High-Throughput Miniaturized Synthesis of PROTAC-Like Molecules.

The development of miniaturized high-throughput in situ screening platforms capable of handling the entire process of drug synthesis to final screening is essential for advancing drug discovery in the future. In this study, an approach based on combinatorial solid-phase synthesis, enabling the efficient synthesis of libraries of proteolysis targeting chimeras (PROTACs) in an array format is presented. This on-chip platform allows direct biological screening without the need for transfer steps.  UV-induced release of target molecules into individual droplets facilitates further on-chip experimentation. Utilizing a mitogen-activated protein kinase kinases (MEK1/2) degrader as a template, a series of 132 novel PROTAC-like molecules is synthesized using solid-phase Ugi reaction. These compounds are further characterized using various methods, including matrix-assisted laser desorption ionization mass spectrometry (MALDI-MS) imaging, while consuming only a few milligrams of starting materials in total. Furthermore, the feasibility of culturing cancer cells on the modified spots and quantifying the effect of MEK suppression is demonstrated. The miniaturized synthesis platform lays a foundation for high-throughput in situ biological screening of potent PROTACs for potential anticancer activity and offers the potential for accelerating the drug discovery process by integrating miniaturized synthesis and biological steps on the same array.

Phylogenomics and biogeography of sawflies and woodwasps (Hymenoptera, Symphyta).

Phylogenomic approaches have recently helped elucidate various insect relationships, but large-scale comprehensive analyses on relationships within sawflies and woodwasps are still lacking. Here, we infer the relationships and long-term biogeographic history of these hymenopteran groups using a large dataset of 354 UCE loci collected from 385 species that represent all major lineages. Early Hymenoptera started diversifying during the Early Triassic âˆ¼249 Ma and spread all over the ancient supercontinent Pangaea. We recovered Xyeloidea as a monophyletic sister group to other Hymenoptera and Pamphilioidea as sister to Unicalcarida. Within the diverse family Tenthredinidae, our taxonomically and geographically expanded taxon sampling highlights the non-monophyly of several traditionally defined subfamilies. In addition, the recent removal of Athalia and related genera from the Tenthredinidae into the separate family Athaliidae is supported. The deep historical biogeography of the group is characterised by independent dispersals and re-colonisations between the northern (Laurasia) and southern (Gondwana) palaeocontinents. The breakup of these landmasses led to ancient vicariance in several Gondwanan lineages, while interchange across the Northern Hemisphere has continued until the Recent. The little-studied African sawfly fauna is likewise a diverse mixture of groups with varying routes of colonization. Our results reveal interesting parallels in the evolution and biogeography of early hymenopterans and other ancient insect groups.

Efficacy and safety of tixagevimab/cilgavimab as passive immunisation against COVID-19 infections in patients with hematological malignancies.

Monoclonal antibodies, as tixagevimab/cilgavimab, have been introduced as prophylaxis against COVID-19 infections in high-risk populations. However, data on efficacy are limited. This study investigates efficacy and tolerability of tixagevimab/cilgavimab in hematological patients under real-life conditions. Tixagevimab/cilgavimab was administered to 155 hematological patients (March-August 2022) at two Austrian centres. S/RBD-antibody assessments were performed before (T0), four weeks (T1), and six months (T2) after application. Side effects, the occurrence of COVID-19 infections, and the course of S/RBD-antibody titres were analysed retrospectively in relation to clinical variables. 155 hematological patients, who refused tixagevimab/cilgavimab, were included as a control group to compare the frequency of COVID-19 infections. Of all immunised patients (52.3% males; 91% triple vaccinated), 25.8% had a COVID-19 breakthrough infection (76% mild) compared to 43.9% in the control group. Patients with chronic lymphocytic leukaemia (CLL)/lymphoma were at highest risk of a COVID-19 infection (OR = 2.21; 95% CI 1.05-4.65; p = 0.037). After immunisation, a steep increase in median antibody levels (1193.4BAU/ml, IQR 0-2318.94) was observed in 67.8%, followed by a rapid decrease between T1 and T2 (465.95BAU/ml, IQR 0-1900.65.3) with the greatest declines in CLL/lymphoma (848.7BAU/ml, IQR 0-1949.6, p = 0.026). Side-effects occurred in 21.2% (CTCAE I/II). These real-world data indicate that S/RBD antibodies respond rapidly after passive immunisation in all hematological patients without safety concerns. Given the rapid decline in S/RBD antibodies, early booster immunisations should be considered for future scenarios in this vulnerable group.

ROP-ET: a prospective phase III trial investigating the efficacy and safety of ropeginterferon alfa-2b in essential thrombocythemia patients with limited treatment options.

Interferon-based therapies, such as ropeginterferon alfa-2b have emerged as promising disease-modifying agents for myeloproliferative neoplasms (MPNs), including essential thrombocythemia (ET). Current ET treatments aim to normalize hematological parameters and reduce the thrombotic risk, but they do not modify the natural history of the disease and hence, have no impact on disease progression. Ropeginterferon alfa-2b (trade name BESREMi®), a novel, monopegylated interferon alfa-2b with an extended administration interval, has demonstrated a robust and sustained efficacy in polycythemia vera (PV) patients. Given the similarities in disease pathophysiology and treatment goals, ropeginterferon alfa-2b holds promise as a treatment option for ET. The ROP-ET trial is a prospective, multicenter, single-arm phase III study that includes patients with ET who are intolerant or resistant to, and/or are ineligible for current therapies, such as hydroxyurea (HU), anagrelide (ANA), busulfan (BUS) and pipobroman, leaving these patients with limited treatment options. The primary endpoint is a composite response of hematologic parameters and disease-related symptoms, according to modified European LeukemiaNet (ELN) criteria. Secondary endpoints include improvements in symptoms and quality of life, molecular response and the safety profile of ropeginterferon alfa-2b. Over a 3-year period the trial assesses longer term outcomes, particularly the effects on allele burden and clinical outcomes, such as disease-related symptoms, vascular events and disease progression. No prospective clinical trial data exist for ropeginterferon alfa-2b in the planned ET study population and this study will provide new findings that may contribute to advancing the treatment landscape for ET patients with limited alternatives. TRIAL REGISTRATION: EU Clinical Trials Register; EudraCT, 2023-505160-12-00; Registered on October 30, 2023.

Upregulation of Checkpoint Ligand Programmed Death-Ligand 1 in Patients with Paroxysmal Nocturnal Hemoglobinuria Explained by Proximal Complement Activation.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hemolytic disease driven by impaired complement regulation. Mutations in genes encoding the enzymes that build the GPI anchors are causative, with somatic mutations in the PIG-A gene occurring most frequently. As a result, the important membrane-bound complement regulators CD55 and CD59 are missing on the affected hematopoietic stem cells and their progeny, rendering those cells vulnerable to complement attack. Immune escape mechanisms sparing affected PNH stem cells from removal are suspected in the PNH pathogenesis, but molecular mechanisms have not been elucidated. We hypothesized that exuberant complement activity in PNH results in enhanced immune checkpoint interactions, providing a molecular basis for the potential immune escape in PNH. In a series of PNH patients, we found increased expression levels of the checkpoint ligand programmed death-ligand 1 (PD-L1) on granulocytes and monocytes, as well as in the plasma of PNH patients. Mechanistically, we demonstrate that complement activation leading to the decoration of particles/cells with C3- and/or C4-opsonins increased PD-L1 expression on neutrophils and monocytes as shown for different in vitro models of classical or alternative pathway activation. We further establish in vitro that complement inhibition at the level of C3, but not C5, inhibits the alternative pathway-mediated upregulation of PD-L1 and show by means of soluble PD-L1 that this observation translates into the clinical situation when PNH patients are treated with either C3 or C5 inhibitors. Together, the presented data show that the checkpoint ligand PD-L1 is increased in PNH patients, which correlates with proximal complement activation.

Nanoliter Scale Parallel Liquid-Liquid Extraction for High-Throughput Purification on a Droplet Microarray.

In the current drug discovery process, the synthesis of compound libraries is separated from biological screenings both conceptually and technologically. One of the reasons is that parallel on-chip high-throughput purification of synthesized compounds is still a major challenge. Here, on-chip miniaturized high-throughput liquid-liquid extraction in volumes down to 150 nL with efficiency comparable to or better than large-scale extraction utilizing separation funnels is demonstrated. The method is based on automated and programmable merging of arrays of aqueous nanoliter droplets with organic droplets. Multi-step extraction performed simultaneously or with changing conditions as well as handling of femtomoles of compounds are demonstrated. In addition, the extraction efficiency is analyzed with a fast optical readout as well as matrix-assisted laser desorption ionization-mass spectrometry on-chip detection. The new massively parallel and miniaturized purification method adds another important tool to the chemBIOS concept combining chemical combinatorial synthesis with biological screenings on the same miniaturized droplet microarray platform, which will be essential to accelerate drug discovery.

Artificial intelligence-based polyp size measurement in gastrointestinal endoscopy using the auxiliary waterjet as a reference.

BACKGROUND: Measurement of colorectal polyp size during endoscopy is mainly performed visually. In this work, we propose a novel polyp size measurement system (Poseidon) based on artificial intelligence (AI) using the auxiliary waterjet as a measurement reference. METHODS: Visual estimation, biopsy forceps-based estimation, and Poseidon were compared using a computed tomography colonography-based silicone model with 28 polyps of defined sizes. Four experienced gastroenterologists estimated polyp sizes visually and with biopsy forceps. Furthermore, the gastroenterologists recorded images of each polyp with the waterjet in proximity for the application of Poseidon. Additionally, Poseidon's measurements of 29 colorectal polyps during routine clinical practice were compared with visual estimates. RESULTS: In the silicone model, visual estimation had the largest median percentage error of 25.1 % (95 %CI 19.1 %-30.4 %), followed by biopsy forceps-based estimation: median 20.0 % (95 %CI 14.4 %-25.6 %). Poseidon gave a significantly lower median percentage error of 7.4 % (95 %CI 5.0 %-9.4 %) compared with other methods. During routine colonoscopies, Poseidon presented a significantly lower median percentage error (7.7 %, 95 %CI 6.1 %-9.3 %) than visual estimation (22.1 %, 95 %CI 15.1 %-26.9 %). CONCLUSION: In this work, we present a novel AI-based method for measuring colorectal polyp size with significantly higher accuracy than other common sizing methods.

Two Predators, One Prey - the Interaction Between Bacteriophage, Bacterivorous Ciliates, and Escherichia coli.

Bacterivorous ciliates and lytic bacteriophages are two major predators in aquatic environments, competing for the same type of prey. This study investigated the possible interaction of these different microorganisms and their influence on the activity of each other. Therefore, two bacterivorous ciliates, Paramecium sp. RB1 and Tetrahymena sp. RB2, were used as representative ciliates; a T4-like Escherichia coli targeting lytic bacteriophage as a model virus; and E. coli ATCC 25922 as a susceptible bacterial host and prey. The growth of the two ciliates with E. coli ATCC 25922 as prey was affected by the presence of phage particles. The grazing activity of the two ciliates resulted in more than a 99% reduction of the phage titer and bacterial cell numbers. However, viable phage particles were recovered from individual washed cells of the two ciliates after membrane filtration. Therefore, ciliates such as Paramecium sp. RB1 and Tetrahymena sp. RB2 can remove bacteriophages present in natural and artificial waters by ingesting the viral particles and eliminating bacterial host cells required for viral replication. The ingestion of phage particles may marginally contribute to the nutrient supply of the ciliates. However, the interaction of phage particles with ciliate cells may contribute to the transmission of bacteriophages in aquatic environments.

Digital assistance systems in the field of incontinence care for individuals in need of long-term care (EASY): study protocol of a stratified randomised controlled trial.

BACKGROUND: In general, urinary and faecal incontinence is a multifaceted problem that is associated with increasing burdens for those affected, a massive impairment of quality of life and economic consequences. Incontinence is associated with a high level of shame, which in particular reduces the self-esteem of those being incontinent and leads to additional vulnerability. Those affected by incontinence often perceive incontinence and the care they receiveas humiliating, hence they can no longer control their own urination; nursing care and cleansing support then lead to additional dependency. People with incontinence in need of care not uncommonly experience a poor communication and many taboos surrounding the issue as well as the use of force when incontinence products are changed. AIMS AND METHODS: This RCT aims to validate the benefits of using a digital assistance system to optimise incontinence care and to enable statements concerning the effect of the assistance technology on nursing and social structures and processes as well as on the quality of life from the perspective of the person in need of care. In a two-arm, stratified, randomised, controlled interventional study, primarily incontinence-affected residents of four inpatient nursing facilities will be examined (n = 80). One intervention group will be equipped with a sensor-based digital assistance system, which will transmit care-related information to the nursing staff (via smartphone). The collected data will be compared to the data of the control group. Primary endpoints are falls occurring; secondary endpoints are quality of life and sleep, sleep disturbances and material consumption. In addition, nursing staff (n = 15-20) will be interviewed regarding the effects, experience, acceptance and satisfaction. DISCUSSION: The RCT aims at the applicability and effect of assistance technologies on nursing structures and processes. It is assumed that, amongst other things, this technology may lead to a reduction of unnecessary checks and material changes, an improvement of life quality, an avoidance of sleep disturbances and thus an improvement of sleep quality as well as to a reduced risk of falling for people with incontinence in need of care. The further development of incontinence care systems is of social interest as this offers the prospect of improving the quality of care for nursing home residents with incontinence. TRAIL REGISTRATION: Approval of the RCT is granted by the Ethics Committee at the University of Applied Sciences Neubrandenburg (Reg.-Nr.: HSNB/190/22). This RCT is registered at the German Clinical Trials Register on July 8th, 2022, under the identification number DRKS00029635.

Uptake and accumulation of microplastic particles by two freshwater ciliates isolated from a local river in South Africa.

Microplastics are considered environmental pollutants of serious concern. In freshwater environments, they can affect aquatic biota and accumulate along the food web. Therefore, this study investigated the capacity of bacterivorous freshwater ciliates, essential members of the aquatic food chain, to ingest plain and fluorescently-labeled polystyrene microspheres. Two holotrich ciliates were isolated from a stream in KwaZulu-Natal (South Africa) and identified as members of the genera Paramecium and Tetrahymena based on morphological characteristics and 18S rRNA gene sequence analysis. While the larger bacterivorous ciliate Paramecium sp. strain RB1 ingested all three sizes of plain polystyrene microbeads tested (2,5,10 µm), the smaller sized Tetrahymena sp. strain RB2 only ingested microbeads of 2 and 5 µm. The two ciliates ingested polystyrene microbeads at rates ranging from 1650 to 3870 particles x ciliate-1 x hour-1 for all particle sizes ingested, matching rates determined for selected microbial prey (E. coli, S. cerevisiae) of similar size. The ability to ingest non-nutritious microplastic particles was confirmed for both ciliates using fluorescently-labeled microbeads as these were detected in food vacuoles by fluorescence microscopy. Therefore, ciliates such as Paramecium sp. strain RB1 and Tetrahymena sp. strain RB2 can contribute to the transfer and bioaccumulation of microplastics in freshwater food webs in South Africa.

Alterations in the Experience of Time, Space, and Intersubjectivity and the Interaction with Pre-Existent Psychopathology during the COVID-19 Pandemic.

BACKGROUND: The COVID-19 pandemic and the measures to protect the physically vulnerable may disproportionately affect people with mental health vulnerabilities, who receive psychotherapeutic inpatient treatment, as many of these measures impact the (inter)subjective space crucial to psychotherapy. OBJECTIVE: We investigate how people with pre-existing mental health conditions and healthcare professionals experienced changes linked to the COVID-19 pandemic. METHODS: During the first COVID-19 outbreak and lockdown in spring 2020, we conducted semi-structured interviews with patients and healthcare professionals at a clinic for psychosomatic medicine in Germany and analyzed them following the principles of descriptive phenomenology focusing on social interactions, intersubjectivity, and the therapeutic space. RESULTS: We conducted a total of >30 h of interviews with 19 patients and 17 healthcare professionals. Analyses revealed that the COVID-19 pandemic and the related measures have led to a sudden loss of a sense of normality. Participants experienced changes in the perception of time, space, self, and embodied interaction with others, resulting in a profound feeling of alienation and "unhomeliness" which seemed to magnify pre-existing psychopathology. The inpatient psychotherapeutic environment provided safety by offering spatial and temporal structures and opportunities for social interaction, supporting people to find new ways to be in a changed world. CONCLUSIONS: Our study shows that despite the threat of infection, it is vital to continue to provide people with psychological vulnerabilities with a safe therapeutic space in which to regain a sense of safety in a changed world. This is particularly important, as those people seem to suffer intensely from the collateral measures of a pandemic.

Evaluation of an elective ultrasound course for medical students.

To evaluate the educational benefits of teaching ultrasound in an elective radiological course for medical students. We conducted a single-center retrospective analysis of a one-week elective ultrasound course in which 39 medical students (25 female; median age 25.8 ± 2.8 years, range 21-35, 4th and 5th years of undergraduate medical education) participated as part of their radiological training. The students completed a pre- and post-course questionnaire using a five-point Likert scale for self-assessment of technical knowledge, confidence in the procedure regarding different organs, motivation for performing ultrasound, and the importance of ultrasound in medical education. The students also assessed the value of ultrasound teaching in the context of their general medical degree. Pre-test and post-test scores showed significantly improved radiology knowledge (p ≤ 0.001) concerning all abdominal organs (liver, spleen, gallbladder, kidney, urinary bladder, aorta and retroperitoneum). A significant improvement was registered in performing ultrasound of peripheral arteries and venous structures (each p = 0.001), and also of the thyroid gland (p = 0.006). General surveys at the end of the elective were overwhelmingly positive, with constructive criticism and complimentary comments. Systematic training in ultrasound markedly improved the students' skills. This was especially pronounced for solid organ structures, while students requested more education regarding the retroperitoneum and vascular structures. Teaching ultrasound in an elective hands-on training course improves anatomical understanding and practical skills associated with increased motivation. The results affirm the necessity and clinical relevance of the course during the radiological training of medical students.

Advancing Sustainable Development Goals with localised nature-based solutions: Opportunity spaces in the Lahn river landscape, Germany.

Nature-based solutions (NBS) are recognized as promising actions to alleviate societal challenges and achieve the United Nation's Sustainable Development Goals (SDGs). One scientific challenge to implement NBS in practice is to locate areas suitable for an effective implementation of NBS (opportunity spaces). Opportunity spaces either already host NBS that need to be safeguarded or restored, or provide the socio-ecological conditions for establishing new NBS. Complex methods have been proposed to model potential locations of selected NBS, but they are often too data and resource intensive to be applied in practice for landscape planning. The aim of this article is to put forward a pragmatic method for identifying NBS opportunity spaces that contribute to advance multiple SDGs, and to test its application in a participatory, extended peer-review process in the Lahn river landscape, Germany. Our method includes: (i) synthesizing a generic catalogue of NBS in river landscapes, (ii) estimating the potential of NBS to achieve simultaneously Lahn development goals (LDGs) and SDGs, and (iii) applying key spatial indicators and best available data to explore opportunity spaces for selected NBS. The generic catalogue provides a systematic overview of 650 individual NBS for river landscapes and their respective potentials for addressing LDGs and SDGs. The NBS Renaturalising floodplains through land use changes, Revitalising historic floodplains, and Creating buffer strips are those actions contributing to the greatest number of local SDGs (locally adapted SDGs that include LDGs). Results of the spatial analysis in the Lahn river landscape showed about 4739 ha of areas where NBS were already in place and need to be safeguarded and additional 1323 ha with opportunities for further NBS creation. The proposed method presents a robust and transferable approach that facilitates spatial mapping of NBS to local SDGs for planning practitioners facing time and resource constraints.

Manual emptying of ventilated improved pit latrines and hygiene challenges - a baseline survey in a peri-urban community in KwaZulu-Natal, South Africa.

The presence of Escherichia coli and Staphylococcus spp. was determined on the skin, personal protective equipment, the municipal vehicle, and various surfaces at ten households in a peri-urban community (KwaZulu-Natal, South Africa) before and after manual emptying of ventilated improved pit latrines. Surface samples (n = 14) were collected using sterile wet wipes, and target bacteria were detected using standard procedures. Additionally, E. coli was enumerated in soil samples from an area of open defecation (log10 3.7 MPN/g) and areas where geophagia occurred (log10 2.7 - log10 3.3 MPN/g), using a most probable number (MPN) method. The detection frequency for the target bacteria on household surfaces (e.g., the walkway between the pit latrine and the municipal vehicle) and on municipal workers' hands (which were frequently contaminated before pit emptying), occasionally increased after the pits were emptied, indicating that manual pit emptying might pose a potential health risk to workers and community members.

The impact of a tailored mindfulness-based program for resident physicians on distress and the quality of care: A randomised controlled trial.

BACKGROUND: Many resident physicians suffer from distress, which endangers their individual health and the quality of care. OBJECTIVE: To examine the impact of a tailored mindfulness-based program (MBP) for resident physicians on distress and the quality of care. METHODS: A single-centre, two-armed, longitudinal randomised controlled trial. The intervention group took part in an 8-week, tailored MBP that included a coursebook. The MBP was followed by a 4-month maintenance phase. The active control group received the coursebook for self-study. Assessments were at baseline (t0, 0 months), after the intervention (t1, 2 months), after the maintenance phase (t2, 6 months), and at follow-up (t3, 12 months). The primary outcome was a change in burnout at t2. Secondary outcomes included perceived stress, mental distress, perceived job strain, depression, anxiety, hair cortisol secretion, self-reported medical errors and third-party ratings by patients, supervisors and colleagues. RESULTS: Seventy-six participants were randomised to the intervention and 71 to the control group. The intervention group showed greater improvements in the primary outcome (burnout at t2, d = 0.32, p = 0.046), in perceived stress (d = 0.31, p = 0.046) and perceived job strain (d = 0.33, p = 0.026) at t1, and in supervisor rated empathy (d = 0.71, p = 0.037) and colleague rated attentiveness (d = 0.85, p = .006) at t2. There was no difference between groups in the other outcomes. CONCLUSION: A tailored MBP for resident physicians improved burnout and might have improved other aspects of distress and the quality of care.

The Role of Nitrogen-doping in the Catalytic Transfer Hydrogenation of Phenol to Cyclohexanone with Formic Acid over Pd supported on Carbon Nanotubes.

Highly selective one-step hydrogenation of phenol to cyclohexanone, an important intermediate in the production of nylon 6 and nylon 66, is desirable but remains a challenge. Pd nanoparticles supported on nitrogen- and oxygen-functionalized carbon nanotubes (NCNTs, OCNTs) were prepared, characterized, and applied in the hydrogenation of phenol to cyclohexanone to study the effect of N-doping. Almost full conversion of phenol with high selectivity to cyclohexanone was achieved over Pd/NCNT under mild reaction conditions using either H2 or formic acid (FA) as a hydrogen source. The effects of reaction temperature and FA/phenol ratio and the reusability were investigated. Separate FA decomposition experiments without and with the addition of phenol were performed to investigate the reaction mechanism, especially the deactivation behavior. Deactivation was observed for both catalysts during the FA decomposition, while only Pd/OCNT rather than Pd/NCNT was deactivated in the transfer hydrogenation with FA and the FA decomposition in the presence of phenol, indicating the unique role of N-doping. Therefore, we assume that deactivation is caused by the strongly bound formates on the active Pd sites, suppressing further FA decomposition and/or transfer hydrogenation on Pd. The nonplanar adsorption of phenol on NCNTs via weak O-H⋅⋅⋅N interactions enables the occurrence of the subsequent hydrogenation by adsorbed formate on Pd.

Development and evaluation of the focused assessment of sonographic pathologies in the intensive care unit (FASP-ICU) protocol.

BACKGROUND: The use of ultrasonography in the intensive care unit (ICU) is steadily increasing but is usually restricted to examinations of single organs or organ systems. In this study, we combine the ultrasound approaches the most relevant to ICU to design a whole-body ultrasound (WBU) protocol. Recommendations and training schemes for WBU are sparse and lack conclusive evidence. Our aim was therefore to define the range and prevalence of abnormalities detectable by WBU to develop a simple and fast bedside examination protocol, and to evaluate the value of routine surveillance WBU in ICU patients. METHODS: A protocol for focused assessments of sonographic abnormalities of the ocular, vascular, pulmonary, cardiac and abdominal systems was developed to evaluate 99 predefined sonographic entities on the day of admission and on days 3, 6, 10 and 15 of the ICU admission. The study was a clinical prospective single-center trial in 111 consecutive patients admitted to the surgical ICUs of a tertiary university hospital. RESULTS: A total of 3003 abnormalities demonstrable by sonography were detected in 1275 individual scans of organ systems and 4395 individual single-organ examinations. The rate of previously undetected abnormalities ranged from 6.4 ± 4.2 on the day of admission to 2.9 ± 1.8 on day 15. Based on the sonographic findings, intensive care therapy was altered following 45.1% of examinations. Mean examination time was 18.7 ± 3.2 min, or 1.6 invested minutes per detected abnormality. CONCLUSIONS: Performing the WBU protocol led to therapy changes in 45.1% of the time. Detected sonographic abnormalities showed a high rate of change in the course of the serial assessments, underlining the value of routine ultrasound examinations in the ICU. Trial registration The study was registered in the German Clinical Trials Register (DRKS, 7 April 2017; retrospectively registered) under the identifier DRKS00010428.

FDG PET correlates weakly with HIF-1α expression in solid tumors: a meta-analysis.

BACKGROUND: Hypoxia-inducible factor (HIF)-1α plays a key role in hypoxic adaptation of tumor cells. Overexpression of HIF-1α is associated with tumor aggressiveness and worse prognosis in several malignancies. Presumably, expression of HIF-1a may be reflected by positron emission tomography with 2-deoxy-2 [fluorine-18] fluoro-D-glucose (18F-FDG PET). There are inconsistent data about relationships between FDG PET and HIF-1α. PURPOSE: To provide evident data about associations between maximum standardized uptake value (SUVmax) and HIF-1α expression in solid tumors. MATERIAL AND METHODS: MEDLINE, SCOPUS, and EMBASE databases were screened for relationships between SUV and HIF-1α up to August 2019. Overall, 21 studies with 1154 patients were identified. The following data were extracted from the literature: authors; year of publication; number of patients; and correlation coefficients. RESULTS: Correlation coefficients between SUVmax and HIF-1α were in the range of -0.51-0.71. The pooled correlation coefficient was 0.27 (95% confidence interval [CI] = 0.14-0.41). Furthermore, correlation coefficients for some tumor entities were calculated. For this sub-analysis, data for primary tumors with >2 reports were included. The calculated correlation coefficients in the analyzed subgroups were as follows: head and neck squamous cell carcinoma: ρ = 0.25 (95% CI = 0.07-0.42); non-small lung cell cancer: ρ = 0.27 (95% CI = -0.14-0.67); uterine cervical cancer: ρ = -0.09 (95% CI = -0.89-0.71); thymic tumors: ρ = 0.39 (95% CI = 0.04-0.58). CONCLUSION: SUVmax of FDG PET correlated weakly with expression of HIF-1α both in overall sample and tumor subgroups. Therefore, FDG PET cannot be used for prediction of hypoxia in clinical practice.

Assessment of a taping method combined with manual therapy as a treatment of non-specific chronic low back pain - a randomized controlled trial.

BACKGROUND: Chronic low back pain is the most frequent medical problem and the condition with the most years lived with disability in Western countries. The objective of this study was to assess a new treatment, Medi-Taping, which aims at reducing complaints by treating pelvic obliquity with a combination of manual treatment of trigger points and kinesio taping in a pragmatic RCT with pilot character. METHODS: One hundred ten patients were randomized at two study centers either to Medi-Taping or to a standard treatment consisting of patient education and physiotherapy as control. Treatment duration was 3 weeks. Measures were taken at baseline, end of treatment and at follow-up after 2 months. Main outcome criteria were low back pain measured with VAS, the Chronic Pain Grade Scale (CPGS) and the Oswestry Low Back Pain Disability Questionnaire (ODQ). RESULTS: Patients of both groups benefited from the treatment by medium to large effect sizes. All effects were pointing towards the intended direction. While Medi-Taping showed slightly better improvement rates, there were no significant differences for the primary endpoints between groups at the end of treatment (VAS: mean difference in change 0.38, 95-CI [- 0.45; 1.21] p = 0.10; ODQ 2.35 [- 0.77; 5.48] p = 0.14; CPGS - 0.19 [- 0.46; 0.08] p = 0.64) and at follow-up. Health-related quality of life was significantly higher (p = .004) in patients receiving Medi-Taping compared to controls. CONCLUSIONS: Medi-Taping, a purported way of correcting pelvic obliquity and chronic tension resulting from it, is a treatment modality similar in effectiveness to complex physiotherapy and patient education. TRIAL REGISTRATION: This trial was registered retrospectively on July 24th, 2019 as Number DRKS00017051 in the German Register of Clinical Trials (Deutsches Register Klinischer Studien). URL of trial registry record: https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00017051 .

A phase 1 study to evaluate the feasibility and efficacy of the addition of ropeginterferon alpha-2b to imatinib treatment in patients with chronic phase chronic myeloid leukemia (CML) not achieving a deep molecular response (molecular remission 4.5)-AGMT_CML 1.

The goal of current management of patients with chronic phase chronic myeloid leukemia (CML) is to reach treatment-free remission with sustained deep molecular remission (DMR) being the prerequisite therefor. Second-generation tyrosine kinase inhibitors can induce deeper and faster remission than imatinib, but are often associated with severe adverse events (AEs). The combination of pegylated interferon (IFN) with imatinib was shown to induce higher molecular remissions than imatinib alone in two studies. Treatment discontinuation rates due to IFN induced AEs were high in both studies. To investigate safety, tolerability (primary objective), and efficacy (secondary objective) of the combination of imatinib with ropeginterferon alpha-2b this phase I study was initiated. Twelve patients were planned to be enrolled. Nine patients completed the study according to protocol. Three patients terminated the study early, one due to occurrence of a dose-limiting toxicity (neutropenia grade 3), one due to an AE (panic attacks grade 2) and one due to the patient's decision. Tolerability was good, non-hematologic AEs were mainly grade 1/2, hematologic AEs were mainly neutropenias. No new AEs were reported for the combination of imatinib and ropeginterferon alpha-2b. In a nondose-dependent manner the addition of ropeginterferon alpha-2b led to the achievement of a DMR in four out of nine patients after a treatment duration of 18 months. The combination of imatinib and ropeginterferon alpha-2b is safe and showed in this phase I study the ability to deepen the molecular response in patients with chronic phase CML not achieving a DMR with imatinib alone.