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In pharmacotherapy, the achievement of a target clinical outcome requires a certain level of medication intake or adherence. Based on Haynes's early empirical definition of sufficient adherence to antihypertensive medications as taking ≥80% of medication, many researchers used this threshold to distinguish adherent from non-adherent patients. However, we propose that different diseases, medications and patient's characteristics influence the cut-off point of the adherence rate above which the clinical outcome is satisfactory (thereafter medication adherence threshold). Moreover, the assessment of adherence and clinical outcomes may differ greatly and should be taken into consideration. To our knowledge, very few studies have defined adherence rates linked to clinical outcomes. We aimed at investigating medication adherence thresholds in relation to clinical outcomes. We searched for studies that determined the relationship between adherence rates and clinical outcomes in the databases PubMed, Embase and Web of Science™ until December 2017, limited to English-language. Our outcome measure was any threshold value of adherence. The inclusion criteria of the retrieved studies were (1) any measurement of medication adherence, (2) any assessment of clinical outcomes, and (3) any method to define medication adherence thresholds in relation to clinical outcomes. We excluded articles considered as a tutorial. Two authors (PB and IA) independently screened titles and abstracts for relevance, reviewed full-texts, and extracted items. The results of the included studies are presented qualitatively. We analyzed 6 articles that assessed clinical outcomes linked to adherence rates in 7 chronic disease states. Medication adherence was measured with Medication Possession Ratio (MPR, = 3), Proportion of Days Covered (PDC, = 1), both ( = 1), or Medication Event Monitoring System (MEMS). Clinical outcomes were event free episodes, hospitalization, cortisone use, reported symptoms and reduction of lipid levels. To find the relationship between the targeted clinical outcome and adherence rates, three studies applied logistic regression and three used survival analysis. Five studies defined adherence thresholds between 46 and 92%. One study confirmed the 80% threshold as valid to distinguish adherent from non-adherent patients. The analyzed studies were highly heterogeneous, predominantly concerning methods of calculating adherence. We could not compare studies quantitatively, mostly because adherence rates could not be standardized. Therefore, we cannot reject or confirm the validity of the historical 80% threshold. Nevertheless, the 80% threshold was clearly questioned as a general standard.

The Polycomb group of proteins is required for the proper orchestration of gene expression due to its role in maintaining transcriptional silencing. It is composed of several chromatin modifying complexes, including Polycomb Repressive Complex 2 (PRC2), which deposits H3K27me2/3. Here, we report the identification of a cofactor of PRC2, EZHIP (EZH1/2 Inhibitory Protein), expressed predominantly in the gonads. EZHIP limits the enzymatic activity of PRC2 and lessens the interaction between the core complex and its accessory subunits, but does not interfere with PRC2 recruitment to chromatin. Deletion of Ezhip in mice leads to a global increase in H3K27me2/3 deposition both during spermatogenesis and at late stages of oocyte maturation. This does not affect the initial number of follicles but is associated with a reduction of follicles in aging. Our results suggest that mature oocytes Ezhip−/− might not be fully functional and indicate that fertility is strongly impaired in Ezhip−/− females. Altogether, our study uncovers EZHIP as a regulator of chromatin landscape in gametes. Polycomb Repressive Complex 2 (PRC2) plays critical roles in transcriptional silencing during development. Here the authors identify EZHIP as a cofactor of PRC2 expressed predominantly in the gonads, finding that EZHIP limits the enzymatic activity of PRC2 in germ cells in mice.

Human methytransferase like proteins (METTL) are part of a large protein family characterized by the presence of binding domains for S-adenosyl methionine, a co-substrate for methylation reactions. Despite the fact that members of this protein family were shown or predicted to be DNA, RNA or protein methyltransferases, most METTL proteins are still poorly characterized. Identification of complexes in which these potential enzymes act could help to understand their function(s) and substrate specificities. Here we systematically studied interacting partners of METTL protein family members in HeLa cells using label-free quantitative mass spectrometry. We found that, surprisingly, many of the METTL proteins appear to function outside of stable complexes whereas others including METTL7B, METTL8 and METTL9 have high-confidence interaction partners. Our study is the first systematic and comprehensive overview of the interactome of METTL protein family that can provide a crucial resource for further studies of these potential novel methyltransferases.

Parkinson disease (PD) is a chronic progressive neurodegenerative disorder leading to motor and non-motor impairment, often resulting in severe loss of quality of life. There are symptomatic treatments without effect on the progression of PD. A disease-modifying treatment that could ideally stop the neurodegenerative process is direly needed. Monosialotetrahexosylganglioside (GM1) is a promising molecule with neuroprotective effects in preclinical models of PD and has yielded encouraging results in patients with PD in a randomized placebo-controlled trial. Talineuren (TLN) is a liposomal formulation of GM1 that has been shown to cross the blood-brain barrier in animals. We assessed the safety and pharmacokinetics (PK) of TLN in patients with PD. We prospectively enrolled 12 patients with PD into a single-center, open-label phase I trial to assess the safety and tolerability of weekly infusions with TLN. The maximum suitable dose of TLN was determined by dose escalation in three patients. All three patients tolerated the predetermined maximal dose of 720 mg. Subsequently, these and nine additional patients received weekly infusions at the maximum suitable dose of 720 mg TLN over two months (1 patient stopped prematurely). PK were determined for the additional nine patients as a secondary outcome measure. Cmax was reached 4 h after infusion start for all but one participant, who reached Cmax after 1 h, while the median plasma half-life was reached at 12.6 h. All adverse events were continuously assessed as the primary objective and coded according to the Medical Dictionary for Regulatory Activities (MedDRA). Clinical manifestations of PD were assessed as secondary outcomes using the Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS), including a levodopa challenge test at baseline and end. In addition to weekly history taking, scales to measure mood, behavior, quality of life, sleepiness, non-motor symptoms of PD, and cognition were used as further secondary outcomes as well as assessing the Levodopa-Equivalent Daily Dose (LEDD). Overall, 304 adverse events (mean: 25.33; 6-75 events per patient) occurred, 267 of which were mild (mean: 22.25; 3-72 events per patient). 23 were considered related to the study treatment (0-8 events per patient). Very mild-to-severe acute infusion reactions at the second, third, or fourth administration of TLN within the first minutes of the infusion occurred in seven patients. All reported back or neck pain. Other acute infusion reactions were urticaria, plethora, nausea, and chest pain. These adverse reactions disappeared within minutes of stopping the infusion and did not recur when TLN administration was resumed at a very low rate. Beyond the fourth administration, infusions could be given at increased rates up to 370 ml/h, and no acute reaction occurred anymore. The mechanism of this acute infusion reaction remains unclear. Some patients reported mild dizziness for a few hours after TLN following many but not all administrations throughout the study. Non-motor symptoms of PD, motor parkinsonian signs off medication, and quality of life improved significantly during the treatment phase, including the MDS-UPDRS total score (mean decrease -11.09; 95% Confidence Interval [CI]; -18, -4.1; p = 0.006), the Parkinson's disease Questionnaire-39 (PDQ-39) summary index (mean decrease -2.91; 95% CI; -4.4, -1.4; p = 0.005), and the Non-Motor Symptoms Questionnaire (NMS-Quest) (mean decrease -4.27; 95% CI; -6.5, -2.1; p = 0.009). No statistically significant improvements were seen in the Montreal Cognitive Assessment (MoCA) (mean decrease -0.73; 95% CI; -2.1, 0.62; p = 0.255), Epworth Sleepiness Scale (mean increase 0.09; 95% CI; -2.6, 2.8; p > 0.999), Beck Depression Inventory (BDI) (mean decrease -1.27; 95% CI; -3.8, 1.3; p = 0.257), and the Starkstein Apathy Scale (mean increase 0.36; 95% CI; -1.6, 2.4; p = 0.822). Dopaminergic medications remained stable during the study (LEDD mean increase 8.18; 95% CI; -7.7, 24; p = 0.423). While clinical improvements indicate a benefit associated with TLN treatment, the trial design does not allow for definite conclusions regarding efficacy. A randomized, placebo-controlled trial will be required to corroborate our exploratory findings. TLN is safe and well-tolerated in general. This prospective phase I trial revealed non-allergic habituating acute infusion reactions at the second, third, or fourth treatment that can be prevented by a slower rate of infusion. Importantly, the exploratory results suggest a consistent improvement of signs and symptoms of PD. The NEON trial is registered at the US National Institutes of Health (ClinicalTrials.gov) #NCT04976127 and in the Swiss National Clinical Trials Portal (SNCTP000004631).

This paper proposes a biosemiotic conception of theories, as non-intentional organic theories, which is based on an analysis and comparison of philosopher Norwood Russell Hanson's account of theories and zoologist Jakob von Uexkiill's theory of organisms. It is argued that Hanson's proposals about scientific theories and their relation to observation are semiotic in nature and that there exists a correspondence between Hanson's depiction of the relationship between theories, observation, and reality and von Uexkiill's views on the relationship between organisms and their environments. This correspondence supports an account of theories that depicts them as organic extensions of our perceptual physiology. Among the epistemological consequences of this account are the following: (1) The kind of correspondence that is established through theories between a subject and reality is related rather to a subject's actions than to a faithful representation of every aspect of the world, (2) it suggests a strong emphasis on the creative aspects of knowledge acquisition, and (3) it urges a reassessment of the evolutionary epistemology of theories.

Purpose Patients undergoing prophylactic central compartment dissection (PCLND) for papillary thyroid cancer (PTC) are often overtreated. This study aimed to determine if molecular fluorescence-guided imaging (MFGI) and spectroscopy can be useful for detecting PTC nodal metastases (NM) and to identify negative central compartments intraoperatively. Methods We used a data-driven prioritization strategy based on transcriptomic profiles of 97 primary PTCs and 80 normal thyroid tissues (NTT) to identify tumor-specific antigens for a clinically available near-infrared fluorescent tracer. Protein expression of the top prioritized antigen was immunohistochemically validated with a tissue microarray containing primary PTC ( n  = 741) and NTT ( n  = 108). Staining intensity was correlated with 10-year locoregional recurrence-free survival (LRFS). A phase 1 study (NCT03470259) with EMI-137, targeting MET, was conducted to evaluate safety, optimal dosage for detecting PTC NM with MFGI, feasibility of NM detection with quantitative fiber-optic spectroscopy, and selective binding of EMI-137 for MET. Results MET was selected as the most promising antigen. A worse LRFS was observed in patients with positive versus negative MET staining (81.9% versus 93.2%; p  = 0.02). In 19 patients, no adverse events related to EMI-137 occurred. 0.13 mg/kg EMI-137 was selected as optimal dosage for differentiating NM from normal lymph nodes using MFGI ( p  < 0.0001) and spectroscopy ( p  < 0.0001). MFGI identified 5/19 levels (26.3%) without NM. EMI-137 binds selectively to MET. Conclusion MET is overexpressed in PTC and associated with increased locoregional recurrence rates. Perioperative administration of EMI-137 is safe and facilitates NM detection using MFGI and spectroscopy, potentially reducing the number of negative PCLNDs with more than 25%. Clinical trial registration. NCT03470259.

Purpose Multifocal disease in PTC is associated with an increased recurrence rate. Multifocal disease (MD) is underdiagnosed with the current gold standard of pre-operative ultrasound staging. Here, we evaluate the use of EMI-137 targeted molecular fluorescence-guided imaging (MFGI) and spectroscopy as a tool for the intra-operative detection of uni- and multifocal papillary thyroid cancer (PTC) aiming to improve disease staging and treatment selection. Methods A phase-1 study (NCT03470259) with EMI-137 was conducted to evaluate the possibility of detecting PTC using MFGI and quantitative fiber-optic spectroscopy. Results Fourteen patients underwent hemi- or total thyroidectomy (TTX) after administration of 0.09 mg/kg ( n  = 1), 0.13 mg/kg ( n  = 8), or 0.18 mg/kg ( n  = 5) EMI-137. Both MFGI and spectroscopy could differentiate PTC from healthy thyroid tissue after administration of EMI-137, which binds selectively to MET in PTC. 0.13 mg/kg was the lowest dosage EMI-137 that allowed for differentiation between PTC and healthy thyroid tissue. The smallest PTC focus detected by MFGI was 1.4 mm. MFGI restaged 80% of patients from unifocal to multifocal PTC compared to ultrasound. Conclusion EMI-137-guided MFGI and spectroscopy can be used to detect multifocal PTC. This may improve disease staging and treatment selection between hemi- and total thyroidectomy by better differentiation between unifocal and multifocal disease. Trial registration NCT03470259

PRC2 promotes methylation of H3K27, a modification that recruits PRC1, which in turn deposits H2A ubiquitin marks. Müller and colleagues use biochemistry approaches to show that H2Aub recruits Jarid–Aebp2–containing PRC2 to promote H3K27 trimethylation on H2Aub nucleosomes, thus forming a positive feedback loop to establish repressed chromatin domains. A key step in gene repression by Polycomb is trimethylation of histone H3 K27 by PCR2 to form H3K27me3. H3K27me3 provides a binding surface for PRC1. We show that monoubiquitination of histone H2A by PRC1-type complexes to form H2Aub creates a binding site for Jarid2–Aebp2–containing PRC2 and promotes H3K27 trimethylation on H2Aub nucleosomes. Jarid2, Aebp2 and H2Aub thus constitute components of a positive feedback loop establishing H3K27me3 chromatin domains.

Background and Objectives: Intramedullary nailing of trochanteric fractures can be challenging and sometimes the clinical situation does not allow perfect implant positioning. The aim of this study was (1) to compare in human cadaveric femoral heads the biomechanical competence of two recently launched cephalic implants inserted in either an ideal (centre–centre) or less-ideal anterior off-centre position, and (2) to investigate the effect of bone cement augmentation on their fixation strength in the less-ideal position. Materials and Methods: Fourty-two paired human cadaveric femoral heads were assigned for pairwise implantation using either a TFNA helical blade or a TFNA screw as head element, implanted in either centre–centre or 7 mm anterior off-centre position. Next, seven paired specimens implanted in the off-centre position were augmented with bone cement. As a result, six study groups were created as follows: group 1 with a centre–centre positioned helical blade, paired with group 2 featuring a centre–centre screw, group 3 with an off-centre positioned helical blade, paired with group 4 featuring an off-centre screw, and group 5 with an off-centre positioned augmented helical blade, paired with group 6 featuring an off-centre augmented screw. All specimens were tested until failure under progressively increasing cyclic loading. Results: Stiffness was not significantly different among the study groups (p = 0.388). Varus deformation was significantly higher in group 4 versus group 6 (p = 0.026). Femoral head rotation was significantly higher in group 4 versus group 3 (p = 0.034), significantly lower in group 2 versus group 4 (p = 0.005), and significantly higher in group 4 versus group 6 (p = 0.007). Cycles to clinically relevant failure were 14,919 ± 4763 in group 1, 10,824 ± 5396 in group 2, 10,900 ± 3285 in group 3, 1382 ± 2701 in group 4, 25,811 ± 19,107 in group 5 and 17,817 ± 11,924 in group 6. Significantly higher number of cycles to failure were indicated for group 1 versus group 2 (p = 0.021), group 3 versus group 4 (p = 0.007), and in group 6 versus group 4 (p = 0.010). Conclusions: From a biomechanical perspective, proper centre–centre implant positioning in the femoral head is of utmost importance. In cases when this is not achievable in a clinical setting, a helical blade is more forgiving in the less ideal (anterior) malposition when compared to a screw, the latter revealing unacceptable low resistance to femoral head rotation and early failure. Cement augmentation of both off-centre implanted helical blade and screw head elements increases their resistance against failure; however, this effect might be redundant for helical blades and is highly unpredictable for screws.