A Comparison of the Performance of SARS-CoV-2 Antibody Assays in Healthcare Workers with COVID-19.

Aims Since its emergence, significant interest surrounds the use of SARS-CoV-2 serological tests as an alternative or as an adjunct to molecular testing. However, given the speed of this pandemic, paralleled with the pressure to develop and provide serological tests in an expediated manner, not every assay has undergone the rigorous evaluation that is usually associated with medical diagnostic assays. We aimed to examine the performance of several commercially available SARS-CoV-2 IgG antibody assays among participants with confirmed COVID-19 disease and negative controls. Methods Serum taken between day 17 and day 40 post onset of symptoms from 41 healthcare workers with RT-PCR confirmed COVID-19 disease, and pre-pandemic serum from 20 negative controls, were tested for the presence of SARS-CoV-2 IgG using 7 different assays including point-of-care (POC) and laboratory-based assays. Results Assay performance varied. The lab-based Abbott diagnostics SARS-CoV-2 IgG assay proved to be the assay with the best positive and negative predictive value, and overall accuracy. The POC Nal von Minden GmbH and Biozek assays also performed well. Conclusion Our research demonstrates the variations in performance of several commercially available SARS-CoV-2 antibody assays. These findings identify the limitations of some serological tests for SARS-CoV-2. This information will help inform test selection and may have particular relevance to providers operating beyond accredited laboratories.

The effects of feedback on stability and maneuverability of a phase-reduced model for cockroach locomotion.

In previous work, we built a neuromechanical model for insect locomotion in the horizontal plane, containing a central pattern generator, motoneurons, muscles actuating jointed legs, and rudimentary proprioceptive feedback. This was subsequently simplified to a set of 24 phase oscillators describing motoneuronal activation of agonist-antagonist muscle pairs, which facilitates analyses and enables simulations over multi-dimensional parameter spaces. Here we use the phase-reduced model to study dynamics and stability over the typical speed range of the cockroach Blaberus discoidalis, the effects of feedback on response to perturbations, strategies for turning, and a trade-off between stability and maneuverability. We also compare model behavior with experiments on lateral perturbations, changes in body mass and moment of inertia, and climbing dynamics, and we present a simple control strategy for steering using exteroceptive feedback.

Abnormal vocal cord movement in patients with and without airway obstruction and asthma symptoms.

BACKGROUND: Abnormal vocal cord movements can cause laryngeal extrathoracic airway obstruction (often called vocal cord dysfunction - VCD) leading to asthma-like symptoms. These aberrant movements are characteristically present during inspiration and termed paradoxical vocal cord movement (PVCM). We have reported PVCM in up to 40% of severe asthmatics, but it is not known if PVCM is detectable in all patients with asthma-like symptoms and if the condition is more often associated with abnormal lung function. OBJECTIVE: We hypothesized that PVCM is frequently associated with asthma symptoms accompanied by airflow limitation. Studies examined whether PVCM is solely linked to experiencing asthma symptoms, or if PVCM is related to airflow limitation and/or other disease characteristics. METHODS: Patients with asthma symptoms were recruited from general practice and severe asthma clinics (n = 155). Pulmonary function measurements were conducted, asthma control and Nijmegen (dysfunctional breathing) questionnaires were administered and skin prick testing was carried out. PVCM was quantified using dynamic 320-slice computerized tomography of the larynx. Groups were divided into patients with FEV1 ≥ 80% predicted or FEV1 < 80% predicted and FEV1 /FVC < 0.7. ATS/ERS definitions of severity were also applied and evaluated. Detection of PVCM in the groups was compared and analyses performed to identify features associated with PVCM. RESULTS: Overall (n = 155), PVCM was detected in 42 cases (27.1%). Patients with FEV1 < 80% predicted had PVCM more often (25/68, 36.8%) than individuals with normal spirometry (17/87, 19.5%; P = 0.016). PVCM was associated with older age (P = 0.003) and with Nijmegen scores > 20 (P = 0.04). Patients with FEV1 < 80% predicted plus Nijmegen scores > 20 were more likely to have PVCM (OR = 9.3, P = 0.02). CONCLUSIONS AND CLINICAL RELEVANCE: Paradoxical vocal cord movement is more often associated with asthma symptoms accompanied by airflow limitation and dysfunctional breathing. Further studies are needed to determine whether PVCM is induced by dysfunctional breathing practices and/or airway obstruction. How PVCM links with symptomatic asthma and VCD also requires evaluation.

Where does the Albumin go? Human Albumin Solution usage following the implementation of a demand management programme.

OBJECTIVE: To outline the Guy's and St Thomas' NHS Foundation Trust (GSTFT) and Evelina London Children's Hospital (ELCH) demand management plan for human albumin solution (HAS) and usage. BACKGROUND: There is no UK-wide guidance governing the use of HAS. A severe shortage in 2015 prompted a Trust demand management programme. Indications were categorised according to locally agreed colour code and ASFA categories. METHODS: Following the implementation of the demand management programme, a 6-month audit of HAS usage was completed. RESULTS: A total of 1303.1 L of HAS was used in 1139 infusions; 737 infusions were 20% HAS, accounting for 175.7 L (13.5%) in 181 patients. Indications for 20% HAS were red in 53.9% (94.7 L), blue in 26.5% (46.5 L) and grey in 19.6% (34.5 L). The remaining 1127.4 L (86.5%) infused were of 4.5 and 5 % HAS. A total of 1102.3 L (97.8%) was used for plasma exchange, 941.4 L (85.4%) ASFA category I, 93.7 L (8.5%) category II, 25.5 L (2.3%) category IV and 41.7 L (3.8%) for indications not specified according to ASFA; 25.1 L (2.2%) were used for a grey indication (volume resuscitation for hypovolaemia). CONCLUSIONS: The demand management programme provides surveillance of indications and retrospective verification of appropriate use. The majority of HAS indications were appropriate. Plasma exchange accounted for 84.6% of HAS usage and will be the focus of further demand management strategies. The demand management programme whilst aiming to promote best transfusion practice also ensures a tool to manage future shortages according to indication and available supply.

Sensory feedback in cockroach locomotion: current knowledge and open questions.

The American cockroach, Periplaneta americana, provides a successful model for the study of legged locomotion. Sensory regulation and the relative importance of sensory feedback vs. central control in animal locomotion are key aspects in our understanding of locomotive behavior. Here we introduce the cockroach model and describe the basic characteristics of the neural generation and control of walking and running in this insect. We further provide a brief overview of some recent studies, including mathematical modeling, which have contributed to our knowledge of sensory control in cockroach locomotion. We focus on two sensory mechanisms and sense organs, those providing information related to loading and unloading of the body and the legs, and leg-movement-related sensory receptors, and present evidence for the instrumental role of these sensory signals in inter-leg locomotion control. We conclude by identifying important open questions and indicate future perspectives.

Cellular and humoral immunogenicity of the COVID-19 vaccine and COVID-19 disease severity in individuals with immunodeficiency.

Background: A well-coordinated adaptive immune response is crucial for limiting COVID-19 disease. Some individuals with immunodeficiency are at a high risk of developing severe COVID-19. Therefore, the development of standardized methods for measuring different arms of the vaccine response in the setting of immunodeficiency is of particular interest. In this study, we compared the vaccine response of individuals living with immunodeficiency with healthy controls in terms of interferon gamma (IFN-γ) production and spike protein-specific antibody level post primary COVID-19 vaccination and booster vaccines. Additionally, the disease severity of those individuals who contracted COVID-19 was assessed. Methods: Whole blood was stimulated overnight from 71 participants and 99 healthy controls. Commercially available PepTivator® peptide pool and trimeric spike protein stimulation were used. ELISA was used to analyze IFN-γ levels. The total SARS-CoV-2 spike protein antibody titre was measured using a Roche Elecsys® S total antibody assay. Patient characteristics, COVID-19 infection status and IDDA 2.1 'Kaleidoscope' scores were recorded. Vaccine responses were scored from zero to three. Results: 99% of healthy controls, 89% of individuals with IEI and 76% with secondary immunodeficiency (SID) had an IFN-γ level above the validated reference range after peptide mix stimulation following primary vaccination. There was an increase in IFN-γ levels in patients with inborn errors of immunity (IEI) following the booster vaccine (p = 0.0156). 100% of healthy controls, 70% of individuals living with IEI and 64% of individuals living with SID had detectable spike protein-specific antibody levels following the primary vaccination. 55% of immunodeficiency patients who had mild COVID-19 and 10% with moderate/severe COVID-19 had detectable antibody and IFN-γ levels post vaccine. The mean pre-infection IDDA 2.1 scores were higher in individuals who developed moderate/severe COVID-19 (25.2 compared to 9.41). Conclusions: Covid whole-blood IGRA is a highly accurate, straightforward and robust assay and can be easily adapted to measure cellular response to COVID-19. A complete evaluation of the vaccine response may be particularly important for individuals living with immunodeficiency. A clinical immunodeficiency score and a validated vaccine response score may be valuable tools in estimating COVID-19 disease risk and identifying individuals living with immunodeficiency who may benefit from enhanced vaccination schedules.

Occupation and cancer in Britain.

BACKGROUND: Prioritising control measures for occupationally related cancers should be evidence based. We estimated the current burden of cancer in Britain attributable to past occupational exposures for International Agency for Research on Cancer (IARC) group 1 (established) and 2A (probable) carcinogens. METHODS: We calculated attributable fractions and numbers for cancer mortality and incidence using risk estimates from the literature and national data sources to estimate proportions exposed. RESULTS: 5.3% (8019) cancer deaths were attributable to occupation in 2005 (men, 8.2% (6362); women, 2.3% (1657)). Attributable incidence estimates are 13 679 (4.0%) cancer registrations (men, 10 063 (5.7%); women, 3616 (2.2%)). Occupational attributable fractions are over 2% for mesothelioma, sinonasal, lung, nasopharynx, breast, non-melanoma skin cancer, bladder, oesophagus, soft tissue sarcoma, larynx and stomach cancers. Asbestos, shift work, mineral oils, solar radiation, silica, diesel engine exhaust, coal tars and pitches, occupation as a painter or welder, dioxins, environmental tobacco smoke, radon, tetrachloroethylene, arsenic and strong inorganic mists each contribute 100 or more registrations. Industries and occupations with high cancer registrations include construction, metal working, personal and household services, mining, land transport, printing/publishing, retail/hotels/restaurants, public administration/defence, farming and several manufacturing sectors. 56% of cancer registrations in men are attributable to work in the construction industry (mainly mesotheliomas, lung, stomach, bladder and non-melanoma skin cancers) and 54% of cancer registrations in women are attributable to shift work (breast cancer). CONCLUSION: This project is the first to quantify in detail the burden of cancer and mortality due to occupation specifically for Britain. It highlights the impact of occupational exposures, together with the occupational circumstances and industrial areas where exposures to carcinogenic agents occurred in the past, on population cancer morbidity and mortality; this can be compared with the impact of other causes of cancer. Risk reduction strategies should focus on those workplaces where such exposures are still occurring.

Reflexes and preflexes: on the role of sensory feedback on rhythmic patterns in insect locomotion.

Neuromuscular systems are stabilized and controlled by both feedforward and feedback signals. Feedforward pathways driven by central pattern generators (CPGs), in conjunction with preflexive mechanical reaction forces and nonlinear muscle properties, can produce stable stereotypical gaits. Feedback is nonetheless present in both slow and rapid running, and preflexive mechanisms can join with neural reflexes originating in proprioceptive sensors to yield robust behavior in uncertain environments. Here, we develop a single degree-of-freedom neuromechanical model representing a joint actuated by an agonist/antagonist muscle pair driven by motoneurons and a CPG in a periodic rhythm characteristic of locomotion. We consider two characteristic feedback modes: phasic and tonic. The former encodes states such as position in the timing of individual spikes, while the latter can transmit graded measures of force and other continuous variables as spike rates. We use results from phase reduction and averaging theory to predict phase relationships between CPG and motoneurons in the presence of feedback and compare them with simulations of the neuromechanical model, showing that both phasic and tonic feedback can shift motoneuronal timing and thereby affect joint motions. We find that phase changes in neural activation can cooperate with preflexive displacement and velocity effects on muscle force to compensate for externally applied forces, and that these effects qualitatively match experimental observations in the cockroach.

Combined action observation and motor imagery facilitates visuomotor adaptation in children with developmental coordination disorder.

The internal modelling deficit (IMD) hypothesis suggests that motor control issues associated with Developmental Coordination Disorder (DCD) are the result of impaired predictive motor control. In this study, we examined the benefits of a combined action observation and motor imagery (AO + MI) intervention designed to alleviate deficits in internal modelling and improve eye-hand coordination during a visuomotor rotation task. Twenty children with DCD were randomly assigned to either an AO + MI group (who watched a video of a performer completing the task whilst simultaneously imagining the kinaesthetic sensations associated with action execution) or a control group (who watched unrelated videos involving no motor content). Each group then attempted to learn a 90° visuomotor rotation while measurements of completion time, eye-movement behaviour and movement kinematics were recorded. As predicted, after training, the AO + MI group exhibited quicker completion times, more target-focused eye-movement behaviour and smoother movement kinematics compared to the control group. No significant after-effects were present. These results offer further support for the IMD hypothesis and suggest that AO + MI interventions may help to alleviate such deficits and improve motor performance in children with DCD.

Nonlinear muscles, passive viscoelasticity and body taper conspire to create neuromechanical phase lags in anguilliform swimmers.

Locomotion provides superb examples of cooperation among neuromuscular systems, environmental reaction forces, and sensory feedback. As part of a program to understand the neuromechanics of locomotion, here we construct a model of anguilliform (eel-like) swimming in slender fishes. Building on a continuum mechanical representation of the body as an viscoelastic rod, actuated by a traveling wave of preferred curvature and subject to hydrodynamic reaction forces, we incorporate a new version of a calcium release and muscle force model, fitted to data from the lamprey Ichthyomyzon unicuspis, that interactively generates the curvature wave. We use the model to investigate the source of the difference in speeds observed between electromyographic waves of muscle activation and mechanical waves of body curvature, concluding that it is due to a combination of passive viscoelastic and geometric properties of the body and active muscle properties. Moreover, we find that nonlinear force dependence on muscle length and shortening velocity may reduce the work done by the swimming muscles in steady swimming.

Neuromechanical models for insect locomotion: Stability, maneuverability, and proprioceptive feedback.

We describe a hierarchy of models for legged locomotion, emphasizing relationships among feedforward (preflexive) stability, maneuverability, and reflexive feedback. We focus on a hexapedal geometry representative of insect locomotion in the ground plane that includes a neural central pattern generator circuit, nonlinear muscles, and a representative proprioceptive sensory pathway. Although these components of the model are rather complex, neglect of leg mass yields a neuromechanical system with only three degrees of freedom, and numerical simulations coupled with a Poincaré map analysis shows that the feedforward dynamics is strongly stable, apart from one relatively slow mode and a neutral mode in body yaw angle. These modes moderate high frequency perturbations, producing slow heading changes that can be corrected by a stride-to-stride steering strategy. We show that the model's response to a lateral impulsive perturbation closely matches that of a cockroach subject to a similar impulse. We also describe preliminary studies of proprioceptive leg force feedback, showing how a reflexive pathway can reinforce the preflexive stability inherent in the system.

Systemic humoral immunity to non-typeable Haemophilus influenzae.

Non-typeable Haemophilus influenzae (NTHi) is a major cause of respiratory but rarely systemic infection. The host defence to this bacterium has not been well defined in patients with chronic airway infection. The aim of this study was to assess the effect of humoral immunity in host defence to NTHi. Responses were measured in control and bronchiectasis subjects who had recurrent bronchial infection. Antibody and complement-mediated killing was assessed by incubating NTHi with serum and the role of the membrane-attack complex and classical/alternate pathways of complement activation measured. The effect of one strain to induce protective immunity against other strains was assessed. The effect of antibody on granulocyte intracellular killing of NTHi was also measured. The results showed that both healthy control subjects and bronchiectasis patients all had detectable antibody to NTHi of similar titre. Both groups demonstrated effective antibody/complement-mediated killing of different strains of NTHi. This killing was mediated through the membrane-attack complex and the classical pathway of complement activation. Immunization of rabbits with one strain of NTHi resulted in protection from other strains in vitro. Antibody activated granulocytes to kill intracellular bacteria. These findings may explain why NTHi rarely causes systemic disease in patients with chronic respiratory mucosal infection and emphasize the potential importance of cellular immunity against this bacterium.

Cytotoxic T lymphocyte and natural killer cell responses to non-typeable Haemophilus influenzae.

Cytotoxic T lymphocytes (CTL) and natural killer (NK) cells have a key role in host defence against infectious pathogens, but their response to bacteria is not well characterized. Non-typeable Haemophilus influenzae is a major cause of respiratory tract infection including otitis media, sinusitis, tonsillitis and chronic bronchitis (especially in chronic obstructive pulmonary disease and bronchiectasis). This bacterium is also present in the pharynx of most healthy adults. The primary factor that may determine whether clinical disease occurs or not is the nature of the lymphocyte response. Here we examined the CTL cell and NK cell responses to nontypeable H. influenzae in healthy control subjects and in subjects who had bronchiectasis and recurrent bronchial infection with this bacterium. Cells were stimulated with live H. influenzae and intracellular cytokine production and release of cytotoxic granules measured. Control subjects had significantly higher levels of interferon gamma production by both CTL and NK cells, while levels of cytotoxic granule release were similar in both groups. The main lymphocyte subsets that proliferated in response to H. influenzae stimulation were the CTL and NK cells. The results suggest that CTL and NK cell responses may be important in preventing disease from nontypeable H. influenzae infection.

On diffusion processes with variable drift rates as models for decision making during learning.

We investigate Ornstein-Uhlenbeck and diffusion processes with variable drift rates as models of evidence accumulation in a visual discrimination task. We derive power-law and exponential drift-rate models and characterize how parameters of these models affect the psychometric function describing performance accuracy as a function of stimulus strength and viewing time. We fit the models to psychophysical data from monkeys learning the task to identify parameters that best capture performance as it improves with training. The most informative parameter was the overall drift rate describing the signal-to-noise ratio of the sensory evidence used to form the decision, which increased steadily with training. In contrast, secondary parameters describing the time course of the drift during motion viewing did not exhibit steady trends. The results indicate that relatively simple versions of the diffusion model can fit behavior over the course of training, thereby giving a quantitative account of learning effects on the underlying decision process.

Immune reconstitution inflammatory syndrome associated with Kaposi's sarcoma.

PURPOSE: A proportion of patients with HIV infection who subsequently receive highly active antiretroviral therapy (HAART) exhibit a deterioration in their clinical status, despite control of virologic and immunologic parameters. This clinical response, known as the immune reconstitution inflammatory syndrome (IRIS), occurs secondary to an immune response against previously diagnosed pathogens. PATIENTS AND METHODS: From our cohort of 5,832 patients treated in the HAART era, we identified 150 therapy-naive patients with a first presentation of Kaposi's sarcoma (KS). Their clinicopathologic features and progress were recorded prospectively. RESULTS: After commencing HAART, ten patients (6.6%) developed progressive KS, which we identify as IRIS-associated KS. In a comparison of these individuals with those whose KS did not progress, we found that IRIS-KS occurred in patients with higher CD4 counts (P = .03), KS-associated edema (P = .01), and therapy with both protease inhibitors and non-nucleosides together (P = .03). Time to treatment failure was similar for both groups, although the CD4 count declined more rapidly at first, in those patients with IRIS-associated KS. Despite this initial decline, in our clinical experience HAART could be successfully continued in those with IRIS-associated KS. CONCLUSION: We have identified IRIS-KS in a cohort of HIV patients with KS who start HAART.

Bronchiectasis.

Bronchiectasis is generally classified into cystic fibrosis and non-cystic fibrosis bronchiectasis. This review article describes non-cystic fibrosis bronchiectasis in adults. Bronchiectasis can be considered a heterogeneous condition characterized by irreversible airway dilatation with chronic bronchial infection/inflammation. It remains a common condition and is a major cause of respiratory morbidity. Many factors are associated with bronchiectasis, but most commonly patients will have idiopathic disease. Important clinical findings include chronic productive cough, rhinosinusitis, fatigue and bi-basal crackles. Patients have usually had symptoms for many years. Diagnosis is confirmed by high-resolution computed tomography scanning using standardized criteria. Spirometry shows moderate airflow obstruction and there is a high prevalence of bronchial hyperreactivity. The most common pathogens are non-typeable Haemophilus influenzae and Pseudomonas aeruginosa. There may be considerable overlap with other chronic airway diseases. Treatment regimens are still not well defined. Patients tend to have ongoing symptoms and decline in respiratory function despite treatment.

Comparison of Australian and international guidelines for grading severity of chronic obstructive pulmonary disease.

AIM: To compare grading of chronic obstructive pulmonary disease (COPD) using Australian guidelines Confirm diagnosis, Optimize function, Prevent deterioration, Develop a self-management plan and manage eXacerbations (COPD-X) versus Global initiative for Obstructive Lung Disease (GOLD) guidelines and to assess whether this is associated with differences in other health domains affected by COPD. Adult outpatients (n = 61) with COPD were studied using lung function measurements, six-minute walk test and body composition assessments. Subjects also completed self-rated dyspnoea scores and health-related quality-of-life scales. For each patient, COPD severity was graded using both COPD-X and GOLD guidelines, and results were collectively analysed. If significant discrepancies were observed, comparisons of other health domains were carried out. After grading severity using COPD-X and GOLD guidelines, significant discrepancies were noted. Of nine subjects with no disease (normal) based on COPD-X, seven were judged to be 'mild' according to GOLD. Similarly, 11 of 12 patients with mild disease (COPD-X) had 'moderate' disease judged by GOLD, and 9 of 23 with moderate severity (COPD-X) had 'severe' COPD using GOLD. Finally, 6 of 17 patients with COPD-X-rated severe disease had 'very severe' disease using the GOLD criteria. Among patients with COPD-X severe disease, those with GOLD discordant (very severe) severity had a poorer quality of life compared with those with GOLD concordant (severe) severity (P = 0.006). Similarly, there was also a trend towards lower six-minute walk test distance and greater subjective dyspnoea in GOLD very severe patients compared with GOLD severe patients. Significant discrepancies in grading of severity exist between Australian and international COPD guidelines. Current Australian guidelines for severity grading may not fully reflect the effect COPD has on other key domains of health.

A single centre cohort experience with a new once daily antiretroviral drug.

BACKGROUND: Atazanavir, an azadipeptide protease inhibitor (PI) with once daily dosing, a lack of insulin resistance, lipid increase, and gastrointestinal toxicities, is approved in combination with other antiretrovirals for the treatment of patients infected with HIV. Unboosted atazanavir is also used in highly active antiretroviral therapy (HAART) naive patients. METHODS: The study prospectively followed up an established cohort of patients who received atazanavir, and for whom one year of follow up data were available. RESULTS: It was found that use of atazanavir in intent to treat and on treatment analyses, maintained and led to virological suppression and increases in CD4 count in both PI naive and experienced patients. Virological failure occurred in 7% of patients and the main toxicity was hyperbilirubinaemia, which led to treatment withdrawal in 2%. Its efficacy and safety profile was similar to that seen in previous randomised studies investigating its use. CONCLUSIONS: These data should provide reassurance for clinicians wishing to introduce a new antiretroviral into an established cohort.

Effect of 3-methylcholanthrene on atherosclerosis in two congenic strains of mice with different susceptibilities to methylcholanthrene-induced tumors.

Inbred mouse strains AKXL-38 and AKXL-38a are congenic strains that differ at the Ah locus, a gene which affects the inducibility of the cytochrome P-450 enzymes. The Ah-responsive strain, AKXL-38a, is more susceptible to 3-methylcholanthrene-induced tumors than the Ah-nonresponsive strain, AKXL-38. We previously reported that 3-methylcholanthrene (MC) increased the number and the size of atherosclerotic lesions in a dose-dependent fashion. We now demonstrate that the effect of MC is greater in Ah-responsive mice than in Ah-nonresponsive mice indicating that Ah-responsive mice not only are more susceptible to MC-induced cancer but also are more susceptible to MC-enhanced atherosclerosis. Mice that received atherogenic diet for 14 weeks but no MC had 1.3-1.4 lesions/mouse regardless of genetic type. When mice were treated with MC, the number of lesions increased to 2.1 +/- 0.1 (SE) in Ah-nonresponsive mice, 2.6 +/- 0.2 in Ah-responsive mice, and 2.3 +/- 0.2 in the F1 hybrid. The total area involved in lesions was 9.3-12.6 micron2 in untreated animals. When mice were treated with MC, the total lesion area increased to 23.5 +/- 5.2 micron2 in Ah-nonresponsive mice, to 43.9 +/- 6.6 micron2 in Ah-responsive mice, and to 36.2 +/- 4.8 micron2 in F1 hybrids. Thus MC increased the lesion area in both strains of mice, but the increase was significantly greater in Ah-responsive than in Ah-nonresponsive animals. High density lipoprotein levels were not significantly affected by MC treatment or Ah genotype. In order to determine whether the increased susceptibility to MC-induced atherosclerosis segregated with the Ah gene, AKXL-38 and AKXL-38a mice were mated and the F1 progeny were backcrossed to the Ah-nonresponsive parent. Backcross progeny were tested for Ah genotype by zoxazolamine sleeping time. Measurements of lesions showed that increased susceptibility to MC-enhanced atherosclerosis segregated with the Ah locus.

Will big data yield new mathematics? An evolving synergy with neuroscience.

New mathematics has often been inspired by new insights into the natural world. Here we describe some ongoing and possible future interactions among the massive data sets being collected in neuroscience, methods for their analysis and mathematical models of the underlying, still largely uncharted neural substrates that generate these data. We start by recalling events that occurred in turbulence modelling when substantial space-time velocity field measurements and numerical simulations allowed a new perspective on the governing equations of fluid mechanics. While no analogous global mathematical model of neural processes exists, we argue that big data may enable validation or at least rejection of models at cellular to brain area scales and may illuminate connections among models. We give examples of such models and survey some relatively new experimental technologies, including optogenetics and functional imaging, that can report neural activity in live animals performing complex tasks. The search for analytical techniques for these data is already yielding new mathematics, and we believe their multi-scale nature may help relate well-established models, such as the Hodgkin-Huxley equations for single neurons, to more abstract models of neural circuits, brain areas and larger networks within the brain. In brief, we envisage a closer liaison, if not a marriage, between neuroscience and mathematics.