Total transcriptome analysis of Candida auris planktonic cells exposed to tyrosol.

Tyrosol, a secondary metabolite of Candida species, regulates fungal morphogenesis, and its application may represent a novel innovative therapy against emerging multi-resistant fungal superbug such as Candida auris. In the current study, the effects of tyrosol on growth, redox homeostasis, intracellular microelement contents and activities of virulence-related enzymes released by C. auris were examined. To gain further information about the effect of tyrosol exposure, we revealed gene transcriptional changes using total transcriptome sequencing (RNA-Seq). At a concentration of 15 mM, tyrosol significantly decrease the growth of fungal cells within 2 h of its addition (5.6 × 107±1.2 × 107 and 2.5 × 107±0.6 × 107 colony forming unit/mL for control and tyrosol-treated cells, respectively). Furthermore, it enhanced the release of reactive oxygen species as confirmed by a dichlorofluorescein (DCF) assay (7.3 ± 1.8 [nmol DCF (OD640)-1] versus 16.8 ± 3.9 [nmol DCF (OD640)-1]), which was coincided with elevated superoxide dismutase, catalase and glutathione peroxidase activities. Tyrosol exerted in a 37%, 25%, 34% and 55% decrease in intracellular manganese, iron, zinc and copper contents, respectively, compared to control cells. The tyrosol treatment led to a 142 and 108 differentially transcripted genes with at least a 1.5-fold increase or decrease in transcription, respectively. Genes related to iron and fatty acid metabolism as well as nucleic acid synthesis were down-regulated, whereas those related to the antioxidative defence, adhesion and oxoacid metabolic processes were up-regulated. This study shows that tyrosol significantly influences growth, intracellular physiological processes and gene transcription in C. auris, which could highly support the development of novel treatment approaches against this important pathogen.

Stretch-Induced Down-Regulation of HCN2 Suppresses Contractile Activity.

Although hyperpolarization-activated and cyclic nucleotide-gated 2 channels (HCN2) are expressed in multiple cell types in the gut, the role of HCN2 in intestinal motility is poorly understood. HCN2 is down-regulated in intestinal smooth muscle in a rodent model of ileus. Thus, the purpose of this study was to determine the effects of HCN inhibition on intestinal motility. HCN inhibition with ZD7288 or zatebradine significantly suppressed both spontaneous and agonist-induced contractile activity in the small intestine in a dose-dependent and tetrodotoxin-independent manner. HCN inhibition significantly suppressed intestinal tone but not contractile amplitude. The calcium sensitivity of contractile activity was significantly suppressed by HCN inhibition. Inflammatory mediators did not affect the suppression of intestinal contractile activity by HCN inhibition but increased stretch of the intestinal tissue partially attenuated the effects of HCN inhibition on agonist-induced intestinal contractile activity. HCN2 protein and mRNA levels in intestinal smooth muscle tissue were significantly down-regulated by increased mechanical stretch compared to unstretched tissue. Increased cyclical stretch down-regulated HCN2 protein and mRNA levels in primary human intestinal smooth muscle cells and macrophages. Overall, our results suggest that decreased HCN2 expression induced by mechanical signals, such as intestinal wall distension or edema development, may contribute to the development of ileus.

Clinician Perceptions of Receiving Different Forms of Feedback on their Opioid Prescribing.

Opioid misuse represents a major public health issue in the United States. One driver is overprescription for acute pain, with the size of initial prescription associated with subsequent long-term use. However, little work has been done to elicit clinician feedback about interventions to reduce opioid prescribing. To address this knowledge gap, qualitative analyses were conducted with clinicians who participated in a randomized controlled trial in which clinicians received monthly emailed feedback notifications about their opioid prescribing behaviors. Semistructured telephone interviews were conducted (N = 12) with urgent care (N = 7) and emergency department (N = 5) clinicians who participated in the trial between November 2020 and April 2021. Clinicians appreciated feedback about their prescribing behavior and found comparative data with peer clinicians to be most useful. Sharing opioid prescribing feedback data with clinicians can be an acceptable way to address opioid prescribing among emergency and urgent care clinicians.

The Effect Of Clinician Feedback Interventions On Opioid Prescribing.

An initial opioid prescription with a greater number of pills is associated with a greater risk for future long-term opioid use, yet few interventions have reliably influenced individual clinicians' prescribing. Our objective was to evaluate the effect of feedback interventions for clinicians in reducing opioid prescribing. The interventions included feedback on a clinician's outlier prescribing (individual audit feedback), peer comparison, and both interventions combined. We conducted a four-arm factorial pragmatic cluster randomized trial at forty-eight emergency department (ED) and urgent care (UC) sites in the western US, including 263 ED and 175 UC clinicians with 294,962 patient encounters. Relative to usual care, there was a significant decrease in pills per prescription both for peer comparison feedback (-0.8) and for the combination of peer comparison and individual audit feedback (-1.2). This decrease was sustained during follow-up. There were no significant changes for individual audit feedback alone, and no interventions changed the proportion of encounters with an opioid prescription.

COVID-19 in pregnancy by race and ethnicity: Implications for development of a vaccination strategy.

OBJECTIVE: COVID-19 and associated morbidity and mortality has disproportionately affected minoritized populations. The epidemiology of spread of COVID-19 among pregnant women by race/ethnicity is not well described. Using data from a large healthcare system in California, we estimated prevalence and spread during pregnancy and recommend a vaccination approach based on minimizing adverse outcomes. METHODS: Patients delivering at Sutter Health are tested (molecular) for COVID-19. These results were combined with antibody test results, using samples drawn at delivery. For each racial/ethnic group, we estimated prevalence of COVID-19, using logistic regression to adjust for known sociodemographic and comorbid risk factors. Testing for immunoglobulin G and immunoglobulin M provided insight into timing of infections. RESULTS: Among 17,446 women delivering May-December, 460 (2.6%) tested positive (molecular). Hispanic women were at 2.6 times the odds of being actively infected as White women (odds ratio = 2.6, 95% confidence interval = 2.0-3.3). August and December were the highest risk periods for active infection (odds ratio = 3.5, 95% confidence interval = 2.1-5.7 and odds ratio = 6.1, 95% confidence interval = 3.8-9.9, compared with May, respectively). Among 4500 women delivering October-December, 425 (9.4%) had positive molecular or antibody tests, ranging from 4.0% (Asian) to 15.7% (Hispanic). Adjusting for covariables, compared with White patients, odds of infection was similar for Black and Asian patients, with Hispanic at 2.4 (1.8-3.3) times the odds. CONCLUSION: COVID-19 prevalence was higher among Hispanic women at delivery and in the last trimester than their White counterparts. Higher rates in Black patients are explained by other risk factors. Resources should be directed to increase vaccination rates among Hispanic women in early stages of pregnancy.

Persistent Cardiometabolic Health Gaps: Can Therapeutic Care Gaps Be Precisely Identified from Electronic Health Records.

The objective of this study was to determine the strengths and limitations of using structured electronic health records (EHR) to identify and manage cardiometabolic (CM) health gaps. We used medication adherence measures derived from dispense data to attribute related therapeutic care gaps (i.e., no action to close health gaps) to patient- (i.e., failure to retrieve medication or low adherence) or clinician-related (i.e., failure to initiate/titrate medication) behavior. We illustrated how such data can be used to manage health and care gaps for blood pressure (BP), low-density lipoprotein cholesterol (LDL-C), and HbA1c for 240,582 Sutter Health primary care patients. Prevalence of health gaps was 44% for patients with hypertension, 33% with hyperlipidemia, and 57% with diabetes. Failure to retrieve medication was common; this patient-related care gap was highly associated with health gaps (odds ratios (OR): 1.23-1.76). Clinician-related therapeutic care gaps were common (16% for hypertension, and 40% and 27% for hyperlipidemia and diabetes, respectively), and strongly related to health gaps for hyperlipidemia (OR = 5.8; 95% CI: 5.6-6.0) and diabetes (OR = 5.7; 95% CI: 5.4-6.0). Additionally, a substantial minority of care gaps (9% to 21%) were uncertain, meaning we lacked evidence to attribute the gap to either patients or clinicians, hindering efforts to close the gaps.