How Much Do We Know about Drug Resistance Due to PrEP Use? Analysis of Experts' Opinion and Its Influence on the Projected Public Health Impact

BACKGROUND: Randomized controlled trials reported that pre-exposure prophylaxis (PrEP) with tenofovir and emtricitabine rarely selects for drug resistance. However, drug resistance due to PrEP is not completely understood. In daily practice, PrEP will not be used under the well-controlled conditions available in the trials, suggesting that widespread use of PrEP can result in increased drug resistance. METHODS: We surveyed expert virologists with questions about biological assumptions regarding drug resistance due to PrEP use. The influence of these assumptions on the prevalence of drug resistance and the fraction of HIV transmitted resistance was studied with a mathematical model. For comparability, 50% PrEP-coverage of and 90% per-act efficacy of PrEP in preventing HIV acquisition are assumed in all simulations. RESULTS: Virologists disagreed on the following: the time until resistance emergence (range: 20–180 days) in infected PrEP users with breakthrough HIV infections; the efficacy of PrEP against drug-resistant HIV (25%-90%); and the likelihood of resistance acquisition upon transmission (10%-75%). These differences translate into projections of 0.6%- 1% and 3.5%—6% infected individuals with detectable resistance 10 years after introducing PrEP, assuming 100% and 50% adherence, respectively. The rate of resistance emergence following breakthrough HIV infection and the rate of resistance reversion after PrEP use is discontinued, were the factors identified as most influential on the expected resistance associated with PrEP. Importantly, 17–23% infected individuals could virologically fail treatment as a result of past PrEP use or transmitted resistance to PrEP with moderate adherence. CONCLUSIONS: There is no broad consensus on quantification of key biological processes that underpin the emergence of PrEP-associated drug resistance. Despite this, the contribution of PrEP use to the prevalence of the detectable drug resistance is expected to be small. However, individuals who become infected despite the use of PrEP should be closely monitored due to higher risk of virological failure when initiating antiretroviral treatment in the future

Enhanced Brain Disposition and Effects of Δ9-Tetrahydrocannabinol in P-Glycoprotein and Breast Cancer Resistance Protein Knockout Mice

The ABC transporters P-glycoprotein (P-gp, Abcb1) and breast cancer resistance protein (Bcrp, Abcg2) regulate the CNS disposition of many drugs. The main psychoactive constituent of cannabis Δ9-tetrahydrocannabinol (THC) has affinity for P-gp and Bcrp, however it is unknown whether these transporters modulate the brain accumulation of THC and its functional effects on the CNS. Here we aim to show that mice devoid of Abcb1 and Abcg2 retain higher brain THC levels and are more sensitive to cannabinoid-induced hypothermia than wild-type (WT) mice. Abcb1a/b (−/−), Abcg2 (−/−) and wild-type (WT) mice were injected with THC before brain and blood were collected and THC concentrations determined. Another cohort of mice was examined for THC-induced hypothermia by measuring rectal body temperature. Brain THC concentrations were higher in both Abcb1a/b (−/−) and Abcg2 (−/−) mice than WT mice. ABC transporter knockout mice exhibited delayed elimination of THC from the brain with the effect being more prominent in Abcg2 (−/−) mice. ABC transporter knockout mice were more sensitive to THC-induced hypothermia compared to WT mice. These results show P-gp and Bcrp prolong the brain disposition and hypothermic effects of THC and offer a novel mechanism for both genetic vulnerability to the psychoactive effects of cannabis and drug interactions between CNS therapies and cannabis

Contribution to the understanding of tribological properties of graphite intercalation compounds with metal chloride

Intrinsic tribological properties of lamellar compounds are usually attributed to the presence of van der Waals gaps in their structure through which interlayer interactions are weak. The controlled variation of the distances and interactions between graphene layers by intercalation of electrophilic species in graphite is used in order to explore more deeply the friction reduction properties of low-dimensional compounds. Three graphite intercalation compounds with antimony pentachloride, iron trichloride and aluminium trichloride are studied. Their tribological properties are correlated to their structural parameters, and the interlayer interactions are deduced from ab initio bands structure calculations

A fresh look at the evolution and diversification of photochemical reaction centers

In this review, I reexamine the origin and diversification of photochemical reaction centers based on the known phylogenetic relations of the core subunits, and with the aid of sequence and structural alignments. I show, for example, that the protein folds at the C-terminus of the D1 and D2 subunits of Photosystem II, which are essential for the coordination of the water-oxidizing complex, were already in place in the most ancestral Type II reaction center subunit. I then evaluate the evolution of reaction centers in the context of the rise and expansion of the different groups of bacteria based on recent large-scale phylogenetic analyses. I find that the Heliobacteriaceae family of Firmicutes appears to be the earliest branching of the known groups of phototrophic bacteria; however, the origin of photochemical reaction centers and chlorophyll synthesis cannot be placed in this group. Moreover, it becomes evident that the Acidobacteria and the Proteobacteria shared a more recent common phototrophic ancestor, and this is also likely for the Chloroflexi and the Cyanobacteria. Finally, I argue that the discrepancies among the phylogenies of the reaction center proteins, chlorophyll synthesis enzymes, and the species tree of bacteria are best explained if both types of photochemical reaction centers evolved before the diversification of the known phyla of phototrophic bacteria. The primordial phototrophic ancestor must have had both Type I and Type II reaction centers

A Call for Action: The Application of the International Health Regulations to the Global Threat of Antimicrobial Resistance

Stephen Harbarth and colleagues argue that the International Health Regulations (IHR) should be applied to the global health threat of antimicrobial resistance

Association between intra-radicular posts and periapical lesions in endodontically treated teeth

Introduction: A significant number of endodontically treated teeth restored with posts have associated periapical lesions, and several authors have discussed the probable causes of the development of these. Attention has been focused on restorative procedures performed after endodontic treatment and their association with the prognosis of endodontic therapy because a number of root-filled teeth will require post- and core-retained restorations. Purpose: The purpose of this study was to evaluate, by examination of periapical radiographs, whether the placement of intra-radicular posts in endodontically treated teeth may act as a risk factor for development of periapical lesions. Material and Methods: This case-control study analyzed periapical radiographs of 72 endodontically treated teeth with coronal restorations. All radiographs were obtained from a single private practice. Specimens were assigned to 2 groups: Group 1 (control) was composed of teeth without periapical lesions and Group 2 (case) was composed of teeth with periapical lesions. The number of teeth with and without posts in each group was recorded. Three calibrated examiners analyzed the radiographs visually under X4 magnification. Results: In Group 1, 28 (65.1%) out of 43 teeth were restored with posts. In Group 2, 24 (82.8%) out of 29 teeth had intra-radicular posts. The interpretation of chi-square test showed that these percentages were not significantly different (x²=2.687; p=0.101). Odds ratio was 2.571 (0.815-8.118), which indicates that there was no statistically significant association between periapical lesions and posts. Conclusion: Intra-radicular posts placed in endodontically treated teeth were not a significant risk factor for development of periapical lesions in the practice where the cohort of patients was treated

Characterization of the Psychological, Physiological and EEG Profile of Acute Betel Quid Intoxication in Naïve Subjects

Betel quid use and abuse is wide spread in Asia but the physiological basis of intoxication and addiction are unknown. In subjects naïve to the habit of betel quid intoxication, the psychological and physiological profile of intoxication has never been reported. We compared the effect of chewing gum or chewing betel quid, and subsequent betel quid intoxication, on psychological assessment, prospective time interval estimation, numerical and character digit span, computerized 2 choice tests and mental tasks such as reading and mathematics with concurrent monitoring of ECG, EEG and face temperature in healthy, non-sleep deprived, male subjects naïve to the habit of chewing betel quid. Betel quid intoxication, dose dependently induced tachycardia (max 30 bpm) and elevated face temperature (0.7°C) (P<0.001) above the effects observed in response to chewing gum (max 12 bpm and 0.3°C) in 12 subjects. Gross behavioral indices of working memory such as numerical or character digit span in 8 subjects, or simple visual-motor performance such as reaction speed or accuracy in a two choice scenario in 8 subjects were not affected by betel quid intoxication. Betel quid intoxication strongly influenced the psychological aspects of perception such as slowing of the prospective perception of passage of a 1 minute time interval in 8 subjects (P<0.05) and perceived increased arousal (P<0.01) and perceived decreased ability to think (P<0.05) in 31 subjects. The EEG spectral profile recorded from mental states associated with open and closed eyes, and mental tasks such as reading and eyes closed mental arithmetic were significantly modified (P<0.05) relative to chewing gum by betel quid intoxication in 10 subjects. The prevalence of betel quid consumption across a range of social and work settings warrants greater investigation of this widespread but largely under researched drug

The Type III Secreted Protein BspR Regulates the Virulence Genes in Bordetella bronchiseptica

Bordetella bronchiseptica is closely related with B. pertussis and B. parapertussis, the causative agents of whooping cough. These pathogenic species share a number of virulence genes, including the gene locus for the type III secretion system (T3SS) that delivers effector proteins. To identify unknown type III effectors in Bordetella, secreted proteins in the bacterial culture supernatants of wild-type B. bronchiseptica and an isogenic T3SS-deficient mutant were compared with iTRAQ-based, quantitative proteomic analysis method. BB1639, annotated as a hypothetical protein, was identified as a novel type III secreted protein and was designated BspR (Bordetella secreted protein regulator). The virulence of a BspR mutant (ΔbspR) in B. bronchiseptica was significantly attenuated in a mouse infection model. BspR was also highly conserved in B. pertussis and B. parapertussis, suggesting that BspR is an essential virulence factor in these three Bordetella species. Interestingly, the BspR-deficient strain showed hyper-secretion of T3SS-related proteins. Furthermore, T3SS-dependent host cell cytotoxicity and hemolytic activity were also enhanced in the absence of BspR. By contrast, the expression of filamentous hemagglutinin, pertactin, and adenylate cyclase toxin was completely abolished in the BspR-deficient strain. Finally, we demonstrated that BspR is involved in the iron-responsive regulation of T3SS. Thus, Bordetella virulence factors are coordinately but inversely controlled by BspR, which functions as a regulator in response to iron starvation

When What's Left Is Right: Visuomotor Transformations in an Aged Population

Background: There has been little consensus as to whether age-related visuomotor adaptation effects are readily observable. Some studies have found slower adaptation, and/or reduced overall levels. In contrast, other methodologically similar studies have found no such evidence of aging effects on visuomotor adaptation. A crucial early step in successful adaptation is the ability to perform the necessary transformation to complete the task at hand. The present study describes the use of a viewing window paradigm to examine the effects of aging in a visuomotor transformation task. Methods: Two groups of participants, a young adult control group (age range 18–33 years old, mean age = 22) and an older adult group (age range 62–74, mean age = 68) completed a viewing window task that was controlled by the user via a computer touchscreen. Four visuomotor ‘‘flip’ ’ conditions were created by varying the relationship between the participant’s movement, and the resultant on-screen movement of the viewing window: 1) No flip 2) X-Axis and Y-axis body movements resulted in the opposite direction of movement of the viewing window. In each of the 3) Flip-X and 4) Flip-Y conditions, the solitary X- or Y-axes were reversed. Response times and movement of the window were recorded. Conclusions: Older participants demonstrated impairments in performing a required visuomotor transformation, as evidenced by more complex scanning patterns and longer scanning times when compared to younger control participants. These results provide additional evidence that the mechanisms involved in visuomotor transformation are negatively affected by age

A Novel Peptide Enhances Therapeutic Efficacy of Liposomal Anti-Cancer Drugs in Mice Models of Human Lung Cancer

Lung cancer is the leading cause of cancer-related mortality worldwide. The lack of tumor specificity remains a major drawback for effective chemotherapies and results in dose-limiting toxicities. However, a ligand-mediated drug delivery system should be able to render chemotherapy more specific to tumor cells and less toxic to normal tissues. In this study, we isolated a novel peptide ligand from a phage-displayed peptide library that bound to non-small cell lung cancer (NSCLC) cell lines. The targeting phage bound to several NSCLC cell lines but not to normal cells. Both the targeting phage and the synthetic peptide recognized the surgical specimens of NSCLC with a positive rate of 75% (27 of 36 specimens). In severe combined immunodeficiency (SCID) mice bearing NSCLC xenografts, the targeting phage specifically bound to tumor masses. The tumor homing ability of the targeting phage was inhibited by the cognate synthetic peptide, but not by a control or a WTY-mutated peptide. When the targeting peptide was coupled to liposomes carrying doxorubicin or vinorelbine, the therapeutic index of the chemotherapeutic agents and the survival rates of mice with human lung cancer xenografts markedly increased. Furthermore, the targeting liposomes increased drug accumulation in tumor tissues by 5.7-fold compared with free drugs and enhanced cancer cell apoptosis resulting from a higher concentration of bioavailable doxorubicin. The current study suggests that this tumor-specific peptide may be used to create chemotherapies specifically targeting tumor cells in the treatment of NSCLC and to design targeted gene transfer vectors or it may be used one in the diagnosis of this malignancy