A prospective cohort study of healthcare visits and rehospitalizations after hospital discharge in community-acquired pneumonia

Background and objective: We aimed to identify the frequency of, reasons for and risk factors associated with additional healthcare visits and rehospitalizations (healthcare interactions) by patients with community-acquired pneumonia (CAP) within 30 days of hospital discharge. Methods: Observational analysis of a prospective cohort of adults hospitalized with CAP at a tertiary hospital (2007-2009). Additional healthcare interactions were defined as the visits to a primary care centre or emergency department and hospital readmissions within 30 days of discharge. Results: Of the 934 hospitalized patients with CAP, 282 (34.1%) had additional healthcare interactions within 30 days of hospital discharge: 149 (52.8%) needed an additional visit to their primary care centre and 177 (62.8%) attended the emergency department. Seventy-two (25.5%) patients were readmitted to hospital. The main reasons for additional healthcare interactions were worsening of signs or symptoms of CAP and new or worsening comorbid conditions independent of pneumonia, mainly cardiovascular and pulmonary diseases. The only independent factor associated with visits to primary care centre or emergency department was alcohol abuse (odds ratio [OR] = 1.65; 95% confidence interval [CI]: 1.03-2.64). Prior hospitalization (≤ 90 days) (OR = 2.47; 95% CI: 1.11-5.52) and comorbidities (OR = 3.99; 95% CI: 1.12-14.23) were independently associated with rehospitalization. Conclusions: Additional healthcare visits and rehospitalizations within 30 days of hospital discharge are common in patients with CAP. This is mainly due to a worsening of signs or symptoms of CAP and/or comorbid conditions. These findings may have implications for discharge planning and follow-up of patients with CAP.

Long-term persistence of immunity induced by OVA-coupled gas-filled microbubble vaccination partially protects mice against infection by OVA-expressing Listeria.

Vaccination aims at generating memory immune responses able to protect individuals against pathogenic challenges over long periods of time. Subunit vaccine formulations based on safe, but poorly immunogenic, antigenic entities must be combined with adjuvant molecules to make them efficient against infections. We have previously shown that gas-filled microbubbles (MB) are potent antigen-delivery systems. This study compares the ability of various ovalbumin-associated MB (OVA-MB) formulations to induce antigen-specific memory immune responses and evaluates long-term protection toward bacterial infections. When initially testing dendritic cells reactivity to MB constituents, palmitic acid exhibited the highest degree of activation. Subcutaneous immunization of naïve wild-type mice with the OVA-MB formulation comprising the highest palmitic acid content and devoid of PEG2000 was found to trigger the more pronounced Th1-type response, as reflected by robust IFN-γ and IL-2 production. Both T cell and antibody responses persisted for at least 6 months after immunization. At that time, systemic infection with OVA-expressing Listeria monocytgenes was performed. Partial protection of vaccinated mice was demonstrated by reduction of the bacterial load in both the spleen and liver. We conclude that antigen-bound MB exhibit promising properties as a vaccine candidate ensuring prolonged maintenance of protective immunity.

A prospective cohort study of healthcare visits and rehospitalizations after hospital discharge in community-acquired pneumonia

Background and objective: We aimed to identify the frequency of, reasons for and risk factors associated with additional healthcare visits and rehospitalizations (healthcare interactions) by patients with community-acquired pneumonia (CAP) within 30 days of hospital discharge. Methods: Observational analysis of a prospective cohort of adults hospitalized with CAP at a tertiary hospital (2007-2009). Additional healthcare interactions were defined as the visits to a primary care centre or emergency department and hospital readmissions within 30 days of discharge. Results: Of the 934 hospitalized patients with CAP, 282 (34.1%) had additional healthcare interactions within 30 days of hospital discharge: 149 (52.8%) needed an additional visit to their primary care centre and 177 (62.8%) attended the emergency department. Seventy-two (25.5%) patients were readmitted to hospital. The main reasons for additional healthcare interactions were worsening of signs or symptoms of CAP and new or worsening comorbid conditions independent of pneumonia, mainly cardiovascular and pulmonary diseases. The only independent factor associated with visits to primary care centre or emergency department was alcohol abuse (odds ratio [OR] = 1.65; 95% confidence interval [CI]: 1.03-2.64). Prior hospitalization (≤ 90 days) (OR = 2.47; 95% CI: 1.11-5.52) and comorbidities (OR = 3.99; 95% CI: 1.12-14.23) were independently associated with rehospitalization. Conclusions: Additional healthcare visits and rehospitalizations within 30 days of hospital discharge are common in patients with CAP. This is mainly due to a worsening of signs or symptoms of CAP and/or comorbid conditions. These findings may have implications for discharge planning and follow-up of patients with CAP.

Classification models for neurocognitive impairment in HIV infection based on demographic and clinical variables

Objective: We used demographic and clinical data to design practical classification models for prediction of neurocognitive impairment (NCI) in people with HIV infection. Methods: The study population comprised 331 HIV-infected patients with available demographic, clinical, and neurocognitive data collected using a comprehensive battery of neuropsychological tests. Classification and regression trees (CART) were developed to btain detailed and reliable models to predict NCI. Following a practical clinical approach, NCI was considered the main variable for study outcomes, and analyses were performed separately in treatment-naïve and treatment-experienced patients. Results: The study sample comprised 52 treatment-naïve and 279 experienced patients. In the first group, the variables identified as better predictors of NCI were CD4 cell count and age (correct classification [CC]: 79.6%, 3 final nodes). In treatment-experienced patients, the variables most closely related to NCI were years of education, nadir CD4 cell count, central nervous system penetration-effectiveness score, age, employment status, and confounding comorbidities (CC: 82.1%, 7 final nodes). In patients with an undetectable viral load and no comorbidities, we obtained a fairly accurate model in which the main variables were nadir CD4 cell count, current CD4 cell count, time on current treatment, and past highest viral load (CC: 88%, 6 final nodes). Conclusion: Practical classification models to predict NCI in HIV infection can be obtained using demographic and clinical variables. An approach based on CART analyses may facilitate screening for HIV-associated neurocognitive disorders and complement clinical information about risk and protective factors for NCI in HIV-infected patients.

HIV-1 Transmission During Recent Infection and During Treatment Interruptions as Major Drivers of New Infections in the Swiss HIV Cohort Study.

BACKGROUND: Reducing the fraction of transmissions during recent human immunodeficiency virus (HIV) infection is essential for the population-level success of "treatment as prevention". METHODS: A phylogenetic tree was constructed with 19 604 Swiss sequences and 90 994 non-Swiss background sequences. Swiss transmission pairs were identified using 104 combinations of genetic distance (1%-2.5%) and bootstrap (50%-100%) thresholds, to examine the effect of those criteria. Monophyletic pairs were classified as recent or chronic transmission based on the time interval between estimated seroconversion dates. Logistic regression with adjustment for clinical and demographic characteristics was used to identify risk factors associated with transmission during recent or chronic infection. FINDINGS: Seroconversion dates were estimated for 4079 patients on the phylogeny, and comprised between 71 (distance, 1%; bootstrap, 100%) to 378 transmission pairs (distance, 2.5%; bootstrap, 50%). We found that 43.7% (range, 41%-56%) of the transmissions occurred during the first year of infection. Stricter phylogenetic definition of transmission pairs was associated with higher recent-phase transmission fraction. Chronic-phase viral load area under the curve (adjusted odds ratio, 3; 95% confidence interval, 1.64-5.48) and time to antiretroviral therapy (ART) start (adjusted odds ratio 1.4/y; 1.11-1.77) were associated with chronic-phase transmission as opposed to recent transmission. Importantly, at least 14% of the chronic-phase transmission events occurred after the transmitter had interrupted ART. CONCLUSIONS: We demonstrate a high fraction of transmission during recent HIV infection but also chronic transmissions after interruption of ART in Switzerland. Both represent key issues for treatment as prevention and underline the importance of early diagnosis and of early and continuous treatment.

Antifungal activity against planktonic and biofilm Candida albicans in an experimental model of foreign-body infection.

OBJECTIVES: The treatment of Candida implant-associated infections remains challenging. We investigated the antifungal activity against planktonic and biofilm Candida albicans in a foreign-body infection model. METHODS: Teflon cages were subcutaneously implanted in guinea pigs, infected with C. albicans (ATCC 90028). Animals were treated intraperitoneally 12 h after infection for 4 days once daily with saline, fluconazole (16 mg/kg), amphotericin B (2.5 mg/kg), caspofungin (2.5 mg/kg) or anidulafungin (20 mg/kg). Planktonic Candida was quantified, the clearance rate and cure rate determined. RESULTS: In untreated animals, planktonic Candida was cleared from cage fluid in 25% (infected with 4.5 × 10(3) CFU/cage), 8% (infected with 4.8 × 10(4) CFU/cage) and 0% (infected with 6.2 × 10(5) CFU/cage). Candida biofilm persisted on all explanted cages. Compared to untreated controls, caspofungin reduced the number of planktonic C. albicans to 0.22 and 0.0 CFU/ml, respectively, and anidulafungin to 0.11 and 0.13 CFU/ml, respectively. Fluconazole cured 2/12 cages (17%), amphotericin B and anidulafungin 1/12 cages (8%) and caspofungin 3/12 cages (25%). CONCLUSION: Echinocandins showed superior activity against planktonic C. albicans. Caspofungin showed the highest cure rate of C. albicans biofilm. However, no antifungal exceeded 25% cure rate, demonstrating the difficulty of eradicating Candida biofilms from implants.

Delivery of antigen to nasal-associated lymphoid tissue microfold cells through secretory IgA targeting local dendritic cells confers protective immunity.

BACKGROUND: Transmission of mucosal pathogens relies on their ability to bind to the surfaces of epithelial cells, to cross this thin barrier, and to gain access to target cells and tissues, leading to systemic infection. This implies that pathogen-specific immunity at mucosal sites is critical for the control of infectious agents using these routes to enter the body. Although mucosal delivery would ensure the best onset of protective immunity, most of the candidate vaccines are administered through the parenteral route. OBJECTIVE: The present study evaluates the feasibility of delivering the chemically bound p24gag (referred to as p24 in the text) HIV antigen through secretory IgA (SIgA) in nasal mucosae in mice. RESULTS: We show that SIgA interacts specifically with mucosal microfold cells present in the nasal-associated lymphoid tissue. p24-SIgA complexes are quickly taken up in the nasal cavity and selectively engulfed by mucosal dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin-positive dendritic cells. Nasal immunization with p24-SIgA elicits both a strong humoral and cellular immune response against p24 at the systemic and mucosal levels. This ensures effective protection against intranasal challenge with recombinant vaccinia virus encoding p24. CONCLUSION: This study represents the first example that underscores the remarkable potential of SIgA to serve as a carrier for a protein antigen in a mucosal vaccine approach targeting the nasal environment.

How to get rid of a pathobiontic bacterium from the stomach mucosa : role of inflammatory monocytes and IL-22 in the vaccine-induced reduction of helicobacter infection

Helicobacter pylori is a bacterium colonizing the human stomach. To prevent or cure this potentially detrimental infection, vaccination might be a suitable alternative to antibiotic therapies. Recently, a study has demonstrated that a vaccine efficiently prevented H pylori infection in human. However, the mechanisms leading to protection remain elusive. In mice, the vaccine-induced protective response relies on CD4+ T cells and especially on Thl7 response. Nevertheless, the factors mediating the reduction of H pylori infection are not fully characterized. Hence, the aim of my thesis was to characterize the factors associated with the Thl7 response. In the context of the vaccine-induced reduction of Helicobacter infection, I first focused on the role of inflammatory monocytes. I showed that CDllb+Ly6CLOW inflammatory monocytes accumulated in the stomach of vaccinated mice in association with the reduction of Helicobacter infection. Remarkably, the depletion of inflammatory monocytes delayed the vaccine-induced protective response. Concerning the role of these cells, I demonstrated that inflammatory monocytes extracted from the stomach of vaccinated mice produced iNOS and killed H pylori in vitro. In a next step, I evaluated the role of IL-22 during the vaccine-induced response. IL-22, which is linked to the Thl7 response, increases innate defense mechanisms of epithelial cells. I demonstrated that IL-22 produced by antigen- specific Thl7 was increased in the stomach of vaccinated mice during the protective response. Interestingly, neutralization of IL-22 was associated with an impaired vaccine-induced protective response. Then, I demonstrated that IL-22 induced antimicrobial peptides (AMPs) secretion by epithelial cells. These AMPs killed H pylori in vitro. In conclusion, I showed that both inflammatory monocytes and IL-22 participated to the vaccine induced reduction of Helicobacter infection. In addition, I demonstrated that the epithelium along with inflammation induced by Thl7 response is a critical factor mediating reduction of Helicobacter infection.

Mouse Model of Respiratory Tract Infection Induced by Waddlia chondrophila.

Waddlia chondrophila, an obligate intracellular bacterium belonging to the Chlamydiales order, is considered as an emerging pathogen. Some clinical studies highlighted a possible role of W. chondrophila in bronchiolitis, pneumonia and miscarriage. This pathogenic potential is further supported by the ability of W. chondrophila to infect and replicate within human pneumocytes, macrophages and endometrial cells. Considering that W. chondrophila might be a causative agent of respiratory tract infection, we developed a mouse model of respiratory tract infection to get insight into the pathogenesis of W. chondrophila. Following intranasal inoculation of 2 x 108 W. chondrophila, mice lost up to 40% of their body weight, and succumbed rapidly from infection with a death rate reaching 50% at day 4 post-inoculation. Bacterial loads, estimated by qPCR, increased from day 0 to day 3 post-infection and decreased thereafter in surviving mice. Bacterial growth was confirmed by detecting dividing bacteria using electron microscopy, and living bacteria were isolated from lungs 14 days post-infection. Immunohistochemistry and histopathology of infected lungs revealed the presence of bacteria associated with pneumonia characterized by an important multifocal inflammation. The high inflammatory score in the lungs was associated with the presence of pro-inflammatory cytokines in both serum and lungs at day 3 post-infection. This animal model supports the role of W. chondrophila as an agent of respiratory tract infection, and will help understanding the pathogenesis of this strict intracellular bacterium.

MALT1 activity controls Kaposi's sarcoma-associated herpesvirus latency and growth of primary effusion lymphoma

The identification of cancer-specific enzymatic activities that can be therapeutically targeted is key to the development of suitable anti-cancer drugs. Primary effusion lymphoma (PEL) is a rare and incurable malignancy that can occur in immunodeficient patients as a consequence of latent infection of B-cells with Kaposi's sarcoma-associated herpesvirus, KSHV (also known as human herpesvirus-8, HHV8). Malignant growth of KSHV-infected B cells requires the constitutive activity of the transcription factor NF-KB, which controls expression of viral genes required for maintenance of viral latency and suppression of the viral lytic program. Here we identify the protease mucosa-associated lymphoid tissue transformation protein 1 (MALTI), a key driver of NF-KB activation in lymphocytes, as an essential component in KSHV-dependent NF-KB activation and growth of latently infected PEL cell lines. Inhibition of the MALTI protease activity induced a switch from the latent to the lytic stage of viral infection, and led to reduced growth and survival of PEL cell lines in vitro and in a xenograft model. These results demonstrate a key role for the proteolytic activity of MALTI in PEL, and provide a rationale for the pharmacological targeting of MALTI in PEL therapy. -- L'identification d'activités enzymatiques propre au cancer est clé dans le développement des nouvaux médicaments anti-cancer. Le lymphome primitif des séreuses est un lymphome rare et incurable qui peut se developer chez les patients immunodéficients. Il est la conséquence d'une infection latente des cellules B, dûe à l'herpes virus 8, plus connu comme herpes virus associé au sarcome de Kaposi (KSHV). La croissance maligne des cellules B infecteés par KSHV requière l'activité constitutive du facteur de transcription NF-KB qui contrôle l'expression des genes viraux requis pour la maintenance latente et la suppression du programme de lyse du virus. Avec cette étude, nous avons identifié la protease MALTI comme un composant essentiel dans l'activation de NF-KB dans les cellules B du lymphome primitif des séreuses. L'inhibition de l'activité de la protéase MALTI induit un virement de la phase latente à la phase lytique du KSHV et conduit à une reduction de la viabilité des cellules tumorales in vitro et dans un modèle de xénogreffe. Ces résultats démontrent un rôle clé pour l'activité protéolytique de MALTI dans le développement du lymphome primitif des séreuses et soutiennent l'idée que MALTI pourrait être une cible pharmacologique dans la thérapie de cette forme rare du lymphome.

Is the presence of an intrathecal synthesis of immunoglobulins associated with neurocognitive impairment in HIV-infected patients?

Worldwide, the incidence of HIV-associated dementia has decreased However, the prevalence of HIV-associated neurocognitive disorders (HAND), mostly the milder forms, i.e. mild neurocognitve disorders (MND) and asymptomatic neurocognitive impairments (ANI) has increased in the combined antiretroviral therapy (cART) era. Indeed, 20% to 60% of well- treated HIV-infected patients, i.e. with undetectable HIV viremia, still present HAND in the cART era. HAND are characterized by psychomotor slowing, memory loss, and attention deficit. Possible explanations for this paradoxical phenomenon encompass: increased survival of HIV- infected patients thank to cART, low grade inflammation of the brain insufficient penetrance of antiretroviral drugs through the blood brain barrier (BBB), or on the contrary, toxic effect of some antiretroviral drugs. These somewhat contradictory hypotheses underline our poor understanding of HAND physiopathology. Here, we aim at determining whether the intrathecal synthesis of immunoglobulins G (IgG), hereafter referred as cerebrospinal fluid oligoclonal band (CSF OB), may help us in better understanding the immunopathogenesis of cognitive disorders. By analogy with other infection, such as syphilis or neuroborreliosis (9, 10), one can assume that, in the case of HIV-infected patients, the CSF OB are directed against HIV proteins (11). Nevertheless, in the case of HIV, the meaning of such CSF OB is unclear. Indeed, it is unknown whether this intrathecal inflammatory reaction is beneficial (viral control) or harmful (brain parenchyma destruction by the different inflammatory factors). Here, we looked at the association between CSF OB and cognitive disorders in HIV-infected patients, hypothesizing that if these CSF OB are protective, one should see an inverse correlation with the presence of cognitive disorders.

Mycobacterium tuberculosis Infection in Young Children: Analyzing the Performance of the Diagnostic Tests

This study evaluated the performance of the Tuberculin Skin Test (TST) and Quantiferon-TB Gold in-Tube (QFT) and the possible association of factors which may modify their results in young children (0-6 years) with recent contact with an index tuberculosis case. Materials and Methods: A cross-sectional study including 135 children was conducted in Manaus, Amazonas-Brazil. The TST and QFT were performed and the tests results were analyzed in relation to the personal characteristics of the children studied and their relationship with the index case. Results: The rates of positivity were 34.8% (TST) and 26.7% (QFT), with 14.1% of indeterminations by the QFT. Concordance between tests was fair (Kappa = 0.35 P<0.001). Both the TST and QFT were associated with the intensity of exposure (Linear OR = 1.286, P = 0.005; Linear OR = 1.161, P = 0.035 respectively) with only the TST being associated with the time of exposure (Linear OR = 1.149, P = 0.009). The presence of intestinal helminths in the TST+ group was associated with negative QFT results (OR = 0.064, P = 0.049). In the TST- group lower levels of ferritin were associated with QFT+ results (Linear OR = 0.956, P = 0.036). Conclusions: Concordance between the TST and QFT was lower than expected. The factors associated with the discordant results were intestinal helminths, ferritin levels and exposure time to the index tuberculosis case. In TST+ group, helminths were associated with negative QFT results suggesting impaired cell-mediated immunity. The TST-&QFT+ group had a shorter exposure time and lower ferritin levels, suggesting that QFT is faster and ferritin may be a potential biomarker of early stages of tuberculosis infection.

Virus Infections in Early Childhood, Cow’s Milk Formula Exposure and Genetic Predisposition in the Development of Diabetes-Associated Autoimmunity

Varhaislapsuuden virusinfektioiden, lehmänmaitopohjaisen äidinmaitovastikeen ja geneettisen alttiuden merkitys diabetekseen liittyvän autoimmuniteetin kehittymisessä Tyypin 1 diabetes on autoimmuunisairaus, joka syntyy haiman insuliinia tuottavien beta-solujen tuhouduttua elimistön oman immuunipuolustusjärjestelmän hyökkäyksen seurauksena. Sekä perimän että ympäristötekijöiden arvellaan vaikuttavan tautiprosessiin, mutta taudin tarkkaa syntymekanismia ei tunneta. Tutkimuksen tarkoituksena oli selvittää varhaislapsuuden ympäristötekijöiden vaikutusta beta-soluautoimmuniteetin syntyyn, erityispaino tutkimuksessa oli ympäristötekijöiden yhteisvaikutuksessa sekä geneettisten riskitekijöiden ja ympäristötekijöiden vuorovaikutuksessa. Varhaislapsuudessa sairastettu sytomegalovirus- tai enterovirusinfektio ei lisännyt beta-soluautoimmuniteetin riskiä lapsilla, joilla on geneettisesti kohonnut riski sairastua tyypin 1 diabetekseen. Ennen puolen vuoden ikää sairastettu rotavirusinfektio lisäsi hieman tyypin 1 diabetekseen liittyvän autoimmuniteetin riskiä. Tarkemmassa analyysissa varhaislapsuuden enterovirusinfektio osoittautui kuitenkin autovasta-aineiden muodostumisen riskitekijäksi niiden lasten joukossa, jotka olivat saaneet lehmänmaitopohjaista äidinmaidon vastiketta ensimmäisten elinkuukausien aikana. Tämä löydös viittaa enterovirusinfektion ja lehmänmaitopohjaisen vastikkeen yhteisvaikutukseen tyypin 1 diabetekseen liittyvän autoimmuniteetin synnyssä. Löydösten mukaan PTPN22 geenin C1858T polymorfismi vaikuttaa CD4+ T solujen aktivaatioon ja proliferaatiovasteeseen, 1858T alleeliin liittyy alentunut T-soluresepto-rivälitteinen aktivaatio. 1858T alleelin kantajuuteen liittyy lisäksi lisääntynyt autovasta-aineiden ja kliinisen diabeteksen ilmaantuvuus. Tämä yhteys rajoittui yksilöihin, jotka olivat altistuneet lehmänmaitopohjaiselle vastikkeelle ennen kuuden kuukauden ikää. Tulosten mukaan sekä ympäristötekijöiden väliset yhteisvaikutukset että perimä vaikuttavat yksittäisen ympäristötekijän merkitykseen tyypin 1 diabetekseen liittyvän autoimmuniteetin synnyssä. Nämä yhteisvaikutukset ympäristötekijöiden kesken ja perimän ja ympäristötekijöiden välillä selittävät aiemmin julkaistujen tulosten ristiriittaisuutta tutkimuksissa, joissa on analysoitu vain yhden ympäristötekijän vaikutusta diabeteksen ilmaantuvuuteen.

Sociodemographic Factors and Clinical Conditions Associated to Hospitalization in Influenza A (H1N1) 2009 Virus Infected Patients in Spain, 2009-2010

The emergence and pandemic spread of a new strain of influenza A (H1N1) virus in 2009 resulted in a serious alarm in clinical and public health services all over the world. One distinguishing feature of this new influenza pandemic was the different profile of hospitalized patients compared to those from traditional seasonal influenza infections. Our goal was to analyze sociodemographic and clinical factors associated to hospitalization following infection by influenza A(H1N1) virus. We report the results of a Spanish nationwide study with laboratory confirmed infection by the new pandemic virus in a case-control design based on hospitalized patients. The main risk factors for hospitalization of influenza A (H1N1) 2009 were determined to be obesity (BMI≥40, with an odds-ratio [OR] 14.27), hematological neoplasia (OR 10.71), chronic heart disease, COPD (OR 5.16) and neurological disease, among the clinical conditions, whereas low education level and some ethnic backgrounds (Gypsies and Amerinds) were the sociodemographic variables found associated to hospitalization. The presence of any clinical condition of moderate risk almost triples the risk of hospitalization (OR 2.88) and high risk conditions raise this value markedly (OR 6.43). The risk of hospitalization increased proportionally when for two (OR 2.08) or for three or more (OR 4.86) risk factors were simultaneously present in the same patient. These findings should be considered when a new influenza virus appears in the human population

Amphotericin B associated with triglyceride-rich nanoemulsion: stability studies and in vitro antifungal activity

Amphotericin B (AB) is the standard drug for invasive fungal infection therapy. It has a broad spectrum of activity and it is the best antifungal available against most yeasts and molds. Its therapeutic use, however, is limited by significant side effects, leading to a low therapeutic index when it is used as the traditional formulation (Fungizone®). Due to self-association, AB can form pores in cholesterol-containing membranes. We propose a triglyceride-rich nanoemulsion as a delivery system for AB in low levels of aggregation to reduce the toxicity against host cells.