Treatment of agitation in terminally ill patients with intranasal midazolam versus subcutaneous midazolam: study protocol for a randomised controlled open-label monocentric trial (MinTU Study).

BACKGROUND: Intranasal (i.n.) drug application is a widely known and low-invasive route of administration that may be able to achieve rapid symptom control in terminally ill patients. According to the German S3 guideline "Palliative care for patients with incurable cancer", benzodiazepines, such as midazolam, are recommended for the treatment of terminal agitation. To the best of our knowledge there is no evidence for i.n. midazolam in terminally ill patients. We aim to assess the use of i.n. midazolam as an alternative to subcutaneous administration of the drug. METHODS: In this monocentric, randomised, controlled, open-label investigator initiated trial, n = 60 patients treated at the palliative care unit of a University Hospital will be treated with 5 mg midazolam i.n. versus 5 mg subcutaneous (s.c.) midazolam in the control arm when terminal agitation occurs (randomly assigned 1:1). The estimated recruitment period is 18 months. Treatment efficacy is defined as an improvement on the Richmond Agitation Sedation Scale (Palliative Version) (RASS-PAL) and a study specific numeric rating scale (NRS) before and after drug administration. Furthermore, plasma concentration determinations of midazolam will be conducted at t1 = 0 min, t2 = 5 min, and t3 = 20 min using liquid chromatography/mass spectrometry (LC-MS). The primary objective is to demonstrate non-inferiority of midazolam i.n. in comparison to midazolam s.c. for the treatment of agitation in terminally ill patients. DISCUSSION: Midazolam i.n. is expected to achieve at least equivalent reduction of terminal agitation compared to s.c. administration. In addition, plasma concentrations of midazolam i.n. are not expected to be lower than those of midazolam s.c. and the dynamics of the plasma concentration with an earlier increase could be beneficial. TRIAL REGISTRATION: German Clinical Trials Registry DRKS00026775, registered 07.07.2022, Eudra CT No.: 2021-004789-36.

DNA identification of species of the Anopheles maculipennis complex and first record of An. daciae in Belgium.

The present study aimed at identifying the members of the Anopheles maculipennis complex (Diptera: Culicidae) occurring in Belgium. Therefore, the second internal transcribed spacer of nuclear ribosomal DNA (ITS2) and the mitochondrial cytochrome oxidase subunit I (COI) loci were sequenced in 175 and 111 specimens, respectively, collected between 2007 and 2019. In parallel, the suitability of two species-diagnostic PCR-RFLP assays was tested. The identified specimens included: An. maculipennis s.s. (N = 105), An. daciae (N = 62), An. atroparvus (N = 6) and An. messeae (N = 2). Each species was characterized by unique ITS2 haplotypes, whereas COI only supported the monophyly of An. atroparvus, a historical malaria vector in Belgium. Species identification results were further supported by unique PCR-RFLP banding patterns. We report for the first time An. daciae in Belgium, where it was found to co-occur with An. maculipennis s.s. The latter was the most prevalent in the collection studied (60%) and appears to have the widest distribution in Belgium. As in other studies, An. daciae and An. messeae appeared the most closely related species, up to the point that their species status remains debatable, while their ecological differences, including vector competences, need further study.

Multidrug-resistant organisms in allogeneic hematopoietic cell transplantation.

OBJECTIVE: Multidrug-resistant organisms (MDRO) are a challenge in allogeneic hematopoietic cell transplantation (HCT). However, in the literature there is no comprehensive analysis on MDRO in HCT. In this retrospective, single-center analysis, we appraised prevalence and clinical impact of MDRO in 98 consecutive allogeneic HCT patients. METHOD: Prior to the conditioning (baseline) and whenever clinically indicated patients underwent a full screening for MDRO (stool and urine cultures, swabs from several body regions). RESULTS: It turned out that 26 patients were colonized by 33 MDRO, either at baseline (n=16) or at any other time until day 100 post-transplantation. Of these 26 patients, eight developed an infection with MDRO, four of them by 4MRGN Pseudomonas aeruginosa, and three of them died MDRO-related. However, there was no significant difference between MDRO-colonized and non-colonized patients regarding overall survival (OS) and non-relapse-mortality (NRM). There was only a trend toward a higher NRM in patients already colonized by MDRO at baseline. This was due to the high NRM in multidrug-resistant P. aeruginosa-colonized patients. CONCLUSION: In summary, colonization with MDRO other than P. aeruginosa had no negative impact on NRM and OS. Patients colonized by multidrug-resistant P. aeruginosa had a dismal outcome. HCT of these patients should be considered with care. Screening for MDRO in the pretransplant work-up is suggested.

[Intrahepatic cholestasis of pregnancy : Rare but important]. / Intrahepatische Schwangerschaftscholestase : Selten, aber relevant.

Intrahepatic cholestasis of pregnancy (ICP) is a liver-specific disorder occurring in approximately 0.5-2.0% of all pregnancies with a considerable variation in certain ethnic groups. ICP usually runs a benign course for the mother and is characterized by maternal pruritus mainly in the third trimester, elevated transaminases and fasting total serum bile salts and increased fetal adverse events. The etiology of ICP is only partially understood but seems to be multifactorial. Cholestasis-inducing effects of certain female sex hormones and their metabolites play an important role in genetically susceptible women. The mechanisms resulting in fetal complications such as spontaneous preterm labour, antepartum passage of meconium, asphyxia events, still birth and fetal death are not well understood. Certain sulfated progesterone metabolites are likely to play a role in the pathogenesis of pruritus in ICP. In contrast to pregnancy-related dermatoses, pruritus does not present with primary skin alterations. However, intense scratching may cause secondary skin changes such as abrasions, excoriations and sometimes prurigo nodularis. Treatment is based on ursodeoxycholate treatment to reduce pruritus and hepatic impairment as well as elective delivery between gestation week 37-38 to pre-empt potential stillbirths. This article reviews clinical symptoms, diagnosis, treatment and in particular pathogenesis of pruritus in ICP.

Monochorial diamniotic dizygotic twins in a German Shepherd Dog: A case report.

CASE REPORT: A 6.5-year-old clinically healthy German Shepherd Dog with regular oestrous cycles of 6 months was presented for pregnancy diagnosis on day 38 after ovulation (p.ov.). Ultrasonography revealed three individual placental sites in progressed resorption and two vital adequately developed foetuses sharing a joint placenta. On days 41 and 48 p.ov., sonographic signs indicated normal development of both foetuses, but on day 52 p.ov., both foetuses were found to be dead. A caesarean section was performed the same day. Examination of the removed uterus confirmed the diagnosis of a "twin" pregnancy with two foetuses sharing the same placental site but separate amniotic membranes. One foetus showed generalized oedema (anasarca). Bacterial culture of swabs taken from inside the placental cavity was negative. At histological examination of the uterus, no signs of inflammation were found. Serum relaxin concentrations (day 38, 41, 48 and 52. p.ov.) were consistent with those of bitches with normal pregnancies. Cytogenetic analysis of the two foetuses revealed dizygotic twins, one male and one female according to SRY-PCR. By genotyping 17 high-polymorphic canine microsatellites, it could be demonstrated that the two foetuses developed from two different oocytes.

Mammalian-target of rapamycin inhibition with temsirolimus in myelodysplastic syndromes (MDS) patients is associated with considerable toxicity: results of the temsirolimus pilot trial by the German MDS Study Group (D-MDS).

The mammalian-target of rapamycin (also termed mechanistic target of rapamycin, mTOR) pathway integrates various pro-proliferative and anti-apoptotic stimuli and is involved in regulatory T-cell (TREG) development. As these processes contribute to the pathogenesis of myelodysplastic syndromes (MDS), we hypothesized that mTOR modulation with temsirolimus (TEM) might show activity in MDS. This prospective multicentre trial enrolled lower and higher risk MDS patients, provided that they were transfusion-dependent/neutropenic or relapsed/refractory to 5-azacitidine, respectively. All patients received TEM at a weekly dose of 25 mg. Of the 9 lower- and 11 higher-risk patients included, only 4 (20%) reached the response assessment after 4 months of treatment and showed stable disease without haematological improvement. The remaining patients discontinued TEM prematurely due to adverse events. Median overall survival (OS) was not reached in the lower-risk group and 296 days in the higher-risk group. We observed a significant decline of bone marrow (BM) vascularisation (P = 0·006) but were unable to demonstrate a significant impact of TEM on the balance between TREG and pro-inflammatory T-helper-cell subsets within the peripheral blood or BM. We conclude that mTOR-modulation with TEM at a dose of 25 mg per week is accompanied by considerable toxicity and has no beneficial effects in elderly MDS patients.

Cumulative radiation exposure from imaging procedures and associated lifetime cancer risk for patients with lymphoma.

The aim of this study was to systematically evaluate the cumulative radiation exposure and the associated lifetime-cancer-risk from diagnostic imaging in patients with Hodgkin-lymphoma-(HL) or diffuse-large-B-cell-lymphoma (DLBCL). 99 consecutive patients (53-males) diagnosed with HL or DLBCL were included in the study and followed. Based on the imaging reports, organ and effective-doses-(ED) were calculated individually for each patient and the excess lifetime risks were estimated. The average ED in the first year after diagnosis was significantly different for men (59 ± 33 mSv) and women (74 ± 33 mSv)-(p < 0.05). The mean cumulative ED in each of the following 5 years was 16 ± 16 mSv without significant differences between men and women-(p > 0.05). Over all years, more than 90% of the ED resulted from CT. The average cumulative radiation risk estimated for the first year was significantly lower for men (0.76 ± 0.41%) as compared to women (1.28 ± 0.54%)-(p < 0.05). The same was found for each of the subsequent 5-years (men-0.18 ± 0.17%; women-0.28 ± 0.25%)-(p < 0.05). In conclusion, for HL and DLBCL patients investigated in this study, a cumulative radiation risk of about 1 excess cancer per 100 patients is estimated for diagnostic imaging procedures performed during both the first year after diagnosis and a follow-up period of 5 years.

Leukocyte DNA damage after reduced and conventional absorbed radiation doses using 3rd generation dual-source CT technology.

PURPOSE: Computed tomography (CT) scans are an important source of ionizing irradiation (IR) in medicine that can induce a variety of DNA damage in human tissues. With technological improvements CT scans at reduced absorbed doses became feasible presumably lowering genotoxic side effects. MATERIALS AND METHODS: For measuring DNA damage we performed γH2AX foci microscopy in peripheral blood mononuclear cells (PBMC) after exposure to reduced and conventional absorbed radiation doses using 3rd generation dual-source CT (DSCT) technology. RESULTS: CT scans performed at reduced absorbed doses of 3 mGy induced significant lower levels (p < 0.0001) of DNA damage (0.05 focus per cell ± 0.01 [mean ± standard error of mean]) at 5 min after IR compared to conventional absorbed doses of 15 mGy (0.30 focus per cell ± 0.03). With ongoing DNA repair background γH2AX foci levels (0.05 focus per cell) were approached at 24 h after CT with both protocols. CONCLUSION: Our results provide evidence that reduced absorbed doses mediated by adjusted tube current in 3rd generation DSCT induce lower levels of DNA damage in PBMC compared to conventional absorbed doses suggesting a lower genotoxic risk for state-of-the-art tube current reduced CT protocols.

Health-Enabling and Ambient Assistive Technologies: Past, Present, Future.

BACKGROUND: During the last decades, health-enabling and ambient assistive technologies became of considerable relevance for new informatics-based forms of diagnosis, prevention, and therapy. OBJECTIVES: To describe the state of the art of health-enabling and ambient assistive technologies in 1992 and today, and its evolution over the last 25 years as well as to project where the field is expected to be in the next 25 years. In the context of this review, we define health-enabling and ambient assistive technologies as ambiently used sensor-based information and communication technologies, aiming at contributing to a person's health and health care as well as to her or his quality of life. METHODS: Systematic review of all original articles with research focus in all volumes of the IMIA Yearbook of Medical Informatics. Surveying authors independently on key projects and visions as well as on their lessons learned in the context of health-enabling and ambient assistive technologies and summarizing their answers. Surveying authors independently on their expectations for the future and summarizing their answers. RESULTS: IMIA Yearbook papers containing statements on health-enabling and ambient assistive technologies appear first in 2002. These papers form a minor part of published research articles in medical informatics. However, during recent years the number of articles published has increased significantly. Key projects were identified. There was a clear progress on the use of technologies. However proof of diagnostic relevance and therapeutic efficacy remains still limited. Reforming health care processes and focussing more on patient needs are required. CONCLUSIONS: Health-enabling and ambient assistive technologies remain an important field for future health care and for interdisciplinary research. More and more publications assume that a person's home and their interaction therein, are becoming important components in health care provision, assessment, and management.

Implant placement under existing removable dental prostheses and its effect on masticatory performance.

OBJECTIVE: The aim of this within-subject study was to evaluate the outcome with implant-tooth-supported removable partial dental prostheses (RPDP group) and implant-supported removable complete dental prostheses (edentulous group) in terms of masticatory performance and self-assessment. MATERIALS AND METHODS: Thirty patients participated in this prospective clinical study (RPDP group: n = 12; edentulous group: n = 18). The prostheses were supported in strategically advantageous regions by placing implants with ball attachments and corresponding matrices in the existing dentures. The masticatory performance was evaluated with the Swallowing Threshold Test Index (STTI), the number of chewing strokes, and the time needed until swallowing at pre-treatment and 6 weeks after integration of ball attachments. Additionally, patients scored chewing satisfaction before and after implantation on a visual analogue scale. RESULTS: The STTI increased significantly (p ≤ 0.05) after implant therapy in the edentulous group but not in the RPDP group. Furthermore, the STTI was significantly higher (p ≤ 0.05) in the RPDP group than in the edentulous group at pre-treatment, however, not after therapy (P > 0.05). All patients were very satisfied after therapy concerning ability of speaking, chewing, and stability of their prosthesis. CONCLUSIONS: Patients of the edentulous group benefit more from strategically placed implants under the existing dentures than patients from the RPDP group. However, according to the subjective assessment, the chewing satisfaction generally increased for both groups after implant therapy. CLINICAL RELEVANCE: Patients with a strongly reduced dentition and edentulous patients benefit from strategically placed implants under the existing removable dentures.

The association of air pollution and depressed mood in 70,928 individuals from four European cohorts.

BACKGROUND: Exposure to ambient air pollution may be associated with impaired mental health, including depression. However, evidence originates mainly from animal studies and epidemiological studies in specific subgroups. We investigated the association between air pollution and depressed mood in four European general population cohorts. METHODS: Data were obtained from LifeLines (the Netherlands), KORA (Germany), HUNT (Norway), and FINRISK (Finland). Residential exposure to particles (PM2.5, PM2.5absorbance, PM10) and nitrogen dioxide (NO2) was estimated using land use regression (LUR) models developed for the European Study of Cohorts for Air Pollution Effects (ESCAPE) and using European wide LUR models. Depressed mood was assessed with interviews and questionnaires. Logistic regression analyses were used to investigate the cohort specific associations between air pollution and depressed mood. RESULTS: A total of 70,928 participants were included in our analyses. Depressed mood ranged from 1.6% (KORA) to 11.3% (FINRISK). Cohort specific associations of the air pollutants and depressed mood showed heterogeneous results. For example, positive associations were found for NO2 in LifeLines (odds ratio [OR]=1.34; 95% CI: 1.17, 1.53 per 10 µg/m(3) increase in NO2), whereas negative associations were found in HUNT (OR=0.79; 95% CI: 0.66, 0.94 per 10 µg/m(3) increase in NO2). CONCLUSIONS: Our analyses of four European general population cohorts found no consistent evidence for an association between ambient air pollution and depressed mood.

Osmotically driven drug delivery through remote-controlled magnetic nanocomposite membranes.

Implantable drug delivery systems can provide long-term reliability, controllability, and biocompatibility, and have been used in many applications, including cancer pain and non-malignant pain treatment. However, many of the available systems are limited to zero-order, inconsistent, or single burst event drug release. To address these limitations, we demonstrate prototypes of a remotely operated drug delivery device that offers controllability of drug release profiles, using osmotic pumping as a pressure source and magnetically triggered membranes as switchable on-demand valves. The membranes are made of either ethyl cellulose, or the proposed stronger cellulose acetate polymer, mixed with thermosensitive poly(N-isopropylacrylamide) hydrogel and superparamagnetic iron oxide particles. The prototype devices' drug diffusion rates are on the order of 0.5-2 µg/h for higher release rate designs, and 12-40 ng/h for lower release rates, with maximum release ratios of 4.2 and 3.2, respectively. The devices exhibit increased drug delivery rates with higher osmotic pumping rates or with magnetically increased membrane porosity. Furthermore, by vapor deposition of a cyanoacrylate layer, a drastic reduction of the drug delivery rate from micrograms down to tens of nanograms per hour is achieved. By utilizing magnetic membranes as the valve-control mechanism, triggered remotely by means of induction heating, the demonstrated drug delivery devices benefit from having the power source external to the system, eliminating the need for a battery. These designs multiply the potential approaches towards increasing the on-demand controllability and customizability of drug delivery profiles in the expanding field of implantable drug delivery systems, with the future possibility of remotely controlling the pressure source.

First isolation of Coxiella burnetii from clinical material by cell-free medium (ACCM2).

A disadvantage in Q fever diagnostics and research is the insensitive and difficult culture of Coxiella burnetii. This intracellular organism can only be isolated using embryonated eggs, animal hosts, or mammalian cell culture. In consequence, it has only been possible to isolate a few strains from human patients. Here, we describe the first isolation of C. burnetii from a clinical specimen using the recently developed cell-free medium acidified citrate cysteine medium 2 (ACCM2). We screened the sera of 217 patients who had undergone valvular transplantation but detected one serum with an antibody constellation indicating chronic Q fever. Polymerase chain reaction (PCR) of the corresponding heart valve revealed 3.1 × 10(5) copies/rxn. The strain was successfully isolated using ACCM2. Genomic investigation by multilocus variable-number of tandem repeat (VNTR) analysis (MLVA) revealed the strain to be a new genotype, A10, closely related to one from sheep. As the sensitivity of ACCM2 for different human strains is unknown, we also investigated combining a robust test, egg propagation, with ACCM2. This combination produced four to six logs of growth of the bacteria. The use of ACCM2 in this combination simplified the otherwise elaborate purification steps. Cultivation in ACCM2 has the potential to simplify the isolation of C. burnetii in a clinical setting. As the success rates of cell culture for virulent C. burnetii strains are variable, the sensitivity of ACCM2 for different strains is unknown, and many specimens may contain much fewer bacteria than in our case, the combination of the robust method of egg propagation with ACCM2 is a good alternative to existing single methods for investigating critical specimens.

[Capacity Building for Prevention and Health Promotion for Children and Parents in a Deprived Urban Quarter: Lenzgesund]. / Strukturbildung für Prävention und Gesundheitsförderung bei Kindern und Eltern in einem benachteiligten Quartier: Lenzgesund.

In 2005 the local health authority Hamburg-Eimsbüttel developed a prevention programme for the disadvantaged quarter "Lenzsiedlung" which has been implemented by the stakeholders committee "Round Table Lenzgesund" and other partners led by the health authority. The Department of Medical Sociology and Health Economics of the University Medical Centre had taken on the accompanying analysis and long-term evaluation with a mixture of qualitative and quantitative methods for health reporting and evaluation and a new instrument for measuring capacity building in the quarter (KEQ).

A novel approach for discovering human behavior patterns using unsupervised methods.

BACKGROUND: As is well known, elderly people gradually lose the ability of self-care. The decline can be reflected in changes in their daily life behavior. A solution to assess their health status is to design sensor-enhanced living environments to observe their behavior, in which unobtrusive sensors are usually used. With respect to information extraction from the dataset collected by means of these kinds of sensors, unsupervised methods have to be relied on for practical application. Under the assumption that human lifestyle is associated with health status, this study intends to propose a novel approach to discover behavior patterns using unsupervised methods. METHODS: To evaluate the feasibility of this approach it was applied to datasets collected in the GAL-NATARS study. The study is part of the Lower Saxony research network Design of Environments for Aging (GAL) and conducted in subjects' home environments. The subjects recruited in GAL-NATARS study are older people (age ≥ 70 years), who are discharged from hospital to live alone again at their homes after treatment of a femoral fracture. RESULTS: The change of lifestyle regularity is measured. By analyzing the correlation between the extracted information and medical assessment results of four subjects, two of them exhibited impressive association and the other two showed less association. CONCLUSIONS: The approach may provide complementary information for health assessment; however, the dominant relationship between the change of behavior patterns and the health status has to be shown and datasets from more subjects must be collected in future studies. LIMITATIONS: Merely environmental data were used and no wearable sensor for activity detection or vital parameter measurement is taken into account. Therefore, this cannot comprehensively reflect reality.

Multimodal sensor-based fall detection within the domestic environment of elderly people.

BACKGROUND: Falls represent a major threat to the health of the elderly and are a growing burden on the healthcare systems. With the growth of the elderly population within most societies efficient fall detection becomes increasingly important; however, existing fall detection systems still fail to produce reliable results. OBJECTIVES: A study was carried out on sensor-based fall detection, analysis of falls with the help of fall protocols and the analysis of user acceptance of fall detection sensor technology through questionnaires. MATERIAL AND METHODS: A total of 28 senior citizens were recruited from a German community-dwelling population. The primary goal was a sensor-based detection of falls with accelerometers, video cameras and microphones. Details of the falls were analyzed with the help of medical geriatric assessments and standardized fall protocols. The study duration was 8 weeks and required a maximum of nine visits per subject. RESULTS: The study participants were 28 subjects with a mean age of 74.3 and a standard deviation (SD) of ± 6.3 years of which 12 were male and 16 female. A total of 1225.7 measurement days were recorded from all participants and the algorithms detected 2.66 falls per day. During the study period 15 falls occurred and 12 of these falls were correctly recognized by the fall detection system. CONCLUSION: Current fall detection technologies work well under laboratory conditions but it is still problematic to produce reliable results when these technologies are applied to real life conditions. Acceptance towards the sensors decreased after study participation although the system was generally perceived as useful or very useful.

Murine solid tumours as a novel model to study bacterial biofilm formation in vivo.

Bacteria of many species are able to invade and colonize solid tumours in mice. We have focused on Salmonella enterica serovar Typhimurium. Detailed analysis revealed that such tumour-invading Salmonella form biofilms, thus providing a versatile in vivo test system for studying bacterial phenotypes and host-pathogen interactions. It appears that biofilm formation by S. typhimurium is induced as a defence against the immune system of the host, and in particular against neutrophils. Further, we extended our work to the clinically more relevant biofilm infection by Pseudomonas aeruginosa. The induction of P. aeruginosa biofilms in neoplastic tissue appears to be elicited as a reaction against the immune system. Reconstitution experiments reveal that T cells are responsible for biofilm induction. Isogenic mutants that are no longer able to form biofilms can be used for comparison studies to determine antimicrobial resistance, especially therapeutic efficacy against P. aeruginosa located in biofilms.

ERG induces a mesenchymal-like state associated with chemoresistance in leukemia cells.

Overexpression of the oncogene ERG (ETS-related gene) is an adverse prognostic factor in acute myeloid and T-cell lymphoblastic leukemia (AML and T-ALL). We hypothesize that ERG overexpression is associated with primary drug resistance thereby influencing the outcome in leukemia. We previously reported a cell-line based model of ERG overexpression which induced a potentially chemo-resistant spindle shape cell type. Herein, we report a specific transcriptional gene signature for the observed spindle shaped morphology. Genes significantly over-expressed after ERG induction strongly resembled adhesive mesenchymal-like genes that included integrins (ITGA10, ITGB5, ITGB3, ITGA2B), CD44, and CD24. Interestingly, the mesenchymal-like signature was accompanied by the repression of DNA chromatin remodeling and DNA repair genes, such as CHEK1, EZH2, SUZ12, and DNMT3a. The ERG-induced mesenchymal-like signature positively correlated with TMPRSS2-ERG prostate tissues and invasive breast cancer mRNA expression datasets reflecting a general ERG-driven pattern of malignancy. Furthermore, inhibitors modulating ERG druggable pathways WNT, PKC, and AKT, and chemotherapeutic agent cytarabine revealed ERG-induced drug resistance. In particular, PKC412 treatment enhanced proliferative rates and promoted spindle shape formation in ERG-induced cells. Nilotinib and dasatinib were effective at abolishing ERG-induced cells. Moreover, ERG overexpression also led to an increase in double strand breaks. This report provides mechanistic clues into ERG-driven drug resistance in the poor prognostic group of high ERG expressers, provides insight to improved drug targeted therapies, and provides novel markers for a mesenchymal-like state in acute leukemia.