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New technologies and disruptions related to Coronavirus disease-2019 have led to expansion of decentralized approaches to clinical trials. Remote tools and methods hold promise for increasing trial efficiency and reducing burdens and barriers by facilitating participation outside of traditional clinical settings and taking studies directly to participants. The Trial Innovation Network, established in 2016 by the National Center for Advancing Clinical and Translational Science to address critical roadblocks in clinical research and accelerate the translational research process, has consulted on over 400 research study proposals to date. Its recommendations for decentralized approaches have included eConsent, participant-informed study design, remote intervention, study task reminders, social media recruitment, and return of results for participants. Some clinical trial elements have worked well when decentralized, while others, including remote recruitment and patient monitoring, need further refinement and assessment to determine their value. Partially decentralized, or “hybrid” trials, offer a first step to optimizing remote methods. Decentralized processes demonstrate potential to improve urban-rural diversity, but their impact on inclusion of racially and ethnically marginalized populations requires further study. To optimize inclusive participation in decentralized clinical trials, efforts must be made to build trust among marginalized communities, and to ensure access to remote technology.
Clinical trials conducted with incarcerated populations are rare. We present a case example of one such jail-based cancer prevention clinical trial to demonstrate the importance of including a theory-driven approach to intervention framing, novel experimental designs to boost access to low-risk trials, and retention strategies for long-term follow-up of hard-to-reach populations. As such we offer a social determinant of health framework to ensure cancer prevention research is conducted through the lenses of health promotion and health equity. Deviations from the gold-standard randomized control design, transparent systematic allotment, and street-based outreach retention strategies contribute to the feasibility of conducting clinical trials in carceral settings and after people leave jail. Best practices presented can be used in design and conduct of future clinical trials with criminal legal system-involved populations.
Blast related characteristics may contribute to the diversity of findings on whether mild traumatic brain injury sustained during war zone deployment has lasting cognitive effects. This study aims to evaluate whether a history of blast exposure at close proximity, defined as exposure within 30 feet, has long-term or lasting influences on cognitive outcomes among current and former military personnel.
Method:
One hundred participants were assigned to one of three groups based on a self-report history of blast exposure during combat deployments: 47 close blast, 14 non-close blast, and 39 comparison participants without blast exposure. Working memory, processing speed, verbal learning/memory, and cognitive flexibility were evaluated using standard neuropsychological tests. In addition, assessment of combat exposure and current post-concussive, posttraumatic stress, and depressive symptoms, and headache was performed via self-report measures. Variables that differed between groups were controlled as covariates.
Results:
No group differences survived Bonferroni correction for family-wise error rate; the close blast group did not differ from non-close blast and comparison groups on measures of working memory, processing speed, verbal learning/memory, or cognitive flexibility. Controlling for covariates did not alter these results.
Conclusion:
No evidence emerged to suggest that a history of close blast exposure was associated with decreased cognitive performance when comparisons were made with the other groups. Limited characterization of blast contexts experienced, self-report of blast distance, and heterogeneity of injury severity within the groups are the main limitations of this study.
Experiments are performed to investigate the effect of nose-tip bluntness on the instability mechanisms leading to boundary-layer transition on a $7^{\circ }$ half-angle cone in a Mach-6 free stream. The development of disturbances is characterized using a combination of high-speed calibrated schlieren images and pressure measurements, and the data are compared with results computed using the parabolized stability equations. The approximately 414 mm long cone model is equipped with an interchangeable nose tip ranging from sharp to 5.08 mm in radius. For nose tips with a radius $R_{N}<2.54\ {\rm mm}$, second-mode instability waves are the dominant mechanism leading to transition. Time-averaged frequency spectra computed from the calibrated schlieren visualizations and pressure measurements are used to compute the second-mode most-amplified frequencies and integrated amplification rates ($N$ factors). Good agreement is observed between the measurements and computations in the linear-growth regime for the sharp-nose configuration at each free-stream condition. Additionally, a bispectral analysis identifies quadratic phase locking of frequency content responsible for the growth of higher harmonics. For nose tips of $R_{N}\geqslant 2.54\ {\rm mm}$, the schlieren visualization region is upstream of the entropy-layer swallowing length, and second-mode waves are no longer visible within the boundary layer; instead, elongated, steeply inclined features believed to be associated with non-modal instability mechanisms develop between the entropy-layer and boundary-layer edges. Simultaneously acquired surface pressure measurements reveal high-frequency pressure oscillations similar to second-mode instability waves associated with the trailing edge of these non-modal features.
Gatherings where people are eating and drinking can increase the risk of getting and spreading SARS-CoV-2 among people who are not fully vaccinated; prevention strategies like wearing masks and physical distancing continue to be important for some groups. We conducted an online survey to characterise fall/winter 2020–2021 holiday gatherings, decisions to attend and prevention strategies employed during and before gatherings. We determined associations between practicing prevention strategies, demographics and COVID-19 experience. Among 502 respondents, one-third attended in person holiday gatherings; 73% wore masks and 84% practiced physical distancing, but less did so always (29% and 23%, respectively). Younger adults were 44% more likely to attend gatherings than adults ≥35 years. Younger adults (adjusted prevalence ratio (aPR) 1.53, 95% CI 1.19–1.97), persons who did not experience COVID-19 themselves or have relatives/close friends experience severe COVID-19 (aPR 1.56, 95% CI 1.18–2.07), and non-Hispanic White persons (aPR 1.57, 95% CI 1.13–2.18) were more likely to not always wear masks in public during the 2 weeks before gatherings. Public health messaging emphasizing consistent application of COVID-19 prevention strategies is important to slow the spread of COVID-19.
In this era of spatially resolved observations of planet-forming disks with Atacama Large Millimeter Array (ALMA) and large ground-based telescopes such as the Very Large Telescope (VLT), Keck, and Subaru, we still lack statistically relevant information on the quantity and composition of the material that is building the planets, such as the total disk gas mass, the ice content of dust, and the state of water in planetesimals. SPace Infrared telescope for Cosmology and Astrophysics (SPICA) is an infrared space mission concept developed jointly by Japan Aerospace Exploration Agency (JAXA) and European Space Agency (ESA) to address these questions. The key unique capabilities of SPICA that enable this research are (1) the wide spectral coverage
$10{-}220\,\mu\mathrm{m}$
, (2) the high line detection sensitivity of
$(1{-}2) \times 10^{-19}\,\mathrm{W\,m}^{-2}$
with
$R \sim 2\,000{-}5\,000$
in the far-IR (SAFARI), and
$10^{-20}\,\mathrm{W\,m}^{-2}$
with
$R \sim 29\,000$
in the mid-IR (SPICA Mid-infrared Instrument (SMI), spectrally resolving line profiles), (3) the high far-IR continuum sensitivity of 0.45 mJy (SAFARI), and (4) the observing efficiency for point source surveys. This paper details how mid- to far-IR infrared spectra will be unique in measuring the gas masses and water/ice content of disks and how these quantities evolve during the planet-forming period. These observations will clarify the crucial transition when disks exhaust their primordial gas and further planet formation requires secondary gas produced from planetesimals. The high spectral resolution mid-IR is also unique for determining the location of the snowline dividing the rocky and icy mass reservoirs within the disk and how the divide evolves during the build-up of planetary systems. Infrared spectroscopy (mid- to far-IR) of key solid-state bands is crucial for assessing whether extensive radial mixing, which is part of our Solar System history, is a general process occurring in most planetary systems and whether extrasolar planetesimals are similar to our Solar System comets/asteroids. We demonstrate that the SPICA mission concept would allow us to achieve the above ambitious science goals through large surveys of several hundred disks within
$\sim\!2.5$
months of observing time.
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.
Aims
To examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics.
Method
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.
Results
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.
Conclusions
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.
Secure forensic mental health services treat patient with high rates of treatment resistant psychoses, typically schizophrenia. These groups have high rates of obesity and medical co-morbidities. Population based studies have identified high risk groups in the event of SARS-CoV-2 infection, including those with long term medical conditions.
Objectives
The aim of this study was to compare the vulnerability to serious adverse outcome in the event of COVID-19 infection in a forensic psychiatric patient population.
Methods
All patients of a complete National Forensic Mental Health Service (n=141) were rated for risk of adverse outcome in the event of SARS-CoV-2 infection, using two structured tools, the COVID-AGE tool and the COVID-Risk tool.
Results
Eighty-two patients (58.2%) met criteria for obesity, 32 had type II diabetes and 28 were hypertensive. Mean chronological age was 45.5 years (SD 11.4, median 44.1), while mean COVID-AGE was 59.1 years (SD 19.4, median 58.0), mean difference 13.6 years (SD 15.6) paired t=10.9, df=140, p=0.000. Three patients (2.1%) were chronologically over 70 years compared to 40 (28.4%) with a COVID-AGE over 70 (X2=6.99, df=1, p=0.008, Fishers exact test p=0.027).
Conclusions
These risk assessments may identify the extent of increased risk among a uniquely medically vulnerable patient group. Patients in secure forensic psychiatric services represent a high-risk group for adverse outcomes in the event of SARS-COV-2 infection. Population based cocooning and self-isolating guidance based on chronological age may not be sufficient. There is an urgent need for better physical health research and treatment in this group.
We have adapted the Vera C. Rubin Observatory Legacy Survey of Space and Time (LSST) Science Pipelines to process data from the Gravitational-wave Optical Transient Observer (GOTO) prototype. In this paper, we describe how we used the LSST Science Pipelines to conduct forced photometry measurements on nightly GOTO data. By comparing the photometry measurements of sources taken on multiple nights, we find that the precision of our photometry is typically better than 20 mmag for sources brighter than 16 mag. We also compare our photometry measurements against colour-corrected Panoramic Survey Telescope and Rapid Response System photometry and find that the two agree to within 10 mmag (1
$\sigma$
) for bright (i.e.,
$\sim 14{\rm th} \mathrm{mag}$
) sources to 200 mmag for faint (i.e.,
$\sim 18{\rm th} \mathrm{mag}$
) sources. Additionally, we compare our results to those obtained by GOTO’s own in-house pipeline, gotophoto, and obtain similar results. Based on repeatability measurements, we measure a
$5\sigma$
L-band survey depth of between 19 and 20 magnitudes, depending on observing conditions. We assess, using repeated observations of non-varying standard Sloan Digital Sky Survey stars, the accuracy of our uncertainties, which we find are typically overestimated by roughly a factor of two for bright sources (i.e.,
$< 15{\rm th} \mathrm{mag}$
), but slightly underestimated (by roughly a factor of 1.25) for fainter sources (
$> 17{\rm th} \mathrm{mag}$
). Finally, we present lightcurves for a selection of variable sources and compare them to those obtained with the Zwicky Transient Factory and GAIA. Despite the LSST Software Pipelines still undergoing active development, our results show that they are already delivering robust forced photometry measurements from GOTO data.
Scanning transmission electron microscopy (STEM) allows for imaging, diffraction, and spectroscopy of materials on length scales ranging from microns to atoms. By using a high-speed, direct electron detector, it is now possible to record a full two-dimensional (2D) image of the diffracted electron beam at each probe position, typically a 2D grid of probe positions. These 4D-STEM datasets are rich in information, including signatures of the local structure, orientation, deformation, electromagnetic fields, and other sample-dependent properties. However, extracting this information requires complex analysis pipelines that include data wrangling, calibration, analysis, and visualization, all while maintaining robustness against imaging distortions and artifacts. In this paper, we present py4DSTEM, an analysis toolkit for measuring material properties from 4D-STEM datasets, written in the Python language and released with an open-source license. We describe the algorithmic steps for dataset calibration and various 4D-STEM property measurements in detail and present results from several experimental datasets. We also implement a simple and universal file format appropriate for electron microscopy data in py4DSTEM, which uses the open-source HDF5 standard. We hope this tool will benefit the research community and help improve the standards for data and computational methods in electron microscopy, and we invite the community to contribute to this ongoing project.
Research career development awards (CDAs) facilitate development of clinician-scientists. This study compared the academic achievements of individuals in a structured institutional “pre-K” CDA program, the Mayo Clinic Kern Scholars program, with individuals who applied for but were not admitted to the Kern program (“Kern applicants”), and awardees of other unstructured internal CDAs.
Methods:
This was a longitudinal cohort study of clinicians engaged in research at Mayo Clinic between 2010 and 2019. The primary outcome was time to the 15th new peer-reviewed publication after the program start, adjusted for baseline number of publications. Secondarily, we described successful awarding of federal funding by the NIH or VA.
Results:
The median (IQR) number of baseline publications was highest among Kern Scholars compared to Kern Applicants or other CDA awardees [16 (12, 29) vs 5 (1, 11) and 8 (5, 16); P < 0.001]. After adjustment for baseline publications, the time to 15th new publication was significantly shorter for Kern Scholars than for the two comparator groups (P<0.001). Similar findings were observed with total new publications within 5 years (P < 0.001), as well as number of new first-/last-author publications within 5 years (P < 0.001). The overall frequency of K-awards, R-awards (or equivalent), or any funding were similar between groups, with the exception of R03 awards, which were significantly more common among Kern Scholars (P = 0.002).
Conclusion:
The Kern Scholars program is a successful training model for clinician-scientists that demonstrated comparatively greater acceleration of scholarly productivity than other internal CDA programs.
The past few decades have seen the burgeoning of wide-field, high-cadence surveys, the most formidable of which will be the Legacy Survey of Space and Time (LSST) to be conducted by the Vera C. Rubin Observatory. So new is the field of systematic time-domain survey astronomy; however, that major scientific insights will continue to be obtained using smaller, more flexible systems than the LSST. One such example is the Gravitational-wave Optical Transient Observer (GOTO) whose primary science objective is the optical follow-up of gravitational wave events. The amount and rate of data production by GOTO and other wide-area, high-cadence surveys presents a significant challenge to data processing pipelines which need to operate in near-real time to fully exploit the time domain. In this study, we adapt the Rubin Observatory LSST Science Pipelines to process GOTO data, thereby exploring the feasibility of using this ‘off-the-shelf’ pipeline to process data from other wide-area, high-cadence surveys. In this paper, we describe how we use the LSST Science Pipelines to process raw GOTO frames to ultimately produce calibrated coadded images and photometric source catalogues. After comparing the measured astrometry and photometry to those of matched sources from PanSTARRS DR1, we find that measured source positions are typically accurate to subpixel levels, and that measured L-band photometries are accurate to $\sim50$ mmag at $m_L\sim16$ and $\sim200$ mmag at $m_L\sim18$. These values compare favourably to those obtained using GOTO’s primary, in-house pipeline, gotophoto, in spite of both pipelines having undergone further development and improvement beyond the implementations used in this study. Finally, we release a generic ‘obs package’ that others can build upon, should they wish to use the LSST Science Pipelines to process data from other facilities.
We describe here efforts to create and study magnetized electron–positron pair plasmas, the existence of which in astrophysical environments is well-established. Laboratory incarnations of such systems are becoming ever more possible due to novel approaches and techniques in plasma, beam and laser physics. Traditional magnetized plasmas studied to date, both in nature and in the laboratory, exhibit a host of different wave types, many of which are generically unstable and evolve into turbulence or violent instabilities. This complexity and the instability of these waves stem to a large degree from the difference in mass between the positively and the negatively charged species: the ions and the electrons. The mass symmetry of pair plasmas, on the other hand, results in unique behaviour, a topic that has been intensively studied theoretically and numerically for decades, but experimental studies are still in the early stages of development. A levitated dipole device is now under construction to study magnetized low-energy, short-Debye-length electron–positron plasmas; this experiment, as well as a stellarator device that is in the planning stage, will be fuelled by a reactor-based positron source and make use of state-of-the-art positron cooling and storage techniques. Relativistic pair plasmas with very different parameters will be created using pair production resulting from intense laser–matter interactions and will be confined in a high-field mirror configuration. We highlight the differences between and similarities among these approaches, and discuss the unique physics insights that can be gained by these studies.
Breeding values for feed intake and feed efficiency in beef cattle are generally derived indoors on high-concentrate (HC) diets. Within temperate regions of north-western Europe, however, the majority of a growing beef animal’s lifetime dietary intake comes from grazed grass and grass silage. Using 97 growing beef cattle, the objective of the current study was to assess the repeatability of both feed intake and feed efficiency across 3 successive dietary test periods comprising grass silage plus concentrates (S+C), grazed grass (GRZ) and a HC diet. Individual DM intake (DMI), DMI/kg BW and feed efficiency-related parameters, residual feed intake (RFI) and gain to feed ratio (G : F) were assessed. There was a significant correlation for DMI between the S+C and GRZ periods (r = 0.32; P < 0.01) as well as between the S+C and HC periods (r = 0.41; P < 0.001), whereas there was no association for DMI between the GRZ and HC periods. There was a significant correlation for DMI/kg BW between the S+C and GRZ periods (r = 0.33; P < 0.01) and between the S+C and HC periods (r = 0.40; P < 0.001), but there was no association for the trait between the GRZ and HC periods. There was a significant correlation for RFI between the S+C and GRZ periods (r = 0.25; P < 0.05) as well as between S+C and HC periods (r = 0.25; P < 0.05), whereas there was no association for RFI between the GRZ and HC periods. Gain to feed ratio was not correlated between any of the test periods. A secondary aspect of the study demonstrated that traits recorded in the GRZ period relating to grazing bite rate, the number of daily grazing bouts and ruminating bouts were associated with DMI (r = 0.28 to 0.42; P < 0.05 - 0.001), DMI/kg BW (r = 0.36 to 0.45; P < 0.01 - 0.001) and RFI (r = 0.31 to 0.42; P < 0.05 - 0.001). Additionally, the number of ruminating boli produced per day and per ruminating bout were associated with G : F (r = 0.28 and 0.26, respectively; P < 0.05). Results from this study demonstrate that evaluating animals for both feed intake and feed efficiency indoors on HC diets may not reflect their phenotypic performance when consuming conserved forage-based diets indoors or when grazing pasture.
Childhood-onset schizophrenia is onset prior to the age of 13 years. Although rare, people who suffer from schizophrenia at an early age appear to have a severe form of the illness with poor long-term prognosis. Antipsychotic medication is one way of managing this serious mental illness.
Aims/objectives
To examine the effects of antipsychotics for childhood-onset schizophrenia.
Methods
We searched the Cochrane Schizophrenia Group Trials Register, inspected references and contacted pharmaceutical companies and authors of trials. We included all randomised clinical trials.
Results
From a total of 2062 citations, we identified six relevant trials. Three comparisons: atypical versus typical, atypical versus atypical and typical versus typical antipsychotic drugs. The only comparison to find any differences was atypical versus typical antipsychotic drugs. A few results from one study favoured the atypical antipsychotic clozapine over haloperidol in treating treatment resistant childhood-onset schizophrenia (n = 21, WMD CGAS 17.00 CI 7.74 to 26.26). Participants on clozapine, however, were three times more likely to have drowsiness (1 RCT, n = 21, RR 3.30 CI 1.23 to 8.85, NNH 2 CI 2 to 17) and half of the children receiving clozapine had neutropenia (1 RCT, n = 21, RR 12, CI 0.75 to192.86).
Conclusions
There are few relevant trials and, presently, there is little conclusive evidence regarding the effects of antipsychotic medication for those with early onset schizophrenia. Some benefits were identified in using the atypical antipsychotic clozapine compared with haloperidol but the benefits were offset by an increased risk of serious adverse effects. Larger, more robust, trials are required.
Childhood-onset schizophrenia, although rare, is schizophrenia with onset prior to the age of 13 years, appear to have a poor long term prognosis. Antipsychotic medication is one way of managing this rare but serious mental illness.
Objectives:
To examine the effects of antipsychotic medication for childhood-onset schizophrenia.
Methods:
We searched the Cochrane Schizophrenia Group Trials Register and inspected references of all identified studies for further trials. We included all RCTs involving children and young people with a diagnosis of childhood onset schizophrenia comparing any antipsychotic drug with another antipsychotic or placebo. We reliably selected, quality assessed and extracted data from trials.
Results:
From a total of 2062 citations, we identified six relevant trials. A few results from one study favoured the atypical antipsychotic clozapine over haloperidol in treating treatment resistant childhood-onset schizophrenia (n = 21, WMD CGAS 17.00 CI 7.74 to 26.26; n = 21, WMD Bunney-Hamburg Psychosis Rating Scale −3.60 CI −6.64 to −0.56).
Participants on clozapine, however, were three times more likely to have drowsiness (1 RCT, n = 21, RR 3.30 CI 1.23 to 8.85, NNH 2 CI 2 to 17) and half of the children receiving clozapine had neutropenia (1 RCT, n = 21, RR 12, CI 0.75 to 192.86).
Conclusions:
There is little conclusive evidence regarding the effects of antipsychotic medication for those with early onset schizophrenia. Some benefits were identified in using the atypical antipsychotic clozapine but the benefits were offset by an increased risk of serious adverse effects. Larger, more robust, trials are required.
Global inequity in access to and availability of essential mental health services is well recognized. The mental health treatment gap is approximately 50% in all countries, with up to 90% of people in the lowest-income countries lacking access to required mental health services. Increased investment in global mental health (GMH) has increased innovation in mental health service delivery in LMICs. Situational analyses in areas where mental health services and systems are poorly developed and resourced are essential when planning for research and implementation, however, little guidance is available to inform methodological approaches to conducting these types of studies. This scoping review provides an analysis of methodological approaches to situational analysis in GMH, including an assessment of the extent to which situational analyses include equity in study designs. It is intended as a resource that identifies current gaps and areas for future development in GMH. Formative research, including situational analysis, is an essential first step in conducting robust implementation research, an essential area of study in GMH that will help to promote improved availability of, access to and reach of mental health services for people living with mental illness in low- and middle-income countries (LMICs). While strong leadership in this field exists, there remain significant opportunities for enhanced research representing different LMICs and regions.
Current techniques for measuring the dry matter intake (DMI) of grazing lactating beef cows are invasive, time consuming and expensive making them impractical for use on commercial farms. This study was undertaken to explore the potential to develop and validate a model to predict DMI of grazing lactating beef cows, which could be applied in a commercial farm setting, using non-invasive animal measurements. The calibration dataset used to develop the model was comprised of 94 measurements recorded on 106 beef or beef–dairy crossbred cows (maternal origin). The potential of body measurements, linear type scoring, grazing behaviour and thermal imaging to predict DMI in combination with known biologically plausible adjustment variables and energy sinks was investigated. Multivariable regression models were constructed for each independent variable using SAS PROC REG and contained milk yield, BW, parity, calving day and maternal origin (dairy or beef). Of the 94 variables tested, 32 showed an association with DMI (P < 0.25) upon multivariable analysis. These variables were incorporated into a backwards linear regression model using SAS PROC REG. Variables were retained in this model if P < 0.05. Five variables; width at pins, full body depth, ruminating mastications, central ligament and rump width score, were retained in the model in addition to milk yield, BW, parity, calving day and maternal origin. The inclusion of these variables in the model increased the predictability of DMI by 0.23 (R2 = 0.68) when compared to a model containing milk yield, BW, parity, calving day and maternal origin only. This model was applied to data recorded on an independent dataset; a herd of 60 lactating beef cows two years after the calibration study. The R2 for the validation was 0.59. Estimates of DMI are required for measuring feed efficiency. While acknowledging challenges in applicability, the findings suggest a model such as that developed in this study may be used as a tool to more easily and less invasively estimate DMI on large populations of commercial beef cows, and therefore measure feed efficiency.
Second-mode wave growth within the hypersonic boundary layer of a slender cone is investigated experimentally using high-speed schlieren visualizations. Experiments were performed in AEDC Tunnel 9 over a range of unit Reynolds number conditions at a Mach number of approximately 14. A thin lens with a known density profile placed within the field of view enables calibration of the schlieren set-up, and the relatively high camera frame rates employed allow for the reconstruction of time-resolved pixel intensities at discrete streamwise locations. The calibration in conjunction with the reconstructed signals enables integrated spatial amplification rates ($N$ factors) to be calculated for each unit Reynolds number condition and compared to $N$ factors computed from both pressure transducer measurements and linear parabolized stability equation (PSE) solutions. Good agreement is observed between $N$ factors computed from the schlieren measurements and those computed from the PSE solutions for the most-amplified second-mode frequencies. The streamwise development of $N$ factors calculated from the schlieren measurements compares favourably to that calculated from the pressure measurements with slight variations in the $N$ factor magnitudes calculated for harmonic frequencies. Finally, a bispectral analysis is carried out to identify nonlinear phase-coupled quadratic interactions present within the boundary layer. Multiple interactions are identified and revealed to be associated with the growth of disturbances at higher harmonic frequencies.