Development and implementation of a breast imaging order panel in the electronic health record: Helping the ordering providers get it right.

Appropriate ordering of breast imaging studies is complex due to the variety of clinical indications and available imaging modalities. Incorrect ordering affects radiology resource allocation due to the different workflows and personnel requirements of screening and diagnostic breast imaging. Through the collaborative efforts of stakeholders in Primary Care, Radiology, and Information Services & Solutions, we developed and implemented a breast imaging order panel in the electronic health record with integrated clinical decision support to facilitate correct order selection for screening patients at average-risk and high-risk of breast cancer and for diagnostic breast imaging of symptomatic patients.

Implementing Risk-Sharing Arrangements for Innovative Medicines: The Experience in Catalonia (Spain).

OBJECTIVES: Publications assessing health and economic outcomes of risk-sharing arrangements (RSAs) are limited. Better knowledge of these outcomes would shed light on the pertinence of such arrangements, informing design improvements for the future. The aim of the study is to describe the different types of RSAs implemented in Catalonia and their health and economic outcomes. METHODS: Retrospective descriptive analysis of RSAs implemented from January 2016 to December 2019 in the Catalan Health Service, CatSalut. Individual RSAs were reviewed and categorized according to standard RSA guidelines. Relevant health and economic outcomes pertaining to the RSAs were analyzed using aggregate data recorded in Catalan central registries. RESULTS: A total of 15 RSAs were implemented over the study period (10 of which are still ongoing). A total of 8 consisted of performance-linked reimbursements (PLRs) and 7 of cost-sharing arrangements (CSAs). The arrangements were implemented in the oncohematology (n = 11), rare disease (n = 3), and neurology (n = 1) areas. A total of 951 patients were included in PLR and 73% achieved the target health outcomes. Total medication costs were €9 295 755 of which 11% were refunded to CatSalut. CSAs involved 2066 patients and resulted in overall refunds of €1 349 564 (2.61%) for CatSalut. CONCLUSIONS: Both PLRs and CSAs were used to manage the different uncertainties related to accessing innovative medicines in Catalonia. The data generated provide relevant information to inform decision-making, allowing an adaptation of the initial recommendation for use and access. Additional efforts are required to increase the RSA assessments and their publication.

Neuromodulation of innate immunity by remote ischaemic conditioning in humans: Experimental cross-over study.

Experimental animal studies on the mechanisms of remote ischaemic conditioning (RIC)-induced cardioprotection against ischaemia/reperfusion injury demonstrate involvement of both neuronal and humoral pathways. Autonomic parasympathetic (vagal) pathways confer organ protection through both direct innervation and/or immunomodulation, but evidence in humans is lacking. During acute inflammation, vagal release of acetylcholine suppresses CD11b expression, a critical ß2-integrin regulating neutrophil adhesion to the endothelium and transmigration to sites of injury. Here, we tested the hypothesis that RIC recruits vagal activity in humans and has an anti-inflammatory effect by reducing neutrophil CD11b expression. Participants (age:50 â€‹± â€‹19 years; 53% female) underwent ultrasound-guided injection of local anaesthetic within the brachial plexus before applying 3 â€‹× â€‹8 min cycles of brachial artery occlusion using a blood pressure cuff (RICblock). RIC was repeated 6 weeks later without brachial plexus block. Masked analysers quantified vagal activity (heart rate, heart rate variability (HRV)) before, and 10 â€‹min after, the last cycle of RIC. RR-interval increased after RIC (reduced heart rate) by 40 â€‹ms (95% confidence intervals (95%CI):13-66; n â€‹= â€‹17 subjects; P â€‹= â€‹0.003). RR-interval did not change after brachial plexus blockade (mean difference: 20 â€‹ms (95%CI:-11 to 50); P â€‹= â€‹0.19). The high-frequency component of HRV was reduced after RICblock, but remained unchanged after RIC (P â€‹< â€‹0.001), indicating that RIC preserved vagal activity. LPS-induced CD16+CD11b+ expression in whole blood (measured by flow cytometry) was reduced by RIC (3615 median fluorescence units (95%CI:475-6754); P = 0.026), compared with 2331 units (95%CI:-3921 to 8582); P = 0.726) after RICblock. These data suggest that in humans RIC recruits vagal cardiac and anti-inflammatory mechanisms via ischaemia/reperfusion-induced activation of sensory nerve fibres that innervate the organ undergoing RIC.

Natural Diversity in Stomatal Features of Cultivated and Wild Oryza Species.

BACKGROUND: Stomata in rice control a number of physiological processes by regulating gas and water exchange between the atmosphere and plant tissues. The impact of the structural diversity of these micropores on its conductance level is an important area to explore before introducing stomatal traits into any breeding program in order to increase photosynthesis and crop yield. Therefore, an intensive measurement of structural components of stomatal complex (SC) of twenty three Oryza species spanning the primary, secondary and tertiary gene pools of rice has been conducted. RESULTS: Extensive diversity was found in stomatal number and size in different Oryza species and Oryza complexes. Interestingly, the dynamics of stomatal traits in Oryza family varies differently within different Oryza genetic complexes. Example, the Sativa complex exhibits the greatest diversity in stomatal number, while the Officinalis complex is more diverse for its stomatal size. Combining the structural information with the Oryza phylogeny revealed that speciation has tended towards increasing stomatal density rather than stomatal size in rice family. Thus, the most recent species (i.e. the domesticated rice) eventually has developed smaller yet numerous stomata. Along with this, speciation has also resulted in a steady increase in stomatal conductance (anatomical, gmax) in different Oryza species. These two results unambiguously prove that increasing stomatal number (which results in stomatal size reduction) has increased the stomatal conductance in rice. Correlations of structural traits with the anatomical conductance, leaf carbon isotope discrimination (∆13C) and major leaf morphological and anatomical traits provide strong supports to untangle the ever mysterious dependencies of these traits in rice. The result displayed an expected negative correlation in the number and size of stomata; and positive correlations among the stomatal length, width and area with guard cell length, width on both abaxial and adaxial leaf surfaces. In addition, gmax is found to be positively correlated with stomatal number and guard cell length. The ∆13C values of rice species showed a positive correlation with stomatal number, which suggest an increased water loss with increased stomatal number. Interestingly, in contrast, the ∆13C consistently shows a negative relationship with stomatal and guard cell size, which suggests that the water loss is less when the stomata are larger. Therefore, we hypothesize that increasing stomatal size, instead of numbers, is a better approach for breeding programs in order to minimize the water loss through stomata in rice. CONCLUSION: Current paper generates useful data on stomatal profile of wild rice that is hitherto unknown for the rice science community. It has been proved here that the speciation has resulted in an increased stomatal number accompanied by size reduction during Oryza's evolutionary course; this has resulted in an increased gmax but reduced water use efficiency. Although may not be the sole driver of water use efficiency in rice, our data suggests that stomata are a potential target for modifying the currently low water use efficiency in domesticated rice. It is proposed that Oryza barthii can be used in traditional breeding programs in enhancing the stomatal size of elite rice cultivars.

MicroRNA signatures of perioperative myocardial injury after elective noncardiac surgery: a prospective observational mechanistic cohort study.

BACKGROUND: Elevated plasma or serum troponin, indicating perioperative myocardial injury (PMI), is common after noncardiac surgery. However, underlying mechanisms remain unclear. Acute coronary syndrome (ACS) is associated with the early appearance of circulating microRNAs, which regulate post-translational gene expression. We hypothesised that if PMI and ACS share pathophysiological mechanisms, common microRNA signatures should be evident. METHODS: We performed a nested case control study of samples obtained before and after noncardiac surgery from patients enrolled in two prospective observational studies of PMI (postoperative troponin I/T>99th centile). In cohort one, serum microRNAs were compared between patients with or without PMI, matched for age, gender, and comorbidity. Real-time polymerase chain reaction quantified (qRT-PCR) relative microRNA expression (cycle quantification [Cq] threshold <37) before and after surgery for microRNA signatures associated with ACS, blinded to PMI. In cohort two, we analysed (EdgeR) microRNA from plasma extracellular vesicles using next-generation sequencing (Illumina HiSeq 500). microRNA-messenger RNA-function pathway analysis was performed (DIANA miRPath v3.0/TopGO). RESULTS: MicroRNAs were detectable in all 59 patients (median age 67 yr [61-75]; 42% male), who had similar clinical characteristics independent of developing PMI. In cohort one, serum microRNA expression increased after surgery (mean fold-change) hsa-miR-1-3p: 3.99 (95% confidence interval [CI: 1.95-8.19]; hsa-miR-133-3p: 5.67 [95% CI: 2.94-10.91]; P<0.001). These changes were not associated with PMI. Bioinformatic analysis of differentially expressed microRNAs from cohorts one (n=48) and two (n=11) identified pathways associated with adrenergic stress and calcium dysregulation, rather than ischaemia. CONCLUSIONS: Circulating microRNAs associated with cardiac ischaemia were universally elevated in patients after surgery, independent of development of myocardial injury.

Acquired loss of cardiac vagal activity is associated with myocardial injury in patients undergoing noncardiac surgery: prospective observational mechanistic cohort study.

BACKGROUND: Myocardial injury is more frequent after noncardiac surgery in patients with preoperative cardiac vagal dysfunction, as quantified by delayed heart rate (HR) recovery after cessation of cardiopulmonary exercise testing. We hypothesised that serial and dynamic measures of cardiac vagal activity are also associated with myocardial injury after noncardiac surgery. METHODS: Serial autonomic measurements were made before and after surgery in patients undergoing elective noncardiac surgery. Cardiac vagal activity was quantified by HR variability and HR recovery after orthostatic challenge (supine to sitting). Revised cardiac risk index (RCRI) was calculated for each patient. The primary outcome was myocardial injury (high-sensitivity troponin ≥15 ng L-1) within 48 h of surgery, masked to investigators. The exposure of interest was cardiac vagal activity (high-frequency power spectral analysis [HFLn]) and HR recovery 90 s from peak HR after the orthostatic challenge. RESULTS: Myocardial injury occurred in 48/189 (25%) patients, in whom 41/48 (85%) RCRI was <2. In patients with myocardial injury, vagal activity (HFLn) declined from 5.15 (95% confidence interval [CI]: 4.58-5.72) before surgery to 4.33 (95% CI: 3.76-4.90; P<0.001) 24 h after surgery. In patients who remained free of myocardial injury, HFLn did not change (4.95 [95% CI: 4.64-5.26] before surgery vs 4.76 [95% CI: 4.44-5.08] after surgery). Before and after surgery, the orthostatic HR recovery was slower in patients with myocardial injury (5 beats min-1 [95% CI: 3-7]), compared with HR recovery in patients who remained free of myocardial injury (10 beats min-1 [95% CI: 7-12]; P=0.02). CONCLUSIONS: Serial HR measures indicating loss of cardiac vagal activity are associated with perioperative myocardial injury in lower-risk patients undergoing noncardiac surgery.

Non-inferiority of retrospective data collection for assessing perioperative morbidity.

Background. Postoperative morbidity has immediate and delayed consequences for surgical patients, including excess risk of premature death. Capturing these data objectively and routinely in large electronic databases using tools such as the Postoperative Morbidity Survey (POMS) would offer tremendous clinical and translational potential. However, POMS has thus far only utilised prospective data collection by research staff. We hypothesised that retrospective data collection from routinely collated hospital data from paper and electronic charts, medical and nursing notes was non-inferior to prospective data collection requiring research staff capturing POMS-defined morbidity in real-time. Methods. Morbidity was recorded by a trained investigator as defined by POMS prospectively on postoperative days 3 and 7. Separately, an independent investigator blinded to prospectively acquired data retrospectively assessed the same patients' morbidity as defined by POMS criteria, using medical charts, nursing summaries and electronic data. Equivalence was accepted when the confidence limits for both modes of data collection fell completely inside the equivalence bounds, with the maximum equivalence difference (i.e., the largest value of the difference in sensitivities deemed to reach a conclusion of equivalence) set a priori at 0.2. Differences for confidence limits between retrospective and prospective data collection were based on Nam's RMLE method. The relationship between morbidity on postoperative day 3 as recorded by each data collection method on time to become morbidity free and length of hospital stay was compared using the log-rank test. Results. POMS data from 85 patients undergoing elective or emergency surgery were analyzed. At postoperative day 3, POMS-defined morbidity was similar regardless of whether data were collected prospectively or retrospectively (95% CI [-0.13-0.013]; p < 0.001). Non-inferiority for sensitivity was observed for all other POMS domains and timepoints. Time to become morbidity free Kaplan-Meier plots were indistinguishable between POMS obtained prospectively or retrospectively (hazard ratio: 1.09 (95% CI [0.76-1.57]); p = 0.33, log rank test). Similarly, the mode of data collection did not alter the association between early postoperative morbidity on postoperative day 3 and delayed hospital discharge. Conclusions. Postoperative morbidity as defined by the Post Operative Morbidity Survey can be assessed retrospectively. These data may therefore be easily captured using electronic patient record systems, thereby expanding the potential for bioinformatics approaches to generate new clinical and translational insights into recovery from surgery.

Individualised oxygen delivery targeted haemodynamic therapy in high-risk surgical patients: a multicentre, randomised, double-blind, controlled, mechanistic trial.

BACKGROUND: Morbidity after major surgery is associated with low oxygen delivery. Haemodynamic therapy aimed at increasing oxygen delivery in an effort to reduce oxygen debt, tissue injury, and morbidity, is controversial. The most appropriate target for this strategy is unclear and might have several off-target effects, including loss of neural (parasympathetic)-mediated cellular protection. We hypothesised that individualised oxygen delivery targeted haemodynamic therapy (goal-directed therapy) in high-risk surgical patients would reduce postoperative morbidity, while secondarily addressing whether goal-directed therapy affected parasympathetic function. METHODS: In this multicentre, randomised, double-blind, controlled trial, adult patients undergoing major elective surgery were allocated by computer-generated randomisation to a postoperative protocol (fluid, with and without dobutamine) targeted to achieve their individual preoperative oxygen delivery value (goal-directed therapy) or standardised care (control). Patients and staff were masked to the intervention. The primary outcome was absolute risk reduction (ARR) in morbidity (defined by Clavien-Dindo grade II or more) on postoperative day 2. We also assessed a secondary outcome focused on parasympathetic function, using time-domain heart rate variability measures. Analyses were done on an intention-to-treat basis. The trial was registered with Controlled Clinical Trials (number ISRCTN76894700). FINDINGS: We enrolled 204 patients between May 20, 2010, and Feb 12, 2014. Intention-to-treat analysis of the 187 (92%) patients who completed the trial intervention period showed that early morbidity was similar between goal-directed therapy (44 [46%] of 95 patients) and control groups (49 [53%] of 92 patients) (ARR -7%, 95% CI -22 to 7; p=0·30). Prespecified secondary analysis showed that 123 (66%) of 187 patients achieved preoperative oxygen delivery (irrespective of intervention). These patients sustained less morbidity (ARR 19%, 95% CI 3-34; p=0·016), including less infectious complications. Goal-directed therapy reduced parasympathetic activity postoperatively (relative risk 1·33, 95% CI 1·01-1·74). INTERPRETATION: Achievement of preoperative oxygen delivery values in the postoperative phase was associated with less morbidity, but this was not affected by the use of an oxygen delivery targeted strategy. Reduced parasympathetic activity after goal-directed therapy was associated with the failure of this intervention to reduce postoperative morbidity. FUNDING: Academy of Medical Sciences and Health Foundation Clinician Scientist Award.

Yeast lipin 1 orthologue pah1p regulates vacuole homeostasis and membrane fusion.

Vacuole homotypic fusion requires a group of regulatory lipids that includes diacylglycerol, a fusogenic lipid that is produced through multiple metabolic pathways including the dephosphorylation of phosphatidic acid (PA). Here we examined the relationship between membrane fusion and PA phosphatase activity. Pah1p is the single yeast homologue of the Lipin family of PA phosphatases. Deletion of PAH1 was sufficient to cause marked vacuole fragmentation and abolish vacuole fusion. The function of Pah1p solely depended on its phosphatase activity as complementation studies showed that wild type Pah1p restored fusion, whereas the phosphatase dead mutant Pah1p(D398E) had no effect. We discovered that the lack of PA phosphatase activity blocked fusion by inhibiting the binding of SNAREs to Sec18p, an N-ethylmaleimide-sensitive factor homologue responsible for priming inactive cis-SNARE complexes. In addition, pah1Δ vacuoles were devoid of the late endosome/vacuolar Rab Ypt7p, the phosphatidylinositol 3-kinase Vps34p, and Vps39p, a subunit of the HOPS (homotypic fusion and vacuole protein sorting) tethering complex, all of which are required for vacuole fusion. The lack of Vps34p resulted in the absence of phosphatidylinositol 3-phosphate, a lipid required for SNARE activity and vacuole fusion. These findings demonstrate that Pah1p and PA phosphatase activity are critical for vacuole homeostasis and fusion.