Banff Lung Report: Current knowledge and future research perspectives for diagnosis and treatment of pulmonary antibody-mediated rejection (AMR).

The Lung session of the 2017 14th Banff Foundation for Allograft Pathology Conference, Barcelona focused on the multiple aspects of antibody-mediated rejection (AMR) in lung transplantation. Multidimensional approaches for AMR diagnosis, including classification, histological and immunohistochemical analysis, and donor- specific antibody (DSA) characterization with their current strengths and limitations were reviewed in view of recent research. The group also discussed the role of tissue gene expression analysis in the context of unmet needs in lung transplantation. The current best practice for monitoring of AMR and the therapeutic approach are summarized and highlighted in this report. The working group reached consensus of the major gaps in current knowledge and focused on the unanswered questions regarding pulmonary AMR. An important outcome of the meeting was agreement on the need for future collaborative research projects to address these gaps in the field of lung transplantation.

Voriconazole and squamous cell carcinoma after lung transplantation: A multicenter study.

This study evaluated the independent contribution of voriconazole to the development of squamous cell carcinoma (SCC) in lung transplant recipients, by attempting to account for important confounding factors, particularly immunosuppression. This international, multicenter, retrospective, cohort study included adult patients who underwent lung transplantation during 2005-2008. Cox regression analysis was used to assess the effects of voriconazole and other azoles, analyzed as time-dependent variables, on the risk of developing biopsy-confirmed SCC. Nine hundred lung transplant recipients were included. Median follow-up time from transplantation to end of follow-up was 3.51 years. In a Cox regression model, exposure to voriconazole alone (adjusted hazard ratio 2.39, 95% confidence interval 1.31-4.37) and exposure to voriconazole and other azole(s) (adjusted hazard ratio 3.45, 95% confidence interval 1.07-11.06) were associated with SCC compared with those unexposed after controlling for important confounders including immunosuppressants. Exposure to voriconazole was associated with increased risk of SCC of the skin in lung transplant recipients. Residual confounding could not be ruled out because of the use of proxy variables to control for some confounders. Benefits of voriconazole use when prescribed to lung transplant recipients should be carefully weighed versus the potential risk of SCC. EU PAS registration number: EUPAS5269.

A Low-Voltage, High-Force Capacity Electroadhesive Clutch Based on Ionoelastomer Heterojunctions.

Electroadhesive devices with dielectric films can electrically program changes in stiffness and adhesion, but require hundreds of volts and are subject to failure by dielectric breakdown. Recent work on ionoelastomer heterojunctions has enabled reversible electroadhesion with low voltages, but these materials exhibit limited force capacities and high detachment forces. It is a grand challenge to engineer electroadhesives with large force capacities and programmable detachment at low voltages (<10 V). In this work, tough ionoelastomer/metal mesh composites with low surface energies are synthesized and surface roughness is controlled to realize sub-ten-volt clutches that are small, strong, and easily detachable. Models based on fracture and contact mechanics explain how clutch compliance and surface texture affect force capacity and contact area, which is validated over different geometries and voltages. These ionoelastomer clutches outperform the best existing electroadhesive clutches by fivefold in force capacity per unit area (102 N cm-2 ), with a 40-fold reduction in operating voltage (± 7.5 V). Finally, the ability of the ionoelastomer clutches to resist bending moments in a finger wearable and as a reversible adhesive in an adjustable phone mount is demonstrated.

Antifungal prophylaxis with voriconazole or itraconazole in lung transplant recipients: hepatotoxicity and effectiveness.

Invasive fungal infections (IFI) are common after lung transplantation and there are limited data for the use of antifungal prophylaxis in these patients. Our aim was to compare the safety and describe the effectiveness of universal prophylaxis with two azole regimens in lung transplant recipients. This is a retrospective study in lung transplant recipients from July 2003 to July 2006 who received antifungal prophylaxis with itraconazole or voriconazole plus inhaled amphotericin B to compare the incidence of hepatotoxicity. Secondary outcomes include describing the incidence of IFI, clinical outcomes after IFI and mortality. Sixty-seven consecutive lung transplants received antifungal prophylaxis, 32 itraconazole and 35 voriconazole and inhaled amphotericin B. There were no significant differences between groups in the acute physiology and chronic health evaluation (APACHE) score at the time of transplantation, demographic characteristics, comorbidities and concomitant use of hepatotoxic medications. Hepatotoxicity occurred in 12 patients receiving voriconazole and inhaled amphotericin B and in no patients receiving itraconazole (p < 0.001). There was no significant difference between groups with regard to the percentage of transplants with IFI, but one case of zygomycosis occurred in a transplant treated with voriconazole. Voriconazole prophylaxis after lung transplantation was associated with a higher incidence of hepatotoxicity and similar clinical effectiveness when compared to itraconazole.

An observational study of inhaled-treprostinil respiratory-related safety in patients with pulmonary arterial hypertension.

Inhaled treprostinil (Tyvaso) has been shown to be a safe and effective addition to pulmonary arterial hypertension (PAH) oral therapies; however, the respiratory-related safety profile of inhaled treprostinil required further elucidation in the setting of routine clinical care. The objectives of this study were to characterize respiratory-related adverse events (AEs) associated with current or recent treatment with inhaled treprostinil and to compare the incidence of respiratory-related AEs in PAH patients treated with inhaled treprostinil with that in patients treated with other Food and Drug Administration (FDA)-approved PAH therapies. This was a long-term, prospective, observational study. All respiratory-related AEs were recorded during the study. The number of PAH patients enrolled was 1,333, 666 treated with inhaled treprostinil and 667 controls (treated with an FDA-approved PAH therapy other than inhaled treprostinil), for a total of 958 and 1,094 patient-years of exposure, respectively. In the inhaled-treprostinil group, 1,281 respiratory-related AEs were reported in 403 patients (61%), and in the control group, 1,295 respiratory-related AEs were reported in 388 patients (58%). Cough, throat irritation, nasal discomfort, and hemoptysis were the most common respiratory-related AEs (occurring in ≥2% of patients in either treatment group) that demonstrated a higher number of events per patient-year of exposure in the inhaled-treprostinil group than in the control group (risk ratio [95% confidence interval]: 1.487 [1.172-1.887], 3.777 [2.050-6.956], 2.039 [1.072-3.879], and 1.957 [1.024-3.741], respectively). Overall, inhaled treprostinil was well tolerated by PAH patients in routine clinical care, with respiratory-related AEs consistent with the known safety profile (trial registration: clinicaltrials.gov identifier: NCT01266265).

The decision to discontinue hemodialysis.

The patient who wishes to discontinue chronic hemodialysis poses a complex dilemma that crosses both ethical and psychiatric boundaries, but clearly demonstrates the role of the liaison psychiatrist in clarifying issues of diagnosis and informed consent. This paper presents an edited transcript of a clinical case conference where a 72-year-old man reviews his reasons for demanding that hemodialysis be discontinued. Issues of differential diagnosis and the question of autonomy and free will are discussed in the context of the tasks for the liaison psychiatrist.

Psychiatric aspects of cigarette smoking.

Smoking has been viewed in divergent ways throughout history. While for some cultures it has been considered a crime, for others it has been invested with magical powers and even medicinal potential. In our century, society has come to realize the health risks associated with smoking. This has led to controversies between government and the tobacco industry as well as between physician and patient. In spite of their knowledge of its deadly consequences, many individuals are unable to stop smoking. The tenacity of this habit can be explained in terms of the various psychological motivations for smoking in combination with the physiologic addiction to nicotine. While some people are able to stop the habit, many relapse in spite of a variety of quitting methods. These range from the doctor's advice to stop, education programs, group and individual psychotherapies, behavioral techniques, hypnosis, and the use of nicotine gum. With a growing understanding of what distinguishes categories of smokers and with a new appreciation for the role of nicotine in addiction to smoking, more effective antismoking strategies can be fashioned to meet the specific needs of the potential quitter.

The classic intrafascial Semm hysterectomy as an alternative to abdominal hysterectomy.

STUDY OBJECTIVE: To compare the classic intrafascial Semm hysterectomy (CISH) with abdominal hysterectomy. DESIGN: Retrospective analysis. SETTING: Community hospital. PATIENTS: The first 100 women with intractable uterine bleeding, leiomyomata, and chronic pelvic pain. INTERVENTIONS: The CISH procedure, initially with the Endo GIA stapler, but later, electrocoagulation and suture to lower costs and eliminate automatic staple complications. MEASUREMENTS AND MAIN RESULTS: Operating time for CISH decreased and our ability to remove larger uteri increased as we became more proficient. Complications were limited to one cystotomy and four transfusions. The average hospital stay was 36 hours and most patients were back to normal activity in 3 weeks. CONCLUSION: Our experience suggests that the CISH is organ preserving, is minimally invasive, decreases recovery time, and can be performed in women in whom an open abdominal approach once would have been the only option.

Determination and metabolism of dithiol chelating agents: the zinc chelate of the dimethyl ester of meso-2,3-dimercaptosuccinic acid increase biliary excretion of cadmium and platinum.

meso-2,3-Dimercaptosuccinic acid is an orally active chelating agent useful for the treatment of lead intoxication. Since it is believed to be extracellular in its distribution, analogs have been synthesized in a search for one that will enter the cell and successfully complete for firmly bound intracellular toxic heavy metals such as cadmium and platinum. The biological properties of the zinc chelate of DiMeDMSA, ([Zn(DiMeDMSA)2]2- with tetramethylammonium or sodium as the counterion, have been investigated in the rat. In short-term (hourly) experiments, [Zn(DiMeDMSA)2]2- increased the biliary excretion of cadmium and platinum. In experiments of longer duration (days), severe renal toxicity was noted even in the absence of any exogenously administered cadmium chloride or cis-dichlorodiammineplatinum(II). The zinc content of the kidneys of rats receiving Na2[Zn(DiMeDMSA)2]2- was found to be about 10-fold greater than rats receiving saline or meso-dimethyldimercaptosuccinic acid. Although it appears that the source of the zinc is the injected [Zn(DiMeDMSA)2]2-, at this time it is unknown as to whether the toxicity is due to the Zn chelate molecule, per se, or Zn derived from the molecule after its degradative biotransformation.

Synthesis and properties of the monomethyl ester of meso-dimercaptosuccinic acid and its chelates of lead (II), cadmium(II), and mercury(II).

The monomethyl ester of meso-dimercaptosuccinic acid (MoMeDMSA) and its chelates with lead(II), cadmium(II), and mercury(II) have been synthesized. The mercury(II) chelate of MoMeDMSA is formed by the coordination of the two sulfur atoms in MoMeDMSA, whereas the lead(II) and cadmium(II) chelates are formed by the coordination of one sulfur and one oxygen atom. The solubilities of the chelates are pH dependent; the mercury(II) chelate dissolves when the uncoordinated carboxylic acid dissociates, but the lead(II) and cadmium(II) chelates are solubilized only after the uncoordinated mercapto group is dissociated. The cadmium(II) chelate is dimeric and the lead(II) and mercury(II) chelates are monomeric at the concentrations and conditions used in this study. The acid dissociation constants of the chelating agent and the uncoordinated groups in its metal chelates have been determined in 50% v/v methanol-water. These acid-base properties in addition to the polarity of the chelating agent contribute to the effectiveness in the in vivo mobilization of intracellular in vivo deposits of cadmium. The biliary excretion of cadmium in rats increased by a factor of 173 upon administration of the relatively toxic, nonpolar dimethyl ester of DMSA whereas the administration of the less toxic, more polar monomethyl ester increased the biliary excretion of cadmium by a factor of 63. On the other hand, meso-DMSA which is highly polar and less toxic is known to be without effect on biliary excretion of cadmium. The monomethyl DMSA, therefore, appears to have properties that are intermediate between those of DMSA and its dimethyl ester, as far as both chelating properties and biliary excretion of cadmium are concerned.

Clinical utility of available methods for determining platelet function.

Determination of platelet function has become increasingly important as new antiplatelet drugs are being developed. Objective means to monitor the pharmacological effects of these agents, in order to maximize efficacy and minimize toxicity, is needed. The available methods for determination of platelet function at the current time are reviewed, including platelet aggregometry, the PFA-100, flow cytometry, platelet contractile force, the rapid platelet function assay, the clot signature analyzer, Sonoclot, and thromboelastography. The principle, advantages, disadvantages, and clinical utility of each method is presented. The uses of the various methods of determining platelet function reported in the literature are summarized, in an effort to provide information regarding the applicability of those different methods.

Usefulness of combining necrosis and platelet markers in triaging patients presenting with chest pain to the emergency department.

BACKGROUND: Myocardial injury and platelet activation play important roles in the pathogenesis of unstable coronary syndromes. We sought to determine whether the combined measurement of platelet and necrosis markers would improve risk stratification, and yield higher diagnostic utility in patients presenting to the emergency department with chest pain. METHODS AND RESULTS: Platelet and soluble P-selectin together with myoglobin, creatine kinase, CK-MB fraction, and troponin I were measured from the autologous samples in 122 consecutive patients. Statistical analysis revealed strong Spearman correlation coefficients (0.141--0.412; p<0.001) between platelet expression of P-selectin and plasma levels of necrosis markers. Platelet P-selectin and necrosis markers were independent predictors (c-index>0.7) for acute myocardial infarction, while plasma P-selectin exhibited random distribution. Elevated soluble P-selectin and myoglobin were the most valuable in identifying patients with congestive heart failure. None of the markers were useful for triaging chest pain patients with unstable angina. Analysis of incremental gains (Chi-squares) reveals that with respect to platelet P-selectin, myoglobin adds 50 % to AMI diagnostic value, and creatine kinase yields an additional 20 % in triaging these patients. The diagnostic value of soluble P-selectin is substantially (72 %) increased by myoglobin measurements, and enhanced even further (44 %) by adding cardiac troponin I for identifying heart failure patients among the chest pain population. CONCLUSION: Simultaneous determination of platelet and necrosis markers improve the early diagnosis of acute myocardial infarction and congestive heart failure among patients with chest pain presenting into the Emergency Department. Well controlled clinical trials are needed to prove the advantage of combining platelet and necrosis data over presently used techniques in emergency medicine.

Moderate alcohol consumption is associated with decreased platelet activity in patients presenting with acute myocardial infarction.

Moderate alcohol consumption (MAC) and platelet inhibition have been independently associated with a reduced risk for the development of acute myocardial infarction (AMI). The effects of MAC on the initial platelet status in patients presenting with AMI are not elucidated. Here we sought to define the effects of MAC on platelet characteristics in AMI patients before applying any reperfusion strategies. The study was designed as an analysis within the cohort study in 23 patients with AMI enrolled in the GUSTO-III. Platelets were investigated by different techniques, including aggregometry, flow cytometry, and ELISA. MAC patients exhibited mild, but consistent, inhibition of platelet aggregability, surface receptor expression, and released substances as compared to non-alcohol consuming patients. These differences were significant for 5 microM ADP (p = 0.04), 10 microM ADP-induced aggregation (p = 0.02); P-selectin (p = 0.01), and PECAM-1 (p = 0.02) platelet-bound expression. Our study confirms that moderate alcohol consumption is associated with diminished platelet activation in patients presenting with AMI. The ability of MAC to favorably modulate the pre-reperfusion platelet status in such patients is of clinical importance, and further investigation in large-scale clinical trials seem warranted.

Human studies with the chelating agents, DMPS and DMSA.

Meso-2,3-dimercaptosuccinic acid (DMSA) is bound to plasma albumin in humans and appears to be excreted in the urine as the DMSA-cysteine mixed disulfide. The pharmacokinetics of DMSA have been determined after its administration to humans po. For the blood, the tmax and t1/2 were 3.0 h + 0.45 SE and 3.2 h + 0.56 SE, respectively. The Cmax was 26.2 microM + 4.7 SE. To determine whether dental amalgams influence the human body burden of mercury, we gave volunteers the sodium salt of 2,3-dimercaptopropane-1-sulfonic acid (DMPS). The diameters of dental amalgams of the subjects were determined to obtain the amalgam score. Administration of 300 mg DMPS by mouth increased the mean urinary mercury excretion of subjects over a 9 h period. There was a positive correlation between the amount of mercury excreted and the amalgam score. DMPS might be useful for increasing the urinary excretion of mercury and thus increasing the significance and reliability of this measure of mercury exposure. DMSA analogs have been designed and synthesized in attempts to increase the uptake by cell membranes of the DMSA prototype chelating agents. The i.v. administration of the monomethyl ester of DMSA, the dimethyl ester of DMSA or the zinc chelate of dimethyl DMSA increases the biliary excretion of platinum and cadmium in rats.