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The year 2020 will be remembered as a moment of omni-crisis at the intersection of public health, politics, and economics. A global pandemic on a scale not seen in a century struck tens of millions and left a wake of devastation. Governments around the world responded in divergent ways, from competent and well organized to chaotic and inept, with predictable consequences for their citizens. Their economies suffered the consequences as well, with many facing skyrocketing rates of unemployment and business failure. Those at the low end of the income spectrum fared the worst: in the United States, employment in the foodservice industry dropped from 12 million to 6 million in a single month, leaving the equivalent of the population of Denmark out of work.
OBJECTIVES/GOALS: Immunomodulatory drugs (IMiDs) are critical to multiple myeloma (MM) disease control. IMiDs act by inducing Cereblon-dependent degradation of IKZF1 and IKZF3, which leads to IRF4 and MYC downregulation (collectively termed the “Ikaros axis”). We therefore hypothesized that IMiD treatment fails to downregulate the Ikaros axis in IMiD resistant MM. METHODS/STUDY POPULATION: To measure IMiD-induced Ikaros axis downregulation, we designed an intracellular flow cytometry assay that measured relative protein levels of IKZF1, IKZF3, IRF4 and MYC in MM cells following ex vivo treatment with the IMiD Pomalidomide (Pom). We established this assay using Pom-sensitive parental and dose-escalated Pom-resistant MM cell lines before assessing Ikaros axis downregulation in CD38+CD138+ MM cells in patient samples (bone marrow aspirates). To assess the Ikaros axis in the context of MM intratumoral heterogeneity, we used a 35-marker mass cytometry panel to simultaneously characterize MM subpopulations in patient samples. Lastly, we determined ex vivo drug sensitivity in patient samples via flow cytometry. RESULTS/ANTICIPATED RESULTS: Our hypothesis was supported in MM cell lines, as resistant lines showed no IMiD-induced decrease in any Ikaros axis proteins. However, when assessed in patient samples, Pom treatment caused a significant decrease in IKZF1, IKZF3 and IRF4 regardless of IMiD sensitivity. Mass cytometry in patient samples revealed that individual Ikaros axis proteins were differentially expressed between subpopulations. When correlating this with ex vivo Pom sensitivity of MM subpopulations, we observed that low IKZF1 and IKZF3 corresponded to Pom resistance. Interestingly, most of these resistant populations still expressed MYC. We therefore assessed whether IMiD resistant MM was MYC dependent by treating with MYCi975. In 88% (7/8) of patient samples tested, IMiD resistant MM cells were sensitive to MYC inhibition. DISCUSSION/SIGNIFICANCE: While our findings did not support our initial hypothesis, our data suggest a mechanism where MYC expression becomes Ikaros axis independent to drive IMiD resistance, and resistant MM is still dependent on MYC. This suggests targeting MYC directly or indirectly via a mechanism to be determined may be an effective strategy to eradicate IMiD resistant MM.
This combined numerical/laboratory study investigates the effect of stratification form on the shoaling characteristics of internal solitary waves propagating over a smooth, linear topographic slope. Three stratification types are investigated, namely (i) thin tanh (homogeneous upper and lower layers separated by a thin pycnocline), (ii) surface stratification (linearly stratified layer overlaying a homogeneous lower layer) and (iii) broad tanh (continuous density gradient throughout the water column). It is found that the form of stratification affects the breaking type associated with the shoaling wave. In the thin tanh stratification, good agreement is seen with past studies. Waves over the shallowest slopes undergo fission. Over steeper slopes, the breaking type changes from surging, through collapsing to plunging with increasing wave steepness $A_w/L_w$ for a given topographic slope, where $A_w$ and $L_w$ are incident wave amplitude and wavelength, respectively. In the surface stratification regime, the breaking classification differs from the thin tanh stratification. Plunging dynamics is inhibited by the density gradient throughout the upper layer, instead collapsing-type breakers form for the equivalent location in parameter space in the thin tanh stratification. In the broad tanh profile regime, plunging dynamics is likewise inhibited and the near-bottom density gradient prevents the collapsing dynamics. Instead, all waves either fission or form surging breakers. As wave steepness in the broad tanh stratification increases, the bolus formed by surging exhibits evidence of Kelvin–Helmholtz instabilities on its upper boundary. In both two- and three-dimensional simulations, billow size grows with increasing wave steepness, dynamics not previously observed in the literature.
In the UK, postnatal depression is more common in British South Asian women than White Caucasion women. Cognitive–behavioural therapy (CBT) is recommended as a first-line treatment, but there is little evidence for the adaptation of CBT for postnatal depression to ensure its applicability to different ethnic groups.
To evaluate the clinical and cost-effectiveness of a CBT-based positive health programme group intervention in British South Asian women with postnatal depression.
We have designed a multicentre, two-arm, partially nested, randomised controlled trial with 4- and 12-month follow-up, comparing a 12-session group CBT-based intervention (positive health programme) plus treatment as usual with treatment as usual alone, for British South Asian women with postnatal depression. Participants will be recruited from primary care and appropriate community venues in areas of high South Asian density across the UK. It has been estimated that randomising 720 participants (360 into each group) will be sufficient to detect a clinically important difference between a 55% recovery rate in the intervention group and a 40% recovery rate in the treatment-as-usual group. An economic analysis will estimate the cost-effectiveness of the positive health programme. A qualitative process evaluation will explore barriers and enablers to study participation and examine the acceptability and impact of the programme from the perspective of British South Asian women and other key stakeholders.
Environmental DNA (eDNA) surveying has potential to become a powerful tool for sustainable parasite control. As trematode parasites require an intermediate snail host that is often aquatic or amphibious to fulfil their lifecycle, water-based eDNA analyses can be used to screen habitats for the presence of snail hosts and identify trematode infection risk areas. The aim of this study was to identify climatic and environmental factors associated with the detection of Galba truncatula eDNA. Fourteen potential G. truncatula habitats on two farms were surveyed over a 9-month period, with eDNA detected using a filter capture, extraction and PCR protocol with data analysed using a generalized estimation equation. The probability of detecting G. truncatula eDNA increased in habitats where snails were visually detected, as temperature increased, and as water pH decreased (P < 0.05). Rainfall was positively associated with eDNA detection in watercourse habitats on farm A, but negatively associated with eDNA detection in watercourse habitats on farm B (P < 0.001), which may be explained by differences in watercourse gradient. This study is the first to identify factors associated with trematode intermediate snail host eDNA detection. These factors should be considered in standardized protocols to evaluate the results of future eDNA surveys.
The coronavirus disease 2019 (COVID-19) pandemic has resulted in shortages of personal protective equipment (PPE), underscoring the urgent need for simple, efficient, and inexpensive methods to decontaminate masks and respirators exposed to severe acute respiratory coronavirus virus 2 (SARS-CoV-2). We hypothesized that methylene blue (MB) photochemical treatment, which has various clinical applications, could decontaminate PPE contaminated with coronavirus.
The 2 arms of the study included (1) PPE inoculation with coronaviruses followed by MB with light (MBL) decontamination treatment and (2) PPE treatment with MBL for 5 cycles of decontamination to determine maintenance of PPE performance.
MBL treatment was used to inactivate coronaviruses on 3 N95 filtering facepiece respirator (FFR) and 2 medical mask models. We inoculated FFR and medical mask materials with 3 coronaviruses, including SARS-CoV-2, and we treated them with 10 µM MB and exposed them to 50,000 lux of white light or 12,500 lux of red light for 30 minutes. In parallel, integrity was assessed after 5 cycles of decontamination using multiple US and international test methods, and the process was compared with the FDA-authorized vaporized hydrogen peroxide plus ozone (VHP+O3) decontamination method.
Overall, MBL robustly and consistently inactivated all 3 coronaviruses with 99.8% to >99.9% virus inactivation across all FFRs and medical masks tested. FFR and medical mask integrity was maintained after 5 cycles of MBL treatment, whereas 1 FFR model failed after 5 cycles of VHP+O3.
MBL treatment decontaminated respirators and masks by inactivating 3 tested coronaviruses without compromising integrity through 5 cycles of decontamination. MBL decontamination is effective, is low cost, and does not require specialized equipment, making it applicable in low- to high-resource settings.
A review of Australian mental health services identified a gap in routine outcome measures addressing social, emotional and behavioural domains for pre-schoolers and infants. The Child and Adolescent Mental Health Information Development Expert Advisory Panel Working Group developed the Health of the Nation Outcome Scales for Infants (HoNOSI), a clinician-reported routine outcome measure for use with those aged under 4 years. Prior psychometric testing showed that the HoNOSI was considered to show face validity, and that it met the standards for concurrent validity and internal consistency.
We aimed to investigate the interrater reliability of the HoNOSI.
Forty-five infant mental health clinicians completed HoNOSI ratings on a set of five case vignettes.
Quadratic weighted kappa interrater reliability estimates showed the HoNOSI to have Almost Perfect interrater reliability for the HoNOSI total score. Of the 15 scales, one had Moderate, seven had Substantial and seven had Almost Perfect interrater reliability. Ten of the fifteen scales and the total score exceeded the COnsensus-based Standards for the Selection of Health Measurement INstruments criteria for interrater reliability (κw ≥ 0.7).
There has been a clear need for a routine outcome measure for use with infants and pre-schoolers. This study provides evidence of interrater reliability. The current findings, combined with the face and concurrent validity studies, support further examination of HoNOSI in real-world settings.
There is global interest in the reconfiguration of community mental health services, including primary care, to improve clinical and cost effectiveness.
This study seeks to describe patterns of service use, continuity of care, health risks, physical healthcare monitoring and the balance between primary and secondary mental healthcare for people with severe mental illness in receipt of secondary mental healthcare in the UK.
We conducted an epidemiological medical records review in three UK sites. We identified 297 cases randomly selected from the three participating mental health services. Data were manually extracted from electronic patient medical records from both secondary and primary care, for a 2-year period (2012–2014). Continuous data were summarised by mean and s.d. or median and interquartile range (IQR). Categorical data were summarised as percentages.
The majority of care was from secondary care practitioners: of the 18 210 direct contacts recorded, 76% were from secondary care (median, 36.5; IQR, 14–68) and 24% were from primary care (median, 10; IQR, 5–20). There was evidence of poor longitudinal continuity: in primary care, 31% of people had poor longitudinal continuity (Modified Modified Continuity Index ≤0.5), and 43% had a single named care coordinator in secondary care services over the 2 years.
The study indicates scope for improvement in supporting mental health service delivery in primary care. Greater knowledge of how care is organised presents an opportunity to ensure some rebalancing of the care that all people with severe mental illness receive, when they need it. A future publication will examine differences between the three sites that participated in this study.
We explore the concept of parameter design applied to the production of glass beads in the manufacture of metal-encapsulated transistors. The main motivation is to complete the analysis hinted at in the original publication by Jim Morrison in 1957, which was an early example of discussing the idea of transmitted variation in engineering design, and an influential paper in the development of analytic parameter design as a data-centric engineering activity. Parameter design is a secondary design activity focused on selecting the nominals of the design variables to achieve the required target performance and to simultaneously reduce the variance around the target. Although the 1957 paper is not recent, its approach to engineering design is modern.
Subglacial sediments have the potential to reveal information about the controls on glacier flow, changes in ice-sheet history and characterise life in those environments. Retrieving sediments from beneath the ice, through hot water drilled access holes at remote field locations, present many challenges. Motivated by the need to minimise weight, corer diameter and simplify assembly and operation, British Antarctic Survey, in collaboration with UWITEC, developed a simple mechanical percussion corer. At depths over 1000 m however, manual operation of the percussion hammer is compromised by the lack of clear operator feedback at the surface. To address this, we present a new auto-release-recovery percussion hammer mechanism that makes coring operations depth independent and improves hammer efficiency. Using a single rope tether for both the corer and hammer operation, this modified percussion corer is relatively simple to operate, easy to maintain, and has successfully operated at a depth of >2130 m.
The Eating Assessment in Toddlers FFQ (EAT FFQ) has been shown to have good reliability and comparative validity for ranking nutrient intakes in young children. With the addition of food items (n 4), we aimed to re-assess the validity of the EAT FFQ and estimate calibration factors in a sub-sample of children (n 97) participating in the Growing Up Milk – Lite (GUMLi) randomised control trial (2015–2017). Participants completed the ninety-nine-item GUMLi EAT FFQ and record-assisted 24-h recalls (24HR) on two occasions. Energy and nutrient intakes were assessed at months 9 and 12 post-randomisation and calibration factors calculated to determine predicted estimates from the GUMLi EAT FFQ. Validity was assessed using Pearson correlation coefficients, weighted kappa (κ) and exact quartile categorisation. Calibration was calculated using linear regression models on 24HR, adjusted for sex and treatment group. Nutrient intakes were significantly correlated between the GUMLi EAT FFQ and 24HR at both time points. Energy-adjusted, de-attenuated Pearson correlations ranged from 0·3 (fibre) to 0·8 (Fe) at 9 months and from 0·3 (Ca) to 0·7 (Fe) at 12 months. Weighted κ for the quartiles ranged from 0·2 (Zn) to 0·6 (Fe) at 9 months and from 0·1 (total fat) to 0·5 (Fe) at 12 months. Exact agreement ranged from 30 to 74 %. Calibration factors predicted up to 56 % of the variation in the 24HR at 9 months and 44 % at 12 months. The GUMLi EAT FFQ remained a useful tool for ranking nutrient intakes with similar estimated validity compared with other FFQ used in children under 2 years.
Life course research embraces the complexity of health and disease development, tackling the extensive interactions between genetics and environment. This interdisciplinary blueprint, or theoretical framework, offers a structure for research ideas and specifies relationships between related factors. Traditionally, methodological approaches attempt to reduce the complexity of these dynamic interactions and decompose health into component parts, ignoring the complex reciprocal interaction of factors that shape health over time. New methods that match the epistemological foundation of the life course framework are needed to fully explore adaptive, multilevel, and reciprocal interactions between individuals and their environment. The focus of this article is to (1) delineate the differences between lifespan and life course research, (2) articulate the importance of complex systems science as a methodological framework in the life course research toolbox to guide our research questions, (3) raise key questions that can be asked within the clinical and translational science domain utilizing this framework, and (4) provide recommendations for life course research implementation, charting the way forward. Recent advances in computational analytics, computer science, and data collection could be used to approximate, measure, and analyze the intertwining and dynamic nature of genetic and environmental factors involved in health development.
Person-centred care is recognized as best practice in dementia care. The purpose of this study was to evaluate the effectiveness of a stakeholder engagement practice change initiative aimed at increasing the provision of person-centred mealtimes in a residential care home (RCH). A single-group, time series design was used to assess the impact of the practice change initiative on mealtime environment across four time periods (pre-intervention, 1-month, 3-month, and 6-month follow-up). Statistically significant improvements were noted in all mealtime environment scales by 6 months, including the physical environment (z = -3.06, p = 0.013), social environment (z = -3.69, p = 0.001), relationship and person-centred scale (z = -3.51, p = 0.003), and overall environment scale (z = -3.60, p = 0.002). This practice change initiative, which focused on enhancing stakeholder engagement, provided a feasible method for increasing the practice of person-centred care during mealtimes in an RCH through the application of supportive leadership, collaborative decision making, and staff engagement.
Jamie Gundry’s dramatic image of a white-tailed eagle (Haliaeetus albicilla) on the cover of this book reflects the twisting changes in fortune experienced by this species, with a revival that can be attributed to a successful interplay of science, policy and practice. White-tailed eagles were historically much more widely distributed than they are today (Yalden, 2007), once breeding across much of Europe, but by the early twentieth century the species was extinct across much of western and southern Europe. The main cause of its decline was persecution by farmers and shepherds, who considered the eagles a threat to their livestock, but, along with other raptors, white-tailed eagles were also seriously affected by DDT in the 1960s and 1970s, which had disastrous effects on the breeding success of remaining populations.
In the Anthropocene, when our environment is changing rapidly and the windows of opportunity for action to prevent further biodiversity loss are narrow, conservation researchers are increasingly encouraged to think and operate beyond the traditional approaches of producing peer-reviewed papers and presenting results to other members of the research community. Indeed, the perception that researchers belong in their ivory tower, from which they deliver evidence for others to interpret, disseminate and use in decision-making, is thankfully now widely recognised as outdated. The rise of fake news, a deliberate lack of consideration for scientific evidence, and changes to the ways of assessing the value of researchers’ work probably all play a role in supporting this shift in perception. Moreover, for many researchers, the prospect of their work ‘making a difference’ and having an impact on wider society is at least as great a motivation for doing research as generating new knowledge, however interesting that may be.