Spherical shock waveform reconstruction by heterodyne interferometry.

The indirect measurement of shock waveforms by acousto-optic sensing requires a method to reconstruct the field from the projected data. Under the assumption of spherical symmetry, one approach is to reconstruct the field by the Abel inversion integral transform. When the acousto-optic sensing modality measures the change in optical phase difference time derivative, as for a heterodyne Mach-Zehnder interferometer, e.g., a laser Doppler vibrometer, the reconstructed field is the fluctuating refractive index time derivative. A technique is derived that reconstructs the fluctuating index directly by assuming plane wave propagation local to a probe beam. With synthetic data, this approach is compared to the Abel inversion integral transform and then applied to experimental data of laser-induced shockwaves. Time waveforms are reconstructed with greater accuracy except for the tail of the waveform that maps spatially to positions near a virtual origin. Furthermore, direct reconstruction of the fluctuating index field eliminates the required time integration and results in more accurate shock waveform peak values, rise times, and positive phase duration.

Tumor monocyte content predicts immunochemotherapy outcomes in esophageal adenocarcinoma.

For inoperable esophageal adenocarcinoma (EAC), identifying patients likely to benefit from recently approved immunochemotherapy (ICI+CTX) treatments remains a key challenge. We address this using a uniquely designed window-of-opportunity trial (LUD2015-005), in which 35 inoperable EAC patients received first-line immune checkpoint inhibitors for four weeks (ICI-4W), followed by ICI+CTX. Comprehensive biomarker profiling, including generation of a 65,000-cell single-cell RNA-sequencing atlas of esophageal cancer, as well as multi-timepoint transcriptomic profiling of EAC during ICI-4W, reveals a novel T cell inflammation signature (INCITE) whose upregulation correlates with ICI-induced tumor shrinkage. Deconvolution of pre-treatment gastro-esophageal cancer transcriptomes using our single-cell atlas identifies high tumor monocyte content (TMC) as an unexpected ICI+CTX-specific predictor of greater overall survival (OS) in LUD2015-005 patients and of ICI response in prevalent gastric cancer subtypes from independent cohorts. Tumor mutational burden is an additional independent and additive predictor of LUD2015-005 OS. TMC can improve patient selection for emerging ICI+CTX therapies in gastro-esophageal cancer.

Urban residence and elevated blood pressure among migrant women in South Africa.

This paper demonstrates that internal migration may be contributing to rising non-communicable disease risk in low- and middle-income countries in gendered and geographically differentiated ways. With 2018 baseline data from the Migrant Health Follow-Up Study, we investigate the relationship between internal migration and elevated blood pressure (BP) among 2163 rural-origin men and women in South Africa, testing for sex differences. To examine the influence of place, we test whether the migration-BP relationship differs by migrants' destination locations, controlling for household composition, social support, prior migration, and housing quality. We find that migration is associated with elevated BP only among women, and that this association is greatest for migrants living in Tembisa township. Our research underscores that gender and migration are important social determinants of noncommunicable disease risk in low-resource, rapidly-urbanizing settings.

A PKPD Case Study: Achieving Clinically Relevant Exposures of AZD5991 in Oncology Mouse Models.

Capturing human equivalent drug exposures preclinically is a key challenge in the translational process. Motivated by the need to recapitulate the pharmacokinetic (PK) profile of the clinical stage Mcl-1 inhibitor AZD5991 in mice, we describe the methodology used to develop a refined mathematical model relating clinically relevant concentration profiles to efficacy. Administration routes were explored to achieve target exposures matching the clinical exposure of AZD5991. Intravenous infusion using vascular access button (VAB) technology was found to best reproduce clinical target exposures of AZD5991 in mice. Exposure-efficacy relationships were evaluated, demonstrating that dissimilar PK profiles result in differences in target engagement and efficacy outcomes. Thus, these data underscore the importance of accurately ascribing key PK metrics in the translational process to enable clinically meaningful predictions of efficacy.

TCR-engineered adoptive cell therapy effectively treats intracranial murine glioblastoma.

BACKGROUND: Adoptive cellular therapies with chimeric antigen receptor T cells have revolutionized the treatment of some malignancies but have shown limited efficacy in solid tumors such as glioblastoma and face a scarcity of safe therapeutic targets. As an alternative, T cell receptor (TCR)-engineered cellular therapy against tumor-specific neoantigens has generated significant excitement, but there exist no preclinical systems to rigorously model this approach in glioblastoma. METHODS: We employed single-cell PCR to isolate a TCR specific for the Imp3D81N neoantigen (mImp3) previously identified within the murine glioblastoma model GL261. This TCR was used to generate the Mutant Imp3-Specific TCR TransgenIC (MISTIC) mouse in which all CD8 T cells are specific for mImp3. The therapeutic efficacy of neoantigen-specific T cells was assessed through a model of cellular therapy consisting of the transfer of activated MISTIC T cells and interleukin 2 into lymphodepleted tumor-bearing mice. We employed flow cytometry, single-cell RNA sequencing, and whole-exome and RNA sequencing to examine the factors underlying treatment response. RESULTS: We isolated and characterized the 3×1.1C TCR that displayed a high affinity for mImp3 but no wild-type cross-reactivity. To provide a source of mImp3-specific T cells, we generated the MISTIC mouse. In a model of adoptive cellular therapy, the infusion of activated MISTIC T cells resulted in rapid intratumoral infiltration and profound antitumor effects with long-term cures in a majority of GL261-bearing mice. The subset of mice that did not respond to the adoptive cell therapy showed evidence of retained neoantigen expression but intratumoral MISTIC T cell dysfunction. The efficacy of MISTIC T cell therapy was lost in mice bearing a tumor with heterogeneous mImp3 expression, showcasing the barriers to targeted therapy in polyclonal human tumors. CONCLUSIONS: We generated and characterized the first TCR transgenic against an endogenous neoantigen within a preclinical glioma model and demonstrated the therapeutic potential of adoptively transferred neoantigen-specific T cells. The MISTIC mouse provides a powerful novel platform for basic and translational studies of antitumor T-cell responses in glioblastoma.

Validity of Self-Report for Ascertaining HIV Status Among Circular Migrants and Permanent Residents in South Africa: A Cross-Sectional, Population-Based Analysis.

While expanded HIV testing is needed in South Africa, increasing accurate self-report of HIV status is an essential parallel goal in this highly mobile population. If self-report can ascertain true HIV-positive status, persons with HIV (PWH) could be linked to life-saving care without the existing delays required by producing medical records or undergoing confirmatory testing, which are especially burdensome for the country's high prevalence of circular migrants. We used Wave 1 data from The Migration and Health Follow-Up Study, a representative adult cohort, including circular migrants and permanent residents, randomly sampled from the Agincourt Health and Demographic Surveillance System in a rural area of Mpumalanga Province. Within the analytic sample (n = 1,918), sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of self-report were calculated with dried blood spot (DBS) HIV test results as the standard. Among in-person participants (n = 2,468), 88.8% consented to DBS-HIV testing. HIV prevalence was 25.3%. Sensitivity of self-report was 43.9% (95% CI: 39.5-48.5), PPV was 93.4% (95% CI: 89.5-96.0); specificity was 99.0% (95% CI: 98.3-99.4) and NPV was 83.9% (95% CI: 82.8-84.9). Self-report of an HIV-positive status was predictive of true status for both migrants and permanent residents in this high-prevalence setting. Persons who self-reported as living with HIV were almost always truly positive, supporting a change to clinical protocol to immediately connect persons who say they are HIV-positive to ART and counselling. However, 56% of PWH did not report as HIV-positive, highlighting the imperative to address barriers to disclosure.

Epidemiology of chronic multimorbidity and temporary migration in a rural South African community in health transition: A cross-sectional population-based analysis.

Introduction: In sub-Saharan African settings, the increasing non-communicable disease mortality is linked to migration, which disproportionately exposes sub-populations to risk factors for co-occurring HIV and NCDs. Methods: We examined the prevalence, patterns, and factors associated with two or more concurrent diagnoses of chronic diseases (i.e., multimorbidity) among temporary within-country migrants. Employing a cross-sectional design, our study sample comprised 2144 residents and non-residents 18-40 years interviewed and with measured biomarkers in 2018 in Wave 1 of the Migrant Health Follow-up Study (MHFUS), drawn from the Agincourt Health and Demographic Surveillance System (AHDSS) in rural north-eastern South Africa. We used modified Poisson regression models to estimate the association between migration status and prevalent chronic multimorbidity conditional on age, sex, education, and healthcare utilisation. Results: Overall, 301 participants (14%; 95% CI 12.6-15.6), median age 31 years had chronic multimorbidity. Multimorbidity was more prevalent among non-migrants (14.6%; 95% CI 12.8-16.4) compared to migrants (12.8%; 95% CI 10.3-15.7). Non-migrants also had the greatest burden of dual-overlapping chronic morbidities, such as HIV-obesity 5.7%. Multimorbidity was 2.6 times as prevalent (PR 2.65. 95% CI 2.07-3.39) among women compared to men. Among migrants, men, and individuals with secondary or tertiary education manifested lower prevalence of two or more conditions. Discussion: In a rural community with colliding epidemics, we found low but significant multimorbidity driven by a trio of conditions: HIV, hypertension, and obesity. Understanding the multimorbidity burden associated with early adulthood exposures, including potential protective factors (i.e., migration coupled with education), is a critical first step towards improving secondary and tertiary prevention for chronic disease among highly mobile marginalised sub-populations.

Therapeutic use of α2-antiplasmin as an antifibrinolytic and hemostatic agent in surgery and regenerative medicine.

The biomaterial fibrin is widely used as a clinical tissue sealant in surgery. In preclinical research, fibrin is also extensively studied as a carrier material for growth factor delivery. In these applications, premature fibrin degradation leads to recurrent bleeding, tissue dehiscence and limited regenerative efficacy. Therefore, fibrinolysis inhibitors have been added to clinical fibrin formulations, for example the bovine-derived serine protease inhibitor aprotinin. Aprotinin is additionally used as a hemostatic agent to prevent excessive bleeding during surgery, in this case protecting endogenous fibrin clots. Nevertheless, aprotinin use has been associated with serious safety issues. Here, we explore the use the human physiological fibrinolysis inhibitor α2-antiplasmin (α2PI) as a substitute for aprotinin. We evaluate the efficacy of α2PI in the three main applications of aprotinin. We first showed that recombinant α2PI can successfully prolong the durability of fibrin biomaterials as compared to aprotinin in a model of subcutaneous implantation in mice mimicking application as a tissue sealant. We then used α2PI to enhance the delivery of engineered vascular endothelial growth factor (VEGF)-A and platelet-derived growth factor (PDGF)-BB in fibrin in promoting diabetic wound healing, which lead to improved wound closure, granulation tissue formation and angiogenesis. Lastly, we demonstrated that α2PI can be as effective as aprotinin as an intravenous hemostatic agent to prevent blood loss, using a tail-vein bleeding model in mice. Therefore, we believe that engineering fibrin biomaterials or endogenous fibrin with α2PI can have a strong impact in surgery and regenerative medicine by providing a competitive substitute to aprotinin that is of human origin.

Effectiveness of technology for braille literacy education for children: a systematic review.

PURPOSE: Despite the well-documented importance of braille for people who are blind or visually impaired, few studies explore technology for facilitating braille literacy education. Evaluations of the impact of using assistive devices on academics for children and youth who are blind or visually impaired are needed. This systematic review aimed to evaluate the effectiveness of technology used to support braille literacy education for children and youth. MATERIALS AND METHODS: The population of interest was defined as children and youth aged 0-21 years who were blind or visually impaired, learning literacy through braille as their primary medium, and had not previously learned to read through sighted methods. Sixteen academic education, health sciences, multidisciplinary, rehabilitation, and engineering databases were searched. RESULTS: Twelve peer-reviewed, English-language articles were included in the review evaluating a total of 176 participants. In general, the quality of research was low with little evidence to support the use of current technology for braille literacy education. CONCLUSIONS: Standards of technology evaluation for braille literacy must be developed. Furthermore, assistive technologies for braille literacy education for children and youth should provide real-time auditory and tactile feedback, enable independent study/practice and editing of work, and be easy to use, motivational, and engaging. IMPLICATIONS FOR REHABILITATIONStandards must be developed to ensure technology evaluation is consistent among researchers and clinicians to achieve the best outcomes.Technologies for braille literacy education for children and youth should provide real-time auditory and tactile feedback, enable independent study/practice and editing of work, and be easy to use, motivational, and engaging.

The impact of COVID-19 on a cohort of origin residents and internal migrants from South Africa's rural northeast.

South Africa has a large temporary migrant population with people commonly moving to metropolitan areas to access employment, while maintaining links with their rural origin households. The COVID-19 pandemic has impacted patterns of movement, livelihoods and health seeking, and the effects on internal, temporary migrants are unclear. Using longitudinal data spanning 2018 to 2020, this paper employs descriptive statistics and regression analyses to assess the impacts of COVID-19 on a cohort of 2971 persons aged 18-40 at baseline, both residents and migrants, from a rural district in South Africa's northeast. In contrast with 2018-2019, in 2020 the share of rural residents initiating a migration decreased by 11 percentage points (p<0.001), while the share of temporary migrants returning to origin households increased by 5 percentage points (p<0.001). Study participants who were continuing migrants reported fewer job losses in comparison with rural-stayers, while 76% of return migrants who were employed in 2019 were no longer employed in 2020. Further, among those who did not experience food shortages in 2019, rural-stayers had 1.42 times the odds of continuing migrants of suffering shortages in 2020. In 2020 health service use in the cohort decreased overall, with return migrants having still lower odds of utilising health services. The results highlight the differential geographic and socioeconomic manifestations of the pandemic, with worsening socioeconomic circumstances observed for rural-staying (disproportionately female) and returning populations, while continuing migrants fared relatively better. It is vital that a COVID-19 response considers the potentially heterogeneous impact of the pandemic on mobile and stable populations. Policy responses may include targeting migrants at their destinations in health promotion of COVID-19 messaging, and strengthening health care and social support in origin communities in recognition that these areas receive return migrants into their catchment population.

Kidney repair and regeneration: perspectives of the NIDDK (Re)Building a Kidney consortium.

Acute kidney injury impacts âˆ¼13.3 million individuals and causes âˆ¼1.7 million deaths per year globally. Numerous injury pathways contribute to acute kidney injury, including cell cycle arrest, senescence, inflammation, mitochondrial dysfunction, and endothelial injury and dysfunction, and can lead to chronic inflammation and fibrosis. However, factors enabling productive repair versus nonproductive, persistent injury states remain less understood. The (Re)Building a Kidney (RBK) consortium is a National Institute of Diabetes and Digestive and Kidney Diseases consortium focused on both endogenous kidney repair mechanisms and the generation of new kidney tissue. This short review provides an update on RBK studies of endogenous nephron repair, addressing the following questions: (i) What is productive nephron repair? (ii) What are the cellular sources and drivers of repair? and (iii) How do RBK studies promote development of therapeutics? Also, we provide a guide to RBK's open access data hub for accessing, downloading, and further analyzing data sets.

Interrupting Pedestrians in Indonesia; Effect of Climate on Perceived Steepness and Stair Climbing Behaviour.

Increased activity during daily life is one public health initiative to reduce population inactivity. Increasing temperature and humidity influence walking for transport by reducing the blood supply available to exercising muscles. This study investigated effects of temperature and humidity on a perceptual cue, estimated stair slant, that can influence behaviour, and on subsequent speed of climbing. Participants (402 males, 423 females) estimated the slant of a 20.4° staircase at a university in Indonesia. Subsequently, the participants were timed covertly while climbing. As temperature and humidity increased, estimated stair slant became more exaggerated. Females estimated stair slant as steeper than males. For stair climbing, speed was reduced as temperature increased, and females climbed slower than males. Estimates of stair slant were not associated with speed of the subsequent climb. Climate influences estimates of stair slant that precede stair climbing and subsequent speed of the ascent. In this study, perception was unrelated to behaviour.

Post-migration emotional well-being among Black South Africans.

Internal migration has been an institutionalized part of life for Black South Africans from the 1800s, when men left their rural homes to work in mines, through apartheid and into the present. Like other settings in the Global South, we know surprisingly little about the emotional well-being of migrants, especially in sub-Saharan African contexts. We investigate changes in the emotional well-being of 2281 working-age Black South Africans after migration, drawing on four waves of data, from 2008 to 2015, from the nationally representative National Income Dynamics Study. Fixed-effects regressions show that migrants exhibit changes in life satisfaction as well as proclivity towards depression but that these outcomes vary by distance of move and type of move-moving within or between provinces. As South Africa's health policies expand beyond addressing infectious diseases, it is important to consider mental health particularly of those who face the necessity of migration to sustain a livelihood.

VEGF-A, PDGF-BB and HB-EGF engineered for promiscuous super affinity to the extracellular matrix improve wound healing in a model of type 1 diabetes.

Chronic non-healing wounds, frequently caused by diabetes, lead to lower quality of life, infection, and amputation. These wounds have limited treatment options. We have previously engineered growth factors to bind to exposed extracellular matrix (ECM) in the wound environment using the heparin-binding domain of placental growth factor-2 (PlGF-2123-144), which binds promiscuously to ECM proteins. Here, in the type 1 diabetic (T1D) NOD mouse model, engineered growth factors (eGFs) improved both re-epithelialization and granulation tissue formation. eGFs were even more potent in combination, and the "triple therapy" of vascular endothelial growth factor-A (VEGF-PlGF-2123-144), platelet-derived growth factor-BB (PDGF-BB-PlGF-2123-144), and heparin-binding epidermal growth factor (HB-EGF-PlGF-2123-144) both improved wound healing and remained at the site of administration for significantly longer than wild-type growth factors. In addition, we also found that changes in the cellular milieu of a wound, including changing amounts of M1 macrophages, M2 macrophages and effector T cells, are most predictive of wound-healing success in the NOD mouse model. These results suggest that the triple therapy of VEGF-PlGF-2123-144, PDGF-BB-PlGF-2123-144, and HB-EGF-PlGF-2123-144 may be an effective therapy for chronic non-healing wounds in that occur as a complication of diabetes.

Vertical and slanted sound propagation in the near-ground atmosphere: Coherence and distributions.

Atmospheric turbulence causes acoustic signals to fluctuate and diminishes their coherence. These phenomena are important in applications such as source localization and sonic boom propagation. This article provides formulations for the spatial, cross-frequency, and temporal coherences of narrowband acoustic signals propagating over vertical and slanted paths in the atmosphere. Formulations for single- and two-point distributions of acoustic signals are also overviewed. The theoretical formulations are compared with data from a comprehensive sound propagation experiment carried out in 2018 at the National Wind Technology Center (Boulder, CO). The theories for sound propagation in a turbulent atmosphere, when combined with turbulence models incorporating shear and buoyancy instabilities, correctly predict the measured spatial coherence, which is primarily affected by small-scale isotropic turbulence. For relatively small coherence times, this approach also correctly predicts the temporal coherence. However, the approach underpredicts the cross-frequency coherence and temporal coherence for relatively large coherence times, which are affected by large-scale anisotropic buoyancy-driven velocity fluctuations. For different regimes ranging from unsaturated to fully saturated scattering, the measured distributions agree well with the theoretical predictions.

Vertical and slanted sound propagation in the near-ground atmosphere: Amplitude and phase fluctuations.

Sound propagation along vertical and slanted paths through the near-ground atmosphere impacts detection and localization of low-altitude sound sources, such as small unmanned aerial vehicles, from ground-based microphone arrays. This article experimentally investigates the amplitude and phase fluctuations of acoustic signals propagating along such paths. The experiment involved nine microphones on three horizontal booms mounted at different heights to a 135-m meteorological tower at the National Wind Technology Center (Boulder, CO). A ground-based loudspeaker was placed at the base of the tower for vertical propagation or 56 m from the base of the tower for slanted propagation. Phasor scatterplots qualitatively characterize the amplitude and phase fluctuations of the received signals during different meteorological regimes. The measurements are also compared to a theory describing the log-amplitude and phase variances based on the spectrum of shear and buoyancy driven turbulence near the ground. Generally, the theory correctly predicts the measured log-amplitude variances, which are affected primarily by small-scale, isotropic turbulent eddies. However, the theory overpredicts the measured phase variances, which are affected primarily by large-scale, anisotropic, buoyantly driven eddies. Ground blocking of these large eddies likely explains the overprediction.

Internal migration and health in South Africa: determinants of healthcare utilisation in a young adult cohort.

BACKGROUND: In South Africa, human geographic mobility is high as people engage in both permanent and temporary relocation, predominantly from rural to urban areas. Such mobility can compromise healthcare access and utilisation. The objective of this paper is to explore healthcare utilisation and its determinants in a cohort of internal migrants and permanent residents (non-migrants) originating from the Agincourt sub-district in South Africa's rural northeast. METHODS: A 5-year cohort study of 3800 individuals aged 18 to 40 commenced in 2017. Baseline data have been collected from 1764 Agincourt residents and 1334 temporary, mostly urban-based, migrants, and are analysed using bivariate analyses, logistic and multinomial regression models, and propensity score matching analysis. RESULTS: Health service utilisation differs sharply by migrant status and sex. Among those with a chronic condition, migrants had 0.33 times the odds of non-migrants to have consulted a health service in the preceding year, and males had 0.32 times the odds of females of having used health services. Of those who utilised services, migration status was further associated with the type of healthcare utilised, with 97% of non-migrant rural residents having accessed government facilities, while large proportions of migrants (31%) utilised private health services or consulted traditional healers (25%) in migrant destinations. The multinomial logistic regression analysis indicated that, in the presence of controls, migrants had 8.12 the relative risk of non-migrants for utilising private healthcare (versus the government-services-only reference category), and 2.40 the relative risk of non-migrants for using a combination of public and private sector facilities. These findings of differential utilisation hold under statistical adjustment for relevant controls and for underlying propensity to migrate. CONCLUSIONS: Migrants and non-migrants in the study population in South Africa were found to utilise health services differently, both in overall use and in the type of healthcare consulted. The study helps improve upon the limited stock of knowledge on how migrants interface with healthcare systems in low and middle-income country settings. Findings can assist in guiding policies and programmes to be directed more effectively to the populations most in need, and to drive locally adapted approaches to universal health coverage.

Home-Based Stair Climbing as an Intervention for Disease Risk in Adult Females; A Controlled Study.

Cardiovascular disease and the metabolic syndrome are major contributors to health care expenditure. Increased physical activity reduces disease risk. The study compared effects of walking up and down stairs at home with continuous, gym-based stair climbing on the disease risk factors of aerobic fitness, serum lipids, body composition, fasting blood glucose, and resting cardiovascular variables. Sedentary women (31.7 ± 1.4 years) were randomly assigned to home-based (n = 26) or gym-based (n = 24) climbing for five days.week-1 over an eight-week period. Each ascent required a 32.8-m climb, with home-based climbing matching the vertical displacement in the gym. Participants progressed from two ascents.day-1 to five ascents.day-1 in weeks 7 and 8. Relative to controls, stair climbing improved aerobic fitness (V˙O2max +1.63 mL.min-1.kg-1, 95% CI = 1.21-2.05), body composition (weight -0.99 kg, 95% CI = 1.38-0.60), and serum lipids (LDL cholesterol -0.20 mmol.L-1, 95% CI = 0.09-0.31; triglycerides -0.21 mmol.L-1, 95% CI = 0.15-0.27), with similar risk reductions for home and gym-based groups. Only the home-based protocol reduced fasting blood glucose. Discussion focuses on stair climbing bouts as time-efficient exercise and the potential benefits of a home-based intervention. Stair use at home offers a low-cost intervention for disease risk reduction to public health.