Explore the vast range of titles available.

Age-related hearing loss (ARHL) is the most common sensory impairment mainly caused by degeneration of sensory hair cells in the cochlea with no causal medical treatment available. Auditory function and sensory hair cell survival critically depend on the Kv7.4 (KCNQ4) channel, a voltage-gated potassium channel expressed in outer hair cells (OHCs), with its impaired function or reduced activity previously associated with ARHL. Here, we investigated the effect of a potent small-molecule Kv7.4 agonist on ARHL in the senescence-accelerated mouse prone 8 (SAMP8) model. For the first time in vivo, we show that Kv7.4 activation can significantly reduce age-related threshold shifts of auditory brainstem responses as well as OHC loss in the SAMP8 model. Pharmacological activation of Kv7.4 thus holds great potential as a therapeutic approach for ARHL as well as other hearing impairments related to Kv7.4 function.

Hepatitis C virus (HCV) infection is a serious cause of chronic liver disease worldwide with more than 170 million infected individuals at risk of developing significant morbidity and mortality 1 , 2 , 3 . Current interferon-based therapies 4 are suboptimal especially in patients infected with HCV genotype 1, and they are poorly tolerated, highlighting the unmet medical need for new therapeutics 5 , 6 . The HCV-encoded NS3 protease is essential for viral replication 7 , 8 and has long been considered an attractive target for therapeutic intervention in HCV-infected patients. Here we identify a class of specific and potent NS3 protease inhibitors and report the evaluation of BILN 2061, a small molecule inhibitor biologically available through oral ingestion and the first of its class in human trials. Administration of BILN 2061 to patients infected with HCV genotype 1 for 2 days resulted in an impressive reduction of HCV RNA plasma levels, and established proof-of-concept in humans for an HCV NS3 protease inhibitor. Our results further illustrate the potential of the viral-enzyme-targeted drug discovery approach for the development of new HCV therapeutics.

Background: Subthalamic nucleus (STN) deep brain stimulation (DBS) has become a routine treatment of advanced Parkinson’s disease (PD). DBS surgery is commonly performed under local anesthesia (LA) to obtain reliable microelectrode recordings. However, procedural sedation and/or analgesia (PSA) is often desirable to improve patient comfort. The impact of PSA in addition to LA on outcome is largely unknown. Therefore, we performed an observational study to assess the effect of PSA compared to LA alone during STN DBS surgery on outcome in PD patients. Methods: Seventy PD patients (22 under LA, 48 under LA + PSA) scheduled for STN DBS implantation were included. Dexmedetomidine, clonidine or remifentanil were used for PSA. The primary outcome was the change in Movement Disorders Society Unified Parkinson’s Disease Rating Score III (MDS-UPDRS III) and levodopa equivalent daily dosage (LEDD) between baseline, one month before surgery, and twelve months postoperatively. Secondary outcome measures were motor function during activities of daily living (MDS-UPDRS II), cognitive alterations and surgical adverse events. Postoperative assessment was conducted in “on” stimulation and “on” medication conditions. Results: At twelve months follow-up, UPDRS III and UPDRS II scores in “on” medication conditions were similar between the LA and PSA groups. The two groups showed a similar LEDD reduction and an equivalent decline in executive function measured by the Stroop Color-Word Test, Trail Making Test-B, and verbal fluency. The incidence of perioperative and postoperative adverse events was similar between groups. Conclusion: This study demonstrates that PSA during STN DBS implantation surgery in PD patients was not associated with differences in motor and non-motor outcome after twelve months compared with LA only.

IntroductionEffective treatment of new-onset headache after craniotomy, especially anterior temporal lobectomy (ATL) and amygdalohippocampectomy for drug-resistant temporal lobe epilepsy, is a challenge. The current practice, acetaminophen combined with opioids is often reported by patients as insufficient and sometimes accompanied by opioid-related adverse effects. Based on expert opinion, anaesthesiologists therefore frequently consider s-ketamine as add-on therapy. This randomised parallel group design trial compares s-ketamine with a placebo as add on medication to a multimodal pain approach.Methods and analysisIn total 62 adult participants, undergoing ATL for drug resistant epilepsy under general anaesthesia, will be randomised to either receive a 0.25 mg/kg bolus followed by a continuous infusion of 0.1 mg/kg/hour of s-ketamine or placebo (0.9% NaCl) starting before incision and continued for 48 hours as an addition to acetaminophen and opioids administered in a patient-controlled analgesia pump. The primary outcome measure is the cumulative postoperative opioid consumption. Patient recruitment started August 2018 and will end in 2021. Secondary outcome measures are postoperative pain intensity scores, psychological parameters, length of hospital stay and adverse events and will be reassessed at 3 and 6 months after surgery, with a baseline measurement preoperatively. All data are collected by researchers who are blinded to the treatment. The data will be analysed by multivariable linear mixed-effects regression.Ethics and disseminationEthical approval has been given by the local medical ethical committee (NL61666.068.17). This study will be conducted in accordance with the Dutch Medical Research Involving Human Subjects Act and the Declaration of Helsinki. The results of this trial will be publicly disclosed and submitted for publication in an international peer-reviewed scientific journal.Trial registration numberNTR6480.

Background: Microelectrode recordings (MER) are used to optimize lead placement during subthalamic nucleus deep brain stimulation (STN-DBS). To obtain reliable MER, surgery is usually performed while patients are awake. Procedural sedation and analgesia (PSA) is often desirable to improve patient comfort, anxiolysis and pain relief. The effect of these agents on MER are largely unknown. The objective of this study was to determine the effects of commonly used PSA agents, dexmedetomidine, clonidine and remifentanil and patient characteristics on MER during DBS surgery. Methods: Data from 78 patients with Parkinson’s disease (PD) who underwent STN-DBS surgery were retrospectively reviewed. The procedures were performed under local anesthesia or under PSA with dexmedetomidine, clonidine or remifentanil. In total, 4082 sites with multi-unit activity (MUA) and 588 with single units were acquired. Single unit firing rates and coefficient of variation (CV), and MUA total power were compared between patient groups. Results: We observed a significant reduction in MUA, an increase of the CV and a trend for reduced firing rate by dexmedetomidine. The effect of dexmedetomidine was dose-dependent for all measures. Remifentanil had no effect on the firing rate but was associated with a significant increase in CV and a decrease in MUA. Clonidine showed no significant effect on firing rate, CV or MUA. In addition to anesthetic effects, MUA and CV were also influenced by patient-dependent variables. Conclusion: Our results showed that PSA influenced neuronal properties in the STN and the dexmedetomidine (DEX) effect was dose-dependent. In addition, patient-dependent characteristics also influenced MER.

Central venous access is indicated for transduction of central venous pressure and the administration of inotropes in the perioperative period. The right internal jugular vein (RIJV) is cannulated preferentially over the left internal jugular vein (LIJV). Cannulation of the LIJV is associated with a higher complication rate and a perceived increased level of difficulty when compared with cannulation of the RIJV. Possible explanations for the higher complication rate include a smaller diameter and more anterior position relative to the corresponding carotid artery (CA) of the LIJV compared with the RIJV. In this study, the RIJV and LIJV were examined in mechanically ventilated patients to determine the validity of these possible explanations. A prospective, nonrandomized cohort study. The operating room of a major teaching hospital. One hundred fifty-one patients scheduled for elective heart surgery. Ultrasound examination of the RIJV and LIJV at the level of the cricoid cartilage with a 12-MHz linear transducer in 151 anesthetized, mechanically ventilated patients in the Trendelenburg position. In 72% of patients, the RIJV was dominant over the LIJV. The diameter and cross-sectional area of the RIJV was larger than the LIJV (P < .001). An anterior position of the LIJV in relation to the left CA was detected more often when compared with the RIJV and right CA (15.1% vs 5.4%, P = .01). This study confirms the smaller diameter and increased frequency of anterior positioning relative to the corresponding CA of the LIJV when compared with the RIJV. This validates them as possible explanations for the higher complication rate of LIJV cannulation compared with RIJV cannulation. •The left and right jugular vein are assymetric with regard to diameter•The RIJV is most often dominant. In 28% of the patients, the LIJV is dominant and theoretically easier to cannulate•Both jugular veins should be scanned by ultrasound before cannulation is performed

In the history of Christian-Muslim relations, the rise of Islam and its encounter with Christianity is often characterized as the competition between two missionary religions, but this is a narrative formed by Western Christianity’s engagement with Islam long after Islam’s formation. It represents an anachronistic understanding of how Christians and Muslims viewed and related to one another in the formational period of Islam. In particular, it neglects the history of Syriac Christians who lived amidst Muslims in the first centuries of Islam’s existence, and therefore a significant part of the earliest engagement between Muslims and Christians has effectively been a lost history. When works on Islam recognize the presence of Syriac Christians (Eastern, non-Chalcedonian Christians), it is generally confined to two areas: their work in translating philosophical and scientific texts into Arabic during the golden age of Islam, and their status as ahl al-dhimmah (protected people). There remains a gap in our understanding of the relationship they had with one another and how this may have shaped each religion’s self-understanding as they navigated a new form of religious pluralism. This study examines the Church of the East and its relation to Islam in the 7th to 9th centuries CE. This will help flesh out our understanding of Christianity’s early relationship to Islam through the lens of the Church of the East with the hope that it may help inform relational possibilities between followers of these religions today.