Computational neuroimaging strategies for single patient predictions

AbstractNeuroimaging increasingly exploits machine learning techniques in an attempt to achieve clinically relevant single-subject predictions. An alternative to machine learning, which tries to establish predictive links between features of the observed data and clinical variables, is the deployment of computational models for inferring on the (patho)physiological and cognitive mechanisms that generate behavioural and neuroimaging responses. This paper discusses the rationale behind a computational approach to neuroimaging-based single-subject inference, focusing on its potential for characterising disease mechanisms in individual subjects and mapping these characterisations to clinical predictions. Following an overview of two main approaches – Bayesian model selection and generative embedding – which can link computational models to individual predictions, we review how these methods accommodate heterogeneity in psychiatric and neurological spectrum disorders, help avoid erroneous interpretations of neuroimaging data, and establish a link between a mechanistic, model-based approach and the statistical perspectives afforded by machine learning

Double-crested cormorant colony effects on soil chemistry, vegetation structure and avian diversity

Effects of Double-crested Cormorants (Phalacrocorax auritus) on vegetation, soil chemistry and tree health have been documented from their breeding colonies in the northern breeding grounds of Canada and the United States (U.S.) but not for areas within the southeastern United States where breeding activity is relatively novel. We compared vegetation and tree metrics such as structure diversity, and soil chemistry among colony islands, uninhabited islands, and abandoned colony islands within Guntersville Reservoir, a temperate forest ecosystem. Avian diversity and community structure were also quantified on these islands. Concentrations of potassium (K), phosphorus (P) and nitrate (NO3 −) in soil were negatively related to cormorant use, while tree diversity was lower on historic (tree mean=4.35 ± 2.46 species) and colony (tree mean=3.91 ± 3.12 species) islands relative to reference islands (tree mean=9.11 ± 3.88 species). Canopy cover was less (min:\u3c20%), and midstories denser on colony and historic islands relative to reference islands. Avian diversity was significantly lower for colony islands (mean=6 ± 3 species) than both reference (11 ± 7 species) and historic (10 ± 7 species) islands. These effects of cormorant nesting can be seen even after 10 years of colony abandonment supporting that cormorants can have long-term effects on insular habitats in temperate forest ecosystems

Leakage-resilient coin tossing

Proceedings 25th International Symposium, DISC 2011, Rome, Italy, September 20-22, 2011.The ability to collectively toss a common coin among n parties in the presence of faults is an important primitive in the arsenal of randomized distributed protocols. In the case of dishonest majority, it was shown to be impossible to achieve less than 1 r bias in O(r) rounds (Cleve STOC ’86). In the case of honest majority, in contrast, unconditionally secure O(1)-round protocols for generating common unbiased coins follow from general completeness theorems on multi-party secure protocols in the secure channels model (e.g., BGW, CCD STOC ’88). However, in the O(1)-round protocols with honest majority, parties generate and hold secret values which are assumed to be perfectly hidden from malicious parties: an assumption which is crucial to proving the resulting common coin is unbiased. This assumption unfortunately does not seem to hold in practice, as attackers can launch side-channel attacks on the local state of honest parties and leak information on their secrets. In this work, we present an O(1)-round protocol for collectively generating an unbiased common coin, in the presence of leakage on the local state of the honest parties. We tolerate t ≤ ( 1 3 − )n computationallyunbounded Byzantine faults and in addition a Ω(1)-fraction leakage on each (honest) party’s secret state. Our results hold in the memory leakage model (of Akavia, Goldwasser, Vaikuntanathan ’08) adapted to the distributed setting. Additional contributions of our work are the tools we introduce to achieve the collective coin toss: a procedure for disjoint committee election, and leakage-resilient verifiable secret sharing.National Defense Science and Engineering Graduate FellowshipNational Science Foundation (U.S.) (CCF-1018064

Neurophysiologically-informed markers of individual variability and pharmacological manipulation of human cortical gamma

The ability to quantify synaptic function at the level of cortical microcircuits from non-invasive data would be enormously useful in the study of neuronal processing in humans and the pathophysiology that attends many neuropsychiatric disorders. Here, we provide proof of principle that one can estimate inter-and intra-laminar interactions among specific neuronal populations using induced gamma responses in the visual cortex of human subjects – using dynamic causal modelling based upon the canonical microcircuit (CMC; a simplistic model of a cortical column). Using variability in induced (spectral) responses over a large cohort of normal subjects, we find that the predominant determinants of gamma responses rest on recurrent and intrinsic connections between superficial pyramidal cells and inhibitory interneurons. Furthermore, variations in beta responses were mediated by inter-subject differences in the intrinsic connections between deep pyramidal cells and inhibitory interneurons. Interestingly, we also show that increasing the self-inhibition of superficial pyramidal cells suppresses the amplitude of gamma activity, while increasing its peak frequency. This systematic and nonlinear relationship was only disclosed by modelling the causes of induced responses. Crucially, we were able to validate this form of neurophysiological phenotyping by showing a selective effect of the GABA re-uptake inhibitor tiagabine on the rate constants of inhibitory interneurons. Remarkably, we were able to recover the pharmacodynamics of this effect over the course of several hours on a per subject basis. These findings speak to the possibility of measuring population specific synaptic function – and its response to pharmacological intervention – to provide subject-specific biomarkers of mesoscopic neuronal processes using non-invasive data. Finally, our results demonstrate that, using the CMC as a proxy, the synaptic mechanisms that underlie the gain control of neuronal message passing within and between different levels of cortical hierarchies may now be amenable to quantitative study using non-invasive (MEG) procedures

Updated adolescent diagnostic criteria for polycystic ovary syndrome: impact on prevalence and longitudinal body mass index trajectories from birth to adulthood

Background: Polycystic ovary syndrome (PCOS) is challenging to diagnose. While the 2003 Rotterdam criteria are widely used for adults, the 2018 international PCOS guideline recommended updated Rotterdam criteria with both hyperandrogenism and oligo-anovulation for adolescents based on evidence-informed expert consensus. This study compared the prevalence of PCOS using updated and original Rotterdam criteria in community-based adolescents and explored long-term body mass index (BMI) trajectories across different diagnostic phenotypes. Methods: Overall, 227 postmenarchal adolescent females from the prospective cohort Raine Study undertook comprehensive PCOS assessment at age 14–16 years. Detailed anthropometric measurements were collected from birth until age 22 years. Cross-sectional and longitudinal BMI were analyzed using t tests and generalized estimating equations. Results: PCOS was diagnosed in 66 (29.1%) participants using original criteria versus 37 (16.3%) participants using updated Rotterdam criteria. Using updated criteria, participants with PCOS had higher BMI than participants without PCOS from prepubertal. Only the phenotype meeting the updated criteria was significantly associated with higher long-term BMI gain whereas other PCOS phenotypes had similar BMI trajectories to participants without PCOS (p < 0.001). Conclusions: The use of the 2018 updated Rotterdam criteria reduces over-diagnosis of PCOS in adolescents and identifies those at the greatest risk of long-term weight gain, a key contributor to disease severity and long-term health implications. The BMI trajectories of females with PCOS on updated criteria diverge prepubertally compared to those without PCOS. This work supports targeting adolescents diagnosed with PCOS on the 2018 updated criteria for early lifestyle interventions to prevent long-term health complications.Chau Thien Tay, Roger J. Hart, Martha Hickey, Lisa J. Moran, Arul Earnest, Dorota A. Doherty, Helena J. Teede and Anju E. Joha

Recommendations from the 2023 International Evidence-based Guideline for the Assessment and Management of Polycystic Ovary Syndrome

STUDY QUESTION: What is the recommended assessment and management of those with polycystic ovary syndrome (PCOS), based on the best available evidence, clinical expertise, and consumer preference? SUMMARY ANSWER: International evidence-based guidelines address prioritized questions and outcomes and include 254 recommendations and practice points, to promote consistent, evidence-based care and improve the experience and health outcomes in PCOS. WHAT IS KNOWN ALREADY: The 2018 International PCOS Guideline was independently evaluated as high quality and integrated multidisciplinary and consumer perspectives from six continents; it is now used in 196 countries and is widely cited. It was based on best available, but generally very low to low quality, evidence. It applied robust methodological processes and addressed shared priorities. The guideline transitioned from consensus based to evidence-based diagnostic criteria and enhanced accuracy of diagnosis, whilst promoting consistency of care. However, diagnosis is still delayed, the needs of those with PCOS are not being adequately met, evidence quality was low and evidence-practice gaps persist. STUDY DESIGN, SIZE, DURATION: The 2023 International Evidence-based Guideline update reengaged the 2018 network across professional societies and consumer organizations, with multidisciplinary experts and women with PCOS directly involved at all stages. Extensive evidence synthesis was completed. Appraisal of Guidelines for Research and Evaluation-II (AGREEII)-compliant processes were followed. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework was applied across evidence quality, feasibility, acceptability, cost, implementation and ultimately recommendation strength and diversity and inclusion were considered throughout. PARTICIPANTS/MATERIALS, SETTING, METHODS: This summary should be read in conjunction with the full Guideline for detailed participants and methods. Governance included a six-continent international advisory and management committee, five guideline development groups, and paediatric, consumer, and translation committees. Extensive consumer engagement and guideline experts informed the update scope and priorities. Engaged international society-nominated panels included paediatrics, endocrinology, gynaecology, primary care, reproductive endocrinology, obstetrics, psychiatry, psychology, dietetics, exercise physiology, obesity care, public health and other experts, alongside consumers, project management, evidence synthesis, statisticians and translation experts. Thirty-nine professional and consumer organizations covering 71 countries engaged in the process. Twenty meetings and five face-to-face forums over 12 months addressed 58 prioritized clinical questions involving 52 systematic and 3 narrative reviews. Evidence-based recommendations were developed and approved via consensus across five guideline panels, modified based on international feedback and peer review, independently reviewed for methodological rigour, and approved by the Australian Government National Health and Medical Research Council (NHMRC). MAIN RESULTS AND THE ROLE OF CHANCE: The evidence in the assessment and management of PCOS has generally improved in the past five years, but remains of low to moderate quality. The technical evidence report and analyses (∼6000 pages) underpins 77 evidence-based and 54 consensus recommendations, with 123 practice points. Key updates include: i) further refinement of individual diagnostic criteria, a simplified diagnostic algorithm and inclusion of anti-Müllerian hormone (AMH) levels as an alternative to ultrasound in adults only; ii) strengthening recognition of broader features of PCOS including metabolic risk factors, cardiovascular disease, sleep apnea, very high prevalence of psychological features, and high risk status for adverse outcomes during pregnancy; iii) emphasizing the poorly recognized, diverse burden of disease and the need for greater healthcare professional education, evidence-based patient information, improved models of care and shared decision making to improve patient experience, alongside greater research; iv) maintained emphasis on healthy lifestyle, emotional wellbeing and quality of life, with awareness and consideration of weight stigma; and v) emphasizing evidence-based medical therapy and cheaper and safer fertility management. LIMITATIONS, REASONS FOR CAUTION: Overall, recommendations are strengthened and evidence is improved, but remains generally low to moderate quality. Significantly greater research is now needed in this neglected, yet common condition. Regional health system variation was considered and acknowledged, with a further process for guideline and translation resource adaptation provided. WIDER IMPLICATIONS OF THE FINDINGS: The 2023 International Guideline for the Assessment and Management of PCOS provides clinicians and patients with clear advice on best practice, based on the best available evidence, expert multidisciplinary input and consumer preferences. Research recommendations have been generated and a comprehensive multifaceted dissemination and translation program supports the Guideline with an integrated evaluation program. STUDY FUNDING/COMPETING INTEREST(S): This effort was primarily funded by the Australian Government via the National Health Medical Research Council (NHMRC) (APP1171592), supported by a partnership with American Society for Reproductive Medicine, Endocrine Society, European Society for Human Reproduction and Embryology, and European Society for Endocrinology. The Commonwealth Government of Australia also supported Guideline translation through the Medical Research Future Fund (MRFCRI000266). HJT and AM are funded by NHMRC fellowships. JT is funded by a Royal Australasian College of Physicians (RACP) fellowship. Guideline development group members were volunteers. Travel expenses were covered by the partnering organizations. Disclosures of interest were strictly managed according to NHMRC policy and are available with the full guideline, technical evidence report, peer review and responses (www.monash.edu/medicine/mchri/pcos). Of named authors HJT, CTT, AD, LM, LR, JBoyle, AM have no conflicts of interest to declare. JL declares grant from Ferring and Merck; consulting fees from Ferring and Titus Health Care; speaker's fees from Ferring; unpaid consultancy for Ferring, Roche Diagnostics and Ansh Labs; and sits on advisory boards for Ferring, Roche Diagnostics, Ansh Labs, and Gedeon Richter. TP declares a grant from Roche; consulting fees from Gedeon Richter and Organon; speaker's fees from Gedeon Richter and Exeltis; travel support from Gedeon Richter and Exeltis; unpaid consultancy for Roche Diagnostics; and sits on advisory boards for Roche Diagnostics. MC declares travels support from Merck; and sits on an advisory board for Merck. JBoivin declares grants from Merck Serono Ltd.; consulting fees from Ferring B.V; speaker's fees from Ferring Arzneimittell GmbH; travel support from Organon; and sits on an advisory board for the Office of Health Economics. RJN has received speaker's fees from Merck and sits on an advisory board for Ferring. AJoham has received speaker's fees from Novo Nordisk and Boehringer Ingelheim. The guideline was peer reviewed by special interest groups across our 39 partner and collaborating organizations, was independently methodologically assessed against AGREEII criteria and was approved by all members of the guideline development groups and by the NHMRC.</p

Low energy scattering cross section ratios of N 14 (p,p) N 14

Background: The slowest reaction in the first CNO cycle is N14(p,γ)O15, therefore its rate determines the overall energy production efficiency of the entire cycle. The cross section presents several strong resonance contributions, especially for the ground-state transition. Some of the properties of the corresponding levels in the O15 compound nucleus remain uncertain, which affects the uncertainty in extrapolating the capture cross section to the low energy range of astrophysical interest. Purpose: The N14(p,γ)O15 cross section can be described by using the phenomenological R matrix. Over the energy range of interest, only the proton and γ-ray channels are open. Since resonance capture makes significant contributions to the N14(p,γ)O15 cross section, resonant proton scattering data can be used to provide additional constraints on the R-matrix fit of the capture data. Methods: A 4 MV KN Van de Graaff accelerator was used to bombard protons onto a windowless gas target containing enriched N14 gas over the proton energy range from Ep=1.0 to 3.0 MeV. Scattered protons were detected at θlab=90, 120°, 135°, 150°, and 160° using ruggedized silicon detectors. In addition, a 10 MV FN Tandem Van de Graaff accelerator was used to accelerate protons onto a solid Adenine (C5H5N5) target, of natural isotopic abundance, evaporated onto a thin self-supporting carbon backing, over the energy range from Ep=1.8 to 4.0 MeV. Scattered protons were detected at 28 angles between θlab=30.4° and 167.7° by using silicon photodiode detectors. Results: Relative cross sections were extracted from both measurements. While the relative cross sections do not provide as much constraint as absolute measurements, they greatly reduce the dependence of the data on otherwise significant systematic uncertainties, which are more difficult to quantify. The data are fit simultaneously using an R-matrix analysis and level energies and proton widths are extracted. Even with relative measurements, the statistics and large angular coverage of the measurements result in more confident values for the energies and proton widths of several levels; in particular, the broad resonance at Ec.m.=2.21 MeV, which corresponds to the 3/2+ level at Ex=9.51 MeV in O15. In particular, the s- and d-wave angular-momentum channels are separated. Conclusion: The relative cross sections provide a consistent set of data that can be used to better constrain a full multichannel R-matrix extrapolation of the capture data. It has been demonstrated how the scattering data reduce the uncertainty through a preliminary Monte Carlo uncertainty analysis, but several other issues remain that make large contributions to the uncertainty, which must be addressed by further capture and lifetime measurements

Non-antibiotic pharmaceuticals exhibit toxicity against Escherichia coli at environmentally relevant concentrations with no evolution of cross-resistance to antibiotics

Antimicrobial resistance can arise in the natural environment via prolonged exposure to the effluent surrounding manufacturing facilities. These facilities also produce non-antibiotic pharmaceuticals, and the effect of these on the surrounding microbial communities is less clear; whether they have inherent toxicity, or whether long-term exposure might select for cross-resistance to antibiotics. To this end, we screened four non-antibiotic pharmaceuticals (acetaminophen, ibuprofen, propranolol, met formin) and titanium dioxide for toxicity against Escherichia coli K-12 MG1655 and conducted a 30 day selection experiment to assess the effect of long-term exposure. All compounds reduced the maximum optical density reached by E. coli at a range of concentrations including one of environmental relevance, with transcriptome analysis identifying upregulated genes related to stress response and multidrug efflux in response ibuprofen treatment. The non-antibiotic pharmaceuticals did not select for significant genetic changes following a 30 day exposure, and no evidence of selection for cross-resistance to antibiotics was observed for population evolved in the presence of ibuprofen in spite of the differential gene expression after exposure to this compound. This work suggests that these non-antibiotic pharmaceuticals, at environmental concentrations, do not select for cross-resistance to antibiotics in E. coli