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Schmidt-hammer exposure-age dating (SHD) was applied at 15 sites with glacially-transported granite boulders in parts of northern and western Ireland and southwest Scotland that had been exposed by retreat of the last British-Irish Ice Sheet (BIIS) or Younger Dryas (YD) ice masses. Seven of these surfaces had previously been dated using terrestrial cosmogenic nuclide (TCN) exposure-age dating. Application of the granite calibration equation of Tomkins et al. (2018c) indicated a close correspondence between the SHD ages and the TCN ages (within 1σ or 2σ uncertainties). These findings demonstrate that SHD ages can be of comparable accuracy, precision, and reliability to TCN ages and are a strong argument for the more extensive use of SHD in some Quaternary dating projects. However, surface ages obtained by both SHD and TCN dating should not be accepted uncritically; they must be assessed in relation to the wider geological, geomorphological, and geochronological evidence. Evaluation of eight SHD ages, for which corresponding TCN ages are not available, indicate that most are consistent with current theory and field evidence, but some anomalous age estimates occur.
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 first fossil potentially assignable to the extant hard tick genus Haemaphysalis CL Koch (1844) (Ixodida: Ixodidae) is described from the Late Cretaceous (ca. 99 Ma) Burmese amber of Myanmar. Haemaphysalis (Alloceraea) cretacea sp. nov. is the oldest and only fossil representative of this genus; living members of which predominantly feed on mammals. Their typical hosts are known since at least the Jurassic and the discovery of a mid-Cretaceous parasite, which might have fed on mammals raises again the question of to what extent ticks are coupled to their (modern) host groups. An inferred Triassic split of Argasidae (soft ticks) into the bird-preferring Argasinae and mammal-preferring Ornithodorinae dates to about the time when dinosaurs (later including birds) and mammaliaforms as potential hosts were emerging. Ixodidae may have split into Prostriata and Metastriata shortly after the end-Permian mass extinction, an event which fundamentally altered the terrestrial vertebrate fauna. Prostriata (the genus Ixodes) prefer birds and mammals today, and some may have used groups like cynodonts in the Triassic. Basal metastriate ticks (e.g. Amblyomma) prefer reptiles, but derived metastriates (including Haemaphysalis) again prefer mammals. Here, we may be looking at a younger (Cretaceous?) shift associated with more recent mammalian radiations.
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.
Tanzania is, like most countries in East Africa, extremely culturally and linguistically diverse. Language counts range from 125 (Lewis, Simons & Fennig, 2016) to 164 living languages mentioned by the ‘Languages of Tanzania project’ (2009). Given this extreme multilingualism, institutional languages had to be chosen on a national level after independence. Kiswahili is the proclaimed national language and lingua franca of the East African region, also spoken in Kenya, Uganda and the Democratic Republic of Congo, for instance, and is used as medium of instruction (MoI) in primary education. English, the former colonial language, is the de facto national working language and medium of instruction in secondary and higher education. However, English remains a minority language, spoken by approximately 5% of the population, most of whom are members of a higher social class (Tibategeza, 2010). This leads to English being an international rather than a second language as in other former British colonies (Schmied, 1990, 1991). Rubanza (2002: 45) goes so far as to argue that ‘the society Tanzanians work and live in does not demand the use of English’. That is why it has been claimed that English will never replace the African languages in Tanzania but remain an additional language in certain spheres (Schmied, 1991).
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.
Amblyomma birmitum sp. nov. is formally described as a new record from 99 Ma old Burmese amber from Myanmar. This confirms the presence of the extant hard tick genus Amblyomma C.L. Koch, 1844 (Ixodida: Ixodidae) in the Late Cretaceous. This discovery is placed in its wider context and some reports of fossil hard ticks, such as a Hyalomma C.L. Koch, 1844 in Eocene Baltic amber, are misidentifications. The genus Amblyomma belongs to the clade Metastriata, a group which probably also accommodates two extinct genera, Cornupalpatum Poinar and Brown, 2003 and Compluriscutata Poinar and Buckley, 2008, also found in Burmese amber. All three fossils are thus only a little younger than published molecular divergence time estimates (ca. 124 ± 17 Ma) for the Metastriata lineage. Amblyomma has a largely Gondwanan distribution today. However, in some biogeographical scenarios, e.g. the Samafrica model, its predicted radiation time postdates the dissolution of the original Gondwana supercontinent raising questions about how its current distribution pattern was achieved.
Naziha Khen-Dunlop, Department of Paediatric Surgery, Necker-Enfants Malades Hospital, Paris, France,
Guillaume Lezmi, Department of Paediatric Pulmonology, Necker-Enfants Malades Hospital, Paris, France,
Christophe Delacourt, Department of Paediatric Pulmonology, Necker-Enfants Malades Hospital, Paris, France,
Yann Revillon, Departments of Paediatric Surgery, Necker-Enfants Malades Hospital, Paris, France
• There are three main congenital lung malformations: cystic forms also named congenital pulmonary airway malformation (CPAM), broncho-pulmonary sequestrations (BPS) and congenital lobar emphysema also named congenital alveolar overdistension. Among them, cystic lung malformations are the most frequent.
• Cystic lung malformations are focal and occur sporadically, suggesting they result from a defect in normal lung development rather from a genetic abnormality.
• The description of hybrid malformation, associating CPAM and sequestration features and the observation of microcystic elements in about half of extralobar sequestrations reflect the complex status of pulmonary malformations.
• Prenatal mediastinal shift is observed in 50% of CPAM and polyhydramnios in 20% of cases; both of these signs do not have to be interpreted as complications and do not lead to impaired lung development or fetal distress. On the opposite, hydrops is present in about 10% of cases and is associated to fetal or neonatal death in more than 95%.
• The ‘disappearance’ of congenital malformations of the lung on last prenatal ultrasound was classically described and interpreted as a complete regression of the malformation, but such evolution is exceptional and only documented for sequestrations. Post-natal thoracic imaging (MRI or CT scan) is required to check the persistence of congenital lung malformations regardless of the prenatal evolution.
• Cystic lesions are congenital lung malformations for which complications are most often reported. Respiratory impairment and lung infection are the two main symptoms but, although exceptional, they are associated to malignant degeneration. If non-operated, asymptomatic cystic lesions have to be followedup into adulthood.
• Over 90% of bronchopulmonary sequestrations are found in the thorax, and less than 10% are located in the abdomen. As respiratory symptoms are rare and no malignancy reported, expectance can then be proposed, provided that there is no cystic component.
• Progressive respiratory signs, secondary to lobar overinflation, are the most common symptoms in congenital lobar emphysema. Signs may have a favourable evolution with clinical and ventilatory parameter improvements. In case of respiratory distress, surgical excision of the malformation is necessary.
Important publications in the speciality
• Morrisey E, Hogan B. Preparing for the first breath: genetic and cellular mechanisms in lung development. Dev Cell 2010; 18:8–23.
We have conducted 1.1 mm ALMA observations of a contiguous 105” × 50” or 1.5 arcmin2 window in the SXDF-UDS-CANDELS. We achieved a 5σ sensitivity of 0.28 mJy, giving a flat sensus of dusty star-forming galaxies with LIR ~6×1011L⊙ (if Tdust=40K) up to z ~ 10 thanks to the negative K-correction at this wavelength. We detected 5 brightest sources (S/N>6) and 18 low-significant sources (5>S/N>4; they may contain spurious detections, though). One of the 5 brightest ALMA sources (S1.1mm = 0.84 ± 0.09 mJy) is extremely faint in the WFC3 and VLT/HAWK-I images, demonstrating that a contiguous ALMA imaging survey uncovers a faint dust-obscured population invisible in the deep optical/near-infrared surveys. We find a possible [CII]-line emitter at z=5.955 or a low-z CO emitting galaxy within the field, allowing us to constrain the [CII] and/or CO luminosity functions across the history of the universe.
Discussion about the official or national language in Tanzania is basically a discussion about Kiswahili and English. These two languages have been competing for official status in Tanzania since Tanganyika (Tanganyika refers to the Tanzania mainland before it united with Zanzibar in 1964) gained its independence from Britain in 1961 (Rubagumya, 1991; Schmied 1991: 195; Mulokozi, 2010). Yahya-Othman & Batibo (1996) describe the competition between English and Kiswahili in Tanzania as a swinging pendulum. In a certain period of time, the status of English rises, and in another period of time the status of Kiswahili rises, and vice versa.
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.
In this article, we present some major lessons drawn from a recently completed research project. Our research dealt with ex ante evaluation, mainly impact assessment (IA).We shed new light on research questions about the control of bureaucracy, the role of IA in decisionmaking, economics and policy learning, and the narrative dimension of appraisal.We identify how our findings stand in relation to conventional arguments about these issues, and reflect on their normative implications. We finally reason on the possible extensions of our arguments to the wider field of policy evaluation, connecting IA and ex post evaluation.