COVID-19 Outcomes in Lung Transplant Recipients Following Pre-Exposure Prophylaxis With Tixagevimab-Cilgavimab During the Omicron BA.5 Surge: A Single Center Analysis.

Lung transplant (LTx) recipients are at high risk for COVID-19 related morbidity and mortality. Data regarding pre-exposure prophylaxis (PrEP) with tixagevimab-cilgavimab in this population are scarce. We therefore evaluated COVID-19 breakthrough infections and COVID-19 related complications after PrEP in a retrospective single-center study, including 264 LTx recipients who received PrEP between June 2022 and December 2022, when Omicron BA.5 was the dominant circulating SARS-CoV-2 variant. PrEP was indicated for fully vaccinated patients with poor seroconversion (anti-S <260 BAU/mL). COVID-19 breakthrough infection after PrEP occurred in 11.0% within the first 3 months, increasing to 17.4% within 6 months. Hospitalization rate rose from 27.6% to 52.9% (p = 0.046), while ICU admissions and COVID-19 mortality remained low, respectively occurring in 6.5% and 4.3% of patients with breakthrough infection within 6 months. COVID-19 breakthrough infection and associated hospitalization remained an important problem during the Omicron BA.5 surge in fully vaccinated LTx recipients with deficient seroconversion, despite PrEP with tixagevimab-cilgavimab. However, ICU admissions and COVID-19 mortality were low. Waning of neutralizing effects of PrEP and changing circulating SARS-CoV-2 variants may explain increases in COVID-19 infections and hospitalizations over time after PrEP, highlighting the need for novel, long-term effective PrEP strategies in these high-risk patients.

Should treatment decisions in septic arthritis of the native hip joint be based on the route of infection?

Background: Surgical management of septic arthritis (SA) of the hip aims at treating the infection by either preserving, resecting or replacing the joint. In some cases, joint preservation should be attempted, whereas other cases would benefit from immediate joint resection or replacement. Prognostic factors have been proposed to guide decision-making. We hypothesized that most of these factors can be simplified to three subgroups based on the route of infection: contiguous spreading, direct inoculation or hematogenous seeding. Methods: A total of 41 patients have been treated surgically for SA of the native hip at our tertiary hospital during the last 16 years. Medical records were studied, and various patient and disease characteristics were collated. Results: Significant differences between (1) level of fitness, (2) condition of the hip joint, (3) micro-organisms and (4) chance of femoral head preservation were found for patients with SA of the native hip resulting from the three aforementioned subgroups. Femoral head resection was necessary at one point in 85 % of patients. Patients with hematogenous infections of undamaged hips had a reasonable chance (53 %) of avoiding joint resection or replacement. Hip arthroplasty was performed on 46.3 % of patients, with an infection rate of 10.5 %. Conclusion: Patients with SA of the native hip resulting from contiguous spreading, hematogenous seeding or direct inoculation differ significantly and should be considered distinct clinical entities. Route of infection is directly related to the chance of femoral head preservation and should, therefore, guide decision-making. Only patients with hematogenous infection to a previously healthy hip had the possibility of femoral head preservation.

FLUIDOT: A Modular Microfluidic Platform for Single-Cell Study and Retrieval, with Applications in Drug Tolerance Screening and Antibody Mining.

Advancements in lab-on-a-chip technologies have revolutionized the single-cell analysis field. However, an accessible platform for in-depth screening and specific retrieval of single cells, which moreover enables studying diverse cell types and performing various downstream analyses, is still lacking. As a solution, FLUIDOT is introduced, a versatile microfluidic platform incorporating customizable microwells, optical tweezers and an interchangeable cell-retrieval system. Thanks to its smart microfluidic design, FLUIDOT is straightforward to fabricate and operate, rendering the technology widely accessible. The performance of FLUIDOT is validated and its versatility is subsequently demonstrated in two applications. First, drug tolerance in yeast cells is studied, resulting in the discovery of two treatment-tolerant populations. Second, B cells from convalescent COVID-19 patients are screened, leading to the discovery of highly affine, in vitro neutralizing monoclonal antibodies against SARS-CoV-2. Owing to its performance, flexibility, and accessibility, it is foreseen that FLUIDOT will enable phenotypic and genotypic analysis of diverse cell samples and thus elucidate unexplored biological questions.

The 20-valent pneumococcal conjugate vaccine (PCV20): expected added value.

OBJECTIVES: Currently existing pneumococcal vaccines have contributed to a major reduction in pneumococcal disease. However, there remains an unmet need for vaccine coverage of serotypes not included in PCV13 to further reduce the burden of disease. The objective of this review is to assess the potential impact of implementation of the investigational 20-valent pneumococcal conjugate vaccine (PCV20) in the childhood and adult immunization programme in Belgium and Europe. METHODS: A literature search was conducted to identify publications and surveillance reports concerning the effectiveness and safety of pneumococcal vaccines, epidemiological data on pneumococcal disease or serotype distribution dynamics after introduction of systematic vaccination. RESULTS: Serotypes included in PCV20 currently account for the majority of pneumococcal disease in Belgium and Europe. In Belgium, PCV20-serotypes accounted for 71.4% of invasive pneumococcal disease (IPD) cases across all age groups in 2019, of which 39.2% were caused by PCV20-non-PCV13-serotypes. In Europe, these seven serotypes accounted for 37,6% of IPD cases in 2018.  PCV20 has proven to be well tolerated in vaccine-naïve adults and elicits a substantial immune response against all serotypes included. CONCLUSION: Due to serotype replacement following the introduction of PCV7 and PCV13, a considerable proportion of pneumococcal disease is currently caused by PCV20-serotypes. PCV20 has the potential of preventing more pneumococcal disease in children and the adult population at risk than the existing conjugate vaccines. The available evidence on safety and immunogenicity of PCV20 is promising, but further research is needed to provide data about vaccine effectiveness, immune response duration and replacement phenomenon after introduction of PCV20.

Anatomical barriers against SARS-CoV-2 neuroinvasion at vulnerable interfaces visualized in deceased COVID-19 patients.

Can SARS-CoV-2 hitchhike on the olfactory projection and take a direct and short route from the nose into the brain? We reasoned that the neurotropic or neuroinvasive capacity of the virus, if it exists, should be most easily detectable in individuals who died in an acute phase of the infection. Here, we applied a postmortem bedside surgical procedure for the rapid procurement of tissue, blood, and cerebrospinal fluid samples from deceased COVID-19 patients infected with the Delta, Omicron BA.1, or Omicron BA.2 variants. Confocal imaging of sections stained with fluorescence RNAscope and immunohistochemistry afforded the light-microscopic visualization of extracellular SARS-CoV-2 virions in tissues. We failed to find evidence for viral invasion of the parenchyma of the olfactory bulb and the frontal lobe of the brain. Instead, we identified anatomical barriers at vulnerable interfaces, exemplified by perineurial olfactory nerve fibroblasts enwrapping olfactory axon fascicles in the lamina propria of the olfactory mucosa.

Molecular detection of SARS-COV-2 in exhaled breath at the point-of-need.

The SARS-CoV-2 pandemic has highlighted the need for improved technologies to help control the spread of contagious pathogens. While rapid point-of-need testing plays a key role in strategies to rapidly identify and isolate infectious patients, current test approaches have significant shortcomings related to assay limitations and sample type. Direct quantification of viral shedding in exhaled particles may offer a better rapid testing approach, since SARS-CoV-2 is believed to spread mainly by aerosols. It assesses contagiousness directly, the sample is easy and comfortable to obtain, sampling can be standardized, and the limited sample volume lends itself to a fast and sensitive analysis. In view of these benefits, we developed and tested an approach where exhaled particles are efficiently sampled using inertial impaction in a micromachined silicon chip, followed by an RT-qPCR molecular assay to detect SARS-CoV-2 shedding. Our portable, silicon impactor allowed for the efficient capture (>85%) of respiratory particles down to 300 nm without the need for additional equipment. We demonstrate using both conventional off-chip and in-situ PCR directly on the silicon chip that sampling subjects' breath in less than a minute yields sufficient viral RNA to detect infections as early as standard sampling methods. A longitudinal study revealed clear differences in the temporal dynamics of viral load for nasopharyngeal swab, saliva, breath, and antigen tests. Overall, after an infection, the breath-based test remains positive during the first week but is the first to consistently report a negative result, putatively signalling the end of contagiousness and further emphasizing the potential of this tool to help manage the spread of airborne respiratory infections.

Non-specific symptoms and post-treatment Lyme disease syndrome in patients with Lyme borreliosis: a prospective cohort study in Belgium (2016-2020).

BACKGROUND: Patients with Lyme borreliosis (LB) may report persisting non-specific symptoms such as fatigue, widespread musculoskeletal pain or cognitive difficulties. When present for more than 6 months and causing a reduction in daily activities, this is often referred to as post-treatment Lyme disease syndrome (PTLDS). This study aimed to compare the occurrence of symptoms between LB patients and controls, to estimate the proportion of LB patients developing PTLDS and to identify risk factors. METHODS: A prospective cohort study was set up including three subpopulations: patients with an erythema migrans (EM) (i) or disseminated/late LB (ii) and a non-LB control group (iii). At 6- and 12-months follow-up, the occurrence of several symptoms, including six symptoms used to define PTLDS, i.e. muscle pain, joint pain, fatigue, memory problems, difficulties concentrating and problems finding words, and impact on daily activities, was compared between LB patients and controls. Finally, the proportion of LB patients developing PTLDS as defined by the Infectious Disease Society of America was estimated, including a time frame for symptoms to be present. RESULTS: Although the risk of presenting PTLDS-related symptoms was significantly higher in EM patients (n = 120) compared to controls (n = 128) at 6 months follow-up, the risk of presenting at least one of these symptoms combined with impact on daily activities was not significantly higher in EM patients, at either 6- or 12-months follow-up. A significant association was found between disseminated/late LB (n = 15) and the occurrence of any PTLDS-symptom with an impact on daily activities at both time points. The proportion of patients with PTLDS was estimated at 5.9% (95% CI 2.7-12.9) in EM patients and 20.9% (95% CI 6.8-64.4) in patients with disseminated/late LB (RR = 3.53, 95% CI 0.98-12.68, p = 0.053). No significant risk factors were identified, which may be explained by small sample sizes. CONCLUSIONS: In our study, PTLDS was present in both LB cohorts, yet with a higher percentage in disseminated/late LB patients. Additional research is needed into risk factors for and causes of this syndrome. In addition, development and validation of standardized methods to assess the PTLDS case definition, easily applicable in practice, is of great importance.

A Novel Homozygous Stop Mutation in IL23R Causes Mendelian Susceptibility to Mycobacterial Disease.

PURPOSE: Mendelian susceptibility to mycobacterial disease (MSMD) is caused by inborn errors of IFN-γ immunity. The most frequent genetic defects are found in IL12 or a subunit of its receptor. IL23R deficiency in MSMD has only been reported once, in two pediatric patients from the same kindred with isolated disseminated Bacille Calmette-Guérin disease. We evaluated the impact of a homozygous stop mutation in IL23R (R381X), identified by whole exome sequencing, in an adult patient with disseminated non-tuberculous mycobacterial disease. METHODS: We performed functional validation of the R381X mutation by evaluating IL23R expression and IL-23 signaling (STAT3 phosphorylation, IFN-γ production) in primary cells (PBMCs, EBV-B cells) and cell lines (HeLa) with or without back-complementation of wild-type IL23R. RESULTS: We report on a 48-year-old male with disseminated non-tuberculous mycobacterial disease. We identified and characterized a homozygous loss-of-function stop mutation underlying IL23R deficiency, resulting in near absent expression of membrane bound IL23R. IL23R deficiency was characterized by impaired IL-23-mediated IFN-γ secretion in CD4+, CD8+ T, and mucosal-associated invariant T (MAIT) cells, and low frequencies of circulating Th17 (CD3+CD45RA-CCR4+CXCR3-RORγT+), Th1* (CD45RA-CCR4-CXCR3+RORγT+), and MAIT (CD3+CD8+Vα7.2+CD161+) cells. Although the patient did not have a history of recurrent fungal infections, impaired Th17 differentiation and blunted IL-23-mediated IL-17 secretion in PBMCs were observed. CONCLUSION: We demonstrate that impaired IL-23 immunity caused by a homozygous R381X mutation in IL23R underlies MSMD, corroborating earlier findings with a homozygous p.C115Y IL23R mutation. Our report further supports a model of redundant contribution of IL-23- to IL-17-mediated anti-fungal immunity.1.

Potent neutralizing anti-SARS-CoV-2 human antibodies cure infection with SARS-CoV-2 variants in hamster model.

Treatment with neutralizing monoclonal antibodies (mAbs) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) contributes to COVID-19 management. Unfortunately, SARS-CoV-2 variants escape several of these recently approved mAbs, highlighting the need for additional discovery and development. In a convalescent patient with COVID-19, we identified six mAbs, classified in four epitope groups, that potently neutralized SARS-CoV-2 D614G, beta, gamma, and delta infection in vitro, with three mAbs neutralizing omicron as well. In hamsters, mAbs 3E6 and 3B8 potently cured infection with SARS-CoV-2 Wuhan, beta, and delta when administered post-viral infection at 5 mg/kg. Even at 0.2 mg/kg, 3B8 still reduced viral titers. Intramuscular delivery of DNA-encoded 3B8 resulted in in vivo mAb production of median serum levels up to 90 µg/mL, and protected hamsters against delta infection. Overall, our data mark 3B8 as a promising candidate against COVID-19, and highlight advances in both the identification and gene-based delivery of potent human mAbs.

Clinical Efficacy and Safety of Vancomycin Continuous Infusion in Patients Treated at Home in an Outpatient Parenteral Antimicrobial Therapy Program.

Vancomycin is commonly used in outpatient parenteral antimicrobial therapy (OPAT) of Gram-positive infections. Therapeutic drug monitoring and adverse event monitoring pose a challenge. Outcome data of vancomycin in OPAT (vOPAT) are limited. The study aim was to report the safety and efficacy of a structured vOPAT program implemented in the University Hospitals Leuven. The program provides continuous elastomeric infusion of vancomycin at home with biweekly follow-up at the outpatient clinic. Demographics, clinical, biochemical and treatment parameters, target attainment parameters and clinical outcomes were recorded. An e-survey was conducted to assess patient satisfaction. Thirty-five vOPAT episodes in 32 patients were included. During 206 follow-up consultations, 203 plasma concentration measurements were registered with a median vancomycin plasma concentration of 22.5 mg/L (range 6.6-32.0). The majority of concentrations (68.5%) were within the therapeutic range (20.0-25.0 mg/L). Adverse event rates, including drug- (5.7%) and catheter-related (5.7%) events, were low. For 32 vOPAT episodes, a clinical cure rate of 100% was observed. All patients who completed the e-survey were satisfied with their vOPAT course. These findings show that a structured vOPAT program with rigorous follow-up provides safe and effective ambulatory treatment of patients with vancomycin in continuous infusion.

Thromboprophylaxis in COVID-19: Weight and severity adjusted intensified dosing.

Background: Venous thromboembolism (VTE) frequently occurs in hospitalized patients with coronavirus disease 2019 (COVID-19). The optimal dose of anticoagulation for thromboprophylaxis in COVID-19 is unknown. Aims: To report VTE incidence and bleeding before and after implementing a hospital-wide intensified thromboprophylactic protocol in patients with COVID-19. Methods: On March 31, 2020, we implemented an intensified thromboprophylactic protocol consisting of 50 IU anti-Xa low molecular weight heparin (LMWH)/kg once daily at the ward, twice daily at the intensive care unit (ICU). We included all patients hospitalized in a tertiary care hospital with symptomatic COVID-19 between March 7 and July 1, 2020. The primary outcome was the incidence of symptomatic or subclinical VTE and major bleeding during admission. Routine ultrasound screening for VTE was performed whenever logistically possible. Results: We included 412 patients, of which 116 were admitted to the ICU. Of 219 patients with standard a prophylactic dose of LMWH, 16 (7.3%) had VTE, 10 of which were symptomatic (4.6%). Of 193 patients with intensified thromboprophylaxis, there were no symptomatic VTE cases, three incidental deep venous thrombosis cases (1.6%), and one incidental pulmonary embolism (0.5%). The major bleeding rate was 1.2% in patients with intensified thromboprophylaxis and 7.7% when therapeutic anticoagulation was needed. Conclusion: In hospitalized patients with COVID-19, there were no additional symptomatic VTEs and a reduction in incidental deep vein thrombosis after implementing systematic thromboprophylaxis with weight-adjusted prophylactic (ward) to intermediate (ICU), but not therapeutic dosed anticoagulation. This intensified thromboprophylaxis was associated with a lower risk of major bleeding compared with therapeutic dosed anticoagulation.

Safety and efficacy of phage therapy in difficult-to-treat infections: a systematic review.

According to the latest reports from WHO, the incidence of antibiotic-resistant bacterial infections is increasing worldwide, resulting in increased morbidity and mortality and a rising pressure on health-care systems. However, the development of new antibiotics is an expensive and time-consuming process, urging scientists to seek alternative antimicrobial strategies. Over the past few decades, the concept of therapeutic administration of bacteriophages (also known as phages) has gained popularity worldwide. Although conceptually promising, the widespread implementation of phage therapy in routine clinical practice is restricted by the scarcity of safety and efficacy data obtained according to the strict standards of the applicable clinical trial regulations. In this systematic review, we list clinical data published between Jan 1, 2000 and Aug 14, 2021 on the safety and efficacy of phage therapy for difficult-to-treat bacterial infections, and provide an overview of trials and case studies on the use of phage therapy in several medical disciplines.

Overall performance of a drug-drug interaction clinical decision support system: quantitative evaluation and end-user survey.

BACKGROUND: Clinical decision support systems are implemented in many hospitals to prevent medication errors and associated harm. They are however associated with a high burden of false positive alerts and alert fatigue. The aim of this study was to evaluate a drug-drug interaction (DDI) clinical decision support system in terms of its performance, uptake and user satisfaction and to identify barriers and opportunities for improvement. METHODS: A quantitative evaluation and end-user survey were performed in a large teaching hospital. First, very severe DDI alerts generated between 2019 and 2021 were evaluated retrospectively. Data collection comprised alert burden, override rates, the number of alert overrides reviewed by pharmacists and the resulting pharmacist recommendations as well as their acceptance rate. Second, an e-survey was carried out among prescribers to assess satisfaction, usefulness and relevance of DDI alerts as well as reasons for overriding. RESULTS: A total of 38,409 very severe DDI alerts were generated, of which 88.2% were overridden by the prescriber. In 3.2% of reviewed overrides, a recommendation by the pharmacist was provided, of which 79.2% was accepted. False positive alerts were caused by a too broad screening interval and lack of incorporation of patient-specific characteristics, such as QTc values. Co-prescribing of a non-vitamin K oral anticoagulant and a low molecular weight heparin accounted for 49.8% of alerts, of which 92.2% were overridden. In 88 (1.1%) of these overridden alerts, concurrent therapy was still present. Despite the high override rate, the e-survey revealed that the DDI clinical decision support system was found useful by prescribers. CONCLUSIONS: Identified barriers were the lack of DDI-specific screening intervals and inclusion of patient-specific characteristics, both leading to a high number of false positive alerts and risk for alert fatigue. Despite these barriers, the added value of the DDI clinical decision support system was recognized by prescribers. Hence, integration of DDI-specific screening intervals and patient-specific characteristics is warranted to improve the performance of the DDI software.

A public health value-based healthcare paradigm for HIV.

BACKGROUND: HIV patients face considerable acute and chronic healthcare needs and battling the HIV epidemic remains of the utmost importance. By focusing on health outcomes in relation to the cost of care, value-based healthcare (VBHC) proposes a strategy to optimize quality of care and cost-efficiency. Its implementation may provide an answer to the increasing pressure to optimize spending in healthcare while improving patient outcomes. This paper describes a pragmatic value-based healthcare framework for HIV care. METHODS: A value-based HIV healthcare framework was developed during a series of roundtable discussions bringing together 16 clinical stakeholder representatives from the Belgian HIV reference centers and 2 VBHC specialists. Each round of discussions was focused on a central question translating a concept or idea to the next level of practical implementation: 1) how can VBHC principles be translated into value-based HIV care drivers; 2) how can these value-based HIV care divers be translated into value-based care objectives and activities; and 3) how can value-based HIV care objectives and activities be translated into value-based care indicators. Value drivers were linked to concrete objectives and activities using a logical framework approach. Finally, specific, measurable, and acceptable structure, process and outcomes indicators were defined to complement the framework. RESULTS: Our framework identifies 4 core value areas where HIV care would benefit most from improvements: Prevention, improvement of the cascade of care, providing patient-centered HIV care and sustaining a state-of-the-art HIV disease management context. These 4 core value areas were translated into 12 actionable core value objectives. For each objective, example activities were proposed. Indicators are suggested for each level of the framework (outcome indicators for value areas and objectives, process indicators for suggested activities). CONCLUSIONS: This framework approach outlines how to define a patient- and public health centered value-based HIV care paradigm. It proposes how to translate core value drivers to practical objectives and activities and suggests defining indicators that can be used to track and improve the framework's implementation in practice.

Repolarization abnormalities on admission predict 1-year outcome in COVID-19 patients.

BACKGROUND: ECG abnormalities in COVID-19 have been widely reported, however data after discharge is limited. The aim was to describe ECG abnormalities on admission and following recovery of COVID-19, and their associated mortality. METHODS: All patients hospitalized in a tertiary care hospital between March 7th and July 1st 2020 with COVID-19 were included in a retrospective registry. The first ECG on admission was collected, together with an ECG after hospital discharge in the absence of acute pathology. Automated measures and clinical ECG interpretations were collected. Multivariate Cox regression analysis was performed to predict 1-year all-cause mortality. RESULTS: In total 420 patients were included, of which 83 patients (19.8%) died during the 1-year follow-up period. Repolarization abnormalities were present in 189 patients (45.0%). The extent of repolarization abnormalities was an independent predictor of 1-year all-cause mortality (HR per region 1.30, 95%CI 1.04-1.64) together with age (/year HR 1.06, 95%CI 1.04-1.08), heart rate (/bpm HR 1.02, 95%CI 1.01-1.03), neurological disorders (HR 2.41, 95%CI 1.47-3.93), active cancer (HR 2.75, 95%CI 1.57-4.82), CRP (per 10 mg/L HR 1.05, 95%CI 1.02-1.08) and eGFR (per 10 mg/L HR 0.90, 95%CI 0.83-0.98).In 245 patients (68.1%) an ECG post discharge was available. New repolarization abnormalities were more frequent in patients who died after discharge (4.7% versus 41.7%, p < 0.001) and 8 (3.3%) had new ventricular conduction defects, none of whom died during follow-up. CONCLUSIONS: The presence and extent of repolarization abnormalities predicted outcome in patients with COVID-19. New repolarization abnormalities after discharge were associated with post-discharge mortality.

Visualizing in deceased COVID-19 patients how SARS-CoV-2 attacks the respiratory and olfactory mucosae but spares the olfactory bulb.

Anosmia, the loss of smell, is a common and often the sole symptom of COVID-19. The onset of the sequence of pathobiological events leading to olfactory dysfunction remains obscure. Here, we have developed a postmortem bedside surgical procedure to harvest endoscopically samples of respiratory and olfactory mucosae and whole olfactory bulbs. Our cohort of 85 cases included COVID-19 patients who died a few days after infection with SARS-CoV-2, enabling us to catch the virus while it was still replicating. We found that sustentacular cells are the major target cell type in the olfactory mucosa. We failed to find evidence for infection of olfactory sensory neurons, and the parenchyma of the olfactory bulb is spared as well. Thus, SARS-CoV-2 does not appear to be a neurotropic virus. We postulate that transient insufficient support from sustentacular cells triggers transient olfactory dysfunction in COVID-19. Olfactory sensory neurons would become affected without getting infected.

Bacteriophage Therapy for Difficult-to-Treat Infections: The Implementation of a Multidisciplinary Phage Task Force (The PHAGEFORCE Study Protocol).

In times where only a few novel antibiotics are to be expected, antimicrobial resistance remains an expanding global health threat. In case of chronic infections caused by therapy-resistant pathogens, physicians have limited therapeutic options, which are often associated with detrimental consequences for the patient. This has resulted in a renewed interest in alternative strategies, such as bacteriophage (phage) therapy. However, there are still important hurdles that currently impede the more widespread implementation of phage therapy in clinical practice. First, the limited number of good-quality case series and clinical trials have failed to show the optimal application protocol in terms of route of administration, frequency of administration, treatment duration and phage titer. Second, there is limited information on the systemic effects of phage therapy. Finally, in the past, phage therapy has been applied intuitively in terms of the selection of phages and their combination as parts of phage cocktails. This has led to an enormous heterogeneity in previously published studies, resulting in a lack of reliable safety and efficacy data for phage therapy. We hereby present a study protocol that addresses these scientific hurdles using a multidisciplinary approach, bringing together the experience of clinical, pharmaceutical and molecular microbiology experts.