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Theresa Mallick-Searle,1,* Jeremy A Adler2,* 1Division Pain Medicine, Stanford Health Care, Redwood City, CA, USA; 2Pacific Pain Medicine Consultants, Encinitas, CA, USA*These authors contributed equally to this workCorrespondence: Jeremy A Adler, Pacific Pain Medicine Consultants, 477 N El Camino Real, Suite B301, Encinitas, CA, 92024, USA, Tel +1 760 753 1104, Fax +1 760 943 6494, Email jadler@pacificpainmed.comAbstract: Painful diabetic peripheral neuropathy (DPN) is a highly prevalent and disabling complication of diabetes that is often misdiagnosed and undertreated. The management of painful DPN involves treating its underlying cause via lifestyle modifications and intensive glucose control, targeting its pathogenesis, and providing symptomatic pain relief, thereby improving patient function and health-related quality of life. Four pharmacologic options are currently approved by the US Food and Drug Administration (FDA) to treat painful DPN. These include three oral medications (duloxetine, pregabalin, and tapentadol extended release) and one topical agent (capsaicin 8% topical system). More recently, the FDA approved several spinal cord stimulation (SCS) devices to treat refractory painful DPN. Although not FDA-approved specifically to treat painful DPN, tricyclic antidepressants, serotonin/norepinephrine reuptake inhibitors, gabapentinoids, and sodium channel blockers are common first-line oral options in clinical practice. Other strategies may be used as part of individualized comprehensive pain management plans. This article provides an overview of the most recent US guidelines for managing painful DPN, with a focus on the two most recently approved treatment options (SCS and capsaicin 8% topical system), as well as evidence for using FDA-approved and guideline-supported drugs and devices. Also discussed are unmet needs for this patient population, and evidence for potential future treatments for painful DPN, including drugs with novel mechanisms of action, electrical stimulation devices, and nutraceuticals.Keywords: neuropathic, pain, painful diabetic peripheral neuropathy, treatment, guidelines, diabetic nerve pain

Jeremy A Adler,1 Theresa Mallick-Searle2 1Pacific Pain Medicine Consultants, Encinitas, CA, USA; 2Division of Pain Medicine, Stanford Outpatient Medical Center, Redwood City, CA, USA Abstract: Despite advances in the treatment of severe intractable pain, opioids remain a critical and appropriate component of treatment. However, abuse, misuse, and diversion of prescription opioids are significant public health concerns. Opioid abuse-deterrent formulations (ADFs) are one component of an opioid risk management plan to manage patient’s pain relief and quality of life while offering some protection against potentially harmful consequences of opioids from misuse and abuse. Opioid ADFs are designed to make manipulation more difficult and administration via non-oral routes less appealing. There are currently nine extended-release and one immediate-release opioid pain medications with US Food and Drug Administration-approved ADF labeling. All use physical/chemical barriers or agonist/antagonist combinations to deter manipulation and abuse. Evidence suggests that opioid ADFs decrease rates of abuse and diversion of opioids in the USA; however, some opioid ADFs are not yet commercially available or have not been on the market long enough to undergo post-marketing data analyses. Opioid ADFs along with the use of prescription drug monitoring programs, clinical assessment tools, toxicology testing, and co-prescribing of naloxone are all tools that can be used to reduce opioid abuse. Patient education on the risks of abuse and diversion is vital and includes a discussion of appropriate use of medication and proper storage. Physician assistants and nurse practitioners are on the “front lines” in battling opioid abuse and serve a key role in recognizing and mitigating the risks of prescription opioid diversion, abuse, and misuse (intentional and unintentional) and in identifying patients at risk for abuse while still providing pain relief to patients. Keywords: abuse, abuse-deterrent, diversion, misuse, opioid

Jeremy A Adler,1 Neona M Lotz2 1Pacific Pain Medicine Consultants, Encinitas, 2Cypress Ambulatory Surgery Center, Santa Maria, CA, USA Objective: Physician assistants (PAs), nurse practitioners (NPs), and registered nurses (RNs) provide professional services on pain management teams. This review provides an overview of the practical management of chronic pain with intrathecal (IT) therapy using an interprofessional approach (eg, physicians and other health care professionals), with a focus on the contributions of PAs, NPs, and RNs.Methods: Narrative review based on literature searches of the Medline database and treatment guidelines on the use of IT therapy in the management of patients with chronic pain.Results: The specific roles and responsibilities of PAs, NPs, and RNs in the management of patients receiving IT therapy vary by practice. In many pain treatment centers, PAs, NPs, and RNs are responsible for patient education, postimplant maintenance, and ongoing supportive care of patients receiving IT therapy. Topics that we address include patient selection, patient expectations and goal setting, medication selection, outcome assessment, and treatment adjustment. Currently, morphine and ziconotide (a nonopioid, selective N-type calcium channel blocker) are the only agents approved by the US Food and Drug Administration for IT analgesia. We provide relevant information on the dosing, titration, and adverse effect management of these medications for PAs, NPs, and RNs responsible for administering IT therapy.Conclusion: PAs, NPs, and RNs are valuable members of IT pain management teams. Treatment success requires ongoing monitoring of efficacy and adverse effects, with corresponding adjustments to medication selection and dosing, in addition to good communication among the health care professionals involved in patient care. Keywords: chronic pain, implantable drug delivery system, morphine, patient education, ziconotide

The programme of the German Congress for Laboratory Medicine 2022 was essentially designed by the divisions of the German Society for Clinical Chemistry and Laboratory Medicine (DGKL). Almost all chairpersons of the divisions organised a 90-min symposium on current topics, i.e. conceptualised the symposia and invited speakers. For this article all chairpersons summarised the lectures that were given within the symposia. The DGKL’s work is structured into 5 areas of expertise: Molecular Diagnostics, Learning & Teaching, Quality & Management, Laboratory & Diagnostics and Biobanks & Informatics. The areas of expertise are in turn subdivided into divisions. About the history of the establishment of this new structure within the DGKL you can find information in the editorial of this issue.

Even though most physicians and professionals in laboratory medicine have received basic training in statistics, experience shows that a general understanding of data analysis is not yet available on a broad scale. Therefore, data literacy, data-driven decision making, and computational thinking should be implemented in future educational training. To evaluate the state of digital competence among young scientists (YS) in laboratory medicine, we launched a worldwide online survey.

In many areas of healthcare, digitization has progressed only slowly so far. The SARS-CoV-2 pandemic in particular has shown how valuable software solutions that are deployable at short notice, can be. In this review we present some selected possibilities of the easy-to-learn programming language R and demonstrate potential applications of the package Shiny in the fields of statistical analysis and laboratory medicine. In addition to a brief tabular overview of published applications, we present two examples of their use in routine laboratory workflows. The first example demonstrates how a Shiny app can be used to estimate the minimal difference (MD) of laboratory analytes, while the second example illustrates how pre- and post-analytical processing steps can be integrated into a fully automated workflow using R and the Shiny package.

Importance: Despite the broad adoption and optimization of electronic health record (EHR) systems across the continuum of care, serious usability and safety problems persist., Objective: To assess whether EHR safety performance is associated with EHR frontline user experience in a national sample of hospitals., Design, Setting, and Participants: This cross-sectional study included all US adult hospitals that used the National Quality Forum Leapfrog Health IT Safety Measure and also used the ARCH Collaborative EHR User experience survey from January 1, 2017, to January 1, 2019. Data analysis was performed from September 2020 to November 2022., Main Outcomes and Measures: The primary outcomes were hospital performance on the Leapfrog Health IT Safety measure (overall and 10 subcomponents) and the ARCH collaborative frontline user experience scores (overall and 8 subcomponents). Ordinary least squares models with survey responses clustered by hospital were used to assess associations between the overall measures and their subcomponents., Results: There were 112 hospitals and 5689 frontline user surveys included in the study. Hospitals scored a mean of 0.673 (range, 0.297-0.973) on the Leapfrog Health IT safety measure; the mean ARCH EHR user experience score was 3.377 (range, 1 [best] to 5 [worst]). The adjusted β coefficient between the overall safety score and overall user experience score was 0.011 (95% CI, 0.006-0.016). The ARCH overall score was also significantly associated with 10 subcategory scores of the Leapfrog Health IT safety score, and the overall Leapfrog score was associated with the 8 subcategory scores of the ARCH user experience score., Conclusions and Relevance: This cross-sectional study found a positive association between frontline user-rated EHR usability and EHR safety performance. This finding suggests that improving EHR usability, which is a current well-known pain point for EHR users, could have direct benefits in terms of improved EHR safety.

Kienbock's disease is a progressive condition characterized by lunate collapse, carpal instability, and eventually perilunate arthritis. Etiology is likely multifactorial, including vascular and anatomic or osseus causes. In cases of advanced disease, disabling pain, limited motion, and decreased grip strength may be present. The preferred treatment options for the nonreconstructable wrist are proximal row carpectomy (PRC), total wrist arthrodesis, and total wrist arthroplasty (TWA). In the following chapter, we will discuss various surgical options for patients with advanced Kienbock's disease., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction: The purpose of this study was to assess the added clinical value of oblique knee radiographs four-view (4V) compared to orthogonal anteroposterior (AP) and lateral radiographs in a two-view (2V) series., Methods: We obtained 200 adult, 4V knee radiographs in 200 patients in the ED and randomly divided them into two groups with 100 series in each group. Ten reviewers - three musculoskeletal radiologists and seven orthopedic surgeons - performed radiograph analyses. These reviewers were randomly divided evenly into group one and group two. Reviewers were blinded to patient data and first reviewed 2V radiographs (AP/lateral) only, and then reviewed 4V radiographs, including AP/lateral, and two additional oblique views for the same patients at least four weeks later. Acute pathology identification and the need for further imaging was assessed for all reviewers, and clinical decision-making (operative vs nonoperative treatment, need for admission, need for additional imaging) was assessed only by the seven orthopaedic surgeon reviewers., Results: Mean sensitivity for pathology identification was 79% with 2V and 81% with 4V (P =0.25). Intra-observer kappa value was 0.81 (range 0.54-1.00). Additional oblique radiographs led orthopaedic reviewers to change their treatment recommendations in 62/329 patients (18.84%) (P <0.001). Eight of 329 radiographic series were identified as "critical misses." (2.43%) (P =0.004), when pathology was reported as normal or reviewers recommended nonoperative treatment on 2V radiographs but changed their recommendation to operative management after the addition of oblique radiographs. The number needed to treat (NNT) for any treatment change and for "critical misses" was 83 and 643, respectively., Conclusion: Although the addition of oblique radiographs may improve a clinician's ability to identify subtle pathologic findings not identified on 2V, it rarely leads to significant changes in treatment recommendations. Given the high NNT, limiting the usage of these oblique radiographs in the general patient population may reduce costs without significantly affecting patient care.

Background: Pulmonary hypertension is a significant risk factor in patients undergoing surgery. The combined effects of general anaesthesia and positive pressure ventilation can aggravate this condition and cause increased pulmonary blood pressures, reduced systemic blood pressures and ventricular contractility. Although perioperative use of inotropic support or vasopressors is almost mandatory for these patients, preference is disputed. In this study, we investigated the effects of norepinephrine and dobutamine and their ability to improve the arterio-ventricular relationship and haemodynamics in pigs suffering from chronic pulmonary hypertension., Method: Pulmonary hypertension was induced in five pigs by banding the pulmonary artery at 2-3 weeks of age. Six pigs served as controls. After 16 weeks of pulmonary artery banding, the animals were re-examined under general anaesthesia using biventricular conductance catheters and a pulmonary artery catheter. After baseline measurements, the animals were exposed to both norepinephrine and dobutamine infusions in incremental doses, with a stabilising period in between the infusions. The hypothesis of differences between norepinephrine and dobutamine with incremental doses was tested using repeated two-way ANOVA and Bonferroni multiple comparisons post-test., Results: At baseline, pulmonary artery-banded animals had increased right ventricular pressure (+ 39%, p = 0.04), lower cardiac index (- 23% p = 0.04), lower systolic blood pressure (- 13%, p = 0.02) and reduced left ventricular end-diastolic volume (- 33%, p = 0.02). When incremental doses of norepinephrine and dobutamine were administered, the right ventricular arterio-ventricular coupling was improved only by dobutamine (p < 0.05). Norepinephrine increased both left ventricular end-diastolic volume and left ventricular contractility to a greater extent (p < 0.05) in pulmonary artery-banded animals. While the cardiac index was improved equally by norepinephrine and dobutamine treatments in pulmonary artery-banded animals, norepinephrine had a significantly greater effect on mean arterial pressure (p < 0.05) and diastolic arterial pressure (p < 0.05)., Conclusion: While norepinephrine and dobutamine improved cardiac index equally, it was obtained in different manners. Dobutamine significantly improved the right ventricular function and the arterio-ventricular coupling. Norepinephrine increased systemic resistance, thereby improving arterial pressures and left ventricular systolic function by maintaining left ventricular end-diastolic volume.

Pronator syndrome (PS) is a compressive neuropathy of the median nerve in the proximal forearm, with symptoms that often overlap with carpal tunnel syndrome (CTS). Because electrodiagnostic studies are often negative in PS, making the correct diagnosis can be challenging. All patients should be initially managed with nonsurgical treatment, but surgical intervention has been shown to result in satisfactory outcomes. Several surgical techniques have been described, with most outcomes data based on retrospective case series. It is essential for clinicians to have a thorough understanding of median nerve anatomy, possible sites of compression, and characteristic clinical findings of PS to provide a reliable diagnosis and treat their patients., (Copyright © 2020 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.)

Background and Aim: This study aimed to assess right ventricular (RV) function during cardiogenic shock due to acute left ventricular (LV) failure, including during LV unloading with Impella CP and an added moderate dose of norepinephrine., Methods: Cardiogenic shock was induced by injecting microspheres in the left main coronary artery in 18 adult Danish Landrace pigs. Conductance catheters were placed in both ventricles and pressure-volume loops were recorded simultaneously., Results: Cardiogenic shock due to LV failure also impaired RV performance, which was partially restored during haemodynamic support with Impella CP, as demonstrated by changes in the ventriculo-arterial coupling (Ea/Ees ratio) (baseline (median [Q1;Q3]) 1.2 [1.1;1.6]), cardiogenic shock (3.0 [2.4;4.5]), Impella CP (2.1 [1.3;2.7]) (p Baseline vs CS < 0.0001, p CS vs Impella = 0.001)). Impella CP support also improved RV stroke work (SW) (cardiogenic shock 333 [263;530] vs Impella CP (830 [717;1121]) (p < 0.001). Moderate norepinephrine infusion concomitant with Impella CP further improved RV SW (Impella CP (818 [751;1065]) vs Impella CP+moderate norepinephrine (1231 [1142;1335]) (p = 0.01)) but at the expense of an increase in LV SW (Impella CP (858 [555;1392]) vs Impella CP+moderate norepinephrine (2101 [1024;2613]) (p = 0.04))., Conclusions: The Impella CP provided efficient LV unloading, improved RV function, and end-organ perfusion. Moderate doses of norepinephrine during Impella support further improved RV function, but at the expense of an increase in SW of the failing LV.

Aims: Early detection of heart failure is important for timely treatment. During the development of heart failure, adaptive intracellular metabolic processes that evolve prior to macro-anatomic remodelling, could provide an early signal of impending failure. We hypothesized that metabolic imaging with hyperpolarized magnetic resonance would detect the early development of heart failure before conventional echocardiography could reveal cardiac dysfunction., Methods and Results: Five 8.5 kg piglets were subjected to pulmonary banding and subsequently examined by [1-13C]pyruvate hyperpolarization, conventional magnetic resonance imaging, echocardiography, and blood testing, every 4 weeks for 16 weeks. They were compared with a weight matched, healthy control group. Conductance catheter examination at the end of the study showed impaired right ventricular systolic function along with compromised left ventricular diastolic function. After 16 weeks, we saw a significant decrease in the conversion ratio of pyruvate/bicarbonate in the left ventricle from 0.13 (0.04) in controls to 0.07 (0.02) in animals with pulmonary banding, along with a significant increase in the lactate/bicarbonate ratio to 3.47 (1.57) compared with 1.34 (0.81) in controls. N-terminal pro-hormone of brain natriuretic peptide was increased by more than 300%, while cardiac index was reduced to 2.8 (0.95) L/min/m2 compared with 3.9 (0.95) in controls. Echocardiography revealed no changes., Conclusion: Hyperpolarization detected a shift towards anaerobic metabolism in early stages of right ventricular dysfunction, as evident by an increased lactate/bicarbonate ratio. Dysfunction was confirmed with conductance catheter assessment, but could not be detected by echocardiography. Hyperpolarization has a promising future in clinical assessment of heart failure in both acquired and congenital heart disease., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Several antineoplastic drugs have been proposed as new compounds for pulmonary arterial hypertension treatment but many have cardiotoxic side effects. The chemotherapeutic agent 6-mercaptopurine may have an effect in treatment of pulmonary arterial hypertension but at the same time, its effects on the afterload adaption of the right ventricle is unpredictable due to interaction with multiple downstream signalling pathways in the cardiomyocytes. We investigated the direct cardiac effects of 6-mercaptopurine in rats with isolated right heart failure caused by pulmonary trunk banding (PTB)., Methods: Male Wistar rat weanlings (112±2 g) were randomized to sham operation (sham, n = 10) or PTB. The PTB animals were randomized to placebo (PTB-control, n = 10) and 6-mercaptopurine (7.5 mg/kg/day) groups with treatment start before the PTB procedure (PTB-prevention, n = 10) or two weeks after (PTB-reversal, n = 10). Right ventricular effects were evaluated by echocardiography, cardiac MRI, invasive pressure-volume measurements, and histological and molecular analyses., Results: PTB increased right ventricular afterload and caused right ventricular hypertrophy and failure. 6-mercaptopurine did not improve right ventricular function nor reduce right ventricular remodelling in both prevention and reversal studies compared with placebo-treated rats., Conclusion: Treatment with 6-mercaptopurine did not have any beneficial or detrimental effects on right ventricular function or remodelling. Our data suggest that treatment of pulmonary arterial hypertension with 6-mercaptopurine is not harmful to the failing right ventricle., Competing Interests: The authors have declared that no competing interests exist.

Background: Combined angiotensin II receptor antagonism and neprilysin inhibition by LCZ696 reduces morbidity and mortality in heart failure patients and works by reducing RAAS activity and increasing cGMP levels. This study aims to evaluate the effects of LCZ696 in rats with pulmonary hypertension and right ventricular (RV) failure., Methods: Pulmonary hypertension was induced in rats (n = 34) by combined exposure to the vascular endothelial growth factor-receptor antagonist SU5416 and hypoxia (SuHx). To distinguish pulmonary vascular from cardiac effects, isolated RV failure was induced by pulmonary trunk banding (PTB) in another group of rats (n = 40). In both models, the development of RV dysfunction was verified before randomization to treatment with LCZ696 (60 mg/kg/day) or vehicle for five weeks., Results: In the SuHx rats, LCZ696 treatment reduced the increase in RV pressure and the development of RV hypertrophy and RV dilatation compared with vehicle treatment. LCZ696 also reduced wall thickness of the smaller pulmonary arteries. In the PTB rats, LCZ696 treatment did not have any effects on RV hypertrophy or function., Conclusions: Combined angiotensin II receptor antagonism and neprilysin inhibition reduced RV systolic pressure, hypertrophy, and dilatation in rats with pulmonary hypertension. These effects seem secondary to pulmonary vascular changes, including reduced pulmonary vascular remodeling, as similar effects were not seen in rats with isolated RV failure. LCZ696 may have a therapeutic potential in the treatment of pulmonary hypertension., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Many obstacles must be overcome to generate new biomedical knowledge from real-world data and then directly apply the newly generated knowledge for decision support. Attempts to bridge the processes of data analysis and technical implementation of analytic results reveal a number of gaps. As one example, the knowledge format used to communicate results from data analysis often differs from the knowledge format required by systems to compute advice. We asked whether a shared format could be used by both processes. To address this question, we developed a data-to-advice pipeline called ScriptNumerate. ScriptNumerate analyzes historical e-prescription data and communicates its results in a compound digital object format. ScriptNumerate then uses these same compound digital objects to compute its advice about whether new e-prescriptions have common, rare, or unprecedented instructions. ScriptNumerate demonstrates that data-to-advice pipelines are feasible. In the future, data-to-advice pipelines similar to ScriptNumerate may help support Learning Health Systems.

Introduction: Drug-induced exanthems are commonly associated with NSAIDs, antibiotics, and anti-epileptics. Pancrelipase is frequently used for conditions resulting in pancreatic exocrine insufficiency. Published case reports of pancrelipase hypersensitivity focus on the respiratory manifestations., Case Report: Here we report a case of skin hypersensitivity resulting from pancrelipase use. To further assess this association, we used a Naranjo nomogram, which determines the likelihood that an adverse drug reaction is the result of the drug itself. Our patient had a score of seven, suggesting our patient had a probably adverse drug reaction., Discussion: As pancrelipase is a commonly prescribed drug, clinicians should be aware of the potential hypersensitivity skin reactions associated with pancrelipase., Competing Interests: Conflict of Interest Statement There are no conflicts of interest and no financial or material support.

Objective: To develop consensus recommendations on urine drug monitoring (UDM) in patients with chronic pain who are prescribed opioids., Methods: An interdisciplinary group of clinicians with expertise in pain, substance use disorders, and primary care conducted virtual meetings to review relevant literature and existing guidelines and share their clinical experience in UDM before reaching consensus recommendations., Results: Definitive (e.g., chromatography-based) testing is recommended as most clinically appropriate for UDM because of its accuracy; however, institutional or payer policies may require initial use of presumptive testing (i.e., immunoassay). The rational choice of substances to analyze for UDM involves considerations that are specific to each patient and related to illicit drug availability. Appropriate opioid risk stratification is based on patient history (especially psychiatric conditions or history of opioid or substance use disorder), prescription drug monitoring program data, results from validated risk assessment tools, and previous UDM. Urine drug monitoring is suggested to be performed at baseline for most patients prescribed opioids for chronic pain and at least annually for those at low risk, two or more times per year for those at moderate risk, and three or more times per year for those at high risk. Additional UDM should be performed as needed on the basis of clinical judgment., Conclusions: Although evidence on the efficacy of UDM in preventing opioid use disorder, overdose, and diversion is limited, UDM is recommended by the panel as part of ongoing comprehensive risk monitoring in patients prescribed opioids for chronic pain., (© 2017 American Academy of Pain Medicine.)

Background: Pleural effusion (PLE) may lead to low blood pressure and reduced cardiac output. Low blood pressure and reduced cardiac output are often treated with fluid loading and vasopressors. This study aimed to determine the impact of fluid loading and norepinephrine infusion on physiologic determinants of cardiac function obtained by ultrasonography during PLE., Methods: In this randomised, blinded, controlled laboratory study, 30 piglets (21.9 ± 1.3 kg) had bilateral PLE (75 mL/kg) induced. Subsequently, the piglets were randomised to intervention as follows: fluid loading (80 mL/kg/h for 1.5 h, n = 12), norepinephrine infusion (0.01, 0.03, 0.05, 0.1, 0.2 and 0.3 μg/kg/min (15 min each, n = 12)) or control (n = 6). Main outcome was left ventricular preload measured as left ventricular end-diastolic area. Secondary endpoints included contractility and afterload as well as global measures of circulation. All endpoints were assessed with echocardiography and invasive pressure-flow measurements., Results: PLE decreased left ventricular end-diastolic area, mean arterial pressure and cardiac output (p values < 0.001), but fluid loading (20 mL/kg) and norepinephrine infusion (0.05 μg/kg/min) restored these values (p values > 0.05) to baseline. Left ventricular contractility increased with norepinephrine infusion (p = 0.002), but was not affected by fluid loading (p = 0.903). Afterload increased in both active groups (p values > 0.001). Overall, inferior vena cava distensibility remained unchanged during intervention (p values ≥ 0.085). Evacuation of PLE caused numerical increases in left ventricular end-diastolic area, but only significantly so in controls (p = 0.006)., Conclusions: PLE significantly reduced left ventricular preload. Both fluid and norepinephrine treatment reverted this effect and normalised global haemodynamic parameters. Inferior vena cava distensibility remained unchanged. The haemodynamic significance of PLE may be underestimated during fluid or norepinephrine administration, potentially masking the presence of PLE.

Background: The association between Staphylococcus haemolyticus and severe nosocomial infections is increasing. However, the extent to which fomites contribute to the dissemination of this pathogen through patients and hospital wards remains unknown., Objectives: In the present study, sphygmomanometers and thermometers were evaluated as potential fomites of oxacillin-resistant S. haemolyticus (ORSH). The influence of oxacillin and vancomycin on biofilm formation by ORSH strains isolated from fomites was also investigated., Methods: The presence of ORSH on swabs taken from fomite surfaces in a Brazilian hospital was assessed using standard microbiological procedures. Antibiotic susceptibility profiles were determined by the disk diffusion method, and clonal distribution was assessed in pulsed-field gel electrophoresis (PFGE) assays. Minimum inhibitory concentrations (MICs) of oxacillin and vancomycin were evaluated via the broth microdilution method. Polymerase chain reaction (PCR) assays were performed to detect the mecA and icaAD genes. ORSH strains grown in media containing 1/4 MIC of vancomycin or oxacillin were investigated for slime production and biofilm formation on glass, polystyrene and polyurethane catheter surfaces., Findings: ORSH strains comprising five distinct PFGE types were isolated from sphygmomanometers (n = 5) and a thermometer (n = 1) used in intensive care units and surgical wards. ORSH strains isolated from fomites showed susceptibility to only linezolid and vancomycin and were characterised as multi-drug resistant (MDR). Slime production, biofilm formation and the survival of sessile bacteria differed and were independent of the presence of the icaAD and mecA genes, PFGE type and subtype. Vancomycin and oxacillin did not inhibit biofilm formation by vancomycin-susceptible ORSH strains on abiotic surfaces, including on the catheter surface. Enhanced biofilm formation was observed in some situations. Moreover, a sub-lethal dose of vancomycin induced biofilm formation by an ORSH strain on polystyrene., Main Conclusions: Sphygmomanometers and thermometers are fomites for the transmission of ORSH. A sub-lethal dose of vancomycin may favor biofilm formation by ORSH on fomites and catheter surfaces.

Objectives: Myocardial infarction and chronic heart failure induce specific metabolic changes in the neonatal myocardium that are closely correlated to outcome. The aim of this study was to examine the metabolic responses to noninfarct heart failure and inotropic treatments in the newborn heart, which so far are undetermined., Design: A total of 28 newborn pigs were instrumented with a microdialysis catheter in the right ventricle, and intercellular citric acid cycle intermediates and adenosine metabolite concentrations were determined at 20-minute intervals. Stunning was induced by 10 cycles of 3 minutes of ischemia, which was performed by occluding the right coronary artery, followed by 3 minutes of reperfusion. Animals were randomized for treatment with epinephrine + milrinone, dopamine + milrinone, dobutamine, or saline., Setting: University hospital animal laboratory., Main Results: Ischemia-reperfusion induced right ventricular stunning and increased the concentrations of pyruvate lactate, succinate, malate, hypoxanthine, and xanthine (all, p < 0.01). During inotrope infusion, no differences in metabolite concentrations were detected between the treatment groups. In nonsurviving animals (n = 8), concentrations of succinate (p < 0.0001), malate (p = 0.009), and hypoxanthine (p = 0.04) increased compared with survivors, while contractility was significantly reduced (p = 0.03)., Conclusions: Accumulation of citric acid cycle intermediates and adenosine metabolites reflects the presence of myocardial stunning and predicts mortality in acute noninfarct right ventricular heart failure in newborn pigs. This phenomenon occurs independently of the type of inotrope, suggesting that citric acid cycle intermediates represent potential markers of acute noninfarct heart failure.

Corynebacterium diphtheriae strains continue to circulate worldwide causing diphtheria and invasive diseases, such as endocarditis, osteomyelitis, pneumonia and catheter-related infections. Presumptive C. diphtheriae infections diagnosis in a clinical microbiology laboratory requires a primary isolation consisting of a bacterial culture on blood agar and agar containing tellurite (TeO3(2-)). In this study, nine genome sequenced and four unsequenced strains of C. diphtheriae from different sources, including three samples from a recent outbreak in Brazil, were characterized with respect to their growth properties on tellurite-containing agar. Levels of tellurite-resistance (Te(R)) were evaluated by determining the minimum inhibitory concentrations of potassium tellurite (K2TeO3) and by a viability reduction test in solid culture medium with K2TeO3. Significant differences in Te(R) levels of C. diphtheriae strains were observed independent of origin, biovar or presence of the tox gene. Data indicated that the standard initial screening with TeO3(2-)-selective medium for diphtheria bacilli identification may lead to false-negative results in C. diphtheriae diagnosis laboratories.

Right ventricular failure (RVF) secondary to pulmonary regurgitation (PR) impairs right ventricular (RV) function and interrupts the interventricular relationship. There are few recommendations for the medical management of severe RVF after prolonged PR. PR was induced in 16 Danish landrace pigs by plication of the pulmonary valve leaflets. Twenty-three pigs served as controls. At reexamination the effect of milrinone, epinephrine, and dopamine was evaluated using biventricular conductance and pulmonary catheters. Seventy-nine days after PR was induced, RV end-diastolic volume index (EDVI) had increased by 33% (P = 0.006) and there was a severe decrease in the load-independent measurement of contractility (PRSW) (-58%; P = 0.003). Lower cardiac index (CI) (-28%; P < 0.0001), mean arterial pressure (-15%; P = 0.01) and mixed venous oxygen saturation (SvO2) (36%; P < 0.0001) were observed compared with the control group. The interventricular septum deviated toward the left ventricle (LV). Milrinone improved RV-PRSW and CI and maintained systemic pressure while reducing central venous pressure (CVP). Epinephrine and dopamine further improved biventricular PRSW and CI equally in a dose-dependent manner. Systemic and pulmonary pressures were higher in the dopamine-treated animals compared with epinephrine-treated animals. None of the treatments improved stroke volume index (SVI) despite increases in contractility. Strong correlation was detected between SVI and LV-EDVI, but not SVI and biventricular contractility. In RVF due to PR, milrinone significantly improved CI, SvO2, and CVP and increased contractility in the RV. Epinephrine and dopamine had equal inotropic effect, but a greater vasopressor effect was observed for dopamine. SV was unchanged due to inability of both treatments to increase LV-EDVI., (Copyright © 2015 the American Physiological Society.)

Corynebacterium diphtheriae, the aetiologic agent of diphtheria, also represents a global medical challenge because of the existence of invasive strains as causative agents of systemic infections. Although tellurite (TeO32-) is toxic to most microorganisms, TeO32--resistant bacteria, including C. diphtheriae, exist in nature. The presence of TeO32--resistance (TeR) determinants in pathogenic bacteria might provide selective advantages in the natural environment. In the present study, we investigated the role of the putative TeR determinant (CDCE8392&#95;813gene) in the virulence attributes of diphtheria bacilli. The disruption of CDCE8392&#95;0813 gene expression in the LDCIC-L1 mutant increased susceptibility to TeO32- and reactive oxygen species (hydrogen peroxide), but not to other antimicrobial agents. The LDCIC-L1 mutant also showed a decrease in both the lethality of Caenorhabditis elegans and the survival inside of human epithelial cells compared to wild-type strain. Conversely, the haemagglutinating activity and adherence to and formation of biofilms on different abiotic surfaces were not regulated through the CDCE8392&#95;0813 gene. In conclusion, the CDCE8392&#95;813 gene contributes to the TeR and pathogenic potential of C. diphtheriae.

Right ventricular (RV) failure due to chronic pressure overload is a main determinant of outcome in congenital heart disease. Medical management is challenging because not only contractility but also the interventricular relationship is important for increasing cardiac output. This study evaluated the effect of milrinone alone and in combination with epinephrine or dopamine on hemodynamics, ventricular performance, and the interventricular relationship. RV failure was induced in 21 Danish landrace pigs by pulmonary artery banding. After 10 wk, animals were reexamined using biventricular pressure-volume conductance catheters. The maximum pressure in the RV increased by 113% (P < 0.0001) and end-diastolic volume by 43% (P < 0.002), while left ventricular (LV) pressure simultaneously decreased (P = 0.006). Concomitantly, mean arterial pressure (MAP; -16%, P = 0.01), cardiac index (CI; -23%, P < 0.0001), and mixed venous oxygen saturation (SvO2 ; -40%, P < 0.0001) decreased. Milrinone increased CI (11%, P = 0.008) and heart rate (HR; 21%, P < 0.0001). Stroke volume index (SVI) decreased (7%, P = 0.03), although RV contractility was improved. The addition of either epinephrine or dopamine further increased CI and HR in a dose-dependent manner but without any significant differences between the two interventions. A more pronounced increase in biventricular contractility was observed in the dopamine-treated animals. LV volume was reduced in both the dopamine and epinephrine groups with increasing doses In the failing pressure overloaded RV, milrinone improved CI and increased contractility. Albeit additional dose-dependent effects of both epinephrine and dopamine on CI and contractility, neither of the interventions improved SVI due to reduced filling of the LV., (Copyright © 2015 the American Physiological Society.)

Through interference with free radicals, the nitroxide tempol potentially increases bioavailability of nitric oxide (NO) and along with modulation of potassium channels reduces blood pressure (BP). We studied whether tempol in pigs lowers BP by mechanisms sensitive to inhibition of NO synthase or large conductance calcium-activated potassium channels (BKCa). The cardiovascular effects of intravenous tempol (25-50mg/kg) were examined in anesthetized pigs with myocardial function being evaluated by echocardiography. While saline-treated animals remained hemodynamically stable, tempol induced fast, dose-dependent and transient reductions in BP lasting 5-10 min with a simultaneous impairment of left ventricular contraction. Pretreatment with the NO synthase (NOS) inhibitor N(G)-nitro-l-arginine methyl ester (l-NAME, 4 mg/kg) or a blocker of BKCa (tetraethylammonium (TEA), 100mg/h) increased baseline BP but also enhanced BP reductions to tempol. Isolated myocardial trabeculae subjected to an identical protocol also demonstrated dose-related reductions in contractility to tempol. This effect was not affected by l-NAME, but attenuated by TEA. In isolated mesenteric resistance arteries contracted with noradrenaline, tempol caused small postjunctional l-NAME sensitive relaxations, while neurogenic contractions were inhibited by tempol by TEA-sensitive mechanisms and mechanisms insensitive to TEA and l-NAME. In conclusion intravenous tempol induces fast transient reductions in BP associated with simultaneous reductions in myocardial contraction. Tempol exerts direct negative inotropic effects which are partly sensitive to BKCa-blockade but independent of NOS inhibition. In addition tempol has direct vasodilatory effects despite NOS and potassium channel blockade. The negative inotropic and hypotensive effects raise concerns using tempol, or structurally similar drugs, for intravenous use., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Oxacillin-resistant Staphylococcus haemolyticus (ORSH) was found as the most prevalent (77.5%) species of coagulase-negative staphylococci associated with bacteremia in neonates making use of intravenous catheters in an intensive care unit of a Brazilian teaching hospital. Thirty-one blood isolates were confirmed as S. haemolyticus by sequencing of the 16S and clustered in 6 pulsed-field gel electrophoresis types (with 58% of the strains belonging to 2 predominant types B and D). S. haemolyticus was mostly oxacillin-resistant (90.3%) displaying multiresistance profiles (70.4%). However, the mecA gene was undetected in 22.6% strains. ORSH exhibited slime production on Congo-Red agar (67.7%), adherence to polystyrene (96.7%), and glass (87%) surfaces. Interestingly, ica-operon was detected in 58% strains, mostly belonging to the B, D, and F genotypes, which is a significantly higher percentage when compared to other studies conducted at different parts of the globe. Data indicated that ica operon and biofilm-forming ORSH are endemic in Brazilian nosocomial environment., (© 2013.)

There is a high incidence of infections caused by betalactamase-producing Gram-negative microorganisms in Brazil. These organisms are of clinical and epidemiological importance, since their mobile genetic elements facilitate cross-infection. The present study was conducted in sentinel rectal swabs from patients admitted to a cardiac surgery hospital in Rio de Janeiro, from January through December 2007, in a consecutive manner. The aim of the study was to characterize the genotype and phenotype of these isolates from colonized patients. Biochemical tests, antimicrobial susceptibility tests, a confirmatory test for the expression of extended spectrum betalactamase (ESBL) production and polymerase chain reaction for the blaTEM, blaSHV, CTX-M1, Toho-1 and AmpC genes were performed at the University Hospital of Universidade do Estado do Rio de Janeiro (UERJ). The most frequently isolated bacteria were Escherichia coli 9/41 (21.95%) and Klebsiella pneumoniae 14/41 (34.1%). In 24/41 (58%), the ESBL genotype was confirmed. The most prevalent genes in samples that expressed ESBL were blaTEM 13/24 (54%), AmpC 12/24 (50%), blaSHV 6/24 (25%), CTX-M1 7/24 (29%), and Toho-1 6/24 (25%). Of these, 14/24 (58%) presented more than one genotype for the tested primers. In nine (37%) samples other than E. coli, K. pneumoniae or Proteus spp., the phenotype for ESBL was found and confirmed by PCR. The most sensitive substrate in the approximation test in ESBL positive samples was ceftriaxone (83%). Fifty percent of the samples expressed AmpC were associated with other genes. Intermediate susceptibility to ertapenem was found in 2/41 (5%).

The right ventricle (RV) tolerates acute pulmonary valvular regurgitation fairly well, however, in the long-term dilatation and failure often ensues. There is little known of the structural and functional myocardial alterations following this pathophysiology, and therefore animal models are sought. We aimed to develop an animal experimental model for RV dilatation emphasizing feasibility, reproducibility and human compatibility. Free pulmonary valve insufficiency and RV dilatation were created with a novel external suture plication technique in nine 5 kg piglets. Six matched animals served as controls. After 10 weeks cardiac dimensions and physiology were assessed with in vivo cardiovascular MRI and conductance technique. RV end-diastolic volume increased 31% in the intervention group (P=0.03). The regurgitation fraction was 37% in the intervention group compared to -2% in controls (P<0.001). Conductance measurements showed preserved RV contractile function, but significant left ventricular diastolic impairment. This study is the first to show that pulmonary valve regurgitation, RV dilatation and functional impairment can be achieved by external leaflet plication. Compared to known methods, the advantages of this model are: 1) no induction of stenosis over time, 2) no risk of stent migration, and 3) very simple and reproducible.

Unlabelled: Use of chronic opioid therapy for chronic noncancer pain has increased substantially. The American Pain Society and the American Academy of Pain Medicine commissioned a systematic review of the evidence on chronic opioid therapy for chronic noncancer pain and convened a multidisciplinary expert panel to review the evidence and formulate recommendations. Although evidence is limited, the expert panel concluded that chronic opioid therapy can be an effective therapy for carefully selected and monitored patients with chronic noncancer pain. However, opioids are also associated with potentially serious harms, including opioid-related adverse effects and outcomes related to the abuse potential of opioids. The recommendations presented in this document provide guidance on patient selection and risk stratification; informed consent and opioid management plans; initiation and titration of chronic opioid therapy; use of methadone; monitoring of patients on chronic opioid therapy; dose escalations, high-dose opioid therapy, opioid rotation, and indications for discontinuation of therapy; prevention and management of opioid-related adverse effects; driving and work safety; identifying a medical home and when to obtain consultation; management of breakthrough pain; chronic opioid therapy in pregnancy; and opioid-related policies., Perspective: Safe and effective chronic opioid therapy for chronic noncancer pain requires clinical skills and knowledge in both the principles of opioid prescribing and on the assessment and management of risks associated with opioid abuse, addiction, and diversion. Although evidence is limited in many areas related to use of opioids for chronic noncancer pain, this guideline provides recommendations developed by a multidisciplinary expert panel after a systematic review of the evidence.

Background: The sensitivity and specificity of the sodium to potassium ratio (Na:K ratio) as a cutoff for recommendation of an adrenocorticotropic hormone (ACTH) stimulation test in dogs suspected of having hypoadrenocorticism (HA) is unknown. Additionally, abnormalities in plasma ionized calcium (iCa2+) and ionized magnesium (iMg2+) concentrations and venous pH of dogs with HA are incompletely documented., Objectives: To define the sensitivity and specificity of the Na:K ratio as a diagnostic aid for HA in dogs and to examine for associations between venous pH and the Na:K ratio, iCa2+ concentration, or iMg2+ concentration in dogs with HA., Animals: Seventy-six dogs with HA and 200 dogs randomly selected from the general hospital population., Methods: Retrospective study. Dogs were included in the study if results of an ACTH stimulation test confirmed a diagnosis of HA, the dog had a serum sodium concentration below the reference range or a serum potassium concentration above the reference range, and the dog was treated with mineralocorticoids. Receiver operating curve analysis was used to determine optimal cutoffs of sensitivity and specificity for the Na:K ratio in diagnosing HA., Results: Use of Na:K ratios of 27 or 28 classified 95% of dogs correctly as diseased or not diseased. The sensitivity of a Na:K ratio of 28 was 93% (CI, 85-98%) and that of 27 was 89% (CI, 80-95%). The specificity of a Na:K ratio of 28 was 96% (CI, 92-98%) and that of 27 was 97% (CI, 93- 99%). The sensitivity and specificity of a Na:K ratio of 24 were 79% (95% CI, 67-86%) and 100% (98%, CI, 97%-100%), respectively., Conclusions and Clinical Importance: Na:K ratios of 27 or 28 identify the highest percentage of dogs with suspected mineralocorticoid and glucocorticoid deficiency correctly. In dogs with a Na:K ratio of 24 or less, the likelihood of confirming a diagnosis of HA with an ACTH stimulation test is high.

To assess longitudinally the effect of living in the vicinity of coal-fired power stations on children with asthma, 99 schoolchildren with a history of wheezing in the previous 12 months were studied for 1 year, using daily diaries and measurements of air quality. The children had been identified in a cross-sectional survey of two coastal areas: Lake Munmorah (LM), within 5 km of two power stations, and Nelson Bay (NB), free from major industry. Daily air quality [sulphur dioxide (SO2) and nitrogen oxides (NOx)], respiratory symptoms, and treatment for asthma were recorded throughout the year. Measurements of SO2 and NOx at LM were well within recommended guidelines although they were several times higher than at NB: maximum daily levels in SO2 (micrograms/m3) were 26 at LM, 11 at NB (standard, 365); yearly average SO2 was 2 at LM, 0.3 at NB (standard, 60); yearly average NOx (micrograms/m3) was 2 at LM, 0.4 at NB (standard, 94). Marked weekly fluctuations occurred in the prevalence of cough, wheezing, and breathlessness, without any substantial differences between LM and NB. Overall, the prevalence of symptoms was low (10% for wheezing, 20% for any symptom). Whether the daily SO2 and NOx levels affected the occurrence of respiratory symptoms was investigated in children at LM using a logistic regression (Korn and Whittemore technique). For these children as a group, air quality measurements were not associated with the occurrence of symptoms.

Respiratory symptoms, atopy, and bronchial reactivity were measured in primary school children living in Lake Munmorah (LM), a coastal town near two power stations, and in Nelson Bay (NB), a coastal town free from any possible major sources of outdoor air pollution. A prevalence survey and longitudinal follow-up study were performed 1 year apart. In both studies, the prevalence of ever wheezed, current wheezing, breathlessness, wheezing with exercise, diagnosed asthma, and use of drugs for asthma at LM were all approximately double the prevalence at NB (all P values less than 0.01). The prevalence of bronchial reactivity was significantly greater at LM than NB (P less than 0.01) at the first but not the second survey. By contrast, no significant differences were found between the two areas for skin test atopy or for parental history of allergic disease. Multivariate analysis supported the conclusion from the univariate analysis that there was more wheezing at LM compared to NB at both studies, when adjusted for atopy, smoking in the home, age, and sex. As expected, a positive skin test reaction to house dust mite was the predominant explanatory variable. Asthma was more common in the community near power stations (LM) than in the NB area. The absence of significant differences in skin test atopy and parental history of allergic disease argued against major genetic differences between the two groups. By contrast, the more common reporting of siblings' chest disease and asthma in Lake Munmorah supported an environmental cause.

Oxytricha fallax and Stylonychia pustulata possess 6 rows of dorsal bristle units. Each dorsal bristle unit consists of a pair of kinetosomes; the anterior kinetosome has a cilium and the posterior kinetosome a ciliary study. The kinetosome pair, located at the bottom of a cortical pit surrounding the cilium and ciliary stub, is surrounded by an asymmetrical fibrillar mass. Future rows 1-4 are formed from 2 sets of primordia originating within mature dorsal rows 1-3. Rows 5 and 6 originate from the anterior regions of both right marginal cirral primorida. Old dorsal bristle units utilized in formation of primordia are presumably maintained in the new rows of the proter and opisthe; those outside the primordia resorbed. The morphogenetic pattern of the Oxytrichidae is similar to those of the Urostylidae and Holostichidae, but quite different from that of the Euplotidae.