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Z-disks, the mechanical integration sites of heart and skeletal muscle cells, link anchorage of myofilaments to force reception and processing. The key molecules that enable the Z-disk to persistently withstand the extreme mechanical forces during muscle contraction have not yet been identified. Here we isolated nexilin (encoded by NEXN) as a novel Z-disk protein. Loss of nexilin in zebrafish led to perturbed Z-disk stability and heart failure. To evaluate the role of nexilin in human heart failure, we performed a genetic association study on individuals with dilated cardiomyopathy and found several mutations in NEXN associated with the disease. Nexilin mutation carriers showed the same cardiac Z-disk pathology as observed in nexilin-deficient zebrafish. Expression in zebrafish of nexilin proteins encoded by NEXN mutant alleles induced Z-disk damage and heart failure, demonstrating a dominant-negative effect and confirming the disease-causing nature of these mutations. Increasing mechanical strain aggravated Z-disk damage in nexilin-deficient skeletal muscle, implying a unique role of nexilin in protecting Z-disks from mechanical trauma.

BackgroundPulmonary artery pressure (PAP) is an important marker in cardiovascular disorders, being closely associated with morbidity and mortality. Noninvasive assessment by Doppler echocardiography is recommended by current guidelines. So far, the reliability of this method has been assessed only in small studies with contradictory results. Therefore, the aim of this study was to analyze the reliability of noninvasive PAP assessment by Doppler echocardiography compared to invasive measurements in a large patient population.Methods and ResultsWe retrospectively analyzed data from a large tertiary cardiology department over 6 years in order to compare invasively measured PAP to estimated PAP from echocardiography examinations. N=15 516 patients fulfilled inclusion criteria and n=1695 patients with timely matched examinations (within 5 days) were analyzed. In n=1221 (72%) patients, pulmonary hypertension (PH) was diagnosed invasively (postcapillary PH: n=1122 [66%]; precapillary PH: n=99 [6%]). Systolic pulmonary artery pressure (sPAP) was 45.3±15.5 mm Hg by Doppler echocardiography and 47.4±16.4 mm Hg by right heart catheterization. Pearson's correlation coefficient was r=0.87 (P<0.0001). Mean right atrial pressure (RAP) was 12.0±5.7 mm Hg by right heart catheterization and was estimated to be 12.1±6.6 mm Hg by echocardiography (r=0.82, P<0.0001). Bland–Altman analysis showed a bias of −2.0 mm Hg for sPAP (95% limits of agreement −18.1 to +14.1 mm Hg) and +1.0 mm Hg for RAP (95% limits of agreement +0.1 to +1.9 mm Hg). Noninvasive diagnosis of pulmonary hypertension with Doppler echocardiography had a good sensitivity (87%) and specificity (79%), positive and negative predictive values (91% and 70%), as well as accuracy (85%) for a sPAP cut‐off value of 36 mm Hg (AUC 0.91, P<0.001, CI 0.90 to 0.93).ConclusionsIn this study, Doppler echocardiography proved to be a reliable method for the assessment of sPAP, being well suited to establish the noninvasive diagnosis of pulmonary hypertension in patients with cardiac diseases.

In MMN, short-term subcutaneous infusion of immunoglobulin is feasible, safe and as effective as intravenous infusion. Subcutaneous administration is an alternative option that adds flexibility to the treatment schedule.

Overall, our data do not support an immediate beneficial effect of PTH replacement therapy on muscle function or QoL. A high frequency of hypercalcemia among our patients may have compromised the potential beneficial effects of reversing the state of PTH insufficiency.

Summary Objective To assess the feasibility and accuracy of seizure detection based on heart rate variability (HRV) using a wearable electrocardiography (ECG) device. Noninvasive devices for detection of convulsive seizures (generalized tonic‐clonic and focal to bilateral tonic‐clonic seizures) have been validated in phase 2 and 3 studies. However, detection of nonconvulsive seizures still needs further research, since currently available methods have either low sensitivity or an extremely high false alarm rate (FAR). Methods In this phase 2 study, we prospectively recruited patients admitted to long‐term video–EEG monitoring (LTM). ECG was recorded using a dedicated wearable device. Seizures were automatically detected using HRV parameters computed off‐line, blinded to all other data. We compared the performance of 26 automated algorithms with the seizure time‐points marked by experts who reviewed the LTM recording. Patients were classified as responders if >66% of their seizures were detected. Results We recruited 100 consecutive patients and analyzed 126 seizures (108 nonconvulsive and 18 convulsive) from 43 patients who had seizures during monitoring. The best‐performing HRV algorithm combined a measure of sympathetic activity with a measure of how quickly HR changes occurred. The algorithm identified 53.5% of the patients with seizures as responders. Among responders, detection sensitivity was 93.1% (95% CI: 86.6%‐99.6%) for all seizures and 90.5% (95% CI: 77.4%‐97.3%) for nonconvulsive seizures. FAR was 1.0/24 h (0.11/night). Median seizure detection latency was 30 s. Typically, patients with prominent autonomic nervous system changes were responders: An ictal change of >50 heartbeats per minute predicted who would be responder with a positive predictive value of 87% and a negative predictive value of 90%. Significance The automated HRV algorithm, using ECG recorded with a wearable device, has high sensitivity for detecting seizures, including the nonconvulsive ones. FAR was low during the night. This approach is feasible in patients with prominent ictal autonomic changes.

Integration of tactile afferent signals with motor commands is crucial for the performance of purposeful movements such as during manipulation of an object in the hand. To study the somatotopic organization of sensorimotor integration we applied electrical peripheral conditioning stimuli to a digit located near (homotopic stimulation) or distant from (heterotopic stimulation) relaxed or isometrically contracted intrinsic hand muscles at variable time intervals prior to transcranial magnetic stimulation (TMS). Cutaneous stimulation has previously been shown to modulate the amplitude of the motor evoked potential (MEP) and to shorten the duration of the silent period (SP) evoked by TMS. In relaxed target muscles the time-dependent modulation of TMS-evoked motor responses by homotopic conditioning stimulation differed from modulation by heterotopic stimulation. Similar differences in the modulation pattern evoked by homotopic and heterotopic conditioning stimulation were observed for two distinct target muscles of the hand (abductor digiti minimi, abductor pollicis brevis muscle). Differences in modulation were maximal when the conditioning stimulation was applied 25-30 ms and 150-200 ms prior to TMS. Comparison of the modulation of the amplitudes of MEPs evoked by transcranial electrical stimulation (TES) and the modulation of those evoked by TMS suggests that differences between homotopic and heterotopic stimulation originate subcortically at 25- to 30-ms and, at least partially, cortically at 150- to 200-ms interstimulus intervals. In isometrically contracted intrinsic hand muscles the degree to which the SP was shortened reflected the location and the timing of the conditioning stimulus. Shortening was maximal when the conditioning stimulus was applied nearest to the contracted target muscle and 20 ms prior to the test stimulus. In contrast to the SP duration, the MEP size in voluntarily contracted target muscles was unaffected by the location of the conditioning stimulus. The somatotopic gradient of SP shortening was abolished when the two target muscles were simultaneously activated isometrically. Together, our findings suggest that somatotopy of input-output relationships is implemented at both a spinal and a cortical level in the human central nervous system and may also depend on the motor task involved.

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