Explore the vast range of titles available.

Synthetic retinoid compounds can kill both growing and persister MRSA cells by disrupting the membrane lipid bilayer, and are effective in a mouse model of chronic MRSA infection. Drugs to beat persistence Bacterial persisters are a subpopulation of cells that can survive lethal antibiotics and other stresses. They are a major challenge for antimicrobial therapy as they cannot be killed by traditional therapeutic agents. Eleftherios Mylonakis and colleagues have developed retinoid compounds that can kill both growing and persister MRSA cells by disrupting the membrane. They develop one of these compounds with an improved cytotoxicity profile, and show that it is effective in treating a mouse model of chronic MRSA infection. Further development of these antibiotics is required to improve safety margins to move the antibiotics closer to being viable clinical candidates. A challenge in the treatment of Staphylococcus aureus infections is the high prevalence of methicillin-resistant S. aureus (MRSA) strains and the formation of non-growing, dormant ‘persister’ subpopulations that exhibit high levels of tolerance to antibiotics 1 , 2 , 3 and have a role in chronic or recurrent infections 4 , 5 . As conventional antibiotics are not effective in the treatment of infections caused by such bacteria, novel antibacterial therapeutics are urgently required. Here we used a Caenorhabditis elegans –MRSA infection screen 6 to identify two synthetic retinoids, CD437 and CD1530, which kill both growing and persister MRSA cells by disrupting lipid bilayers. CD437 and CD1530 exhibit high killing rates, synergism with gentamicin, and a low probability of resistance selection. All-atom molecular dynamics simulations demonstrated that the ability of retinoids to penetrate and embed in lipid bilayers correlates with their bactericidal ability. An analogue of CD437 was found to retain anti-persister activity and show an improved cytotoxicity profile. Both CD437 and this analogue, alone or in combination with gentamicin, exhibit considerable efficacy in a mouse model of chronic MRSA infection. With further development and optimization, synthetic retinoids have the potential to become a new class of antimicrobials for the treatment of Gram-positive bacterial infections that are currently difficult to cure.

ObjectiveTo assess existing literature on the effectiveness of mental health training courses for non-specialist health workers, based on the WHO guidelines (2008).DesignA systematic review was carried out, complying with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist.Data sourcesAfter examination of key studies in the literature, a comprehensive search was performed within the following electronic databases on 31 May 2017: PubMed, PsycINFO, CINAHL (using EBSCOHost interface), Cochrane, Web of Science.Eligibility criteriaSearches were conducted for articles published in English from January 2008 to May 2017, using search terms related to mental health, training, community care and evaluation/outcome, following the Participants, Interventions, Comparators and Outcomes process for evidence-based practice.OutcomesData were collected across the following categories: trainees (number and background), training course (curriculum, teaching method, length), evaluation method (timing of evaluation, collection method and measures assessed) and evaluation outcome (any improvement recorded from baseline). In addition, studies were assessed for their methodological quality using the framework established by Liu et al (2016).Results29 studies with relevant training courses met the inclusion criteria. These were implemented across 16 countries since 2008 (over half between 2014 and 2017), with 10 in three high-income countries. Evaluation methods and outcomes showed high variability across studies, with courses assessing trainees’ attitude, knowledge, clinical practice, skills, confidence, satisfaction and/or patient outcome. All 29 studies found some improvement after training in at least one area, and 10 studies found this improvement to be significant.ConclusionsTraining non-specialist workers in mental healthcare is an effective strategy to increase global provision and capacity, and improves knowledge, attitude, skill and confidence among health workers, as well as clinical practice and patient outcome. Areas for future focus include the development of standardised evaluation methods and outcomes to allow cross-comparison between studies, and optimisation of course structure.PROSPERO registration numberCRD42016033269

Background Although currently most widely used in mechanical ventilation and cardiopulmonary resuscitation, features of the carbon dioxide (CO 2 ) waveform produced through capnometry have been shown to correlate with V/Q mismatch, dead space volume, type of breathing pattern, and small airway obstruction. This study applied feature engineering and machine learning techniques to capnography data collected by the N-Tidal™ device across four clinical studies to build a classifier that could distinguish CO 2 recordings (capnograms) of patients with COPD from those without COPD. Methods Capnography data from four longitudinal observational studies (CBRS, GBRS, CBRS2 and ABRS) was analysed from 295 patients, generating a total of 88,186 capnograms. CO 2 sensor data was processed using TidalSense’s regulated cloud platform, performing real-time geometric analysis on CO 2 waveforms to generate 82 physiologic features per capnogram. These features were used to train machine learning classifiers to discriminate COPD from ‘non-COPD’ (a group that included healthy participants and those with other cardiorespiratory conditions); model performance was validated on independent test sets. Results The best machine learning model (XGBoost) performance provided a class-balanced AUROC of 0.985 ± 0.013, positive predictive value (PPV) of 0.914 ± 0.039 and sensitivity of 0.915 ± 0.066 for a diagnosis of COPD. The waveform features that are most important for driving classification are related to the alpha angle and expiratory plateau regions. These features correlated with spirometry readings, supporting their proposed properties as markers of COPD. Conclusion The N-Tidal™ device can be used to accurately diagnose COPD in near-real-time, lending support to future use in a clinical setting. Trial registration: Please see NCT03615365, NCT02814253, NCT04504838 and NCT03356288.

Tobacco smoking is the primary cause of chronic obstructive pulmonary disease (COPD) globally. Capnography data was collected twice daily for up to 6 months from 147 COPD participants across multiple studies using TidalSense’s N-Tidal device. Waveform features from the alpha angle region of the capnogram showed strong association with pack year history, indicating that capnography can quantify a dose-response relationship between smoking exposure and airway remodelling. This non-linear association reached an inflection around 25 pack years, potentially indicating a ‘tipping point’ beyond which the likelihood of retaining normal lung function significantly diminishes. This provides valuable mechanistic insights and could help estimate disease risk and support early preventative interventions. Trial registration ClinicalTrials.gov NCT02814253 (registered on 27 June 2016), ClinicalTrials.gov NCT03615365 (registered on 3 August 2018), ClinicalTrials.gov NCT04939558 (registered on 25 June 2021).

Abstract Background: Falsified medicines are deliberately fraudulent drugs that pose a direct risk to patient health and undermine healthcare systems, causing global morbidity and mortality. Objective: To produce an overview of anti-falsifying public health interventions deployed at international, national and local scales in low and middle income countries (LMIC). Data sources: We conducted a systematic search of the PubMed, Web of Science, Embase and Cochrane Central Register of Controlled Trials databases for healthcare or pharmaceutical policies relevant to reducing the burden of falsified medicines in LMIC. Results: Our initial search identified 660 unique studies, of which 203 met title/abstract inclusion criteria and were categorised according to their primary focus: international; national; local pharmacy; internet pharmacy; drug analysis tools. Eighty-four were included in the qualitative synthesis, along with 108 articles and website links retrieved through secondary searches. Discussion: On the international stage, we discuss the need for accessible pharmacovigilance (PV) global reporting systems, international leadership and funding incorporating multiple stakeholders (healthcare, pharmaceutical, law enforcement) and multilateral trade agreements that emphasise public health. On the national level, we explore the importance of establishing adequate medicine regulatory authorities and PV capacity, with drug screening along the supply chain. This requires interdepartmental coordination, drug certification and criminal justice legislation and enforcement that recognise the severity of medicine falsification. Local healthcare professionals can receive training on medicine quality assessments, drug registration and pharmacological testing equipment. Finally, we discuss novel technologies for drug analysis which allow rapid identification of fake medicines in low-resource settings. Innovative point-of-purchase systems like mobile phone verification allow consumers to check the authenticity of their medicines. Conclusions: Combining anti-falsifying strategies targeting different levels of the pharmaceutical supply chain provides multiple barriers of protection from falsified medicines. This requires the political will to drive policy implementation; otherwise, people around the world remain at risk.

This study investigates the efficacy of nebivolol (NBV) in experimental models of toxoplasmosis, focusing on parasite burden reduction and neuronal protection. In the acute model of experimental toxoplasmosis, Swiss mice infected with RH strain tachyzoites received oral NBV chlorhydrate doses of 2 mg/kg/day and 4 mg/kg/day for 8 days. Treatment with NBV significantly reduced parasite burden compared to vehicle and standard drug (PYR) groups. In the chronic model of experimental toxoplasmosis, C57/BL6 mice infected with the ME49 strain received NBV chlorhydrate 41 days post-infection and were evaluated after 10 days of treatment. NBV chlorhydrate effectively reduced cyst number and area, as well as bradyzoite burden compared to controls. Histological analysis demonstrated that NBV chlorhydrate preserved neuronal count, with the 4 mg/kg/day dose yielding counts similar to non-infected mice. Statistical analysis confirmed significant differences compared to control groups. Furthermore, immunohistochemical analysis revealed a significant reduction in iNOS labeling in the brains of mice treated with NBV chlorhydrate, indicating a decrease in nitric oxide production compared to control groups. These findings suggest NBV’s potential as a promising candidate for toxoplasmosis treatment, highlighting its ability to reduce parasite burden and protect neuronal integrity. Further research is warranted to elucidate NBV’s mechanisms of action and its clinical application in managing toxoplasmosis.

In the current agricultural context, sustainable crops such as perennial grains have the potential to further secure the world's demand in cereals. Under northern climates, perennial grains are as vulnerable as annual grains to early and late frost events that cause important damages and economic losses. Therefore, the understanding of cold-acclimation in perennials grasses, that is the process by which temperate plants prime their defence against freezing stress, is necessary to cultivate them at their full potential under northern latitudes. Here, we tested the newly developed perennial grasses model B. sylvaticum in its capacity to facilitate the study of cold-acclimation and freezing tolerance in perennial grasses. Accordingly, our hypothesis is that B. sylvaticum can cold-acclimate in response to low temperatures and increase its freezing tolerance level, and that a phenotypic range in the capacity to cold-acclimate will be observed across different accessions. To verify this, we first determined the survival of non-acclimated and cold-acclimated live plants to freezing stress. We observed an increase of 2 °C in the freezing tolerance of cold-acclimated plants in nine tested accessions, themselves differentiated by a diversity in cold-acclimation capacity. This was followed by the determination of cold-responsive genes transcript accumulation profiles in B. sylvaticum. Consequently, we determined that three cold-responsive genes BsCOR413, BsCOR410 and BsCBF2.1 were differentially regulated in response to cold in nine accessions of B. sylvaticum, which indicates that this plant most likely possesses the molecular mechanisms that allow cold-acclimation and the subsequent increase in its freezing tolerance. In addition, we tested a high-efficiency transformation protocol for B. sylvaticum under our laboratory conditions. We report the transformation of a B. sylvaticum plant that overexpresses by thirtyfold the acetyltransferase GCN5, an epigenetic modifier that was previously linked to cold response in plants. Therefore, B. sylvaticum's capacity to cold-acclimate through the observed underlying molecular mechanisms as well as its ability to be transformed under laboratory conditions highlights its potential in being used as a model to study cold response in perennial grasses. Findings made in B. sylvaticum could thus be transferred and applied to economically important perennial grains crop in order to increase their freezing tolerance.

BACKGROUNDVaccines that block human-to-mosquito Plasmodium transmission are needed for malaria eradication, and clinical trials have targeted zygote antigen Pfs25 for decades. We reported that a Pfs25 protein-protein conjugate vaccine formulated in alum adjuvant induced serum functional activity in both US and Malian adults. However, antibody levels declined rapidly, and transmission-reducing activity required 4 vaccine doses. Functional immunogenicity and durability must be improved before advancing transmission-blocking vaccines further in clinical development. We hypothesized that the prefertilization protein Pfs230 alone or in combination with Pfs25 would improve functional activity.METHODSTransmission-blocking vaccine candidates based on gamete antigen Pfs230 or Pfs25 were conjugated with Exoprotein A, formulated in Alhydrogel, and administered to mice, rhesus macaques, and humans. Antibody levels were measured by ELISA and transmission-reducing activity was assessed by the standard membrane feeding assay.RESULTSPfs25-EPA/Alhydrogel and Pfs230D1-EPA/Alhydrogel induced similar serum functional activity in mice, but Pfs230D1-EPA induced significantly greater activity in rhesus monkeys that was enhanced by complement. In US adults, 2 vaccine doses induced complement-dependent activity in 4 of 5 Pfs230D1-EPA/Alhydrogel recipients but no significant activity in 5 Pfs25-EPA recipients, and combination with Pfs25-EPA did not increase activity over Pfs230D1-EPA alone.CONCLUSIONThe complement-dependent functional immunogenicity of Pfs230D1-EPA represents a significant improvement over Pfs25-EPA in this comparative study. The rhesus model is more predictive of the functional human immune response to Pfs230D1 than is the mouse model.TRIAL REGISTRATIONClinicalTrials.gov NCT02334462.FUNDINGIntramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health.

A cure for HIV-1 remains unattainable as only one case has been reported, a decade ago 1 , 2 . The individual—who is known as the ‘Berlin patient’—underwent two allogeneic haematopoietic stem-cell transplantation (HSCT) procedures using a donor with a homozygous mutation in the HIV coreceptor CCR5 (CCR5Δ32/Δ32) to treat his acute myeloid leukaemia. Total body irradiation was given with each HSCT. Notably, it is unclear which treatment or patient parameters contributed to this case of long-term HIV remission. Here we show that HIV-1 remission may be possible with a less aggressive and toxic approach. An adult infected with HIV-1 underwent allogeneic HSCT for Hodgkin’s lymphoma using cells from a CCR5Δ32/Δ32 donor. He experienced mild gut graft-versus-host disease. Antiretroviral therapy was interrupted 16 months after transplantation. HIV-1 remission has been maintained over a further 18 months. Plasma HIV-1 RNA has been undetectable at less than one copy per millilitre along with undetectable HIV-1 DNA in peripheral CD4 T lymphocytes. Quantitative viral outgrowth assays from peripheral CD4 T lymphocytes show no reactivatable virus using a total of 24 million resting CD4 T cells. CCR5-tropic, but not CXCR4-tropic, viruses were identified in HIV-1 DNA from CD4 T cells of the patient before the transplant. CD4 T cells isolated from peripheral blood after transplantation did not express CCR5 and were susceptible only to CXCR4-tropic virus ex vivo. HIV-1 Gag-specific CD4 and CD8 T cell responses were lost after transplantation, whereas cytomegalovirus-specific responses were detectable. Similarly, HIV-1-specific antibodies and avidities fell to levels comparable to those in the Berlin patient following transplantation. Although at 18 months after the interruption of treatment it is premature to conclude that this patient has been cured, these data suggest that a single allogeneic HSCT with homozygous CCR5Δ32 donor cells may be sufficient to achieve HIV-1 remission with reduced intensity conditioning and no irradiation, and the findings provide further support for the development of HIV-1 remission strategies based on preventing CCR5 expression. An adult infected with HIV-1 who underwent allogeneic haematopoietic stem-cell transplantation for Hodgkin’s lymphoma using cells from a CCR5Δ32/Δ32 donor achieved full remission of HIV-1 for 18 months after transplantation and 16 months after cessation of antiretroviral therapy.

To estimate the rates of maternal-fetal transmission of Zika virus, adverse fetal/neonatal outcomes, and subsequent rates of asymptomatic/symptomatic congenital Zika virus infections up to the first week of life. Cohort study with prospective data collection and subsequent review of fetal/neonatal outcomes. Referral centre for prenatal diagnosis of the French Guiana Western Hospital. Pregnant women at any stage of pregnancy with a laboratory confirmed symptomatic or asymptomatic Zika virus infection during the epidemic period in western French Guiana. The cohort enrolled 300 participants and prospectively followed their 305 fetuses/newborns. Rate of maternal-fetal transmission of Zika virus (amniotic fluid, fetal and neonatal blood, urine, cerebrospinal fluid, and placentas); clinical, biological, and radiological outcomes (blindly reviewed); and adverse outcomes defined as moderate signs potentially related to congenital Zika syndrome (CZS), severe complications compatible with CZS, or fetal loss. Associations between a laboratory confirmed congenital Zika virus infection and adverse fetal/neonatal outcomes were evaluated. Maternal-fetal transmission was documented in 26% (76/291) of fetuses/newborns with complete data. Among the Zika virus positive fetuses/newborns, 45% (34/76) presented with no signs/complications at birth, 20% (15/76) with moderate signs potentially related to CZS, 21% (16/76) with severe complications compatible with CZS, and 14% (11/76) with fetal loss. Compared with the Zika virus positive fetuses/neonates, those that were identified as negative for Zika virus (215/291) were less likely to present with severe complications (5%; 10/215) or fetal loss (0.5%; 1/215; relative risk 6.9, 95% confidence interval 3.6 to 13.3). Association between a positive Zika virus test and any adverse fetal/neonatal outcome was also significant (relative risk 4.4, 2.9 to 6.6). The population attributable fraction estimates that a confirmed congenital Zika virus infection contributes to 47% of adverse outcomes and 61% of severe adverse outcomes observed. In cases of a known maternal Zika virus infection, approximately a quarter of fetuses will become congenitally infected, of which a third will have severe complications at birth or fetal loss. The burden of CZS might be lower than initially described in South America and may not differ from other congenital infections.