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Blood biomarkers of Alzheimer's disease (AD) may allow for the early detection of AD pathology in mild cognitive impairment (MCI) due to AD (MCI-AD) and as a co-pathology in MCI with Lewy bodies (MCI-LB). However not all cases of MCI-LB will feature AD pathology. Disease-general biomarkers of neurodegeneration, such as glial fibrillary acidic protein (GFAP) or neurofilament light (NfL), may therefore provide a useful supplement to AD biomarkers. We aimed to compare the relative utility of plasma Aβ42/40, p-tau181, GFAP and NfL in differentiating MCI-AD and MCI-LB from cognitively healthy older adults, and from one another.
Plasma samples were analysed for 172 participants (31 healthy controls, 48 MCI-AD, 28 possible MCI-LB and 65 probable MCI-LB) at baseline, and a subset (n = 55) who provided repeated samples after ≥1 year. Samples were analysed with a Simoa 4-plex assay for Aβ42, Aβ40, GFAP and NfL, and incorporated previously-collected p-tau181 from this same cohort.
Probable MCI-LB had elevated GFAP (p < 0.001) and NfL (p = 0.012) relative to controls, but not significantly lower Aβ42/40 (p = 0.06). GFAP and p-tau181 were higher in MCI-AD than MCI-LB. GFAP discriminated all MCI subgroups, from controls (AUC of 0.75), but no plasma-based marker effectively differentiated MCI-AD from MCI-LB. NfL correlated with disease severity and increased with MCI progression over time (p = 0.011).
Markers of AD and astrocytosis/neurodegeneration are elevated in MCI-LB. GFAP offered similar utility to p-tau181 in distinguishing MCI overall, and its subgroups, from healthy controls.
To understand which anthropometric diagnostic criteria best discriminate higher from lower risk of death in children and explore programme implications.
A multiple cohort individual data meta-analysis of mortality risk (within 6 months of measurement) by anthropometric case definitions. Sensitivity, specificity, informedness and inclusivity in predicting mortality, face validity and compatibility with current standards and practice were assessed and operational consequences were modelled.
Community-based cohort studies in twelve low-income countries between 1977 and 2013 in settings where treatment of wasting was not widespread.
Children aged 6 to 59 months.
Of the twelve anthropometric case definitions examined, four (weight-for-age Z-score (WAZ) <−2), (mid-upper arm circumference (MUAC) <125 mm), (MUAC < 115 mm or WAZ < −3) and (WAZ < −3) had the highest informedness in predicting mortality. A combined case definition (MUAC < 115 mm or WAZ < −3) was better at predicting deaths associated with weight-for-height Z-score <−3 and concurrent wasting and stunting (WaSt) than the single WAZ < −3 case definition. After the assessment of all criteria, the combined case definition performed best. The simulated workload for programmes admitting based on MUAC < 115 mm or WAZ < −3, when adjusted with a proxy for required intensity and/or duration of treatment, was 1·87 times larger than programmes admitting on MUAC < 115 mm alone.
A combined case definition detects nearly all deaths associated with severe anthropometric deficits suggesting that therapeutic feeding programmes may achieve higher impact (prevent mortality and improve coverage) by using it. There remain operational questions to examine further before wide-scale adoption can be recommended.
To compare the prognostic value of mid-upper arm circumference (MUAC), weight-for-height Z-score (WHZ) and weight-for-age Z-score (WAZ) for predicting death over periods of 1, 3 and 6 months follow-up in children.
Pooled analysis of twelve prospective studies examining survival after anthropometric assessment. Sensitivity and false-positive ratios to predict death within 1, 3 and 6 months were compared for three individual anthropometric indices and their combinations.
Community-based, prospective studies from twelve countries in Africa and Asia.
Children aged 6–59 months living in the study areas.
For all anthropometric indices, the receiver operating characteristic curves were higher for shorter than for longer durations of follow-up. Sensitivity was higher for death with 1-month follow-up compared with 6 months by 49 % (95 % CI (30, 69)) for MUAC < 115 mm (P < 0·001), 48 % (95 % CI (9·4, 87)) for WHZ < -3 (P < 0·01) and 28 % (95 % CI (7·6, 42)) for WAZ < -3 (P < 0·005). This was accompanied by an increase in false positives of only 3 % or less. For all durations of follow-up, WAZ < -3 identified more children who died and were not identified by WHZ < -3 or by MUAC < 115 mm, 120 mm or 125 mm, but the use of WAZ < -3 led to an increased false-positive ratio up to 16·4 % (95 % CI (12·0, 20·9)) compared with 3·5 % (95 % CI (0·4, 6·5)) for MUAC < 115 mm alone.
Frequent anthropometric measurements significantly improve the identification of malnourished children with a high risk of death without markedly increasing false positives. Combining two indices increases sensitivity but also increases false positives among children meeting case definitions.
Researchers in the decision making tradition usually analyze multiple decisions within experiments by aggregating choices across individuals and using the individual subject as the unit of analysis. This approach can mask important variations and patterns within the data. Specifically, it ignores variations in decisions across a task or game and possible influences of characteristics of the subject or the experiment on these variations. We demonstrate, by reanalyzing data from two previously published articles, how a mixed model analysis addresses these limitations. Our results, with a modified Iowa gambling task and a prisoner's dilemma game, illustrate the ways in which such an analysis can test hypotheses not possible with other techniques, is more parsimonious, and is more likely to be faithful to theoretical models.
Double-cropping winter rye cover crops (CC) with soybean in the North Central US could help with the global effort to sustainably intensify agriculture. Studies addressing the management of these systems are limited. Therefore, a field study was conducted from 2017 to 2019 in Central Iowa, US to evaluate winter rye CC biomass production, aboveground N accumulation, estimated economics, estimated within-field energy balance and estimated greenhouse gas (GHG) emissions under three N application rates (0, 60, 120 kg N ha−1) and three planting methods (pre- and post-harvest broadcast and post-harvest drilling). Averaged over N rates, all planting methods resulted in >5.0 Mg ha−1 year−1 rye aboveground biomass dry matter. Averaged over the 2-year study and compared with unfertilized treatments, applying 60 kg N ha−1 produced 1.1 Mg ha−1 more aboveground biomass (6.1 vs 5.0 Mg ha−1), accumulated 30 kg ha−1 more N in aboveground biomass (88 vs 58 kg N ha−1), and led to 20 GJ ha−1 more net energy. Biomass production was not significantly higher with 120 kg N ha−1 compared with the 60 kg N ha−1 rate. Even when accounting for an estimated 0.75 Mg ha−1 of above ground rye biomass left in the field after harvesting, more N was removed than applied at the 60 kg N ha−1 rate. The minimum rye prices over the 2-year study needed for double-cropping winter rye CC to be profitable (breakeven prices) averaged $117 and $104 Mg−1 for the 0 and 60 kg N ha−1 rates, which factors in estimated soybean yield reductions in 2019 compared with local averages but not off-site transportation. GHG emissions were estimated to increase approximately threefold between the unfertilized and 60 kg N ha−1 rates without considering bioenergy offsets. While environmental tradeoffs need further study, results suggest harvesting fertilized rye CC biomass before planting soybean is a promising practice for the North Central US to maximize total crop and net energy production.
To examine the costs and cost-effectiveness of mirtazapine compared to placebo over 12-week follow-up.
Economic evaluation in a double-blind randomized controlled trial of mirtazapine vs. placebo.
Community settings and care homes in 26 UK centers.
People with probable or possible Alzheimer’s disease and agitation.
Primary outcome included incremental cost of participants’ health and social care per 6-point difference in CMAI score at 12 weeks. Secondary cost-utility analyses examined participants’ and unpaid carers’ gain in quality-adjusted life years (derived from EQ-5D-5L, DEMQOL-Proxy-U, and DEMQOL-U) from the health and social care and societal perspectives.
One hundred and two participants were allocated to each group; 81 mirtazapine and 90 placebo participants completed a 12-week assessment (87 and 95, respectively, completed a 6-week assessment). Mirtazapine and placebo groups did not differ on mean CMAI scores or health and social care costs over the study period, before or after adjustment for center and living arrangement (independent living/care home). On the primary outcome, neither mirtazapine nor placebo could be considered a cost-effective strategy with a high level of confidence. Groups did not differ in terms of participant self- or proxy-rated or carer self-rated quality of life scores, health and social care or societal costs, before or after adjustment.
On cost-effectiveness grounds, the use of mirtazapine cannot be recommended for agitated behaviors in people living with dementia. Effective and cost-effective medications for agitation in dementia remain to be identified in cases where non-pharmacological strategies for managing agitation have been unsuccessful.
The transition from military service to civilian life is a high-risk period for suicide attempts (SAs). Although stressful life events (SLEs) faced by transitioning soldiers are thought to be implicated, systematic prospective evidence is lacking.
Participants in the Army Study to Assess Risk and Resilience in Servicemembers (STARRS) completed baseline self-report surveys while on active duty in 2011–2014. Two self-report follow-up Longitudinal Surveys (LS1: 2016–2018; LS2: 2018–2019) were subsequently administered to probability subsamples of these baseline respondents. As detailed in a previous report, a SA risk index based on survey, administrative, and geospatial data collected before separation/deactivation identified 15% of the LS respondents who had separated/deactivated as being high-risk for self-reported post-separation/deactivation SAs. The current report presents an investigation of the extent to which self-reported SLEs occurring in the 12 months before each LS survey might have mediated/modified the association between this SA risk index and post-separation/deactivation SAs.
The 15% of respondents identified as high-risk had a significantly elevated prevalence of some post-separation/deactivation SLEs. In addition, the associations of some SLEs with SAs were significantly stronger among predicted high-risk than lower-risk respondents. Demographic rate decomposition showed that 59.5% (s.e. = 10.2) of the overall association between the predicted high-risk index and subsequent SAs was linked to these SLEs.
It might be possible to prevent a substantial proportion of post-separation/deactivation SAs by providing high-risk soldiers with targeted preventive interventions for exposure/vulnerability to commonly occurring SLEs.
Impaired olfaction may be a biomarker for early Lewy body disease, but its value in mild cognitive impairment with Lewy bodies (MCI-LB) is unknown. We compared olfaction in MCI-LB with MCI due to Alzheimer’s disease (MCI-AD) and healthy older adults. We hypothesized that olfactory function would be worse in probable MCI-LB than in both MCI-AD and healthy comparison subjects (HC).
Cross-sectional study assessing olfaction using Sniffin’ Sticks 16 (SS-16) in MCI-LB, MCI-AD, and HC with longitudinal follow-up. Differences were adjusted for age, and receiver operating characteristic (ROC) curves were used for discriminating MCI-LB from MCI-AD and HC.
Participants were recruited from Memory Services in the North East of England.
Thirty-eight probable MCI-LB, 33 MCI-AD, 19 possible MCI-LB, and 32HC.
Olfaction was assessed using SS-16 and a questionnaire.
Participants with probable MCI-LB had worse olfaction than both MCI-AD (age-adjusted mean difference (B) = 2.05, 95% CI: 0.62–3.49, p = 0.005) and HC (B = 3.96, 95% CI: 2.51–5.40, p < 0.001). The previously identified cutoff score for the SS-16 of ≤ 10 had 84% sensitivity for probable MCI-LB (95% CI: 69–94%), but 30% specificity versus MCI-AD. ROC analysis found a lower cutoff of ≤ 7 was better (63% sensitivity for MCI-LB, with 73% specificity vs MCI-AD and 97% vs HC). Asking about olfactory impairments was not useful in identifying them.
MCI-LB had worse olfaction than MCI-AD and normal aging. A lower cutoff score of ≤ 7 is required when using SS-16 in such patients. Olfactory testing may have value in identifying early LB disease in memory services.
The present study aimed to clarify the neuropsychological profile of the emergent diagnostic category of Mild Cognitive Impairment with Lewy bodies (MCI-LB) and determine whether domain-specific impairments such as in memory were related to deficits in domain-general cognitive processes (executive function or processing speed).
Patients (n = 83) and healthy age- and sex-matched controls (n = 34) underwent clinical and imaging assessments. Probable MCI-LB (n = 44) and MCI-Alzheimer’s disease (AD) (n = 39) were diagnosed following National Institute on Aging-Alzheimer’s Association (NIA-AA) and dementia with Lewy bodies (DLB) consortium criteria. Neuropsychological measures included cognitive and psychomotor speed, executive function, working memory, and verbal and visuospatial recall.
MCI-LB scored significantly lower than MCI-AD on processing speed [Trail Making Test B: p = .03, g = .45; Digit Symbol Substitution Test (DSST): p = .04, g = .47; DSST Error Check: p < .001, g = .68] and executive function [Trail Making Test Ratio (A/B): p = .04, g = .52] tasks. MCI-AD performed worse than MCI-LB on memory tasks, specifically visuospatial (Modified Taylor Complex Figure: p = .01, g = .46) and verbal (Rey Auditory Verbal Learning Test: p = .04, g = .42) delayed recall measures. Stepwise discriminant analysis correctly classified the subtype in 65.1% of MCI patients (72.7% specificity, 56.4% sensitivity). Processing speed accounted for more group-associated variance in visuospatial and verbal memory in both MCI subtypes than executive function, while no significant relationships between measures were observed in controls (all ps > .05)
MCI-LB was characterized by executive dysfunction and slowed processing speed but did not show the visuospatial dysfunction expected, while MCI-AD displayed an amnestic profile. However, there was considerable neuropsychological profile overlap and processing speed mediated performance in both MCI subtypes.
Electroencephalographic (EEG) abnormalities are greater in mild cognitive impairment (MCI) with Lewy bodies (MCI-LB) than in MCI due to Alzheimer’s disease (MCI-AD) and may anticipate the onset of dementia. We aimed to assess whether quantitative EEG (qEEG) slowing would predict a higher annual hazard of dementia in MCI across these etiologies. MCI patients (n = 92) and healthy comparators (n = 31) provided qEEG recording and underwent longitudinal clinical and cognitive follow-up. Associations between qEEG slowing, measured by increased theta/alpha ratio, and clinical progression from MCI to dementia were estimated with a multistate transition model to account for death as a competing risk, while controlling for age, cognitive function, and etiology classified by an expert consensus panel.
Over a mean follow-up of 1.5 years (SD = 0.5), 14 cases of incident dementia and 5 deaths were observed. Increased theta/alpha ratio on qEEG was associated with increased annual hazard of dementia (hazard ratio = 1.84, 95% CI: 1.01–3.35). This extends previous findings that MCI-LB features early functional changes, showing that qEEG slowing may anticipate the onset of dementia in prospectively identified MCI.
Studying phenotypic and genetic characteristics of age at onset (AAO) and polarity at onset (PAO) in bipolar disorder can provide new insights into disease pathology and facilitate the development of screening tools.
To examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics.
Genome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (n = 12 977) and PAO (n = 6773) were conducted in patients with bipolar disorder from 34 cohorts and a replication sample (n = 2237). The association of onset with disease characteristics was investigated in two of these cohorts.
Earlier AAO was associated with a higher probability of psychotic symptoms, suicidality, lower educational attainment, not living together and fewer episodes. Depressive onset correlated with suicidality and manic onset correlated with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in single-nucleotide variant-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased PGS for autism spectrum disorder (β = −0.34 years, s.e. = 0.08), major depression (β = −0.34 years, s.e. = 0.08), schizophrenia (β = −0.39 years, s.e. = 0.08), and educational attainment (β = −0.31 years, s.e. = 0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO.
AAO and PAO are associated with indicators of bipolar disorder severity. Individuals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents and phenotype definitions introduce significant heterogeneity, affecting analyses.
Adolescent females are at elevated risk for the development of depression. In this study, we addressed two questions: Are pubertal hormones associated with adolescent mental health? Might this association depend on pubertal development? We tested the hypothesis that estradiol, which has been associated with adolescent social sensitivity, might interact with pubertal stage to predict depression risk at three time points in ninth and tenth grade. Hormones and pubertal development were measured ninth-grade females. Linear regression analyses were used to predict fall ninth-grade (N = 79), spring ninth-grade (N = 76), and spring tenth-grade (N = 67) Children's Depression Inventory (CDI) scores. The hypothesized model was not statistically significant, but exploratory analyses revealed that two- and three-way interactions incorporating estradiol, puberty (stage and perceived onset), and cortisol predicted current and future CDI scores. Our exploratory model did not predict changes in CDI but did account for future (spring of ninth grade) CDI scores. Specifically, estradiol was positively correlated with fall and spring ninth-grade depressive symptoms in participants with high cortisol who also reported earlier stages and later perceived onset of pubertal development. These findings suggest that hormones associated with sensitivity to the social environment deserve consideration in models of adolescent depression risk.
Dopaminergic imaging is an established biomarker for dementia with Lewy bodies, but its diagnostic accuracy at the mild cognitive impairment (MCI) stage remains uncertain.
To provide robust prospective evidence of the diagnostic accuracy of dopaminergic imaging at the MCI stage to either support or refute its inclusion as a biomarker for the diagnosis of MCI with Lewy bodies.
We conducted a prospective diagnostic accuracy study of baseline dopaminergic imaging with [123I]N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane single-photon emission computerised tomography (123I-FP-CIT SPECT) in 144 patients with MCI. Images were rated as normal or abnormal by a panel of experts with access to striatal binding ratio results. Follow-up consensus diagnosis based on the presence of core features of Lewy body disease was used as the reference standard.
At latest assessment (mean 2 years) 61 patients had probable MCI with Lewy bodies, 26 possible MCI with Lewy bodies and 57 MCI due to Alzheimer's disease. The sensitivity of baseline FP-CIT visual rating for probable MCI with Lewy bodies was 66% (95% CI 52–77%), specificity 88% (76–95%) and accuracy 76% (68–84%), with positive likelihood ratio 5.3.
It is over five times as likely for an abnormal scan to be found in probable MCI with Lewy bodies than MCI due to Alzheimer's disease. Dopaminergic imaging appears to be useful at the MCI stage in cases where Lewy body disease is suspected clinically.
Perinatal mental illnesses are a major public health issue, which untreated can have devastating impacts on women and their families. Problems with emotion regulation are a common feature across perinatal mental illnesses.
This study sought to evaluate the impacts of dialectical behaviour therapy (DBT) skills groups for mothers and babies in a community perinatal service. We hypothesised that community perinatal DBT skills groups that included babies would reduce distress and improve emotional regulation.
A mixed-methods within-subjects design was utilised with outcome measures collected pre- and post-intervention. Qualitative interviews exploring mothers’ experiences of bringing their baby to group were also conducted.
Results indicated that DBT skills groups significantly improved levels of psychological distress and emotional regulation.
Community perinatal DBT skills groups are effective when babies are present. Moreover, benefits of including babies were identified, under the themes of Self as Mother, Shared Experience, and Impact of Babies.
Archaeologists have long subjected Clovis megafauna kill/scavenge sites to the highest level of scrutiny. In 1987, a Columbian mammoth (Mammuthus columbi) was found in spatial association with a small artifact assemblage in Converse County, Wyoming. However, due to the small tool assemblage, limited nature of the excavations, and questions about the security of the association between the artifacts and mammoth remains, the site was never included in summaries of human-killed/scavenged megafauna in North America. Here we present the results of four field seasons of new excavations at the La Prele Mammoth site that confirm the presence of an associated cultural occupation based on geologic context, artifact attributes, spatial distributions, protein residue analysis, and lithic microwear analysis. This new work identified a more extensive cultural occupation including the presence of multiple discrete artifact clusters in close proximity to the mammoth bone bed. This study confirms the presence of a second Clovis mammoth kill/scavenge site in Wyoming and shows the value in revisiting proposed terminal Pleistocene kill/scavenge sites.
Perfectionism is a transdiagnostic risk factor across psychopathology. The Clinical Perfectionism Questionnaire (CPQ) was developed to assess change in order to provide clinical utility, but currently the psychometric properties of the CPQ with adolescents is unknown.
To assess the factor structure and construct validity of the CPQ in female adolescents.
The CPQ was administered to 267 females aged 14–19 years of age. Confirmatory factor analysis (CFA) was used to examine the validity of the two-factor model and a second-order factor model. Pearson correlations were used to evaluate the relationships between the CPQ and a wide range of measures of perfectionism, psychopathology and personality traits.
The study demonstrated internal consistency, construct validity and incremental validity of the CPQ in a sample of female adolescents. The CFA in the present study confirmed the two-factor model of the CPQ with Factor 1 relating to perfectionistic strivings and Factor 2 representing perfectionistic concerns. The second-order two factor model indicated no deterioration in fit.
The two-factor model of the CPQ fits with the theoretical definition of clinical perfectionism where the over-dependence of self-worth on achievement and concern over mistakes are key elements. The CPQ is suitable for use with female adolescents in future research that seeks to better understand the role of perfectionism in the range of mental illnesses that impact youth.
Both India and Nepal are prone to a wide range of natural and man-made disasters. Almost 85% of India’s area is vulnerable to one or more hazards, and more than 80% of the total population of Nepal is at risk of natural hazards. In terms of the number of people affected in reported disastrous events, India is in the top 10 and Nepal is in the top 20 globally. Over the last two decades, India and Nepal have taken steps to establish their respective National Disaster Management organizations, which provide essential disaster responses. However, key gaps still remain in trained clinical capacity for managing impacts from various disasters. Our review of the region has shown that large parts of the population suffer injuries, diseases, disabilities, psychosocial, and other health-related problems from disasters.
Develop disaster medicine clinical capacity to reduce morbidities and mortalities from disasters.
Independent published data and work undertaken by the lead author in various disasters in India and Nepal since 1993 formed the basis of establishing the Faculty of Disaster Medicine for South Asia. The Faculty of Disaster Medicine - India and Nepal (FDMIN) was launched from Pune in March 2015. This initiative is supported by the National Association of Primary Care (UK), Public Health England, Faculty of Pre-hospital Care of Royal College of Surgeons - Edinburgh and CRIMEDIM (Novara) - Italy.
FDMIN has international expert advisors and has outlined 16 modules training curriculum for health care professionals. FDMIN currently has partnerships for teaching disaster medicine program with 3 medical universities and 12 major health care providers. Six pilot training programmes have been conducted in Pune, Delhi, Chennai, and Kochin. Work is underway to submit an application to the Indian regulatory bodies for approval to establish a post-graduate diploma and Master’s for Disaster Medicine.