Discovery of ultrafast spontaneous spin switching in an antiferromagnet by femtosecond noise correlation spectroscopy.

Owing to their high magnon frequencies, antiferromagnets are key materials for future high-speed spintronics. Picosecond switching of antiferromagnetic spin systems has been viewed a milestone for decades and pursued only by using ultrafast external perturbations. Here, we show that picosecond spin switching occurs spontaneously due to thermal fluctuations in the antiferromagnetic orthoferrite Sm0.7Er0.3FeO3. By analysing the correlation between the pulse-to-pulse polarisation fluctuations of two femtosecond optical probes, we extract the autocorrelation of incoherent magnon fluctuations. We observe a strong enhancement of the magnon fluctuation amplitude and the coherence time around the critical temperature of the spin reorientation transition. The spectrum shows two distinct features, one corresponding to the quasi-ferromagnetic mode and another one which has not been previously reported in pump-probe experiments. Comparison to a stochastic spin dynamics simulation reveals this new mode as smoking gun of ultrafast spontaneous spin switching within the double-well anisotropy potential.

Risk factors for behavioral and psychotic dysregulation at the epilepsy monitoring unit in patients with intracranial electrodes.

OBJECTIVE: Aberrant behavior in patients with epilepsy (PWE) admitted to an epilepsy monitoring unit (EMU) can endanger their safety. We sought to identify predictive factors for post-ictal behavioral dysregulation and psychosis in patients with refractory epilepsy being monitored at an EMU. METHODS: Retrospective data were gathered from electronic patient files of all patients with refractory epilepsy who underwent intracranial registration at our EMU. We assessed behavioral and psychotic dysregulations by reviewing clinical notes, administered emergency medication, and reports of injuries or casualties in patients and nurses. In addition, we compared patient demographic characteristics, clinical characteristics, and antiepileptic drug (AED) profiles between patients with and without behavioral and/or psychotic dysregulation. RESULTS: Out of 73 admissions, 23 patients (32%) experienced behavioral dysregulation, and five patients experienced psychosis (7%). Behavioral dysregulation was only significantly associated with a previous history of interictal or postictal psychosis. Psychotic dysregulation is significantly associated with a psychiatric history, including a history of agitation or psychosis, whether or not epilepsy-related. For both types of dysregulations, there was no relation with a pre-admission frequency of seizures, clustering of seizures during monitoring, or a temporal focus of seizures. We could not report a relationship between AED use, tapering, and the occurrence of dysregulation. CONCLUSION: We conclude that a psychiatric history, including a history of agitation and psychosis, is related to an increased risk of behavioral and psychotic dysregulation in patients undergoing invasive seizure monitoring at the EMU.

Willingness to vaccinate children against COVID-19 declined during the pandemic.

OBJECTIVES: To document the level of vaccine hesitancy in caregivers' of children younger than 12 years of age over the course of the pandemic in Pediatric Emergency Departments (ED). Study design Ongoing multicenter, cross-sectional survey of caregivers presenting to 19 pediatric EDs in the USA, Canada, Israel, and Switzerland during first months of the pandemic (phase1), when vaccines were approved for adults (phase2) and most recently when vaccines were approved for children (phase3). RESULTS: Willingness to vaccinate rate declined over the study period (59.7%, 56.1% and 52.1% in the three phases). Caregivers who are fully vaccinated, who have higher education, and those worried their child had COVID-19 upon arrival to the ED, were more likely to plan to vaccinate in all three phases. Mothers were less likely to vaccinate early in the pandemic, but this hesitancy attenuated in later phases. Older caregivers were more willing to vaccinate, and caregivers of older children were less likely to vaccinate their children in phase 3. During the last phase, willingness to vaccinate was lowest in those who had a primary care provider but did not rely on their advice for medical decisions (34%). Those with no primary care provider and those who do and rely on their medical advice, had similar rates of willingness to vaccinate (55.1% and 52.1%, respectively). CONCLUSIONS: COVID-19 vaccine hesitancy is widespread and growing over time, and public health measures should further try to leverage identified factors associated with hesitancy in order to enhance vaccination rates among children.

Requirements for home-based upper extremity rehabilitation using wearable motion sensors for stroke patients: a user-centred approach.

PURPOSE: Telerehabilitation systems have the potential to enable therapists to monitor and assist stroke patients in achieving high-intensity upper extremity exercise in the home environment. We adopted an iterative user-centred approach, including multiple data sources and meetings with end-users and stakeholders to define the user requirements for home-based upper extremity rehabilitation using wearable motion sensors for subacute stroke patients. METHODS: We performed a requirement analysis consisting of the following steps: 1) context & groundwork; 2) eliciting requirements; 3) modelling & analysis; 4) agreeing requirements. During these steps, a pragmatic literature search, interviews and focus groups with stroke patients, physiotherapists and occupational therapists were performed. The results were systematically analysed and prioritised into "must-haves", "should-haves", and "could-haves". RESULTS: We formulated 33 functional requirements: eighteen must-have requirements related to blended care (2), exercise principles (7), exercise delivery (3), exercise evaluation (4), and usability (2); ten should-haves; and five could-haves. Six movement components, including twelve exercises and five combination exercises, are required. For each exercise, appropriate exercise measures were defined. CONCLUSION: This study provides an overview of functional requirements, required exercises, and required exercise measures for home-based upper extremity rehabilitation using wearable motion sensors for stroke patients, which can be used to develop home-based upper extremity rehabilitation interventions. Moreover, the comprehensive and systematic requirement analysis used in this study can be applied by other researchers and developers when extracting requirements for designing a system or intervention in a medical context.

This study provides an extensive overview of user requirements for home-based upper extremity rehabilitation using wearable motion sensors in stroke patients.These requirements can be used as a basis for developing home-based UE telerehabilitation interventions.Including these requirements may facilitate the clinical implementation of such telerehabilitation systems.The comprehensive and systematic approach used in this sudy can be applied by other researchers and developers when extracting requirements for designing a system or intervention in a medical context.

Polarized phonons carry angular momentum in ultrafast demagnetization.

Magnetic phenomena are ubiquitous in nature and indispensable for modern science and technology, but it is notoriously difficult to change the magnetic order of a material in a rapid way. However, if a thin nickel film is subjected to ultrashort laser pulses, it loses its magnetic order almost completely within femtosecond timescales1. This phenomenon is widespread2-7 and offers opportunities for rapid information processing8-11 or ultrafast spintronics at frequencies approaching those of light8,9,12. Consequently, the physics of ultrafast demagnetization is central to modern materials research1-7,13-28, but a crucial question has remained elusive: if a material loses its magnetization within mere femtoseconds, where is the missing angular momentum in such a short time? Here we use ultrafast electron diffraction to reveal in nickel an almost instantaneous, long-lasting, non-equilibrium population of anisotropic high-frequency phonons that appear within 150-750 fs. The anisotropy plane is perpendicular to the direction of the initial magnetization and the atomic oscillation amplitude is 2 pm. We explain these observations by means of circularly polarized phonons that quickly absorb the angular momentum of the spin system before macroscopic sample rotation. The time that is needed for demagnetization is related to the time it takes to accelerate the atoms. These results provide an atomistic picture of the Einstein-de Haas effect and signify the general importance of polarized phonons for non-equilibrium dynamics and phase transitions.

Transduction profiles in minipig following MRI guided delivery of AAV-5 into thalamic and corona radiata areas.

BACKGROUND: As a step towards clinical use of AAV-mediated gene therapy, brains of large animals are used to settle delivery parameters as most brain connections, and relative sizes in large animals and primates, are reasonably common. Prior to application in the clinic, approaches that have shown to be successful in rodent models are tested in larger animal species, such as dogs, non-human primates, and in this case, minipigs. NEW METHOD: We evaluated alternate delivery routes to target the basal ganglia by injections into the more superficial corona radiata, and, deeper into the brain, the thalamus. Anatomically known connections can be used to predict the expression of the transgene following infusion of AAV5. For optimal control over delivery of the vector with regards to anatomical location in the brain and spread in the tissue, we have used magnetic resonance image-guided convection-enhanced diffusion delivery. RESULTS: While the transduction of the cortex was observed, only partial transduction of the basal ganglia was achieved via the corona radiata. Thalamic administration, on the other hand, resulted in widespread transduction from the midbrain to the frontal cortex COMPARISON WITH EXISTING METHODS: Compared to other methods, such as delivery directly to the striatum, thalamic injection may provide an alternative when for instance, injection into the basal ganglia directly is not feasible. CONCLUSIONS: The study results suggest that thalamic administration of AAV5 has significant potential for indications where the transduction of specific areas of the brain is required.

Effect of the use of an iPad on the attention span of a child with Smith Magenis Syndrome: A single case study.

AIMS: To assess the effectiveness of iPad use on the attention span of a child with Smith Magenis Syndrome (n = 1), compared to attention span while working on the same tasks manually. METHODS: An AB design with a baseline and an intervention phase was used. Three manual tasks were chosen for the baseline, which matched the participant's intellectual age by the Early Intervention Method: a jigsaw puzzle (six pieces), a shape sorter, and matching pictures. These same tasks were performed on an iPad during the intervention phase. Six baseline and nine intervention phase films were included in the analysis. The 15 films were independently scored twice by two observers: once to observe the types of distractions that occurred (such as standing up from the chair, calling the teacher, or turning around on the chair), and a second time to measure the effective working time. RESULTS: iPad use led to a 45% decrease in the number of total distractions. The effective working time improved by 8% and showed a more consistent range compared to working on tasksbmanually. While task enjoyment was not directly measured, the observers and teachers agreed that working on the iPad appeared to be more enjoyable. CONCLUSIONS: In this single case study the participant showed that in his case iPad use can be effective in decreasing his distractions and therefore can improve his attention span. Enjoyment was higher while working with the iPad than performing tasks manually. This technology could therefore create more learning engagement for the participant, which could positively impact his behavior. Further research into iPad implementation for children with intellectual disabilities, poor fine motor skills, and/or attention deficits is needed.

Capillary Refill-The Key to Assessing Dermal Capillary Capacity and Pathology in Optical Coherence Tomography Angiography.

BACKGROUND/OBJECTIVES: Standard optical coherence tomography angiography (OCTA) has been limited to imaging blood vessels actively undergoing perfusion, providing a temporary picture of surface microvasculature. Capillary perfusion in the skin is dynamic and changes in response to the surrounding tissue's respiratory, nutritional, and thermoregulatory needs. Hence, OCTA often represents a given perfusion state without depicting the actual extent of the vascular network. Here we present a method for obtaining a more accurate anatomic representation of the surface capillary network in human skin using OCTA, along with proposing a new parameter, the Relative Capillary Capacity (RCC), a quantifiable proxy for assessing capillary dilation potential and permeability. METHODS: OCTA images were captured at baseline and after compression of the skin. Baseline images display ambient capillary perfusion, while images taken upon capillary refill display the network of existing capillaries at full capacity. An optimization-based automated vessel segmentation method was used to automatically analyze and compare OCTA image sequences obtained from two volunteers. RCC was then compared with visual impressions of capillary viability. RESULTS: Our OCTA imaging sequence provides a method for mapping cutaneous capillary networks independent of ambient perfusion. Differences between baseline and refill images clearly demonstrate the shortcomings of standard OCTA imaging and produce the RCC biometric as a quantifiable proxy for assessing capillary dilation potential and permeability. CONCLUSION: Future dermatological OCTA diagnostic studies should implement the Capillary Refill Methods over standard imaging techniques and further explore the relevance of RCC to differential diagnosis and dermatopathology. Lasers Surg. Med. © The Authors. Lasers in Surgery and Medicine published by Wiley Periodicals, Inc.

Polymeric microspheres for the sustained release of a protein-based drug carrier targeting the PDGFß-receptor in the fibrotic kidney.

Injectable sustained release drug delivery systems are an attractive alternative for the intravenous delivery of therapeutic proteins. In particular, for chronic diseases such as fibrosis, this approach could improve therapy by reducing the administration frequency while avoiding large variations in plasma levels. In fibrotic tissues the platelet-derived growth factor receptor beta (PDGFßR) is highly upregulated, which provides a target for site-specific delivery of drugs. Our aim was to develop an injectable sustained release formulation for the subcutaneous delivery of the PDGFßR-targeted drug carrier protein pPB-HSA, which is composed of multiple PDGFßR-recognizing moieties (pPB) attached to human serum albumin (HSA). We used blends of biodegradable multi-block copolymers with different swelling degree to optimize the release rate using the model protein HSA from microspheres produced via a water-in-oil-in-water double emulsion evaporation process. The optimized formulation containing pPB-HSA, showed complete release in vitro within 14days. After subcutaneous administration to mice suffering from renal fibrosis pPB-HSA was released from the microspheres and distributed into plasma for at least 7days after administration. Furthermore, we demonstrated an enhanced accumulation of pPB-HSA in the fibrotic kidney. Altogether, we show that subcutaneously administered polymeric microspheres present a suitable sustained release drug delivery system for the controlled systemic delivery for proteins such as pPB-HSA.

AAV5-miHTT gene therapy demonstrates suppression of mutant huntingtin aggregation and neuronal dysfunction in a rat model of Huntington's disease.

Huntington's disease (HD) is a fatal progressive neurodegenerative disorder caused by a mutation in the huntingtin (HTT) gene. To date, there is no treatment to halt or reverse the course of HD. Lowering of either total or only the mutant HTT expression is expected to have therapeutic benefit. This can be achieved by engineered micro (mi)RNAs targeting HTT transcripts and delivered by an adeno-associated viral (AAV) vector. We have previously showed a miHTT construct to induce total HTT knock-down in Hu128/21 HD mice, while miSNP50T and miSNP67T constructs induced allele-selective HTT knock-down in vitro. In the current preclinical study, the mechanistic efficacy and gene specificity of these selected constructs delivered by an AAV serotype 5 (AAV5) vector was addressed using an acute HD rat model. Our data demonstrated suppression of mutant HTT messenger RNA, which almost completely prevented mutant HTT aggregate formation, and ultimately resulted in suppression of DARPP-32-associated neuronal dysfunction. The AAV5-miHTT construct was found to be the most efficient, although AAV5-miSNP50T demonstrated the anticipated mutant HTT allele selectivity and no passenger strand expression. Ultimately, AAV5-delivered-miRNA-mediated HTT lowering did not cause activation of microglia or astrocytes suggesting no immune response to the AAV5 vector or therapeutic precursor sequences. These preclinical results suggest that using gene therapy to knock-down HTT may provide important therapeutic benefit for HD patients and raised no safety concerns, which supports our ongoing efforts for the development of an RNA interference-based gene therapy product for HD.

Strategies for the Activation and Release of the Membranolytic Peptide Melittin from Liposomes Using Endosomal pH as a Trigger.

Endosomolytic peptides are often coupled to drug delivery systems to enhance endosomal escape, which is crucial for the delivery of macromolecular drugs that are vulnerable to degradation in the endolysosomal pathway. Melittin is a 26 amino acid peptide derived from bee venom that has a very high membranolytic activity. However, such lytic peptides also impose a significant safety risk when applied in vivo as they often have similar activity against red blood cells and other nontarget cell membranes. Our aim is to control the membrane-disrupting capacity of these peptides in time and space by physically constraining them to a nanocarrier surface in such a way that they only become activated when delivered inside acidic endosomes. To this end, a variety of chemical approaches for the coupling of lytic peptides to liposomes via functionalized PEG-lipids were explored, including maleimide-thiol chemistry, click-chemistry, and aldehyde-hydrazide chemistry. The latter enables reversible conjugation via a hydrazone bond, allowing for release of the peptide under endosomal conditions. By carefully choosing the conjugation site and by using a pH activated analog of the melittin peptide, lytic activity toward a model membrane is completely inhibited at physiological pH. At endosomal pH the activity is restored by hydrolysis of the acid-labile hydrazone bond, releasing the peptide in its most active, free form. Furthermore, using an analogue containing a nonhydrolyzable bond as a control, it was shown that the activity observed can be completely attributed to release of the peptide, validating dynamic covalent conjugation as a suitable strategy to maintain safety during circulation.

Role of miRNAs and alternative mRNA 3'-end cleavage and polyadenylation of their mRNA targets in cardiomyocyte hypertrophy.

miRNAs play critical roles in heart disease. In addition to differential miRNA expression, miRNA-mediated control is also affected by variable miRNA processing or alternative 3'-end cleavage and polyadenylation (APA) of their mRNA targets. To what extent these phenomena play a role in the heart remains unclear. We sought to explore miRNA processing and mRNA APA in cardiomyocytes, and whether these change during cardiac hypertrophy. Thoracic aortic constriction (TAC) was performed to induce hypertrophy in C57BL/6J mice. RNA extracted from cardiomyocytes of sham-treated, pre-hypertrophic (2 days post-TAC), and hypertrophic (7 days post-TAC) mice was subjected to small RNA- and poly(A)-test sequencing (PAT-Seq). Differential expression analysis matched expectations; nevertheless we identified ~400 mRNAs and hundreds of noncoding RNA loci as altered with hypertrophy for the first time. Although multiple processing variants were observed for many miRNAs, there was little change in their relative proportions during hypertrophy. PAT-Seq mapped ~48,000 mRNA 3'-ends, identifying novel 3' untranslated regions (3'UTRs) for over 7000 genes. Importantly, hypertrophy was associated with marked changes in APA with a net shift from distal to more proximal mRNA 3'-ends, which is predicted to decrease overall miRNA repression strength. We independently validated several examples of 3'UTR proportion change and showed that alternative 3'UTRs associate with differences in mRNA translation. Our work suggests that APA contributes to altered gene expression with the development of cardiomyocyte hypertrophy and provides a rich resource for a systems-level understanding of miRNA-mediated regulation in physiological and pathological states of the heart.

Interplay between quantum shells and orientation in quasifission.

The quasifission mechanism hinders fusion in heavy systems through breakup within zeptoseconds into two fragments with partial mass equilibration. Its dependence on the structure of both the collision partners and the final fragments is a key question. Our original approach is to combine an experimental measurement of the fragments' mass-angle correlations in (40)Ca+(238)U with microscopic quantum calculations. We demonstrate an unexpected interplay between the orientation of the prolate deformed (238)U with quantum shell effects in the fragments. In particular, calculations show that only collisions with the tip of (238)U produce quasifission fragments in the magic Z=82 region, while collisions with the side are the only ones that may result in fusion.

48Ca+249Bk fusion reaction leading to element Z = 117: long-lived α-decaying 270Db and discovery of 266Lr.

The superheavy element with atomic number Z=117 was produced as an evaporation residue in the (48)Ca+(249)Bk fusion reaction at the gas-filled recoil separator TASCA at GSI Darmstadt, Germany. The radioactive decay of evaporation residues and their α-decay products was studied using a detection setup that allowed measuring decays of single atomic nuclei with half-lives between sub-µs and a few days. Two decay chains comprising seven α decays and a spontaneous fission each were identified and are assigned to the isotope (294)117 and its decay products. A hitherto unknown α-decay branch in (270)Db (Z = 105) was observed, which populated the new isotope (266)Lr (Z = 103). The identification of the long-lived (T(1/2) = 1.0(-0.4)(+1.9) h) α-emitter (270)Db marks an important step towards the observation of even more long-lived nuclei of superheavy elements located on an "island of stability."

The role of big data and advanced analytics in drug discovery, development, and commercialization.

In recent years, few ideas have captured the imagination of health-care practitioners as much as the advent of "big data" and the advanced analytical methods and technologies used to interpret it-it is a trend seen as having the potential to revolutionize biology, medicine, and health care.(1,2,3) As new types of data and tools become available, a unique opportunity is emerging for smarter and more effective discovery, development, and commercialization of innovative biopharmaceutical drugs.

Polytrauma at the Emergency Department; can we relate arterial blood gas analysis to a shock classification?

OBJECTIVE: Shock is defined as a change of circulation which results in hypoxia at the tissue level. Lactate and base deficit (BD) are associated with a high risk of multiple organ dysfunction in trauma patients. In this study we evaluated the influence of early recognition of shock in trauma patients. METHODS: In a retrospective study, relevant data were collected from the Radboud University Nijmegen Medical Centre (RUNMC) database between January 2009 and December 2010. Vital parameters were taken at the accident scene, and patients were divided into four shock classes. Arterial blood gas analysis was performed on arrival in the emergency department. Statistical analysis was performed with SPSS version 17.0. Statistical significance was assumed at p ≤ 0.05. RESULTS: A total of 255 patients were included. Patients who suffered from prehospital shock, and those who were intubated prior to hospital admittance showed a bad outcome, presenting with a more severe metabolic acidosis, higher ISS and higher mortality. There was a significant difference for bicarbonate and BD between shockclass I + II and shockclass III + IV, respectively 22.7 vs. 19.7 and -3.4 vs. -6.9. Intubated patients had a decreased bicarbonate and BD compared to not intubated patients, respectively 21.81 vs. 23.24 and -5.08 vs. -2.38. Mortality and ISS were higher in patients in shock class III and IV. Significant differences in serum lactate levels were not found. CONCLUSIONS: Prehospital shock influences patient outcome; outcome of patients is related to initial shock classification. Further validation of our shock classification, however, is necessary.

The first five days: field and laboratory investigations during the early stages of the equine influenza outbreak in Australia, 2007.

Until August 2007, Australia was one of only three countries internationally recognised to be free of equine influenza (EI). This report documents the diagnosis of the first cases of EI in Australian horses and summarises the investigations that took place over the next 5 days. During that time, a multifocal outbreak was identified across eastern New South Wales and south-eastern Queensland. The use of an influenza type A pan-reactive real-time reverse transcription polymerase chain reaction allowed rapid confirmation of suspect cases of EI.

Predominant time scales in fission processes in reactions of S, Ti and Ni with W: zeptosecond versus attosecond.

The inhibition of fusion by quasifission is crucial in limiting the formation of superheavy elements in collisions of heavy nuclei. Time scales of ∼10(-18) s inferred for fissionlike events from recent crystal blocking measurements were interpreted to show either that quasifission itself is slower than previously believed, or that the fraction of slow fusion-fission is higher than expected. New measurements of mass-angle distributions for (48)Ti and (64)Ni bombarding W targets show that in these reactions quasifission is the dominant process, typically occurring before the system formed after contact has made a single rotation, corresponding to time scales of ≤10(-20) s.

Disentangling effects of nuclear structure in heavy element formation.

Forming the same heavy compound nucleus with different isotopes of the projectile and target elements allows nuclear structure effects in the entrance channel (resulting in static deformation) and in the dinuclear system to be disentangled. Using three isotopes of Ti and W, forming 232Cm, with measurement spanning the capture barrier energies, alignment of the heavy prolate deformed nucleus is shown to be the main reason for the broadening of the mass distribution of the quasifission fragments as the beam energy is reduced. The complex, consistently evolving mass-angle correlations that are observed carry more information than the integrated mass or angular distributions, and should severely test models of quasifission.

Cognitive performance in neurokinin 3 receptor knockout mice.

RATIONALE: The neurokinin 3 (NK(3)) receptor is a novel target under investigation for improvement of the symptoms of schizophrenia due to its ability to modulate dopaminergic signaling. However, research on effects of NK(3) antagonism with animal models has been hindered because of species differences in the receptor between humans, rats, and mice. OBJECTIVES: The aim of the present study is to further knowledge on the role of NK(3) in cognitive functioning by testing the effect of knockout of the NK(3) receptor on tests of working memory, spatial memory, and operant responding. MATERIALS AND METHODS: NK(3) knockout mice generated on a C57Bl/6 background were tested in delayed matching to position (DMTP), spontaneous alternation, Morris water maze, and active avoidance tasks. RESULTS: NK(3) knockout mice showed better performance in the DMTP task, though not delay dependently, which points to an effect on operant performance but not on working memory. No differences were seen between the groups in spontaneous alternation, another indication that working memory is not affected in NK(3) knockouts. There was no impairment in knockout mice in Morris water maze training, and the mice also showed faster response latency in the active avoidance task during training. CONCLUSIONS: Collectively, these results support a role for the NK(3) receptor in performance of operant tasks and in spatial learning but not in working memory.