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Maximal standard-of-care (SOC) management could not stop the life-threatening progression of a necrotizing fasciitis induced by Panton-Valentine Leukocidin-producing Methicillin-Resistant Staphylococcus aureus (MRSA) in a 12-year-old boy. Multi-route phage therapy was initiated along with antibiotics against Staphylococcus aureus, Pseudomonas aeruginosa and Stenotrophomonas maltophilia , eventually leading to full recovery with no reported adverse events., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Van Nieuwenhuyse, Balcaen, Chatzis, Haenecour, Derycke, Detaille, Clément de Cléty, Boulanger, Belkhir, Yombi, De Greef, Cornu, Docquier, Lentini, Menten, Rodriguez-Villalobos, Verroken, Djebara, Merabishvili, Griselain, Pirnay, Houtekie and Van der Linden.)

Infections due to antimicrobial-resistant bacteria have become a major threat to global health. Some patients may carry resistant bacteria in their gut microbiota. Specific risk factors may trigger the conversion of these carriages into infections in hospitalized patients. Preventively eradicating these carriages has been postulated as a promising preventive intervention. However, previous attempts at such eradication using oral antibiotics or probiotics have led to discouraging results. Phage therapy, the therapeutic use of bacteriophage viruses, might represent a worthy alternative in this context. Taking inspiration from this clinical challenge, we built Gut-On-A-Chip (GOAC) models, which are tridimensional cell culture models mimicking a simplified gut section. These were used to better understand bacterial dynamics under phage pressure using two relevant species: Pseudomonas aeruginosa and Escherichia coli . Model mucus secretion was documented by ELISA assays. Bacterial dynamics assays were performed in GOAC triplicates monitored for 72 h under numerous conditions, such as pre-, per-, or post-bacterial timing of phage introduction, punctual versus continuous phage administration, and phage expression of mucus-binding properties. The potential genomic basis of bacterial phage resistance acquired in the model was investigated by variant sequencing. The bacterial "escape growth" rates under phage pressure were compared to static in vitro conditions. Our results suggest that there is specific bacterial prosperity in this model compared to other in vitro conditions. In E. coli assays, the introduction of a phage harboring unique mucus-binding properties could not shift this balance of power, contradicting previous findings in an in vivo mouse model and highlighting the key differences between these models. Genomic modifications were correlated with bacterial phage resistance acquisition in some but not all instances, suggesting that alternate ways are needed to evade phage predation, which warrants further investigation.

In contrast to the many reports of successful real-world cases of personalized bacteriophage therapy (BT), randomized controlled trials of non-personalized bacteriophage products have not produced the expected results. Here we present the outcomes of a retrospective observational analysis of the first 100 consecutive cases of personalized BT of difficult-to-treat infections facilitated by a Belgian consortium in 35 hospitals, 29 cities and 12 countries during the period from 1 January 2008 to 30 April 2022. We assessed how often personalized BT produced a positive clinical outcome (general efficacy) and performed a regression analysis to identify functional relationships. The most common indications were lower respiratory tract, skin and soft tissue, and bone infections, and involved combinations of 26 bacteriophages and 6 defined bacteriophage cocktails, individually selected and sometimes pre-adapted to target the causative bacterial pathogens. Clinical improvement and eradication of the targeted bacteria were reported for 77.2% and 61.3% of infections, respectively. In our dataset of 100 cases, eradication was 70% less probable when no concomitant antibiotics were used (odds ratio = 0.3; 95% confidence interval = 0.127-0.749). In vivo selection of bacteriophage resistance and in vitro bacteriophage-antibiotic synergy were documented in 43.8% (7/16 patients) and 90% (9/10) of evaluated patients, respectively. We observed a combination of antibiotic re-sensitization and reduced virulence in bacteriophage-resistant bacterial isolates that emerged during BT. Bacteriophage immune neutralization was observed in 38.5% (5/13) of screened patients. Fifteen adverse events were reported, including seven non-serious adverse drug reactions suspected to be linked to BT. While our analysis is limited by the uncontrolled nature of these data, it indicates that BT can be effective in combination with antibiotics and can inform the design of future controlled clinical trials. BT100 study, ClinicalTrials.gov registration: NCT05498363 ., (© 2024. The Author(s).)

Post-operative bacterial infections are a leading cause of mortality and morbidity after ongoing liver transplantation. Bacteria causing these infections in the hospital setting can exhibit high degrees of resistance to multiple types of antibiotics, which leads to major therapeutic hurdles. Alternate ways of treating these antibiotic-resistant infections are thus urgently needed. Phage therapy is one of them and consists in using selected bacteriophage viruses - viruses who specifically prey on bacteria, naturally found in various environmental samples - as bactericidal agents in replacement or in combination with antibiotics. The use of phage therapy raises various research questions to further characterize what determines therapeutic success or failure. In this work, we report the story of a toddler who suffered from extensively drug-resistant Pseudomonas aeruginosa sepsis after liver transplantation. He was treated by a bacteriophage-antibiotic intravenous combination therapy for 86 days. This salvage therapy was well tolerated, without antibody-mediated phage neutralization. It was associated with objective clinical and microbiological improvement, eventually allowing for liver retransplantation and complete resolution of all infections. Clear in vitro phage-antibiotic synergies were observed. The occurrence of bacterial phage resistance did not result in therapeutic failure, possibly due to phage-induced virulence tradeoffs, which we investigated in different experimental models., (© 2022. The Author(s).)

Background: Despite effective treatments, blood pressure (BP) control remains suboptimal., Objective: The SIMPLIFY study aimed at identifying key factors related to therapeutic inertia in Belgium and Luxembourg, and evaluating how uncontrolled treated hypertension is managed in primary care., Methods: In a 2017 cross-sectional survey, 245 general practitioners (GP) collected routine clinical data from 1,852 consecutive uncontrolled (Office SBP/DBP ≥ 140/90 mmHg) hypertensive adult patients taking at least one antihypertensive drug., Results: Patients were 64 years old on average, 48% were women, 61% had dyslipidemia, 33% had diabetes mellitus and 22% had established cardiovascular disease. Half of the patients had 2 or more comorbidities. Patients had been treated for hypertension for an average period of 8 years, 40% of patients were in hypertensive stages 2-3, 44% were treated with monotherapy only, 28% with free combinations and 28% with at least one single pill combination (SPC). Therapeutic adherence was rated as 'good' in 62% of patients. AHT treatment was modified in 84% of patients. In the group of patients with stage 2-3 hypertension, treatment remained unchanged in 5%. In the group of patients with stage 1 hypertension, treatment remained unchanged in 23% of patients. Patients treated for longer than 10 years were less likely to undergo treatment change (81%) compared to patients treated for less than 10 years (87%). Patients with 1 or 2 comorbidities were more likely to have their treatment modified (87%) compared to those with no comorbidities (61%) and those with ≥ 3 comorbidities (79%). If treatment was modified, a SPC was introduced in 90% of cases; 91% in stage 1-2 hypertension and 84% in stage 3 hypertension. SPCs were less frequently initiated in patients without comorbidities. Main reasons for the GPs to switch from a free association towards SPC were 'better BP control' (55%), 'better therapeutic compliance' (53%) and 'simplicity for the patient' (50%)., Conclusion: The SIMPLIFY study confirms therapeutic inertia in hypertension management. After an average of 8 years hypertension treatment, almost 1 in 2 uncontrolled treated patients are on monotherapy. The key inertia drivers seem to be age, mild grade hypertension, isolated systolic hypertension, longer duration of antihypertensive treatment and better therapeutic adherence. When treatment is updated by the GP, the currently preferred strategy is switching towards SPC based therapy to improve BP control, and enhance therapeutic compliance by simplifying treatment for the patient., Trial Registration: pharma.be visa number: VI 17/01/20/01 ISRCTN registered study: ISRCTN16199080., Competing Interests: The authors have read the journal’s policy and have the following competing interests: BVN is an employee of Servier Benelux, which also provided support to develop the study documents, cover the article processing charges, and pay the CRF completion fee of the participating GPs. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development or marketed products associated with this research to declare.

Objective: This study evaluates the actual blood pressure control rate and its estimation by general practitioners, the use of single-pill or free combinations, and the attitude towards single-pill combinations in primary care., Methods: Cross-sectional observational survey in primary care between January 2015 and September 2016 in Belgium and Luxembourg. The participating general practitioners enrolled hypertensive patients taking at least 2 antihypertensive molecules (as fixed or free associations)., Results: 742 general practitioners included a total of 8,006 patients, with a mean age of 66 ± 12 years. Systolic blood pressure and diastolic blood pressure were respectively 141 ± 17 mmHg and 82 ± 10 mmHg (means ± SD). These patients had a blood pressure control rate of 45%, whereas it was estimated by general practitioners to be 60%. General practitioners with 11-25 years' experience performed better than general practitioners with 36-51 years' experience in the evaluation of blood pressure control. Combinations used were free in 39%, single-pill in 34% and mixed in 27% of the patients. Patients receiving single-pill combinations were younger than those treated with free combinations (63 ± 12 vs. 68 ± 12 years, p < 0.001), with fewer comorbidities (39 vs. 55%, p < 0.001). In patients treated solely with free pill associations, 66% of patient cases, general practitioners were willing to switch to a single-pill combination. The main reasons were improved adherence (76%) and better blood pressure control (64%)., Conclusion: In patients requiring at least two antihypertensive drugs, blood pressure control rate remains low and is overestimated by general practitioners. Free combinations remain largely used although many general practitioners seem willing to shift to single-pill combinations. Treatment simplification could improve adherence and blood pressure control rate, which has been shown to lead to reduced morbidity and mortality., Competing Interests: Bregt Van Nieuwenhuyse is an employee of Servier BeLux and Josse R. Thomas is an employee of PharmaCS. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

Background: Vagus Nerve Stimulation (VNS) has seizure-suppressing effects but the underlying mechanism is not fully understood. To further elucidate the mechanisms underlying VNS-induced seizure suppression at a neurophysiological level, the present study examined effects of VNS on hippocampal excitability using dentate gyrus evoked potentials (EPs) and hippocampal electroencephalography (EEG)., Methods: Male Sprague-Dawley rats were implanted with a VNS electrode around the left vagus nerve. A bipolar stimulation electrode was implanted in the left perforant path and a bipolar recording electrode was implanted in the left dentate gyrus for EEG and dentate field EP recording. Following recovery, VNS was applied in freely moving animals, using a duty cycle of 7 s on/18 s off, 30 Hz frequency, 250 µs pulse width, and an intensity of either 0 (SHAM), 25 µA or 1000 µA, while continuously monitoring EEG and dentate field EPs., Results: VNS at 1000 µA modulated dentate field EPs by decreasing the field excitatory post-synaptic potential (fEPSP) slope and increasing the latency and amplitude of the population spike. It additionally influenced hippocampal EEG by slowing theta rhythm from 7 Hz to 5 Hz and reducing theta peak and gamma band power. No effects were observed in the SHAM or 25 µA VNS conditions., Conclusion: VNS modulated hippocampal excitability of freely moving rats in a complex way. It decreased synaptic efficacy, reflected by decreased fEPSP slope and EEG power, but it simultaneously facilitated dentate granule cell discharge indicating depolarization of dentate granule cells., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose: The effects of deep brain stimulation (DBS) have been studied primarily by cellular studies, which lack the ability to elucidate DBS-related responses on a whole-brain scale. 2-Deoxy-2-[(18)F]fluoro-D-glucose positron emission tomography ([(18)F]FDG-PET) reflects changes in neural activity throughout the entire brain volume. The aim of this study was to investigate the whole-brain effect of DBS on the glucose utilization in healthy rats., Procedures: Seven rats were implanted with a DBS electrode in the right hippocampus and injected with [(18)F]FDG to measure the glucose metabolism during DBS., Results: Analysis reveals significant DBS-induced decreases in the glucose metabolism in the bilateral hippocampus and other limbic structures., Conclusions: This study demonstrates that DBS exhibits not only a local effect around the electrode tip but also in other limbic regions. [(18)F]FDG-PET studies have the potential to provide better insight into the mechanism of action of DBS by simultaneously observing activity at multiple sites in the brain.

Purpose: Hippocampal deep brain stimulation (DBS) is an experimental therapy for patients with pharmacoresistant temporal lobe epilepsy (TLE). Despite the successful clinical application of DBS, the optimal stimulation parameters are undetermined. We evaluate the efficacy of a new form of DBS, using continuous stimuli with Poisson distributed intervals (Poisson distributed stimulation, PDS) in the kainate (KA) rat model, a validated model for human TLE., Methods: Status epilepticus was elicited by injection of KA (i.p.). After development of spontaneous seizures, rats were implanted with hippocampal DBS- and depth electroencephalography (EEG) electrodes. After baseline EEG monitoring, one group of rats (n = 13) was treated with PDS and a second (n = 11) received regular high frequency stimulation (HFS) at 130 Hz. Stimulation intensity was 100 μA below the threshold for induction of epileptiform EEG activity., Results: Stimulation intensity was significantly lower for PDS (156 ± 20 μA) than HFS (207 ± 23 μA; p < 0.02). Seven (54%) of 13 rats treated with PDS and 5 (45%) of 11 rats treated with HFS experienced a significant reduction in seizure frequency. In PDS-improved rats, seizure frequency was reduced to 33% (p < 0.01) of baseline value and in HFS-improved rats to 50% (p < 0.01). After termination of PDS, seizure rate returned to baseline value., Discussion: Continuous hippocampal PDS significantly reduces the number of spontaneous seizures. Compared to regular HFS, there is a slightly larger number of improved rats and a larger efficacy at a considerably lower stimulus intensity. The first two observations leave room for optimization, whereas a lower intensity is beneficial for battery life., (Wiley Periodicals, Inc. © 2010 International League Against Epilepsy.)

Deep brain stimulation (DBS) is a promising experimental approach to treat various neurological disorders. However, the optimal stimulation paradigm and the precise mechanism of action of DBS are unknown. Neuro-imaging by means of Single Photon Emission Computed Tomography (SPECT) is a non-invasive manner of evaluating regional cerebral blood flow (rCBF) changes, which are assumed to reflect changes in neural activity. In this study, rCBF changes induced by hippocampal DBS are evaluated by subtraction analysis of stimulation on/off using small animal microSPECT of the rat brain. Rats (n=13) were implanted with a multi-contact DBS electrode in the right hippocampus and injected with 10 mCi of HMPAO-Tc99(m) during application of various hippocampal DBS paradigms and amplitudes and during sham stimulation. Subtraction analysis revealed that hippocampal DBS caused a significant decrease in relative rCBF, both in the ipsi- (the side of the implanted electrode) and contralateral hippocampus. Hypoperfusion spread contralaterally with increasing stimulation amplitude. A clear distinction in spatial extent and intensity of hypoperfusion was observed between stimulation paradigms: bipolar Poisson Distributed Stimulation induced significant hypoperfusion ipsi- and contralaterally (p<0.01), while during other stimulation paradigms, rCBF-changes were less prominent. In conclusion, small animal microSPECT allows us to draw conclusions on the location, spatial extent and intensity of the hypoperfusion observed in the ipsi- and contralateral hippocampus, induced by hippocampal DBS. Our study demonstrates an innovative approach to visualize the effects of DBS and can be a useful tool in evaluating the effect of various stimulation paradigms and target areas for DBS., (Copyright 2010 Elsevier Inc. All rights reserved.)