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"Moreland, Robert"
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Evidence for an indigenous female mouse urobiome
Mice have been used as a valuable model for understanding pathophysiological mechanisms of urinary tract infection for almost six decades. Mice offer many advantages including genetic manipulation to test the role of genes and mechanisms, the availability of germ-free mice, and similarities to humans in innate immune defenses and the strain-dependent presence of vesicoureteral reflux. However, like with humans, the mouse bladder urine above the urinary sphincter has generally been assumed to be sterile. Yet, given the presence of urobiomes in other mammals and the emerging role of the human urobiome in the defense of the urinary bladder and upper urinary tract, the existence of a mouse urobiome should be critically examined as indigenous microbiota may influence experimental results. To determine if an indigenous murine urobiome exists, we obtained voided urine from two sets of female C57BL/6J mice during three different intervals using two different extraction and sequencing methods and analyzed them simultaneously by a single method. For one set, we also obtained urine by suprapubic aspiration, which we compared to the paired voided urine samples. We conclude that an indigenous murine urobiome exists and that voided urine contains post-urethral microbes.
Journal Article
Polymicrobial urine cultures: reconciling contamination with the urobiome while recognizing the pathogens
Polymicrobial or mixed urine cultures of more than one predominant microbe confound clinical urinary tract infection diagnosis. The current College of American Pathologists clinical laboratory standard states that a urine sample cultured with more than two isolates with >10,000 colony forming units/ml is to be considered contaminated. However, the presence of urinary sample bacteria in individuals without urinary symptoms (referred to as asymptomatic bacteriuria) is common especially in older people and in pregnant individuals. Furthermore, the discovery of an indigenous urinary microbiome (urobiome) in healthy humans throughout life from shortly after birth to death conflicts with the long-standing notion that urine derived from sterile filtered blood should be sterile above the urethral sphincter. Polymicrobial infections are not consistent with Koch’s postulates that a single pathogen is causal for disease. In this review, we will discuss current standards of contamination, how to reconcile the sterility of urine with the existence of the urobiome, a history of polymicrobial infections, and why re-examining current practices is essential for the practice of medicine, improving quality of life, and potentially saving lives.
Journal Article
High performance with fewer labels using semi-weakly supervised learning for pulmonary embolism diagnosis
This study proposes a semi-weakly supervised learning approach for pulmonary embolism (PE) detection on CT pulmonary angiography (CTPA) to alleviate the resource-intensive burden of exhaustive medical image annotation. Attention-based CNN-RNN models were trained on the RSNA pulmonary embolism CT dataset and externally validated on a pooled dataset (Aida and FUMPE). Three configurations included weak (examination-level labels only), strong (all examination and slice-level labels), and semi-weak (examination-level labels plus a limited subset of slice-level labels). The proportion of slice-level labels varying from 0 to 100%. Notably, semi-weakly supervised models using approximately one-quarter of the total slice-level labels achieved an AUC of 0.928, closely matching the strongly supervised model’s AUC of 0.932. External validation yielded AUCs of 0.999 for the semi-weak and 1.000 for the strong model. By reducing labeling requirements without sacrificing diagnostic accuracy, this method streamlines model development, accelerates the integration of models into clinical practice, and enhances patient care.
Journal Article
Quantification of TRPV1 Protein Levels in Rat Tissues to Understand its Physiological Roles
Transient receptor potential subfamily V, member 1 (TRPV1) is a nonselective cation channel expressed in both the peripheral and central nervous systems (CNS). TRPV1 protein levels in rat tissues were determined under normal and pain states using enzyme-linked immunosorbent assay. In naive rats, brain TRPV1 protein concentrations ranged from 1.5 to 4 ng/mg in hippocampus, cortex, hypothalamus, and cerebellum. Rat spinal cord TRPV1 protein levels were 40–50 ng/mg in L1–L5 of the lumbar regions, but increased to 97 ± 9.3 ng/mg toward the end of the lumbar region (L6–S1). In the complete Freund’s adjuvant (CFA)-induced inflammatory pain model, TRPV1 protein level significantly increased on both the contralateral (36.5 %,
p
< 0.05) and ipsilateral (31.4 %,
p
< 0.05) L4–L6 dorsal root ganglia (DRG). TRPV1 protein levels also increased 33.3 % (
p
< 0.05) on the ipsilateral sciatic nerve, but no significant change in the lumbar spinal cord of CFA rats. In the monoiodoacetate-induced rat knee joint pain model, TRPV1 protein level was significantly reduced in the ipsilateral L3–L5 DRG (33.3 %,
p
< 0.01), no significant difference was detected in the lumbar region of the spinal cord. Quantitative determination of TRPV1 protein levels may help to elucidate the TRPV1 physiological roles and regulatory mechanisms in various pain states.
Journal Article
Photoplethysmography using a smartphone application for assessment of ulnar artery patency: a randomized clinical trial
Radial artery access is commonly performed for coronary angiography and invasive hemodynamic monitoring. Despite limitations in diagnostic accuracy, the modified Allen test (manual occlusion of radial and ulnar arteries followed by release of the latter and assessment of palmar blush) is used routinely to evaluate the collateral circulation to the hand and, therefore, to determine patient eligibility for radial artery access. We sought to evaluate whether a smartphone application may provide a superior alternative to the modified Allen test.
We compared the modified Allen test with a smartphone heart rate–monitoring application (photoplethysmography readings detected using a smartphone camera lens placed on the patient’s index finger) in patients undergoing a planned cardiac catheterization. Test order was randomly assigned in a 1:1 fashion. All patients then underwent conventional plethysmography of the index finger, followed by Doppler ultrasonography of the radial and ulnar arteries (the diagnostic standard). The primary outcome was diagnostic accuracy of the heart rate–monitoring application.
Among 438 patients who were included in the study, we found that the heart rate–monitoring application had a superior diagnostic accuracy compared with the modified Allen test (91.8% v. 81.7%, p = 0.002), attributable to its greater specificity (93.0% v. 82.8%, p = 0.001). We also found that this application had greater diagnostic accuracy for assessment of radial or ulnar artery patency in the ipsilateral and contralateral wrist (94.0% v. 84.0%, p < 0.001).
A smartphone application used at the bedside was diagnostically superior to traditional physical examination for confirming ulnar patency before radial artery access. This study highlights the potential for smartphone-based diagnostics to aid in clinical decision-making at the patient’s bedside. Trial registration: Clinicaltrials.gov, no. NCT02519491.
Journal Article
Performance of Plasma Adenosine as a Biomarker for Predicting Cardiovascular Risk
Adenosine boasts promising preclinical and clinical data supporting a vital role in modulating vascular homeostasis. Its widespread use as a diagnostic and therapeutic agent have been limited by its short half‐life and complex biology, though adenosine‐modulators have shown promise in improving vascular healing. Moreover, circulating adenosine has shown promise in predicting cardiovascular (CV) events. We sought to delineate whether circulating plasma adenosine levels predict CV events in patients undergoing invasive assessment for coronary artery disease. Patients undergoing invasive angiography had clinical data prospectively recorded in the Cardiovascular and Percutaneous ClInical TriALs (CAPITAL) revascularization registry and blood samples collected in the CAPITAL Biobank from which adenosine levels were quantified. Tertile‐based analysis was used to assess prediction of major adverse cardiovascular events (MACE; composite of death, myocardial infarction, unplanned revascularization, and cerebrovascular accident). Secondary analyses included MACE subgroups, clinical subgroups and adenosine levels. There were 1,815 patients undergoing angiography who had blood collected with adenosine quantified in 1,323. Of those quantified, 51.0% were revascularized and 7.3% experienced MACE in 12 months of follow‐up. Tertile‐based analysis failed to demonstrate any stratification of MACE rates (log rank, P = 0.83), when comparing low‐to‐middle (hazard ratio (HR) 1.10, 95% confidence interval (CI) 0.68–1.78, P = 0.70) or low‐to‐high adenosine tertiles (HR 0.95, 95% CI 0.56–1.57, P = 0.84). In adjusted analysis, adenosine similarly failed to predict MACE. Finally, adenosine did not predict outcomes in patients with acute coronary syndrome nor in those revascularized or treated medically. Plasma adenosine levels do not predict subsequent CV outcomes or aid in patient risk stratification.
Journal Article
Sustained Contraction in Vascular Smooth Muscle by Activation of L-type Ca2+ Channels Does Not Involve Ca2+ Sensitization or Caldesmon
Vascular smooth muscle (VSM) is unique in its ability to maintain an intrinsic level of contractile force, known as tone. Vascular tone is believed to arise from the constitutive activity of membrane-bound L-type Ca2+ channels (LTCC). This study used a pharmacological agonist of LTCC, Bay K8644, to elicit a sustained, sub-maximal contraction in VSM that mimics tone. Downstream signaling was investigated in order to determine what molecules are responsible for tone. Medial strips of swine carotid artery were stimulated with 100 nM Bay K8644 to induce a sustained level of force. Force and phosphorylation levels of myosin light chain (MLC), MAP kinase, MYPT1, CPI-17, and caldesmon were measured during Bay K8644 stimulation in the presence and absence of nifedipine, ML-7, U0126, bisindolylmaleimide (Bis), and H-1152. Nifedipine and ML-7 inhibited force and MLC phosphorylation in response to Bay K8644. Inhibition of Rho kinase (H-1152) but not PKC (Bis) inhibited Bay K8644 induced force. U0126 significantly increased Bay K8644-dependent force with no effect on MLC phosphorylation. Neither CPI-17 nor caldesmon phosphorylation were increased during the maintenance of sustained force. Our results suggest that force due to the influx of calcium through LTCCs is partially MLC phosphorylation-dependent but does not involve PKC or caldesmon. Interestingly, inhibition of MLC kinase (MLCK) and PKC significantly increased MAP kinase phosphorylation suggesting that MLCK and PKC may directly or indirectly inhibit MAP kinase activity during prolonged contractions induced by Bay K8544.
Journal Article
Corrigendum: Sustained Contraction in Vascular Smooth Muscle by Activation of L-type Ca2+ Channels Does Not Involve Ca2+ Sensitization or Caldesmon
[This corrects the article on p. 516 in vol. 7, PMID: 28082901.].[This corrects the article on p. 516 in vol. 7, PMID: 28082901.].
Journal Article
Impact of atrial fibrillation on the risk of major adverse cardiac events following coronary revascularisation
ObjectiveAtrial fibrillation (AF) remains a highly prevalent arrhythmia with significant burden on morbidity and mortality. The impact of AF in the revascularised population remains incompletely described. Given the high prevalence of AF in the revascularised population, we sought to evaluate the incidence and prognosis in patients with pre-existing and new-onset AF following revascularisation.MethodsWe used the University of Ottawa Heart Institute Revascularisation Registry to identify patients who underwent revascularisation between August 2015 and March 2020, who were prospectively followed for an average of one year. We conducted a retrospective cohort study analysing the association between AF and clinical outcomes. The primary outcome of interest was 1-year major adverse cardiac events (MACE) defined as a composite of death, myocardial infarction, unplanned revascularisation and cerebrovascular accidents. Moreover, secondary outcomes include the individual components of MACE and bleeding.ResultsA total of 6704 patients underwent revascularisation and completed 1-year clinical follow-up. Median time to follow-up was 12.8 (IQR 11.2–15.9) months. One-year MACE occurred in 166 (21.8%) and 683 (11.5%) patients in AF and non-AF groups, respectively (adjusted HR, 1.61; 95% CI 1.29 to 2.01; p<0.0001). AF was independently predictive of 1-year mortality, myocardial infarction, unplanned revascularisation, cerebrovascular accident and bleeding. Within 1 year, 299 (4.5%) episodes of new-onset AF was observed. New-onset AF following revascularisation was also associated with 1-year MACE, mortality, myocardial infarction, cerebrovascular accident and unplanned revascularisation.ConclusionsPreprocedural and new-onset AF following revascularisation remains highly predictive 1-year MACE. AF should be considered in addition to traditional risk factors for adverse outcomes following revascularisation.
Journal Article