The developmental mechanisms through which the cerebral cortex increased in size and complexity during primate evolution are essentially unknown. To uncover genetic networks active in the developing cerebral cortex, we combined three-dimensional reconstruction of human fetal brains at midgestation and whole genome expression profiling. This novel approach enabled transcriptional characterization of neurons from accurately defined cortical regions containing presumptive Broca and Wernicke language areas, as well as surrounding associative areas. We identified hundreds of genes displaying differential expression between the two regions, but no significant difference in gene expression between left and right hemispheres. Validation by qRTPCR and in situ hybridization confirmed the robustness of our approach and revealed novel patterns of area- and layer-specific expression throughout the developing cortex. Genes differentially expressed between cortical areas were significantly associated with fast-evolving non-coding sequences harboring human-specific substitutions that could lead to divergence in their repertoires of transcription factor binding sites. Strikingly, while some of these sequences were accelerated in the human lineage only, many others were accelerated in chimpanzee and/or mouse lineages, indicating that genes important for cortical development may be particularly prone to changes in transcriptional regulation across mammals. Genes differentially expressed between cortical regions were also enriched for transcriptional targets of FoxP2, a key gene for the acquisition of language abilities in humans. Our findings point to a subset of genes with a unique combination of cortical areal expression and evolutionary patterns, suggesting that they play important roles in the transcriptional network underlying human-specific neural traits.

Several methods exist for measuring medication adherence. The Time4Med^TM device (Adherence Innovations, Hong Kong) is a small, electronic card to affix on medication packaging that records date and time of intakes when a button is pushed. We aimed to validate the device with an emphasis on polypharmacy. Twenty volunteers used Time4Med^TM devices with a virtual thrice daily intake over 14 days. Diary-recorded date and time were compared to electronically-stored events. Functionality, reliability and recovery for different stress conditions were calculated. User‘s acceptability was assessed with the System Usability Scale (SUS). Eleven elderly outpatients (mean age 80.2 ± 8.1 years) taking >3 medications daily used the device over 4 weeks. Volunteers logged 847 events. Functionality (100%), sensitivity (94.9%), specificity (99.4%) and recovery (100%) were high. Dropping the smart card and storing it in a refrigerator caused either the recording of false events or no recording at all. The mean SUS score was 82.6 (SD 14.8), demonstrating excellent acceptability. Satisfaction was very high for volunteers and patients, except for pushing the button. Time4Med^TM devices are highly accurate in recording, retaining and delivering electronic data of multiple medication intake. They are well accepted by elderly patients. They can be recommended in clinical studies and for practitioners who desire to elucidate adherence patterns of ambulatory patients.

Patients with polypharmacy are challenged with the management of their daily medication. Medication management strategies for direct oral anticoagulants (DOAC) are especially important to guarantee medication adherence and to prevent thromboembolic events. Patients are often left alone with finding an appropriate strategy. To explore medication management strategies, to measure adherence to DOAC with the aim of deducing recommendations for practice. Face-to-face semi-structured interviews were conducted at the home of outpatients who were taking ≥4 medications daily including a DOAC, and self-managing their medication. A small electronic device (Time4Med™) was given to record medication intake during the four following weeks. During a second home visit, participants saw a graph of their medication intake as dot chart, and obtained a feedback. Interviews were transcribed verbatim and thematically analysed. Medication adherence was calculated with electronic data. Eighteen individuals (61.1% female; median age 77.5 years) were interviewed and reported 30 different medication management strategies, together with triggers, advantages and limitations. They combined at least five strategies, composed of internal (memory-based) and external (packaging-based or intake-based) strategies. The number of strategies was neither associated with the number of medications nor with medication adherence. Taking adherence was <100% for eight patients (44.4%). The inability of any medication management strategy to adapt to ageing and cognitive decline emerged as its most dramatic limitation, especially because individuals would fail to notice when their strategy became unsuited. Elderly patients develop manifold medication management strategies, which can inspire future medication users. Limitations are present such as forgetting medication intake in spite of a management strategy. The moment to adapt the strategy to ageing or cognitive decline is crucial and often goes unnoticed. It is therefore decisive that healthcare professionals regularly re-evaluate the appropriateness of the medication management strategies during counselling or ideally during home visits.

Background: Therapy with oral anticoagulation (OAC) can be challenging, especially in high risk groups such as chronic patients. Gaps in patient knowledge about OAC are linked to reduced effectiveness and safety of treatment. The objectives of this study were i) to assess OAC knowledge gathered during an intermediate medication review (MR) in patients taking vitamin K antagonists (VKA) or non-vitamin K antagonist oral anticoagulants (NOAC); ii) to assess OAC knowledge two weeks after the MR, and iii) to evaluate patient satisfaction with the MR service in community pharmacies. Methods: Chronic OAC patients were invited for a regular MR service in Swiss community pharmacies, the so-called “Polymedication-Check” (PMC). OAC knowledge was assessed with seven newly generated items asked face-to-face during a PMC and by telephone two weeks later. Knowledge gaps, pharmacists’ spontaneous interventions, and patient satisfaction were documented by observing pharmacy students. Treatment groups were compared. Results: Of all patients (n = 81), the number of patients with one or more knowledge gaps decreased from 66% to 31.3% after PMC (p < 0.001). NOAC patients (n = 31) had more knowledge gaps than VKA patients (n = 50; p < 0.05). Most patients (98.6%) were satisfied with the counselling provided by the pharmacists. Conclusion: The majority of chronic OAC patients shows knowledge gaps. Although spontaneous, the provision of tailored education during a PMC increased patient OAC knowledge.

To describe how stroke survivors with atrial fibrillation implement direct oral anticoagulant treatment and propose appropriate metrics to describe adherence. Stroke patients with atrial fibrillation electronically recorded their self-administered direct oral anticoagulants (apixaban, dabigatran, edoxaban, rivaroxaban) during a 6-month observation phase after hospitalisation for ischemic stroke. Taking and timing adherence, correct dosing days, drug holidays, time of the day and day of the week subsets, dose-to-dose intervals and longest intervals between two consecutive doses were calculated from electronic monitoring data to describe and discuss the implementation phase of adherence. Data from 41 patients were analysed. Median age was 77 (IQR = 69-84), 63.4% were male and the majority suffered a mild stroke (median NIHSS: 1). Mean taking and timing adherence exceeded 90%. Correct dosing occurred in 86.6% of the days. Seven patients (17.1%) had intake pauses of three or more consecutive days. Patients with twice-daily regimen (70.7%) had higher taking adherence in the morning than in the evening (94.4% versus 89.9%; p = 0.001). No therapy- or anamneses-related characteristic was associated with taking adherence. Although adherence to direct oral anticoagulants of stroke patients with atrial fibrillation exceeded 90%, deviant intake patterns such as drug holidays and missed evening doses were common and raise concerns. Appropriate adherence metrics calculated from electronic monitoring data may guide healthcare professionals elucidating patient-tailored adherence-enhancing interventions. ClinicalTrials.gov registration number: NCT03344146.

Introduction Multicompartment compliance aids (MCA) are widely used by patients. They support the management of medication and reduce unintentional nonadherence. MCA are filled with medicines unpacked from their original packaging. Swiss pharmacists currently provide MCA for 1–2 weeks, although little and controversial information exists on the stability of repackaged medicines. Objective We aimed to validate the usefulness of a simple screening method capable of detecting visual stability problems with repackaged medicines. Methods We selected eight criteria for solid formulations from The International Pharmacopoeia: (1) rough surface, (2) chipping, (3) cracking, (4) capping, (5) mottling, (6) discoloration, (7) swelling, and (8) crushing. A selection of 24 critical medicines was repackaged in three different MCA (Pharmis^®, SureMed™, and self-produced blister) and stored at room temperature for 4 weeks. Pharmis^® was additionally stored at accelerated conditions. Appearance was scored weekly. Results Six alterations (rough surface, cracking, mottling, discoloration, swelling, and crushing) were observed at accelerated conditions. No alteration was observed at room temperature, except for the chipping of tablets that had been stuck to cold seal glue. Conclusion The eight criteria can detect alterations of the appearance of oral solid medicines repackaged in MCA. In the absence of specific guidelines, they can serve as a simple screening method in community pharmacies for identifying medicines unsuitable for repackaging.