Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The guidance in this report is for evaluation and treatment of patients with complications from smallpox vaccination in the preoutbreak setting. Information is also included related to reporting adverse events and seeking specialized consultation and therapies for these events. The frequencies of smallpox vaccine-associated adverse events were identified in studies of the 1960s. Because of the unknown prevalence of risk factors among today's population, precise predictions of adverse reaction rates after smallpox vaccination are unavailable. The majority of adverse events are minor, but the less-frequent serious adverse reactions require immediate evaluation for diagnosis and treatment. Agents for treatment of certain vaccine-associated severe adverse reactions are vaccinia immune globulin (VIG), the first-line therapy, and cidofovir, the second-line therapy. These agents will be available under Investigational New Drug (IND) protocols from CDC and the U.S. Department of Defense (DoD). Smallpox vaccination in the preoutbreak setting is contraindicated for persons who have the following conditions or have a close contact with the following conditions: 1) a history of atopic dermatitis (commonly referred to as eczema), irrespective of disease severity or activity; 2) active acute, chronic, or exfoliative skin conditions that disrupt the epidermis; 3) pregnant women or women who desire to become pregnant in the 28 days after vaccination; and 4) persons who are immunocompromised as a result of human immunodeficiency virus or acquired immunodeficiency syndrome, autoimmune conditions, cancer, radiation treatment, immunosuppressive medications, or other immunodeficiencies. Additional contraindications that apply only to vaccination candidates but do not include their close contacts are persons with smallpox vaccine-component allergies, women who are breastfeeding, those taking topical ocular steroid medications, those with moderate-to-severe intercurrent illness, and persons aged < 18 years. In addition, history of Darier disease is a contraindication in a potential vaccinee and a contraindication if a household contact has active disease. In the event of a smallpox outbreak, outbreak-specific guidance will be disseminated by CDC regarding populations to be vaccinated and specific contraindications to vaccination. Vaccinia can be transmitted from a vaccinee's unhealed vaccination site to other persons by close contact and can lead to the same adverse events as in the vaccinee. To avoid transmission of vaccinia virus (found in the smallpox vaccine) from vaccinees to their close contacts, vaccinees should wash their hands with warm soapy water or hand rubs containing > or = 60% alcohol immediately after they touch their vaccination site or change their vaccination site bandages. Used bandages should be placed in sealed plastic bags and can be disposed of in household trash. Smallpox vaccine adverse reactions are diagnosed on the basis of clinical examination and history, and certain reactions can be managed by observation and supportive care. Adverse reactions that are usually self-limited include fever, headache, fatigue, myalgia, chills, local skin reactions, nonspecific rashes, erythema multiforme, lymphadenopathy, and pain at the vaccination site. Other reactions are most often diagnosed through a complete history and physical and might require additional therapies (e.g., VIG, a first-line therapy and cidofovir, a second-line therapy). Adverse reactions that might require further evaluation or therapy include inadvertent inoculation, generalized vaccinia (GV), eczema vaccinatum (EV), progressive vaccinia (PV), postvaccinial central nervous system disease, and fetal vaccinia. Inadvertent inoculation occurs when vaccinia virus is transferred from a vaccination site to a second location on the vaccinee or to a close contact. Usually, this condition is self-limited and no additional care is needed. Inoculations of the eye and eyelid require evaluation by an ophthalmologist and might require therapy with topical antiviral or antibacterial medications, VIG, or topical steroids. GV is characterized by a disseminated maculopapular or vesicular rash, frequently on an erythematous base, which usually occurs 6-9 days after first-time vaccination. This condition is usually self-limited and benign, although treatment with VIG might be required when the patient is systemically ill or found to have an underlying immunocompromising condition. Infection-control precautions should be used to prevent secondary transmission and nosocomial infection. EV occurs among persons with a history of atopic dermatitis (eczema), irrespective of disease severity or activity, and is a localized or generalized papular, vesicular, or pustular rash, which can occur anywhere on the body, with a predilection for areas of previous atopic dermatitis lesions. Patients with EV are often systemically ill and usually require VIG. Infection-control precautions should be used to prevent secondary transmission and nosocomial infection. PV is a rare, severe, and often fatal complication among persons with immunodeficiencies, characterized by painless progressive necrosis at the vaccination site with or without metastases to distant sites (e.g., skin, bones, and other viscera). This disease carries a high mortality rate, and management of PV should include aggressive therapy with VIG, intensive monitoring, and tertiary-level supportive care. Anecdotal experience suggests that, despite treatment with VIG, persons with cell-mediated immune deficits have a poorer prognosis than those with humoral deficits. Infection-control precautions should be used to prevent secondary transmission and nosocomial infection. Central nervous system disease, which includes postvaccinial encephalopathy (PVE) and postvaccinial encephalomyelitis (or encephalitis) (PVEM), occur after smallpox vaccination. PVE is most common among infants aged < 12 months. Clinical symptoms of central nervous system disease indicate cerebral or cerebellar dysfunction with headache, fever, vomiting, altered mental status, lethargy, seizures, and coma. PVE and PVEM are not believed to be a result of replicating vaccinia virus and are diagnoses of exclusion. Although no specific therapy exists for PVE or PVEM, supportive care, anticonvulsants, and intensive care might be required. Fetal vaccinia, resulting from vaccinial transmission from mother to fetus, is a rare, but serious, complication of smallpox vaccination during pregnancy or shortly before conception. It is manifested by skin lesions and organ involvement, and often results in fetal or neonatal death. No known reliable intrauterine diagnostic test is available to confirm fetal infection. Given the rarity of congenital vaccinia among live-born infants, vaccination during pregnancy should not ordinarily be a reason to consider termination of pregnancy. No known indication exists for routine, prophylactic use of VIG in an unintentionally vaccinated pregnant woman; however, VIG should not be withheld if a pregnant woman develops a condition where VIG is needed. Other less-common adverse events after smallpox vaccination have been reported to occur in temporal association with smallpox vaccination, but causality has not been established. Prophylactic treatment with VIG is not recommended for persons or close contacts with contraindications to smallpox vaccination who are inadvertently inoculated or exposed. These persons should be followed closely for early recognition of adverse reactions that might develop, and clinicians are encouraged to enroll these persons in the CDC registry by calling the Clinician Information Line at 877-554-4625. To request clinical consultation and IND therapies for vaccinia-related adverse reactions for civilians, contact your state health department or CDC's Clinician Information Line (877-554-4625). Clinical evaluation tools are available at http.//www.bt.cdc.gov/agent/smallpox/vaccination/clineval. Clinical specimen-collection guidance is available at http://www.bt.cdc.gov/agent/smallpox/vaccination/vaccinia-specimen-collection.asp. Physicians at military medical facilities can request VIG or cidofovir by calling the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID) at 301-619-2257 or 888-USA-RIID.
 ...
PMID:Smallpox vaccination and adverse reactions. Guidance for clinicians. 1261 10

Only some twenty years has passed since the first discovery of severe immunodeficiency among previously healthy homosexual men through the discovery of the causing virus and till the status today where the knowledge on the HIV virus and the pathogenic mechanisms induced by the virus are extensive, though still incomplete. Furthermore, steadily better treatments have been introduced at a paste that is probably without precedents. These processes have been fuelled by various molecular biological methods. The abilities to quantify viremia and to sequence virus and hence describe the evolution of the virus represent valuable tools for understanding the pathogenic processes. The current thesis describes some of the findings obtained. While it was initially thought that the virological profile mimicked the clinical with an acute infection followed for years by clinical latency and only after on average ten years signs of severe immunodeficiency, this understanding has been revised. There is no virological latency. The viral replication is on going throughout the infection. However, the virological profile does resemble the clinical. Viremia is high shortly after infection; hereafter declines, and stabilises around what has been termed the viral set point. This level of viremia is predictive of the clinical course of the infection. We have shown that the viremic levels, measured both as HIV RNA load and proviral DNA load, early in infection carry significant information about the course of the infection. It is; however, not only early viral loads that carry prognostic information, also viral load during late-stage infection is clinically informative. Viral load measurements have evolved as the major tool for monitoring the efficacy of antiretroviral therapy. HIV RNA has been shown to be a good surrogate marker for the clinical efficacy of antiretroviral treatment. How to use the measurements most optimally has however not been fully delineated. Various methods for describing virological response might yield different results, and it is recommended that the pros and cons of the various methods be investigated. In a cohort of patients who had obtained good virological suppression on antiretroviral therapy followed prospectively for two years we found that only few patients experienced high-grade viremia. Furthermore, baseline HIV DNA differed between the patients with various longitudinal HIV RNA profiles. The patients with the most pronounced HIV RNA suppression had lowest proviral load at baseline, with a clear gradient across the groups. The interplay between proviral load and treatment response deserves further investigations. Resistance can develop against all the available antiretrovirals. The high turnover rate of HIV along with the error-prone reverse transcriptase leads to the possibility of steady accumulation of resistance mutations if the viremic suppression is incomplete. While the interplay between viremia and resistance development is clear-cut for some antiretrovirals i.e. Lamivudine, the pattern is more complex for i.e. Zidovudine. With the availability of assays for resistances testing the knowledge on this issue has been ever evolving. How to use resistance testing in the clinical monitoring of patients remains to be clarified. Resistance testing can aid in the process of choosing salvage therapy for patients experiencing virological failure. Whether resistance testing will be of clinical benefit in other situations remains to be determined. Investigation of the viral sequences and evolution herein has not only been used for resistance analyses, but also for tracing the spread of the infection. HIV-1 exists in many subtypes, with various geographic distributions. Hence subtype analyses have been used to investigate the introduction and spread of the HIV infection into many countries. Phylogenetic analyses have also been used to investigate nosocomial transmission events. We used analyses of env and gag sequences to trace a case of nosocomial infection at the Department of Infectious Diseases, Rigshospitalet, Denmark. The study underlines the importance of steady awareness of the infection control precautions and possible breaks herein. The usefulness of this type of analyses was confirmed. In the early years of the AIDS epidemic various replicative patterns were described. Virus obtained from patients with late-stage infection often had virus that could induce syncytium formation (SI) when cultured, while virus obtained from patients in the early stages of infection did not have this ability. A correlation between the SI ability and the ability to yield high virus titres rapidly as well as the ability to establish infection in certain cell lines was found. Patients infected with SI virus experience more rapid clinical deterioration. We found that patients harbouring SI virus have HIV RNA loads no different from patients harbouring NSI virus. This is in line with the findings of other groups. Though patients harbouring SI virus had a more rapid development of resistance when treated with nucleoside reserve transcriptase inhibitor (NRTI's) monotherapy, this was not the case when treated with highly active antiretroviral therapy (HAART). HAART is today considered the treatment modality of choice; both for established HIV-infection and in cases where post exposure prophylaxis (PEP) is given in order to prevent establishment of infection after exposure. In a case of transfusion of HIV-contaminated though HIV antibody negative blood the recipient was treated with HAART. As the risk of infection is close to 100% under these circumstances the fact that the recipient remained uninfected is probably attributable to the prompt initiation and thorough maintenance of PEP. PEP is recommended to health care workers after percutaneous HIV exposure as well as after sexual exposure. Even with NRTI monotherapy PEP has been shown to be efficacious. While the explanation for the dichotomy (SI vs. NSI) was for many years unresolved, it is now known that this is due to the requirements of the virus for different co-receptors for cell entry. SI virus uses mainly CXCR4 while NSI virus uses CCR5. Being heterozygous for a 32 basepair deletion in the gene encoding CCR5 leads to slower disease progression. We have shown that heterozygotes have lower HIV RNA levels in the early years of the infection, possibly explaining the clinical advantage of having the deletion. HIV replicates in activated cells, and there is an intriguing interplay between HIV replication and immune activation. HIV-infected patients have elevated levels of immunoglobulins. HIV induces polygonal immunoglobulin production. We found that patients experiencing good virological suppression of HAART had lower IgA levels than patients with less complete viral suppression. Whether IgA can be used as a marker for imminent viral break-through remains to be determined. The full understanding of the interplay between immune activation and HIV replication awaits further studies. The finding of increased viremia in conjunction with acute bacterial or viral infection led to concerns about the safety of vaccinating HIV-infected patients against influenza and pneumococcal infection. We found no difference in HIV RNA levels measured before and median 42 days after anti-pneumococcal vaccination. This is in line with many other studies showing either no or only transient increases in viremia. In conclusion, the knowledge on HIV virology has expanded tremendously. This has led to significant improvements in treatments in the Western World leading to declines in HIV morbidity and mortality. The ability to quantify viral load and to perform sequence analyses represent valuable tools both for understanding the pathogenic actions of the virus and for the clinical monitoring of HIV-infected patients. The optimal usage of these tools in the clinical setting, however, still remains to be defined. The progresses obtained have unfortunately been restricted to the Western World and the calamities of HIV is spreading and worsening in the Developing World. The progress in the development of a vaccine has been disappointing and it is urgently necessary that the progresses obtained within the fields of prevention and treatment are translated into useful strategies in the parts of the world mostly affected by the HIV pandemic.
 ...
PMID:Molecular biological assessment methods and understanding the course of the HIV infection. 1462 50

Around one million people in Japan are suffering from adenoviral conjunctivitis every year and it is recognized as one of the major pathogens of nosocomial infection. Several complications, such as corneal erosion and conjunctival pseudomembrane, are observed in some of the cases and corneal sube- pithelial opacity may bring visual impairment. Moreover, no specific anti-adenoviral agent has been discovered and an effective treatment has not been established for adenoviral infection. We have researched new medical treatment for viral conjunctivitis based on recent findings in adenoviral conjunctivitis. Firstly, anti-adenoviral activity was evaluated in vitro in agents which could possibly act as anti-adenoviral drugs. Twelve candidates, such as zalcitabin, interferon beta, etc., were selected among antiviral drugs, adenoviral receptor inhibitors, natural products and anti-inflammatory drugs. Remarkable anti-adenoviral effect was observed in zalcitabin, sanilbudine, interferon beta and anti-osteopontin peptide. Two anti-human immunodeficiency virus (HIV) drugs with anti-adenoviral activity, zalcitabin and sanilbudine, are nucleoside reverse transcriptase inhibitors, but, in contrast, non-nucleoside reverse transcriptase inhibitors and protease inhibitors were ineffective against adenovirus. Interferon beta and anti-osteopontin peptide displayed anti-adenoviral effects by absorption inhibition. Secondly, side effects caused by possible anti-adenoviral eye drops, including cidofovir whose development as eye drops against eyeball and ocular adnexa had been suspended, were analyzed in a white rabbit model. In animals given cidofovir locally, significant narrowing of lacrimal canaliculus, redness of eyelid and conjunctival injection was observed, but obstruction of the lacrimal duct was not found. Although zalcitabin and sanilbudine eye drops induced eyelid redness, no change was observed in the lacrimal route and conjunctiva. In animals treated by cidofovir, inflammation histologically suggesting mainly allergic change was observed. These results indicate that these four drugs are possible candidate for safe eye drops against adenoviral conjunctivitis. These four agents are divided into two categories, inhibitors of adenoviral replication, zalcitabin and sanilbudine; and suppressors of adenoviral infection, interferon beta and anti-osteopontin peptide. It is expected that eye drops for specific treatment of adenoviral conjunctivitis are going to be available in the near future following investigation of therapeutic effect in adenoviral infected animals and clinical trials in humans.
 ...
PMID:[New medical treatment for viral conjunctivitis]. 1640 91

Twenty two cases of nosocomial infection caused by Trichosporon asahii, detected during a period of six years (1999-2005) is described. The patients were predominantly males with an average age of 47.3 years-old. The predominant diseases in the study group were respiratory insufficiency, cancer, diabetes, chronic renal insufficiency, cirrhosis and AIDS. The main predisposing conditions were antibiotic therapy, mechanical ventilation, urethral catheterization, catheter, corticoids, transplant, immunosuppressive therapy, chemotherapy, granulocytopenia, surgical procedures and continuous ambulatory peritoneal dialysis. The most used antifungal drugs were fluconazole and amphotericin B. In some cases several antifungals were administered. Five patients did not receive antifungal treatment, and one patient received granulocyte colony stimulating factor (G-CSF). Nine patients showed clinical improvement, nine died and the progress of four patients is unknown. T. asahii is an emergent pathogen in patients with immunodeficiency and its presence in these type hosts can not be considered colonization, as there is an important risk of invasive infection. So, in susceptible patients to develop trichosporonosis it is advisable to take into consideration this disease especially in intensive clinical care units.
 ...
PMID:[Nosocomial infection due to Trichosporon asahii: clinical revision of 22 cases]. 1685 83

Premature birth, chronic lung disease of prematurity (CLD), congenital heart disease and immunodeficiency predispose to a higher morbidity and mortality in respiratory syncytial virus (RSV) infection. This study describes the preterms hospitalised with RSV infection from the prospective German DSM RSV Paed database. The DMS RSV Paed database was designed for the prospective multicentre documentation and analysis of clinically relevant aspects of the management of inpatients with RSV infection. This study covers six consecutive RSV seasons (1999-2005); the surveillance took place in 14 paediatric hospitals in Germany. Of the 1,568 prospectively documented RSV infections, 26% (n=406) were observed in preterms [vs. 1,162 children born at term (74%)] and 3% (n=50) had CLD, of which 49 had received treatment in the last 6 months ('CLDplus'). A significantly higher proportion in the preterm group had congenital heart disease, nosocomial infection, and neuromuscular impairment. There were significantly more children older than 24 months in the preterm group. The attributable mortality was 0.2% (n=2) in children born at term vs. 1.2% (n=5) in the preterm group (p=0.015) [preterm plus CLD 8.0% (n=4 of 50); McIntosh grade 1, 8.6% (n=3 of 35) and McIntosh Grade 4, 15% (n=3 of 20)]. Eight patients were categorized as 'palivizumab failures'. In the multivariate analysis, premature birth, CLD(plus), and nosocomial infection were significantly and independently associated with the combined outcome 'complicated course of disease'. In conclusion, this is the first prospective multicentre study from Germany that confirms the increased risk for severe RSV disease in preterms, in particular in those with CLD treated in the last 6 months before the onset of the infection. From the perspective of our results, the statements of the German Society of Paediatric Infectious Diseases considering the use of passive immunisation (2003) seem reasonable.
 ...
PMID:Respiratory syncytial virus infection in 406 hospitalized premature infants: results from a prospective German multicentre database. 1794 13

Permanent drainage of the urinary tract by catheters or tubes causes bacteriuria. The potential harmful effects of the indwelling catheter's bacteriuria are related to: time since the insertion of the catheter; location of the catheter (urethra, bladder, kidney); catheter composition (latex, silicone, etc.); type of ineffective bacteria and specific pathogenic mechanisms; health status of the urinary tract being drained (prior radiation therapy, tumors, etc.); patient's health status (diabetes, immunodeficiency) and mobility; incidents and manipulations of the catheter, such as obstruction, irrigation, or retrieval. The evaluation of all mentioned factors enables strategies for prevention of septic episodes in relation with indwelling catheters, strategies that can be individualized for greater efficiency. Despite these preventive measures, infections secondary to the indwelling catheter may cause extremely severe septic episodes. Today, the indwelling catheter bacteriuria constitutes the greater source of nosocomial infection and its prevention and treatment a health care action of the highest importance. The study of mechanisms implied in the formation of biofilms, their pathogenic potential and preventive measures have been an attractive field of clinical and experimental research over the last years. The objective of this review is to make a synthesis of the works performed by our group.
 ...
PMID:[Infections of the urinary tract caused by permanent catheterization. Natural history, infective mechanisms and prevention strategies. An overall review based on our clinical experience and research]. 1807 51

The aims of this study were to examine the extent of gastroenteric virus contamination in a pediatric primary immunodeficiency (PPI) ward and a general pediatric ward over a winter season and to determine whether changes to hospital infection control interventions would have an impact on environmental contamination levels within pediatric units. Environmental swabs were collected weekly from 11 sites in both wards from 15 December 2005 to 3 March 2006 and examined for the presence of norovirus (NoV), astrovirus, and rotavirus (RV) by reverse transcriptase PCR. Viruses were detected in 17% and 19% of swabs from both wards. Virus contamination for NoV and RV decreased from 20% to 6% and 15% to 10% of swabs, respectively, in the PPI ward from the 2004 study by Gallimore et al. (C. I. Gallimore, C. Taylor, A. R. Gennery, A. J. Cant, A. Galloway, M. Iturriza-Gomara, and J. J. Gray, J. Clin. Microbiol. 44:395-399, 2006). Overall, changes to cleaning protocols were deemed to have reduced the level of environmental contamination with gastroenteric viruses, but contamination still occurred due to a breakdown in infection control procedures indicated by contamination in areas frequented by parents but used only occasionally by staff.
 ...
PMID:Contamination of the hospital environment with gastroenteric viruses: comparison of two pediatric wards over a winter season. 1861 56

Abdominal infections are associated with significant morbidity and mortality. Nearly all bacteria causing abdominal infections are derived from the endogenous flora of the alimentary tract. The resulting infection is typically polymicrobial and comprised of both aerobic and anaerobic microbes. They can be classified by their severity as uncomplicated and complicated or by their origin as community or hospital acquired. Escherichia coli and Bacteroides fragilis are the most frequently isolated bacteria in community-acquired abdominal infections. Nosocomial infections typically involve a more resistant flora (e.g. Pseudomonas spp., Acinetobacter spp., Gram-negative bacilli producing extended-spectrum beta-lactamases [ESBL], vancomycin-resistant enterococci [VRE] and methicillin-resistant Staphylococcus aureus [MRSA]). Antimicrobial therapy should be guided by microbiological testing and frequently requires other interventions as well. In uncomplicated infections antimicrobial prophylaxis for < 24h may be considered. Patients with underlying or acquired immunodeficiency, i.e. organ transplant recipients and other patients on complex immunosuppressant regimens require special attention and antimicrobial coverage. We discuss the relevant microbiota, a rational diagnostic and therapeutic approach including strategies to handle challenging infections. The application of novel compounds and/or drug classes for abdominal infections such as glycylcyclines (i.e. tigecycline), glycopeptides (i.e. dalbavancin, telavancin, oritavancin), carbapenems (i.e. doripenem), and forth generation cephalosporins (i.e. ceftaroline, ceftobiprole) as well as patents on metalloproteinase and caspase inhibitors, interleukin antagonists, fusion proteins and nitric oxide donators is critically reviewed. The information is summarized in flow charts and algorithms for use in daily clinical practice and the review article also shows the useful information of the patents for the treatment of abdominal infections.
 ...
PMID:Management of severe abdominal infections. 1914 97

Mycobacterium fortuitum, a rapidly growing atypical mycobacteria, is commonly found in soil and water. This organism is most often known to cause skin, bone, and soft tissue infections associated with local trauma, surgical procedures, and in patients with immunodeficiency. Nosocomial infections associated with a variety of contaminated devices and equipment have also been widely documented. This report presents the first cases of M. fortuitum infection following laparoscopic gastric banding procedures. Both patients had complicated clinical courses necessitating removal of their banding devices and long-term antibiotic therapy.
 ...
PMID:Mycobacterium fortuitum infections associated with laparoscopic gastric banding. 2033 91

Occupational hazardous exposure in healthcare workers is any contact with a material that carries the risk of acquiring an infection during their working activities. Among the most frequent viral occupational infections are those transmitted by blood such as hepatitis B virus (HBV), hepatitis C virus (HCV) and human immunodeficiency virus (HIV). Therefore, they represent a significant public health problem related to the majority of documented cases of professionally acquired infections. Reporting of occupational exposures in University Hospital Dubrava has been implemented in connection with the activity of the Committee for Hospital Infections since January 2002. During the period of occupational exposures' monitoring (from January 2002 to December 2011) 451 cases were reported. The majority of occupational exposures were reported by nurses and medical technicians (55.4%). The most common type of exposure was the needlestick injury (77.6%). 27.9% of the accidents occurred during the blood sampling and 23.5% during the surgical procedure. In 59.4% of the exposed workers aHBs-titer status was assessed as satisfactory. Positive serology with respect to HBV was confirmed in 1.6% of patients, HCV in 2.2% of patients and none for HIV. Cases of professionally acquired infections were not recorded in the registry. Consequences of the occupational exposure could include the development of professional infection, ban or inability to work further in health care services and last but not least a threat to healthcare workers life. It is therefore deemed necessary to prevent occupational exposure to blood-borne infections. The most important preventive action in respect to HBV, HCV and HIV infections is nonspecific pre-exposure prophylaxis.
 ...
PMID:Occupational exposures in healthcare workers in University Hospital Dubrava--10 year follow-up study. 2434 41


<< Previous 1 2 3 4 5 Next >>