Edouard Battegay

Diagnostic performance of reproducible chest wall tenderness to rule out acute coronary syndrome in acute chest pain: a prospective diagnostic study

Objectives Acute chest pain (ACP) is a leading cause of hospital emergency unit consultation. As there are various underlying conditions, ranging from musculoskeletal disorders to acute coronary syndrome (ACS), thorough clinical diagnostics are warranted. The aim of this prospective study was to assess whether reproducible chest wall tenderness (CWT) on palpation in patients with ACP can help to rule out ACS. Methods In this prospective, double-blinded diagnostic study, all consecutive patients assessed in the emergency unit at the University Hospital Zurich because of ACP between July 2012 and December 2013 were included when a member of the study team was present. Reproducible CWT on palpation was the initial step and was recorded before further examinations were initiated. The final diagnosis was adjudicated by a study-independent physician. Results 121 patients (60.3% male, median age 47 years, IQR 34–66.5 years) were included. The prevalence of ACS was 11.6%. Non-reproducible CWT had a high sensitivity of 92.9% (95% CI 66.1% to 98.8%) for ACS and the presence of reproducible CWT ruled out ACS (p=0.003) with a high negative predictive value (98.1%, 95% CI 89.9% to 99.7%). Conversely non-reproducible CWT ruled in ACS with low specificity (48.6%, 95% CI 38.8% to 58.5%) and low positive predictive value (19.1%, 95% CI 10.6% to 30.5%). Conclusions This prospective diagnostic study supports the concept that reproducible CWT helps to rule out ACS in patients with ACP in an early stage of the evaluation process. However, ACS and other diagnoses should be considered in patients with a negative CWT test. Trial registration number ClinicalTrial.gov: NCT01724996.

Therapeutic Conflicts in Emergency Department Patients with Multimorbidity: A Cross-Sectional Study

Background Patients with multimorbidity are an increasing concern in healthcare. Clinical practice guidelines, however, do not take into account potential therapeutic conflicts caused by co-occurring medical conditions. This makes therapeutic decisions complex, especially in emergency situations. Objective The aim of this study was to identify and quantify therapeutic conflicts in emergency department patients with multimorbidity. Methods We reviewed electronic records of all patients ≥18 years with two or more concurrent active medical conditions, admitted from the emergency department to the hospital ward of the University Hospital Zurich in January 2009. We cross-tabulated all active diagnoses with treatments recommended by guidelines for each diagnosis. Then, we identified potential therapeutic conflicts and classified them as either major or minor conflicts according to their clinical significance. Results 166 emergency inpatients with multimorbidity were included. The mean number of active diagnoses per patient was 6.6 (SD±3.4). We identified a total of 239 therapeutic conflicts in 49% of the of the study population. In 29% of the study population major therapeutic conflicts, in 41% of the patients minor therapeutic conflicts occurred. Conclusions Therapeutic conflicts are common among multimorbid patients, with one out of two experiencing minor, and one out of three experiencing major therapeutic conflicts. Clinical practice guidelines need to address frequent therapeutic conflicts in patients with co-morbid medical conditions.

Endothelial Rictor is crucial for midgestational development and sustained and extensive FGF2-induced neovascularization in the adult.

To explore the general requirement of endothelial mTORC2 during embryonic and adolescent development, we knocked out the essential mTORC2 component Rictor in the mouse endothelium in the embryo, during adolescence and in endothelial cells in vitro. During embryonic development, Rictor knockout resulted in growth retardation and lethality around embryonic day 12. We detected reduced peripheral vascularization and delayed ossification of developing fingers, toes and vertebrae during this confined midgestational period. Rictor knockout did not affect viability, weight gain, and vascular development during further adolescence. However during this period, Rictor knockout prevented skin capillaries to gain larger and heterogeneously sized diameters and remodeling into tortuous vessels in response to FGF2. Rictor knockout strongly reduced extensive FGF2-induced neovascularization and prevented hemorrhage in FGF2-loaded matrigel plugs. Rictor knockout also disabled the formation of capillary-like networks by FGF2-stimulated mouse aortic endothelial cells in vitro. Low RICTOR expression was detected in quiescent, confluent mouse aortic endothelial cells, whereas high doses of FGF2 induced high RICTOR expression that was associated with strong mTORC2-specific protein kinase Cα and AKT phosphorylation. We demonstrate that the endothelial FGF-RICTOR axis is not required during endothelial quiescence, but crucial for midgestational development and sustained and extensive neovascularization in the adult.

Determinants of diagnostic performance of 18F-FDG PET/CT in patients with fever of unknown origin.

ObjectivesThere is uncertainty about patient selection and the adequate timing at which fluorine-18 fluorodeoxyglucose (18F-FDG) PET/computed tomography (CT) is indicated in the diagnostic work-up of fever of unknown origin (FUO). The aim of this study was to determine the diagnostic performance of 18F-FDG PET/CT in patients with FUO. MethodsAll consecutive patients who underwent 18F-FDG PET/CT at the University Hospital Zurich because of FUO between 2006 and 2012 were included in this retrospective, observational study. ResultsA total of 76 patients [70% men, median (interquartile range) age 60 (47–67) years] were included. 18F-FDG PET/CT showed characteristically increased 18F-FDG activity in 56 patients (74%), leading to confirmation of or change in the suspected cause of FUO in 57 and 17%, respectively. The final diagnosis after 18F-FDG PET/CT included infection (21%), malignancy (22%), noninfectious inflammatory disease (12%), others (5%), or an unknown cause (40%). The success rate, sensitivity, and specificity of 18F-FDG PET/CT were 60, 77, and 31%, respectively. Sensitivity was highest in patients with suspected malignancy (100%, 95% confidence interval 79–100%). Diagnostic performance was independent of the investigated variables other than suspected infection as a cause of FUO (odds ratio 0.1, 95% confidence interval 0.01–0.8, P=0.033). ConclusionThe diagnostic performance of 18F-FDG PET/CT was significantly higher in patients with suspected malignancy causing a FUO compared with suspected infection or noninfectious inflammatory disease. However, it was independent of the baseline characteristics and duration of fever. This supports the recommendation to perform 18F-FDG PET/CT early in the diagnostic work-up of FUO, which may shorten disease duration and lower health costs, particularly when infection or malignancy is suspected.

Deletion of Rictor in brain and fat alters peripheral clock gene expression and increases blood pressure.

The mammalian target of rapamycin complex 2 (mTORC2) contains the essential protein RICTOR and is activated by growth factors. mTORC2 in adipose tissue contributes to the regulation of glucose and lipid metabolism. In the perivascular adipose tissue, mTORC2 ensures normal vascular reactivity by controlling expression of inflammatory molecules. To assess whether RICTOR/mTORC2 contributes to blood pressure regulation, we applied a radiotelemetry approach in control and Rictor knockout (RictoraP2KO) mice generated using adipocyte protein-2 gene promoter–driven CRE recombinase expression to delete Rictor. The 24-hour mean arterial pressure was increased in RictoraP2KO mice, and the physiological decline in mean arterial pressure during the dark period was impaired. In parallel, heart rate and locomotor activity were elevated during the dark period with a pattern similar to blood pressure changes. This phenotype was associated with mild cardiomyocyte hypertrophy, decreased cardiac natriuretic peptides, and their receptor expression in adipocytes. Moreover, clock gene expression was reduced or phase-shifted in perivascular adipose tissue. No differences in clock gene expression were observed in the master clock suprachiasmatic nucleus, although Rictor gene expression was also lower in brain of RictoraP2KO mice. Thus, this study highlights the importance of RICTOR/mTORC2 for interactions between vasculature, adipocytes, and brain to tune physiological outcomes, such as blood pressure and locomotor activity.

The multimorbidity interaction severity index (MISI): A proof of concept study

Abstract Therapeutic decision-making for patients with multimorbidity (MM) is challenging. Clinical practice guidelines inadequately address harmful interactions and resulting therapeutic conflicts within and among diseases. A patient-specific measure of MM severity that takes account of this conflict is needed. As a proof of concept, we evaluated whether the new Multimorbidity Interaction Severity Index (MISI) could be used to reliably differentiate patients in terms of lower versus higher potential for harmful interactions. Two hypothetical patient cases were generated, each with 6 concurrent morbidities. One case had a low (i.e., low conflict case) and the other a high (i.e., high conflict case) potential for harmful interactions. All possible interactions between conditions and treatments were extracted from each cases record into a multimorbidity interaction matrix. Experienced general internists (N = 18) judged each interaction in the matrix in terms of likely resource utilization needed to manage the interaction. Based on these judgements, a composite index of MM interaction severity, that is, the MISI, was generated for each physician and case. The difference between each physicians MISI score for the 2 cases (MISIdiff) was computed. Based on MISIdiff, the high conflict case was judged to be of significantly greater MM severity than was the low conflict case. The positive values of the inter-quartile range, a measure of variation (or disagreement) between the 2 cases, indicated general consistency of individual physicians in judging MM severity. The data indicate that the MISI can be used to reliably differentiate hypothetical multimorbid patients in terms of lesser versus greater severity of potentially harmful interactive effects. On this basis, the MISI will be further developed for use in patient-specific assessment and management of MM. The clinical relevance of the MISI as an alternative approach to defining MM severity is discussed.

Chronic Pain: How Challenging Are DDIs in the Analgesic Treatment of Inpatients with Multiple Chronic Conditions?

Background Chronic pain is common in multimorbid patients. However, little is known about the implications of chronic pain and analgesic treatment on multimorbid patients. This study aimed to assess chronic pain therapy with regard to the interaction potential in a sample of inpatients with multiple chronic conditions. Methods and Findings We conducted a retrospective study with all multimorbid inpatients aged ≥18 years admitted to the Department of Internal Medicine of University Hospital Zurich in 2011 (n = 1,039 patients). Data were extracted from the electronic health records and reviewed. We identified 433 hospitalizations of patients with chronic pain and analyzed their combinations of chronic conditions (multimorbidity). We then classified all analgesic prescriptions according to the World Health Organization (WHO) analgesic ladder. Furthermore, we used a Swiss drug-drug interactions knowledge base to identify potential interactions between opioids and other drug classes, in particular coanalgesics and other concomitant drugs. Chronic pain was present in 38% of patients with multimorbidity. On average, patients with chronic pain were aged 65.7 years and had a mean number of 6.6 diagnoses. Hypertension was the most common chronic condition. Chronic back pain was the most common painful condition. Almost 90% of patients were exposed to polypharmacotherapy. Of the chronic pain patients, 71.1% received opioids for moderate to severe pain, 43.4% received coanalgesics. We identified 3,186 potential drug-drug interactions, with 17% classified between analgesics (without coanalgesics). Conclusions Analgesic drugs-related DDIs, in particular opioids, in multimorbid patients are often complex and difficult to assess by using DDI knowledge bases alone. Drug-multimorbidity interactions are not sufficiently investigated and understood. Today, the scientific literature is scarce for chronic pain in combination with multiple coexisting medical conditions and medication regimens. Our work may provide useful information to enable further investigations in multimorbidity research within the scope of potential interactions and chronic pain.

Basal mTORC2 activity and expression of its components display diurnal variation in mouse perivascular adipose tissue.

In adipose tissue mTOR complex 2 (mTORC2) contributes to the regulation of glucose/lipid metabolism and inflammatory molecule expression. Both processes display diurnal variations during the course of the day. RICTOR and mSIN1 are unique and essential components of mTORC2, which is activated by growth factors including insulin. To assess whether mTORC2 components display diurnal variations, we analyzed steady state mRNA expression levels of Rictor, mSin1, and mTor in various adipose tissues during a 24 h period. Diurnally regulated expression of Rictor was detected in brown adipose tissues displaying highest mRNA expression levels at the beginning of the 12 h light period (zeitgeber time 2, ZT2). Gene expression patterns of mSin1 and mTor displayed a similar diurnal regulation as Rictor in PVAT while smaller changes were detected for these genes in aorta during the course of the day. Basal mTORC2 activity was measured by phosphorylation of protein kinase C (PKC) α at serine 657 was higher at ZT14 as compared with ZT2 in PVAT. In line, gene expression of inflammatory molecules nitric oxide synthase 2 and tumor necrosis factor α was lower at ZT 14 compared to ZT2. Our findings provide evidence for a diurnal regulation of expression of mTORC2 components and activity. Hence, mTORC2 is possibly an integral part of diurnally regulated signaling pathways in PVAT and possibly in other adipose tissues.

Tracing the decision-making process of physicians with a Decision Process Matrix

BackgroundDecision-making processes in a medical setting are complex, dynamic and under time pressure, often with serious consequences for a patient’s condition.ObjectiveThe principal aim of the present study was to trace and map the individual diagnostic process of real medical cases using a Decision Process Matrix [DPM]).MethodsThe naturalistic decision-making process of 11 residents and a total of 55 medical cases were recorded in an emergency department, and a DPM was drawn up according to a semi-structured technique following four steps: 1) observing and recording relevant information throughout the entire diagnostic process, 2) assessing options in terms of suspected diagnoses, 3) drawing up an initial version of the DPM, and 4) verifying the DPM, while adding the confidence ratings.ResultsThe DPM comprised an average of 3.2 suspected diagnoses and 7.9 information units (cues). The following three-phase pattern could be observed: option generation, option verification, and final diagnosis determination. Residents strove for the highest possible level of confidence before making the final diagnoses (in two-thirds of the medical cases with a rating of practically certain) or excluding suspected diagnoses (with practically impossible in half of the cases).DiscussionThe following challenges have to be addressed in the future: real-time capturing of emerging suspected diagnoses in the memory of the physician, definition of meaningful information units, and a more contemporary measurement of confidence.ConclusionsDPM is a useful tool for tracing real and individual diagnostic processes. The methodological approach with DPM allows further investigations into the underlying cognitive diagnostic processes on a theoretical level and improvement of individual clinical reasoning skills in practice.

The frequent and underrecognised co-occurrence of acute exacerbated COPD and depression warrants screening: a systematic review

Patients with acute exacerbated chronic obstructive pulmonary disease (AECOPD) and concurrent depression suffer significant psychological stress and decreased quality of life. The aim of this study was to collate data, guidelines and recommendations from publications on the screening and management of depressive mood disorders in patients hospitalised with AECOPD. We systematically searched four databases for publications reporting screening or management of depression in patients hospitalised for AECOPD. The identification of articles was based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Out of 1494 original articles screened, 35 met all inclusion criteria. These report a prevalence of depression in AECOPD ranging between 9.5% and 85.6%. Some studies report high postadmission mortality rates for depressive AECOPD patients, and higher readmission rates in depressive versus nondepressive AECOPD patients. Importantly, none of the 35 publications included suggestions on the screening and management of depression in AECOPD. Depression and AECOPD frequently co-occur, and this worsens outcomes. Yet we did not find recommendations on management, and few interventional studies. Patients hospitalised with AECOPD should be systematically screened for depression and treatment recommendations should be developed for these patients. Randomised studies on how to screen and treat depression in hospitalised AECOPD are necessary. Patients hospitalised for AECOPD should be screened for depression and treatment recommendations should be developed http://ow.ly/p1g430bspOA