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Patients with major depressive disorder (MDD) often do not respond to antidepressant (ADT) monotherapy alone and may require adjunctive treatment to provide adequate symptom relief. Cariprazine (CAR) is a dopamine D3-preferring D3/D2 and serotonin 5-HT1A receptor partial agonist approved to treat adults with schizophrenia and manic, mixed, or depressive episodes of bipolar I disorder. Post hoc analysis of data from a randomized controlled trial evaluated clinically relevant improvements in depressive symptom severity with adjunctive cariprazine in patients with MDD and inadequate response to ADT monotherapy.
Post hoc analysis evaluated data from a randomized, double-blind, placebo-controlled MDD trial (NCT03738215) in patients treated with CAR (1.5 mg/d or 3 mg/d) + ADT or placebo + ADT; the primary outcome was change from baseline to week 6 in Montgomery-Åsberg Depression Rating Scale (MADRS) total score. Post hoc analysis evaluated category shifts from baseline to week 6 in MADRS severity (normal <6, mild 7–19, moderate 20–34, severe ≥35). MADRS severity shifts were reported as the percentage of patients with no change or worsened severity, 1 category improvement, ≥1 category improvement, and ≥2 category improvement. Examples of categorical shifts in depressive symptoms at week 6 include change from severe at baseline to moderate (1 category improvement) and change from severe at baseline to mild (2 category improvement).
Of the 751 patients in the intent-to-treat (ITT) population (CAR: 1.5 mg/d=250, 3.0 mg/d=252; placebo=249), baseline MADRS severity was mild in 1.5%, moderate in 64%, and severe in 35%. Fewer CAR + ADT patients compared to placebo + ADT had no change or worsened MADRS severity at week 6 (CAR: 1.5 mg/d=32%, 3.0 mg/d=33%; placebo=42%). Approximately 68% of patients treated with CAR + ADT demonstrated a MADRS severity improvement of 1 category or greater by week 6 (CAR: 1.5 mg/d=68%, 3.0 mg/d=67%; placebo=58%). A greater percentage of patients in the CAR 1.5 mg/d group also had a 2 or greater category improvement versus CAR 3.0 mg/d or placebo 6 (CAR: 1.5 mg/d=28%, 3.0 mg/d=17%; placebo=19%).
In this post hoc analysis, CAR + ADT was associated with a greater proportion of patients with improvements in depressive symptom severity categories compared with placebo + ADT. These results may suggest that CAR + ADT is associated with clinically meaningful depressive symptom improvement in MDD patients.
An important goal for humanoid robots is to achieve fast, flexible and stable walking. In previous research, the structure and walking algorithms evolved separately, resulting in a slow evolution speed and lack of an initial design basis. This paper proposes comprehensively considering body morphology and walking patterns, exploring the relationship between them and their influence on the motion ability. The method parameterizes the body morphology and walking patterns. Then a response surface model is established to describe the complex relationship between these parameters and finally obtain the optimized parameters, which provides a reference for the structural design and gait generation.
The degree to which suicide risk aggregates in US families is unknown. The authors aimed to determine the familial risk of suicide in Utah, and tested whether familial risk varies based on the characteristics of the suicides and their relatives.
A population-based sample of 12 160 suicides from 1904 to 2014 were identified from the Utah Population Database and matched 1:5 to controls based on sex and age using at-risk sampling. All first through third- and fifth-degree relatives of suicide probands and controls were identified (N = 13 480 122). The familial risk of suicide was estimated based on hazard ratios (HR) from an unsupervised Cox regression model in a unified framework. Moderation by sex of the proband or relative and age of the proband at time of suicide (<25 v. ⩾25 years) was examined.
Significantly elevated HRs were observed in first- (HR 3.45; 95% CI 3.12–3.82) through fifth-degree relatives (HR 1.07; 95% CI 1.02–1.12) of suicide probands. Among first-degree relatives of female suicide probands, the HR of suicide was 6.99 (95% CI 3.99–12.25) in mothers, 6.39 in sisters (95% CI 3.78–10.82), and 5.65 (95% CI 3.38–9.44) in daughters. The HR in first-degree relatives of suicide probands under 25 years at death was 4.29 (95% CI 3.49–5.26).
Elevated familial suicide risk in relatives of female and younger suicide probands suggests that there are unique risk groups to which prevention efforts should be directed – namely suicidal young adults and women with a strong family history of suicide.
The coronavirus disease 2019 (COVID-19) pandemic has resulted in shortages of personal protective equipment (PPE), underscoring the urgent need for simple, efficient, and inexpensive methods to decontaminate masks and respirators exposed to severe acute respiratory coronavirus virus 2 (SARS-CoV-2). We hypothesized that methylene blue (MB) photochemical treatment, which has various clinical applications, could decontaminate PPE contaminated with coronavirus.
The 2 arms of the study included (1) PPE inoculation with coronaviruses followed by MB with light (MBL) decontamination treatment and (2) PPE treatment with MBL for 5 cycles of decontamination to determine maintenance of PPE performance.
MBL treatment was used to inactivate coronaviruses on 3 N95 filtering facepiece respirator (FFR) and 2 medical mask models. We inoculated FFR and medical mask materials with 3 coronaviruses, including SARS-CoV-2, and we treated them with 10 µM MB and exposed them to 50,000 lux of white light or 12,500 lux of red light for 30 minutes. In parallel, integrity was assessed after 5 cycles of decontamination using multiple US and international test methods, and the process was compared with the FDA-authorized vaporized hydrogen peroxide plus ozone (VHP+O3) decontamination method.
Overall, MBL robustly and consistently inactivated all 3 coronaviruses with 99.8% to >99.9% virus inactivation across all FFRs and medical masks tested. FFR and medical mask integrity was maintained after 5 cycles of MBL treatment, whereas 1 FFR model failed after 5 cycles of VHP+O3.
MBL treatment decontaminated respirators and masks by inactivating 3 tested coronaviruses without compromising integrity through 5 cycles of decontamination. MBL decontamination is effective, is low cost, and does not require specialized equipment, making it applicable in low- to high-resource settings.
We present a general simulation approach for fluid–solid interactions based on the fully Eulerian reference map technique. The approach permits the modelling of one or more finitely deformable continuum solid bodies interacting with a fluid and with each other. A key advantage of this approach is its ease of use, as the solid and fluid are discretized on the same fixed grid, which greatly simplifies the coupling between the phases. We use the method to study a number of illustrative examples involving an incompressible Navier–Stokes fluid interacting with multiple neo-Hookean solids. Our method has several useful features including the ability to model solids with sharp corners and the ability to model actuated solids. The latter permits the simulation of active media such as swimmers, which we demonstrate. The method is validated favourably in the flag-flapping geometry, for which a number of experimental, numerical and analytical studies have been performed. We extend the flapping analysis beyond the thin-flag limit, revealing an additional destabilization mechanism to induce flapping.
Sample geometry effects on mechanical strengths of gold micro-cantilevers are evaluated by a micro-bending test. Six micro-cantilevers with the same length of 50 μm are prepared, and the width and the thickness are varied to examine individual effects on the yield stress. The yield stress increases from 428 to 519 MPa when the thickness decreases from 11.1 to 6.0 μm. No obvious dependency is observed when varying the width. The results reveal that the thickness and the width each has a different influence on the yield stresses of micro-cantilevers evaluated by the bending test, which is the sample geometry effect.
Genetic variants and medication adherence have been identified to be the main factors contributing to lithium treatment response in bipolar disorders.
To simultaneously examine effects of variant glutamate decarboxylase-like protein 1 (GADL1) and medication adherence on response to lithium maintenance treatment in Han Chinese patients with bipolar I (BPI) disorder.
Frequencies of manic and depressive episodes between carriers and non-carriers of the effective GADL1 rs17026688 T allele during the cumulative periods of off-lithium, poor adherence to lithium treatment and good adherence to lithium treatment were compared in Han Chinese patients with BPI disorder (n = 215).
GADL1 rs17026688 T carriers had significantly lower frequencies of recurrent affective episodes than non-T carriers during the cumulative period of good adherence, but not during those of poor adherence.
GADL1 rs17026688 and medication adherence jointly predict response to lithium maintenance treatment in Han Chinese BPI patients.
Stability, high response quality and rapidity are required for reactive omnidirectional walking in humanoids. Early schemes focused on generating gaits for predefined footstep locations and suffered from the risk of falling over because they lacked the ability to suitably adapt foot placement. Later methods combining stride adaptation and center of mass (COM) trajectory modification experienced difficulties related to increasing computing loads and an unwanted bias from the desired commands. In this paper, a hierarchical planning framework is proposed in which the footstep adaption task is separated from that of COM trajectory generation. A novel omnidirectional vehicle model and the inequalities deduced therefrom are adopted to describe the inter-pace connection relationship. A constrained nonlinear optimization problem is formulated and solved based on these inequalities to generate the optimal strides. A black-box optimization problem is then constructed and solved to determine the model constants using a surrogate-model-based approach. A simulation-based verification of the method and its implementation on a physical robot with a strictly limited computing capacity are reported. The proposed method is found to offer improved response quality while maintaining rapidity and stability, to reduce the online computing load required for reactive walking and to eliminate unnecessary bias from walking intentions.
This work reports the fabrication and characterization of superstrate-type Zn1-xMgxO/CdTe heterojunction solar cells on both CdxSnyO and commercial SnO2:F transparent conducting oxides (TCOs) in which the ZMO and CTO layers are produced for the first time by hollow cathode sputtering. The sputtering is conducted in a reactive mode using metal or alloyed metal targets fitted to a custom-made linear cathode. It is notable that the CdS buffer layer conventionally employed in CdTe solar cells is entirely replaced by the ZMO window layer. The use of ZMO is found to eliminate the blue loss associated with CdS optical absorption and further results in a higher open-circuit voltage. Key parameters were found to be the conduction band offset at the ZMO/CdTe interface and the ZMO thickness. It was discovered that the ZMO exhibits intense photoluminescence even at room temperature. Most of the solar cells were fabricated in the FTO/ZMO/CdTe configuration although CTO/ZMO/CdTe solar cells were also demonstrated. The CTO was produced with an electron mobility of 46 cm2 V-1s-1 without any post-deposition annealing or treatment.
A retrospective rating plan, whose insurance premium depends upon an insured's actual loss during the policy period, is a special insurance agreement widely used in liability insurance. In this paper, the design of an optimal retrospective rating plan is analyzed from the perspective of the insured who seeks to minimize its risk exposure in the sense of convex order. In order to reduce the moral hazard, we assume that both the insured and the insurer are obligated to pay more for a larger realization of the loss. Under the further assumptions that the minimum premium is zero, the maximum premium is proportional to the expected indemnity, and the basic premium is the only free parameter in the formula for retrospective premium given by Meyers (2004) and that the basic premium is determined in such a way that the expected retrospective premium equates to the expected indemnity with a positive safety loading, we formally establish the relationship that the insured will suffer more risk for a larger loss conversion factor or a higher maximum premium. These findings suggest that the insured prefers an insurance policy with the expected value premium principle, which is a special retrospective premium principle with zero loss conversion factor. In addition, we show that any admissible retrospective rating plan is dominated by a stop-loss insurance policy. Finally, the optimal retention of a stop-loss insurance is derived numerically under the criterion of minimizing the risk-adjusted value of the insured's liability where the liability valuation is carried out using the cost-of-capital approach based on the conditional value at risk.
Mechanical properties are vital for living cells, and various models have been developed to study the mechanical behavior of cells. However, there is debate regarding whether a cell behaves more similarly to a “cortical shell – liquid core” structure (membrane-like) or a homogeneous solid (cytoskeleton-like) when experiencing stress by mechanical forces. Unlike most experimental methods, which concern the small-strain deformation of a cell, we focused on the mechanical behavior of a cell undergoing small to large strain by conducting microinjection experiments on zebrafish embryo cells. The power law with order of 1.5 between the injection force and the injection distance indicates that the cell behaves as a homogenous solid at small-strain deformation. The linear relation between the rupture force and the microinjector radius suggests that the embryo behaves as membrane-like when subjected to large-strain deformation. We also discuss the possible reasons causing the debate by analyzing the mechanical properties of F-actin filaments.
Biped walking can be regarded as a global limit cycle whose stability is difficult to verify by only local sensory feedback. This paper presents a control strategy combining global sensory reflex and leg synchronization. The inverted pendulum angle is utilized as global motion feedback to ensure global stability, and joint synchronization between legs is designed to stabilize bifurcations. The proposed strategy can achieve a stable gait and stabilize bifurcations. The robustness of this approach was evaluated against external disturbances. Walking experiments of a biped actuated by pneumatic muscles were conducted to confirm the validity of the proposed method. Instead of tracking predetermined trajectories, this method uses sensory reflexes to activate motor neurons and coincides with the biological idea wherein inessential degrees-of-freedom are barely controlled rather than strictly controlled.
Although mature seeds of the monogeneric conifer family Cephalotaxaceae sensu stricto have underdeveloped embryos, no definitive studies have been done to classify dormancy in this family. Our primary purpose was to determine the kind of dormancy in seeds of Cephalotaxus wilsoniana and to put the results into a broad phylogenetic context for gymnosperms. The species is of horticultural and medicinal value, and information is needed on how to propagate it efficiently from seeds. Embryo growth and germination were monitored for seeds at warm, cold and warm plus cold temperatures, and germination was monitored for seeds subjected to: (1) cold → warm → cold → warm; and (2) warm → cold → warm → cold → warm temperature sequences. The effects of gibberellic acids GA3 and GA4 were tested on radicle emergence in ungerminated seeds and on shoot emergence in root-emerged seeds. Germination was promoted by ≥ 36 weeks of warm stratification followed by ≥ 8 weeks of cold stratification, but only if seeds were returned to high temperatures. The underdeveloped embryo must increase in length by >120% before the radicle emerges. Neither GA3 nor GA4 was effective in promoting radicle emergence; however, both plant growth regulators increased rate (but not percentage) of shoot emergence in root-emerged seeds. We conclude that seeds of C. wilsoniana have the deep simple level of morphophysiological dormancy (MPD), C1b-C3-B1b; thus, warm stratification followed by cold stratification and then warm-temperature incubation are required for germination. In gymnosperms, MPD is known in cycads, Ginkgo and now in three families of conifers.
In our previous work, a random-sampling-based footstep planner has been proposed for global biped navigation. Goal-probability threshold (GPT) is the key parameter that controls the convergence rate of the goal-biased nonuniform sampling in the planner. In this paper, an approach to optimized GPT adaptation is explained by a benchmarking planning problem. We first construct a benchmarking model, in which the biped navigation problem is described in selected parameters, to study the relationship between these parameters and the optimized GPT. Then, a back-propagation (BP) neural network is employed to fit this relationship. With a trained BP neural network modular, the optimized GPT can be automatically generated according to the specifications of a planning problem. Compared with previous methods of manual and empirical tuning of GPT for individual planning problems, the proposed approach is self-adaptive. Numerical experiments verified the performance of the proposed approach and furthermore showed that planning with BP-generated GPTs is more stable. Besides the implementation in specific parameterized environments studied in this paper, we attempt to provide the frame of the proposed approach as a reference for footstep planning in other environments.
The Mogao Grottoes site at Dunhuang is one of the largest stone cave temples in China. The site features 735 caves with Buddhist mural paintings. To investigate the chronology of early caves of the Mogao Grottoes, radiocarbon dates were measured by accelerator mass spectrometry (AMS) on plant remains collected from 4 caves: 268, 272, 275, and 285. Caves 268, 272, and 275 are regarded (by archaeological analysis) to be the earliest existing caves in the Mogao Grottoes. The fourth cave, 285, features inscriptions on the north wall mentioning the oldest dates of the Chinese Mogao era. Plant materials, taken from the plaster layer of mural paintings and core materials from statues, were collected as samples (n = 11) for AMS 14C dating at Nagoya University. Two samples from cave 275 gave calibrated 14C ages of cal AD 380–430 (1 σ). The other samples resulted in a time interval of cal AD 400–550. The calibrated 14C ages obtained for the samples taken from painted murals and the statues in cave 285 are consistent with the date given by the inscription remaining on the cave's north wall.
This paper presents a control algorithm for biped walking by extension of previous work in the fields of central pattern generator (CPG) and passive walking. The algorithm takes advantage of the passive dynamics of walking, assisting only when necessary with an intermittent sinusoidal oscillator. The parameterized oscillator is used to drive the hip joint; the triggering and ceasing of the oscillator during a walking cycle can be modulated by the sensory feedback. The results from simulation indicate a stable, efficient gait, and robustness against model inaccuracy and environmental variation. We also examine the effects of oscillator parameters and link parameters on the gait, and design a controller to suppress the bifurcation phenomenon based on the error of prior step periods.