Cardiovascular response to closed-loop intraneural stimulation of the right vagus nerve: a proof-of-concept study.

Vagus nerve stimulation (VNS) is an FDA-approved technique for the neuromodulation of the autonomic nervous system. There are many therapeutic applications where VNS could be used as a therapy, such as cardiovascular diseases, epilepsy, depression, and inflammatory conditions. Cardiovascular applications are particularly relevant, since cardiovascular diseases are the top causes of death worldwide. VNS clinical trials have been performed in the last 15 years for the treatment of heart failure (HF), achieving controversial results. Typically VNS is applied with a cuff electrode placed around the nerve, in an open-loop or cardiac synchronized design. The effectiveness of this approach is hindered by the multifunctional nature of the VN, which is involved in a variety of homeostatic controls. When a high current is applied, adverse effects arise from the stimulation of undesired fibers. An alternative strategy is represented by intraneural stimulation, which can guarantee higher selectivity. Moreover, closed-loop modalities allow the delivery of electrical current inside the nerves only if needed, with a reduced risk of untargeted nerve activation and lower energy consumption. Here we propose a closed-loop intraneural stimulation of the right cervical VN in a clinically relevant animal model. The intraneural was designed according to the internal structure of the VN. A threshold-based closed-loop algorithm was developed using HR as a control variable to produce a chronotropic effect.Clinical Relevance-This work analyzes the closed-loop intraneural VNS for the treatment of cardiovascular disorders, and supports the possibility of developing fully implantable devices with a high degree of selectivity in stimulation and prolonged lifespan.

Neural Stimulation Hardware for the Selective Intrafascicular Modulation of the Vagus Nerve.

The neural stimulation of the vagus nerve is able to modulate various functions of the parasympathetic response in different organs. The stimulation of the vagus nerve is a promising approach to treating inflammatory diseases, obesity, diabetes, heart failure, and hypertension. The complexity of the vagus nerve requires highly selective stimulation, allowing the modulation of target-specific organs without side effects. Here, we address this issue by adapting a neural stimulator and developing an intraneural electrode for the particular modulation of the vagus nerve. The neurostimulator parameters such as amplitude, pulse width, and pulse shape were modulated. Single-, and multi-channel stimulation was performed at different amplitudes. For the first time, a polyimide thin-film neural electrode was designed for the specific stimulation of the vagus nerve. In vivo experiments were performed in the adult minipig to validate to elicit electrically evoked action potentials and to modulate physiological functions, validating the spatial selectivity of intraneural stimulation. Electrochemical tests of the electrode and the neurostimulator showed that the stimulation hardware was working correctly. Stimulating the porcine vagus nerve resulted in spatially selective modulation of the vagus nerve. ECAP belonging to alpha and beta fibers could be distinguished during single- and multi-channel stimulation. We have shown that the here presented system is able to activate the vagus nerve and can therefore modulate the heart rate, diastolic pressure, and systolic pressure. The here presented system may be used to restore the cardiac loop after denervation by implementing biomimetic stimulation patterns. Presented methods may be used to develop intraneural electrodes adapted for various applications.

Publisher's Note: Direct Lifetime Measurements of the Excited States in

This corrects the article DOI: 10.1103/PhysRevLett.116.122502.

First Exploration of Neutron Shell Structure below Lead and beyond N=126.

The nuclei below lead but with more than 126 neutrons are crucial to an understanding of the astrophysical r process in producing nuclei heavier than A∼190. Despite their importance, the structure and properties of these nuclei remain experimentally untested as they are difficult to produce in nuclear reactions with stable beams. In a first exploration of the shell structure of this region, neutron excitations in ^{207}Hg have been probed using the neutron-adding (d,p) reaction in inverse kinematics. The radioactive beam of ^{206}Hg was delivered to the new ISOLDE Solenoidal Spectrometer at an energy above the Coulomb barrier. The spectroscopy of ^{207}Hg marks a first step in improving our understanding of the relevant structural properties of nuclei involved in a key part of the path of the r process.

Pseudospin Symmetry and Microscopic Origin of Shape Coexistence in the

Lifetime measurements of excited states of the light N=52 isotones ^{88}Kr, ^{86}Se, and ^{84}Ge have been performed, using the recoil distance Doppler shift method and VAMOS and AGATA spectrometers for particle identification and gamma spectroscopy, respectively. The reduced electric quadrupole transition probabilities B(E2;2^{+}→0^{+}) and B(E2;4^{+}→2^{+}) were obtained for the first time for the hard-to-reach ^{84}Ge. While the B(E2;2^{+}→0^{+}) values of ^{88}Kr, ^{86}Se saturate the maximum quadrupole collectivity offered by the natural valence (3s, 2d, 1g_{7/2}, 1h_{11/2}) space of an inert ^{78}Ni core, the value obtained for ^{84}Ge largely exceeds it, suggesting that shape coexistence phenomena, previously reported at N≲49, extend beyond N=50. The onset of collectivity at Z=32 is understood as due to a pseudo-SU(3) organization of the proton single-particle sequence reflecting a clear manifestation of pseudospin symmetry. It is realized that the latter provides actually reliable guidance for understanding the observed proton and neutron single particle structure in the whole medium-mass region, from Ni to Sn, pointing towards the important role of the isovector-vector ρ field in shell-structure evolution.

Evidence for Coexisting Shapes through Lifetime Measurements in

The lifetimes of the first excited 2^{+}, 4^{+}, and 6^{+} states in ^{98}Zr were measured with the recoil-distance Doppler shift method in an experiment performed at GANIL. Excited states in ^{98}Zr were populated using the fission reaction between a 6.2 MeV/u ^{238}U beam and a ^{9}Be target. The γ rays were detected with the EXOGAM array in correlation with the fission fragments identified by mass and atomic number in the VAMOS++ spectrometer. Our result shows a very small B(E2;2_{1}^{+}→0_{1}^{+}) value in ^{98}Zr, thereby confirming the very sudden onset of collectivity at N=60. The experimental results are compared to large-scale Monte Carlo shell model and beyond-mean-field calculations. The present results indicate the coexistence of two additional deformed shapes in this nucleus along with the spherical ground state.

Neutron Skin Effects in Mirror Energy Differences: The Case of

Energy differences between analogue states in the T=1/2 ^{23}Mg-^{23}Na mirror nuclei have been measured along the rotational yrast bands. This allows us to search for effects arising from isospin-symmetry-breaking interactions (ISB) and/or shape changes. Data are interpreted in the shell model framework following the method successfully applied to nuclei in the f_{7/2} shell. It is shown that the introduction of a schematic ISB interaction of the same type of that used in the f_{7/2} shell is needed to reproduce the data. An alternative novel description, applied here for the first time, relies on the use of an effective interaction deduced from a realistic charge-dependent chiral nucleon-nucleon potential. This analysis provides two important results: (i) The mirror energy differences give direct insight into the nuclear skin; (ii) the skin changes along the rotational bands are strongly correlated with the difference between the neutron and proton occupations of the s_{1/2} "halo" orbit.

First Measurement of the g Factor in the Chiral Band: The Case of the

The g factor of the 56 ns half-life isomeric state in ^{128}Cs has been measured using the time-differential perturbed angular distribution method. This state is the bandhead of the positive-parity chiral rotational band, which emerges when an unpaired proton, an unpaired neutron hole, and an even-even core are coupled such that their angular momentum vectors are aplanar (chiral configuration). g-factor measurements can give important information on the relative orientation of the three angular momentum vectors. The measured g factor g=+0.59(1) shows that there is an important contribution of the core rotation in the total angular momentum of the isomeric state. Moreover, a quantitative theoretical analysis supports the conclusion that the three angular momentum vectors lie almost in one plane, which suggests that the chiral configuration in ^{128}Cs demonstrated in previous works by characteristic patterns of electromagnetic transitions appears only above some value of the total nuclear spin.

Isomeric Character of the Lowest Observed 4

Previous experiments observed a 4^{+} state in the N=28 nucleus ^{44}S and suggested that this state may exhibit a hindered E2-decay rate, inconsistent with being a member of the collective ground state band. We populate this state via two-proton knockout from a beam of exotic ^{46}Ar projectiles and measure its lifetime using the recoil distance method with the GRETINA γ-ray spectrometer. The result, 76(14)_{stat}(20)_{syst} ps, implies a hindered transition of B(E2;4^{+}→2_{1}^{+})=0.61(19) single-particle or Weisskopf units strength and supports the interpretation of the 4^{+} state as a K=4 isomer, the first example of a high-K isomer in a nucleus of such low mass.

Direct Lifetime Measurements of the Excited States in (72)Ni.

The lifetimes of the first excited 2^{+} and 4^{+} states in ^{72}Ni were measured at the National Superconducting Cyclotron Laboratory with the recoil-distance Doppler-shift method, a model-independent probe to obtain the reduced transition probability. Excited states in ^{72}Ni were populated by the one-proton knockout reaction of an intermediate energy ^{73}Cu beam. γ-ray-recoil coincidences were detected with the γ-ray tracking array GRETINA and the S800 spectrograph. Our results provide evidence of enhanced transition probability B(E2;2^{+}→0^{+}) as compared to ^{68}Ni, but do not confirm the trend of large B(E2) values reported in the neighboring isotope ^{70}Ni obtained from Coulomb excitation measurement. The results are compared to shell model calculations. The lifetime obtained for the excited 4_{1}^{+} state is consistent with models showing decay of a seniority ν=4, 4^{+} state, which is consistent with the disappearance of the 8^{+} isomer in ^{72}Ni.

Isospin Mixing in

The isospin mixing was deduced in the compound nucleus ^{80}Zr at an excitation energy of E^{*}=54 MeV from the γ decay of the giant dipole resonance. The reaction ^{40}Ca+^{40}Ca at E_{beam}=136 MeV was used to form the compound nucleus in the isospin I=0 channel, while the reaction ^{37}Cl+^{44}Ca at E_{beam}=95 MeV was used as the reference reaction. The γ rays were detected with the AGATA demonstrator array coupled with LaBr_{3}:Ce detectors. The temperature dependence of the isospin mixing was obtained and the zero-temperature value deduced. The isospin-symmetry-breaking correction δ_{C} used for the Fermi superallowed transitions was extracted and found to be consistent with ß-decay data.

Quadrupole transition strength in the (74)Ni nucleus and core polarization effects in the neutron-rich Ni isotopes.

The reduced transition probability B(E2;0(+)→2(+)) has been measured for the neutron-rich nucleus (74)Ni in an intermediate energy Coulomb excitation experiment performed at the National Superconducting Cyclotron Laboratory at Michigan State University. The obtained B(E2;0(+)→2(+))=642(-226)(+216) e(2) fm(4) value defines a trend which is unexpectedly small if referred to (70)Ni and to a previous indirect determination of the transition strength in (74)Ni. This indicates a reduced polarization of the Z=28 core by the valence neutrons. Calculations in the pfgd model space reproduce well the experimental result indicating that the B(E2) strength predominantly corresponds to neutron excitations. The ratio of the neutron and proton multipole matrix elements supports such an interpretation.

Determining the rp-process flow through 56Ni: resonances in 57Cu(p,γ)58Zn identified with GRETINA.

An approach is presented to experimentally constrain previously unreachable (p, γ) reaction rates on nuclei far from stability in the astrophysical rp process. Energies of all critical resonances in the (57)Cu(p,γ)(58)Zn reaction are deduced by populating states in (58)Zn with a (d, n) reaction in inverse kinematics at 75 MeV/u, and detecting γ-ray-recoil coincidences with the state-of-the-art γ-ray tracking array GRETINA and the S800 spectrograph at the National Superconducting Cyclotron Laboratory. The results reduce the uncertainty in the (57)Cu(p,γ) reaction rate by several orders of magnitude. The effective lifetime of (56)Ni, an important waiting point in the rp process in x-ray bursts, can now be determined entirely from experimentally constrained reaction rates.

ß+ Gamow-Teller transition strengths from 46Ti and stellar electron-capture rates.

The Gamow-Teller strength in the ß(+) direction to (46)Sc was extracted via the (46)Ti(t,(3)He + γ) reaction at 115 MeV/u. The γ-ray coincidences served to precisely measure the very weak Gamow-Teller transition to a final state at 991 keV. Although this transition is weak, it is crucial for accurately estimating electron-capture rates in astrophysical scenarios with relatively low stellar densities and temperatures, such as presupernova stellar evolution. Shell-model calculations with different effective interactions in the pf shell-model space do not reproduce the experimental Gamow-Teller strengths, which is likely due to sd-shell admixtures. Calculations in the quasiparticle random phase approximation that are often used in astrophysical simulations also fail to reproduce the experimental Gamow-Teller strength distribution, leading to strongly overestimated electron-capture rates. Because reliable theoretical predictions of Gamow-Teller strengths are important for providing astrophysical electron-capture reaction rates for a broad set of nuclei in the lower pf shell, we conclude that further theoretical improvements are required to match astrophysical needs.

Nuclear structure towards N = 40 60Ca: in-beam γ-ray spectroscopy of 58,60Ti.

Excited states in the neutron-rich N = 38, 36 nuclei (60)Ti and (58)Ti were populated in nucleon-removal reactions from (61)V projectiles at 90 MeV/nucleon. The γ-ray transitions from such states in these Ti isotopes were detected with the advanced γ-ray tracking array GRETINA and were corrected event by event for large Doppler shifts (v/c ∼ 0.4) using the γ-ray interaction points deduced from online signal decomposition. The new data indicate that a steep decrease in quadrupole collectivity occurs when moving from neutron-rich N = 36, 38 Fe and Cr toward the Ti and Ca isotones. In fact, (58,60)Ti provide some of the most neutron-rich benchmarks accessible today for calculations attempting to determine the structure of the potentially doubly magic nucleus (60)Ca.

Evolution of collectivity in 72Kr: evidence for rapid shape transition.

The transition rates from the yrast 2+ and 4+ states in the self-conjugate 72Kr nucleus were studied via lifetime measurements employing the GRETINA array with a novel application of the recoil-distance method. The large collectivity observed for the 4+→2+ transition suggests a prolate character of the excited states. The reduced collectivity previously reported for the 2+→0+ transition was confirmed. The irregular behavior of collectivity points to the occurrence of a rapid oblate-prolate shape transition in 72Kr, providing stringent tests for advanced theories to describe the shape coexistence and its evolution.

ERCC1/BRCA1 expression and gene polymorphisms as prognostic and predictive factors in advanced NSCLC treated with or without cisplatin.

BACKGROUND: The FAST was a factorial trial in first-line treatment of advanced non-small-cell lung cancer (NSCLC), addressing the role of replacing cisplatin with a non-platinum agent. The prognostic and predictive effect of ERCC1/BRCA1 expression and ERCC1/XPD/XRCC1-3 gene polymorphisms on outcomes of patients was examined. METHODS: Patients were randomised to receive treatment with or without cisplatin. ERCC1/BRCA1 expression was determined by immunohistochemistry. ERCC1 (C8092A, C118T), XPD (Lys751Gln), XRCC1 (Arg399Gln) and XRCC3 (Thr241Met) gene polymorphisms were evaluated on tumour DNA by TaqMan allelic discrimination assay. RESULTS: Tumour samples were available from 110 of 433 patients enrolled: 54.7% were ERCC1 positive and 51.4% were BRCA1 positive. Overall, ERCC1-negative patients had better response rate (P=0.004), progression-free survival (P=0.023) and overall survival (P=0.012) compared with positive ones, with no statistically significant treatment interaction. The BRCA1-positive patients showed numerically better outcomes, although not statistically significant, with no treatment interaction. Among DNA repair gene polymorphisms, only XRCC1 Gln/Gln genotype evidenced a potential prognostic role (P=0.036). CONCLUSION: This study confirms the prognostic role of ERCC1 expression and XRCC1 (Arg399Gln) polymorphism in advanced NSCLC treated with first-line chemotherapy. None of these biomarkers was shown to be a specific predictive factor of cisplatin efficacy.

Triplets versus doublets, with or without cisplatin, in the first-line treatment of stage IIIB-IV non-small cell lung cancer (NSCLC) patients: a multicenter randomised factorial trial (FAST).

BACKGROUND: The FAST is a 2 × 2 factorial trial addressing two questions: (1) the role of replacing cisplatin (P) with a non-platinum agent, vinorelbine (N), and (2) the role of adding a third agent, ifosfamide (I), in a doublet based on gemcitabine (G). METHODS: A total of 433 stage IIIB-IV non-small cell lung cancer (NSCLC) patients were randomised to one of four arms: gemcitabine-cisplatin (GP), gemcitabine-vinorelbine, gemcitabine-ifosfamide-cisplatin or gemcitabine-ifosfamide-vinorelbine. Two comparisons were performed: N- vs P-containing regimens and I-triplets vs non-I doublets. RESULTS: For N- vs P-containing regimens, adjusted overall survival was 9.7 vs 11.3 months (P=0.044), progression-free survival was 4.9 vs 6.4 months (P=0.020) and response rate was 24% vs 31% (P=0.124), respectively. No statistically significant difference was observed between doublets and triplets. Grade 3-4 haematological toxicity was significantly more frequent in P-containing therapy; grade 3-4 leucopenia was significantly more common in triplets. Concerning non-haematological toxicity, grade 3-4 nausea-vomiting was significantly increased in P-containing regimens. CONCLUSIONS: This trial provides evidence of a slight survival superiority of GP-containing regimens over platinum-free N-containing chemotherapy. This trial also confirms that the addition of a third chemotherapy agent (I) to a standard G-based doublet does not improve treatment outcome.

Evidence for a spin-aligned neutron-proton paired phase from the level structure of (92)Pd.

Shell structure and magic numbers in atomic nuclei were generally explained by pioneering work that introduced a strong spin-orbit interaction to the nuclear shell model potential. However, knowledge of nuclear forces and the mechanisms governing the structure of nuclei, in particular far from stability, is still incomplete. In nuclei with equal neutron and proton numbers (N = Z), enhanced correlations arise between neutrons and protons (two distinct types of fermions) that occupy orbitals with the same quantum numbers. Such correlations have been predicted to favour an unusual type of nuclear superfluidity, termed isoscalar neutron-proton pairing, in addition to normal isovector pairing. Despite many experimental efforts, these predictions have not been confirmed. Here we report the experimental observation of excited states in the N = Z = 46 nucleus (92)Pd. Gamma rays emitted following the (58)Ni((36)Ar,2n)(92)Pd fusion-evaporation reaction were identified using a combination of state-of-the-art high-resolution γ-ray, charged-particle and neutron detector systems. Our results reveal evidence for a spin-aligned, isoscalar neutron-proton coupling scheme, different from the previous prediction. We suggest that this coupling scheme replaces normal superfluidity (characterized by seniority coupling) in the ground and low-lying excited states of the heaviest N = Z nuclei. Such strong, isoscalar neutron-proton correlations would have a considerable impact on the nuclear level structure and possibly influence the dynamics of rapid proton capture in stellar nucleosynthesis.

Coherent contributions to isospin mixing in the mirror pair 67As and 67Se.

Isospin symmetry breaking has been investigated in mass A=67 mirror nuclei through the experimental determination of the E1 strengths of analog electromagnetic transitions. Lifetimes of excited states have been measured in (67)Se and (67)As with the centroid shift method. Through the comparison of the B(E1) strengths of the mirror 9/2(+)-->7/2(-) transitions, the isovector and the isoscalar components of the electromagnetic transition amplitude were extracted. The presence of a large isoscalar component provides evidence for coherent contributions to isospin mixing, probably involving the isovector giant monopole resonance.