To send content items to your account,
please confirm that you agree to abide by our usage policies.
If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account.
Find out more about sending content to .
To send content items to your Kindle, first ensure email@example.com
is added to your Approved Personal Document E-mail List under your Personal Document Settings
on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part
of your Kindle email address below.
Find out more about sending to your Kindle.
Note you can select to send to either the @free.kindle.com or @kindle.com variations.
‘@free.kindle.com’ emails are free but can only be sent to your device when it is connected to wi-fi.
‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.
Major depressive disorder (MDD) is a common, debilitating, phenotypically heterogeneous disorder with heritability ranges from 30% to 50%. Compared to other psychiatric disorders, its high prevalence, moderate heritability, and strong polygenicity have posed major challenges for gene-mapping in MDD. Studies of common genetic variation in MDD, driven by large international collaborations such as the Psychiatric Genomics Consortium, have confirmed the highly polygenic nature of the disorder and implicated over 100 genetic risk loci to date. Rare copy number variants associated with MDD risk were also recently identified. The goal of this review is to present a broad picture of our current understanding of the epidemiology, genetic epidemiology, molecular genetics, and gene–environment interplay in MDD. Insights into the impact of genetic factors on the aetiology of this complex disorder hold great promise for improving clinical care.
Patients with schizophrenia and individuals with schizotypy, a subclinical group at risk for schizophrenia, have been found to have impairments in cognitive control. The Dual Mechanisms of Cognitive Control (DMC) framework hypothesises that cognitive control can be divided into proactive and reactive control. However, it is unclear whether individuals with schizotypy have differential behavioural impairments and neural correlates underlying these two types of cognitive control.
Twenty-five individuals with schizotypy and 26 matched healthy controls (HCs) completed both reactive and proactive control tasks with electroencephalographic data recorded. The proportion of congruent and incongruent trials was manipulated in a classic colour-word Stroop task to induce proactive or reactive control. Proactive control was induced in a context with mostly incongruent (MI) trials and reactive control in a context with mostly congruent (MC) trials. Two event-related potential (ERP) components, medial frontal negativity (MFN, associated with conflict detection) and conflict sustained potential (conflict SP, associated with conflict resolution) were examined.
There was no significant difference between the two groups in terms of behavioural results. In terms of ERP results, in the MC context, HC exhibited significantly larger MFN (360–530 ms) and conflict SP (600–1000 ms) amplitudes than individuals with schizotypy. The two groups did not show any significant difference in MFN or conflict SP in the MI context.
The present findings provide initial evidence for dissociation of neural activation between proactive and reactive cognitive control in individuals with schizotypy. These findings help us understand cognitive control deficits in the schizophrenia spectrum.
Late-life depression has substantial impacts on individuals, families and society. Knowledge gaps remain in estimating the economic impacts associated with late-life depression by symptom severity, which has implications for resource prioritisation and research design (such as in modelling). This study examined the incremental health and social care expenditure of depressive symptoms by severity.
We analysed data collected from 2707 older adults aged 60 years and over in Hong Kong. The Patient Health Questionnaire-9 (PHQ-9) and the Client Service Receipt Inventory were used, respectively, to measure depressive symptoms and service utilisation as a basis for calculating care expenditure. Two-part models were used to estimate the incremental expenditure associated with symptom severity over 1 year.
The average PHQ-9 score was 6.3 (standard deviation, s.d. = 4.0). The percentages of respondents with mild, moderate and moderately severe symptoms and non-depressed were 51.8%, 13.5%, 3.7% and 31.0%, respectively. Overall, the moderately severe group generated the largest average incremental expenditure (US$5886; 95% CI 1126–10 647 or a 272% increase), followed by the mild group (US$3849; 95% CI 2520–5177 or a 176% increase) and the moderate group (US$1843; 95% CI 854–2831, or 85% increase). Non-psychiatric healthcare was the main cost component in a mild symptom group, after controlling for other chronic conditions and covariates. The average incremental association between PHQ-9 score and overall care expenditure peaked at PHQ-9 score of 4 (US$691; 95% CI 444–939), then gradually fell to negative between scores of 12 (US$ - 35; 95% CI - 530 to 460) and 19 (US$ -171; 95% CI - 417 to 76) and soared to positive and rebounded at the score of 23 (US$601; 95% CI -1652 to 2854).
The association between depressive symptoms and care expenditure is stronger among older adults with mild and moderately severe symptoms. Older adults with the same symptom severity have different care utilisation and expenditure patterns. Non-psychiatric healthcare is the major cost element. These findings inform ways to optimise policy efforts to improve the financial sustainability of health and long-term care systems, including the involvement of primary care physicians and other geriatric healthcare providers in preventing and treating depression among older adults and related budgeting and accounting issues across services.
To describe epidemiologic and genomic characteristics of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak in a large skilled nursing facility (SNF), and the strategies that controlled transmission.
Design, Setting, and Participants:
Cohort study during March 22–May 4, 2020 of all staff and residents at a 780-bed SNF in San Francisco, California.
Contact tracing and symptom screening guided targeted testing of staff and residents; respiratory specimens were also collected through serial point prevalence surveys (PPS) in units with confirmed cases. Cases were confirmed by real-time reverse transcription–polymerase chain reaction testing for SARS-CoV-2; whole genome sequencing (WGS) characterized viral isolate lineages and relatedness. Infection prevention and control (IPC) interventions included restricting from work any staff who had close contact to a confirmed case; restricting movements between units; implementing surgical face masking facility-wide; and recommended PPE (isolation gown, gloves, N95 respirator and eye protection) for clinical interactions in units with confirmed cases.
Of 725 staff and residents tested through targeted testing and serial PPS, twenty-one (3%) were SARS-CoV-2-positive; sixteen (76%) staff and 5 (24%) residents. Fifteen (71%) were linked to a single unit. Targeted testing identified 17 (81%) cases; PPS identified 4 (19%). Most (71%) cases were identified prior to IPC intervention. WGS was performed on SARS-CoV-2 isolates from four staff and four residents; five were of Santa Clara County lineage and the three others were distinct lineages.
Early implementation of targeted testing, serial PPS, and multimodal IPC interventions limited SARS-CoV-2 transmission within the SNF.
Over the past decades, anti-cancer treatments have evolved rapidly from cytotoxic chemotherapies to targeted therapies including oral targeted medications and injectable immunooncology and cell therapies. New anti-cancer medications come to markets at increasingly high prices, and health insurance coverage is crucial for patient access to these therapies. State laws are intended to facilitate insurance coverage of anti-cancer therapies.
Using Massachusetts as a case study, we identified five current cancer coverage state laws and interviewed experts on their perceptions of the relevance of the laws and how well they meet the current needs of cancer care given rapid changes in therapies. Interviewees emphasized that cancer therapies, as compared to many other therapeutic areas, are unique because insurance legislation targets their coverage. They identified the oral chemotherapy parity law as contributing to increasing treatment costs in commercial insurance. For commercial insurers, coverage mandates combined with the realities of new cancer medications — including high prices and often limited evidence of efficacy at approval — compound a difficult situation. Respondents recommended policy approaches to address this challenging coverage environment, including the implementation of closed formularies, the use of cost-effectiveness studies to guide coverage decisions, and the application of value-based pricing concepts. Given the evolution of cancer therapeutics, it may be time to evaluate the benefits and challenges of cancer coverage mandates.
Non-medical opioid use (NMOU) is a growing crisis. Cancer patients at elevated risk of NMOU (+risk) are frequently underdiagnosed. The aim of this paper was to develop a nomogram to predict the probability of +risk among cancer patients receiving outpatient supportive care consultation at a comprehensive cancer center.
3,588 consecutive patients referred to a supportive care clinic were reviewed. All patients had a diagnosis of cancer and were on opioids for pain. All patients were assessed using the Edmonton Symptom Assessment Scale (ESAS), Screener and Opioid Assessment for Patients with Pain (SOAPP-14), and CAGE-AID (Cut Down-Annoyed-Guilty-Eye Opener) questionnaires. “+risk” was defined as an SOAPP-14 score of ≥7. A nomogram was devised based on the risk factors determined by the multivariate logistic regression model to estimate the probability of +risk.
731/3,588 consults were +risk. +risk was significantly associated with gender, race, marital status, smoking status, depression, anxiety, financial distress, MEDD (morphine equivalent daily dose), and CAGE-AID score. The C-index was 0.8. A nomogram was developed and can be accessed at https://is.gd/soappnomogram. For example, for a male Hispanic patient, married, never smoked, with ESAS scores for depression = 3, anxiety = 3, financial distress = 7, a CAGE score of 0, and an MEDD score of 20, the total score is 9 + 9+0 + 0+6 + 10 + 23 + 0+1 = 58. A nomogram score of 58 indicates the probability of +risk of 0.1.
Significance of results
We established a practical nomogram to assess the +risk. The application of a nomogram based on routinely collected clinical data can help clinicians establish patients with +risk and positively impact care planning.
Schizotypy refers to schizophrenia-like traits below the clinical threshold in the general population. The pathological development of schizophrenia has been postulated to evolve from the initial coexistence of ‘brain disconnection’ and ‘brain connectivity compensation’ to ‘brain connectivity decompensation’.
In this study, we examined the brain connectivity changes associated with schizotypy by combining brain white matter structural connectivity, static and dynamic functional connectivity analysis of diffusion tensor imaging data and resting-state functional magnetic resonance imaging data. A total of 87 participants with a high level of schizotypal traits and 122 control participants completed the experiment. Group differences in whole-brain white matter structural connectivity probability, static mean functional connectivity strength, dynamic functional connectivity variability and stability among 264 brain sub-regions of interests were investigated.
We found that individuals with high schizotypy exhibited increased structural connectivity probability within the task control network and within the default mode network; increased variability and decreased stability of functional connectivity within the default mode network and between the auditory network and the subcortical network; and decreased static mean functional connectivity strength mainly associated with the sensorimotor network, the default mode network and the task control network.
These findings highlight the specific changes in brain connectivity associated with schizotypy and indicate that both decompensatory and compensatory changes in structural connectivity within the default mode network and the task control network in the context of whole-brain functional disconnection may be an important neurobiological correlate in individuals with high schizotypy.
Although luminescence sensitivity of quartz grains of desert sands has been used in discriminating provenance, it still remains unclear about its spatiotemporal variations and climatic implications. In this paper, the luminescence sensitivity of quartz grains from the northern margin of the Chinese Loess Plateau (CLP) was studied using single-aliquot optically stimulated luminescence (OSL) and “pseudo” single-grain OSL measurements. Our results indicate that the OSL sensitivities have lower values in sand/loess beds and higher values in paleosols. We suggest that the variations in OSL sensitivity of quartz grains with depth on the CLP are mainly influenced by the origin of the quartz grains as they are related to the loess-sized material production processes and the migration of desert regions. More quartz grains of glacial origin with lower luminescence sensitivity, together with the reduced durations of irradiation and exposure cycles induced by shorter transport distance due to desert expansion, account for the lower luminescence sensitivity of glacial periods. Moreover, both the mountain processes and the retreat–advance of deserts are ultimately related to climatic changes, therefore, the orbital scale variations of luminescence sensitivity are controlled by glacial–interglacial oscillations on the CLP.
In this paper, the generation of relativistic electron mirrors (REM) and the reflection of an ultra-short laser off the mirrors are discussed, applying two-dimension particle-in-cell simulations. REMs with ultra-high acceleration and expanding velocity can be produced from a solid nanofoil illuminated normally by an ultra-intense femtosecond laser pulse with a sharp rising edge. Chirped attosecond pulse can be produced through the reflection of a counter-propagating probe laser off the accelerating REM. In the electron moving frame, the plasma frequency of the REM keeps decreasing due to its rapid expansion. The laser frequency, on the contrary, keeps increasing due to the acceleration of REM and the relativistic Doppler shift from the lab frame to the electron moving frame. Within an ultra-short time interval, the two frequencies will be equal in the electron moving frame, which leads to the resonance between laser and REM. The reflected radiation near this interval and corresponding spectra will be amplified due to the resonance. Through adjusting the arriving time of the probe laser, a certain part of the reflected field could be selectively amplified or depressed, leading to the selective adjustment of the corresponding spectra.
We investigate the phased evolution and variation of the South Asian monsoon and resulting weathering intensity and physical erosion in the Himalaya–Karakoram Mountains since late Pliocene time (c. 3.4 Ma) using a comprehensive approach. Neodymium and strontium isotopic compositions and single-grain zircon U–Pb age spectra reveal the sources of the deposits in the east Arabian Sea, and show a combination of sources from the Himalaya and the Karakoram–Kohistan–Ladakh Mountains, with sediments from the Indian Peninsula such as the Deccan Traps or Craton. We interpret shifts in the sediment sources to have been forced by sea-level changes that correlate with South Asian monsoon rainfall variation since late Pliocene time. We collected 908 samples from the International Ocean Discovery Program Hole U1456A, which was drilled in the east Arabian Sea. Time series of hematite content and grain size of the sediments were examined downcore. We found South Asian monsoon precipitation and weathering intensity experienced three phases from late Pliocene time. Lower monsoon precipitation, with a lower variability and strong weathering intensity, occurred during 3.4–2.4 Ma; an increased and more variable South Asian monsoon rainfall, along with strengthened but fluctuating weathering intensity, occurred at 1.8–1.1 Ma; and a reduced rainfall with lower South Asian monsoon precipitation variability and moderate weathering intensity marked the period 1.1–0.1 Ma. Maximum entropy spectral analysis and wavelet transform show that there were orbital-dominated cycles of periods c. 100 and c. 41 ka in these proxy-based time series. We propose that the monsoon, sea level, global temperature and insolation together forced the weathering and erosion in SW Asia.
In recent years, men who have sex with men (MSM) constitute a major group of HIV transmission in China. High primary drug-resistance (PDR) rate in MSM also represents a serious challenge for the Chinese antiretroviral therapy (ART) program. To assess the efficiency of ART in controlling HIV/AIDS infection among MSM, we developed a compartmental model for the annually reported HIV/AIDS MSM from 2007 to 2019 in the Zhejiang Province of China. R0 was 2.3946 (95% CI (2.2961–2.4881)). We predict that 90% of diagnosed HIV/AIDS individuals will have received treatment till 2020, while the proportion of the diagnosed remains as low as 40%. Even when the proportion of the diagnosed reaches 90%, R0 is still larger than the level of AIDS epidemic elimination. ART can effectively control the spread of HIV, even in the presence of drug resistance. The 90-90-90 strategy alone may not eliminate the HIV epidemic in Chinese MSM. Behavioural and biologic interventions are the most effective interventions to control the HIV/AIDS epidemic among MSM.
Fluid motion has two well-known fundamental processes: the vector transverse process characterized by vorticity, and the scalar longitudinal process consisting of a sound mode and an entropy mode, characterized by dilatation and thermodynamic variables. The existing theories for the sound mode involve the multi-variable issue and its associated difficulty of source identification. In this paper, we define the source of sound inside the fluid by the objective causality inherent in dynamic equations relevant to a longitudinal process, which naturally favours the material time-rate operator
rather than the local time-rate operator
, and describes the sound mode by inhomogeneous advective wave equations. The sources of sound physical production inside the fluid are then examined at two levels. For the conventional formulation in terms of thermodynamic variables at the first level, we show that the universal kinematic source can be condensed to a scalar invariant of the surface deformation tensor. Further, in the formulation in terms of dilatation at the second level, we find that the sound mode in viscous and heat-conducting flow has sources from rich nonlinear couplings of vorticity, entropy and surface deformation, which cannot be disclosed at the first level. Preliminary numerical demonstration of the theoretical findings is made for two typical compressible flows, i.e. the interaction of two corotating Gaussian vortices and the unsteady type IV shock/shock interaction. The results obtained in this study provide a new theoretical basis for, and physical insight into, understanding various nonlinear longitudinal processes and the interactions therein.
Many family characteristics were reported to increase the risk of bipolar disorder (BPD). The development of BPD may be mediated through different pathways, involving diverse risk factor profiles. We evaluated the associations of family characteristics to build influential causal-pie models to estimate their contributions on the risk of developing BPD at the population level. We recruited 329 clinically diagnosed BPD patients and 202 healthy controls to collect information in parental psychopathology, parent-child relationship, and conflict within family. Other than logistic regression models, we applied causal-pie models to identify pathways involved with different family factors for BPD. The risk of BPD was significantly increased with parental depression, neurosis, anxiety, paternal substance use problems, and poor relationship with parents. Having a depressed mother further predicted early onset of BPD. Additionally, a greater risk for BPD was observed with higher numbers of paternal/maternal psychopathologies. Three significant risk profiles were identified for BPD, including paternal substance use problems (73.0%), maternal depression (17.6%), and through poor relationship with parents and conflict within the family (6.3%). Our findings demonstrate that different aspects of family characteristics elicit negative impacts on bipolar illness, which can be utilized to target specific factors to design and employ efficient intervention programs.
Cariprazine is a potent dopamine D3 and D2 receptor partial agonist with preferential binding to D3 receptors.
Summarize data from two Phase III, randomized, double-blind, placebo-controlled, flexible-dose, 3-week trials of cariprazine 3-12mg/d (NCT01058096) and cariprazine 3-6mg/d or 6-12mg/d (NCT01058668) in adults with bipolar I disorder and acute manic or mixed episodes.
Evaluate the efficacy, safety, and tolerability of cariprazine in mania associated with bipolar I disorder.
Primary and secondary efficacy parameters were change from baseline to Week 3 on the Young Mania Rating Scale (YMRS) and Clinical Global Impressions-Severity (CGI-S), respectively, and were analyzed using a mixed-effects model for repeated measures.
Randomized patient populations: 312 (NCT01058096; 154 placebo, 158 cariprazine 3–12mg/d) and 497 (NCT01058668; 161 placebo, 167 cariprazine 3–6mg/d, 169 cariprazine 6–12mg/d). Improvement from baseline to Week 3 on YMRS was significantly greater for each cariprazine group vs placebo (P<0.001): least square mean difference (LSMD) was −4.3 (3–12mg/d), −6.1 (3–6mg/d) and −5.9 (6–12mg/d). For each cariprazine group, significantly more patients met YMRS response and remission criteria vs placebo. Cariprazine also was significantly superior to placebo on the CGI-S: LSMD was −0.4 (3–12mg/d, P=.0027), −0.6 (3–6mg/d, P<.001), −0.6 (6–12mg/d, P<.001). The only common cariprazine-related TEAEs (≥5% and twice rate of placebo) that occurred in both studies were akathisia and tremor. Changes in metabolic parameters were small and similar to placebo in both studies.
Cariprazine was effective and generally well tolerated in the treatment of bipolar mania.
Cariprazine is a potent dopamine D3 and D2 receptor partial agonist with preferential binding to D3 receptors.
Summarize data from 2 Phase III, randomized, double-blind (6-week), placebo-controlled trials of fixed-dose cariprazine (3mg/d and 6mg/d, NCT01104766) and flexible-dose cariprazine (3–6mg/d and 6–9mg/d, NCT01104779) in adults with acute exacerbation of schizophrenia.
Evaluate the efficacy, safety, and tolerability of cariprazine in schizophrenia.
Primary and secondary efficacy parameters were change from baseline to Week 6 in Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impressions-Severity (CGI-S), respectively, and were analyzed using a mixed-effects model for repeated measures.
Randomized patient populations: 617 (NCT01104766; 153 placebo, 155 cariprazine 3mg/d, 157 cariprazine 6mg/d, 152 aripiprazole) and 446 (NCT01104779; 147 placebo, 151 cariprazine 3–6mg/d, 148 cariprazine 6–9mg/d). Improvement from baseline to Week 6 on PANSS total scores was significantly greater with cariprazine vs placebo: least square mean difference (LSMD) was −6.0 (3mg/d, P=.0044), −6.8 (3–6mg/d, P=.0029), −8.8 (6mg/d, P<.0001), and −9.9 (6–9mg/d, P<.0001). Cariprazine was significantly superior to placebo on CGI-S: LSMD was −0.4 (3mg/d, P=.0044), −0.3 (3–6mg/d, P=.0115), −0.5 (6mg/d, P<.0001), and −0.5 (6–9mg/d, P=.0002). Aripiprazole (active control, NCT01104766) was superior to placebo on both measures (LSMD: PANSS=−7.0, P=.0008; CGI-S=−0.4, P=.0001). The only common cariprazine-related TEAE (≥5% and twice rate of placebo) that occurred in both studies was akathisia. Changes in metabolic parameters were small and similar to placebo in both studies.
Cariprazine was effective and generally well tolerated in the treatment of schizophrenia.
Until the past half-century, all agriculture and land management was framed by local institutions strong in social capital. But neoliberal forms of development came to undermine existing structures, thus reducing sustainability and equity. The past 20 years, though, have seen the deliberate establishment of more than 8 million new social groups across the world. This restructuring and growth of rural social capital within specific territories is leading to increased productivity of agricultural and land management systems, with particular benefits for those previously excluded. Further growth would occur with more national and regional policy support.
Seasonal influenza virus epidemics have a major impact on healthcare systems. Data on population susceptibility to emerging influenza virus strains during the interepidemic period can guide planning for resource allocation of an upcoming influenza season. This study sought to assess the population susceptibility to representative emerging influenza virus strains collected during the interepidemic period. The microneutralisation antibody titers (MN titers) of a human serum panel against representative emerging influenza strains collected during the interepidemic period before the 2018/2019 winter influenza season (H1N1-inter and H3N2-inter) were compared with those against influenza strains representative of previous epidemics (H1N1-pre and H3N2-pre). A multifaceted approach, incorporating both genetic and antigenic data, was used in selecting these representative influenza virus strains for the MN assay. A significantly higher proportion of individuals had a ⩾four-fold reduction in MN titers between H1N1-inter and H1N1-pre than that between H3N2-inter and H3N2-pre (28.5% (127/445) vs. 4.9% (22/445), P < 0.001). The geometric mean titer (GMT) of H1N1-inter was significantly lower than that of H1N1-pre (381 (95% CI 339–428) vs. 713 (95% CI 641–792), P < 0.001), while there was no significant difference in the GMT between H3N2-inter and H3N2-pre. Since A(H1N1) predominated the 2018–2019 winter influenza epidemic, our results corroborated the epidemic subtype.