Emergent biomarker derived from next-generation sequencing to identify pain patients requiring uncommonly high opioid doses.

Next-generation sequencing (NGS) provides unrestricted access to the genome, but it produces 'big data' exceeding in amount and complexity the classical analytical approaches. We introduce a bioinformatics-based classifying biomarker that uses emergent properties in genetics to separate pain patients requiring extremely high opioid doses from controls. Following precisely calculated selection of the 34 most informative markers in the OPRM1, OPRK1, OPRD1 and SIGMAR1 genes, pattern of genotypes belonging to either patient group could be derived using a k-nearest neighbor (kNN) classifier that provided a diagnostic accuracy of 80.6±4%. This outperformed alternative classifiers such as reportedly functional opioid receptor gene variants or complex biomarkers obtained via multiple regression or decision tree analysis. The accumulation of several genetic variants with only minor functional influences may result in a qualitative consequence affecting complex phenotypes, pointing at emergent properties in genetics.

[Cross-sectional subject 14--training in pain]. / Querschnittsfach 14--Lehre zum Thema Schmerz.

The introduction of pain medicine (cross-sectional subject 14, QF 14) into the Human Medicine study program is a great opportunity. A knowledge gap concerning the treatment of pain patients outside of specialized pain centers has been recognized for many years. This gap might be closed or at least reduced by a compulsory curriculum in pain medicine. If implementation of new lessons for QF 14 is not possible, pain medicine could be represented by labelled elements in the existing curriculum, in order to highlight the field. The core curriculum must now be converted into appropriate teaching and test formats. Due to the autonomy and heterogeneity of German medical faculties, no uniform solution will be achieved. In contrast, this diversity and the entirely new implementation of the cross-sectional subject will allow structured evaluation of different teaching and examination formats with respect to teaching outcome in benchmarking investigations in the coming semesters. Practically experienced lecturers and theory-driven medical educationalists are called upon to get involved with the development, implementation, and evaluation of pain medicine in undergraduate education in Germany. Teaching enthusiasts are encouraged to dedicate themselves to the strenuous, but stimulating task of implementing QF 14. The Deutsche Schmerzgesellschaft (German Pain Society) will offer support for this.

[Multimodal therapy programs for chronic pain]. / Multimodale Therapieprogramme für chronische Schmerzen.

Chronic pain is a common and disabling disorder with major consequences for patient quality of life and it is also a major economic burden to society. The management of chronic pain comprises a large range of different intervention strategies including pharmacological therapy, non-medicinal and invasive therapeutic options. While non-pharmacological and multimodal options are underused, monomodal options, especially pharmacotherapy and invasive therapies are overused. The effectiveness of multidisciplinary and multimodal treatment programs including physical and rehabilitation interventions and psychological treatment has been extensively studied in the last two decades. Evidence from randomized controlled trials demonstrates that there is low quality evidence for the effectiveness of exercise therapy alone, there is some evidence for the effectiveness of behavioral therapy and there is at least moderate evidence for the effectiveness of multidisciplinary and multimodal treatment and other active treatment reducing pain and increasing functional capacity at short and intermediate term. Therefore, blanket coverage with provision of adequate treatment programs for chronic pain as well as studies evaluating the best composition of treatment elements are needed. The characteristics of chronic pain, the necessary assessment procedures and treatment types are described.

[Medical educational evaluation of the German Pain Congress 2012. In the context of the CanMEDS physician competency framework]. / Deutscher Schmerzkongress 2012 aus medizindidaktischer Sicht. Bewertung unter Berücksichtigung der im Rahmenmodell CanMEDS definierten Arztrollen.

BACKGROUND: Professionals in the medical field are expected to participate in continuing medical education in the sense of lifelong learning. The authors took this occasion to evaluate the most important national convention in pain medicine concerning its role in medical education. MATERIAL AND METHODS: The participants of the 37th German Pain Congress (17-20 October 2012 in Mannheim) were asked to complete a questionnaire concerning content and design of the convention. The aim of this study was to analyze the distribution of different physician competencies in the program. For this purpose the congress program was analyzed with respect to the various medical role models as defined in the Canadian medical education directions for specialists (CanMEDS) framework. RESULTS: The participants considered the quality of the different sessions of the German Pain Congress to be good. The poster sessions were considered to be the second most important educational format in the congress following the live sessions. Concerning the content of the congress the participants wished more emphasis on the role of interprofessional partners, such as nursing and psychotherapy. The CanMEDS physician roles of manager, communicator, health advisor and professional paragon were underrepresented in the congress program in this study. CONCLUSION: Regarding content and educational value, the congress design could benefit from additional Praktikerseminaren (practical seminars). The role of interprofessional partners should be more emphasized. In addition the program could become more attractive through a more balanced distribution of the CanMEDS roles.

[Pain medicine as a cross-sectional subject in German medical schools. An opportunity for general pain management]. / Das Querschnittsfach "Schmerzmedizin". Chance für die Allgemeine Schmerzmedizin.

BACKGROUND: Unrelieved pain is a substantial public health concern owing in part to deficits in clinical expertise among physicians. In most medical faculties worldwide, teaching on pain and pain management is either nonexistent or limited to a small number of students attending voluntary courses. In light of the fact that pain is the most frequent reason to seek medical advice, the lack of formal training of pain medicine is considered the leading reason for inadequate pain management. Therefore, the patients' unmet needs for adequate diagnosis and therapy call for action. SITUATION: Pain assessment and effective pain management should be a priority in the health care system. The limited number of pain specialists available in hospitals and primary care and CME (continuous medical education) activities focusing on pain are not sufficient to solve the problem. Every practicing physician should, therefore, have basic knowledge of the most prominent painful conditions and management strategies. To achieve this goal, pain medicine should become an integral part of the undergraduate curriculum for medical students. In Germany, pain medicine became a mandatory subject in undergraduate medical studies in 2012. PERSPECTIVE: The introduction of pain medicine into the undergraduate curriculum in Germany is a major challenge regarding the development and implementation processes. This article describes current instruments and implementation strategies for pain medicine as a new cross-sectional subject in Germany.

Dermoscopy of acral melanoma: a multicenter study on behalf of the international dermoscopy society.

BACKGROUND: Most studies on dermoscopy of acral lesions were conducted in Asian populations. In this study, we analyzed these features in a predominantly Caucasian population. OBJECTIVE: Estimate the prevalence of dermoscopic features in acral lesions, and assess their level of agreement between observers. METHODS: In this retrospective multicenter study, 167 acral lesions (66 melanomas) were evaluated for 13 dermoscopic patterns by 26 physicians, via a secured Internet platform. RESULTS: Parallel furrow pattern, bizarre pattern, and diffuse pigmentation with variable shades of brown had the highest prevalence. The agreement for lesion patterns between physicians was variable. Agreement was dependent on the level of diagnostic difficulty. CONCLUSION: Lesions with a diameter >1 cm were more likely to be melanoma. We found as well that a benign pattern can be seen in parts of melanomas. For this reason one should evaluate an acral lesion for the presence of malignant patterns first.

Megathrust earthquake drives drastic organic carbon supply to the hadal trench.

The giant 2011 Tohoku-oki earthquake has been inferred to remobilise fine-grained, young surface sediment enriched in organic matter from the slope into the >7 km deep Japan Trench. Yet, this hypothesis and assessment of its significance for the carbon cycle has been hindered by limited data density and resolution in the hadal zone. Here we combine new high-resolution bathymetry data with sub-bottom profiler images and sediment cores taken during 2012-2016 in order to map for the first time the spatial extent of the earthquake-triggered event deposit along the hadal Japan Trench. We quantify a sediment volume of ~0.2 km3 deposited from spatially-widespread remobilisation of young surficial seafloor slope sediments triggered by the 2011 earthquake and its aftershock sequence. The mapped volume and organic carbon content in sediment cores encompassing the 2011 event reveals that this single tectonic event delivered >1 Tg of organic carbon to the hadal trench. This carbon supply is comparable to high carbon fluxes described for other Earth system processes, shedding new light on the impact of large earthquakes on long-term carbon cycling in the deep-sea.

Correlation of in vitro and in vivo models for the oral absorption of peptide drugs.

The aim of this study was to evaluate two in vitro models, Caco-2 monolayer and rat intestinal mucosa, regarding their linear correlation with in vivo bioavailability data of therapeutic peptide drugs after oral administration in rat and human. Furthermore the impact of molecular mass (Mm) of the according peptides on their permeability was evaluated. Transport experiments with commercially available water soluble peptide drugs were conducted using Caco-2 cell monolayer grown on transwell filter membranes and with freshly excised rat intestinal mucosa mounted in Using type chambers. Apparent permeability coefficients (P (app)) were calculated and compared with in vivo data derived from the literature. It was shown that, besides a few exceptions, the Mm of peptides linearly correlates with permeability across rat intestinal mucosa (R (2) = 0.86; y = -196.22x + 1354.24), with rat oral bioavailability (R (2) = 0.64; y = -401.90x + 1268.86) as well as with human oral bioavailability (R (2) = 0.91; y = -359.43x + 1103.83). Furthermore it was shown that P (app) values of investigated hydrophilic peptides across Caco-2 monolayer displayed lower permeability than across rat intestinal mucosa. A correlation between P (app) values across rat intestinal mucosa and in vivo oral bioavailability in human (R (2) = 0.98; y = 2.11x + 0.34) attests the rat in vitro model to be a very useful prediction model for human oral bioavailability of hydrophilic peptide drugs. Presented correlations encourage the use of the rat in vitro model for the prediction of human oral bioavailabilities of hydrophilic peptide drugs.

Distribution of technetium-99m sulfur colloid in mice bearing melanomas or mammary carcinomas.

Three groups of 24 C57BL/6J black mice were studied. One group was implanted with B16 malignant melanoma, another was implanted with mammary adenocarcinoma, and the third was not given tumor implants. After 14 to 17 days, the mice were given injections i.v. of technetium-99m sulfur colloid and killed 30 min later. Organs were weighed, and radioactivity was counted. The ratios of specific radioactivities of the spleens to those of the liver were higher only in the group of mice bearing malignant melanomas. This finding suggests that the "hot spleen" phenomenon observed in humans with malignant melanomas may be due to increased specific activity rather than increased splenic volume.

Inhibition of growth of B16 murine malignant melanoma by exogenous interferon.

We previously reported that polyinosinic-polycytidylic acid, a potent interferon inducer, inhibits the growth of B16 malignant melanoma in the C57BL/6 mouse. Two experiments were done to evaluate the effectiveness of interferon in tumor inhibition in vivo. In the first, mice were implanted with melanoma and divided into four groups, according to treatment: interferon preparation; interferon control preparation ("breakthrough fraction"); phosphate-buffered saline control; and murine serum albumin control. Daily, each mouse was given i.p. injections of 200,000 NIH reference units (hereafter called units) of interferon or of one of the control substances. The second experiment was similar to the first, except that bovine serum albumin was an additional control. In both experiments, the average tumor volume in interferon-treated mice was statistically significantly smaller than that of each control group. Mouse interferon preparations also inhibited the multiplication of B16 malignant melanoma cells in culture. This inhibition was statistically significant from interferon levels as low as 5 to as high as 5000 units/ml. The degree of inhibition markedly increased from 5 up to 500 units, the inhibition reaching its maximum at this concentration. The inhibitory effect of interferon was abrogated by anti-murine interferon serum produced in a rabbit. These findings suggest that the in vivo inhibition of the growth of B16 melanoma demonstrated with polyinosinicpolycytidylic acid and with exogenous interferon probably results, at least in part, from a direct effect of interferon on the tumor cells themselves.

Combinatorial refinement of thin-film microstructure, properties and process conditions: iterative nanoscale search for self-assembled TiAlN nanolamellae.

Because of the tremendous variability of crystallite sizes and shapes in nano-materials, it is challenging to assess the corresponding size-property relationships and to identify microstructures with particular physical properties or even optimized functions. This task is especially difficult for nanomaterials formed by self-organization, where the spontaneous evolution of microstructure and properties is coupled. In this work, two compositionally graded TiAlN films were (i) grown using chemical vapour deposition by applying a varying ratio of reacting gases and (ii) subsequently analysed using cross-sectional synchrotron X-ray nanodiffraction, electron microscopy and nanoindentation in order to evaluate the microstructure and hardness depth gradients. The results indicate the formation of self-organized hexagonal-cubic and cubic-cubic nanolamellae with varying compositions and thicknesses in the range of ∼3-15 nm across the film thicknesses, depending on the actual composition of the reactive gas mixtures. On the basis of the occurrence of the nanolamellae and their correlation with the local film hardness, progressively narrower ranges of the composition and hardness were refined in three steps. The third film was produced using an AlCl3/TiCl4 precursor ratio of ∼1.9, resulting in the formation of an optimized lamellar microstructure with ∼1.3 nm thick cubic Ti(Al)N and ∼12 nm thick cubic Al(Ti)N nanolamellae which exhibits a maximal hardness of ∼36 GPa and an indentation modulus of ∼522 GPa. The presented approach of an iterative nanoscale search based on the application of cross-sectional synchrotron X-ray nanodiffraction and cross-sectional nanoindentation allows one to refine the relationship between (i) varying deposition conditions, (ii) gradients of microstructure and (iii) gradients of mechanical properties in nanostructured materials prepared as thin films. This is done in a combinatorial way in order to screen a wide range of deposition conditions, while identifying those that result in the formation of a particular microstructure with optimized functional attributes.

Lentigo maligna melanoma has no better prognosis than other types of melanoma.

We studied 48 patients with lentigo maligna melanoma (LMM) and compared the clinical stage I patients with non-LMM melanoma patients (matched by site and thickness) to see if prognosis differed. There was no significant difference in mortality from melanoma between the two groups (P = .68) after a mean follow-up time of five years (67.5 months for LMM, 60.5 months for non-LMM). In addition, a Cox multivariate analysis of the entire matched group showed that only thickness was significantly associated with death from melanoma (P = .0007) while histology (LMM v non-LMM) did not make a significant contribution (P = .61). Our data suggest that after accounting for primary tumor thickness and site, LMM and non-LMM have the same prognosis and biologic behavior, in contrast to the widely held belief that LMM has a better prognosis than other forms of melanoma.

Prognosis of clinical stage I melanoma patients with positive elective regional node dissection.

We tested 12 clinical and histologic variables to see which ones best predicted death from melanoma in 66 patients with positive elective regional node dissections (clinical stage I, pathologic stage II [CSI, PSII]). Despite the presence of lymph node metastases, not all patients had poor prognoses. Patients with tumors less than or equal to 3.5 mm and a percentage of positive nodes less than or equal to 20% had a 7-year survival rate of 66%. Within this low-risk group the subset with primary lesions on the trunk or extremities (except hands and feet) had a 7-year survival rate of 76%. This compares with poor 7-year survivals of 29% and 30% observed in other defined high-risk groups. Our results confirm and extend earlier observations concerning the prognoses of CSI, PSII melanoma patients and are relevant to any ongoing and future studies concerning elective regional node dissection (ERND) or adjuvant therapy trials in melanoma.

Retention of antimelanoma effect of polyinosinic-polycytidylic acid in neonatally thymectomized, irradiated, leukopenic mice.

Polyinosinic-polycytidylic acid (PIC), a synthetic polyribonucleotide, inhibits the growth of B16 malignant melanoma in C57BL/6 mice. Since PIC has been reported to augment immune responses, we tested the hypothesis that the antitumor effect of PIC against B16 melanoma is via immune stimulation. Mice were neonatally thymectomized or neonatally thymectomized and subsequently irradiated to suppress their immune reactivity. In such animals PIC retained its ability to inhibit the growth of B16 melanoma, in the face of profound leukopenia and lymphopenia, suggesting that its antimelanoma effect is probably not mediated by augmentation of the host's immune antitumor response.

Early death from clinical stage I melanoma.

We studied 13 prognostic factors in 582 patients with clinical stage I melanoma to determine which factor or combination of factors was associated with death from melanoma within the first 24 months following diagnosis. Thirty-six patients died during this period. Only 2 deaths occurred in patients with primary tumors thinner than 1.70 mm, and only 2 patients of 189 died with tumors located on the non-BANS extremities, excluding the hands and feet. Individual factors associated with high risk for death within 2 years included level V tumors, acral location, thickness greater than or equal to 3.65 mm, histologic ulceration greater than 3 mm, nodular type, presence of microscopic satellites, greater than 6 mitoses/mm2, positive elective node dissection, absence of lymphocyte response at the tumor base, and absence of an associated nevus histologically. Many of the preceding individual factors are highly correlated. By the use of logistic regression analysis, only one very high risk group was found: 71 percent of patients with level V tumors greater than 1.70 mm thick with histologic ulceration width greater than 3 mm located in an area other than the extremities (excluding hands and feet) had died within 2 years of diagnosis. The ability to select high-risk groups should be useful to investigators involved with the design and evaluation of adjuvant therapy studies.