The wooden artifacts from Schöningen's Spear Horizon and their place in human evolution.

Ethnographic records show that wooden tools played a pivotal role in the daily lives of hunter-gatherers including food procurement tools used in hunting (e.g., spears, throwing sticks) and gathering (e.g. digging sticks, bark peelers), as well as, domestic tools (e.g., handles, vessels). However, wood rarely survives in the archeological record, especially in Pleistocene contexts and knowledge of prehistoric hunter-gatherer lifeways is strongly biased by the survivorship of more resilient materials such as lithics and bones. Consequently, very few Paleolithic sites have produced wooden artifacts and among them, the site of Schöningen stands out due to its number and variety of wooden tools. The recovery of complete wooden spears and throwing sticks at this 300,000-y-old site (MIS 9) led to a paradigm shift in the hunter vs. scavenger debate. For the first time and almost 30 y after their discovery, this study introduces the complete wooden assemblage from Schöningen 13 II-4 known as the Spear Horizon. In total, 187 wooden artifacts could be identified from the Spear Horizon demonstrating a broad spectrum of wood-working techniques, including the splitting technique. A minimum of 20 hunting weapons is now recognized and two newly identified artifact types comprise 35 tools made on split woods, which were likely used in domestic activities. Schöningen 13 II-4 represents the largest Pleistocene wooden artifact assemblage worldwide and demonstrates the key role woodworking had in human evolution. Finally, our results considerably change the interpretation of the Pleistocene lakeshore site of Schöningen.

[A naturalistic study on the effects of antidepressants (e. g. SSRI) and acetyl salicylic acid (ASA) on the self-rated perception of the psychotherapeutic process of inpatient psychosomatic treatment and its results: Could ASA be beneficial?] / Eine naturalistische Untersuchung zur Auswirkung häufiger antidepressiver Medikationen (wie SSRI) und der Acetylsalicylsäure (ASS) auf die Selbstbeurteilungen der Wahrnehmung und des Ergebnisses stationärer Psychotherapie: Könnte ASS förderlich sein?

Objectives: Psychic perceptions are at the core of psychotherapeutic processes and modifiable by certain psychopharmacologic agents including antidepressants and cyclooxygenase (COX) inhibitors like acetylsalicylic acid (ASA). Methods: We analyzed the medical records of 208 participants, and used the weekly mean dosages and the number of weeks in therapy to predict ward experience (Stationserfahrungsbogen) and symptom burden (symptom-check list 90-R) by means of linear regression analyses and four repeated measures. Results: Time predicted symptom relief. ASA signified a more favorable ward experience and a trend towards less suffering. Antidepressants did not predict symptom burden or ward experience, except for amitriptyline's inverse relationship with process perception. Discussion: Regarding process perception and therapy outcome, amitriptyline might have unfavorable effects at dose reductions, whereas COX-inhibition could be beneficial at higher dosages. Similar findings have already been described with regard to COX-inhibition in depression and schizophrenia.

Eating disorder related research using Amazon Mechanical Turk (MTurk): Friend or foe?: Commentary on Burnette et al. (2021).

Burnette et al. reported a study that they sought to undertake to validate common eating disorder questionnaires in sexual and gender minorities. The researchers took advantage of the online recruitment platform Amazon Mechanical Turk (MTurk). Contrary to their expectations, the study proved not feasible due to invalid answering. Thus, Burnette et al. raise concerns against the trustworthiness of crowd-sourced data that may be undermined by financial interests and other kinds of motivations. Our commentary highlights the potential of the COVID-19 pandemic to inflate especially those intentions, which are monetary. Against the background of the COVID-19 pandemic, a further problem seems to be that the anonymity of online crowd sourcing platforms might tempt participants to provide inconsistent answers, possibly reflecting tendencies of reactance. The reported pattern of paradoxical responses in Burnette et al.'s work does not reflect malingering; rather we believe that the study might have served some participants as an outlet for negative emotions. We discuss mechanisms of quality control and highlight the lack of interpersonal interaction associated with online data collections.

Emotion processing and regulation in major depressive disorder: A 7T resting-state fMRI study.

Dysfunctions in bottom-up emotion processing (EP), as well as top-down emotion regulation (ER) are prominent features in pathophysiology of major depressive disorder (MDD). Nonetheless, it is not clear whether EP- and ER-related areas are regionally and/or connectively disturbed in MDD. In addition, it is yet to be known how EP- and ER-related areas are interactively linked to regulatory behavior, and whether this interaction is disrupted in MDD. In our study, regional amplitude of low frequency fluctuations (ALFF) and whole-brain functional connectivity (FC) of meta-analytic-driven EP- and ER-related areas were compared between 32 healthy controls (HC) and 20 MDD patients. Then, we aimed to investigate whether the EP-related areas can predict the ER-related areas and regulatory behavior in both groups. Finally, the brain-behavior correlations between the EP- and ER-related areas and depression severity were assessed. We found that: (a) affective areas are regionally and/or connectively disturbed in MDD; (b) EP-ER interaction seems to be disrupted in MDD; overburden of emotional reactivity in amygdala may inversely affect cognitive control processes in prefrontal cortices, which leads to diminished regulatory actions. (c) Depression severity is correlated with FC of affective areas. Our findings shed new lights on the neural underpinning of affective dysfunctions in depression.

A highly specific and sensitive serological assay detects SARS-CoV-2 antibody levels in COVID-19 patients that correlate with neutralization.

OBJECTIVE: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic challenges national health systems and the global economy. Monitoring of infection rates and seroprevalence can guide public health measures to combat the pandemic. This depends on reliable tests on active and former infections. Here, we set out to develop and validate a specific and sensitive enzyme linked immunosorbent assay (ELISA) for detection of anti-SARS-CoV-2 antibody levels. METHODS: In our ELISA, we used SARS-CoV-2 receptor-binding domain (RBD) and a stabilized version of the spike (S) ectodomain as antigens. We assessed sera from patients infected with seasonal coronaviruses, SARS-CoV-2 and controls. We determined and monitored IgM-, IgA- and IgG-antibody responses towards these antigens. In addition, for a panel of 22 sera, virus neutralization and ELISA parameters were measured and correlated. RESULTS: The RBD-based ELISA detected SARS-CoV-2-directed antibodies, did not cross-react with seasonal coronavirus antibodies and correlated with virus neutralization (R2 = 0.89). Seroconversion started at 5 days after symptom onset and led to robust antibody levels at 10 days after symptom onset. We demonstrate high specificity (99.3%; N = 1000) and sensitivity (92% for IgA, 96% for IgG and 98% for IgM; > 10 days after PCR-proven infection; N = 53) in serum. CONCLUSIONS: With the described RBD-based ELISA protocol, we provide a reliable test for seroepidemiological surveys. Due to high specificity and strong correlation with virus neutralization, the RBD ELISA holds great potential to become a preferred tool to assess thresholds of protective immunity after infection and vaccination.

[Postoperative Dissociation after Knee Replacement and its Influence on the Course of Pain]. / Postoperative Dissoziation nach Totalem Kniegelenkersatz und ihr Einfluss auf den Schmerzverlauf.

OBJECTIVE: Even after successful knee replacement, one in 5 patients complains of chronic pain. Previous studies suggest that surgical interventions trigger postoperative traumatic stress in some patients. The aim of this explorative study is to investigate whether postoperative dissociation occurs as a manifestation of postoperative traumatic stress after total knee replacement. In addition, it should be investigated whether these patients have more chronic postoperative pain 1 year postoperatively and to what extent the course of pain differs from the other patients. METHODS: 201 Patients who underwent primary knee TEP were studied. They answered questionnaires on knee pain (WOMAC) and dissociation (FDS-20) at 3 measurement points: 1 day preoperatively (T1), 10 weeks postoperatively (T2) and 1 year postoperatively (T3). RESULTS: Data from 145 patients could be analyzed. The incidence for postoperative dissociation is 8.3%. Not only do patients with postoperative dissociation report more chronic postoperative pain after 1 year (p=0,016), but also their postoperative pain levels decreases less than in the patients without postoperative dissociation (p=0,025). DISCUSSION: The findings provide evidence that postoperative dissociation occurs as a manifestation of postoperative traumatic stress after total knee replacement. Even if dissociation seems to be a defense mechanism for the regulation of overstraining affects in the short term, it is associated with more chronic postoperative pain in the long term. Furthermore, the patients with postoperative dissociation benefit less in a 1-year follow-up from total knee replacement in terms of pain reduction. CONCLUSION: Strategies to reduce dissociation could lead to better results after knee TEP implementation and should be investigated in future intervention studies.

Local glutamate in cingulate cortex subregions differentially correlates with affective network activations during face perception.

The cingulate cortex is involved in emotion recognition/perception and regulation. Rostral and caudal subregions belong to different brain networks with distinct roles in affective perception. Despite recent accounts of the relevance of cingulate cortex glutamate (Glu) on blood-oxygen-level-dependent (BOLD) responses, the specificity of the subregional Glu levels during emotional tasks remains unclear. Seventy-two healthy participants (age = 27.33 ± 6.67, 32 women) performed an affective face-matching task and underwent magnetic resonance spectroscopy (MRS) at 7 Tesla. Correlations between the BOLD response during emotion perception and Glu concentration in the pregenual anterior cingulate cortex (pgACC) and anterior midcingulate cortex (aMCC) were compared on a whole-brain level. Post hoc specificity of the association with an affect was assessed. Lower Glu in the pgACC correlated with stronger activation differences between negative and positive faces in the left inferior and superior frontal gyrus (L IFG and L SFG). In contrast, lower Glu in the aMCC correlated with BOLD contrasts in the posterior cingulate cortex (PCC). Furthermore, negative face detection was associated with prolonged response time (RT). Our results demonstrate a subregion-specific involvement of cingulate cortex Glu in interindividual differences during viewing of affective facial expressions. Glu levels in the pgACC were correlated with frontal area brain activations, whereas Glu in the salience network component aMCC modulated responses in the PCC-precuneus. We show that region-specific metabolite mapping enables specific activation of different BOLD signals in the brain underlying emotional perception.

Severe pressure ulcers requiring surgery impair the functional outcome after acute spinal cord injury.

STUDY DESIGN: Retrospective matched cohort study. OBJECTIVES: Assessing the influence of surgically managed grade 3 and 4 pressure ulcers (PU) in the acute phase after spinal cord injury (SCI) on the neurological and functional outcome after 1 year. SETTING: Specialized SCI-unit within a level 1 trauma center in Murnau, Germany. METHODS: We performed a retrospective matched cohort study. For every patient with acute SCI and a PU requiring surgery, we identified matched controls within our database in a 1:3 ratio. Matching criteria were: AIS-grade (American Spinal Injury Association Impairment Scale), neurological level and age. The scores of the SCIM-III (Spinal Cord Independence Measure) and the ISNCSCI (International Standards for Neurological Classification of Spinal Cord Injury) as well as the total length of stay (LOS) at the hospital were used as outcome parameters. We applied a stratified analysis using a conditional logistic regression to test for group differences in each outcome parameter of the study. RESULTS: In a 6-year period (2010-2015) 28 patients required flap surgery due to 3-4° PU in the acute phase after SCI. Of these patients, 15 had complete data sets according to the EMSCI (European Multicenter Study about Spinal Cord Injury) protocol. Patients with severe PUs during the acute SCI phase had a significantly impaired functional outcome. After 1 year the improvement of the SCIM score was significantly lower in the PU group compared to the control group (17.4 versus 30.5; p < 0.006). However, the change in AIS grade after 1 year was not significantly affected. The LOS was prolonged by a mean of 48 days in the PU group (p < 0.006). CONCLUSIONS: Severe PUs requiring surgery in the acute phase after SCI impair the functional outcome and increase LOS. Preventive measures should be applied to all acute SCI patients. Patients should be transferred to specialized SCI-centers as soon as possible.

Novel CB1-ligands maintain homeostasis of the endocannabinoid system in ω3- and ω6-long-chain-PUFA deficiency.

Mammalian ω3- and ω6-PUFAs are synthesized from essential fatty acids (EFAs) or supplied by the diet. PUFAs are constitutive elements of membrane architecture and precursors of lipid signaling molecules. EFAs and long-chain (LC)-PUFAs are precursors in the synthesis of endocannabinoid ligands of Gi/o protein-coupled cannabinoid receptor (CB)1 and CB2 in the endocannabinoid system, which critically regulate energy homeostasis as the metabolic signaling system in hypothalamic neuronal circuits and behavioral parameters. We utilized the auxotrophic fatty acid desaturase 2-deficient (fads2-/-) mouse, deficient in LC-PUFA synthesis, to follow the age-dependent dynamics of the PUFA pattern in the CNS-phospholipidome in unbiased dietary studies of three cohorts on sustained LC-PUFA-free ω6-arachidonic acid- and DHA-supplemented diets and their impact on the precursor pool of CB1 ligands. We discovered the transformation of eicosa-all cis-5,11,14-trienoic acid, uncommon in mammalian lipidomes, into two novel endocannabinoids, 20:35,11,14-ethanolamide and 2-20:35,11,14-glycerol. Their function as ligands of CB1 has been characterized in HEK293 cells. Labeling experiments excluded Δ8-desaturase activity and proved the position specificity of FADS2. The fads2-/- mutant might serve as an unbiased model in vivo in the development of novel CB1 agonists and antagonists.

[A review on psychosomatic factors affecting the outcome after total knee-arthroplasty (TKA)]. / Übersicht zu psychosomatischen Aspekten des Kniegelenksersatzes (TKA).

A review on psychosomatic factors affecting the outcome after total knee-arthroplasty (TKA) Objectives: In today's ageing Western societies, arthroplasty is a common treatment for endstage osteoarthritis. Despite highly developed implants and surgery, however, this treatment does not always succeed in relieving pain and restoring joint function, i.e., in restoring satisfactory algofunction. Clinicians partly blame psychological factors for this discrepancy, especially in the absence of objective medical complications. METHODS: The present review summarizes previous studies on the role of psychosomatic interactions affecting the course after total knee arthroplasty (TKA). RESULTS: During the perioperative period, patients with TKA suffer from marked psychic distress that is also linked to the postoperative algofunction. CONCLUSIONS: We discuss the theoretical and clinical implications of the findings reviewed.

Analytics of nonpeptidic erythropoietin mimetic agents in sports drug testing employing high-resolution/high-accuracy liquid chromatography-mass spectrometry.

Since its release as anti-anemic drug, recombinant erythropoietin (rEPO) gradually entered the illicit way to sports competitions as endurance-enhancing drug. Novel modifications biopharmaceutically introduced into the rEPO molecule in the form of carbohydrate or polyethylene glycol moieties made robust and sensitive test methods vital to doping controls in order to provide the necessary tools enabling the conviction of dishonest athletes. Modern protein analysis by means of gel electrophoretic separation and western blotting represents the status quo in rEPO anti-doping analysis. However, new therapeutically promising erythropoietin receptor activating compounds have been developed that exhibit cytokine hormone-mimicking properties but lack any protein structure. Progression to evade parenteral application and substitute for rEPO by low molecular mass and orally available compounds is still one of the major objectives in pharmaceutical research. In this approach, four promising in-house synthesized nonpeptidic erythropoietin mimetic agents, namely compound 129, compound 163, A1B10C1, and A5B10C4 were thoroughly evaluated by employing high-resolution/high-accuracy liquid chromatography tandem mass spectrometry experiments. Characteristic product ions were determined supporting the identification of these drugs and putative metabolites as well as related compounds in future doping controls. Test methods employing direct urine injection and receptor affinity purification strategies were assessed, which demonstrated that EPO receptor purification is of limited utility for nonpeptidic EPOR agonists while direct urine injection allowed for comprehensive method characterization. Thereby, achieved limits of detection were 1 ng/mL for compounds 129/163 and 5 ng/mL for A1B10C1/A5B10C4.

Isolation, enrichment, and analysis of erythropoietins in anti-doping analysis by receptor-coated magnetic beads and liquid chromatography-mass spectrometry.

Human erythropoietin (hEPO) is an erythropoiesis stimulating hormone frequently employed in antianemia therapy. Its capability to increase the amount of red blood cells however makes hEPO and its derivatives also attractive to dishonest athletes aiming at an artificial and illicit enhancement of their endurance performance. A major objective of the international antidoping fight is the elimination of drug misuse and prevention of severe adverse effects caused by nontherapeutic administrations of highly potent drugs. The emergence of novel and innovative erythropoietin-mimetic agents (EMAs) has been continuously growing in the last years, and the option of using dedicated monoclonal antibodies (mAb) for analytical and sample preparation approaches is gradually reaching limits. In the present study the common ability and property of all EMAs, to bind on the human erythropoietin receptor (hEPOR), is therefore exploited. An alternative methodology to isolate and analyze EMAs, in particular endogenous EPO and the recombinant forms EPOzeta, darbepoetin alfa, and C.E.R.A., from human urine is described, employing conventional ultrafiltration for preconcentration of the target analytes followed by EMA-specific isolation via hEPOR-bound magnetic beads. Analytical data were generated by means of gel-based electrophoretic analysis and nanoliquid chromatography/high resolution/high accuracy tandem mass spectrometry. Limits of detection enabled by the established sample preparation protocols were approximately 20 pg/mL for EPOzeta, 30 pg/mL for darbepoetin alfa, and 80 pg/mL for C.E.R.A.

Isotope-dilution mass spectrometric quantification of the prodrug lisdexamfetamine in human urine in doping control analysis.

RATIONALE: Therapeutic approaches concerning attention-deficit hyperactivity disorder (ADHD) commonly include the administration of drugs amplifying cerebral dopamine and norepinephrine signals. Among these, compounds belonging to the Prohibited List as established by the World Anti-Doping Agency (WADA) are present such as amfetamine or methylphenidate, and abuse of these can result in sanctions for athletes. The recently approved therapeutic lisdexamfetamine represents a slow-release prodrug of amfetamine for ADHD treatment. In order to support doping control laboratories in differentiating the abuse of amfetamine from a therapeutic administration of lisdexamfetamine, the determination of the prodrug from urine is desirable. Since approximately 2% of lisdexamfetamine are eliminated intact into urine, a liquid chromatography/high-resolution/high accuracy mass spectrometric method was developed, allowing the target analyte and one of its metabolites (4-hydroxyamfetamine sulfate) to be accurately quantified. METHODS: Urine samples were fortified with fourfold deuterated lisdexamfetamine and analyzed directly using ultrahigh-performance liquid chromatography (UHPLC) interfaced via electrospray ionization to a second-generation quadrupole-orbitrap mass spectrometer. The assay was characterized concerning specificity, limits of quantification (0.15-5 ng/mL), intraday and interday imprecision (4-22%), accuracy (90-120%), linearity, and ion suppression/enhancement effects. A patient's urine samples were analyzed to provide proof-of-principle data demonstrating that the intact prodrug lisdexamfetamine is detectable in urine up to 11 h post-administration at concentrations up to 80 ng/mL. Moreover, amfetamine and sulfoconjugated 4-hydroxyamfetamine were measured, yielding up to 1146 and 56 ng/mL, respectively. CONCLUSIONS: Considering the observed comparably low urinary concentrations of lisdexamfetamine and 4-hydroxyamfetamine sulfate, the preferred minimally labor-intense sample preparation, and the necessity of fast and robust result generation, the employed instrumental setup proved fit-for-purpose in sports drug testing.

Sulfonylureas exert antidiabetic action on adipocytes by inhibition of PPARγ serine 273 phosphorylation.

OBJECTIVE: Sulfonylureas (SUs) are still among the mostly prescribed antidiabetic drugs with an established mode of action: release of insulin from pancreatic ß-cells. In addition, effects of SUs on adipocytes by activation of the nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) have been described, which might explain their insulin-sensitizing potential observed in patients. However, there is a discrepancy between the impact of SUs on antidiabetic action and their rather moderate in vitro effect on PPARγ transcriptional activity. Recent studies have shown that some PPARγ ligands can improve insulin sensitivity by blocking PPARγ Ser-273 phosphorylation without having full agonist activity. It is unknown if SUs elicit their antidiabetic effects on adipocytes by inhibition of PPARγ phosphorylation. Here, we investigated if binding of SUs to PPARγ can interfere with PPARγ Ser-273 phosphorylation and determined their antidiabetic actions in vitro in primary human white adipocytes and in vivo in high-fat diet (HFD) obese mice. METHODS: Primary human white preadipocytes were differentiated in the presence of glibenclamide, glimepiride and PPARγ ligands rosiglitazone and SR1664 to compare PPARγ Ser-273 phosphorylation, glucose uptake and adipokine expression. Transcriptional activity at PPARγ was determined by luciferase assays, quantification of PPARγ Ser-273 phosphorylation was determined by Western blotting and CDK5 kinase assays. In silico modelling was performed to gain insight into the binding characteristics of SUs to PPARγ. HFD mice were administered SUs and rosiglitazone for 6 days. PPARγ Ser-273 phosphorylation in white adipose tissue (WAT), body composition, glucose tolerance, adipocyte morphology and expression levels of genes involved in PPARγ activity in WAT and brown adipose tissue (BAT) were evaluated. RESULTS: SUs inhibit phosphorylation of PPARγ at Ser-273 in primary human white adipocytes and exhibit a positive antidiabetic expression profile, which is characterized by up regulation of insulin-sensitizing and down regulation of insulin resistance-inducing adipokines. We demonstrate that SUs directly bind to PPARγ by in silico modelling and inhibit phosphorylation in kinase assays to a similar extend as rosiglitazone and SR1664. In HFD mice SUs reduce PPARγ phosphorylation in WAT and have comparable effects on gene expression to rosiglitazone. In BAT SUs increase UCP1 expression and reduce lipid droplets sizes. CONCLUSIONS: Our findings indicate that a part of SUs extra-pancreatic effects on adipocytes in vitro and in vivo is probably mediated via their interference with PPARγ phosphorylation rather than via classical agonistic activity at clinical concentrations.

Quantification of AICAR-ribotide concentrations in red blood cells by means of LC-MS/MS.

AICAR (5-amino-4-imidazolecarboxyamide ribonucleoside) arguably provides performance-enhancing properties even in the absence of physical exercise and, therefore, the substance is banned in elite sports since 2009. Due to the natural presence of AICAR in human blood and urine, uncovering the misuse by direct qualitative analysis is not possible. Entering the circulation, the riboside is immediately incorporated into red blood cells (RBCs) and transformed into the corresponding ribotide (5'-monophosphate) form. Within the present study, an analytical method was developed to determine AICAR-ribotide concentrations in RBC concentrates by means of liquid chromatography-tandem mass spectrometry. The method was validated enabling quantitative result interpretation considering the parameters specificity, precision (intra- and interday), linearity, recovery, accuracy (LOD/LOQ), stability and ion suppression. By analysing 99 RBC samples of young athletes, normal physiological levels of AICAR-ribotide were determined (10-500 ng/mL), and individual levels were found to be stable for several days. Employing in vitro incubation experiments with AICAR riboside in fresh whole blood samples, the ribotide concentrations were observed to increase significantly within 30 min from baseline to 1-10 µg/mL. These levels are considered conserved for the lifetime of the erythrocyte and, thus, the results of the in vitro model strongly support the hypothesis that measuring abnormally high AICAR-ribotide concentrations in RBC of elite athletes has the potential to uncover the misuse of this substance for a long period of time.

Detachment, compartmentalization, and schizophrenia: linking dissociation and psychosis by subtype.

To explain the phenomenological overlap between dissociation and schizophrenia, a dissociative subtype of schizophrenia has been proposed as a possibility. Dissociation is often believed to be organized on a continuum, although 2 qualitatively different phenomena can be distinguished in theory, research, and clinical practice: (a) states of separation from self or environment (detachment dissociation) and (b) inaccessibility of normally accessible mental contents (compartmentalization dissociation). This study used the Positive and Negative Syndrome Scale (PANSS) and the Association for Methodology and Documentation in Psychiatry module for the interview assessment of dissociation to investigate the relationships between PANSS subscales, detachment dissociation, and compartmentalization dissociation in a sample of 72 patients with schizophrenia. A confirmatory factor analysis sustained the bipartite model, yielding factors that grouped dissociative items around amnesia and depersonalization/derealization. The latter factor also contained identity disturbances and was therefore not entirely consistent with the theoretical formulations of detachment dissociation. It is important to note that the structure of those factors may be influenced by the symptoms of schizophrenia to which they were specifically linked: The factor containing depersonalization/derealization was connected to the positive symptoms subscale of the PANSS, whereas the factor containing amnesia was associated with the negative subscale. Hence, a dichotomy of dissociation is confirmed inasmuch as its subtypes are as distinguishable as PANSS subscales. This has implications on theoretical and clinical levels.

A Predictive Model to Identify Treatment-related Risk Factors for Odontoid Fracture Nonunion Using Machine Learning.

STUDY DESIGN: Multicenter retrospective analysis of routinely collected data. OBJECTIVE: The underlying aim of this study was to identify potential treatment-related risk factors for odontoid fracture nonunion while accounting for known patient- and injury-related risk factors. SUMMARY OF BACKGROUND DATA: Type II and III odontoid fractures represent the most common cervical spine fracture in elderly patients and are associated with a relatively high nonunion rate. The management of odontoid fractures is controversial and treatment strategies range from conservative treatment to extensive surgical stabilization and fusion. METHODS: A total of 415 individuals who sustained odontoid fracture and were treated in either of four tertiary referral centers in Austria and Germany were included in the study. We included the following potential contributing factors for fracture nonunion in cross-validated extreme gradient boosted (XGBoost) and binary logistic regression models: age, gender, fracture displacement, mechanism of injury (high vs. low energy), fracture classification (Anderson II vs. III), presence of comorbidities (Charlson comorbidity index), and treatment (conservative, anterior screw fixation with one or two screws, posterior C1/C2 spondylodesis, cervico-occipital C0-C4 fusion). RESULTS: In our cohort, 187 (45%) had radiologically confirmed odontoid nonunion six months postinjury. The odds for nonunion increase significantly with age, and are lower in type III compared to type II fractures. Also, odds for nonunion are significantly lower in posterior C1/C2 spondylodesis, and C0-C4 fusion compared to conservative treatment. Importantly, odds are not statistically significantly lower in the group treated with anterior screw fixation compared to conservative treatment. The factors gender, fracture displacement, mechanism of injury, and the presence of comorbidities did not produce significant odds. CONCLUSION: Higher age, type II fractures, and conservative treatment are the main risk factors for odontoid nonunion. Anterior screw fixation did not differ significantly from conservative treatment in terms of fracture union. LEVEL OF EVIDENCE: 3.

Neurotensin(8-13) analogs as dual NTS1 and NTS2 receptor ligands with enhanced effects on a mouse model of Parkinson's disease.

The modulatory interactions between neurotensin (NT) and the dopaminergic neurotransmitter system in the brain suggest that NT may be associated with the progression of Parkinson's disease (PD). NT exerts its neurophysiological effects by interactions with the human NT receptors type 1 (hNTS1) and 2 (hNTS2). Therefore, both receptor subtypes are promising targets for the development of novel NT-based analogs for the treatment of PD. In this study, we used a virtually guided molecular modeling approach to predict the activity of NT(8-13) analogs by investigating the docking models of ligands designed for binding to the human NTS1 and NTS2 receptors. The importance of the residues at positions 8 and/or 9 for hNTS1 and hNTS2 receptor binding affinity was experimentally confirmed by radioligand binding assays. Further in vitro ADME profiling and in vivo studies revealed that, compared to the parent peptide NT(8-13), compound 10 exhibited improved stability and BBB permeability combined with a significant enhancement of the motor function and memory in a mouse model of PD. The herein reported NTS1/NTS2 dual-specific NT(8-13) analogs represent an attractive tool for the development of therapeutic strategies against PD and potentially other CNS disorders.

Immobility-associated thromboprotection is conserved across mammalian species from bear to human.

Venous thromboembolism (VTE) comprising deep venous thrombosis and pulmonary embolism is a major cause of morbidity and mortality. Short-term immobility-related conditions are a major risk factor for the development of VTE. Paradoxically, long-term immobilized free-ranging hibernating brown bears and paralyzed spinal cord injury (SCI) patients are protected from VTE. We aimed to identify mechanisms of immobility-associated VTE protection in a cross-species approach. Mass spectrometry-based proteomics revealed an antithrombotic signature in platelets of hibernating brown bears with heat shock protein 47 (HSP47) as the most substantially reduced protein. HSP47 down-regulation or ablation attenuated immune cell activation and neutrophil extracellular trap formation, contributing to thromboprotection in bears, SCI patients, and mice. This cross-species conserved platelet signature may give rise to antithrombotic therapeutics and prognostic markers beyond immobility-associated VTE.

The effects of shift work on physical and mental health.

Occupational engagement is a pre-requisite for continuous income opportunities. Among the changing social circumstances work-related conditions play an increasingly eminent role in psychological and mental well-being. The public discusses the question of a possible association between the demands of modern work life and the increases of psychological, psychosomatic and cardiovascular disorders. Given the socioeconomic implications of psychiatric and psychosomatic suffering in the general population, there is a need to further elucidate the causes of their increasing incidence. From a medical point of view, any organization of work disrupting the phased circadian rhythms for bio-psycho-social processes and functioning of the individual are interesting against the background of clock genes and certain biological functions that are organized in a circadian fashion. The authors review the influence of shift work as a form of systematic desynchronization of inner clock systems on the endocrine, the physical, and the mental level. The significance of the findings in the field is discussed along with future directions of conclusive research.