Advances in rectal cancer: Real-world evidence suggests limited gains in prognosis for elderly patients.

BACKGROUND: Rectal cancer treatment has improved considerably due to the introduction of total meso-rectal excision, radio-chemotherapy, and high-resolution imaging. The aim of this observational cohort study was to quantify the effectiveness of these advances using high-quality data from a representative cohort of patients. METHODS: 20 281 non-metastasized cases retrieved from the Munich Cancer Registry database were divided into three time periods corresponding to before (1988-1997), partial (1998-2007), and full implementation (2008-2019) of clinical advances. Early-onset (<50 yrs.), middle-aged, elderly patient subgroups (> 70 yrs.) were compared. The overall effectiveness of evidence-based guideline adherence was also examined. RESULTS: Median survival improved by 1.5 yrs. from the first to the last time period. Relative survival increased from 74.9% (5-yr 95%CI[73.3 - 76.6]) to 79.2% (95%CI[77.8 - 80.5]). The incidence of locoregional recurrences was reduced dramatically by more than half (5-yr 17.7% (95%CI[16.5 - 18.8]); 6.7% (95%CI[6.1 - 7.3])). Gains in 5-yr relative survival were limited to early-onset and middle-aged patients with no significant improvement seen in elderly patients (Female 68.6% [63.9 - 73.3] to 67.6% [64.0 - 71.2]; Male 71.7% [65.9 - 77.4] to 74.0% [70.8 - 77.2]). CONCLUSIONS: Real-world evidence suggests that recent treatment advances have lead to an increase in prognosis for rectal cancer patients. However, more effort should be made to improve the implementation of new developments in elderly patients. Especially considering, that these cases represent a growing majority of diagnosed patients.

Deep learning-based classification of dermatological lesions given a limited amount of labelled data.

BACKGROUND: Artificial intelligence (AI) techniques are promising in early diagnosis of skin diseases. However, a precondition for their success is the access to large-scaled annotated data. Until now, obtaining this data has only been feasible with very high personnel and financial resources. OBJECTIVES: The aim of this study was to overcome the obstacle caused by the scarcity of labelled data. METHODS: To simulate the scenario of label shortage, we discarded a proportion of labels of the training set. The training set consisted of both labelled and unlabelled images. We then leveraged a self-supervised learning technique to pretrain the AI model on the unlabelled images. Next, we fine-tuned the pretrained model on the labelled images. RESULTS: When the images in the training dataset were fully labelled, the self-supervised pretrained model achieved 95.7% of accuracy, 91.7% of precision and 90.7% of sensitivity. When only 10% of the data were labelled, the model could still yield 87.7% of accuracy, 81.7% of precision and 68.6% of sensitivity. In addition, we also empirically verified that the AI model and dermatologists are consistent in visually inspecting the skin images. CONCLUSIONS: The experimental results demonstrate the great potential of the self-supervised learning in alleviating the scarcity of annotated data.

Monocarboxylate transporter-1 (MCT1) protein expression in head and neck cancer affects clinical outcome.

Treatment of locally advanced, unresectable head and neck squamous cell carcinoma (HNSCC) often yields only modest results with radiochemotherapy (RCT) as standard of care. Prognostic features related to outcome upon RCT might be highly valuable to improve treatment. Monocarboxylate transporters-1 and -4 (MCT1/MCT4) were evaluated as potential biomarkers. A cohort of HNSCC patients without signs for distant metastases was assessed eliciting 82 individuals eligible whereof 90% were diagnosed with locally advanced stage IV. Tumor specimens were stained for MCT1 and MCT4 in the cell membrane by immunohistochemistry. Obtained data were evaluated with respect to overall (OS) and progression-free survival (PFS). Protein expression of MCT1 and MCT4 in cell membrane was detected in 16% and 85% of the tumors, respectively. Expression of both transporters was not statistically different according to the human papilloma virus (HPV) status. Positive staining for MCT1 (n = 13, negative in n = 69) strongly worsened PFS with a hazard ratio (HR) of 3.1 (95%-confidence interval 1.6-5.7, p < 0.001). OS was likewise affected with a HR of 3.8 (2.0-7.3, p < 0.001). Multivariable Cox regression confirmed these findings. We propose MCT1 as a promising biomarker in HNSCC treated by primary RCT.

A MEMS nanoindenter with an integrated AFM cantilever gripper for nanomechanical characterization of compliant materials.

This work presents the development of a MEMS nanoindenter that uses exchangeable AFM probes for quasi-static nanomechanical characterization of compliant and ultra-compliant materials. While the electrostatic micro-force transducer of the MEMS nanoindenter provides a maximum indentation depth up to 9.5 µm with a maximum output force of 600 µN, experimental investigations reveal that it can achieve a depth and force resolution better than 4 pm Hz-1/2 and 0.3 nN Hz-1/2, in air for f≥ 1 Hz. A passive AFM probe gripper is integrated into the MEMS nanoindenter, allowing the nanoindenter to utilize various AFM probes as an indenter for material testing. A proof-of-principle experimental setup has been built to investigate the performance of the MEMS nanoindenter prototype. In proof-of-principle experiments, the prototype with a clamped diamond AFM probe successfully identified an atomic step (∼0.31 nm) within a Si < 111 > ultraflat sample using the scanning probe microscopy mode. The nanomechanical measurement capability of the MEMS nanoindenter prototype has been verified by means of measurements of reference polymer samples using a silicon AFM probe and by means of measurements of the elastic properties of a PDMS sample using a spherical diamond-coated AFM probe. Owing to its compact and low-cost but high-resolution capacitive readout system, this MEMS nanoindenter head can be further applied for in-situ quantitative nanomechanical measurements in AFMs and SEMs.

Lack of health insurance among juvenile offenders: a predictor of inappropriate healthcare use and reincarceration?

OBJECTIVES: Relationships between the health insurance status and healthcare use among justice-involved youths transitioning into adulthood is an underexplored topic, even if transition to adulthood is a crucial time period for healthcare outcomes. To fill in these knowledge gaps, this study had two aims: (1) to examine trajectories of health insurance coverage and healthcare use among serious juvenile offenders transitioning into adulthood; and (2) to explore associations between the lack of health insurance, healthcare use and reincarceration. STUDY DESIGN: We conducted a secondary analysis on the data of the US longitudinal Pathways to Desistance study between ages 20 and 23 years (2000-2010). METHODS: Participant data on health insurance coverage, healthcare use, reincarceration and sociodemographic variables (n = 1215) were extracted and analysed using descriptive statistics, generalized linear regressions and cross-lagged panel models. RESULTS: About half of the young offenders had no health insurance coverage or intermittent coverage between the age of 20 and 23 years. Emergency services were used (≥17.4%), notably more by insured participants and were increasingly used over time. Being uninsured at the age of 20 years was associated with reincarceration at the age of 23 years (b = -0.052, p = 0.014, odd-ratio = 0.95), but incarceration at the age of 20 years did not predict the insurance status at the age of 23 years (b = 0.009, p = 0.792). CONCLUSIONS: Serious juvenile offenders, especially if uninsured, faced major barriers to accessing health care and often reported an inappropriate healthcare use. This likely led to reincarceration. The lack of continuity of care and of access to health care may, therefore, increase health disparities, and efforts are needed to mitigate detrimental outcomes, by effective in and out of detention coordination of health insurance coverage and among health services.

Syphilis, human immunodeficiency virus, herpes genital and hepatitis B in a women's prison in Cochabamba, Bolivia: prevalence and risk factors.

OBJECTIVE: To determine the prevalence and factors associated with syphilis, human immunodeficiency virus (HIV), hepatitis B (HBV) and herpes type 2 (HSV2) among women in the prison of San Sebastian in Cochabamba (Bolivia). MATERIAL AND METHODS: We carried out a cross-sectional study including a standardized questionnaire to assess socio-demographics characteristics and risk factors (sexual practices and exposure to blood); and serological tests for syphilis, HSV2, VIH, and HBV. We performed bivariate and multivariate analyses to test the associations between variables of interest and infections. RESULTS: A total of 219 out of 220 prisoners (99.5%) participated in the study. For syphilis, 12.8% of participants had both reactive tests (RPR+/TPPA+). The prevalence of HSV2 and VIH was 62.6% and 1.4%, respectively. Anti-HBc, indicating a resolved or chronic HBV, was positive in 11.9% of participants and 0.5% had active HBV (HBsAg positive). A low level of education was associated with syphilis, HSV2 and HBV. Having occasional sexual partners was associated with syphilis and HSV2. Being over 36 years old and having more than 3 children were associated with HBV. The number of sexual partners, history of prostitution and rape, having sexual intercourses in prison and detention time were not associated with any of these infections. DISCUSSION: The prevalence of syphilis, HIV, HSV2 and HBV was higher in this vulnerable female population than in the general population in Bolivia. Control measures in detention are needed to limit the spread of these infections both in prisons and in the community.

A novel glycocluster molecule prevents timothy-induced allergic airway inflammation in mice.

BACKGROUND: Allergen-specific immunotherapy (SIT) effectively alleviates type I allergic diseases characterized by T helper (Th)2-type immunity. Our recent studies have shown that a synthetic trivalent glycocluster, triacedimannose (TADM), suppresses the Th2-type allergic inflammation. The aim of this study was to compare TADM with two well-known adjuvants, unmethylated cytosine-phosphate-guanine oligodeoxynucleotide (CpG) and monophosphoryl lipid A (MPLA) in a grass allergen-induced chronic allergic inflammation model in mice. METHODS: Female BALB/c mice were intranasally sensitized with 50 µL of timothy grass pollen extract (TE) twice a week for a period of 15 weeks. Therapeutic intranasal treatments were then performed once a week after the tenth intranasal TE instillation using TADM (10 or 25 µg/50 µL), CpG-ODN (20 µg/50 µL) or MPLA (2 µg/50 µL). Groups of 9-10 animals per treatment were killed 24 hours after the last timothy dosage. Blood, bronchoalveolar lavage (BAL) fluids and lung biopsies were taken for subsequent analysis. RESULTS: When mice were repeatedly exposed to TE for 15 weeks, the number of eosinophils and lymphocytes increased in the BAL fluids. The eosinophil and lymphocyte counts decreased dose-dependently and were practically abolished in the mice treated with TADM. Treatments with MPLA or CpG significantly increased the numbers of neutrophils, while CpG nonsignificantly decreased eosinophilia compared to timothy exposure. CONCLUSIONS: A novel synthetic glycocluster molecule inhibited the development of grass-induced eosinophilic pulmonary inflammation in mice when administrated in the airways. This compound could be a candidate to be used either as an adjuvant in SIT or as a topical anti-inflammatory treatment.

Nasal protein profiles in work-related asthma caused by different exposures.

BACKGROUND: The mechanisms of work-related asthma (WRA) are incompletely delineated. Nasal cell samples may be informative about processes in the lower airways. Our aim was to determine the nasal protein expression profiles of WRA caused by different kind of exposures. METHODS: We collected nasal brush samples from 82 nonsmoking participants, including healthy controls and WRA patients exposed to (i) protein allergens, (ii) isocyanates and (iii) welding fumes the day after relevant exposure. The proteome changes in samples were analysed by two-dimensional difference gel electrophoresis, and the differentially regulated proteins found were identified by mass spectrometry. Immunological comparison was carried out using Western blot. RESULTS: We detected an average of 2500 spots per protein gel. Altogether, 228 protein spots were chosen for identification, yielding 77 different proteins. Compared to the controls, exposure to protein allergens had the largest effects on the proteome. Hierarchical clustering revealed that protein allergen- and isocyanate-related asthma had similar profiles, whereas asthma related to welding fumes differed. The highly overrepresented functional categories in the asthma groups were defence response, protease inhibitor activity, inflammatory and calcium signalling, complement activation and cellular response to oxidative stress. Immunological analysis confirmed the found abundance differences in galectin 10 and protein S100-A9 between the groups. CONCLUSIONS: Work-related asthma patients exposed to protein allergens and isocyanates elicit similar nasal proteome responses and the profiles of welders and healthy controls were alike. Revealed biological activities of the protein expression changes are associated with allergic inflammation and asthma.

Rapid diagnostic testing to improve access to screening for syphilis in prison.

OBJECTIVES: To assess the accuracy of on-site rapid treponemal test for syphilis diagnosis in women deprived of liberty in Bolivia. MATERIAL AND METHODS: Serological tests for syphilis were performed on 219 women deprived of liberty from the San Sebastián prison in Cochabamba, Bolivia. Syphilis was diagnosed using RPR (bioMérieux) and TPPA (Fujirebio) serological tests, and the results were compared to on-site rapid treponemal test (Alere DetermineTM Syphilis TP) in whole blood. Diagnostic performance of two FTA tests were also compared (bioMérieux and Biocientífica). RESULTS: All participants (28) with RPR+/TPPA+ had the rapid syphilis test positive (sensitivity 100%). Eleven participants had rapid syphilis test positive without RPR and TPPA both positive; nevertheless 7 of them had RPR or TPPA positive. Of 33 participants with FTA-bioMérieux positive, 22 (66.6%) had FTA-Biocientífica positive. DISCUSSION: The rapid syphilis test Determine shows excellent performance as a screening tool among women deprived of liberty affected by high prevalence of syphilis. This test is particularly indicated when there are barriers for access to conventional serological tests. It is inexpensive, easy to use and does not require electricity and laboratory infrastructure. The FTA test performed with reagents from Biocientífica had a suboptimal sensitivity.

Presentation of a variation of the chorioallantoic membrane set up as a potential model for individual therapy for squamous cell carcinoma of the oropharynx.

The chorioallantoic membrane of fertilized chicken eggs in an early phase of breeding presents an approved test situation for the growth and treatment of human cancer cells.These models work due to the inoculation of cells into the membrane that stays within the egg shell during the time of investigation. In this study a modification of this model is presented. Samples of native tumors, rather than cell lines, are transplanted into the membrane and the body of the egg is taken out of the shell and placed in a plastic bowl. These modifications lead to an enhanced accessibility to the chorioallantoic membrane and the surrounding vessels thus facilitating intra venous access and application of pharmaceuticals and a focused radiotherapy. With the current modifications the embryo was kept alive and additionally, the vascularized tumor environment was preserved.

Persistent infectious and tropical diseases in immigrant correctional populations.

A number of infectious diseases amongst travelers and the immigrant populations are a major public health concern. Some have a long incubation period or remain asymptomatic or paucisymptomatic for many years before leading to significant clinical manifestations and/or complications. HIV, hepatitis B and C, tuberculosis or latent syphilis are among the most significant persistent diseases in migrants. Schistosomiasis and strongyloidiasis, for instance, are persistent helminthic infections that may cause significant morbidity, particularly in patients co-infected with HIV, hepatitis B and C. Chagas disease, which was initially confined to Latin America, must also now be considered in immigrants from endemic countries. Visceral leishmaniasis and malaria are other examples of parasitic diseases that must be taken into account by physicians treating incarcerated migrants. The focus of this review article is on the risk of neglected tropical diseases in particularly vulnerable correctional populations and on the risk of infectious diseases that commonly affect migrants but which are often underestimated.

Evaluation of the biomarker candidate MFAP4 for non-invasive assessment of hepatic fibrosis in hepatitis C patients.

BACKGROUND: The human microfibrillar-associated protein 4 (MFAP4) is located to extracellular matrix fibers and plays a role in disease-related tissue remodeling. Previously, we identified MFAP4 as a serum biomarker candidate for hepatic fibrosis and cirrhosis in hepatitis C patients. The aim of the present study was to elucidate the potential of MFAP4 as biomarker for hepatic fibrosis with a focus on the differentiation of no to moderate (F0-F2) and severe fibrosis stages and cirrhosis (F3 and F4, Desmet-Scheuer scoring system). METHODS: MFAP4 levels were measured using an AlphaLISA immunoassay in a retrospective study including n = 542 hepatitis C patients. We applied a univariate logistic regression model based on MFAP4 serum levels and furthermore derived a multivariate model including also age and gender. Youden-optimal cutoffs for binary classification were determined for both models without restrictions and considering a lower limit of 80 % sensitivity (correct classification of F3 and F4), respectively. To assess the generalization error, leave-one-out cross validation (LOOCV) was performed. RESULTS: MFAP4 levels were shown to differ between no to moderate fibrosis stages F0-F2 and severe stages (F3 and F4) with high statistical significance (t test on log scale, p value <2.2·10(-16)). In the LOOCV, the univariate classification resulted in 85.8 % sensitivity and 54.9 % specificity while the multivariate model yielded 81.3 % sensitivity and 61.5 % specificity (restricted approaches). CONCLUSIONS: We confirmed the applicability of MFAP4 as a novel serum biomarker for assessment of hepatic fibrosis and identification of high-risk patients with severe fibrosis stages in hepatitis C. The combination of MFAP4 with existing tests might lead to a more accurate non-invasive diagnosis of hepatic fibrosis and allow a cost-effective disease management in the era of new direct acting antivirals.

Diagnosis and Treatment of Nasopharyngeal Carcinoma in Children and Adolescents - Recommendations of the GPOH-NPC Study Group.

Nasopharyngeal carcinoma (NPC) is a rare malignant tumor arising from epithelial cells of the nasopharynx. Its incidence is highest in Southeast Asia. Age distribution of NPC is bimodal, with one peak in young adolescents and another in patients 55-59 years of age. EBV appears to be the primary etiologic agent in the pathogenesis, environmental factors such as nitrosamines and genetic factors are contributory. NPC is most commonly diagnosed in locally advanced stages, with lymph node metastases occurring in up to 90% of patients. About 5-10% of patients present with distant metastases. Diagnosis of NPC is made histologically, supported by an abnormal anti-EBV-VCA IgA titer and elevated plasma EBV-DNA load. Superior results in children and adolescents with advanced locoregional NPC, with overall and event-free survival rates>90%, have been achieved by neoadjuvant chemotherapy with 5-fluoruracil and cisplatin, followed by synchronous radiochemotherapy and subsequent maintenance therapy with interferon-ß as demonstrated by the 2 prospective studies GPOH-NPC-91 and -2003. Response to therapy can be assessed by PET-imaging and in patients with complete remission after neoadjuvant chemotherapy, the radiation dose to the primary tumor can be safely reduced from 59.4 to 54.4 Gy. Since the majority of long term sequalae such as xerostomia, skin and tissue fibrosis are caused by high radiation dosages, radiotherapy modalities such as intensity-modulated radiotherapy should be used to efficiently spare non-tumorous tissue. For patients with metastatic disease and relapse, survival chances are low. New treatment strategies, such as the application of EBV-specific T-lymphocytes should be considered for these patients.

MFAP4: a candidate biomarker for hepatic and pulmonary fibrosis?

BACKGROUND: Several comparable mechanisms have been identified for hepatic and pulmonary fibrosis. The human microfibrillar associated glycoprotein 4 (MFAP4), produced by activated myofibroblasts, is a ubiquitous protein playing a potential role in extracellular matrix (ECM) turnover and was recently identified as biomarker for hepatic fibrosis in hepatitis C patients. The current study aimed to evaluate serum levels of MFAP4 in patients with pulmonary fibrosis in order to test its potential as biomarker in clinical practice. A further aim was to determine whether MFAP4 deficiency in mice affects the formation of pulmonary fibrosis in the bleomycin model of lung fibrosis. METHODS: 91 patients with idiopathic pulmonary fibrosis (IPF), 23 with hypersensitivity pneumonitis (HP) and 31 healthy subjects were studied. In the mouse model, C57BL/6 Mfap4+/+ and Mfap4-/- mice between 6-8 weeks of age were studied. Serum levels of MFAP4 were measured by ELISA in patients and in mice. Surfactant protein D (SP-D) and LDH were measured as comparison biomarkers in patients with pulmonary fibrosis. Morphometric assessment and the Sircol kit were used to determine the amount of collagen in the lung tissue in the mouse model. RESULTS: Serum levels of MFAP4 were not elevated in lung fibrosis - neither in the patients with IPF or HP nor in the animal model. Furthermore no significant correlations with pulmonary function tests of IPF patients could be found for MFAP4. MFAP4 levels were increased in BAL of bleomycin treated mice with pulmonary fibrosis. CONCLUSIONS: MFAP4 is not elevated in sera of patients with pulmonary fibrosis or bleomycin treated mice with pulmonary fibrosis. This may be due to different pathogenic mechanisms of liver and lung fibrogenesis. MFAP4 seems to be useful as serum biomarker for hepatic but not for lung fibrosis.

[Originators and eponyms of dermatomyositis : Ernst Leberecht Wagner (1821-1888) and Heinrich Unverricht (1853-1912)]. / Erstbeschreiber und Namensgeber der Dermatomyositis : Ernst Leberecht Wagner (1821-1888) und Heinrich Unverricht (1853-1912).

Dermatomyositis is a rare muscle disease that was first described by Ernst Leberecht Wagner and Heinrich Unverricht.After providing a survey on both scientists' life works, this contribution describes the most significant subsequent works on the diagnostics and classification of clinical symptoms and the progress of the disease that the author has been observing for more than three decades.Polymyositis/dermatomyositis (also known as Unverricht-Wagner or Wagner-Unverricht syndrome) was described in two publications by Ernst Leberecht Wagner in 1863 and 1887. Wagner was - probably uniquely in Germany - consecutively professor of pathology and also, as a successor to K. A. Wunderlich, of internal medicine at the University of Leipzig. The most frequently used designation for polymyositis/dermatomyositis today was originated by Heinrich Unverricht in 1891. After his education in his home town of Breslau, Unverricht was first employed as head of the clinic for internal medicine in Jena. From 1886 he was a professor in Dorpat, but he left this university when the language of teaching was changed to Russian in 1892. Unverricht then became the first director of the newly founded Sudenburg Hospital in Magdeburg (Medical Academy from 1954 to 1991).During the subsequent decades, further medical scientists have studied the disease and brought about today's precise classification criteria for diagnostics - based on Wagner's and Unverricht's findings.

A novel mannoside-glycocluster adjuvant: Compared in vitro to CpG ODN and MPL and tested in vivo in mouse asthma model.

BACKGROUND: Allergen-specific immunotherapy balances the Th2-biased immunity towards Th1 and Treg responses. Adjuvants are used in allergen preparations to intensify the immune responses. The increased prevalence of allergies in developed societies has been associated with decreased microbial load during childhood. This has initiated a search for microbial structures to be used as adjuvants. Our study has shown that a synthetic triacedimannose (TADM) may suppress the Th2-type allergic inflammatory response. The aim of this study was to compare the properties of TADM with capacities of other adjuvants, CpG ODN and MPL, to modulate cytokine production in PBMC and regulate sensitisation in an OVA-sensitised mouse asthma model. METHODS: The effects of TADM were studied in vitro on birch stimulated PBMC cultures of birch allergic rhinitis patients with other known adjuvants. Cytokines in supernatants were measured by Luminex. Effects of TADM were analysed in vivo in a mouse model of OVA-induced allergic asthma by analysing BAL, cytokine mRNA and serum antibodies. RESULTS: TADM was the only adjuvant that significantly suppressed the production of all birch induced Th2-type cytokines. In a murine model, TADM significantly suppressed the specific IgE production and enhanced IFN-γ production. CONCLUSIONS: TADM suppresses the birch allergen induced Th2-type cytokine responses in allergic subjects more efficiently than the two other adjuvants, MPL and CpG ODN. TADM is immunomodulatory also in vivo and decreases the IgE levels and increases the IFN-γ responses in a murine model. These results suggest that TADM may be a promising candidate for novel adjuvants in immunotherapy.