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Most people who develop dementia will never be diagnosed, and therefore lack access to treatment and care from specialists in the field. This new edition provides updated guidance on how behavioral symptom reflect the changes occurring in the brain, and how these can help generalist clinicians to accurately diagnose neurodegenerative diseases. This practical book is aimed at healthcare professionals working in neurology, psychiatry and neuropsychology wanting to enhance the skills and knowledge needed to successfully manage these diseases. Simple approaches to bedside mental status testing, differential diagnosis and treatment, and interpreting neuropsychological testing and neuroimaging findings are covered. Introductory chapters outline dementia epidemiology and dementia neuropathology whilst chapters new to this edition describe the improvements in diagnostic capabilities in recent years, including blood based and cerebrospinal biomarkers and emerging biologically based therapies. Chapters on sleep disorders, and chronic traumatic encephalopathy and traumatic brain injury have also been expanded.
Background: Treatment for sagittal craniosynostosis often involves endoscopic suturectomy (ES) followed by helmet therapy, with cranial shape improvement assessed via cephalic index (CI). The effect of adding barrel-stave osteotomy (BSO) to ES on CI outcomes remains controversial. This study evaluated the impact of BSO on operative burden and postoperative cranial deformity in patients undergoing surgical correction of sagittal craniosynostosis. Methods: A retrospective review of 85 patients treated for sagittal craniosynostosis at BC Children’s Hospital (2010–2021) compared patients undergoing ES alone (n=18) and ES+BSO (n=67). Demographics, operative burden (anesthesia and surgical time, blood loss, hospital stay), and longitudinal CI measurements were analyzed. Mixed effects modeling controlled for age, preoperative CI, and helmet duration. Results: Operative burden did not differ significantly between treatment groups (p > 0.05). The median follow-up duration for CI measurements was 56.0 months. While preoperative CI was similar (67.4 vs. 66.8, p=0.61), CI was significantly improved in the ES+BSO group at all postoperative intervals (p ≤ 0.02). Mixed effects modeling confirmed that BSO independently improved CI (effect size 2.21, p=0.001). Conclusions: In our series, the addition of BSO to ES significantly improved immediate and long-term cranial deformity without increasing operative burden, supporting its use in sagittal craniosynostosis correction.
Multicenter clinical trials are essential for evaluating interventions but often face significant challenges in study design, site coordination, participant recruitment, and regulatory compliance. To address these issues, the National Institutes of Health’s National Center for Advancing Translational Sciences established the Trial Innovation Network (TIN). The TIN offers a scientific consultation process, providing access to clinical trial and disease experts who provide input and recommendations throughout the trial’s duration, at no cost to investigators. This approach aims to improve trial design, accelerate implementation, foster interdisciplinary teamwork, and spur innovations that enhance multicenter trial quality and efficiency. The TIN leverages resources of the Clinical and Translational Science Awards (CTSA) program, complementing local capabilities at the investigator’s institution. The Initial Consultation process focuses on the study’s scientific premise, design, site development, recruitment and retention strategies, funding feasibility, and other support areas. As of 6/1/2024, the TIN has provided 431 Initial Consultations to increase efficiency and accelerate trial implementation by delivering customized support and tailored recommendations. Across a range of clinical trials, the TIN has developed standardized, streamlined, and adaptable processes. We describe these processes, provide operational metrics, and include a set of lessons learned for consideration by other trial support and innovation networks.
Older adults with treatment-resistant depression (TRD) benefit more from treatment augmentation than switching. It is useful to identify moderators that influence these treatment strategies for personalised medicine.
Aims
Our objective was to test whether age, executive dysfunction, comorbid medical burden, comorbid anxiety or the number of previous adequate antidepressant trials could moderate the superiority of augmentation over switching. A significant moderator would influence the differential effect of augmentation versus switching on treatment outcomes.
Method
We performed a preplanned moderation analysis of data from the Optimizing Outcomes of Treatment-Resistant Depression in Older Adults (OPTIMUM) randomised controlled trial (N = 742). Participants were 60 years old or older with TRD. Participants were either (a) randomised to antidepressant augmentation with aripiprazole (2.5–15 mg), bupropion (150–450 mg) or lithium (target serum drug level 0.6 mmol/L) or (b) switched to bupropion (150–450 mg) or nortriptyline (target serum drug level 80–120 ng/mL). Treatment duration was 10 weeks. The two main outcomes of this analysis were (a) symptom improvement, defined as change in Montgomery–Asberg Depression Rating Scale (MADRS) scores from baseline to week 10 and (b) remission, defined as MADRS score of 10 or less at week 10.
Results
Of the 742 participants, 480 were randomised to augmentation and 262 to switching. The number of adequate previous antidepressant trials was a significant moderator of depression symptom improvement (b = −1.6, t = −2.1, P = 0.033, 95% CI [−3.0, −0.1], where b is the coefficient of the relationship (i.e. effect size), and t is the t-statistic for that coefficient associated with the P-value). The effect was similar across all augmentation strategies. No other putative moderators were significant.
Conclusions
Augmenting was superior to switching antidepressants only in older patients with fewer than three previous antidepressant trials. This suggests that other intervention strategies should be considered following three or more trials.
Posttraumatic stress disorder (PTSD) has been associated with advanced epigenetic age cross-sectionally, but the association between these variables over time is unclear. This study conducted meta-analyses to test whether new-onset PTSD diagnosis and changes in PTSD symptom severity over time were associated with changes in two metrics of epigenetic aging over two time points.
Methods
We conducted meta-analyses of the association between change in PTSD diagnosis and symptom severity and change in epigenetic age acceleration/deceleration (age-adjusted DNA methylation age residuals as per the Horvath and GrimAge metrics) using data from 7 military and civilian cohorts participating in the Psychiatric Genomics Consortium PTSD Epigenetics Workgroup (total N = 1,367).
Results
Meta-analysis revealed that the interaction between Time 1 (T1) Horvath age residuals and new-onset PTSD over time was significantly associated with Horvath age residuals at T2 (meta β = 0.16, meta p = 0.02, p-adj = 0.03). The interaction between T1 Horvath age residuals and changes in PTSD symptom severity over time was significantly related to Horvath age residuals at T2 (meta β = 0.24, meta p = 0.05). No associations were observed for GrimAge residuals.
Conclusions
Results indicated that individuals who developed new-onset PTSD or showed increased PTSD symptom severity over time evidenced greater epigenetic age acceleration at follow-up than would be expected based on baseline age acceleration. This suggests that PTSD may accelerate biological aging over time and highlights the need for intervention studies to determine if PTSD treatment has a beneficial effect on the aging methylome.
Palmer amaranth, a competitive weed in cotton and soybeans, poses challenges due to its rapid growth, high fertility, and herbicide resistance. Effective management strategies targeting sex ratios could reduce seed production by female plants. Protoporphyrinogen oxidase (PPO-) inhibiting herbicides play a role in the evolving resistance of Amaranthus spp. in the US Midwest. These herbicides may also affect the male-to-female ratio of Palmer amaranth. A 2-yr field experiment (2015 and 2016) was conducted in a soybean field in Collinsville, IL, evaluating various preemergence and postemergence PPO-inhibiting herbicide treatments. Untreated Palmer amaranth populations exhibited a bias toward females. Preemergence application of sulfentrazone and flumioxazin effectively reduced Palmer amaranth density (1.66 plants m–2) throughout the season, whereas postemergence applications of fomesafen and lactofen provided limited control (27 and 31 plants m–2, respectively). Early-season mortality was high (96%) among Palmer amaranth seedlings, especially with pyroxasulfone + fluthiacet-methyl treatment. Fomesafen increased female biomass (28.8%) while reducing male biomass compared to the nontreated control. In 2015, pyroxasulfone + fluthiacet-methyl and acetochlor altered the male-to-female sex ratio compared to the nontreated control, with pyroxasulfone + fluthiacet-methyl reducing the proportion of females (–0.11 M/F) and acetochlor slightly increasing the proportion of males (0.03 M/F), though not different from a 1:1 ratio. In 2016, pendimethalin and flumioxazin (71 g ai ha–1) resulted in a strong female-biased sex ratio, with an almost exclusively female population. In both years, the nontreated control plots (–0.58 and –0.55 M/F) maintained a naturally female-biased sex ratio, deviating significantly from a 1:1 ratio. These findings suggest that specific herbicide treatments can alter the sex ratio. Understanding sex determination in Palmer amaranth holds promise for developing more effective control strategies in the future.
The global population and status of Snowy Owls Bubo scandiacus are particularly challenging to assess because individuals are irruptive and nomadic, and the breeding range is restricted to the remote circumpolar Arctic tundra. The International Union for Conservation of Nature (IUCN) uplisted the Snowy Owl to “Vulnerable” in 2017 because the suggested population estimates appeared considerably lower than historical estimates, and it recommended actions to clarify the population size, structure, and trends. Here we present a broad review and status assessment, an effort led by the International Snowy Owl Working Group (ISOWG) and researchers from around the world, to estimate population trends and the current global status of the Snowy Owl. We use long-term breeding data, genetic studies, satellite-GPS tracking, and survival estimates to assess current population trends at several monitoring sites in the Arctic and we review the ecology and threats throughout the Snowy Owl range. An assessment of the available data suggests that current estimates of a worldwide population of 14,000–28,000 breeding adults are plausible. Our assessment of population trends at five long-term monitoring sites suggests that breeding populations of Snowy Owls in the Arctic have decreased by more than 30% over the past three generations and the species should continue to be categorised as Vulnerable under the IUCN Red List Criterion A2. We offer research recommendations to improve our understanding of Snowy Owl biology and future population assessments in a changing world.
The goals of this investigation were to 1) identify and measure exposures inside homes of individuals with chemical intolerance (CI), 2) provide guidance for reducing these exposures, and 3) determine whether our environmental house calls (EHCs) intervention could reduce both symptoms and measured levels of indoor air contaminants.
Background:
CI is an international public health and clinical concern, but few resources are available to address patients’ often disabling symptoms. Numerous studies show that levels of indoor air pollutants can be two to five (or more) times higher than outdoor levels. Fragranced consumer products, including cleaning supplies, air fresheners, and personal care products, are symptom triggers commonly reported by susceptible individuals.
Methods:
A team of professionals trained and led by a physician/industrial hygienist and a certified indoor air quality specialist conducted a series of 5 structured EHCs in 37 homes of patients reporting CI.
Results:
We report three case studies demonstrating that an appropriately structured home intervention can teach occupants how to reduce indoor air exposures and associated symptoms. Symptom improvement, documented using the Quick Environmental Exposure and Sensitivity Inventory Symptom Star, corresponded with the reduction of indoor air volatile organic compounds, most notably fragrances. These results provide a deeper dive into 3 of the 37 cases described previously in Perales et al. (2022).
Discussion:
We address the long-standing dilemma that worldwide reports of fragrance sensitivity have not previously been confirmed by human or animal challenge studies. Our ancient immune systems’ ‘first responders’, mast cells, which evolved 500 million years ago, can be sensitized by synthetic organic chemicals whose production and use have grown exponentially since World War II. We propose that these chemicals, which include now-ubiquitous fragrances, trigger mast cell degranulation and inflammatory mediator release in the olfactory-limbic tract, thus altering cerebral blood flow and impairing mood, memory, and concentration (often referred to as ‘brain fog’). The time has come to translate these research findings into clinical and public health practice.
We study the association of shareholder returns with liberalization in government policy during Britain's railway run-up of 1844–5. The findings sustain two main claims. First, the railway returns during the run-up were associated with the advent of liberalizing policies, especially related to free trade, enhanced transparency and governance of firms, and industry consolidation. Second, analysis of cross-sectional variation reveals higher returns to large railways in the South and Midlands of England, several of which were leading consolidators. This study is the first to report an association between policy liberalization and run-up returns and to identify consolidators as the prime beneficiaries of the liberalization.
Bipolar I disorder (BD-I) is a chronic and recurrent mood disorder characterized by alternating episodes of depression and mania; it is also associated with substantial morbidity and mortality and with clinically significant functional impairments. While previous studies have used functional magnetic resonance imaging (fMRI) to examine neural abnormalities associated with BD-I, they have yielded mixed findings, perhaps due to differences in sampling and experimental design, including highly variable mood states at the time of scan.
Objectives
The purpose of this study is to advance our understanding of the neural basis of BD-I and mania, as measured by fMRI activation studies, and to inform the development of more effective brain-based diagnostic systems and clinical treatments.
Methods
We conducted a large-scale meta-analysis of whole-brain fMRI activation studies that compared participants with BD-I, assessed during a manic episode, to age-matched healthy controls. Following PRISMA guidelines, we conducted a comprehensive PubMed literature search using two independent coding teams to evaluate primary studies according to pre-established inclusion criteria. We then used multilevel kernel density analysis (MKDA), a well-established, voxel-wise, whole-brain, meta-analytic approach, to quantitatively synthesize all qualifying primary fMRI activation studies of mania. We used ensemble thresholding (p<0.05-0.0001) to minimize cluster size detection bias, and 10,000 Monte Carlo simulations to correct for multiple comparisons.
Results
We found that participants with BD-I (N=2,042), during an active episode of mania and relative to age-matched healthy controls (N=1,764), exhibit a pattern of significantly (p<0.05-0.0001; FWE-corrected) different activation in multiple brain regions of the cerebral cortex and basal ganglia across a variety of experimental tasks.
Conclusions
This study supports the formulation of a robust neural basis for BD-I during manic episodes and advances our understanding of the pattern of abnormal activation in this disorder. These results may inform the development of novel brain-based clinical tools for bipolar disorder such as diagnostic biomarkers, non-invasive brain stimulation, and treatment-matching protocols. Future studies should compare the neural signatures of BD-I to other related disorders to facilitate the development of protocols for differential diagnosis and improve treatment outcomes in patients with BD-I.
Australian Aboriginal and Torres Strait Islander peoples are disproportionately affected by diet-related disease such as type 2 diabetes, the rate of which is 20 fold higher than that of non-Indigenous young Australians(1). Before colonisation, Gomeroi and other First Nations people harvested, threshed and ground native grass seeds with water into a paste before cooking(2). The introduction of white refined flour has meant that time-consuming grass seed processing has mainly ceased, and native grains are no longer eaten habitually. The aim of this study was to determine the effect of 10% incorporation of two native grain flours on postprandial blood glucose response and Glycemic Index (GI). Five male and five female subjects, with a mean age of 30 ± 0.9 and BMI of 21.6 ± 0.4 and normoglycemic, participated in GI testing of three flour + water pancake compositions matched for available carbohydrate: 100% wheat (Wheat) and 90% wheat:10% native grains (Native_a and Native_b). Effect on satiety was determined using subjective ratings of hunger/fullness over the time course of the GI testing. In comparison to the plain flour pancake, replacing 10% plain wheat flour with Native_b flour significantly reduced the GI by 28.8% from 73 ± 5 to 48 ± 5, having a profound effect on postprandial blood glucose levels in 9 of 10 subjects (p<0.05, paired t-test). The GI of 10% Native_a flour pancake was not different from 100% wheat flour pancake (75 ± 5). Satiety tended to be greater when native grains were incorporated but this study was not powered to detect effect on satiety. In conclusion, replacing only 10% of plain wheat flour with Native_b flour was sufficient to significantly reduce the blood glycemic response to the pancake. This replacement could be easily implemented for prevention and treatment of type 2 diabetes. For Aboriginal people with access to grain Country, the nutritional health benefits associated with eating native grains, as well as the cultural benefits of caring for Country, will have a direct transformational impact on local communities. Our vision is to revitalise Gomeroi grains and to guide a sustainable Indigenous-led industry to heal Country and people through co-designed research.
OBJECTIVES/GOALS: Cachexia is the involuntary and irreversible loss of muscle and fat and is a major cause of morbidity and mortality in head and neck cancer (HNC). It remains a poorly understood disease diagnosed by weight loss and a confluence of symptoms. We explored the metabolic and inflammatory mechanisms of cachexia symptoms via an multiomics network algorithm. METHODS/STUDY POPULATION: Prior to chemoradiotherapy, HNC subjects completed questionnaires and donated blood for untargeted (metabolites) and targeted (lipids and cytokines) assays. Metabolites and lipids were measured by liquid chromatography mass spectrometry. Cytokines were measured by multiplex assays. We plotted a multiomics network graph by estimating partial least squares correlations amongst metabolites, lipids, cytokines, and common cachexia symptoms—max percent weight loss over 1 year, baseline BMI, fatigue, performance, albumin, hemoglobin, and white blood cell count. To interpret the network, an algorithm identified highly correlated clusters of metabolites-lipids-cytokines-symptoms representing possible biological relatedness, which were functionally annotated via metabolic enrichment analysis. RESULTS/ANTICIPATED RESULTS: In 123 subjects (59 years of age, 72% male, 84% white, avg weight loss of 13%), we analyzed 186 metabolites, 54 lipids, 7 cytokines and 7 cachexia symptoms. We required a correlation >0.25 and P-value <.05 to be included in the network graph, resulting in 323 connections and 3 identified clusters. Max weight loss and baseline BMI were in a cluster enriched by unsaturated fatty acid biosynthesis (P<.0001) and arachidonic acid (P=.01) metabolic pathways but not linked to inflammation cytokines. The five other cachexia symptoms were in a cluster with 4 cytokines (C-reactive protein, interleukin 6, IL10, IL1, Tumor necrosis factor receptor 2) and enriched by aminoacyl tRNA (P<.01) and valine biosynthesis (P=.02). We observed no meaningful differences when we stratified the analysis by human papillomavirus. DISCUSSION/SIGNIFICANCE: Cachexia symptoms in head and neck cancer may be linked to specific metabolic dysregulation—weight loss and BMI were linked to fatty acids; fatigue, anemia and others were linked to amino acids and inflammation. This information may allow for the recognition of a cachexic-metabolic subtype or provide novel targets for metabolic intervention.
The dehydration reaction of kerolite was investigated using high-pressure differential thermal analysis at pressures as high as 600 bars. The peak associated with the dehydration is broad, suggesting the presence of a series of overlapping reactions ranging from the release of adsorbed water to interlayer water. The peak temperature is 136°C at 1.8 bars and increases to 516°C at 586 bars. The primary reaction represents loss of adsorbed water having a bond energy of 1.5 ± 1 kJ/mole. A small amount of water may be present as interlayer water and has a bond energy of 7.5 ± 3 kJ/mole.
Emile Benvcniste may be used to introduce the topic. The French linguist begins an essay on “Euphemisms Ancient and Modern” with a paradox about the early Greek definitions of euphemism. “To speak words which augur well” is one meaning given, but another is “to maintain silence”. This initial contradiction is further compounded by yet a third expression, “to shout in triumph”. The dilemma is, however, easily dissolved. To speak words which augur well implies, for special occasions, an exhortation even to shout triumphantly, “to assent by an, auspicious outcry”: it further implies, again depending on the circumstances, “to avoid words which augur ill”, hence, if necessary, to say nothing. As one definition explains “avoid all unlucky words during sacred rites: hence, as the surest mode of avoiding them, keep a religious silence” (original emphasis). Paradox terminates; we are merely dealing with “a euphemism for a euphemism” taking an expression of Benveniste out of context.
Observations of radiocarbon (14C) in Earth’s atmosphere and other carbon reservoirs are important to quantify exchanges of CO2 between reservoirs. The amount of 14C is commonly reported in the so-called Delta notation, i.e., Δ14C, the decay- and fractionation-corrected departure of the ratio of 14C to total C from that ratio in an absolute international standard; this Delta notation permits direct comparison of 14C/C ratios in the several reservoirs. However, as Δ14C of atmospheric CO2, Δ14CO2 is based on the ratio of 14CO2 to total atmospheric CO2, its value can and does change not just because of change in the amount of atmospheric14CO2 but also because of change in the amount of total atmospheric CO2, complicating ascription of change in Δ14CO2 to change in one or the other quantity. Here we suggest that presentation of atmospheric 14CO2 amount as mole fraction relative to dry air (moles of 14CO2 per moles of dry air in Earth’s atmosphere), or as moles or molecules of 14CO2 in Earth’s atmosphere, all readily calculated from Δ14CO2 and the amount of atmospheric CO2 (with slight dependence on δ13CO2), complements presentation only as Δ14CO2, and can provide valuable insight into the evolving budget and distribution of atmospheric 14CO2.
The residual kaolin deposits near Lastarria, South-Central Chile, were formed by weathering of subvolcanic quartz porphyry stocks, which intruded the metamorphic basement of the Coastal Cordillera. The clay fractions (<2 µm) consist mainly of poorly-ordered, very fine-grained kaolinite and lath-shaped illite (17–38 wt. %) with minor amounts of quartz, sanidine, and goethite. A sample from the top of the deposit contains major quantities of gibbsite morphologically indistinguishable from kaolinite flakes. The gibbsite-free clays contain 35.5–36.6 wt. % Al2O3, 0.4–2.6 wt. % Fe2O3, 1.3–3.9 wt. % K2O, and have low TiO2 concentrations (<0.02 wt. %). The absence of quartz veining, the abundance of melt inclusions, and the scarcity of secondary fluid inclusions in quartz phenocrysts from altered rocks imply a lack of significant hydrothermal activity in the quartz porphyries. The δ 18O and δD values of the kaolins indicate formation in a weathering environment at significantly higher annual mean air temperatures (∼12°C) than present mean temperatures of ∼9.4°C. Uplift of the region alone probably cannot account for the change in climate. The stable isotope composition of gibbsite is consistent with an origin of desilication of kaolinite at superficial temperatures. Various criteria proposed to distinguish supergene from hypogene kaolins are discussed.
In this brief communication, we discuss the current landscape and unmet needs of pediatric to adult transition care in neurology. Optimizing transition care is a priority for patients, families, and providers with growing discussion in neurology. We also introduce the activities of the University of Toronto Pediatric-Adult Transition Working Group – a collaborative interdivisional and inter-subspeciality group of faculty, advanced-practice providers, trainees, and patient-family advisors pursuing collaboration with patients, families, and universities from across Canada. We envision that these efforts will result in a national neurology transition strategy that will inform designation of health authority attention and funding.
We present and evaluate the prospects for detecting coherent radio counterparts to gravitational wave (GW) events using Murchison Widefield Array (MWA) triggered observations. The MWA rapid-response system, combined with its buffering mode ($\sim$4 min negative latency), enables us to catch any radio signals produced from seconds prior to hours after a binary neutron star (BNS) merger. The large field of view of the MWA ($\sim$$1\,000\,\textrm{deg}^2$ at 120 MHz) and its location under the high sensitivity sky region of the LIGO-Virgo-KAGRA (LVK) detector network, forecast a high chance of being on-target for a GW event. We consider three observing configurations for the MWA to follow up GW BNS merger events, including a single dipole per tile, the full array, and four sub-arrays. We then perform a population synthesis of BNS systems to predict the radio detectable fraction of GW events using these configurations. We find that the configuration with four sub-arrays is the best compromise between sky coverage and sensitivity as it is capable of placing meaningful constraints on the radio emission from 12.6% of GW BNS detections. Based on the timescales of four BNS merger coherent radio emission models, we propose an observing strategy that involves triggering the buffering mode to target coherent signals emitted prior to, during or shortly following the merger, which is then followed by continued recording for up to three hours to target later time post-merger emission. We expect MWA to trigger on $\sim$$5-22$ BNS merger events during the LVK O4 observing run, which could potentially result in two detections of predicted coherent emission.
Mental health service delivery needs radical reimagination in the United States where unmet needs for care remain large and most metrics on the burden of mental health problems have worsened, despite significant numbers of mental health professionals, spending on service provision and research. The COVID-19 pandemic has exacerbated the need for mental health care. One path to a radical reimagination is “Community Initiated Care (CIC)” which equips and empowers communities to address by providing brief psychosocial interventions by people in community settings. We co-developed a theory of change (ToC) for CIC with 24 stakeholders including representatives from community-based, advocacy, philanthropic and faith-based organizations to understand how CIC could be developed and adapted for specific contexts. We present a ToC which describes ways in which the CIC initiative can promote and strengthen mental health in communities in the United States with respect to community organization and leadership; community care and inclusion and normalizing mental health. We propose 10 strategies as part of CIC and propose a way forward for implementation and evaluation. This CIC model is a local, tailored approach which can expand the role of community members to strengthen our response to mental health needs in the United States.