The role of CD4+ T cells in the control of persistent viral infections beyond the provision of cognate help remains unclear. We used polychromatic flow cytometry to evaluate the production of the ...cytokines interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, and interleukin (IL)-2, the chemokine macrophage inflammatory protein (MIP)-1beta, and surface mobilization of the degranulation marker CD107a by CD4+ T cells in response to stimulation with cytomegalovirus (CMV)-specific major histocompatibility complex class II peptide epitopes. Surface expression of CD45RO, CD27, and CD57 on responding cells was used to classify CD4+ T cell maturation. The functional profile of virus-specific CD4+ T cells in chronic CMV infection was unique compared with that observed in other viral infections. Salient features of this profile were: (a) the simultaneous production of MIP-1beta, TNF-alpha, and IFN-gamma in the absence of IL-2; and (b) direct cytolytic activity associated with surface mobilization of CD107a and intracellular expression of perforin and granzymes. This polyfunctional profile was associated with a terminally differentiated phenotype that was not characterized by a distinct clonotypic composition. Thus, mature CMV-specific CD4+ T cells exhibit distinct functional properties reminiscent of antiviral CD8+ T lymphocytes.
This study examined the impact of “New” and “#1 Prescribed” market claims and quantitative efficacy information on perceptions of a hypothetical prescription drug in a direct‐to‐consumer (DTC) print ...advertisement. We examined two market claims (New and #1 Prescribed), two efficacy levels (higher and lower), and a control condition without this information. Participants with diabetes were randomized to review one ad version and asked their perceptions of the ad's message, the drug's benefits, side effects and risks, doctors' opinions about the drug, and behavioral intention to use the drug, as well as recall and recognition of drug benefits and risks. Results suggest the market claim affects personal perceptions and perceptions of the ad's message about drug benefits and perceptions about doctors' opinions of the drug. Inclusion of quantitative information about product efficacy did not show a large influence on perceptions. These findings can help inform stakeholders and policy makers as they work to ensure DTC prescription drug promotion does not mislead patients.
Left ventricular (LV) pacing through the coronary sinus is the standard approach for cardiac resynchronization therapy. When this route is unavailable, the alternatives have major limitations. LV ...endocardial pacing through the interventriuclar septum may offer a simpler solution. We describe an initial case series to demonstrate technical feasibility and to describe our refinement of the puncture technique.
Ten patients with previous failed coronary sinus lead implant or with nonresponse to cardiac resynchronization therapy and a suboptimal LV lead position were selected. All patients were anticoagulated. Left ventriculography and coronary angiography were performed to identify LV borders and septal vessels. Subclavian vein access was used for a superior approach ventricular transseptal puncture under fluoroscopic guidance, using a steerable sheath and a standard transseptal needle, radiofrequency needle, or radiofrequency energy delivered through a guidewire. An active-fixation pacing lead was successfully delivered to the endocardial wall of the lateral LV in all patients (9 men; age, 62±10 years). LV lead implant procedure time shortened with experience. The use of radiofrequency energy delivered through a guidewire was the most effective technique. Mean threshold and R wave at implant were 0.8±0.3 V and 10.8±3.9 mV. At follow-up (mean, 8.7 months; minimum, 0; and maximum 19), thresholds were stable, and there were no thromboembolic events. Of 9 patients, 8 were classed as clinical responders (1 had inadequate follow-up to assess response).
LV endocardial pacing through a ventricular septal puncture is a feasible approach for cardiac resynchronization therapy.
Massive electrons signify correlations
Thirty years on, and the mechanism of superconductivity in copper-oxide superconductors remains a mystery. Knowledge of their normal nonsuperconducting state is ...also incomplete; however, we do know that the more robust the superconductivity, the higher the magnetic fields required to suppress it. Ramshaw
et al.
studied samples of three different compositions of the copper-oxide YBa
2
Cu
3
O
6+δ
in magnetic fields exceeding 90 T. They found that as the oxygen content increased toward the point of the maximum transition temperature, the conducting electrons became heavier and heavier. This mass enhancement reflected an increase in electronic correlations, which in turn may be a signature of a quantum critical point.
Science
, this issue p.
317
Quantum oscillation measurements track the doping dependence of the effective electron mass in the cuprate YBa
2
Cu
3
O
6+δ
.
In the quest for superconductors with higher transition temperatures (
T
c
), one emerging motif is that electronic interactions favorable for superconductivity can be enhanced by fluctuations of a broken-symmetry phase. Recent experiments have suggested the existence of the requisite broken-symmetry phase in the high-
T
c
cuprates, but the impact of such a phase on the ground-state electronic interactions has remained unclear. We used magnetic fields exceeding 90 tesla to access the underlying metallic state of the cuprate YBa
2
Cu
3
O
6+δ
over a wide range of doping, and observed magnetic quantum oscillations that reveal a strong enhancement of the quasiparticle effective mass toward optimal doping. This mass enhancement results from increasing electronic interactions approaching optimal doping, and suggests a quantum critical point at a hole doping of
p
crit
≈ 0.18.
The spectrum of phenotypes associated with heterozygous deletions of neurexin-1 (NRXN1) is diverse and includes: autism spectrum disorder, attention deficit hyperactivity disorder, intellectual ...disability, seizures, schizophrenia, mood disorders and congenital malformations. Reduced penetrance and variable expressivity of deletions in this gene remain a challenge for genetic counselling. We clinically reviewed 67 NRXN1 deletions from 34 families to document the phenotype and determine odds ratio. Thirty-four probands (5 adults, 29 children (<16 years)) were initially identified from a cohort clinically referred for arrayCGH. A further 33 NRXN1 deletions (16 with established phenotype) from the families were identified following cascade screening. Speech and language delay was a consistent clinical presentation. Pedigree analysis of the inherited group revealed numerous untested relatives with a history of mental health and developmental issues, most notably in the NRXN1β isoform patients. Our study highlights the complex nature of the NRXN1 phenotype in this population.
The Afar region presents a unique example of a juvenile R‐R‐R triple junction with the arms evolved to various stages of maturity. The lithosphere in this area has been modified heterogeneously by ...the nearby Afar mantle plume. To gain a comprehensive and consistent understanding of the link between crustal geometry and geodynamics of the region and facilitate comparisons across different tectonic elements, we developed a high‐resolution crustal thickness map of the region that resolves major tectonic features. The calculation involved a well‐constrained 3‐D inversion of upper mantle‐corrected crustal Bouguer gravity anomalies computed with the help of tomography‐derived densities. Our results match earlier localized crustal thickness estimates, illustrating the method's efficacy. A thinner crust (∼20–26 km) is revealed in the Afar compared to adjacent continental regions. The Main Ethiopian Rift has the thickest crust in the central part of the rift (∼38–40 km) and thinner to the north (∼30 km) and south (∼35 km). The crustal thickness along the Gulf of Aden changes from east (∼5 km) to west (∼17 km) in the west, consistent with a westward transition from seafloor spreading to continental rifting. The southern Red Sea is characterized by asymmetric crustal thickness, with a thicker crust (∼17 km) on the eastern flank compared to the western flank (∼11 km), which we attribute to the influence of a sub‐lithospheric channel from the Afar mantle plume. We propose a model describing the channel leading to asymmetric features of the southern Red Sea, such as crustal accretion, marginal topography, and volcanism.
Plain Language Summary
The Afar region is a divergent triple junction where the Main Ethiopian Rift, the Red Sea, and the Gulf of Aden converge and is the site of impingement of the Afar mantle plume on the lithosphere. We have developed a high‐resolution crustal thickness map using gravity inversion techniques to study how deep geodynamics affect the rifting process and crustal geometry of the region. We isolated the gravity signals caused by shallow geological features by removing the deeper components. These shallow signals and crustal thickness data provide insights into the evolution of the triple junction arms and the influence of the mantle plume. We found a transition from seafloor spreading to continental rifting in the Gulf of Aden. There is discontinuous crustal accretion in the central Red Sea and continuous accretion in the south. Moreover, the computed crustal thickness suggests that crustal accretion is not symmetric in the southern Red Sea. We suggest seafloor spreading in the southern Red Sea occurs above a lateral sub‐lithospheric channel from the Afar plume, which may also cause crustal thickness asymmetry, uneven rift margin topography, and volcanism in the region.
Key Points
Crustal thickness asymmetry in the southern Red Sea reveals differential crustal accretion under the influence of the Afar plume channel
Custal gravity anomalies reveal the heterogeneous nature of the Red Sea and the westward spreading‐rifting transition in the Gulf of Aden
Proposed a model linking the horizontal plume channel with the observed asymmetry around the southern Red Sea
The use of timber harvest residue as an energy source is thought to have environmental benefits relative to food‐based crops, yet the ecological impact of this practice remains largely unknown. We ...assessed whether the abundance and diversity of wild bees (Apoidea) were influenced by the removal of harvest residue and associated soil compaction within managed conifer forest in western Oregon, USA. We sampled bees over two years (2014–2015) on study plots that were subjected to five treatments representing gradients in removal of harvest residue and soil compaction. We collected >7,500 bee specimens from 92 distinct species/morphospecies that represented five of the seven bee families. We trapped 3x more individuals in the second year of the study despite identical sampling effort in both years, with most trapped bees classified as ground‐nesting species. Members of the sweat bee family (Halictidae) comprised more than half of all specimens, and the most abundant genus was composed of metallic green bees (Agapostemon, 33.6%), followed by long‐horned bees (Melissodes, 16.5%), sweat bees (Halictus, 15.9%), and bumble bees (Bombus, 13.6%). In both years, abundance and observed species richness were greatest in the most intensive harvest residue treatment, with other treatments having similar values for both measures. Our study indicates that early successional managed conifer forest that has experienced removal of harvest residue can harbor a surprising diversity of wild bees, which are likely to have important contributions to the broader ecological community through the pollination services they provide.
Despite interest in forest harvest residues as an alternative to fossil fuels, little is known about how removing these components from forests influences native pollinators. The results from this study found that the removal of forest harvest residues and associated organic materials was linked to increased bee diversity, likely because it provided new nesting habitat that was suitable for ground‐nesting bee species.
Abstract
Introduction
The PRAETORIAN-DFT trial hypothesises that subcutaneous implantable cardioverter defibrillator (S-ICD) implant without defibrillation test (DFT) but with PRAETORIAN score is ...non-inferior to S-ICD implant with DFT with regard to first shock efficacy in spontaneous events. Various anesthesia protocols are used for S-ICD implant, ranging from local to general anesthesia. Sedation of the patient during S-ICD implantation is required because of DFT. Without the need for DFT, local anesthesia may suffice, thereby reducing the logistical burden associated with sedation and general anesthesia. However, data comparing the effects of various anesthesia methods are lacking.
Purpose
This prespecified analysis of the PRAETORIAN-DFT trial aims to investigate the effect of three different anesthesia methods on (post-)operative pain during S-ICD implant.
Methods
In the PRAETORIAN-DFT trial (NCT03495297), 965 patients were randomised to DFT (N=483) or no DFT with PRAETORIAN Score calculation (N=482). Choice of anesthesia protocol was per local routine and physician discretion and was listed as local anesthesia (LA), monitored anesthesia care (MAC) or general anesthesia (GA). Patients under LA who underwent DFT, had MAC or GA during the test. Pain scores were assessed using the Numerical Rating Scale (NRS), prior to implant (baseline) and at 1-3 hours, 5-7 hours and 1 day post implant. Mean change in NRS compared to baseline was calculated at every time point. Exact pain scores as well as mean change in NRS were compared between anesthesia methods using a Kruskal Wallis Test.
Results
Pre-implant pain questionnaires were completed by 97% of patients. In the complete study cohort, 149/965 (15%) of implants were performed under LA, 327/965 (34%) under MAC and 489/965 (51%) under GA. This distribution did not differ between the randomised arms (p=0.301). There was no difference in NRS or mean change compared to baseline between the groups at any time post implant. The mean change in NRS compared to baseline was highest at 5-7 hours post implant in all groups (Figure). Analysis with patients under LA and MAC or GA during DFT as independent group showed similar results.
Conclusion
There was no difference in pain perception after S-ICD implantation between implant under local anesthesia, MAC and general anesthesia. These results confirm that S-ICD implantation under local anesthesia is feasible and sedation may be no longer necessary if defibrillation testing becomes redundant.Mean changes in NRS compared to baseline
Abstract
Aims
Evidence regarding post-procedural antithrombotic regimen other than used in randomized trials assessing percutaneous left atrial appendage (LAA) closure is limited. The present work ...aimed to compare different antithrombotic strategies applied in the real-world EWOLUTION study.
Methods and results
A total of 998 patients with successful WATCHMAN implantation were available for the present analysis. The composite ischaemic endpoint of stroke, transitory ischaemic attack, systemic embolism and device thrombus, and the bleeding endpoint defined as at least major bleeding were assessed during an initial period (from implant until first medication change) and long-term period (from first change up to 2 years). The antithrombotic medication chosen in the initial phase was dual antiplatelet therapy (DAPT) in 60%, oral anticoagulation (OAC) in 27%, single antiplatelet therapy (SAPT) in 7%, and no medication in 6%. In the second long-term phase, SAPT was used in 65%, DAPT in 23%, no therapy in 8%, and OAC in 4%. No significant differences were found between the groups regarding the ischaemic endpoint both in the initial period (Kaplan–Meier estimated rate 2.9% for DAPT vs. 4.3% for OAC vs. 3.9% for SAPT or no therapy) and in the second period (4.2% for SAPT vs. 1.8% for DAPT vs. 3.5% for no therapy). With respect to bleeding events, the only difference was found in the initial phase with a higher incidence in patients under SAPT or no therapy.
Conclusions
Tailored antithrombotic treatment using even very reduced strategies such as SAPT or no therapy showed no significant differences regarding ischaemic complications after LAA closure.
Splice modulation therapy has shown great clinical promise in Duchenne muscular dystrophy, resulting in the production of dystrophin protein. Despite this, the relationship between restoring ...dystrophin to established dystrophic muscle and its ability to induce clinically relevant changes in muscle function is poorly understood. In order to robustly evaluate functional improvement, we used in situ protocols in the mdx mouse to measure muscle strength and resistance to eccentric contraction-induced damage. Here, we modelled the treatment of muscle with pre-existing dystrophic pathology using antisense oligonucleotides conjugated to a cell-penetrating peptide. We reveal that 15% homogeneous dystrophin expression is sufficient to protect against eccentric contraction-induced injury. In addition, we demonstrate a >40% increase in specific isometric force following repeated administrations. Strikingly, we show that changes in muscle strength are proportional to dystrophin expression levels. These data define the dystrophin restoration levels required to slow down or prevent disease progression and improve overall muscle function once a dystrophic environment has been established in the mdx mouse model.
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