of the main risk factors for COPD and in the wider use of evidence-based management for COPD.


title: Upsetting the Balance: When Viruses Manipulate Cell Polarity Control

text: The central importance of cell polarity control is emphasized by the frequency with which it is targeted by many diverse viruses. It is clear that in targeting key polarity control proteins, viruses affect not only host cell polarity, but also influence many cellular processes, including transcription, replication, and innate and acquired immunity. Examination of the interactions of different virus proteins with the cell and its polarity controls during the virus life cycles, and in virally‐induced cell transformation shows ever more clearly how intimately all cellular processes are linked to the control of cell polarity.


Lysozyme and Mucin cDNAs as Tools for the Study of Serous and Mucous Cell Differentiation


title: Community-acquired pneumonia among children: the latest evidence for an updated management()

text: OBJECTIVE: To provide cutting-edge information for the management of community-acquired pneumonia in children under 5 years, based on the latest evidence published in the literature. DATA SOURCE: A comprehensive search was conducted in PubMed, by using the expressions: “community-acquired pneumonia” AND “child” AND “etiology” OR “diagnosis” OR “severity” OR “antibiotic”. All articles retrieved had the title and the abstract read, when the papers reporting the latest evidence on each subject were identified and downloaded for complete reading. DATA SYNTHESIS: In the era of largely implemented bacterial conjugate vaccines and widespread use of amplification nucleic acid techniques, respiratory viruses have been identified as the most frequent causative agents of community-acquired pneumonia in patients under 5 years. Hypoxemia (oxygen saturation ≤96%) and increased work of breathing are signs most associated with community-acquired pneumonia. Wheezing detected on physical examination independently predicts viral infection and the negative predictive value (95% confidence interval) of normal chest X-ray and serum procalcitonin <0.25 ng/dL was 92% (77–98%) and 93% (90–99%), respectively. Inability to drink/feed, vomiting everything, convulsions, lower chest indrawing, central cyanosis, lethargy, nasal flaring, grunting, head nodding, and oxygen saturation <90% are predictors of death and can be used as indicators for hospitalization. Moderate/large pleural effusions and multilobar infiltrates are predictors of severe disease. Orally administered amoxicillin is the first line outpatient treatment, while ampicillin, aqueous penicillin G, or amoxicillin (initiated initially by intravenous route) are the first line options to treat inpatients. CONCLUSIONS: Distinct aspects of childhood community-acquired pneumonia have changed during the last three decades.


Conclusion


title: Glycomics and Proteomics Approaches to Investigate Early Adenovirus–Host Cell Interactions

text: Adenoviruses as most viruses rely on glycan and protein interactions to attach to and enter susceptible host cells. The Adenoviridae family comprises more than 80 human types and they differ in their attachment factor and receptor usage, which likely contributes to the diverse tropism of the different types. In the past years, methods to systematically identify glycan and protein interactions have advanced. In particular sensitivity, speed and coverage of mass spectrometric analyses allow for high-throughput identification of glycans and peptides separated by liquid chromatography. Also, developments in glycan microarray technologies have led to targeted, high-throughput screening and identification of glycan-based receptors. The mapping of cell surface interactions of the diverse adenovirus types has implications for cell, tissue, and species tropism as well as drug development. Here we review known adenovirus interactions with glycan- and protein-based receptors, as well as glycomics and proteomics strategies to identify yet elusive virus receptors and attachment factors. We finally discuss challenges, bottlenecks, and future research directions in the field of non-enveloped virus entry into host cells.


title: Exhaled Air and Aerosolized Droplet Dispersion During Application of a Jet Nebulizer

text: BACKGROUND: As part of our influenza pandemic preparedness, we studied the dispersion distances of exhaled air and aerosolized droplets during application of a jet nebulizer to a human patient simulator (HPS) programmed at normal lung condition and different severities of lung injury. METHODS: The experiments were conducted in a hospital isolation room with a pressure of − 5 Pa. Airflow was marked with intrapulmonary smoke. The jet nebulizer was driven by air at a constant flow rate of 6 L/min, with the mask reservoir filled with sterile water and attached to the HPS via a nebulizer mask. The exhaled leakage jet plume was revealed by a laser light sheet and images captured by high-definition video. Smoke concentration in the plume was estimated from the light scattered by smoke and droplet particles. FINDINGS: The maximum dispersion distance of smoke particles through the nebulizer side vent was 0.45 m lateral to the HPS at normal lung condition (oxygen consumption, 200 mL/min; lung compliance, 70 mL/cm H(2)O), but it increased to 0.54 m in mild lung injury (oxygen consumption, 300 mL/min; lung compliance, 35 mL/cm H(2)O), and beyond 0.8 m in severe lung injury (oxygen consumption, 500 mL/min; lung compliance, 10 mL/cm H(2)O). More extensive leakage through the side vents of the nebulizer mask was noted with more severe lung injury. INTERPRETATION: Health-care workers should take extra protective precaution within at least 0.8 m from patients with febrile respiratory illness of unknown etiology receiving treatment via a jet nebulizer even in an isolation room with negative pressure.


title: Introduction and Executive Summary: Care of the Critically Ill and Injured During Pandemics and Disasters: CHEST Consensus Statement

text: Natural disasters, industrial accidents, terrorism attacks, and pandemics all have the capacity to result in large numbers of critically ill or injured patients. This supplement provides suggestions for all of those involved in a disaster or pandemic with multiple critically ill patients, including front-line clinicians, hospital administrators, professional societies, and public health or government officials. The current Task Force included a total of 100 participants from nine countries, comprised of clinicians and experts from a wide variety of disciplines. Comprehensive literature searches were conducted to identify studies upon which evidence-based recommendations could be made. No studies of sufficient quality were identified. Therefore, the panel developed expert-opinion-based suggestions that are presented in this supplement using a modified Delphi process. The ultimate aim of the supplement is to expand the focus beyond the walls of ICUs to provide recommendations for the management of all critically ill or injured adults and children resulting from a pandemic or disaster wherever that care may be provided. Considerations for the management of critically ill patients include clinical priorities and logistics (supplies, evacuation, and triage) as well as the key enablers (systems planning, business continuity, legal framework, and ethical considerations) that facilitate the provision of this care. The supplement also aims to illustrate how the concepts of mass critical care are integrated across the spectrum of surge events from conventional through contingency to crisis standards of care.


title: Outcomes of hematopoietic stem cell transplantation for Hurler's syndrome in Europe: a risk factor analysis for graft failure

text: Hurler's syndrome (HS), the most severe form of mucopolysaccharidosis type-I, causes progressive deterioration of the central nervous system and death in childhood. Allogeneic stem cell transplantation (SCT) before the age of 2 years halts disease progression. Graft failure limits the success of SCT. We analyzed data on HS patients transplanted in Europe to identify the risk factors for graft failure. We compared outcomes in 146 HS patients transplanted with various conditioning regimens and grafts. Patients were transplanted between 1994 and 2004 and registered to the European Blood and Marrow Transplantation database. Risk factor analysis was performed using logistic regression. ‘Survival’ and ‘alive and engrafted’-rate after first SCT was 85 and 56%, respectively. In multivariable analysis, T-cell depletion (odds ratio (OR) 0.18; 95% confidence interval (CI) 0.04–0.71; P=0.02) and reduced-intensity conditioning (OR 0.08; 95% CI 0.02–0.39; P=0.002) were the risk factors for graft failure. Busulfan targeting protected against graft failure (OR 5.76; 95% CI 1.20–27.54; P=0.028). No difference was noted between cell sources used (bone marrow, peripheral blood stem cells or cord blood (CB)); however, significantly more patients who received CB transplants had full-donor chimerism (OR 9.31; 95% CI 1.06–82.03; P=0.044). These outcomes may impact the safety/efficacy of SCT for ‘inborn-errors of metabolism’ at large. CB increased the likelihood of sustained engraftment associated with normal enzyme levels and could therefore be considered as a preferential cell source in SCT for ‘inborn errors of metabolism’.


title: The Contribution of Respiratory Viruses to Severe Exacerbations of Asthma in Adults

text: Viral infections are known to be associated with severe exacerbations of asthma in children. In contrast, there is limited data that viral infections evoke acute episodes of asthma that require emergency care in adults. To determine the role of viral infections in exacerbations of asthma in adults, we examined 33 patients who presented to the emergency room with 35 exacerbations of asthma between September 1990 and March 1991 for the presence of a viral infection. A nasal swab was obtained for virus isolation by culture and rapid antigen detection by fluorescent staining. In 16 patients, serum was collected at initial presentation and 3 to 4 weeks later for acute and convalescent viral antibody titers. All patients had acute episodes of asthma ascertained by medical history and physical examination. About 56% of the patients with asthma exacerbations had symptoms suggestive of viral illness. Rapid antigen detection and viral cultures for influenza A and B, parainfluenza-1, 2, 3, respiratory syncytial virus, adenovirus, and rhinovirus were negative on all patients. Likewise, in all 16 patients tested, acute and convalescent serologic studies did not show a significant rise in titer by complement fixation test. Thus, despite symptoms consistent with viral infection, viral pathogens could not be shown by current virologic techniques. This study suggests that viral infection may not be as prevalent a precipitate of asthma in adults requiring emergency room treatment as is generally thought.


title: Deciphering the Nucleotide and RNA Binding Selectivity of the Mayaro Virus Macro Domain

text: Mayaro virus (MAYV) is a member of Togaviridae family, which also includes Chikungunya virus as a notorious member. MAYV recently emerged in urban areas of the Americas, and this emergence emphasized the current paucity of knowledge about its replication cycle. The macro domain (MD) of MAYV belongs to the N-terminal region of its non-structural protein 3, part of the replication complex. Here, we report the first structural and dynamical characterization of a previously unexplored Alphavirus MD investigated through high-resolution NMR spectroscopy, along with data on its ligand selectivity and binding properties. The structural analysis of MAYV MD reveals a typical “macro” (ββαββαβαβα) fold for this polypeptide, while NMR-driven interaction studies provide in-depth insights into MAYV MD–ligand adducts. NMR data in concert with thermodynamics and biochemical studies provide convincing experimental evidence for preferential binding of adenosine diphosphate ribose (ADP‐r) and adenine-rich RNAs to MAYV MD, thus shedding light on the structure–function relationship of a previously unexplored viral MD. The emerging differences with any other related MD are expected to enlighten distinct functions.


A 57-Year-Old Woman With Fever and Abnormal Chest CT Findings


title: US Public Health Service Commissioned Corps Nurses: Responding in Times of National Need

text: The US Public Health Service (PHS) is one of 7 uniformed services operating for the nation. Nurses form the largest category of personnel in the PHS and are integral members of teams identified to deploy in times of national need. PHS nurses serve “in harm's way” to protect and defend the public health of the nation during national emergencies and disasters of great magnitude, such as 9/11, Hurricane Katrina, the H1N1 virus outbreak, and so forth. In this article, the authors discuss how active-duty Commissioned Corps nurses in the US PHS respond during times of national need. Military nurses may be asked to serve in war zones, participate in humanitarian missions, and care for military beneficiaries. By contrast, the role of nurses in the Commissioned Corps is to protect, defend, and advance the public health of the nation. PHS nurses are critical members of interdisciplinary health care teams organized to provide health care to diverse populations in the United States and abroad.


title: Virus membrane fusion

text: Membrane fusion of enveloped viruses with cellular membranes is mediated by viral glycoproteins (GP). Interaction of GP with cellular receptors alone or coupled to exposure to the acidic environment of endosomes induces extensive conformational changes in the fusion protein which pull two membranes into close enough proximity to trigger bilayer fusion. The refolding process provides the energy for fusion and repositions both membrane anchors, the transmembrane and the fusion peptide regions, at the same end of an elongated hairpin structure in all fusion protein structures known to date. The fusion process follows several lipidic intermediate states, which are generated by the refolding process. Although the major principles of viral fusion are understood, the structures of fusion protein intermediates and their mode of lipid bilayer interaction, the structures and functions of the membrane anchors and the number of fusion proteins required for fusion, necessitate further investigations.


title: Airflows Around Oxygen Masks: A Potential Source of Infection

text: Patients with respiratory infections often require the use of supplemental oxygen via oxygen masks, which, in the hospital, may become sources of aerosolized infectious pathogens. To assess this risk, a human lung model (respiration rate, 12 breaths/min) was designed to test the potential for a simple oxygen mask at a common setting (4 L/min) to disperse potentially infectious exhaled air into the surrounding area. A laser sheet was used to illuminate the exhaled air from the mask, which contained fine tracer smoke particles. An analysis of captured digital images showed that the exhaled air at the peak of simulated exhalation reached a distance of approximately 0.40 m.


title: Job satisfaction and its related factors: A questionnaire survey of hospital nurses in Mainland China

text: BACKGROUND: The widespread nursing shortage is of concern in Mainland China and globally. Factors underpinning the increased mobility of the nursing workforce and their contribution to nurses’ turnover thus merit attention. Understanding nurses’ job satisfaction is important, as this is a key factor in nurses’ turnover. OBJECTIVE: The study aimed to explore nurses’ views and experience regarding different components of their working lives in Mainland China. METHODS: A cross-sectional survey design was selected and 512 nurses working in the medical and surgical departments in two teaching hospitals in Beijing completed questionnaires yielding a response rate of 81%. RESULTS: More than half of nurses (53.7%; n=275) were satisfied or very satisfied with their jobs and 15% (n=77) felt moderate to extreme occupational stress. The majority of the sample reported a high level of organizational commitment (63.7%; n=326) and professional commitment (85.9%; n=440) and only 5.9% (n=30) and 10.0% (n=51), respectively reported role conflict and role ambiguity often or very often. Nurses with a diploma or associate degree reported greater professional commitment and a lower level of role conflict than those with a bachelor degree (p<0.05), but there were no significant differences in job satisfaction, organizational commitment, occupational stress and role ambiguity by educational programme (p>0.05). CONCLUSIONS: Hospital nurses’ positive feelings regarding their working lives may be influenced by developments in the health care system and the nursing profession in Mainland China. Nurses’ educational level is an influencing factor on nurses’ views and experiences of their working lives with the findings suggesting the need to develop a clinical career ladder for nursing staff in Mainland China.


title: Phosphorylation of PI3K/Akt and MAPK/ERK in an early entry step of enterovirus 71

text: Viruses have been known to subvert the anti-apoptotic pathways of the host cell in order to delay apoptosis. However, the mechanisms utilized by enterovirus 71 (EV71) to mediate anti-apoptotic activity remained undetermined. We observed that EV71 infection induced an early activation of both phosphatidylinositol 3-kinase (PI3K)/Akt and MAPK/ERK signaling pathways. The activity of GSK3β, a downstream target of these pathways, was negatively regulated by the activation of both MAPK/ERK and PI3K/Akt. The phosphorylation of GSK3 could be inhibited by treatment with the specific inhibitors of MAPK/ERK and PI3K/Akt. Other Akt downstream targets, BAD, caspase-9 and the Forkhead transcription factor (FKHR), were not phosphorylated during the course of infection by EV71. We further demonstrated that infection by UV-irradiated, inactivated virus triggered early Akt activation but was insufficient to trigger late Akt activation. These data suggest that with the phosphorylation of MAPK/ERK and PI3K/Akt the subsequent inactivation of GSK3β is utilized by EV71 as a potential mechanism to delay host cell apoptosis.