Factors associated with increased suicidality risk following referral for isotretinoin commencement.

OBJECTIVE: To establish whether there is a significant change in suicidality risk following psychiatric assessment for commencement of isotretinoin and identify factors that underpin any potential risk change. METHOD: Retrospective cohort study. Suicidality risk was defined as a combination of the following: (i) actual/intended self-harm and/or attempted/completed suicide, and (ii) increased service utilisation associated with suicidal ideation/behaviour. All patients referred to Psychiatry for assessment prior to commencement of isotretinoin between 2014 and 2019 were examined. Inclusion criteria: >16 years of age, assessed for commencement of isotretinoin, complete clinical records. Data were collected by reviewing the Electronic Patient Records. Fifty-seven patients were eligible. We employed descriptive statistics, parametric/non-parametric/normality tests and logistic regression analysis, using socio-demographic and clinical characteristics as independent parameters, and suicidality risk as the dependent parameter. RESULTS: Actual/intended self-harm/attempted suicide decreased significantly following assessment without significant change in service utilisation. Female gender, absence of protective factors and assessment by Consultation-Liaison Psychiatry were linked to increased suicidality risk, after controlling for age, ethnicity, recommendation for isotretinoin, and substance misuse. CONCLUSIONS: Psychiatric assessment is helpful before commencing isotretinoin. Female gender, and absence of ongoing psychopharmacological and/or psychological intervention and/or regular psychiatric follow-up predict increased suicidality risk among patients assessed for prescription of isotretinoin.

Microbiome-derived carnitine mimics as previously unknown mediators of gut-brain axis communication.

Alterations to the gut microbiome are associated with various neurological diseases, yet evidence of causality and identity of microbiome-derived compounds that mediate gut-brain axis interaction remain elusive. Here, we identify two previously unknown bacterial metabolites 3-methyl-4-(trimethylammonio)butanoate and 4-(trimethylammonio)pentanoate, structural analogs of carnitine that are present in both gut and brain of specific pathogen-free mice but absent in germ-free mice. We demonstrate that these compounds are produced by anaerobic commensal bacteria from the family Lachnospiraceae (Clostridiales) family, colocalize with carnitine in brain white matter, and inhibit carnitine-mediated fatty acid oxidation in a murine cell culture model of central nervous system white matter. This is the first description of direct molecular inter-kingdom exchange between gut prokaryotes and mammalian brain cells, leading to inhibition of brain cell function.

In vitro efficacy of imipenem-relebactam and cefepime-AAI101 against a global collection of ESBL-positive and carbapenemase-producing Enterobacteriaceae.

OBJECTIVES: To evaluate the potential clinical in vitro efficacy of novel ß-lactam/ß-lactamase-inhibitor combinations - including imipenem-relebactam (IPM-REL) and cefepime-AAI101 (enmetazobactam) (FEP-AAI) - against contemporary multidrug-resistant (MDR) Enterobacteriaceae. METHODS: Agar-based MIC screening against MDR Enterobacteriaceae (n = 264) was used to evaluate the in vitro efficacy of IPM-REL and FEP-AAI, to compare the results with established combinations, and to investigate alternative ß-lactam partners for relebactam (REL) and enmetazobactam (AAI). The inhibition activities of REL, AAI and the comparators avibactam (AVI) and tazobactam, against isolated recombinant ß-lactamases covering representatives from all four Ambler classes of ß-lactamases, were tested using a fluorescence-based assay. RESULTS: Using recombinant proteins, all four inhibitors were highly active against the tested class A serine ß-lactamases (SBLs). REL and AVI showed moderate activity against the Class C AmpC from Pseudomonas aeruginosa and the Class D OXA-10/-48 SBLs, but outperformed tazobactam and AAI. All tested inhibitors lacked activity against Class B metallo-ß-lactamases (MBLs). In the presence of REL and IPM, but not AAI, susceptibility increased against Klebsiella pnuemoniae carbapenemase (KPC)-positive and OXA-48-positive isolates. Both aztreonam-AVI and ceftolozane-tazobactam were more effective than IPM-REL. In all the tested combinations, AAI was a more effective inhibitor of class A ß-lactamases (ESBLs) than the established inhibitors. CONCLUSION: The results lead to the proposal of alternative combination therapies involving REL and AAI to potentiate the use of ß-lactams against clinical Gram-negative isolates expressing a variety of lactamases. They highlight the potential of novel combinations for combating strains not covered by existing therapies.

Identifying Small-Molecule Binding Sites for Epigenetic Proteins at Domain-Domain Interfaces.

Epigenetics is a rapidly growing field in drug discovery. Of particular interest is the role of post-translational modifications to histones and the proteins that read, write, and erase such modifications. The development of inhibitors for reader domains has focused on single domains. One of the major difficulties of designing inhibitors for reader domains is that, with the notable exception of bromodomains, they tend not to possess a well-enclosed binding site amenable to small-molecule inhibition. As many of the proteins in epigenetic regulation have multiple domains, there are opportunities for designing inhibitors that bind at a domain-domain interface which provide a more suitable interaction pocket. Examination of X-ray structures of multiple domains involved in recognising and modifying post-translational histone marks using the SiteMap algorithm identified potential binding sites at domain-domain interfaces. For the tandem plant homeodomain-bromodomain of SP100C, a potential inter-domain site identified computationally was validated experimentally by the discovery of ligands by X-ray crystallographic fragment screening.

Comparison of Hepatic 2D Sandwich Cultures and 3D Spheroids for Long-term Toxicity Applications: A Multicenter Study.

Primary human hepatocytes (PHHs) are commonly used for in vitro studies of drug-induced liver injury. However, when cultured as 2D monolayers, PHH lose crucial hepatic functions within hours. This dedifferentiation can be ameliorated when PHHs are cultured in sandwich configuration (2Dsw), particularly when cultures are regularly re-overlaid with extracellular matrix, or as 3D spheroids. In this study, the 6 participating laboratories evaluated the robustness of these 2 model systems made from cryopreserved PHH from the same donors considering both inter-donor and inter-laboratory variability and compared their suitability for use in repeated-dose toxicity studies using 5 different hepatotoxins with different toxicity mechanisms. We found that expression levels of proteins involved in drug absorption, distribution, metabolism, and excretion, as well as catalytic activities of 5 different CYPs, were significantly higher in 3D spheroid cultures, potentially affecting the exposure of the cells to drugs and their metabolites. Furthermore, global proteomic analyses revealed that PHH in 3D spheroid configuration were temporally stable whereas proteomes from the same donors in 2Dsw cultures showed substantial alterations in protein expression patterns over the 14 days in culture. Overall, spheroid cultures were more sensitive to the hepatotoxic compounds investigated, particularly upon long-term exposures, across testing sites with little inter-laboratory or inter-donor variability. The data presented here suggest that repeated-dosing regimens improve the predictivity of in vitro toxicity assays, and that PHH spheroids provide a sensitive and robust system for long-term mechanistic studies of drug-induced hepatotoxicity, whereas the 2Dsw system has a more dedifferentiated phenotype and lower sensitivity to detect hepatotoxicity.

Epidemiological status of kissing-bugs in South East Asia: A preliminary assessment.

Kissing-bugs (Triatominae) are being increasingly reported as a biting nuisance in SE Asia, with severe bite reactions sometimes leading to anaphylactic shock. In addition, they pose a risk for vector-borne transmission of trypanosomiasis, with potential diagnostic difficulties due to the range of trypanosome species in the region. Here, we review available information about Triatominae in Asia, and present additional comparisons using morphometry, cytogenetics, and new DNA sequence data, to clarify their relationship with each other and with the better known American species. We deduce that all Asian Triatominae have probably derived from forms originally spread during the 15-18th centuries on sailing ships, from the area that now forms the southern USA.

Audit of informed consent practice within a Community Mental Health Team.

The letters from a Community Mental Health Team to patients' general practitioners were reviewed to identify the standard of informed consent documentation. A tool was developed to achieve the expected standards for informed consent documentation and its effects on practice evaluated. Statistically significant improvements were shown using our tool in documentation of discussion of risks; increased by 36% (P ≤ 0.0017, CI 15-58%) benefits of the treatment plan, increased by 56% (P ≤ 0.010-4, CI 38-74%) risks and benefits of no treatment, increased by 52% (P ≤ 0.010-4, CI 33-71%); side-effects, increased by 25% (P ≤ 0.0298, CI 3-47%) and written material improved by 28% (P ≤ 0.0109, CI 7-48%). There are significant clinical implications for the results of this audit as informed consent is fundamental to good practice; this intervention is quick, simple and enables clinicians to demonstrate valid consent, protecting the patient and clinician.

Progress towards the eradication of Tsetse from the Loos islands, Guinea.

BACKGROUND: The tsetse fly Glossina palpalis gambiensis is the main vector of sleeping sickness (Human African Trypanosomiasis - HAT) in West Africa, in particular in littoral Guinea where this disease is currently very active. The Loos islands constitute a small archipelago some 5 km from mainland Guinea, where G. p. gambiensis is well known as a nuisance and potential disease vector by inhabitants of the three main islands, Fotoba, Room, and Kassa. The National Control Program against HAT of Guinea has decided to eradicate tsetse in Loos islands in order to sustainably protect humans and economic activities. After baseline data collection, tsetse control began on the islands in 2006. On each of the three islands a specific combination of control methods was implemented according to the entomological situation found. RESULTS: Starting densities before control operations were 10, 3 and 1 tsetse/trap/day in Kassa, Room and Fotoba respectively, but by July 2010, tsetse were no longer caught in any of the sentinel traps used for monitoring. The reduction rate was faster where several control methods were implemented as a combination (impregnated traps and targets ITT, selective groundspraying, epicutaneous insecticide treatment of pigs, and impregnated fences around pig pens), whereas it was slower when ITT were used as the only control method. CONCLUSIONS: This 100% suppression is a promising step in the eradication process, but G. p. gambiensis may still occur at very low, undetectable, densities on the archipelago. Next step will consist in assessing a 0.05 probability of tsetse absence to ascertain a provisional eradication status. Throughout these operations, a key factor has been the involvement of local teams and local communities without whom such results would be impossible to obtain. Work will continue thanks to the partners involved until total eradication of the tsetse on Loos islands can be declared.

Common variants near ATM are associated with glycemic response to metformin in type 2 diabetes.

Metformin is the most commonly used pharmacological therapy for type 2 diabetes. We report a genome-wide association study for glycemic response to metformin in 1,024 Scottish individuals with type 2 diabetes with replication in two cohorts including 1,783 Scottish individuals and 1,113 individuals from the UK Prospective Diabetes Study. In a combined meta-analysis, we identified a SNP, rs11212617, associated with treatment success (n = 3,920, P = 2.9 × 10(-9), odds ratio = 1.35, 95% CI 1.22-1.49) at a locus containing ATM, the ataxia telangiectasia mutated gene. In a rat hepatoma cell line, inhibition of ATM with KU-55933 attenuated the phosphorylation and activation of AMP-activated protein kinase in response to metformin. We conclude that ATM, a gene known to be involved in DNA repair and cell cycle control, plays a role in the effect of metformin upstream of AMP-activated protein kinase, and variation in this gene alters glycemic response to metformin.

Trypanosomiasis vector control in Africa and Latin America.

Vectors of trypanosomiasis - tsetse (Glossinidae) in Africa, kissing-bugs (Triatominae) in Latin America - are very different insects but share demographic characteristics that render them highly vulnerable to available control methods. For both, the main operational problems relate to re-invasion of treated areas, and the solution seems to be in very large-scale interventions covering biologically-relevant areas rather than adhering to administrative boundaries. In this review we present the underlying rationale, operational background and progress of the various trypanosomiasis vector control initiatives active in both continents.

The future of Chagas disease control.

In the past 15 years, there have been major advances in the control of Chagas disease in most of the countries endemic for this infection. Attention now turns to the future continuity of surveillance and control interventions - especially in regions where control has been so successful that the epidemiological significance of Chagas disease is in steep decline. The effort and expenditure of the recent past cannot continue indefinitely, but a degree of surveillance and selective intervention will be required because of the risk of new infestations and infections resulting from adventitious silvatic vectors accidentally entering houses. In this review, we summarize the progress of multinational control initiatives against Chagas disease. In addition, we suggest that the most sustainable approach to future surveillance involves both the primary healthcare system and university-based teams, with progressively greater attention given to case detection and treatment. Such an idea is not new, but we believe that it merits extensive discussion because of the different ways that research and health interventions are financed and because of the need to establish clearer reporting links between the research communities and the national health authorities.

21 years of parasitology.

Every parasitologist must have seen the first issue of Parasitology Today in July 1985. More than 13 000 copies were sent to those on society and World Health Organization mailing lists. Modelled on the hugely successful Immunology Today, the new journal aimed to provide well-written digests covering all aspects of parasitology, spiced with smaller items of general interest--including the elegant cartoons of Len Goodwin and occasional acerbic comments on style and semantics. The format seemed well appreciated, and subscriptions quickly climbed to commercially sustainable figures, reflected in the increasing willingness of the publisher, Elsevier, to finance colour printing. Within the first year, the journal went "glossy", and under its later title--Trends in Parasitology--it is now ranked highest of all similar organs, with an impact factor of 6.788. As the journal celebrates its "coming of age", I was asked--as founder Editor--to reflect on key changes during these eventful 21 years.

Dynamics between sylvatic, peridomestic and domestic populations of Triatoma brasiliensis (Hemiptera: Reduviidae) in Ceara State, Northeastern Brazil.

Triatoma brasiliensis is the most important Chagas disease vector in the drier regions of the "Brazilian Caatinga", colonizing both sylvatic and domestic environments, usually forming abundant colonies. Control trials using insecticides against domestic and peridomestic populations suggest that the T. brasiliensis has a high capacity to repopulate treated habitats from the neighboring sylvatic populations, making its elimination more complex. The aim of this work was to determine genetic variability among sylvatic, peridomestic and domestic populations of T. brasiliensis using head morphometry and random amplified polymorphic DNA (RAPD). Both morphometric analysis and RAPD patterns showed a separation between sylvatic and domestic populations, being the peridomestic ones between them. Based on this data, we suggest that there exists a flow between natural and artificial environments, being the peridomestic population mainly responsible for this interchange. It is possible that the peridomestic environment is maintaining the variability on the insects found on artificial habitats, which guarantee T. brasiliensis success on adaptation in both environments and also increase the risk of introduction of new Trypanosoma cruzi strains in the domestic cycle of Chagas disease in this region.

Mitochondrial DNA variation of Triatoma infestans populations and its implication on the specific status of T. melanosoma

DNA sequence comparison of 412 base-pairs fragments of the mitochondrial cytochrome B gene was used to infer the genetic structure of nine geographical Triatoma infestans populations and their phylogenetic relationship with T. melanosoma and T. brasiliensis. T. infestans and T. melanosoma were compared by morphometry, allozyme and cytogenetic analyses, as well as subjected to reciprocal crosses, in order to clarify the taxonomic status of the latter. No differences were found to distinguish the two species and the crosses between them yielded progeny. T. infestans populations presented four haplotypes that could be separated in two clusters: one formed by the samples from Bolivia (Andes and Chaco) and the other formed by samples from Argentina and Brazil. Silvatic and domestic T. infestans populations from Bolivia (Andes) were genetically identical.

Population biology of Rhodnius domesticus Neiva & Pinto, 1923 (Hemiptera: Reduviidae) under laboratory conditions

The entire life cicle of Rhodnius domesticus, fed weekly on mice, was studied under controlled conditions. Aspects related to hatching, life time, mortality, feeding behaviour and fecundity for each stage of the insect life-cycle were evaluated. The hatching rate observed in 100 eggs was 57 per cent and the mean time of hatching was 15.6 days. Forth-six nymphs (80.7 per cent) completed the cycle and the mean time from NI to adult was 93.8 days. The average span in days for each stage was 12.4 for NI, 9.8 for NII, 14.2 for NIII, 16.8 for NIV and 25.0 for NV. The number of bloodmeals in each nymphal stage varied from 1 to 3. The mortality rate was 12.3 per cent for NI, 3.5 per cent for NII and 1.7 per cent for NIII and NIV nymphs. The mean number of eggs laid per female in a 9-month period was 333.1. Average adult survival rates were 287.6 + 133 and 328 + 73 days for males and females respectively.

Estimación de las tasas de incidencia de infecciones y parasitosis crónicas a partir de la prevalencia: La enfermedad de Chagas en América Latina / Estimating incidence rates on chronic infections from prevalence data: Chagas' disease in Latin America

Estimating incidence rates of chronic infections from prevalence data: Chagas' disease in Latin America

Estimación de las tasas de incidencia de infecciones y parasitosis crónicas a partir de la prevalencia: La enfermedad de Chagas en América Latina / Estimating incidence rates on chronic infections from prevalence data: Chagas' disease in Latin America

Estimating incidence rates of chronic infections from prevalence data: Chagas' disease in Latin America