Phenotypes in Pulmonary Hypertension.

The clinical classification of pulmonary hypertension (PH) has guided diagnosis and treatment of patients with PH for several decades. Discoveries relating to underlying mechanisms, pathobiology, and responses to treatments for PH have informed the evolution in this clinical classification to describe the heterogeneity in PH phenotypes. In more recent years, advances in imaging, computational science, and multi-omic approaches have yielded new insights into potential phenotypes and sub-phenotypes within the existing clinical classification. Identification of novel phenotypes in pulmonary arterial hypertension (PAH) with unique molecular profiles, for example, could lead to new precision therapies. Recent phenotyping studies have also identified groups of patients with PAH that more closely resemble patients with left heart disease (group 2 PH) and lung disease (group 3 PH), which has important prognostic and therapeutic implications. Within group 2 and group 3 PH, novel phenotypes have emerged that reflect a persistent and severe pulmonary vasculopathy that is associated with worse prognosis but still distinct from PAH. In group 4 PH (chronic thromboembolic pulmonary disease) and sarcoidosis (group 5 PH) the current approach to patient phenotyping integrates clinical, hemodynamic and imaging characteristics to guide treatment but applications of multi-omic approaches to sub-phenotyping in these areas are sparse. The next iteration of the PH clinical classification is likely to reflect several emerging PH phenotypes and improve the next generation of prognostication tools, clinical trial design, and improve treatment selection in clinical practice.

Cost-Effectiveness of Plasma Microbial Cell-Free DNA Sequencing When Added to Usual Care Diagnostic Testing for Immunocompromised Host Pneumonia.

INTRODUCTION: Immunocompromised host pneumonia (ICHP) is an important cause of morbidity and mortality, yet usual care (UC) diagnostic tests often fail to identify an infectious etiology. A US-based, multicenter study (PICKUP) among ICHP patients with hematological malignancies, including hematological cell transplant recipients, showed that plasma microbial cell-free DNA (mcfDNA) sequencing provided significant additive diagnostic value. AIM: The objective of this study was to perform a cost-effectiveness analysis (CEA) of adding mcfDNA sequencing to UC diagnostic testing for hospitalized ICHP patients. METHODS: A semi-Markov model was utilized from the US third-party payer's perspective such that only direct costs were included, using a lifetime time horizon with discount rates of 3% for costs and benefits. Three comparators were considered: (1) All UC, which included non-invasive (NI) and invasive testing and early bronchoscopy; (2) All UC & mcfDNA; and (3) NI UC & mcfDNA & conditional UC Bronch (later bronchoscopy if the initial tests are negative). The model considered whether a probable causative infectious etiology was identified and if the patient received appropriate antimicrobial treatment through expert adjudication, and if the patient died in-hospital. The primary endpoints were total costs, life-years (LYs), equal value life-years (evLYs), quality-adjusted life-years (QALYs), and the incremental cost-effectiveness ratio per QALY. Extensive scenario and probabilistic sensitivity analyses (PSA) were conducted. RESULTS: At a price of $2000 (2023 USD) for the plasma mcfDNA, All UC & mcfDNA was more costly ($165,247 vs $153,642) but more effective (13.39 vs 12.47 LYs gained; 10.20 vs 9.42 evLYs gained; 10.11 vs 9.42 QALYs gained) compared to All UC alone, giving a cost/QALY of $16,761. NI UC & mcfDNA & conditional UC Bronch was also more costly ($162,655 vs $153,642) and more effective (13.19 vs 12.47 LYs gained; 9.96 vs 9.42 evLYs gained; 9.96 vs 9.42 QALYs gained) compared to All UC alone, with a cost/QALY of $16,729. The PSA showed that above a willingness-to-pay threshold of $50,000/QALY, All UC & mcfDNA was the preferred scenario on cost-effectiveness grounds (as it provides the most QALYs gained). Further scenario analyses found that All UC & mcfDNA always improved patient outcomes but was not cost saving, even when the price of mcfDNA was set to $0. CONCLUSIONS: Based on the evidence available at the time of this analysis, this CEA suggests that mcfDNA may be cost-effective when added to All UC, as well as in a scenario using conditional bronchoscopy when NI testing fails to identify a probable infectious etiology for ICHP. Adding mcfDNA testing to UC diagnostic testing should allow more patients to receive appropriate therapy earlier and improve patient outcomes.

Tenecteplase versus alteplase before stroke thrombectomy: outcomes after system-wide transitions in Pennsylvania.

INTRODUCTION: United States stroke systems are increasingly transitioning from alteplase (TPA) to tenecteplase (TNK). Real-world data on the safety and effectiveness of replacing TPA with TNK before large vessel occlusion (LVO) stroke endovascular treatment (EVT) are lacking. METHODS: Four Pennsylvania stroke systems transitioned from TPA to TNK during the study period 01/2020-06/2023. LVO stroke patients who received intravenous thrombolysis with TPA or TNK before EVT were reviewed. Multivariate logistic analysis was conducted adjusting for age, sex, National Institute of Health Stroke Scale (NIHSS), occlusion site, last-known-well-to-intravenous thrombolysis time, interhospital-transfer and stroke system. RESULTS: Of 635 patients, 309 (48.7%) received TNK and 326 (51.3%) TPA prior to EVT. The site of occlusion was the M1 middle cerebral artery (MCA) (47.7%), M2 MCA (25.4%), internal carotid artery (14.0%), tandem carotid with M1 or M2 MCA (9.8%) and basilar artery (3.1%). A favorable functional outcome (90-day mRS ≤ 2) was observed in 47.6% of TNK and 49.7% of TPA patients (p = 0.132). TNK versus TPA groups had similar rates of early recanalization (11.9% vs. 8.4%, p = 0.259), successful endovascular reperfusion (93.5% vs. 89.3%, p = 0.627), symptomatic intracranial hemorrhage (3.2% vs. 3.4%, p = 0.218) and 90-day all-cause mortality (23.1% vs. 21.5%, p = 0.491). CONCLUSIONS: This U.S. multicenter real-world clinical experience demonstrated that switching from TPA to TNK before EVT for LVO stroke resulted in similar endovascular reperfusion, safety, and functional outcomes.

Femoral versus radial access for middle meningeal artery embolization for chronic subdural hematomas: multicenter propensity score matched study.

BACKGROUND: With transradial access (TRA) being more progressively used in neuroendovascular procedures, we compared TRA with transfemoral access (TFA) in middle meningeal artery embolization (MMAE) for chronic subdural hematoma (cSDH). METHODS: Consecutive patients undergoing MMAE for cSDH at 14 North American centers (2018-23) were included. TRA and TFA groups were compared using propensity score matching (PSM) controlling for: age, sex, concurrent surgery, previous surgery, hematoma thickness and side, midline shift, and pretreatment antithrombotics. The primary outcome was access site and overall complications, and procedure duration; secondary endpoints were surgical rescue, radiographic improvement, and technical success and length of stay. RESULTS: 872 patients (median age 73 years, 72.9% men) underwent 1070 MMAE procedures (54% TFA vs 46% TRA). Access site hematoma occurred in three TFA cases (0.5%; none required operative intervention) versus 0% in TRA (P=0.23), and radial-to-femoral conversion occurred in 1% of TRA cases. TRA was more used in right sided cSDH (58.4% vs 44.8%; P<0.001). Particle embolics were significantly higher in TFA while Onyx was higher in TRA (P<0.001). Following PSM, 150 matched pairs were generated. Particles were more utilized in the TFA group (53% vs 29.7%) and Onyx was more utilized in the TRA group (56.1% vs 31.5%) (P=0.001). Procedural duration was longer in the TRA group (median 68.5 min (IQR 43.1-95) vs 59 (42-84); P=0.038), and radiographic success was higher in the TFA group (87.3% vs 77.4%; P=0.036). No differences were noted in surgical rescue (8.4% vs 10.1%, P=0.35) or technical failures (2.4% vs 2%; P=0.67) between TFA and TRA. Sensitivity analysis in the standalone MMAE retained all associations but differences in procedural duration. CONCLUSIONS: In this study, TRA offered comparable outcomes to TFA in MMAE for cSDH in terms of access related and overall complications, technical feasibility, and functional outcomes. Procedural duration was slightly longer in the TRA group, and radiographic success was higher in the TFA group, with no differences in surgical rescue rates.

Ventilator strategies in congenital diaphragmatic hernia.

This review focuses on contemporary mechanical ventilator practices used in the initial management of neonates born with congenital diaphragmatic hernia (CDH). Both conventional and non-conventional ventilation modes in CDH are reviewed. Special emphasis is placed on the rationale for gentle ventilation and the current evidence-based clinical practice guidelines that are recommended for supporting these fragile infants. The interplay between CDH lung hypoplasia and other key cardiopulmonary elements of the disease, namely a reduced pulmonary vascular bed, abnormal pulmonary vascular remodeling, and left ventricular hypoplasia, are discussed. Finally, we provide insights into future avenues for mechanical ventilator research in CDH.

Quantitative pupillometry as a biomarker for prediction of return to play in mild traumatic brain injury: a Military Traumatic Brain Injury Initiative study.

OBJECTIVE: This study aimed to determine the validity of quantitative pupillometry to predict the length of time for return to full activity/duty after a mild traumatic brain injury (mTBI) in a cohort of injured cadets at West Point. METHODS: Each subject received baseline (T0) quantitative pupillometry, in addition to evaluation with the Balance Error Scoring System (BESS), Standardized Assessment of Concussion (SAC), and Sport Concussion Assessment Tool 5th Edition Symptom Survey (SCAT5). Repeat assessments using the same parameters were conducted within 48 hours of injury (T1), at the beginning of progressive return to activity (T2), and at the completion of progressive return to activity protocols (T3). Pupillary metrics were compared on the basis of length of time to return to full play/duty and the clinical scores. RESULTS: The authors' statistical analyses found correlations between pupillometry measures at T1, including end-initial diameter and maximum constriction velocity, with larger change and faster constriction predicting earlier return to play. There was also an association with maximum constriction velocity at baseline (T0), predicting faster return to play. CONCLUSIONS: The authors conclude that that pupillometry may be a valuable tool for assessing time to return to duty from mTBI by providing a measure of baseline resiliency to mTBI and/or autonomic dysfunction in the acute phase after mTBI.

Epidemiology of Travel-Associated Dengue from 2007 to 2022: A GeoSentinel Analysis.

BACKGROUND: Dengue is a leading cause of febrile illness among international travellers. We aimed to describe the epidemiology and clinical characteristics of imported dengue in returning travellers evaluated at GeoSentinel sites from 2007-2022. METHODS: We retrieved GeoSentinel records of dengue among travellers residing in non-endemic countries. We considered dengue confirmed when diagnosed by a positive DENV-specific RT-PCR, positive NS-1 antigen, and/or anti-DENV IgG seroconversion, and probable when diagnosed by single anti-DENV IgM or high titre anti-DENV IgG detection. Severe dengue was defined as evidence of clinically significant plasma leakage or bleeding, organ failure, or shock, according to the 2009 WHO guidance. Complicated dengue was defined as either severe dengue or dengue with presence of any warning sign. Analyses were descriptive. RESULTS: This analysis included 5958 travellers with confirmed (n = 4859; 81.6%) or probable (n = 1099; 18.4%) dengue. The median age was 33 years (range: < 1-91); 3007 (50.5%) travellers were female. The median travel duration was 21 days (interquartile range [IQR]: 15-32). The median time between illness onset and GeoSentinel site visit was 7 days (IQR: 4-15). The most frequent reasons for travel were tourism (67.3%), visiting friends or relatives (12.2%), and business (11.0%). The most frequent regions of acquisition were Southeast Asia (50.4%), South-Central Asia (14.9%), the Caribbean (10.9%), and South America (9.2%). Ninety-five (1.6%) travellers had complicated dengue, of whom 27 (0.5%) had severe dengue, and one died. Of 2710 travellers with data available, 724 (26.7%) were hospitalized. The largest number of cases (n = 835) was reported in 2019. CONCLUSIONS: A broad range of international travellers should be aware of the risk of acquiring dengue and receive appropriate pretravel counselling regarding preventive measures. Prospective cohort studies are needed to further elucidate dengue risk by destination and over time, as well as severe outcomes and prolonged morbidity (long-dengue) due to travel-related dengue.

Vitamin D and its associations with blood pressure in the Chronic Kidney Disease in Children (CKiD) cohort.

BACKGROUND: Vitamin D (25OHD) can modulate pathways and mechanisms that regulate blood pressure (BP). Observational studies in children and adults have shown an inverse association between 25OHD and BP. Studies evaluating associations between 25OHD and BP in pediatric chronic kidney disease are limited. METHODS: We evaluated the associations between 25OHD and BP using data from the Chronic Kidney Disease in Children (CKiD) study. Clinic or ambulatory BP index was defined as participant's BP divided by 95th age-sex-height-specific BP percentile, an index > 1 suggests hypertension. Primary outcomes of interest were changes in systolic and diastolic clinic and ambulatory BP indices over follow-up. Linear mixed-effects models were used to evaluate associations between BP indices and 25OHD. RESULTS: The study cohort consisted of 370 participants who contributed 970 person-visits. A subset of 194 participants with ambulatory BP data contributed 465 person-visits. There was an association between baseline 25OHD levels and clinic systolic BP index such that for every 10 ng/ml lower 25OHD, clinic systolic BP index was 1.0% higher (95%CI: 0.2-1.8, p = 0.016) between participants. The association between clinic diastolic BP index with baseline 25OHD was not significant. For within-person changes, longitudinal decreases in 25OHD were not significantly associated with concomitant increases in clinic systolic or diastolic BP index. There were no significant associations between 25OHD levels at baseline or longitudinally with 24-h ABPM indices. CONCLUSIONS: Low 25OHD levels were associated with higher clinic systolic BP in children with CKD. Vitamin D supplementation to maintain normal 25OHD levels might be a useful adjunctive treatment in optimizing BP control in these high-risk patients.

Nutritional management of the child with chronic kidney disease and on dialysis.

While it is widely accepted that the nutritional management of the infant with chronic kidney disease (CKD) is paramount to achieve normal growth and development, nutritional management is also of importance beyond 1 year of age, particularly in toddlers, to support the delayed infantile stage of growth that may extend to 2-3 years of age. Puberty is also a vulnerable period when nutritional needs are higher to support the expected growth spurt. Inadequate nutritional intake throughout childhood can result in failure to achieve full adult height potential, and there is an increased risk for abnormal neurodevelopment. Conversely, the rising prevalence of overweight and obesity among children with CKD underscores the necessity for effective nutritional strategies to mitigate the risk of metabolic syndrome that is not confined to the post-transplant population. Nutritional management is of primary importance in improving metabolic equilibrium and reducing CKD-related imbalances, particularly as the range of foods eaten by the child widens as they get older (including increased consumption of processed foods), and as CKD progresses. The aim of this review is to integrate the Pediatric Renal Nutrition Taskforce (PRNT) clinical practice recommendations (CPRs) for children (1-18 years) with CKD stages 2-5 and on dialysis (CKD2-5D). We provide a holistic approach to the overall nutritional management of the toddler, child, and young person. Collaboration between physicians and pediatric kidney dietitians is strongly advised to ensure comprehensive and tailored nutritional care for children with CKD, ultimately optimizing their growth and development.

Optimizing word embeddings for small dataset: a case study on patient portal messages from breast cancer patients.

Patient portal messages often relate to specific clinical phenomena (e.g., patients undergoing treatment for breast cancer) and, as a result, have received increasing attention in biomedical research. These messages require natural language processing and, while word embedding models, such as word2vec, have the potential to extract meaningful signals from text, they are not readily applicable to patient portal messages. This is because embedding models typically require millions of training samples to sufficiently represent semantics, while the volume of patient portal messages associated with a particular clinical phenomenon is often relatively small. We introduce a novel adaptation of the word2vec model, PK-word2vec (where PK stands for prior knowledge), for small-scale messages. PK-word2vec incorporates the most similar terms for medical words (including problems, treatments, and tests) and non-medical words from two pre-trained embedding models as prior knowledge to improve the training process. We applied PK-word2vec in a case study of patient portal messages in the Vanderbilt University Medical Center electric health record system sent by patients diagnosed with breast cancer from December 2004 to November 2017. We evaluated the model through a set of 1000 tasks, each of which compared the relevance of a given word to a group of the five most similar words generated by PK-word2vec and a group of the five most similar words generated by the standard word2vec model. We recruited 200 Amazon Mechanical Turk (AMT) workers and 7 medical students to perform the tasks. The dataset was composed of 1389 patient records and included 137,554 messages with 10,683 unique words. Prior knowledge was available for 7981 non-medical and 1116 medical words. In over 90% of the tasks, both reviewers indicated PK-word2vec generated more similar words than standard word2vec (p = 0.01).The difference in the evaluation by AMT workers versus medical students was negligible for all comparisons of tasks' choices between the two groups of reviewers ( p = 0.774 under a paired t-test). PK-word2vec can effectively learn word representations from a small message corpus, marking a significant advancement in processing patient portal messages.

Development of an Injectable, ECM-Derivative Embolic for the Treatment of Cerebral Saccular Aneurysms.

Cerebral aneurysms are a source of neurological morbidity and mortality, most often as a result of rupture. The most common approach for treating aneurysms involves endovascular embolization using nonbiodegradable medical devices, such as platinum coils. However, the need for retreatment due to the recanalization of coil-treated aneurysms highlights the importance of exploring alternative solutions. In this study, we propose an injectable extracellular matrix-derived embolic formed in situ by Michael addition of gelatin-thiol (Gel-SH) and hyaluronic acid vinyl sulfone (HA-VS) that may be delivered with a therapeutic agent (here, RADA-SP) to fill and remodel aneurysmal tissue without leaving behind permanent foreign bodies. The injectable embolic material demonstrated rapid gelation under physiological conditions, forming a highly porous structure and allowing for cellular infiltration. The injectable embolic exhibited thrombogenic behavior in vitro that was comparable to that of alginate injectables. Furthermore, in vivo studies in a murine carotid aneurysm model demonstrated the successful embolization of a saccular aneurysm and extensive cellular infiltration both with and without RADA-SP at 3 weeks, with some evidence of increased vascular or fibrosis markers with RADA-SP incorporation. The results indicate that the developed embolic has inherent potential for acutely filling cerebrovascular aneurysms and encouraging the cellular infiltration that would be necessary for stable, chronic remodeling.

The prognostic relevance of exercise pulmonary hypertension in cardiac and pulmonary diseases.

PURPOSE OF REVIEW: In this review, we provide an overview of the prognostic implications of exPH in patients with various common cardiac and pulmonary diseases. RECENT FINDINGS: Exercise pulmonary hypertension (exPH) has been recently re-introduced in the current European Society of Cardiology/European Respiratory Society pulmonary hypertension guidelines. Accordingly, exPH is defined as a mean pulmonary arterial pressure (mPAP)/cardiac output (CO) slope greater than 3 mmHg/l/min. Key considerations for this re-introduction included increasing understanding on normal pulmonary hemodynamics during exercise and the broadly available evidence on the association of an abnormal mPAP/CO slope with poor survival in the general population and in different disease entities. SUMMARY: Exercise (patho-)physiology has opened a new field for clinical research facilitating recognition of cardiovascular and pulmonary vascular diseases in an early stage. Such early recognition with significant prognostic and possibly therapeutic relevance, but being undetectable at rest, makes exercise pulmonary hemodynamics particularly interesting for common diseases, such as valvular heart disease, left heart disease, and chronic pulmonary disease.

Intracranial aneurysms and abducent nerve palsy.

Background: Cranial nerve (CN) palsy may manifest as an initial presentation of intracranial aneurysms or due to the treatment. The literature reveals a paucity of studies addressing the involvement of the 6th CN in the presentation of cerebral aneurysms. Methods: Clinical patient data, aneurysmal characteristics, and CN 6th palsy outcome were retrospectively reviewed and analyzed. Results: Out of 1311 cases analyzed, a total of 12 cases were identified as having CN 6th palsy at the presentation. Eight out of the 12 were found in the unruptured aneurysm in the cavernous segment of the internal carotid artery (ICA). The other four cases of CN 6th palsy were found in association with ruptured aneurysms located exclusively at the posterior inferior cerebellar artery (PICA). For the full functional recovery of the CN 6th palsy, there was 50% documented full recovery in the eight cases of the unruptured cavernous ICA aneurysm. On the other hand, all four patients with ruptured PICA aneurysms have a full recovery of CN 6th palsy. The duration for recovery for CN palsy ranges from 1 to 5 months. Conclusion: The association between intracranial aneurysms and CN 6th palsy at presentation may suggest distinct patterns related to aneurysmal location and size. The abducent nerve palsy can be linked to unruptured cavernous ICA and ruptured PICA aneurysms. The recovery of CN 6th palsy may be influenced by aneurysm size, rupture status, location, and treatment modality.

Consistency of metabolite associations with measured glomerular filtration rate in children and adults.

Background: There is interest in identifying novel filtration markers that lead to more accurate GFR estimates than current markers (creatinine and cystatin C) and are more consistent across demographic groups. We hypothesize that large-scale metabolomics can identify serum metabolites that are strongly influenced by glomerular filtration rate (GFR) and are more consistent across demographic variables than creatinine, which would be promising filtration markers for future investigation. Methods: We evaluated the consistency of associations between measured GFR (mGFR) and 887 common, known metabolites quantified by an untargeted chromatography- and spectroscopy-based metabolomics platform (Metabolon) performed on frozen blood samples from 580 participants in Chronic Kidney Disease in Children (CKiD), 674 participants in Modification of Diet in Renal Disease (MDRD) Study and 962 participants in African American Study of Kidney Disease and Hypertension (AASK). We evaluated metabolite-mGFR correlation association with metabolite class, molecular weight, assay platform and measurement coefficient of variation (CV). Among metabolites with strong negative correlations with mGFR (r < -0.5), we assessed additional variation by age (height in children), sex, race and body mass index (BMI). Results: A total of 561 metabolites (63%) were negatively correlated with mGFR. Correlations with mGFR were highly consistent across study, sex, race and BMI categories (correlation of metabolite-mGFR correlations between 0.88 and 0.95). Amino acids, carbohydrates and nucleotides were more often negatively correlated with mGFR compared with lipids, but there was no association with metabolite molecular weight, liquid chromatography/mass spectrometry platform and measurement CV. Among 114 metabolites with strong negative associations with mGFR (r < -0.5), 27 were consistently not associated with age (height in children), sex or race. Conclusions: The majority of metabolite-mGFR correlations were negative and consistent across sex, race, BMI and study. Metabolites with consistent strong negative correlations with mGFR and non-association with demographic variables may represent candidate markers to improve estimation of GFR.

Anal human papillomavirus (HPV) disagreement by Linear Array compared to SPF10 PCR-DEIA-LiPA25 system in young sexual minority men.

Introduction: Young sexual minority men (SMM) bear the greatest burden of anal human papillomavirus (HPV) infections. We assessed anal HPV genotype discordance between the Linear Array (LA) and SPF10 PCR-DEIA-LiPA25 (LiPA25). Methods: Discordance was assessed between LA and LiPA25 using self-collected anal swabs from 120 SMM aged 18-29 who were recruited in 2014-2016. Multiple-type infection was explored as a potential confounder of testing agreement, along with clinical and behavioral factors such as HIV status, syphilis status, incarceration history, health insurance coverage, having 3 or more sex partners in the past 6 months, and co-infection with HPV-16. Results: Significant discordance was found for HPV-6, -11, -16, -31, -42, -54, and -59. Exploratory analyses suggest higher prevalence of genotype discordance in those living with HIV, those with 3 or more sex partners, and those who were positive for 4 or more HPV types. Conclusions: Our results highlight the importance of HPV detection methods which may inform different interpretations of research assessing anal HPV natural history among SMM at highest risk for HPV.

Discovery of the Lipopeptides Albubactins A-H from Streptomyces albidoflavus RKJM0023 via Chemical Elicitation with Rhamnolipids and Synthesis of Albubactin A.

The marine tunicate-derived Streptomyces albidoflavus RKJM0023 was cultured in the presence of a rhamnolipid mixture in an effort to elicit the production of silent natural products. MS/MS-based molecular networking analysis enhanced with nonparametric statistics highlighted the upregulation of a molecular cluster (Kruskal-Wallis p = 1.6 e-6 for 1) in which no MS/MS features had library matches. Targeted isolation of these features resulted in the discovery of nine new N-acylated lipopeptides, albubactins A-H (1-8) each containing a unique glutamine tripeptide and a C-terminal ethyl ester moiety. Three related albubactin acids A-C (9-11) lacking the ethyl ester were also identified. NMR spectroscopy and UPLC-HR-ESI-MS/MS demonstrated that the albubactins were obtained as mixtures that shared a common m/z and differed only in their acylated terminal groups. Due to the complex spectroscopic elucidation with many overlapping shifts, a total synthesis of albubactin A (1) was completed and used to determine the absolute configuration of the new albubactins.