Protocol for combined N-of-1 trials to assess cerebellar neurostimulation for movement disorders in children and young adults with dyskinetic cerebral palsy.

BACKGROUND: Movement and tone disorders in children and young adults with cerebral palsy are a great source of disability. Deep brain stimulation (DBS) of basal ganglia targets has a major role in the treatment of isolated dystonias, but its efficacy in dyskinetic cerebral palsy (DCP) is lower, due to structural basal ganglia and thalamic damage and lack of improvement of comorbid choreoathetosis and spasticity. The cerebellum is an attractive target for DBS in DCP since it is frequently spared from hypoxic ischemic damage, it has a significant role in dystonia network models, and small studies have shown promise of dentate stimulation in improving CP-related movement and tone disorders. METHODS: Ten children and young adults with DCP and disabling movement disorders with or without spasticity will undergo bilateral DBS in the dorsal dentate nucleus, with the most distal contact ending in the superior cerebellar peduncle. We will implant Medtronic Percept, a bidirectional neurostimulator that can sense and store brain activity and deliver DBS therapy. The efficacy of cerebellar DBS in improving quality of life and motor outcomes will be tested by a series of N-of-1 clinical trials. Each N-of-1 trial will consist of three blocks, each consisting of one month of effective stimulation and one month of sham stimulation in a random order with weekly motor and quality of life scales as primary and secondary outcomes. In addition, we will characterize abnormal patterns of cerebellar oscillatory activity measured by local field potentials from the intracranial electrodes related to clinical assessments and wearable monitors. Pre- and 12-month postoperative volumetric structural and functional MRI and diffusion tensor imaging will be used to identify candidate imaging markers of baseline disease severity and response to DBS. DISCUSSION: Our goal is to test a cerebellar neuromodulation therapy that produces meaningful changes in function and well-being for people with CP, obtain a mechanistic understanding of the underlying brain network disorder, and identify physiological and imaging-based predictors of outcomes useful in planning further studies. TRIAL REGISTRATION: ClinicalTrials.gov NCT06122675, first registered November 7, 2023.

Demonstrating a Continuous Set of Two-Qubit Gates for Near-Term Quantum Algorithms.

Quantum algorithms offer a dramatic speedup for computational problems in material science and chemistry. However, any near-term realizations of these algorithms will need to be optimized to fit within the finite resources offered by existing noisy hardware. Here, taking advantage of the adjustable coupling of gmon qubits, we demonstrate a continuous two-qubit gate set that can provide a threefold reduction in circuit depth as compared to a standard decomposition. We implement two gate families: an imaginary swap-like (iSWAP-like) gate to attain an arbitrary swap angle, θ, and a controlled-phase gate that generates an arbitrary conditional phase, ϕ. Using one of each of these gates, we can perform an arbitrary two-qubit gate within the excitation-preserving subspace allowing for a complete implementation of the so-called Fermionic simulation (fSim) gate set. We benchmark the fidelity of the iSWAP-like and controlled-phase gate families as well as 525 other fSim gates spread evenly across the entire fSim(θ,ϕ) parameter space, achieving a purity-limited average two-qubit Pauli error of 3.8×10^{-3} per fSim gate.

Diabatic Gates for Frequency-Tunable Superconducting Qubits.

We demonstrate diabatic two-qubit gates with Pauli error rates down to 4.3(2)×10^{-3} in as fast as 18 ns using frequency-tunable superconducting qubits. This is achieved by synchronizing the entangling parameters with minima in the leakage channel. The synchronization shows a landscape in gate parameter space that agrees with model predictions and facilitates robust tune-up. We test both iswap-like and cphase gates with cross-entropy benchmarking. The presented approach can be extended to multibody operations as well.

Fluctuations of Energy-Relaxation Times in Superconducting Qubits.

Superconducting qubits are an attractive platform for quantum computing since they have demonstrated high-fidelity quantum gates and extensibility to modest system sizes. Nonetheless, an outstanding challenge is stabilizing their energy-relaxation times, which can fluctuate unpredictably in frequency and time. Here, we use qubits as spectral and temporal probes of individual two-level-system defects to provide direct evidence that they are responsible for the largest fluctuations. This research lays the foundation for stabilizing qubit performance through calibration, design, and fabrication.

Observation of Classical-Quantum Crossover of 1/f Flux Noise and Its Paramagnetic Temperature Dependence.

By analyzing the dissipative dynamics of a tunable gap flux qubit, we extract both sides of its two-sided environmental flux noise spectral density over a range of frequencies around 2k_{B}T/h≈1 GHz, allowing for the observation of a classical-quantum crossover. Below the crossover point, the symmetric noise component follows a 1/f power law that matches the magnitude of the 1/f noise near 1 Hz. The antisymmetric component displays a 1/T dependence below 100 mK, providing dynamical evidence for a paramagnetic environment. Extrapolating the two-sided spectrum predicts the linewidth and reorganization energy of incoherent resonant tunneling between flux qubit wells.

Mold-sensitivity in children with moderate-severe asthma is associated with HLA-DR and HLA-DQ.

BACKGROUND: Several epidemiologic studies in the United States and Europe have linked Alternaria sensitivity to both persistence and severity of asthma. In this study, we examined T cell responses and HLA class II alleles in children with moderate-severe asthma. METHODS: Ninety-six children with moderate-severe asthma were compared to 90 children with mild asthma. HLA class II genotyping was performed to determine HLA allelic frequencies. Th1/Th2 Alternaria-specific T cell cytokine responses were determined by the use of Alternaria-stimulated cultures. HLA class II restriction was examined by inhibition of Alternaria-stimulated lymphoproliferative responses with blocking anti-HLA class II monoclonal antibodies. RESULTS: Children with moderate-severe asthma had significantly increased sensitivities to Aspergillus fumigatus; sensitivities to Alternaria were similar in both moderate-severe and mild asthmatics. The frequency of HLA-DRB1*13 alleles were increased in mold-sensitive moderate-severe asthmatic children. HLA-DRB1*03 tended to be increased in mold-sensitive moderate-severe asthmatics. The frequency of HLA-DQB1*03 alleles was significantly decreased in mold and Alternaria-sensitive moderate-severe asthma. HLA class II blocking monoclonal antibodies demonstrated HLA-DR restriction. Alternaria-stimulated IL-5 and IL-13 synthesis was significantly increased in moderate-severe asthmatics. IL-5 and IL-13 synthesis was significantly increased in Alternaria-stimulated lymphocyte cultures of HLA-DQB1*03- asthmatics compared to HLA-DQB1*03+ asthmatics. CONCLUSIONS: In children with Alternaria-sensitive moderate-severe asthma, there was increased Th2 sensitivity to Alternaria stimulation. This was associated with HLA-DR restriction and with increased frequency of HLA-DRB1*13 and HLA-DRB1*03. There was decreased frequency of HLA-DQB1*03 in Alternaria-sensitive moderate-severe asthma, suggesting HLA-DQB1*03 may be protective of the development of Alternaria-sensitive severe asthma.

Flash hydrogenation of a bituminous coal.

Flash heating of Illinois coal (to 700 degrees C in 1 second) in flowing hydrogen at 100 atmospheres, limiting the vapor residence time at 700 degrees C to 3 seconds, converts 14 percent of the coal's carbon to methane, 7 percent to ethane, and 10 percent to benzene, toluene, and xylenes. The remainder is coke; the carbon balance shows that heavy tar, if any exists, is less than 3 percent.

Agglomeration of ash in fluidized beds gasifying coal: the godel phenomenon.

In a bed of anthracite or bituminous coke fluidized by air at 10 to 15 meters per second at 1200 degrees to 1400 degrees C, molten ash forms beads on the surface of a coke particle, some exuding from its interior. The beads merge and detach them-selves to grow further as loose fluidized ash agglomerates of low carbon content.

A blueprint for demonstrating quantum supremacy with superconducting qubits.

A key step toward demonstrating a quantum system that can address difficult problems in physics and chemistry will be performing a computation beyond the capabilities of any classical computer, thus achieving so-called quantum supremacy. In this study, we used nine superconducting qubits to demonstrate a promising path toward quantum supremacy. By individually tuning the qubit parameters, we were able to generate thousands of distinct Hamiltonian evolutions and probe the output probabilities. The measured probabilities obey a universal distribution, consistent with uniformly sampling the full Hilbert space. As the number of qubits increases, the system continues to explore the exponentially growing number of states. Extending these results to a system of 50 qubits has the potential to address scientific questions that are beyond the capabilities of any classical computer.

Marked histoincompatibility between and within sublines of AKR mice used in a syngeneic leukemia model.

Sublines of AKR mice differed significantly in their histoincompatibility to AKR/J mice, as indicated by their ability to reject AKR/J skin grafts and an AKR transplantable leukemia. Further, all sublines tested demonstrated some degree of heterogeneity, because isografts were rejected in 5-97% of the mice, depending on the subline. The presence of excessive heterogeneity among and within sublines poses a serious problem for experimental oncologists using these sublines in their tumor models.

Cardiac failure and upper extremity arteriovenous dialysis fistulas. Case reports and a review of the literature.

Nine patients with high-output cardiac failure from arteriovenous forearm dialysis fistulas are reviewed, and six new cases are presented. Decreases in cardiac output with temporary fistula occlusion ranged from 0.3 to 11.0 liters/min (mean, 2.9 liters/min); fistula flow rates varied from 0.6 to 2.9 liter/min (mean, 1.5 liters/min). Surgical correction of high-flow fistulas resulted in notable improvement of cardiac failure in 13 of 14 patients. Although cardiac failure in individuals who are receiving long-term dialysis treatment is usually caused by intrinsic cardiac disease, volume overload, or anemia, forearm fistulas with large flow rates may be an important contributing factor. Correction of these large flow rates may be an important contributing factor. Correction of these large flow rates by banding or closure can substantially improve cardiac function in selected patients.

Combinatorial therapy for triple negative breast cancer using hyperstar polymer-based nanoparticles.

We report the ability of a novel combinatorial therapy obtained from nanoparticles of hyperstar polymers encompassing drugs to selectively target triple negative breast cancer (TNBC) cell proliferation through STAT3 and topoisomerase-II pathways. This nano-cocktail was at least two to four fold better than the individual drugs and 6-20 times more selective than the parent drugs.

A revised strategy for cloning antibody gene fragments in bacteria.

The ability to clone and overexpress genes encoding mouse Fab (antigen-binding fragment) proteins in bacteria led to the development of a methodology which has the potential to replace traditional hybridoma technology [Huse et al., Science 246 (1989) 1275-1281]; however, several observations have suggested that clones with desirable chemical properties may be missed in immunoscreens of large combinatorial libraries due to low levels of functional Ab protein. To increase the efficiency of cloning and characterization of Ab gene fragments, we have reconsidered several features of the original cloning vehicles. These studies show that at the present time a unique expression system cannot adequately accommodate the requirements of plaque-lift immunoassays for clonal selection and biochemical assays for further characterization in vitro. A monocistronic arrangement of heavy- and light-chain-encoding genes using two lacP promoters produces sufficient amounts of functional Ab protein for clonal selection from phage lambda libraries and minimizes interference with the lytic cycle of recombinant vectors. In liquid culture, a strong coliphage promoter and a relatively abundant RNA polymerase can be used to produce quantities of Ab protein sufficient for further characterization in vitro. A rapid purification protocol obviates the need for fusing heavy-chain protein to a decapeptide sequence, an affinity-tail sequence which slows the folding and assembly of the Ig heterodimer. These results have been used to formulate a new strategy for cloning and characterization of Ab gene fragments in bacteria.

Partially modified retro-inverso pseudopeptides as non-natural ligands for the human class I histocompatibility molecule HLA-A2.

Syntheses of a series of partially modified retro-inverso analogues of the antigenic peptide M58-66 derived from the influenza virus matrix protein are reported. The retro-inverso modification phi(NH-CO) was obtained by replacement of two successive amino acid residues with a 2-substituted malonate derivative and gem-diaminoalkyl residue. The resulting compounds 1-8 were tested for their binding to the human histocompatibility class I molecule HLA-A2 in an assembly assay using lysates of peptide transporter-deficient cells T2. Specific peptide-dependent HLA-A2 assembly was revealed by an enzyme-linked immunosorbent assay. Significant HLA-A2 assembly was detected in the presence of analogues [gGly58-(S)mLeu59]-M58-66 (1a), [gGly61-(R,S)mPhe62]M58-66 (4), [gVal63-(R,S)mPhe64]M58-66 (6), and [gPhe64-(R,S)mAla65]M58-66 (7). The introduction of the retro-inverso modification between P2-P3, P3-P4, P5-P6, and P8-P9 (compounds 2, 3, 5, and 8, respectively) however led to a dramatic reduction in peptide binding to HLA-A2. Interestingly, compound 1a which contains modification between P1-P2 was found to be the most potent analogue, being able to retain the original HLA-A2 binding profile of the parent peptide M58-66. Taken together, these results and recent binding data obtained in the context of murine MHC class I molecule H-2Kd suggest that the incorporation of peptide bond surrogates in MHC class I-restricted epitopes is a useful approach to design molecules having both increased stability and high MHC-binding capacity. Depending on their agonist or antagonist effects at the T-cell receptor, such non-natural MHC ligands are likely to find many applications in the development of peptide-based vaccines or as potential therapeutic agents in the treatment of allergies and autoimmune diseases.

Time-response studies of the cellular immune response to cell membrane antigens.

It was the objective of these experiments to study the time-related changes in the responsiveness of the cellular elements of the immune system following contact with single non-H-2 or multiple H-2 histocompatibility antigens. The reactivity of spleen cells from mice that received injections of spleen cells bearing H-1c, H-3c, H-13a, or H-2b cell membrane alloantigens was characterized at intervals following antigen contact. Spleen cells taken from mice not receiving injections showed no in vitro proliferative or cytolytic responsiveness to cells bearing individual non-H-2 antigens; after in vivo antigen contact with single non-H-2 antigens there was an interval of specific cellular unresponsiveness followed by alternating periods of responsiveness and unresponsiveness. The duration of the unresponsiveness immediately following injection correlated with the strength of the injected antigen--specifically, the stronger the antigen, the shorter the period of unresponsiveness. The data indicate fluctuation in the level of helper T lymphocyte activity, as well as cytotoxic T lymphocyte activity. In contrast, in vitro responsiveness elicited by H-2b antigens with and without prior in vivo antigen contact was of a similar magnitude, and both persisted at a relatively constant level. Suppressor mechanisms were not studied. Of particular interest was the observation that in vivo contact with non-H-2 antigens resulted in suppression of spleen cell production of IL-2 in response to lectin stimulation and fluctuation in the magnitude of the primary response of cytotoxic T lymphocytes to H-2 antigens.

Prolongation of murine skin allografts by prostaglandin E1.

The effects of 16,16-dimethyl prostaglandin E2 methyl ester (di-M-PGE2) and indomethacin (an inhibitor of endogenous prostaglandin biosynthesis) on mouse skin allograft survival were studies in B10.D2 female mice receiving skin allografts from (B10.BR X B10.D2)F1 mice. Control animals with and without i.p. diluent injections had a mean allograft survival of 13.8+/-0.6 and 13.5+/-0.5 days, respectively. Daily administration of di-M-PGE2 (200 microng/kg) prolonged mean allograft survival, both when administered alone, 16.7+/-0.6 days (P less than 0.001), or with indomethacin, 4 mg/kg thrice weekly, 16.0+/0.6 days (P less than 0.005). Increasing concentrations of indomethacin (4, 6, and 8 mg/kg thrice weekly) were inversely corrleated with allograft survival ((12.7+/-0.2, 11.8+/-0.2, and 10.9+/-0.4 days, respectively), coefficient of correlation=-0.6986; P less than 0.001. Mean plasma PGE levels at the time of total allograft rejection were 879+/-80 pg/ml in control, 717+/-59 pg/ml in 100 micron g of indomethacin-treated mice, and 654+/-59 pg/ml in 200 microng of indomethacin-treated mice (P less than 0.05). Exogenous di-M-PGE2 prolonged skin allograft survival in mice. Inhibition of endogenous prostaglandin biosynthesis by indomethacin chortened allograft survival, but this effect was completely abrogated by concurrent injection of di-M-PGE2.

Scalp and limb defects with cutis marmorata telangiectatica congenita: Adams-Oliver syndrome?

We report on a boy with congenital scalp and limb defects, consistent with a diagnosis of Adams-Oliver syndrome (aplasia cutis congenita with terminal transverse limb defects). An additional finding present in this child and in his mother was cutis marmorata telangiectatica congenita. Although this boy fits the diagnostic criteria for Adams-Oliver syndrome, his mother does not. We discuss whether this condition is highly variable, or heterogeneous.

Serum lactic dehydrogenase and irreversible renal allograft rejection.

The relationship between serum lactic dehydrogenase (SLDH) values and renal allograft rejection was examined in the dog and in man. Nine dogs with renal allografts and four with autografts had similar maximal elevations of SLDH during the first five postoperative days (mean, 420 +/- 213 and 433 +/- 80 I.U. per liter, respectively). During rejection of the allografts between days 7 and 14 the maximum SLDH was 810 +/- 285 I.U. per liter, and in autografts the peak SLDH was 233 +/- 22 I.U. per liter (p less than 0.01). The isoenzyme pattern of maximum SLDH during rejection was prominent in LDH5 and corresponded with renal tissue LDH isoenzyme composition. In 93 episodes of initial acute human renal allograft rejection reactions, the SLDH peaked above 500 I.U. per liter in 23 cases and remained below 500 I.U. per liter in 70 cases. SLDH levels above 500 I.U. per liter were associated with complete rejection of the kidney in 91 percent of patients and SLDH levels persistently below 500 I.U. per liter corresponded with reversal of rejection reaction in 99 percent of patients (p less than 0.01). Marked SLDH elevation is associated with severe, usually complete renal allograft rejection and may be useful in identifying patients with irreversible rejection reactions.

Blood flow measurements in arteriovenous dialysis fistulas.

Blood flows were measured in 75 arteriovenous dialysis fistulas (AVF) at the time of fistula construction. End cephalic vein to side of radial artery AVF had a mean flow of 242 +/- 89 ml. per minute which was similar to bovine heterograft AVF that also originated from the radial artery (291 +/- 67 ml. per minute). AVF originating from the brachial artery had flow rates twice those originating from the radial artery (599 +/- 163 vs. 251 +/- 89 ml. per minute), respectively). Flow rates were similar for straight arm (641 +/- 111 ml. per minute), curved forearm (561 +/- 187 ml. per minute), and curved thigh (592 +/- 134 ml. per minute) bovine AVF. Initial blood flow through arteriovenous dialysis fistulas is too low to cause heart failure, except in patients with previously compromised cardiac function. In such patients AVF from the radial artery theoretically would be preferred over brachial or femoral artery AVF.

Colorectal complications of renal allograft transplantation.

The occurrence of perforated sigmoid diverticulitis in a renal transplant recipient stimulated a review of colorectal complications in renal allograft recipients. One hundred twenty-five renal transplantations were performed in 113 patients between January 1968 and December 1975. Six patients (5%) were identified as having colorectal complications and five of these patients died as a direct result. Chart analysis of these 113 transplant recipients identified 55 patients as having undergone colonic evaluation (contrast enema, postmortem examination), with seven of these 55 (13%) found to have diverticulosis and major colonic complications eventually developing in four of these seven. Since the mortality from the complications of colorectal diseases in immunosuppressed patients is so prohibitive, in patients with diverticulosis and a previous history suggestive of diverticulitis, consideration should be given to exclusion from transplantation or elective segmental colectomy prior to transplantation.