Leishmaniasis is widely regarded as a vaccine-preventable disease, but the costs required to reach pivotal Phase 3 studies and uncertainty about which candidate vaccines should be progressed into human studies significantly limits progress in vaccine development for this neglected tropical disease. Controlled human infection models (CHIMs) provide a pathway for accelerating vaccine development and to more fully understand disease pathogenesis and correlates of protection. Here, we describe the isolation, characterization and GMP manufacture of a new clinical strain of Leishmania major. Two fresh strains of L. major from Israel were initially compared by genome sequencing, in vivo infectivity and drug sensitivity in mice, and development and transmission competence in sand flies, allowing one to be selected for GMP production. This study addresses a major roadblock in the development of vaccines for leishmaniasis, providing a key resource for CHIM studies of sand fly transmitted cutaneous leishmaniasis.

• MeSH
• fylogeneze MeSH
• hmyz - vektory parazitologie   MeSH
• Leishmania major genetika   růst a vývoj   fyziologie   MeSH
• leishmanióza kožní parazitologie   přenos   MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• myši inbrední BALB C MeSH
• paraziti genetika   MeSH
• Psychodidae parazitologie   MeSH
• sekvenování celého genomu MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Izrael MeSH

The leishmaniases are globally important parasitic diseases for which no human vaccines are currently available. To facilitate vaccine development, we conducted an open-label observational study to establish a controlled human infection model (CHIM) of sand fly-transmitted cutaneous leishmaniasis (CL) caused by Leishmania major. Between 24 January and 12 August 2022, we exposed 14 participants to L. major-infected Phlebotomus duboscqi. The primary objective was to demonstrate effectiveness of lesion development (take rate) and safety (absence of CL lesion at 12 months). Secondary and exploratory objectives included rate of lesion development, parasite load and analysis of local immune responses by immunohistology and spatial transcriptomics. Lesion development was terminated by therapeutic biopsy (between days 14 and 42 after bite) in ten participants with clinically compatible lesions, one of which was not confirmed by parasite detection. We estimated an overall take rate for CL development of 64% (9/14). Two of ten participants had one and one of ten participants had two lesion recurrences 4-8 months after biopsy that were treated successfully with cryotherapy. No severe or serious adverse events were recorded, but as expected, scarring due to a combination of CL and the biopsy procedure was evident. All participants were lesion free at >12-month follow-up. We provide the first comprehensive map of immune cell distribution and cytokine/chemokine expression in human CL lesions, revealing discrete immune niches. This CHIM offers opportunities for vaccine candidate selection based on human efficacy data and for a greater understanding of immune-mediated pathology. ClinicalTrials.gov identifier: NCT04512742 .

• MeSH
• dospělí MeSH
• Leishmania major * imunologie   MeSH
• leishmanióza kožní * imunologie   parazitologie   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• parazitární zátěž MeSH
• Phlebotomus parazitologie   imunologie   MeSH
• zvířata MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• pozorovací studie MeSH

• MeSH
• HIV infekce farmakoterapie   MeSH
• katalogy léků jako téma MeSH
• sexuálně přenosné nemoci farmakoterapie   MeSH

• Konspekt
• Lékařské vědy. Lékařství
• NLK Obory
• dermatovenerologie
• farmacie a farmakologie
• dermatovenerologie
• dermatovenerologie
• farmakoterapie
• NLK Publikační typ
• publikace WHO

The parasitic protozoan Toxoplasma gondii infects about one-third of the population of developed countries. The life-long presence of dormant stages of this parasite in the brain and muscular tissues of infected humans is usually considered asymptomatic from the clinical point of view. In the past 20 years, research performed mostly on military personnel, university students, pregnant women and blood donors has shown that this 'asymptomatic' disease has a large influence on various aspects of human life. Toxoplasma-infected subjects differ from uninfected controls in the personality profile estimated with two versions of Cattell's 16PF, Cloninger's TCI and Big Five questionnaires. Most of these differences increase with the length of time since the onset of infection, suggesting that Toxoplasma influences human personality rather than human personality influencing the probability of infection. Toxoplasmosis increases the reaction time of infected subjects, which can explain the increased probability of traffic accidents in infected subjects reported in three retrospective and one very large prospective case-control study. Latent toxoplasmosis is associated with immunosuppression, which might explain the increased probability of giving birth to a boy in Toxoplasma-infected women and also the extremely high prevalence of toxoplasmosis in mothers of children with Down syndrome. Toxoplasma-infected male students are about 3 cm taller than Toxoplasma-free subjects and their faces are rated by women as more masculine and dominant. These differences may be caused by an increased concentration of testosterone. Toxoplasma also appears to be involved in the initiation of more severe forms of schizophrenia. At least 40 studies confirmed an increased prevalence of toxoplasmosis among schizophrenic patients. Toxoplasma-infected schizophrenic patients differ from Toxoplasma-free schizophrenic patients by brain anatomy and by a higher intensity of the positive symptoms of the disease. Finally, five independent studies performed in blood donors, pregnant women and military personnel showed that RhD blood group positivity, especially in RhD heterozygotes, protects infected subjects against various effects of latent toxoplasmosis, such as the prolongation of reaction times, an increased risk of traffic accidents and excessive pregnancy weight gain. The modern human is not a natural host of Toxoplasma. Therefore, it can only be speculated which of the observed effects of latent toxoplasmosis are the result of the manipulation activity of the Toxoplasma aimed to increase the probability of its transmission from a natural intermediate to the definitive host by predation, and which are just side effects of chronic infection.

• MeSH
• chování MeSH
• fenotyp MeSH
• interakce hostitele a parazita * MeSH
• lidé MeSH
• osobnost * MeSH
• reakční čas MeSH
• schizofrenie etiologie   parazitologie   MeSH
• těhotenství MeSH
• Toxoplasma fyziologie   MeSH
• toxoplazmóza epidemiologie   patologie   patofyziologie   psychologie   MeSH
• velikost těla MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

In clinical practice, there is considerable variation in the timing of the initiation of maintenance dialysis for patients with stage V chronic kidney disease, with a worldwide trend toward early initiation. In this study, conducted at 32 centers in Australia and New Zealand, we examined whether the timing of the initiation of maintenance dialysis influenced survival among patients with chronic kidney disease. METHODS: We randomly assigned patients 18 years of age or older with progressive chronic kidney disease and an estimated glomerular filtration rate (GFR) between 10.0 and 15.0 ml per minute per 1.73 m2 of body-surface area (calculated with the use of the Cockcroft-Gault equation) to planned initiation of dialysis when the estimated GFR was 10.0 to 14.0 ml per minute (early start) or when the estimated GFR was 5.0 to 7.0 ml per minute (late start). The primary outcome was death from any cause. RESULTS: Between July 2000 and November 2008, a total of 828 adults (mean age, 60.4 years; 542 men and 286 women; 355 with diabetes) underwent randomization, with a median time to the initiation of dialysis of 1.80 months (95% confidence interval [CI], 1.60 to 2.23) in the early-start group and 7.40 months (95% CI, 6.23 to 8.27) in the late-start group. A total of 75.9% of the patients in the late-start group initiated dialysis when the estimated GFR was above the target of 7.0 ml per minute, owing to the development of symptoms. During a median follow-up period of 3.59 years, 152 of 404 patients in the early-start group (37.6%) and 155 of 424 in the late-start group (36.6%) died (hazard ratio with early initiation, 1.04; 95% CI, 0.83 to 1.30; P=0.75). There was no significant difference between the groups in the frequency of adverse events (cardiovascular events, infections, or complications of dialysis). CONCLUSIONS: In this study, planned early initiation of dialysis in patients with stage V chronic kidney disease was not associated with an improvement in survival or clinical outcomes. (Funded by the National Health and Medical Research Council of Australia and others; Australian New Zealand Clinical Trials Registry number, 12609000266268.)

• MeSH
• časové faktory MeSH
• chronické selhání ledvin komplikace   mortalita   terapie   MeSH
• dialýza ledvin metody   škodlivé účinky   MeSH
• dospělí MeSH
• financování organizované MeSH
• hodnoty glomerulární filtrace MeSH
• infekce etiologie   mortalita   MeSH
• Kaplanův-Meierův odhad MeSH
• kardiovaskulární nemoci etiologie   mortalita   MeSH
• kvalita života MeSH
• lidé středního věku MeSH
• lidé MeSH
• proporcionální rizikové modely MeSH
• randomizované kontrolované studie jako téma MeSH
• uremie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• multicentrická studie MeSH

This paper presents an innovative mathematical model for assessing the dynamics and optimal control of Nipah virus (NiV) with imperfect vaccination. The model formulation considers transmissions through contaminated food and human-to-human contacts. It also incorporates the potential virus transmission through contact with a deceased body infected with NiV. Initially, the NiV model is assessed theoretically, identifying three distinct equilibrium states: the NiV-endemic equilibrium state, the NiV-free equilibrium state, and the equilibrium state involving infected flying foxes. Furthermore, the stability results of the model in the case of constant controls are thoroughly analyzed at the NiV-free equilibrium. Some of the parameters of the model are estimated based on the infected cases documented in Bangladesh from 2001 to 2017. We further perform sensitivity analysis to determine the most influential parameters and formulate effective time-dependent controls. Numerical simulations indicate the optimal course of action for eradicating the disease and provide a comparative analysis of controlling the infection under constant and time-varying interventions. The simulation confirms that the implementation of time-varying interventions is effective in minimizing disease incidence.

• MeSH
• infekce viry z rodu Henipavirus * přenos   prevence a kontrola   epidemiologie   MeSH
• lidé MeSH
• počítačová simulace MeSH
• teoretické modely MeSH
• vakcinace * MeSH
• virus Nipah * imunologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Bangladéš MeSH

• MeSH
• antituberkulotika terapeutické užití   MeSH
• HIV infekce komplikace   farmakoterapie   epidemiologie   MeSH
• hodnocení výsledků pacienta * MeSH
• Kaplanův-Meierův odhad MeSH
• koinfekce farmakoterapie   mikrobiologie   virologie   MeSH
• kontrola infekčních nemocí normy   MeSH
• lidé MeSH
• multirezistentní tuberkulóza komplikace   farmakoterapie   epidemiologie   MeSH
• prevalence MeSH
• přežití bez známek nemoci MeSH
• proporcionální rizikové modely MeSH
• regresní analýza MeSH
• riziko MeSH
• sběr dat MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• dopisy MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Evropa MeSH
• Německo MeSH

AIM: This study aimed to quantify types and frequencies of missed infection control care and to develop a theoretical model for estimating nurses' consensus scores about this form of missed care. DESIGN: A non-experimental research design using self-audit data was selected to collect information about the types and frequencies of missed infection control care from nurses employed in hospitals located in three different countries. Data collection commenced mid-year 2018. METHODS: A multivariate approach was used to apply the consensus scores of 1.911 internationally based nurses in the missed opportunities for maintaining infection control. RESULTS/FINDINGS: Thirteen variables exert direct effects on the nurses' total scores underpinning missed infection control care. These include the methods used to prevent hospital-acquired infections, surveillance and hand hygiene practices. Significant nurses' demographic factors also included their countries of origin, employment status, employer type, job retention intentions, work intensity, length of clinical experience and staff development attendance. CONCLUSION: In magnitude of importance and having the largest effect on missed infection control care is missed care related to reducing hospital-acquired infections followed closely by surveillance. Missed infection control care can be quantified, and variances in its practices can be accounted by exploring the nurses' differing demographic factors, including the nurses' country of origin. IMPACT: Variations in missed infection control care can be accounted for across three countries. While ward hygiene is underestimated by staff as a mechanism to minimize nosocomial infections, infection control surveillance remains the key to reducing hospital-acquired infections. The study's outcomes invite the use of an ongoing, whole-of-organization approach to infection control with scrutiny being needed for improved staff adherence particularly with hand hygiene.

• MeSH
• hygiena rukou * MeSH
• infekce spojené se zdravotní péčí * prevence a kontrola   MeSH
• kontrola infekce MeSH
• lidé MeSH
• nemocnice MeSH
• personál sesterský nemocniční * MeSH
• úmysl MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

One of the major challenges in modern biology is the use of large omics datasets for the characterization of complex processes such as cell response to infection. These challenges are even bigger when analyses need to be performed for comparison of different species including model and non-model organisms. To address these challenges, the graph theory was applied to characterize the tick vector and human cell protein response to infection with Anaplasma phagocytophilum, the causative agent of human granulocytic anaplasmosis. A network of interacting proteins and cell processes clustered in biological pathways, and ranked with indexes representing the topology of the proteome was prepared. The results demonstrated that networks of functionally interacting proteins represented in both infected and uninfected cells can describe the complete set of host cell processes and metabolic pathways, providing a deeper view of the comparative host cell response to pathogen infection. The results demonstrated that changes in the tick proteome were driven by modifications in protein representation in response to A. phagocytophilum infection. Pathogen infection had a higher impact on tick than human proteome. Since most proteins were linked to several cell processes, the changes in protein representation affected simultaneously different biological pathways. The method allowed discerning cell processes that were affected by pathogen infection from those that remained unaffected. The results supported that human neutrophils but not tick cells limit pathogen infection through differential representation of ras-related proteins. This methodological approach could be applied to other host-pathogen models to identify host derived key proteins in response to infection that may be used to develop novel control strategies for arthropod-borne pathogens.

• MeSH
• Anaplasma phagocytophilum růst a vývoj   MeSH
• anaplasmóza patologie   MeSH
• biologické jevy MeSH
• buněčné linie MeSH
• členovci - vektory * MeSH
• interakce hostitele a patogenu * MeSH
• klíšťata MeSH
• lidé MeSH
• mapy interakcí proteinů MeSH
• proteiny analýza   MeSH
• proteom analýza   MeSH
• teoretické modely * MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

BACKGROUND: The effects of antiretroviral therapy on risk of severe bacterial infections in people with high CD4 cell counts have not been well described. In this study, we aimed to quantify the effects of immediate versus deferred ART on the risk of severe bacterial infection in people with high CD4 cell counts in a preplanned analysis of the START trial. METHODS: The START trial was a randomised controlled trial in ART-naive HIV-positive patients with CD4 cell count of more than 500 cells per μL assigned to immediate ART or deferral until their CD4 cell counts were lower than 350 cells per μL. We used Cox proportional hazards regression to model time to severe bacterial infection, which was defined as a composite endpoint of bacterial pneumonia (confirmed by the endpoint review committee), pulmonary or extrapulmonary tuberculosis, or any bacterial infectious disorder of grade 4 severity, that required unscheduled hospital admissions, or caused death. This study is registered with ClinicalTrials.gov, number NCT00867048. FINDINGS: Patients were recruited from April 15, 2009, to Dec 23, 2013. The data cutoff for follow-up was May 26, 2015. Of 4685 HIV-positive people enrolled, 120 had severe bacterial infections (immediate-initiation group n=34, deferred-initiation group n=86; median 2·8 years of follow-up). Immediate ART was associated with a reduced risk of severe bacterial infection compared with deferred ART (hazard ratio [HR] 0·39, 95% CI 0·26-0·57, p<0·0001). In the immediate-initiation group, average neutrophil count over follow-up was 321 cells per μL higher, and average CD4 cell count 194 cells per μL higher than the deferred-initiation group (p<0·0001). In univariable analysis, higher time-updated CD4 cell count (0·78, 0·71-0·85, p=0·0001) was associated with reduced risk of severe bacterial infection. Time-updated neutrophil count was not associated with severe bacterial infection. After adjustment for time-updated factors in multivariable analysis, particularly the CD4 cell count, the HR for immediate-initiation group moved closer to 1 (HR 0·84, 0·50-1·41, p=0·52). These results were consistent when subgroups of the severe bacterial infection composite were analysed separately. INTERPRETATION: Immediate ART reduces the risk of several severe bacterial infections in HIV-positive people with high CD4 cell count. This is partly explained by ART-induced increases in CD4 cell count, but not by increases in neutrophil count. FUNDING: National Institute of Allergy and Infectious Diseases National Institutes of Health, Agence Nationale de Recherches sur le SIDA et les Hépatites Virales, Bundesministerium für Bildung und Forschung, European AIDS Treatment Network, Australian National Health and Medical Research Council, UK National Institute for Health Research and Medical Research Council, Danish National Research Foundation.

• MeSH
• bakteriální infekce epidemiologie   imunologie   MeSH
• bakteriální pneumonie epidemiologie   MeSH
• dospělí MeSH
• HIV infekce komplikace   farmakoterapie   imunologie   virologie   MeSH
• látky proti HIV škodlivé účinky   terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• oportunní infekce doprovázející AIDS epidemiologie   MeSH
• počet CD4 lymfocytů * MeSH
• proporcionální rizikové modely MeSH
• regresní analýza MeSH
• rozvrh dávkování léků MeSH
• tuberkulóza epidemiologie   MeSH
• virová nálož MeSH
• vysoce aktivní antiretrovirová terapie * škodlivé účinky   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky MeSH
• randomizované kontrolované studie MeSH
• Geografické názvy
• Austrálie MeSH