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The Genomics Used to Improve DEpresssion Decisions (GUIDED) trial assessed outcomes associated with combinatorial pharmacogenomic (PGx) testing in patients with major depressive disorder (MDD). Analyses used the 17-item Hamilton Depression (HAM-D17) rating scale; however, studies demonstrate that the abbreviated, core depression symptom-focused, HAM-D6 rating scale may have greater sensitivity toward detecting differences between treatment and placebo. However, the sensitivity of HAM-D6 has not been tested for two active treatment arms. Here, we evaluated the sensitivity of the HAM-D6 scale, relative to the HAM-D17 scale, when assessing outcomes for actively treated patients in the GUIDED trial.
Outpatients (N=1,298) diagnosed with MDD and an inadequate treatment response to >1 psychotropic medication were randomized into treatment as usual (TAU) or combinatorial PGx-guided (guided-care) arms. Combinatorial PGx testing was performed on all patients, though test reports were only available to the guided-care arm. All patients and raters were blinded to study arm until after week 8. Medications on the combinatorial PGx test report were categorized based on the level of predicted gene-drug interactions: ‘use as directed’, ‘moderate gene-drug interactions’, or ‘significant gene-drug interactions.’ Patient outcomes were assessed by arm at week 8 using HAM-D6 and HAM-D17 rating scales, including symptom improvement (percent change in scale), response (≥50% decrease in scale), and remission (HAM-D6 ≤4 and HAM-D17 ≤7).
At week 8, the guided-care arm demonstrated statistically significant symptom improvement over TAU using HAM-D6 scale (Δ=4.4%, p=0.023), but not using the HAM-D17 scale (Δ=3.2%, p=0.069). The response rate increased significantly for guided-care compared with TAU using both HAM-D6 (Δ=7.0%, p=0.004) and HAM-D17 (Δ=6.3%, p=0.007). Remission rates were also significantly greater for guided-care versus TAU using both scales (HAM-D6 Δ=4.6%, p=0.031; HAM-D17 Δ=5.5%, p=0.005). Patients taking medication(s) predicted to have gene-drug interactions at baseline showed further increased benefit over TAU at week 8 using HAM-D6 for symptom improvement (Δ=7.3%, p=0.004) response (Δ=10.0%, p=0.001) and remission (Δ=7.9%, p=0.005). Comparatively, the magnitude of the differences in outcomes between arms at week 8 was lower using HAM-D17 (symptom improvement Δ=5.0%, p=0.029; response Δ=8.0%, p=0.008; remission Δ=7.5%, p=0.003).
Combinatorial PGx-guided care achieved significantly better patient outcomes compared with TAU when assessed using the HAM-D6 scale. These findings suggest that the HAM-D6 scale is better suited than is the HAM-D17 for evaluating change in randomized, controlled trials comparing active treatment arms.
Major depressive disorder (MDD) is a leading cause of disease burden worldwide, with lifetime prevalence in the United States of 17%. Here we present the results of the first prospective, large-scale, patient- and rater-blind, randomized controlled trial evaluating the clinical importance of achieving congruence between combinatorial pharmacogenomic (PGx) testing and medication selection for MDD.
1,167 outpatients diagnosed with MDD and an inadequate response to ≥1 psychotropic medications were enrolled and randomized 1:1 to a Treatment as Usual (TAU) arm or PGx-guided care arm. Combinatorial PGx testing categorized medications in three groups based on the level of gene-drug interactions: use as directed, use with caution, or use with increased caution and more frequent monitoring. Patient assessments were performed at weeks 0 (baseline), 4, 8, 12 and 24. Patients, site raters, and central raters were blinded in both arms until after week 8. In the guided-care arm, physicians had access to the combinatorial PGx test result to guide medication selection. Primary outcomes utilized the Hamilton Depression Rating Scale (HAM-D17) and included symptom improvement (percent change in HAM-D17 from baseline), response (50% decrease in HAM-D17 from baseline), and remission (HAM-D17<7) at the fully blinded week 8 time point. The durability of patient outcomes was assessed at week 24. Medications were considered congruent with PGx test results if they were in the ‘use as directed’ or ‘use with caution’ report categories while medications in the ‘use with increased caution and more frequent monitoring’ were considered incongruent. Patients who started on incongruent medications were analyzed separately according to whether they changed to congruent medications by week8.
At week 8, symptom improvement for individuals in the guided-care arm was not significantly different than TAU (27.2% versus 24.4%, p=0.11). However, individuals in the guided-care arm were more likely than those in TAU to achieve remission (15% versus 10%; p<0.01) and response (26% versus 20%; p=0.01). Remission rates, response rates, and symptom reductions continued to improve in the guided-treatment arm until the 24week time point. Congruent prescribing increased to 91% in the guided-care arm by week 8. Among patients who were taking one or more incongruent medication at baseline, those who changed to congruent medications by week 8 demonstrated significantly greater symptom improvement (p<0.01), response (p=0.04), and remission rates (p<0.01) compared to those who persisted on incongruent medications.
Combinatorial PGx testing improves short- and long-term response and remission rates for MDD compared to standard of care. In addition, prescribing congruency with PGx-guided medication recommendations is important for achieving symptom improvement, response, and remission for MDD patients.
Funding Acknowledgements: This study was supported by Assurex Health, Inc.
Vitamin D deficiency is recognised as a public health problem globally, and a high prevalence of deficiency has previously been reported in Australia. This study details the prevalence of vitamin D deficiency in a nationally representative sample of Australian adults aged ≥25 years, using an internationally standardised method to measure serum 25-hydroxyvitamin D (25(OH)D) concentrations and identifies demographic and lifestyle factors associated with vitamin D deficiency. We used data from the 2011–2013 Australian Health Survey (n 5034 with complete information on potential predictors and serum 25(OH)D concentrations). Serum 25(OH)D concentrations were measured by a liquid chromatography-tandem MS that is certified to the reference measurement procedures developed by the National Institute of Standards and Technology, Ghent University and the US Centers for Disease Control and Prevention. Vitamin D deficiency and insufficiency were defined as serum 25(OH)D concentrations <50 nmol/l and 50 to <75 nmol/l, respectively. Overall, 20 % of participants (19 % men; 21 % women) were classified as vitamin D deficient, with a further 43 % classified as insufficient (45 % men; 42 % women). Independent predictors of vitamin D deficiency included being born in a country other than Australia or the main English-speaking countries, residing in southern (higher latitude) states of Australia, being assessed during winter or spring, being obese, smoking (women only), having low physical activity levels and not taking vitamin D or Ca supplements. Given our increasingly indoor lifestyles, there is a need to develop and promote strategies to maintain adequate vitamin D status through safe sun exposure and dietary approaches.
Persisting symptoms after treatment for major depressive disorder (MDD) contribute to ongoing impairment and relapse risk. Whether cognitive behavior therapy (CBT) or antidepressant medications result in different profiles of residual symptoms after treatment is largely unknown.
Three hundred fifteen adults with MDD randomized to treatment with either CBT or antidepressant medication in the Predictors of Remission in Depression to Individual and Combined Treatments (PReDICT) study were analyzed for the frequency of residual symptoms using the Montgomery Asberg Depression Rating Scale (MADRS) item scores at the end of the 12-week treatment period. Separate comparisons were made for treatment responders and non-responders.
Among treatment completers (n = 250) who responded to CBT or antidepressant medication, there were no significant differences in the persistence of residual MADRS symptoms. However, non-responders treated with medication were significantly less likely to endorse suicidal ideation (SI) at week 12 compared with those treated with CBT (non-responders to medication: 0/54, 0%, non-responders to CBT: 8/30, 26.7%; p = .001). Among patients who terminated the trial early (n = 65), residual MADRS item scores did not significantly differ between the CBT- and medication-treated groups.
Depressed adults who respond to CBT or antidepressant medication have similar residual symptom profiles. Antidepressant medications reduce SI, even among patients for whom the medication provides little overall benefit.
The anabolic potential of a dietary protein is determined by its ability to elicit postprandial rises in circulating essential amino acids and insulin. Minimal data exist regarding the bioavailability and insulinotropic effects of non-animal-derived protein sources. Mycoprotein is a sustainable and rich source of non-animal-derived dietary protein. We investigated the impact of mycoprotein ingestion, in a dose–response manner, on acute postprandial hyperaminoacidaemia and hyperinsulinaemia. In all, twelve healthy young men completed five experimental trials in a randomised, single-blind, cross-over design. During each trial, volunteers consumed a test drink containing either 20 g milk protein (MLK20) or a mass matched (not protein matched due to the fibre content) bolus of mycoprotein (20 g; MYC20), a protein matched bolus of mycoprotein (40 g; MYC40), 60 g (MYC60) or 80 g (MYC80) mycoprotein. Circulating amino acid, insulin and uric acid concentrations, and clinical chemistry profiles, were assessed in arterialised venous blood samples during a 4-h postprandial period. Mycoprotein ingestion resulted in slower but more sustained hyperinsulinaemia and hyperaminoacidaemia compared with milk when protein matched, with overall bioavailability equivalent between conditions (P>0·05). Increasing the dose of mycoprotein amplified these effects, with some evidence of a plateau at 60–80 g. Peak postprandial leucine concentrations were 201 (sem 24) (30 min), 118 (sem 10) (90 min), 150 (sem 14) (90 min), 173 (sem 23) (45 min) and 201 (sem 21 (90 min) µmol/l for MLK20, MYC20, MYC40, MYC60 and MYC80, respectively. Mycoprotein represents a bioavailable and insulinotropic dietary protein source. Consequently, mycoprotein may be a useful source of dietary protein to stimulate muscle protein synthesis rates.
Commonly observed distortions in decision-making among patients with major depressive disorder (MDD) may emerge from impaired reward processing and cognitive biases toward negative events. There is substantial theoretical support for the hypothesis that MDD patients overweight potential losses compared with gains, though the neurobiological underpinnings of this bias are uncertain.
Twenty-one unmedicated patients with MDD were compared with 25 healthy controls (HC) using functional magnetic resonance imaging (fMRI) together with an economic decision-making task over mixed lotteries involving probabilistic gains and losses. Region-of-interest analyses evaluated neural signatures of gain and loss coding within a core network of brain areas known to be involved in valuation (anterior insula, caudate nucleus, ventromedial prefrontal cortex).
Usable fMRI data were available for 19 MDD and 23 HC subjects. Anterior insula signal showed negative coding of losses (gain > loss) in HC subjects consistent with previous findings, whereas MDD subjects demonstrated significant reversals in these associations (loss > gain). Moreover, depression severity further enhanced the positive coding of losses in anterior insula, ventromedial prefrontal cortex, and caudate nucleus. The hyper-responsivity to losses displayed by the anterior insula of MDD patients was paralleled by a reduced influence of gain, but not loss, stake size on choice latencies.
Patients with MDD demonstrate a significant shift from negative to positive coding of losses in the anterior insula, revealing the importance of this structure in value-based decision-making in the context of emotional disturbances.
Variation in human cognitive ability is of consequence to a large number of health and social outcomes and is substantially heritable. Genetic linkage, genome-wide association, and copy number variant studies have investigated the contribution of genetic variation to individual differences in normal cognitive ability, but little research has considered the role of rare genetic variants. Exome sequencing studies have already met with success in discovering novel trait-gene associations for other complex traits. Here, we use exome sequencing to investigate the effects of rare variants on general cognitive ability. Unrelated Scottish individuals were selected for high scores on a general component of intelligence (g). The frequency of rare genetic variants (in n = 146) was compared with those from Scottish controls (total n = 486) who scored in the lower to middle range of the g distribution or on a proxy measure of g. Biological pathway analysis highlighted enrichment of the mitochondrial inner membrane component and apical part of cell gene ontology terms. Global burden analysis showed a greater total number of rare variants carried by high g cases versus controls, which is inconsistent with a mutation load hypothesis whereby mutations negatively affect g. The general finding of greater non-synonymous (vs. synonymous) variant effects is in line with evolutionary hypotheses for g. Given that this first sequencing study of high g was small, promising results were found, suggesting that the study of rare variants in larger samples would be worthwhile.
Elevation of prolactin level is a known adverse effect of antipsychotics. Long-standing hyperprolactinaemia may inhibit reproductive function by impairing gonadal steroidogenesis and is associated with a number of adverse effects such as galactorrhoea, amenorrhoea, gynecomastia, impotence and decreased bone mineral density. Lurasidone is a recently approved atypical antipsychotic agent for the treatment of schizophrenia.
To compare the incidence of treatment-emergent adverse events (TEAEs) related to hyperprolactinaemia in patients treated with lurasidone or active comparators.
Pooled data from two 52-week studies that evaluated the long-term safety and efficacy of lurasidone compared with quetiapine XR or risperidone in patients with schizophrenia were reviewed post-hoc for prolactin levels and TEAEs considered to be related to hyperprolactinaemia.
Prolactin levels decreased marginally in the lurasidone group (median -8.00 pmol/L, N=624) and quetiapine XR group (median -17.39 pmol/L, N=85), and increased in the risperidone group (median 385.00 pmol/L, N=199) (LOCF). The incidence of markedly abnormally high prolactin values (≥5× upper limit of normal) was 2.0%, 1.4% and 4.0% in the three groups, respectively. The hyperprolactinaemia-related TEAEs breast mass, gynecomastia, breast enlargement, breast tenderness, hypogonadism, infertility, pituitary tumors and mammary gland tumors were absent from all groups. Low rates (≤2.5%) of galactorrhoea, amenorrhoea and erectile dysfunction were seen in the lurasidone and risperidone groups, while no TEAEs were recorded in the quetiapine XR group.
This post-hoc review shows that long-term treatment with lurasidone was not associated with a clinically significant increase in prolactin levels and the incidence of associated TEAEs was low.
rTMS is an emerging treatment for major depressive disorder (MDD) refractory to medications and psychotherapy. The conventional target for rTMS in MDD is the dorsolateral prefrontal cortex (DLPFC). However, convergent evidence from lesion, stimulation, and neuroimaging studies suggests that the dorsomedial prefrontal cortex (DMPFC) may play a more central role in emotion regulation. We have recently demonstrated robust and potentially superior antidepressant properties for excitatory rTMS of the DMPFC. However, one of the enduring limitations of rTMS is the long duration of each treatment session under conventional protocols, which require ~40 minutes per day over 20-30 sessions for maximum efficacy using conventional 10 Hz stimulation. More recent studies have suggested that theta-burst stimulation (TBS) protocols can achieve stronger and more durable effects in markedly less time. Intermittent theta-burst stimulation (iTBS) generates robust and long-lasting excitatory effects with 600 pulses over ~3 min. Pilot studies have previously reported antidepressant effects with TBS over the DLPFC. However, TBS over the DMPFC has not previously been studied. Here we report robust antidepressant effects for a 7 min course of iTBS, administered bilaterally over the DMPFC with MRI-guidance at 120% resting motor threshold, over 20-30 sessions, in an open-label series of 40 patients with refractory MDD. Safety, efficacy, and tolerability are comparable to a 10 Hz rTMS protocol requiring 30-40 min of treatment. iTBS of the DMPFC may effectively reduce the duration (and cost) of rTMS >4-fold, thus increasing patient capacity per clinic and improving the overall accessibility of rTMS in refractory MDD.
rTMS is currently being explored as a potential adjunctive treatment for anorexia and bulimia nervosa. Previous studies have found, at best, modest efficacy for rTMS in this setting using the conventional target in the dorsolateral prefrontal cortex (DLPFC). However, neuroimaging studies suggest that the dorsomedial prefrontal cortex (DMPFC) may be more central to inhibiting impulsive thoughts and behaviours such as binge and purge episodes. We have previously reported serendipitous rapid, complete, and durable remission of binge and purge behaviours in a patient with severe bulimia nervosa who was undergoing rTMS of the DMPFC for comorbid major depression (Downar et al., 2012). Here we extend this finding in a larger case series of 15 patients with either anorexia or bulimia nervosa and bingeing and purging behaviours refractory to medications and therapy despite several years of treatment. MRI-guided rTMS of the DMPFC (10 Hz stimulation, 120% resting motor threshold, bilateral, 3000 pulses per hemisphere) achieved full remission from binge and purge episodes in a majority of patients, with parallel improvements in mood and anxiety symptoms. Patients with BMI in the normal range showed a more robust response to treatment. Individual cases also spontaneously reported improvement in comorbid impulse control disorder symptoms, such as kleptomania. Individuals with comorbid obsessive-compulsive disorder (OCD) also reported marked improvements in these symptoms. A subset of patients with lower BMIs showed minimal response. rTMS of the DMPFC may represent an effective adjunct to conventional treatment for binge-purge behaviours. A randomized controlled trial of this approach may be warranted.
Patients with Obsessive-Compulsive Disorder (OCD) often show minimal response to either pharmacotherapy or psychotherapy. Repetitive transcranial magnetic stimulation (rTMS) is being explored as a new treatment for OCD. rTMS targeting the dorsolateral prefrontal cortex (DLPFC) has not shown robust efficacy; however, neuroimaging studies of OCD have shown more consistent volumetric grey matter reductions along the medial rather than the lateral prefrontal cortex, specifically in the dorsomedial prefrontal cortex (DMPFC). rTMS targeting medial motor areas such as the supplementary motor area (SMA) and pre-SMA has shown some efficacy in OCD. However, the DMPFC proper, just anterior to the pre-SMA, has not previously been targeted. We have previously used a novel rTMS technique to target DMPFC with robust effects in refractory depression. Here we apply this technique in an open-label series of 10 consecutive patients with refractory OCD. Under MRI-guidance, patients received bilateral DMPFC-rTMS at 10 Hz, 120% resting motor threshold, 6000 pulses per day for 20 - 30 sessions over 4-6 weeks. Robust improvements were achieved, with YBOCS scores dropping by more than half in the large majority of cases and full remission achieved in several cases. Scores continued dropping after treatment in some cases, suggesting durable improvements in capacity to suppress intrusive thoughts and behaviours. Improvements were durable at 3-6 months. Pre- and post-treatment functional MRI revealed changes in resting-state connectivity to DMPFC following treatment. A sham-controlled trial may be warranted as a next step. If successful, DMPFC-rTMS may represent a new, effective therapeutic option in refractory OCD.
We have used high-resolution, HST WFC3/IR, near-infrared imaging to conduct a detailed bulge-disk decomposition of the morphologies of ≃ 200 of the most massive (M* > 1011 M⊙) galaxies at 1 < z < 3 in the CANDELS-UDS field. We find that, while such massive galaxies at low redshift are generally bulge-dominated, at redshifts 1<z<2 they are predominantly mixed bulge+disk systems, and by z > 2 they are mostly disk-dominated. Interestingly, we find that while most of the quiescent galaxies are bulge-dominated, a significant fraction (25–40%) of the most quiescent galaxies, have disk-dominated morphologies. Thus, our results suggest that the physical mechanisms which quench star-formation activity are not simply connected to those responsible for the morphological transformation of massive galaxies.
We have exploited the new, deep, near-infrared Y,J,H,Ks UltraVISTA imaging of the COSMOS field, in tandem with deep optical and mid-infrared imaging, to conduct a new search for luminous galaxies at redshifts z ≃ 7. We have utilised this unique multi-wavelength dataset to select galaxy candidates at redshifts z > 6.5 by searching first for Y+J-detected objects which are undetected in the CFHT and HST optical data. This sample was then refined using a photometric redshift fitting code, enabling the rejection of lower-redshift galaxy contaminants and cool galactic M, L, T dwarf stars. The final result of this process is a small sample of (at most) ten credible galaxy candidates at z > 6.5 (from over 200,000 galaxies detected in the year-one UltraVISTA data). The new z ≃ 7 galaxies reported here are the first credible z ≃ 7 Lyman-break galaxies discovered in the COSMOS field and, as the most UV-luminous discovered to date at these redshifts, are prime targets for deep follow-up spectroscopy. We explore their physical properties, and briefly consider the implications of their inferred number density for the form of the galaxy luminosity function at z ≃ 7.
Treatment nonadherence is a concern among patients with bipolar disorder and posttraumatic stress disorder (PTSD). PTSD is common among patients with bipolar disorder and those with this comorbidity often have a more severe course of illness. While many factors have been associated with nonadherence in bipolar disorder patients and in PTSD patients, almost no research has focused on the factors associated with non-adherence in bipolar disorder patients with comorbid PTSD. Studies in primary bipolar disorder samples reveal patient, illness, drug and clinician characteristics associated with nonadherence while studies in primary PTSD samples reveal a significantly shorter list of patient, illness and drug characteristics. Shared risk factors between these two populations and the characteristics that predict noncompliance in only one population but often present in the other, suggest a high likelihood of nonadherence in the bipolar disorder-PTSD population. For bipolar disorder-PTSD patients with early childhood trauma, noncompliance may be related to the trauma-related meanings attributed to interactions with their physicians and their prescribed medications. Given the high side effect burden of bipolar disorder treatments and the importance of lifelong adherence, clinicians should vigilantly monitor for nonadherence in their bipolar disorder-PTSD patients and be particularly aware of patient-physician psychodynamics that might contribute to this behavior.
Nonlinear wave-driven processes in plasmas are normally described by either a monochromatic pump wave that couples to other monochromatic waves, or as a random phase wave coupling to other random phase waves. An alternative approach involves a random or broadband pump coupling to monochromatic and/or coherent structures in the plasma. This approach can be implemented through the wave-kinetic model. In this model, the incoming pump wave is described by either a bunch (for coherent waves) or a sea (for random phase waves) of quasi-particles. This approach has been applied to both photon acceleration in laser wakefields and drift wave turbulence in magnetized plasma edge configurations. Numerical simulations have been compared to experiments, varying from photon acceleration to drift mode-zonal flow turbulence, and good qualitative correspondences have been found in all cases.
The effects of deficit irrigation (DI) and partial rootzone drying (PRD) on the growth and mineral nutrition of citrus rootstock seedlings in the glasshouse were determined, as well as the potential of DI and PRD to trigger root-to-shoot signalling of abscisic acid (ABA) to increase the growth per amount of water used (water use efficiency (WUE)). In the DI study, 3-month-old seedlings of the important citrus rootstock Swingle citrumelo with intact roots received three irrigation treatments: control (1·00 evapotranspiration (ET)), 0·75 ET and 0·50 ET. DI clearly decreased growth, the net assimilation of CO2 (ACO2), WUE and the total content of N and K in leaves, even though concentrations of leaf N and K were increased in the drought-stressed smaller plants. Root K was not affected by DI treatments. Leaf ABA concentration increased linearly with DI. For the PRD study, root systems of 6-month-old Swingle citrumelo were split into half and allowed to become established in adjacent pots. There were three irrigation treatments: control (1·00 of the total crop ET, 0·50 in each pot), PRD 50-0 (0·50 ET by weight applied to only one-half of root zone) and DI 25-25 (0·50 ET in total, with 0·25 ET applied to each root half). Although the total root length was decreased by the DI 25-25 treatment, PRD 50-0 did not affect any growth characteristics compared to control plants. The dry root zone of the PRD 50-0 treatment had a higher specific root length, longer roots per dry weight, than the wet root zone. Leaf ACO2 and WUE of the DI 25-25 treatment were significantly lower than control plants after 11 weeks. Although the total contents of N and K in leaves were not affected by either PRD treatment, the concentrations of N and K in leaves were increased by DI 25-25. Root K was decreased by PRD treatments. Leaf ABA concentration was increased by PRD 50-0 but not by DI 25-25. Although all drought stress treatments increased the levels of ABA in leaves, DI and PRD treatments did not affect the whole plant WUE. Compared to well-irrigated control plants, DI reduced growth, whereas PRD 50-0 did not.
The Late Carboniferous whip spider Graeophonus anglicus Pocock, 1911 (Arachnida: Amblypygi), is redescribed on the basis of the holotype and nine other specimens all preserved in sideritic nodules from the British Middle Coal Measures of Coseley, Staffordshire, UK. This species is clearly basal with respect to most living whip spiders, expressing numerous plesiomorphic character states and can be referred to both the suborder Paleoamblypygi and the ‘living fossil’ family Paracharontidae (with one Recent species), the latter based on an explict character of dorsal spination on the pedipalp femur. This suggests that crown-group Amblypygi originated by at least the mid-Palaeozoic.