The aim of this study was to synthesize a series of quinoline–pyrimidine hybrids and to evaluate their in vitro antimalarial activity as well as cytotoxicity. The hybrids were brought about in a ...two-step nucleophilic substitution process involving quinoline and pyrimidine moieties. They were screened alongside chloroquine (CQ), pyrimethamine (PM) and fixed combinations thereof against the D10 and Dd2 strains of Plasmodium falciparum. The cytotoxicity was determined against the mammalian Chinese Hamster Ovarian cell line. The compounds were all active against both strains. However, hybrid (21) featuring piperazine linker stood as the most active of all. It was found as potent as CQ and PM against the D10 strain, and possessed a moderately superior potency over CQ against the Dd2 strain (IC50: 0.157 vs 0.417μM, ∼threefold), and also displayed activity comparable to that of the equimolar fixed combination of CQ and PM against both strains.
The aim of this study was to synthesize a series of quinolineapyrimidine hybrids and to evaluate their in vitro antimalarial activity as well as cytotoxicity. The hybrids were brought about in a ...two-step nucleophilic substitution process involving quinoline and pyrimidine moieties. They were screened alongside chloroquine (CQ), pyrimethamine (PM) and fixed combinations thereof against the D10 and Dd2 strains of Plasmodium falciparum. The cytotoxicity was determined against the mammalian Chinese Hamster Ovarian cell line. The compounds were all active against both strains. However, hybrid (21) featuring piperazine linker stood as the most active of all. It was found as potent as CQ and PM against the D10 strain, and possessed a moderately superior potency over CQ against the Dd2 strain (IC50: 0.157 vs 0.417 mu M, similar to threefold), and also displayed activity comparable to that of the equimolar fixed combination of CQ and PM against both strains.
The true importance of cell-free DNA in human biology, together with the potential scale of its clinical utility, is tarnished by a lack of understanding of its composition and origin. In ...investigating the cell-free DNA present in the growth medium of cultured 143B cells, we previously demonstrated that the majority of cell-free DNA is neither a product of apoptosis nor necrosis. In the present study, we investigated the composition and origin of this cell-free DNA population using next-generation sequencing. We found that the cell-free DNA comprises mainly of repetitive DNA, including α-satellite DNA, mini satellites, and transposons that are currently active or exhibit the capacity to become reactivated. A significant portion of these cell-free DNA fragments originates from specific chromosomes, especially chromosomes 1 and 9. In healthy adult somatic cells, the centromeric and pericentromeric regions of these chromosomes are normally densely methylated. However, in many cancer types, these regions are preferentially hypomethylated. This can lead to double-stranded DNA breaks or it can directly impair the formation of proper kinetochore structures. This type of chromosomal instability is a precursor to the formation of nuclear anomalies, including lagging chromosomes and anaphase bridges. DNA fragments derived from these structures can recruit their own nuclear envelope and form secondary nuclear structures known as micronuclei, which can localize to the nuclear periphery and bud out from the membrane. We postulate that the majority of cell-free DNA present in the growth medium of cultured 143B cells originates from these micronuclei.
The anthropogenic impact on wildlife is ever increasing. With shrinking habitats, wild populations are being pushed to co-exist in proximity to humans leading to an increased threat of infectious ...diseases. Therefore, understanding the immune system of a species is key to assess its resilience in a changing environment. The innate immune system (IIS) is the body's first line of defense against pathogens. High variability in IIS genes, like toll-like receptor (TLR) genes, appears to be associated with resistance to infectious diseases. However, few studies have investigated diversity in TLR genes in vulnerable species for conservation. Large predators are threatened globally including leopards and cheetahs, both listed as 'vulnerable' by IUCN. To examine IIS diversity in these sympatric species, we used next-generation-sequencing to compare selected TLR genes in African leopards and cheetahs. Despite differences, both species show some TLR haplotype similarity. Historic cheetahs from all subspecies exhibit greater genetic diversity than modern Southern African cheetahs. The diversity in investigated TLR genes is lower in modern Southern African cheetahs than in African leopards. Compared to historic cheetah data and other subspecies, a more recent population decline might explain the observed genetic impoverishment of TLR genes in modern Southern African cheetahs. However, this may not yet impact the health of this cheetah subspecies.
Female sex workers (FSW) and adolescent girls and young women (AGYW) face a disproportionately high risk of HIV in South Africa. Oral preexposure prophylaxis (PrEP) can avert new infections, but its ...effectiveness is linked to consistent use. Early discontinuation of PrEP in this population is high, but less is known about longitudinal patterns of PrEP use, including patterns of re-initiation and cycling.
Longitudinal descriptive analysis of routine program data.
Between 2016 and 2021, 40 681 FSW and AGYW initiated PrEP at TB HIV Care, the largest PrEP provider to this population in South Africa and were included. Using survival analyses and group-based trajectory modeling, we described patterns of initiation, discontinuation, re-initiation, and cycling.
Total initiations increased over the life of the program for both FSW and AGYW. About 40% of FSW 0.41, 95% confidence interval (CI) 0.40-0.42 and AGYW (0.38, 95% CI 0.37-0.38) remained on PrEP at one month. FSW were more likely to restart PrEP, however <10% restarted PrEP within a year of initiation. Three latent trajectory groups of PrEP use were identified for FSW (low use, early cycling, and ongoing cycling) and two for AGYW (low use and ongoing cycling). Persistence was negatively associated with initiation among AGYW, but there was no clear relationship among FSW. Those initiating later in the program and older women had a reduced risk of discontinuation.
Persistence on PrEP was low, but cycling on and off PrEP was common, with early missed visits and inconsistent, but ongoing use. A push to increase PrEP initiations needs to factor in readiness and persistence support, to achieve public health impact.
Abstract Introduction Field-based monitoring methods have been developed for respirable dust and respirable crystalline silica (RCS) to enable exposure results to be obtained on the same day. This ...study aimed to use these field-based monitoring methods to evaluate respirable dust and RCS concentrations in the workplace air of a clay brick factory. Methodology Area monitoring was performed using NIOSH 7602 and the Nanozen DustCount 9000i. Both sampling trains were fixed to a tripod and placed in one of four work areas close to workers for a period of approximately five hours. A total of 13 sets of measurements were collected. Prior to analysis using infrared spectrometry (KBr pellet), 37 mm filters underwent direct-on-filter analysis for silica using a portable FT-IR instrument and NIOSH FAST software. Results Median time-weighted average (TWA) concentrations were 0.313 mg/m3 (max = 1.659 mg/m3) for respirable dust and 0.090 mg/m3 (max =0.289 mg/m3) for RCS. Significant positive relationships were found between the two methods for respirable dust (Spearman r = 0.853; p<0.01) and RCS (Spearman r = 0.934; p<0.0001). The direct-on-filter analysis of 37 mm filters also correlated strongly with infrared spectrometry (KBr pellet) (Spearman r = 0.990; p<0.0001). Additionally, the DustCount enabled the identification of peak concentrations (max = 7.548 mg/m3) and data showed that the dominant particle sizes were 0.375 µm and 0.468 µm. Conclusions The results of this study show on a small scale that field-based techniques can be combined with conventional monitoring techniques to obtain quicker exposure results and more detailed data to better understand exposure to for respirable dust and RCS.
Sex workers have endured a high burden of HIV infection in and across HIV epidemics. A comprehensive, community empowerment-based HIV prevention intervention emphasizes sex worker organization and ...mobilization to address HIV risk and often includes community-led peer education, condom distribution, and other activities. Meta-analysis of such interventions suggests a potential 51% reduction in inconsistent condom use. Mathematical modeling exercises provide theoretical insight into potential impacts of the intervention on HIV incidence and burden in settings where interventions have not yet been implemented.
We used a deterministic model, Goals, to project the impact on HIV infections when the community empowerment interventions were scaled up among female sex workers in Kenya, Thailand, Brazil, and Ukraine. Modeling scenarios included expansion of the comprehensive community empowerment-based HIV prevention intervention from baseline coverage over a 5-year period (5-65% in Kenya and Ukraine; 10-70% in Thailand and Brazil), while other interventions were held at baseline levels. A second exercise increased the intervention coverage simultaneously with equitable access to ART for sex workers. Impacts on HIV outcomes among sex workers and adults are observed from 2012-2016 and, compared to status quo when all interventions are held constant.
Optimistic but feasible coverage (65%-70%) of the intervention demonstrated a range of impacts on HIV: 220 infections averted over 5 yrs. among sex workers in Thailand, 1,830 in Brazil, 2,220 in Ukraine, and 10,800 infections in Kenya. Impacts of the intervention for female sex workers extend to the adult population, cumulatively averting 730 infections in Thailand to 20,700 adult infections in Kenya. Impacts vary by country, influenced by HIV prevalence in risk groups, risk behaviors, intervention use, and population size.
A community empowerment approach to HIV prevention and access to universal ART for female sex workers is a promising human rights-based solution to overcoming the persistent burden of HIV among female sex workers across epidemic settings.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
•What is currently known about this topic?Comparative morbidity outcomes for antibiotics with similar microbiological spectrum of activity in treatment of acute appendicitis is unknown.•What new ...information is contained in this article?Despite increased surgical site infection with single agent antibiotic treatment (amoxicillin/clavulanic acid), overall morbidity relating to ICU admission, relook rate and length of hospital stay is similar, when compared to traditional triple agent cover for paediatric post-operative complicated appendicitis treatment.
Antibiotic choice for complicated appendicitis should be based on both microbiological effectiveness as well as ease of administration and cost especially in lower resourced settings. Data is limited on comparative morbidity outcomes for antibiotics with similar microbiological spectrum of activity.
Incidence and morbidity of surgical site infection after appendectomy for complicated appendicitis was assessed after protocol change from triple antibiotic (ampicillin, gentamycin, and metronidazole) regimen to single agent (amoxycillin/clavulanic acid).
Surgical site infection (SSI) rate, relook surgery rate and length of hospital stay were retrospectively compared in patients treated for acute appendicitis preceding (2014, 2015; “triple-therapy, TT”) and following (2017, 2018; “single agent, SA”) antibiotic protocol change.
The rate of complicated appendicitis was similar between groups; 72.6% in TT and 66% in SA (p = 0.239). Significantly, SSI occurred in 22.7% of the SA group compared to 13.3% in TT group (OR 1.920, 95% CI 1.000–3.689, p = 0.048).
Use of laparoscopy increased from 31% in TT to 89% in SA, but with subgroup analysis this was not associated with increased SSI (17.3% in open and 20.6% in laparoscopic; OR 0.841, 95% CI 0.409–1.728, p = 0.637). Relook rate (OR 1.444, 95% CI 0.595–3.507, p = 0.093) length of hospital stay (U = 6859, z = -1.163, p = 0.245), and ICU admission (U = 7683, z = 0.634 p = 0.522) were equivocal. Neither group had mortalities.
Despite increased SSI with SA, overall morbidity relating to ICU admission, relook rate and length of hospital stay was similar in both groups. More prospective research is required to confirm equivalent overall morbidity and that single agent therapy is more cost-effective with acceptable clinical outcomes.
Graphical abstract Proposed model of intestinal macrophage activation in ASH/NASH cirrhosis. Following changes in bacterial flora, intestinal macrophage activation occurs. CD14+ iNOS+ intestinal ...macrophages release NO and IL-6. In addition CCL-13, IL-8, and CCL-2/MCP-1 are produced that may attract monocytes from the circulation.
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