Personalized bacteriophage therapy outcomes for 100 consecutive cases:a multicentre, multinational, retrospective observational study

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.</p

Antihypertensive treatment in a general uncontrolled hypertensive population in Belgium and Luxembourg in primary care : therapeutic inertia and treatment simplification : the SIMPLIFY study

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

Suppression of hippocampal epileptic seizures in the kainate rat by Poisson distributed stimulation

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 mu A below the threshold for induction of epileptiform EEG activity. Results: Stimulation intensity was significantly lower for PDS (156 +/- 20 mu A) than HFS (207 +/- 23 mu A; 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

High resolution mu SPECT for brain activation analysis in small animals

A stimulus on/off imaging study is often used to evaluate the brain's response to a presented visual, electrical or chemical trigger. Clinical software and human templates already exist but given the recent advent of ultrahigh resolution μ SPECT and μ PET, a larger need rises for a post processing platform to perform these subtraction molecular imaging studies also in small animals. We have designed such a multimodal framework to perform μ SPECT activation studies in rats thereby making use of μ CT and MRI for anatomical land marking. Our software solution is a combination of Amide, MRIcroN and a custom made Matlab implementation. We have studied the performance of different deep brain stimulations for which 6 rats were implanted with a multi-polar stimulation electrode in the right hippocampus. Each animal underwent a 99mTc-HMPAO μ SPECT with the Milabs U-SPECT-II and a μ CT scan with the GMI X-O CT before and after stimulation. Two line markers in oblique positions filled with low activity of 125I are used to register the μ SPECT and μ CT images. Afterwards the animals were sacrificed, their electrode was removed and a MRI scan was performed using the wrist coil of a Siemens Trio 3T. A semi-automated five step procedure delivers the activation map: (i) first the stimulus-on μ CT and the MRI are registered to the stimulus-off μ CT followed by (ii) the fusion of the off/on μ SPECT scans with their off/on μ CT counterparts. From the MRI, (iii) the rat brain is extracted, which is used as a mask for the calculation. Afterwards, (iv) both off/on μ SPECT scans are normalized and subtracted within this MRI brain mask. Finally, (v) the Z-score, representing the activation map, is achieved by dividing the result with the standard deviation of the masked stimulus-off μ SPECT. This semi-automated approach allows the experimental neu-roscientist to draw conclusions on the location, spatial extent and intensity of the small animal brains response to the stimulus