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Treatment-resistant depression (TRD) is commonly defined as non-response to ≥2 antidepressant treatment courses of adequate doses and durations in the current episode in patients with major depressive disorder (MDD). Esketamine (ESK) nasal spray was approved by the Food and Drug Administration in March 2019 for the treatment of TRD in adults in conjunction with an oral antidepressant (AD). This study assessed changes in depressive symptoms following ESK initiation among patients with TRD in a real-world setting.
Methods
The study was a retrospective longitudinal observational cohort study of adults with TRD who initiated esketamine treatment between March 2019 and June 2022. Data were sourced from the PremiOM™ MDD Dataset (OM1, Boston, MA), a continuously updated cohort of over 440,000 patients with MDD in the United States with linked claims and electronic medical record data. Patients were classified as having TRD if they had ≥1 diagnosis of MDD during the 6 months prior to or on the index date (defined as ESK initiation) and a record of ≥2 unique ADs of adequate dose and duration at any time prior to the index date within the same major depressive episode (MDE; defined as no clean period of ≥180 days without ADs and/or MDD diagnoses). The Patient Health Questionnaire-9 (PHQ-9) was used to measure depressive symptoms. A machine learning model was used to estimate PHQ-9 scores for patients with no documented scores. The latest PHQ-9 score among questionnaires administered in the six months prior to or on the date of first ESK treatment was used as the baseline score. Baseline scores were compared to the latest scores in the 0-3-month and 3-6 month windows after first ESK treatment. A sensitivity analysis excluding the estimated scores was conducted. Marginal models were used to test for differences in post-treatment scores relative to baseline.
Results
The study cohort included 163 patients with a mean age of 49.5 years (standard deviation [SD]=15.4). Most patients were female (58.3%). At baseline, the mean PHQ-9 score was 15.0 (SD=6.7) and 55.8% of patients had either moderately severe or severe depression (PHQ-9 ≥15). Patients experienced statistically significant reductions in PHQ-9 scores of 2.9 points (95% CI: 1.7 to 4.1, p<0.001) in the 0–3-month interval and 4.4 points (95% CI: 3.2 to 5.6, p<0.001) in the 3–6-month interval relative to baseline. The percentage of patients with moderately severe or severe depression (PHQ-9 ≥15) decreased to 34.4% at the 0-3 month interval and 20.9% at the 3-6 month interval. Results were consistent when estimated PHQ-9 scores were excluded.
Conclusions
Among patients with TRD in a real-world setting, PHQ-9 scores significantly decreased in the 6 months following initiation of ESK treatment. Further investigation of longer-term effectiveness of ESK and among key subgroups is warranted.
Funding
Janssen Pharmaceuticals, the manufacturer of esketamine
Post-traumatic stress disorder (PTSD) is associated with cognitive impairments. It is unclear whether problems persist after PTSD symptoms remit.
Methods
Data came from 12 270 trauma-exposed women in the Nurses' Health Study II. Trauma and PTSD symptoms were assessed using validated scales to determine PTSD status as of 2008 (trauma/no PTSD, remitted PTSD, unresolved PTSD) and symptom severity (lifetime and past-month). Starting in 2014, cognitive function was assessed using the Cogstate Brief Battery every 6 or 12 months for up to 24 months. PTSD associations with baseline cognition and longitudinal cognitive changes were estimated by covariate-adjusted linear regression and linear mixed-effects models, respectively.
Results
Compared to women with trauma/no PTSD, women with remitted PTSD symptoms had a similar cognitive function at baseline, while women with unresolved PTSD symptoms had worse psychomotor speed/attention and learning/working memory. In women with unresolved PTSD symptoms, past-month PTSD symptom severity was inversely associated with baseline cognition. Over follow-up, both women with remitted and unresolved PTSD symptoms in 2008, especially those with high levels of symptoms, had a faster decline in learning/working memory than women with trauma/no PTSD. In women with remitted PTSD symptoms, higher lifetime PTSD symptom severity was associated with a faster decline in learning/working memory. Results were robust to the adjustment for sociodemographic, biobehavioral, and health factors and were partially attenuated when adjusted for depression.
Conclusion
Unresolved but not remitted PTSD was associated with worse cognitive function assessed six years later. Accelerated cognitive decline was observed among women with either unresolved or remitted PTSD symptoms.
Despite replicated cross-sectional evidence of aberrant levels of peripheral inflammatory markers in individuals with major depressive disorder (MDD), there is limited literature on associations between inflammatory tone and response to sequential pharmacotherapies.
Objectives
To assess associations between plasma levels of pro-inflammatory markers and treatment response to escitalopram and adjunctive aripiprazole in adults with MDD.
Methods
In a 16-week open-label clinical trial, 211 participants with MDD were treated with escitalopram 10– 20 mg daily for 8 weeks. Responders continued on escitalopram while non-responders received adjunctive aripiprazole 2–10 mg daily for 8 weeks. Plasma levels of pro-inflammatory markers – C-reactive protein, Interleukin (IL)-1β, IL-6, IL-17, Interferon gamma (IFN)-Γ, Tumour Necrosis Factor (TNF)-α, and Chemokine C–C motif ligand-2 (CCL-2) - measured at baseline, and after 2, 8 and 16 weeks were included in logistic regression analyses to assess associations between inflammatory markers and treatment response.
Results
Pre-treatment levels of IFN-Γ and CCL-2 were significantly higher in escitalopram non-responders compared to responders. Pre-treatment IFN-Γ and CCL-2 levels were significantly associated with a lower of odds of response to escitalopram at 8 weeks. Increases in CCL-2 levels from weeks 8 to 16 in escitalopram non-responders were significantly associated with higher odds of non-response to adjunctive aripiprazole at week 16.
Conclusions
Pre-treatment levels of IFN-Γ and CCL-2 were predictive of response to escitalopram. Increasing levels of these pro-inflammatory markers may predict non-response to adjunctive aripiprazole. These findings require validation in independent clinical populations.
The goal in system-level design is to generate a diverse set of high-performing design configurations that allow trade-offs across different objectives and avoid early concretization. We use deep generative models to learn a manifold of the valid design space, followed by Monte Carlo sampling to explore and optimize design over the learned manifold, producing a diverse set of optimal designs. We demonstrate the efficacy of our proposed approach on the design of an SAE race vehicle and propeller.
The current study was undertaken to identify the sources of tolerance to bruchid in cowpea, by screening a set of germplasm accessions as a source for natural resistance. A total of 103 diverse accessions of cowpea were evaluated for resistance to Callosobruchus maculatus Fab. under no-choice artificial infestation conditions. Significant differences among the cowpea accessions were observed for oviposition, adult emergence, exit holes and per cent seed weight loss (PSWL) caused by the bruchid infestation. The accessions showed variation in physical seed parameters viz., colour, shape, testa texture, length, width and seed hardness. Among the seed biochemical parameters studied, per cent sugar content ranged from 0.322 (IC330950) to 1.493 (IC249137), and per cent phenol content ranged from 0.0326 (EC390261) to 1.081 (EC528423). Correlation studies indicated that PSWL had significant positive correlation (r = 0.335) with exit holes, oviposition (r = 0.219), adult emergence (r = 0.534) and seed roundness (r = 0.219). Adult emergence had a significant negative correlation with seed hardness (r = −0.332). Correlation with biochemical parameters indicated that PSWL had a significant positive correlation (r = 0.231) with sugar content and a significant negative correlation with phenol content (r = −0.219). None of the accessions were found to be immune to bruchid infestation. However, out of studied accessions, EC528425 and EC528387 were identified as resistant based on PSWL and moderately resistant based on adult emergence. These resistance sources of cowpea germplasm can be used as potential donors for development of bruchid tolerant/resistant cultivars.
Seven half-day regional listening sessions were held between December 2016 and April 2017 with groups of diverse stakeholders on the issues and potential solutions for herbicide-resistance management. The objective of the listening sessions was to connect with stakeholders and hear their challenges and recommendations for addressing herbicide resistance. The coordinating team hired Strategic Conservation Solutions, LLC, to facilitate all the sessions. They and the coordinating team used in-person meetings, teleconferences, and email to communicate and coordinate the activities leading up to each regional listening session. The agenda was the same across all sessions and included small-group discussions followed by reporting to the full group for discussion. The planning process was the same across all the sessions, although the selection of venue, time of day, and stakeholder participants differed to accommodate the differences among regions. The listening-session format required a great deal of work and flexibility on the part of the coordinating team and regional coordinators. Overall, the participant evaluations from the sessions were positive, with participants expressing appreciation that they were asked for their thoughts on the subject of herbicide resistance. This paper details the methods and processes used to conduct these regional listening sessions and provides an assessment of the strengths and limitations of those processes.
Herbicide resistance is ‘wicked’ in nature; therefore, results of the many educational efforts to encourage diversification of weed control practices in the United States have been mixed. It is clear that we do not sufficiently understand the totality of the grassroots obstacles, concerns, challenges, and specific solutions needed for varied crop production systems. Weed management issues and solutions vary with such variables as management styles, regions, cropping systems, and available or affordable technologies. Therefore, to help the weed science community better understand the needs and ideas of those directly dealing with herbicide resistance, seven half-day regional listening sessions were held across the United States between December 2016 and April 2017 with groups of diverse stakeholders on the issues and potential solutions for herbicide resistance management. The major goals of the sessions were to gain an understanding of stakeholders and their goals and concerns related to herbicide resistance management, to become familiar with regional differences, and to identify decision maker needs to address herbicide resistance. The messages shared by listening-session participants could be summarized by six themes: we need new herbicides; there is no need for more regulation; there is a need for more education, especially for others who were not present; diversity is hard; the agricultural economy makes it difficult to make changes; and we are aware of herbicide resistance but are managing it. The authors concluded that more work is needed to bring a community-wide, interdisciplinary approach to understanding the complexity of managing weeds within the context of the whole farm operation and for communicating the need to address herbicide resistance.
This study explores the formation of circular thin-film hydraulic jumps caused by the normal impact of a jet on an infinite planar surface. For more than a century, it has been believed that all hydraulic jumps are created due to gravity. However, we show that these thin-film hydraulic jumps result from energy loss due to surface tension and viscous forces alone. We show that, at the jump, surface tension and viscous forces balance the momentum in the liquid film and gravity plays no significant role. Experiments show no dependence on the orientation of the surface and a scaling relation balancing viscous forces and surface tension collapses the experimental data. A theoretical analysis shows that the downstream transport of surface energy is the previously neglected critical ingredient in these flows, and that capillary waves play the role of gravity waves in a traditional jump in demarcating the transition from the supercritical to subcritical flow associated with these jumps.
Major depressive disorder (MDD) is a highly heterogeneous condition in terms of symptom presentation and, likely, underlying pathophysiology. Accordingly, it is possible that only certain individuals with MDD are well-suited to antidepressants. A potentially fruitful approach to parsing this heterogeneity is to focus on promising endophenotypes of depression, such as neuroticism, anhedonia, and cognitive control deficits.
Methods
Within an 8-week multisite trial of sertraline v. placebo for depressed adults (n = 216), we examined whether the combination of machine learning with a Personalized Advantage Index (PAI) can generate individualized treatment recommendations on the basis of endophenotype profiles coupled with clinical and demographic characteristics.
Results
Five pre-treatment variables moderated treatment response. Higher depression severity and neuroticism, older age, less impairment in cognitive control, and being employed were each associated with better outcomes to sertraline than placebo. Across 1000 iterations of a 10-fold cross-validation, the PAI model predicted that 31% of the sample would exhibit a clinically meaningful advantage [post-treatment Hamilton Rating Scale for Depression (HRSD) difference ⩾3] with sertraline relative to placebo. Although there were no overall outcome differences between treatment groups (d = 0.15), those identified as optimally suited to sertraline at pre-treatment had better week 8 HRSD scores if randomized to sertraline (10.7) than placebo (14.7) (d = 0.58).
Conclusions
A subset of MDD patients optimally suited to sertraline can be identified on the basis of pre-treatment characteristics. This model must be tested prospectively before it can be used to inform treatment selection. However, findings demonstrate the potential to improve individual outcomes through algorithm-guided treatment recommendations.
India has few mental health professionals to treat the large number of people suffering from mental disorders. Rural areas are particularly disadvantaged due to lack of trained health workers. Ways to improve care could be by training village health workers in basic mental health care, and by using innovative methods of service delivery. The ongoing Systematic Medical Appraisal, Referral and Treatment Mental Health Programme will assess the acceptability, feasibility and preliminary effectiveness of a task-shifting mobile-based intervention using mixed methods, in rural Andhra Pradesh, India.
Method.
The key components of the study are an anti-stigma campaign followed by a mobile-based mental health services intervention. The study will be done across two sites in rural areas, with intervention periods of 1 year and 3 months, respectively. The programme uses a mobile-based clinical decision support tool to be used by non-physician health workers and primary care physicians to screen, diagnose and manage individuals suffering from depression, suicidal risk and emotional stress. The key aim of the study will be to assess any changes in mental health services use among those screened positive following the intervention. A number of other outcomes will also be assessed using mixed methods, specifically focussed on reduction of stigma, increase in mental health awareness and other process indicators.
Conclusions.
This project addresses a number of objectives as outlined in the Mental Health Action Plan of World Health Organization and India's National Mental Health Programme and Policy. If successful, the next phase will involve design and conduct of a cluster randomised controlled trial.
Although dietary fiber (DF) negatively affects energy and nutrient digestibility, there is growing interest for the inclusion of its fermentable fraction in pig diets due to their functional properties and potential health benefits beyond supplying energy to the animals. This paper reviews some of the relevant information available on the role of different types of DF on digestion of nutrients in different sections of the gut, the fermentation process and its influence on gut environment, especially production and utilization of metabolites, microbial community and gut health of swine. Focus has been given on DF from feed ingredients (grains and coproducts) commonly used in pig diets. Some information on the role DF in purified form in comparison with DF in whole matrix of feed ingredients is also presented. First, composition and fractions of DF in different feed ingredients are briefly reviewed. Then, roles of different fractions of DF on digestion characteristics and physiological functions in the gastrointestinal tract (GIT) are presented. Specific roles of different fractions of DF on fermentation characteristics and their effects on production and utilization of metabolites in the GIT have been discussed. In addition, roles of DF fermentation on metabolic activity and microbial community in the intestine and their effects on intestinal health are reviewed and discussed. Evidence presented in this review indicates that there is wide variation in the composition and content of DF among feed ingredients, thereby their physico-chemical properties in the GIT of swine. These variations, in turn, affect the digestion and fermentation characteristics in the GIT of swine. Digestibility of DF from different feed ingredients is more variable and lower than that of other nutrients like starch, sugars, fat and CP. Soluble fractions of DF are fermented faster, produce higher amounts of volatile fatty acid than insoluble fractions, and favors growth of beneficial microbiota. Thus, selective inclusion of DF in diets can be used as a nutritional strategy to optimize the intestinal health of pigs, despite its lower digestibility and consequential negative effect on digestibility of other nutrients.
The electronic structure of CeAg2Ge2 single crystal has been investigated by using resonant valence band photoemission and angle-resolved photoemission spectroscopy at different photon energies. Resonant photoemission has been observed near the 4d threshold of Ce at 121 eV. The constant initial state spectra show two photoemission features having 4f character near the Fermi level that exhibits Fano-like sharp resonance profile. Experimental energy bands have been mapped from the normal-emission photoelectron spectra of CeAg2Ge2 (001) surface along the Γ–Z direction. Four photoemission features are observed to show the dispersion related to the Ce 4f states and the hybridized Ag 4d with Ge 4p states. The experimental spectra have been interpreted with the help of calculations based on full potential linear augmented plane wave method using density functional theory.
The understanding of the fate of the various pollutants and its mobility in the catchments of Nagarjun Sagar dam built on the Krishna river is of utmost important .As the Pedaguttu and Lambarpur catchments area has a proposed Uranium mining sites and Nagarjuna Sagar dam is the third largest man made dam which is the ultimate destination of all the rivulets in the Pedaguttu catchments. The concept of the distribution coefficient is invoked to understand the residence time of radionuclide on its nature. Expressions are derived to estimate the value of soil erosion constant using naturally occurring radionuclide. Based on 210Pb profile in the sediment core, the sedimentary load of 0.24 gm m−2y−1 was observed in the Pedaguttu and Lambarpur side of the Dam. The retention time and the transport coefficient of the pollutant were further obtained by using the appropriate modeling equation and was found 3776 and 2.7 × 10−5 respectively. The comparative exercise of the retention time and transport coefficient was done with the other studied catchments of the world for the further validation of the result.
An investigation on the distribution of Radium activity levels in the entire south-eastern coast of Tamilnadu, India, from Chennai to Kanyakumari was carried out. Insitu preconcentration technique was adopted by passing 1000 liters of seawater through MnO2 impregnated cartridge filters at all the locations. In the coastal waters, 226Ra and 228Ra concentration was observed to be in the range of 1 to 1.81 mBq/l and 3.1 to 7.5 mBq/l respectively with an average of 1.52 and 4.53 mBq/l respectively, while the sediment samples showed 226Ra activity levels from 8.1 to 129.0 Bq/kg and 228Ra varied from 14.7 to 430.01 Bq/kg. The concentration of 228Ra was observed to be more than 226Ra in all the locations. The activity ratio of 228Ra/ 226Ra in the Bay of Bengal showed a ratio varying from 0.8 to 2.4 with a mean of 2.1. In the present study, activity ratio varies from 1.9 to 2.4 at Karaikkal. But the regions of Rameswaram and Kanyakumari which comprises the high natural background region reflects different ratio varying from 3.5 to 6.9, reflecting different sources of weathered material for 228Ra. The findings supported the fact that the area also comes under natural high radiation background at the south west of Indian peninsula due to the presence of heavy mineral containing monazite. The spatial distribution of the activity with respect to location is discussed in the paper. The radioactive database obtained represents reference values for coastal environment of Tamil Nadu.
The chromosomes of Platynereis dumerilii (Audouin & Milne-Edwards) are described here for the first time. A modal chromosome number of 2n=28 was recorded, based on counts conducted on metaphase spreads prepared from 24-h-old larvae. The karyotype comprises seven pairs, each of relatively large median (arm ratio, p/q=l.00–0.59) and submedian (arm ratio, 0.59–0.33) chromosomes. Attempts were also made to band the chromosomes using C-banding and silver staining methods. C-band-positive regions were localized on four chromosome pairs (three median, one submedian). A further two chromosome pairs (both median) were observed to have terminal nucleolar organizer regions (NORs). To our knowledge, this is the first time that these banding methods have been successfully applied to any polychaete species. These results are discussed in relation to the karyotypic variation within the class Polychaeta, and the family Nereidae in particular. A stable karyotype consisting of a moderate number of large and morphologically well-differentiated chromosomes, coupled with the ease of culture under laboratory conditions and short generation time, suggests that P. dumerilii is a potentially suitable model for evaluating marine contaminants for genotoxic activity.