Compressible jets impinging on a perpendicular surface can produce high-intensity, discrete-frequency tones. The character of these tones is a function of nozzle shape, jet Mach number, impingement-plate geometry, and the distance between nozzle and plate. Though it has long been recognised that these tones are associated with a resonance cycle, the exact mechanism by which they are generated has remained a topic of some debate. In this work, we present evidence for a number of distinct tone-generation mechanisms, reconciling some of the different findings of prior authors. We demonstrate that the upstream-propagating waves that close resonance can be confined within the jet, or external to it. These waves can be either weak and relatively linear, or strong and nonlinear from their inception. The waves can undergo coalescence or merging, and in some configurations, pairs of waves rather than singletons appear. We discuss both historical and new evidence for multiple distinct processes by which upstream-propagating waves are produced: direct vortex sound, shock leakage, wall-jet-boundary fluctuations, and wall-jet shocklets. We link these various mechanisms to the disparate collection of upstream-propagating waves observed in the data. We also demonstrate that multiple mechanisms can be provoked by a single vortex, providing an explanation as to why sometimes pairs of waves or merging waves are observed. Through this body of work, we demonstrate that rather than being in opposition, the various pieces of past research on this topic were simply identifying different mechanisms that can support resonance.

Embedding mandatory investment guarantees in individual retirement accounts (IRAs) can protect workers from equity market shortfalls, but policymakers must understand the economic costs of such guarantees as well as their incidence. Using a life cycle model calibrated for Germany, where investors have access to stocks, bonds, and tax-qualified IRAs, we show that abandoning the guarantee could enhance old-age consumption for over 75% of retirees without harming pre-retirement consumption. Investors averse to equity losses accumulate only moderately more in guaranteed accounts, as these offer only limited protection against market crashes.

This study identifies two previously unrecognised screech modes in non-axisymmetric jets. Spectral proper orthogonal decomposition (SPOD) of ultra-high-speed schlieren images reveals a bi-axial flapping mode in a rectangular jet and a quasi-helical mode in an elliptical jet. To educe the complex three-dimensional structure of these new modes, SPOD is performed on datasets from different viewing perspectives, produced by rotating the nozzle with respect to the schlieren path to an azimuthal angle $\theta$. The bi-axial flapping mode is strongly antisymmetric from any perspective. However, the SPOD eigenvalue at the screech frequency ($\lambda _s$) varies with $\theta$ and the axial distance of the SPOD domain from the nozzle lip. This mode most closely resembles a flapping mode in the minor-axis plane close to the nozzle lip and a wagging mode in the major-axis plane further downstream. This transition from flapping to wagging at the same frequency correlates with the axis switching defined by the shock-cell structure in the mean flow. The quasi-helical mode in the elliptical jet is characterised by an antisymmetric structure present in the SPOD spatial modes whose eigenvalue $\lambda _s$ is insensitive to both $\theta$ and the axial domain. These findings indicate that the spatial evolution of the mean flow in non-axisymmetric jets may allow them to support a range of additional screech modes that differ significantly from those supported by the original three-dimensional shape of the jet.

This work presents models for the behaviour of both upstream- and downstream-travelling waves in screeching elliptical jets. Proper orthogonal decomposition is performed on experimental velocity data in both the major and minor axis planes, for an aspect ratio $AR=2$ converging elliptical jet operating at nozzle pressure ratios of $2.6$ and $3.4$. From this decomposition, the radial and axial structure of the guided-jet mode (GJM) and the Kelvin–Helmholtz instability are educed. Linear-stability analysis (LSA) is performed using both the experimentally obtained mean flow, and one obtained using Reynolds-averaged Navier–Stokes (RANS) at matched conditions. It is shown that the wavenumber predicted by LSA for both waves are within the range of experimentally observed wavenumbers. Furthermore, the model accurately predicts the structure of these waves at multiple axial locations, using either the experimental or RANS mean flow. Most critically, it is demonstrated that the GJM is only predicted to be neutrally stable at the screech frequency for a relatively limited streamwise domain, the size and location of which is dependent on the nozzle pressure ratio. A comparison with the amplitude envelope for the GJM extracted from the experimental measurements indicates that the maximum fluctuations associated with the GJM are collocated with this region of the flow that is predicted to support the GJM. While there have been extensive discussions about the frequency dependence of the GJM, this is the first demonstration that its existence is highly dependent on streamwise position within the flow.

Guided-jet waves have been shown to close resonance loops in a myriad of problems such as screech and impingement tones in jets. These discrete, upstream-travelling waves have long been identified in linear-stability models of jet flows, but in this work they are instead considered in the context of an acoustic-scattering problem. It is shown that the guided-jet mode results from total internal reflection and transmission of acoustic waves, arising from the shear layer behaving like a duct with some given wall impedance. After total reflection, only discrete streamwise wavenumbers may be supported by the flow, with these wavenumbers dictated by the fact that the standing wave formed inside of the jet must fit between the two shear layers. Close to the sonic line, the transmission of this mode to the outside is maximum, leading to a net-energy flux directed upstream, which dictates the direction of propagation of this mode, providing a clear connection to the better understood soft-duct mode (Towne et al., J. Fluid Mech., vol. 825, 2017, pp. 1113–1152). The model also indicates that these waves are generated in the core of the flow and can only be efficiently transmitted to the quiescent region under certain conditions, providing an explanation as to why screech is only observed at conditions where the discrete mode is supported by the flow. The present results explain, for the first time, the nature and characteristics of the guided-jet waves.

There is currently considerable interest in the guided-jet mode, as a result of recent works demonstrating it being the upstream component of various resonant systems in high-speed flows. For given jet operating conditions, the mode is known to exist over only a finite-frequency range that, for a twin-jet system, has been observed to vary with both jet separation and solution symmetry. Vortex-sheet and finite-thickness linear stability models are here employed to consider the behaviour of the guided-jet mode as the two jets are brought together, for both a planar and round twin-jet system. It is demonstrated that in both cases as the twin-jet system merges it forms a higher-order mode of an equivalent single-jet geometry. This then imposes a constraint on the guided-jet mode as the finite-frequency range must change to meet that of the equivalent geometry the system merges to, explaining the previously observed dependence on jet separation.

Linear stability theory (LST) is often used to model the large-scale flow structures in the turbulent mixing region and near pressure field of high-speed jets. For perfectly expanded single round jets, these models predict the dominance of azimuthal wavenumbers $m=0$ and $m = 1$ helical modes for the lower frequency range, in agreement with empirical data. When LST is applied to twin-jet systems, four solution families appear following the odd/even behaviour of the pressure field about the symmetry planes. The interaction between the unsteady pressure fields of the two jets also results in their coupling. The individual modes of the different solution families no longer correspond to helical motions, but to flapping oscillations of the jet plumes. In the limit of large jet separations, when the jet coupling vanishes, the eigenvalues corresponding to the $m=1$ mode in each family are identical, and a linear combination of them recovers the helical motion. Conversely, as the jet separation decreases, the eigenvalues for the $m=1$ modes of each family diverge, thus favouring a particular flapping oscillation over the others and preventing the appearance of helical motions. The dominant mode of oscillation for a given jet Mach number $M_j$ and temperature ratio $T_R$ depends on the Strouhal number $St$ and jet separation $s$. Increasing both $M_j$ and $T_R$ independently is found to augment the jet coupling and modify the $(St,s)$ map of the preferred oscillation mode. Present results predict the preference of two modes when the jet interaction is relevant, namely varicose and especially sinuous flapping oscillations on the nozzles’ plane.

Obesity is one of the major contributors to the excess mortality seen in people with severe mental illness (SMI) and in low- and middle-income countries people with SMI may be at an even greater risk. In this study, we aimed to determine the prevalence of obesity and overweight in people with SMI and investigate the association of obesity and overweight with sociodemographic variables, other physical comorbidities, and health-risk behaviours. This was a multi-country cross-sectional survey study where data were collected from 3989 adults with SMI from three specialist mental health institutions in Bangladesh, India, and Pakistan. The prevalence of overweight and obesity was estimated using Asian BMI thresholds. Multinomial regression models were then used to explore associations between overweight and obesity with various potential determinants. There was a high prevalence of overweight (17·3 %) and obesity (46·2 %). The relative risk of having obesity (compared to normal weight) was double in women (RRR = 2·04) compared with men. Participants who met the WHO recommendations for fruit and vegetable intake had 2·53 (95 % CI: 1·65–3·88) times greater risk of having obesity compared to those not meeting them. Also, the relative risk of having obesity in people with hypertension is 69 % higher than in people without hypertension (RRR = 1·69). In conclusion, obesity is highly prevalent in SMI and associated with chronic disease. The complex relationship between diet and risk of obesity was also highlighted. People with SMI and obesity could benefit from screening for non-communicable diseases, better nutritional education, and context-appropriate lifestyle interventions.

It is acknowledged that health technology assessment (HTA) is an inherently value-based activity that makes use of normative reasoning alongside empirical evidence. But the language used to conceptualise and articulate HTA's normative aspects is demonstrably unnuanced, imprecise, and inconsistently employed, undermining transparency and preventing proper scrutiny of the rationales on which decisions are based. This paper – developed through a cross-disciplinary collaboration of 24 researchers with expertise in healthcare priority-setting – seeks to address this problem by offering a clear definition of key terms and distinguishing between the types of normative commitment invoked during HTA, thus providing a novel conceptual framework for the articulation of reasoning. Through application to a hypothetical case, it is illustrated how this framework can operate as a practical tool through which HTA practitioners and policymakers can enhance the transparency and coherence of their decision-making, while enabling others to hold them more easily to account. The framework is offered as a starting point for further discussion amongst those with a desire to enhance the legitimacy and fairness of HTA by facilitating practical public reasoning, in which decisions are made on behalf of the public, in public view, through a chain of reasoning that withstands ethical scrutiny.

Spatial linear stability analysis is used to study the axisymmetric screech tones generated by twin converging round nozzles at low supersonic Mach numbers. Vortex-sheet and finite-thickness models allow for identification of the different waves supported by the flow at different conditions. Regions of the frequency–wavenumber domain for which the upstream-propagating guided jet modes are observed to be neutrally stable are observed to vary as a function of solution symmetry, jet separation, $S$, and the velocity profile used. Screech-frequency predictions performed using wavenumbers obtained from both models agree well with experimental data. Predictions obtained from the finite-thickness model better align with the screech tones measured experimentally and so are seen to be an improvement on predictions made with the vortex sheet. Additionally, results from the finite-thickness model predict both symmetric and antisymmetric screech tones for low $S$ that are found in the vortex-sheet model only at greater $S$. The present results indicate that the feedback loop generating these screech tones is similar to that observed for single-jet resonance, with equivalent upstream and downstream modes.

We investigate the intermittency of the coupling behaviour in screeching twin round supersonic jets at low Mach numbers across a range of nozzle spacings. Application of proper orthogonal decomposition combined with time-frequency wavelet analysis and spectral proper orthogonal decomposition shows that intermittency can manifest in twin jets as either a competition between the two symmetries, or the jets uncoupling and recoupling. The time scales on which symmetry switching occurs can vary strongly, ranging from $O(10^2)$ to $O(10^3)$ screech cycles. A transition from one symmetry to another is accompanied by a slight change in the screech frequency ranging from 0.30 % to 0.63 %. It was observed that complete uncoupling occurred only at the largest nozzle spacing of $s/D=6$ and at Mach numbers close to modal staging. When the jets are uncoupled they screech at slightly different frequencies, with a disparity of approximately 0.6 %. The coupling is particularly intermittent in the transition from the A1 to A2 branch, where the A2 mode is first observed, and tends toward steady coupling with increasing Mach number.

OBJECTIVES/GOALS: Glioblastomas (GBMs) are heterogeneous, treatment-resistant tumors that are driven by populations of cancer stem cells (CSCs). In this study, we perform an epigenetic-focused functional genomics screen in GBM organoids and identify WDR5 as an essential epigenetic regulator in the SOX2-enriched, therapy resistant cancer stem cell niche. METHODS/STUDY POPULATION: Despite their importance for tumor growth, few molecular mechanisms critical for CSC population maintenance have been exploited for therapeutic development. We developed a spatially resolved loss-of-function screen in GBM patient-derived organoids to identify essential epigenetic regulators in the SOX2-enriched, therapy resistant niche. Our niche-specific screens identified WDR5, an H3K4 histone methyltransferase responsible for activating specific gene expression, as indispensable for GBM CSC growth and survival. RESULTS/ANTICIPATED RESULTS: In GBM CSC models, WDR5 inhibitors blocked WRAD complex assembly and reduced H3K4 trimethylation and expression of genes involved in CSC-relevant oncogenic pathways. H3K4me3 peaks lost with WDR5 inhibitor treatment occurred disproportionally on POU transcription factor motifs, required for stem cell maintenance and including the POU5F1(OCT4)::SOX2 motif. We incorporated a SOX2/OCT4 motif driven GFP reporter system into our CSC cell models and found that WDR5 inhibitor treatment resulted in dose-dependent silencing of stem cell reporter activity. Further, WDR5 inhibitor treatment altered the stem cell state, disrupting CSC in vitro growth and self-renewal as well as in vivo tumor growth. DISCUSSION/SIGNIFICANCE: Our results unveiled the role of WDR5 in maintaining the CSC state in GBM and provide a rationale for therapeutic development of WDR5 inhibitors for GBM and other advanced cancers. This conceptual and experimental framework can be applied to many cancers, and can unmask unique microenvironmental biology and rationally designed combination therapies.

Shock-containing supersonic jets undergoing resonance processes are challenging from both a measurement and simulation perspective. These jets are host to a broad range of complex fluid phenomena: intense acoustic waves, turbulence, wavepackets and strong shock waves. Strong shocks present a challenge to both the experimental and numerical researcher. In the paper of Léon et al. (J. Fluid Mech., vol. 947, 2022, A36), a novel optical technique based on multi-axis digital holographic interferometry is applied to the study of a highly underexpanded screeching jet, producing density measurements of unprecedented clarity and resolution. Where prior studies have been restricted to extrapolating the three-dimensional field from two-dimensional slices or projections, in this work the authors directly measure the three-dimensional helical structure of the wavepacket associated with jet screech.

The 2020 presidential election brought expanded vote-by-mail opportunities, a rise in attacks on this process’s integrity, and the implementation of novel programs such as California’s Where’s My Ballot? system to ensure confidence in mail balloting. Can heightening awareness of this ballot-tracking system and other election protections alleviate fraud concerns and raise turnout? We assess whether messages reinforcing election integrity increased participation in the 2020 election through a large-scale voter mobilization field experiment. California registrants were mailed a letter that described either existing safeguards to prevent vote-by-mail fraud or the ability to track one’s ballot and ensure that it was counted. Analysis of state voter records reveals that neither message increased turnout over a simple election reminder or even no contact, even among subgroups where larger effects might be expected. In the context of a high-profile, high-turnout presidential election, assurances about ballot and electoral integrity did not increase turnout.