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Objective: The objective of this study was to identify place features associated with increased risk of drug-involved fatalities and generate a composite score measuring risk based on the combined effects of features of the built environment., Methods: We conducted a geospatial analysis of overdose data from 2022 to 2023 provided by the St. Louis County Medical Examiner's Office to test whether drug-involved deaths were more likely to occur near 54 different place features using Risk Terrain Modeling (RTM). RTM was used to identify features of the built environment that create settings of heightened overdose risk. Risk was estimated using Relative Risk Values (RRVs) and a composite score measuring Relative Risk Scores (RRS) across the county was produced for drugs, opioids, and stimulants, as well as by Black and White decedents., Results: In the model including all drugs, deaths were more likely to occur in close proximity to hotels/motels (RRV=39.65, SE=0.34, t-value=10.81 p<.001), foreclosures (RRV=4.42, SE=0.12, t-value = 12.80, p<.001), police departments (RRV=3.13, SE=0.24, t-score=4.86, p<.001), and restaurants (RRV=2.33, SE=0.12, t-value=7.16, p<.001). For Black decedents, deaths were more likely to occur near foreclosures (RRV=9.01, SE=0.18, t-value =11.92, p<.001), and places of worship (RRV= 2.51, SE=0.18, t-value = 11.92, p<.001). For White decedents, deaths were more likely to occur in close proximity to hotels/motels (RRV=38.97, SE=0.39, t-value=9.30, p<.001) foreclosures (RRV=2.57, SE=0.16, t-value =5.84, p<.001), restaurants (RRV=2.52, SE=0.17, t-value=5.33, p<.001) and, auto painting/repair shops (RRV=0.04, SE=0.18, t-value =3.39, p<.001)., Conclusion: These findings suggest that places of worship, the hospitality industry, and housing authorities may be physical features of the environment that reflect social conditions that are conducive to overdose. The scaling up of harm reduction strategies could be enhanced by targeting places where features are co-located., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: In Germany, homeless people are entitled to health care within the regular health care system. However, due to their specific living conditions they make little use of these services. In 2013, three Medical centres for the homeless (MCH) were opened in Hamburg to provide general health care. This study aims to analyse the consultation reasons and diagnoses prevalent among the homeless in comparison to regular primary care patients. It also examines the means and obstacles of integrating the homeless into Germany's regular health care system., Methods: From 2013 to 2014, routine medical data of all patients of the MCH consenting to participate in the study were analysed descriptively, in particular consultation reasons (categorised by ICPC-2), ICD-10 diagnoses and data on health insurance status and the use of the regular health care system. Consultation reasons and diagnoses of homeless patients were compared descriptively with data from regular general practices. Additionally, anonymous data on patient numbers, gender and insurance status was exported from the MCH's software and analysed descriptively for the years 2013 to 2020., Results: A total of 840 homeless patients in 2013 and 2014 gave consent to the evaluation of consultation reasons and diagnoses. The most frequent consultation reasons in the MCH in 2013 were skin conditions (24%), musculoskeletal conditions (16%) and psychological disorders (14%), in GP practices these were musculoskeletal conditions (22%), conditions affecting the digestive system (14%) and skin conditions (12%). Essential (primary) hypertension, diabetes mellitus type 2 and back pain are among the top-10-diagnoses in GP practices, as well as in MCH. With regard to the other top-10-diagnoses, there are clear differences between GP practices and MCH: "Psychological behavioural disorder due to alcohol" and diagnoses in connection with trauma, skin infections and acute respiratory infections stand out in MCH. 35% of the homeless patients reported a lack of health insurance as the reason for "not making use of" the regular health care system, while 10% reported they were unable to visit a regular general practitioner due to physical or psychological reasons. In the years 2013-2020 46% to 73% of the 8.380 MCH patients had no health care insurance., Conclusion: Patients consulting the MCH suffer from medical conditions typical for the homeless, namely skin diseases, wounds, injuries and behavioural disorders due to alcohol abuse, but also from "typical" symptoms in regular GP care as cough or lower back symptoms. Consultation reasons mostly are acute illnesses. Chronic diseases are equally present in regular GP and MCH patients, but pose a great challenge for the homeless among other things due to their irregular contact with the health care system. The lack of health insurance poses the greatest hurdle to the integration of the homeless into the regular health care system., (© 2023. The Author(s).)

Introduction: Foam Rolling (FR) as a technique of self-massage has become a widely used intervention in clinical and sports practice. It is assumed that FR leads to an increased intramuscular microvascular blood flow (MBF), and therefore is commonly recommended as a warm-up or regeneration method. However, no data validate the effects of FR on MBF. This study aimed to assess whether FR increases intramuscular MBF using contrast-enhanced ultrasound (CEUS)., Methods: Ten healthy athletes performed a standardized FR intervention applied to the lateral thigh (3 sets: 45 s FR, 20 s rest). Intramuscular perfusion was determined by CEUS under resting conditions (t 0 ), immediately (t 1 ), and 30 min (t 2 ) after the intervention. Peak enhancement (PE), wash-in rate (WiR), and wash-in perfusion index (WiPI) were evaluated as quantitative perfusion parameters in vastus lateralis (VL) and intermedius (VI) muscle separately via regions of interest mapping., Results: Immediately after the intervention (t 1 ), perfusion parameters showed a non-significant decrease in VL (p = 0.3; PE: -32.1%, WiPI: -29.6%, WiR: -50.4%) and VI (p = 0.4; PE: -10.3%, WiPI: -6.4%, WiR: -35.6%). A non-significant decrease was found at t 2 in VL (p = 0.2; PE: -34%, WiPI -33.9%, WiR -61.2%) and VI (p = 0.2; PE -17.6%, WiPI -13.8%, WiR -43.2%)., Conclusions: The common assumption of intramuscular MBF improvement due to FR could not be confirmed for up to 30 min after the intervention. If an increase in intramuscular metabolism or MBF is intended, we recommend that alternative methods (i.e., traditional warm-up) should be preferred., Competing Interests: Declaration of competing interest None declared., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Purpose: Even though the number of hematological cancer survivors suffering from long-term and late consequences of their disease is growing, knowledge about their situation regarding partnership, sexuality, and fertility-related communication is sparse to date., Methods: We recruited survivors of hematological malignancies (≥ 3 years after diagnosis) from two cancer registries in Germany. We applied validated instruments and study-specific items on satisfaction with partnership, sexual functioning, and fertility-related communication with physicians. We provided descriptive statistics and conducted multiple regression analyses to identify associations of the outcomes with patient factors and well-being (anxiety, depression, and quality of life)., Results: Of 2001 eligible survivors, 922 (46%) participated. Fifty-seven percent were male, and the mean age was 64 years. Ninety percent and 60% reported to be satisfied with their partnership and sexual life, respectively. However, 81% and 86% reported being sexually impaired by physical or mental symptoms, respectively. Seventy-four percent of those with incomplete family planning had a fertility-related conversation with a physician. Female gender (p < .05, Beta =  - .09), older age (p < .01, Beta = .10), and chemotherapy (p < .01, Beta = .10) were associated with less sexual pleasure caused by physical impairment. Satisfaction with partnership (p < .001, Beta = .22), satisfaction with sexual life (p < .001, Beta = .28), and conversation about fertility (p < .05, Beta = .26) were associated with better quality of life., Conclusion: Even though long-term survivors seem to be generally satisfied with their partnership and sexual life, they may suffer from specific impairments. Our findings need to be verified in longitudinal studies., (© 2022. The Author(s).)

Background: During eye development the lens placode invaginates to form the lens pit. Further bending of lens epithelium and separation from ectoderm leads eventually to a spherical lens vesicle with enclosed extracellular fluid. Changes in epithelial morphology involve the actin cytoskeleton and its regulators. The myosin Myo9b is simultaneously an actin-based motor and Rho GTPase-activating protein that regulates actin cytoskeleton organization. Myo9b-deficient adult mice and embryos were analyzed for eye malformations and alterations in lens development., Results: Myo9b-deficient mice showed a high incidence of microphthalmia and cataracts with occasional blepharitis. Formation of the lens vesicle during embryonic lens development was disordered in virtually all embryos. Lens placode invagination was less deep and gave rise to a conical structure instead of a spherical pit. At later stages either no lens vesicle was formed or a significantly smaller one that was not enclosed by the optic cup. Expression of the cell fate marker Pax6 was not altered. Staining of adherens junctions and F-actin was most intense at the tip of conical invaginations, suggesting that mechanical forces are not properly coordinated between epithelial cells that form the pit., Conclusions: Myo9b is a critical regulator of ocular lens vesicle morphogenesis during eye development., (© 2022 The Authors. Developmental Dynamics published by Wiley Periodicals LLC on behalf of American Association for Anatomy.)

Background: Recovery housing plays an important role in supporting individuals in their recovery by building recovery capital and providing stable living environments; however, the extent to which medications for opioid use disorder (MOUD), the gold standard for OUD treatment, are accepted in recovery housing settings is unclear. The purpose of this study, as part of a larger statewide evaluation of Missouri recovery homes, was to identify the extent to which Missouri recovery houses were accepting of methadone, buprenorphine, and naltrexone as well as the extent to which the acceptance of each medication was linked to whether the recovery home encouraged tapering off MOUDs., Methods: Sixty-four recovery housing managers and/or staff, out of 66 eligible recovery homes in Missouri completed the survey., Results: Results indicated that methadone was the least accepted medication for long-term use followed by buprenorphine and then naltrexone. Recovery houses that had significantly lower overall acceptance of methadone encouraged tapering; however, the overall acceptance for buprenorphine and naltrexone was not significantly related to the encouragement of tapering off MOUDs., Conclusion: This work highlights the need to develop reliable instruments to measure and assess MOUD-capable recovery homes and to increase knowledge and acceptance of MOUD within recovery home settings., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The primary goal of this study is the formulation of a soft sensor that predicts industrially relevant mechanical properties for freeform bending. This serves as the foundation of a closed-loop property control. It is hypothesized that by inline measurement of hardness, predictions regarding residual hoop stresses, local strength and strain level can be achieved. A novel hardness-based correlation scheme is introduced, which is implemented into an extended Kalman filter (EKF) and allows an inline prediction of local strength, residual hoop stresses and plasticity. Furthermore, the ultrasonic contact impedance (UCI) method is validated as a suitable inline measuring solution.

To migrate, cells assume a polarized morphology, extending forward with a leading edge with their trailing edge retracting back toward the cell body. Both cell extension and retraction critically depend on the organization and dynamics of the actin cytoskeleton, and the small, monomeric GTPases Rac and Rho are important regulators of actin. Activation of Rac induces actin polymerization and cell extension, whereas activation of Rho enhances acto-myosin II contractility and cell retraction. To coordinate migration, these processes must be carefully regulated. The myosin Myo9b, a Rho GTPase-activating protein (GAP), negatively regulates Rho activity and deletion of Myo9b in leukocytes impairs cell migration through increased Rho activity. However, it is not known whether cell motility is regulated by global or local inhibition of Rho activity by Myo9b. Here, we addressed this question by using Myo9b-deficient macrophage-like cells that expressed different recombinant Myo9b constructs. We found that Myo9b accumulates in lamellipodial extensions generated by Rac-induced actin polymerization as a function of its motor activity. Deletion of Myo9b in HL-60-derived macrophages altered cell morphology and impaired cell migration. Reintroduction of Myo9b or Myo9b motor and GAP mutants revealed that local GAP activity rescues cell morphology and migration. In summary, Rac activation leads to actin polymerization and recruitment of Myo9b, which locally inhibits Rho activity to enhance directional cell migration., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Novel treatments for glioblastoma, the most common malignant primary brain tumor, are urgently required. Type I interferons (IFN) are natural cytokines primarily involved in the defense against viral infections, which may also serve a role in the control of cancer, notably in the suppression of the cancer stem cell phenotype. TG02 is a novel orally available cyclin-dependent kinase 9 inhibitor which induces glioma cell apoptosis without profound caspase activation, which is currently explored in early clinical trials in newly diagnosed and recurrent glioblastoma. In the present study, human glioma-initiating cell line models were used to explore whether IFN-β modulates the anti-glioma activity of TG02. The present study employed immunoblotting to assess protein levels, several viability assays and gene silencing strategies to assess gene function. Pre-exposure to IFN-β sensitized human glioma models to a subsequent exposure to TG02. Combination treatment was associated with increased DEVD-amc cleaving caspase activity that was blocked by the anti-apoptotic protein, BCL2. However, BCL2 did not protect from the synergistic effects of IFN and TG02 on glioma cell growth. Furthermore, although IFN strongly induced pro-apoptotic XIAP-associated factor (XAF) expression, disrupting XAF expression did not abrogate the synergy with TG02. Consistent with that, caspase 3 gene silencing did not abrogate the effects of TG02 or IFN-β alone or in combination. Finally, it was observed that IFN-β may indeed modulate the effects of TG02 upstream in the signaling cascade since inhibition of RNA polymerase II phosphorylation, a direct readout of the pharmacodynamic activity of TG02, was facilitated when glioma cells were pre-exposed to IFN-β. In summary, these data suggest that type I IFN may be combined with TG02 to limit glioblastoma growth, but that the well characterized effects of IFN and TG02 on apoptotic signaling are dispensable for synergistic tumor growth inhibition. Instead, exploring how IFN signaling primes glioma cells for TG02-mediated direct target inhibition may help to design novel and effective pharmacological approaches to glioblastoma., (Copyright: © Lohmann et al.)

Background: Type I interferons (IFN-α/β) are cytokines that are typically expressed in response to double-stranded RNA associated with viral infections. Glioblastomas are the most common malignant primary brain tumors, characterized by an infiltrative growth pattern and prominent angiogenic activity, and thought to be maintained by a subpopulation of glioma-initiating (stem-like) cells (GICs). The growth of human GIC lines is highly sensitive to IFN-β., Methods: Repetitive pulse stimulation with IFN-β1a (IS) was used to generate IS sublines that had acquired resistance to IFN-β-induced suppression of sphere formation. These cell lines were characterized by analyses of type 1 IFN signaling, growth patterns, and transcriptomic profiles., Results: Here we report that repetitive IFN-β1a stimulation (IS) induces a stable phenotype (referred to as IS) at the level of maintaining sphere formation, although classical IFN signaling defined by the expression of both IFN receptors, myxovirus resistance protein A (MxA) accumulation, and STAT1 induction is unaffected. Furthermore, this stably altered IS phenotype is characterized by constitutively decreased sphere formation capacity and morphological features of senescence and autophagy. Transcriptional profiling reveals increased type I IFN signaling in these IS cells, but decreased expression of genes involved in receptor signaling and cell migration., Conclusions: Altogether, these data suggest a role for promoting IFN-β signaling in glioblastoma and might provide clues to design future therapeutic approaches., (© The Author(s) 2020. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

TG02 is a novel cyclin-dependent kinase (CDK) inhibitor and thought to act mainly via CDK-9 inhibition-dependent depletion of short-lived oncoproteins such as MCL-1 or c-MYC. We studied the activity of TG02 in 9 human long-term glioma cell lines (LTC) and 5 glioma-initiating cell lines (GIC) using various cell death assays in vitro and in the LN-229 LTC and ZH-161 GIC models in vivo. TG02 exhibits strong anti-tumor cell activity with EC 50 concentrations in the nanomolar range. Median survival in the LN-229 and ZH-161 models was moderately prolonged by TG02. Neither constitutive CDK levels nor those of MCL-1 or c-MYC correlated with sensitivity to TG02. Cdk-9 or cdk-5 gene silencing alone did not fully reproduce the effects of TG02. C-myc gene silencing inhibited cell growth, but did not modulate TG02 activity. Electron microscopy revealed cell death to be essentially apoptotic. High concentrations of TG02 induced annexin V binding and minor caspase 3 cleavage, but the pan-caspase inhibitor, zVAD-fmk, or BCL-2 or MCL-1 gene transfer only moderately attenuated TG02-induced cell death, and caspase inhibition did not prevent loss of MCL-1 or c-MYC. TG02 activity was independent of O 6 -methylguanine DNA methyltransferase expression. Repetitive exposure to TG02 did not generate an acquired TG02 resistance phenotype, but accumulation of MCL-1, loss of c-MYC, or senescence. TG02 is a highly potent apoptosis-inducing agent in glioma cells in vitro. Caspase inhibition does not rescue TG02-treated cells and repetitive exposure fails to confer acquired resistance, supporting the clinical evaluation of TG02 in glioblastoma., (© 2018 UICC.)

The poor prognosis associated with advanced age in patients with glioblastoma remains poorly understood. Glioblastoma in the elderly has been particularly associated with vascular endothelial growth factor (VEGF)-dependent angiogenesis, and early uncontrolled studies suggested that the anti-angiogenic agent bevacizumab (BEV), an antibody to VEGF, might be preferentially active in this patient population. Accordingly, we explored host age-dependent differences in survival and benefit from radiotherapy (RT) or BEV in syngeneic mouse glioma models. Survival was inferior in older mice in the SMA-540 and and less so in SMA-560, but not in the SMA-497 or GL-261 models. Detailed flow cytometric studies revealed increased myeloid and decreased effector T cell population frequencies in SMA-540 tumors of old compared to young mice, but no such difference in the SMA-497 model. Bone marrow transplantation (BMT) from young to old mice had no effect, whereas survival was reduced with BMT from old to young mice. BEV significantly decreased vessel densities in gliomas of old, but not young mice. Accordingly, old, but not young SMA-540 tumor-bearing mice benefited from BEV alone or in combination with RT. End-stage tumors of old BEV- and BEV/RT-treated mice exhibited increased infiltration of T helper and cytotoxic T cells compared to tumors of young mice. The SMA-540 model may provide a valuable tool to evaluate the influence of host age on glioblastoma progression and treatment response. The biological host factors that modulate glioma growth in old as opposed to young mice remain to be identified., Competing Interests: CONFLICTS OF INTEREST HGW received compensation from Roche for advisory boards. GT received research and travel grants and honoraria for lectures and advisory board participation from Roche and BMS. MW has received research grants from Acceleron, Actelion, Bayer, Isarna, MSD, Merck & Co, Novocure, Piqur and Roche and honoraria for lectures or advisory board participation or consulting from BMS, Celldex, Immunocellular Therapeutics, Isarna, Magforce, MSD, Merck & Co, Northwest Biotherapeutics, Novocure, Pfizer, Roche, Teva and Tocagen. The other authors declare no conflicts of interest.

Background: Pro-inflammatory cytokines are known to have deleterious effects on Schwann cells (SCs). Interleukin 17 (IL-17) is a potent pro-inflammatory cytokine that exhibits relevant effects during inflammation in the peripheral nervous system (PNS), and IL-17-secreting cells have been reported within the endoneurium in proximity to the SCs., Methods: Here, we analyzed the effects of IL-17 on myelination and the immunological properties of SCs. Dorsal root ganglia (DRG) co-cultures containing neurons and SCs from BL6 mice were used to define the impact of IL-17 on myelination and on SC differentiation; primary SCs were analyzed for RNA and protein expression to define the putative immunological alignment of the SCs., Results: SCs were found to functionally express the IL-17 receptors A and B. In DRG cultures, stimulation with IL-17 resulted in reduced myelin synthesis, while pro-myelin gene expression was suppressed at the mRNA level. Neuronal outgrowth and SC viability, as well as structural myelin formation, remained unaffected. Co-cultures exhibited SC-relevant pro-inflammatory markers, such as matrix metalloproteinase 9 and SCs significantly increased the expression of the major histocompatibility complex (MHC) I and exhibited a slight, nonsignificant increase in expression of MHCII, and a transporter associated with antigen presentation (TAP) II molecules relevant for antigen processing and presentation., Conclusions: IL-17 may act as a myelin-suppressive mediator in the peripheral nerve, directly propagating SC-mediated demyelination, paralleled by an inflammatory alignment of the SCs. Further analyses are warranted to elucidate the role of IL-17 during inflammation in the PNS in vivo, which could be useful in the development of target therapies.

This note addresses the problem of instability in frequency weighted controller reduction methods based on similarity transformations. The aim is to reduce the complexity of the controllers derived by modern controller design packages for practical applications. For a given controller a framework is proposed that parameterizes a set of reduced controllers that preserve the stability of the closed loop system. Then based on this result a complementary algorithm to obtain a stabilizing stable reduced controller based on the two sided frequency weighted reduction method is presented. In addition, a sufficient condition for the existence of such a framework is derived.

We have investigated the electron impact single ionization of the hydrogen molecule, with fully determined kinematics. The experimental and theoretical results are compared with He ionization under the same conditions. The results indicate that the ejected electron angular distribution for H(2) is modified due to Young-type interference between ionization amplitudes for scattering from the two centers in the hydrogen molecule. The observable result is a suppression of the backward scattering (recoil) peak compared with the binary peak.

There is a considerable discrepancy in the literature concerning the sensitivity of parathyroid scintigraphy (PS) with 99mTc-MIBI. We therefore analyzed our own data and compared them to the literature in a metaanalysis. All patients who received 99mTc -MIBI scintigraphy and subsequent surgery in our department for the detection of enlarged parathyroid glands in primary (pHPT) or secondary (sHPT) hyperparathyroidism between 1991 and 1999 were included in our retrospective analysis. The results of surgery served as the gold standard. For a true positive result, the scintigraphy had to predict the exact location of parathyroid adenoma (PA) or parathyroid hyperplasia (PH). We then compared these data to the results of a nonstatistical systematic metaanalysis of the literature. Patients (178) underwent PS between 1991 and 1999; 139 were operated on and included in this study. Of these, 109 had pHPT and 30 had sHPT. The sensitivity and specificity of the PS were found to be 45%/94% for pHPT and 39%/40% for sHPT. Fifty-two studies concerning PS were included in the metaanalysis. Sensitivities reported varied from 39% to >90%. Consideration of the different possible techniques used for PS could not explain these discrepancies. Our data show that the sensitivity of PS in clinical routine may be lower than expected from the literature. Our data are consistent with other studies and with partially unpublished clinical observations from other university hospitals. We believe that a well-designed and properly conducted prospective study is necessary to evaluate the reasons for the differences observed.

We recently reported that activation of the highly efficient phospholipase C (PLC) stimulatory m3 muscarinic acetylcholine receptor (mAChR) can induce a long-lasting Gi-mediated heterologous potentiation of PLC stimulation in human embryonic kidney (HEK) 293 cells, which was accompanied by an increased cellular level of the PLC substrate phosphatidylinositol-4,5-bisphosphate [PtdIns(4,5)P2]. Here, we examined whether such a potentiated PLC response is also induced by the rather poorly PLC stimulatory m2 mAChR and the endogenously expressed purinergic and lysophosphatidic acid receptors. Pretreatment of m2 mAChR-expressing HEK 293 cells for 2 min with carbachol, followed by agonist washout and measurement of PLC activity >/=40 min later, caused a long-lasting (up to approximately 90 min) heterologous potentiation of receptor- and G protein-mediated PLC stimulation. A similar heterologous potentiation of receptor-mediated PLC stimulation was induced by short term activation of lysophosphatidic acid and purinergic receptors. Either of the three receptor agonists increased the cellular level of PtdIns(4,5)P2 by approximately 50%. The mAChR-induced PLC potentiation was fully prevented by either pertussis toxin or the protein kinase C (PKC) inhibitors staurosporine and Gö 6976, which did not affect acute PLC stimulation. On the other hand, the rise in PtdIns(4,5)P2 was prevented only by combined treatment of HEK 293 cells with pertussis toxin and PKC inhibitors. In conclusion, we demonstrated that activation of poorly PLC stimulatory receptors can also induce a long-lasting Gi-mediated heterologous potentiation of PLC signaling in HEK 293 cells and that this novel PLC regulatory process is under the control of PKC.

A total of 20 patients of both sexes received total parenteral nutrition with an all-in-one solution (excluding fat). All patients underwent a medium-sized surgical intervention. The solution was applied throughout 4 postoperative days in a medium dosage of 30 ml/kg B.w./day. Additional electrolyte solutions (200-500 ml/day) were allowed, to substitute fluid losses. Routine laboratory parameters remained in hemostasis; even blood sugar was stabilized between 120 and 150 mg% (x) without insulin. The authors conclude that short-term parenteral nutrition using this all-in-one solution exclusively could achieve hemostasis in clinically relevant parameters. No side effects were detected.