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The rift setting of eastern Africa preserves exceptional records of mammalian (including hominin) fossils and archeology. The Afar region is host to multiple deposits with sediments ranging in age from>9 Ma to the present (Chorowicz, 2005; Katoh et al., 2016) and plays a major role in our understanding of human origins. The Gona project area contains fossiliferous deposits that span ca. 6.3 to <0.15 Ma (Quade et al., 2008); the duration of this record means that it can make a distinct contribution to understanding the environmental context for human evolution within the Afar and in eastern Africa (Figures 17.1 and 17.2). The primary units at Gona include the late Miocene Adu-Asa Formation, which contains fossils of Ardipithecus kaddaba; the early Pliocene Sagantole Formation with fossils of Ardipithecus ramidus; the mid- to late-Pliocene Hadar Formation; and the Busidima Formation (ca. 2.7 Ma to <0.15 Ma), which contains a record of the earliest Oldowan stone tools, fossils of Homo erectus, and Acheulean artifacts (Figure 17.2).
Response to lithium in patients with bipolar disorder is associated with clinical and transdiagnostic genetic factors. The predictive combination of these variables might help clinicians better predict which patients will respond to lithium treatment.
To use a combination of transdiagnostic genetic and clinical factors to predict lithium response in patients with bipolar disorder.
This study utilised genetic and clinical data (n = 1034) collected as part of the International Consortium on Lithium Genetics (ConLi+Gen) project. Polygenic risk scores (PRS) were computed for schizophrenia and major depressive disorder, and then combined with clinical variables using a cross-validated machine-learning regression approach. Unimodal, multimodal and genetically stratified models were trained and validated using ridge, elastic net and random forest regression on 692 patients with bipolar disorder from ten study sites using leave-site-out cross-validation. All models were then tested on an independent test set of 342 patients. The best performing models were then tested in a classification framework.
The best performing linear model explained 5.1% (P = 0.0001) of variance in lithium response and was composed of clinical variables, PRS variables and interaction terms between them. The best performing non-linear model used only clinical variables and explained 8.1% (P = 0.0001) of variance in lithium response. A priori genomic stratification improved non-linear model performance to 13.7% (P = 0.0001) and improved the binary classification of lithium response. This model stratified patients based on their meta-polygenic loadings for major depressive disorder and schizophrenia and was then trained using clinical data.
Using PRS to first stratify patients genetically and then train machine-learning models with clinical predictors led to large improvements in lithium response prediction. When used with other PRS and biological markers in the future this approach may help inform which patients are most likely to respond to lithium treatment.
Approximately one-third of individuals in a major depressive episode will not achieve sustained remission despite multiple, well-delivered treatments. These patients experience prolonged suffering and disproportionately utilize mental and general health care resources. The recently proposed clinical heuristic of ‘difficult-to-treat depression’ (DTD) aims to broaden our understanding and focus attention on the identification, clinical management, treatment selection, and outcomes of such individuals. Clinical trial methodologies developed to detect short-term therapeutic effects in treatment-responsive populations may not be appropriate in DTD. This report reviews three essential challenges for clinical intervention research in DTD: (1) how to define and subtype this heterogeneous group of patients; (2) how, when, and by what methods to select, acquire, compile, and interpret clinically meaningful outcome metrics; and (3) how to choose among alternative clinical trial design options to promote causal inference and generalizability. The boundaries of DTD are uncertain, and an evidence-based taxonomy and reliable assessment tools are preconditions for clinical research and subtyping. Traditional outcome metrics in treatment-responsive depression may not apply to DTD, as they largely reflect the only short-term symptomatic change and do not incorporate durability of benefit, side effect burden, or sustained impact on quality of life or daily function. The trial methodology will also require modification as trials will likely be of longer duration to examine the sustained impact, raising complex issues regarding control group selection, blinding and its integrity, and concomitant treatments.
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.
In the Cordillera Darwin, southernmost South America, we used 10Be and 14C dating, dendrochronology, and historical observations to reconstruct the glacial history of the Dalla Vedova valley from deglacial time to the present. After deglacial recession into northeastern Darwin and Dalla Vedova, by ~16 ka, evidence indicates a glacial advance at ~13 ka coeval with the Antarctic Cold Reversal. The next robustly dated glacial expansion occurred at 870 ± 60 calendar yr ago (approximately AD 1150), followed by less-extensive dendrochronologically constrained advances from shortly before AD 1836 to the mid-twentieth century. Our record is consistent with most studies within the Cordillera Darwin that show that the Holocene glacial maximum occurred during the last millennium. This pattern contrasts with the extensive early- and mid-Holocene glacier expansions farther north in Patagonia; furthermore, an advance at 870 ± 60 yr ago may suggest out-of-phase glacial advances occurred within the Cordillera Darwin relative to Patagonia. We speculate that a southward shift of westerlies and associated climate regimes toward the southernmost tip of the continent, about 900–800 yr ago, provides a mechanism by which some glaciers advanced in the Cordillera Darwin during what is generally considered a warm and dry period to the north in Patagonia.
Over the years, attempts have been made to classify depressive syndromes based on various criteria. For several decades, the term reactive depression was used to describe cases involving an obvious precipitant, whereas endogenous depression lacked a recent stressor. Alternatively, the term secondary depression has been used in reference to cases related to a defined medical condition, as opposed to examples of primary depression. In the current classification scheme, the Diagnostic and Statistics Manual of Mental Disorders, 5th edition (DSM-V) lists fifteen distinct diagnoses related to disorders of mood, which are shown in Table 4.1. Eight of these disorders are considered depressive disorders, whereas seven categorize patients within the bipolar spectrum of illness.
ABSTRACT IMPACT: This work may provide new targets for vaccine and immunotherapeutic development against MRSA infections. OBJECTIVES/GOALS: Staphylococcus aureus is the leading cause of skin and skin structure infection (SSSI), a primary portal of entry for invasive infection. Patients with SA SSSI have a high 1-year recurrence. We have shown innate memory protects mice against SA SSSI. The goal of this project is to determine epigenetic mechanisms of protective memory against SA SSSI. METHODS/STUDY POPULATION: We have shown macrophages (Mf) afford protective memory against recurrent SA SSSI in mice. Priming by prior infection reduced skin lesion size and MRSA burden, which correlated with increased Mf in abscesses and lymph nodes. Priming potentiated the opsonophagocytic killing of SA by bone-marrow derived Mf (BMDM) in vitro, and their adoptive transfer into naive skin afforded protective efficacy in vivo. Here, we investigated epigenetic mechanisms of anti-SA efficacy in BMDMs. BMDM from naive (uninfected) or primed (SA SSSI) wild-type C57Bl/6 mice were cultured ex vivo. DNA from BMDM groups were isolated and analyzed for methylation changes using reduced representation bisulfite sequencing (RRBS). Pathway analyses of methylation changes were determined with Panther. RESULTS/ANTICIPATED RESULTS: Present findings indicate the protective memory afforded by BMDM was mediated by epigenetic modifications of the DNA. Using RRBS, we profiled differentially methylated regions (DMR) in DNA from naive vs. primed BMDM. Primed BMDM exhibited significantly different DMRs as compared to naive BMDM. Proximity to known genes were mapped using GREAT. Pathway analyses revealed DMRs predominant in genes integral to immune modulation, such as integrin signaling, cytokine/chemokine networks, and growth regulation. For example, SA-primed BMDM were hypermethylated proximate to GIMAP8 versus naive BMDM, suggesting repression of this protein. Gimap family ligands are small GTPase immune-associated proteins expressed in immune cells known to regulate macrophage lysosomal fusion during parasite infection. DISCUSSION/SIGNIFICANCE OF FINDINGS: These findings reveal epigenetic mechanisms of macrophage innate memory against recurrent MRSA infection. Functional testing of these genes in response to SA infection is needed to confirm their protective role. These insights may provide new targets for vaccine and immunotherapeutic development against MRSA.
Health disparities between Appalachia and the rest of the country are widening. To address this, the Appalachian Translational Research Network (ATRN) organizes an annual ATRN Health Summit. The most recent Summit was held online September 22–23, 2020, and hosted by Wake Forest Clinical and Translational Science Institute in partnership with the Northwest Area Health Education Center. The Summit, titled “Community-Engaged Research in Translational Science: Innovations to Improve Health in Appalachia,” brought together a diverse group of 141 stakeholders from communities, academic institutions, and the National Center for Advancing Translational Science (NCATS) to highlight current research, identify innovative approaches to translational science and community-engaged research, develop cross-regional research partnerships, and establish and disseminate priorities for future Appalachian-focused research. The Summit included three plenary presentations and 39 presentations within 12 concurrent breakout sessions. Here, we describe the Summit planning process and implementation, highlight some of the research presented, and outline nine emergent themes to guide future Appalachian-focused research.
Radiocarbon (14C) ages cannot provide absolutely dated chronologies for archaeological or paleoenvironmental studies directly but must be converted to calendar age equivalents using a calibration curve compensating for fluctuations in atmospheric 14C concentration. Although calibration curves are constructed from independently dated archives, they invariably require revision as new data become available and our understanding of the Earth system improves. In this volume the international 14C calibration curves for both the Northern and Southern Hemispheres, as well as for the ocean surface layer, have been updated to include a wealth of new data and extended to 55,000 cal BP. Based on tree rings, IntCal20 now extends as a fully atmospheric record to ca. 13,900 cal BP. For the older part of the timescale, IntCal20 comprises statistically integrated evidence from floating tree-ring chronologies, lacustrine and marine sediments, speleothems, and corals. We utilized improved evaluation of the timescales and location variable 14C offsets from the atmosphere (reservoir age, dead carbon fraction) for each dataset. New statistical methods have refined the structure of the calibration curves while maintaining a robust treatment of uncertainties in the 14C ages, the calendar ages and other corrections. The inclusion of modeled marine reservoir ages derived from a three-dimensional ocean circulation model has allowed us to apply more appropriate reservoir corrections to the marine 14C data rather than the previous use of constant regional offsets from the atmosphere. Here we provide an overview of the new and revised datasets and the associated methods used for the construction of the IntCal20 curve and explore potential regional offsets for tree-ring data. We discuss the main differences with respect to the previous calibration curve, IntCal13, and some of the implications for archaeology and geosciences ranging from the recent past to the time of the extinction of the Neanderthals.
Incumbent city councillors have an almost insurmountable advantage in Canadian municipal elections. This article aims to improve our understanding of the municipal incumbency advantage by considering the ability of electors to correctly identify the two most competitive candidates in one's ward and the factors associated with being able to do so. Using survey data from the Canadian Municipal Election Study (CMES), we consider the case of the 2018 elections in Mississauga, a city with typically high rates of incumbent re-election. Survey respondents were asked to identify the two most competitive candidates in their local ward races. We find that comparatively few electors are able to recognize which challenger serves as the strongest threat to a sitting councillor, a finding that suggests that coordination problems may help to contribute to high rates of incumbent success. We identify several individual-level and ward-level correlates of correctly identifying the first-place and second-place finishers. We do note, however, that there is a significant amount of variation among the thousands of municipalities in Canada, so findings from this case should be tested in other settings, including larger or smaller cities where levels of information might be different.
Prestigious journals are widely admired for publishing quality scholarship, yet the primary indicators of journal prestige (i.e., impact factors) do not directly assess audience admiration. Moreover, the publication landscape has changed substantially in the last 20 years, with electronic publishing changing the way we consume scientific research. Given that it has been 18 years since the publication of the last journal prestige survey of SIOP members, the authors conducted a new survey and used these results to reflect on changing practices within industrial and organizational (I-O) psychology. SIOP members (n = 557) rated the prestige and relevance of I-O and management journals. Responses were analyzed according to job setting, and were compared to a survey conducted by Zickar and Highhouse (2001) in 2000. There was considerable consistency in prestige ratings across settings (i.e., management department vs. psychology department; academic vs. applied), especially among the top journals. There was considerable variance, however, in the perceived usefulness of different journals. Results also suggested considerable consistency across the two time periods, but with some increases in prestige among OB-oriented journals. Changes in the journal landscape are discussed, including the rise of OHP as a topic of concentration in I-O. We suggest that I-O programs will continue to attract the top researchers in talent management and OHP, which should result in the use of a broader set of journals for judging I-O program impact.
Carbapenem-resistant Enterobacterales (CRE) are common causes of healthcare-associated infections and are often multidrug resistant with limited therapeutic options. Additionally, CRE can spread within and between healthcare facilities, amplifying potential harms.
To better understand the burden, risk factors, and source of acquisition of carbapenemase genes in clinical Escherichia coli and Klebsiella spp isolates from patients in Washington to guide prevention efforts.
Multicenter prospective surveillance study.
Escherichia coli and Klebsiella spp isolates meeting the Washington state CRE surveillance case definition were solicited from clinical laboratories and tested at Washington Public Health Laboratories using polymerase chain reaction (PCR) for the 5 most common carbapenemase genes: blaKPC, blaNDM, blaIMP, blaVIM, and blaOXA-48. Case patients positive by PCR were investigated by the public health department.
From October 2012 through December 2017, 363 carbapenem-resistant E. coli and Klebsiella spp isolates were tested. Overall, 45 of 115 carbapenem-resistant K. pneumoniae (39%), 1 of 8 K. oxytoca (12.5%), and 28 of 239 carbapenem-resistant E. coli (11.7%) were carbapenemase positive. Of 74 carbapenemase-positive isolates, blaKPC was most common (47%), followed by blaNDM (30%), blaOXA-48 (22%), and blaIMP (1%). Although all cases had healthcare exposure, blaKPC acquisition was associated with US health care, whereas non-blaKPC acquisition was associated with international health care or travel.
We report that blaKPC, the most prevalent carbapenemase in the United States, accounts for nearly half of carbapenemase cases in Washington state and that most KPC-cases are likely acquired through in-state health care.
Academic medical centers (AMCs) face challenges in conducting research among traditionally marginalized communities due to long-standing community mistrust. Evidence suggests that some AMC faculty and staff lack an understanding of the history of distrust and social determinants of health (SDH) affecting their communities. Wake Forest Clinical and Translational Science Institute Program in Community Engagement (PCE) aims to build bridges between communities and Wake Forest Baptist Health by equipping faculty, clinicians, administrators, and staff (FCAS) with a better understanding of SDH. The PCE collaborated with community partners to develop and implement community tours to improve cross-community AMC understanding and communication, enhance knowledge of SDH, and build awareness of community needs, priorities, and assets. Nine day-long tours have been conducted with 92 FCAS. Tours included routes through under-resourced neighborhoods and visits to community assets. Participant evaluations assessed program quality; 89% reported enhanced understanding of access-to-care barriers and how SDH affect health; 86% acknowledged the experience would improve future interactions with participants and patients; and 96% agreed they would recommend the tour to colleagues. This work supports the use of community tours as a strategy to improve cross-community AMC communication, build trust, and raise awareness of community needs, priorities, and assets.
Posttraumatic stress disorder (PTSD) is often complicated by the after-effects of mild traumatic brain injury (mTBI). The mixture of brain conditions results in abnormal affective and cognitive functioning, as well as maladaptive behavior. To better understand how brain activity explains cognitive and emotional processes in these conditions, we used an emotional N-back task and functional magnetic resonance imaging (fMRI) to study neural responses in US military veterans after deployments to Iraq and Afghanistan. Additionally, we sought to examine whether hierarchical dimensional models of maladaptive personality could account for the relationship between combat-related brain conditions and fMRI responses under cognitive and affective challenge. FMRI data, measures of PTSD symptomatology (PTSS), blast-induced mTBI (bmTBI) severity, and maladaptive personality (MMPI-2-RF) were gathered from 93 veterans. Brain regions central to emotion regulation were selected for analysis, and consisted of bilateral amygdala, bilateral dorsolateral prefrontal (dlPFC), and ventromedial prefrontal/subgenual anterior cingulate (vmPFC-sgACC). Cognitive load increased activity in dlPFC and reduced activity in emotional responding brain regions. However, individuals with greater PTSS showed blunted deactivations in bilateral amygdala and vmPFC-sgACC, and weaker responses in right dlPFC. Additionally, we found that elevated emotional/internalizing dysfunction (EID), specifically low positive emotionality (RC2), accounted for PTSS-related changes in bilateral amygdala under increased cognitive load. Findings suggest that PTSS might result in amygdala and vmPFC-sgACC activity resistant to moderation by cognitive demands, reflecting emotion dysregulation despite a need to marshal cognitive resources. Anhedonia may be an important target for interventions that improve the affective and cognitive functioning of individuals with PTSD.
Accurate perception of visual contours is essential for seeing and differentiating objects in the environment. Both the ability to detect visual contours and the influence of perceptual context created by surrounding stimuli are diminished in people with schizophrenia (SCZ). The central aim of the present study was to better understand the biological underpinnings of impaired contour integration and weakened effects of perceptual context. Additionally, we sought to determine whether visual perceptual abnormalities reflect genetic factors in SCZ and are present in other severe mental disorders.
We examined behavioral data and event-related potentials (ERPs) collected during the perception of simple linear contours embedded in similar background stimuli in 27 patients with SCZ, 23 patients with bipolar disorder (BP), 23 first-degree relatives of SCZ, and 37 controls.
SCZ exhibited impaired visual contour detection while BP exhibited intermediate performance. The orientation of neighboring stimuli (i.e. flankers) relative to the contour modulated perception across all groups, but SCZ exhibited weakened suppression by the perceptual context created by flankers. Late visual (occipital P2) and cognitive (centroparietal P3) neural responses showed group differences and flanker orientation effects, unlike earlier ERPs (occipital P1 and N1). Moreover, behavioral effects of flanker context on contour perception were correlated with modulation in P2 & P3 amplitudes.
In addition to replicating and extending findings of abnormal contour integration and visual context modulation in SCZ, we provide novel evidence that the abnormal use of perceptual context is associated with higher-order sensory and cognitive processes.
Early detection and intervention strategies in patients at clinical high-risk (CHR) for syndromal psychosis have the potential to contain the morbidity of schizophrenia and similar conditions. However, research criteria that have relied on severity and number of positive symptoms are limited in their specificity and risk high false-positive rates. Our objective was to examine the degree to which measures of recency of onset or intensification of positive symptoms [a.k.a., new or worsening (NOW) symptoms] contribute to predictive capacity.
We recruited 109 help-seeking individuals whose symptoms met criteria for the Progression Subtype of the Attenuated Positive Symptom Psychosis-Risk Syndrome defined by the Structured Interview for Psychosis-Risk Syndromes and followed every three months for two years or onset of syndromal psychosis.
Forty-one (40.6%) of 101 participants meeting CHR criteria developed a syndromal psychotic disorder [mostly (80.5%) schizophrenia] with half converting within 142 days (interquartile range: 69–410 days). Patients with more NOW symptoms were more likely to convert (converters: 3.63 ± 0.89; non-converters: 2.90 ± 1.27; p = 0.001). Patients with stable attenuated positive symptoms were less likely to convert than those with NOW symptoms. New, but not worsening, symptoms, in isolation, also predicted conversion.
Results suggest that the severity and number of attenuated positive symptoms are less predictive of conversion to syndromal psychosis than the timing of their emergence and intensification. These findings also suggest that the earliest phase of psychotic illness involves a rapid, dynamic process, beginning before the syndromal first episode, with potentially substantial implications for CHR research and understanding the neurobiology of psychosis.
Use latent class analysis (LCA) to identify patterns of cognitive functioning in a sample of older adults with clinical depression and without dementia and assess demographic, psychiatric, and neurobiological predictors of class membership.
Neuropsychological assessment data from 121 participants in the Alzheimer’s Disease Neuroimaging Initiative-Depression project (ADNI-D) were analyzed, including measures of executive functioning, verbal and visual memory, visuospatial and language functioning, and processing speed. These data were analyzed using LCA, with predictors of class membership such as depression severity, depression and treatment history, amyloid burden, and APOE e4 allele also assessed.
A two-class model of cognitive functioning best fit the data, with the Lower Cognitive Class (46.1% of the sample) performing approximately one standard deviation below the Higher Cognitive Class (53.9%) on most tests. When predictors of class membership were assessed, carrying an APOE e4 allele was significantly associated with membership in the Lower Cognitive Class. Demographic characteristics, age of depression onset, depression severity, history of psychopharmacological treatment for depression, and amyloid positivity did not predict class membership.
LCA allows for identification of subgroups of cognitive functioning in a mostly cognitively intact late life depression (LLD) population. One subgroup, the Lower Cognitive Class, more likely to carry an APOE e4 allele, may be at a greater risk for subsequent cognitive decline, even though current performance on neuropsychological testing is within normal limits. These findings have implications for early identification of those at greatest risk, risk factors, and avenues for preventive intervention.
Treatment for hoarding disorder is typically performed by mental health professionals, potentially limiting access to care in underserved areas.
We aimed to conduct a non-inferiority trial of group peer-facilitated therapy (G-PFT) and group psychologist-led cognitive–behavioural therapy (G-CBT).
We randomised 323 adults with hording disorder 15 weeks of G-PFT or 16 weeks of G-CBT and assessed at baseline, post-treatment and longitudinally (≥3 months post-treatment: mean 14.4 months, range 3–25). Predictors of treatment response were examined.
G-PFT (effect size 1.20) was as effective as G-CBT (effect size 1.21; between-group difference 1.82 points, t = −1.71, d.f. = 245, P = 0.04). More homework completion and ongoing help from family and friends resulted in lower severity scores at longitudinal follow-up (t = 2.79, d.f. = 175, P = 0.006; t = 2.89, d.f. = 175, P = 0.004).
Peer-led groups were as effective as psychologist-led groups, providing a novel treatment avenue for individuals without access to mental health professionals.
Declaration of interest
C.A.M. has received grant funding from the National Institutes of Health (NIH) and travel reimbursement and speakers’ honoraria from the Tourette Association of America (TAA), as well as honoraria and travel reimbursement from the NIH for serving as an NIH Study Section reviewer. K.D. receives research support from the NIH and honoraria and travel reimbursement from the NIH for serving as an NIH Study Section reviewer. R.S.M. receives research support from the National Institute of Mental Health, National Institute of Aging, the Hillblom Foundation, Janssen Pharmaceuticals (research grant) and the Alzheimer's Association. R.S.M. has also received travel support from the National Institute of Mental Health for Workshop participation. J.Y.T. receives research support from the NIH, Patient-Centered Outcomes Research Institute and the California Tobacco Related Research Program, and honoraria and travel reimbursement from the NIH for serving as an NIH Study Section reviewer. All other authors report no conflicts of interest.