Evaluation of tuberculosis diagnostic test accuracy using Bayesian latent class analysis in the presence of conditional dependence between the diagnostic tests used in a community-based tuberculosis screening study

Diagnostic accuracy studies in pulmonary tuberculosis (PTB) are complicated by the lack of a perfect reference standard. This limitation can be handled using latent class analysis (LCA), assuming independence between diagnostic test results conditional on the true unobserved PTB status. Test results could remain dependent, however, e.g. with diagnostic tests based on a similar biological basis. If ignored, this gives misleading inferences. Our secondary analysis of data collected during the first year (May 2018 -May 2019) of a community-based multi-morbidity screening program conducted in the rural uMkhanyakude district of KwaZulu Natal, South Africa, used Bayesian LCA. Residents of the catchment area, aged >/=15 years and eligible for microbiological testing, were analyzed. Probit regression methods for dependent binary data sequentially regressed each binary test outcome on other observed test results, measured covariates and the true unobserved PTB status. Unknown model parameters were assigned Gaussian priors to evaluate overall PTB prevalence and diagnostic accuracy of 6 tests used to screen for PTB: any TB symptom, radiologist conclusion, Computer Aided Detection for TB version 5 (CAD4TBv5>/=53), CAD4TBv6>/=53, Xpert Ultra (excluding trace) and culture. Before the application of our proposed model, we evaluated its performance using a previously published childhood pulmonary TB (CPTB) dataset. Standard LCA assuming conditional independence yielded an unrealistic prevalence estimate of 18.6% which was not resolved by accounting for conditional dependence among the true PTB cases only. Allowing, also, for conditional dependence among the true non-PTB cases produced a 1.1% plausible prevalence. After incorporating age, sex, and HIV status in the analysis, we obtained 0.9% (95% CrI: 0.6, 1.3) overall prevalence. Males had higher PTB prevalence compared to females (1.2% vs. 0.8%). Similarly, HIV+ had a higher PTB prevalence compared to HIV- (1.3% vs. 0.8%). The overall sensitivity for Xpert Ultra (excluding trace) and culture were 62.2% (95% CrI: 48.7, 74.4) and 75.9% (95% CrI: 61.9, 89.2), respectively. Any chest X-ray abnormality, CAD4TBv5>/=53 and CAD4TBv6>/=53 had similar overall sensitivity. Up to 73.3% (95% CrI: 61.4, 83.4) of all true PTB cases did not report TB symptoms. Our flexible modelling approach yields plausible, easy-to-interpret estimates of sensitivity, specificity and PTB prevalence under more realistic assumptions. Failure to fully account for diagnostic test dependence can yield misleading inferences

The respiratory pressure-abdominal volume curve in a porcine model

Background: Increasing intra-abdominal volume (IAV) can lead to intra-abdominal hypertension (IAH) or abdominal compartment syndrome. Both are associated with raised morbidity and mortality. IAH can increase airway pressures and impair ventilation. The relationship between increasing IAV and airway pressures is not known. We therefore assessed the effect of increasing IAV on airway and intra-abdominal pressures (IAP). Methods: Seven pigs (41.4 +/−8.5 kg) received standardized anesthesia and mechanical ventilation. A latex balloon inserted in the peritoneal cavity was inflated in 1-L increments until IAP exceeded 40 cmH2O. Peak airway pressure (pPAW), respiratory compliance, and IAP (bladder pressure) were measured. Abdominal compliance was calculated. Different equations were tested that best described the measured pressure-volume curves. Results: An exponential equation best described the measured pressure-volume curves. Raising IAV increased pPAW and IAP in an exponential manner. Increases in IAP were associated with parallel increases in pPAW with an approximate 40% transmission of IAP to pPAW. The higher the IAP, the greater IAV effected pPAW and IAP. Conclusions: The exponential nature of the effect of IAV on pPAW and IAP implies that, in the presence of high grades of IAH, small reductions in IAV can lead to significant reductions in airway and abdominal pressures. Conversely, in the presence of normal IAP levels, large increases in IAV may not affect airway and abdominal pressures

Biological modelling of the radiation dose escalation effect of regional hyperthermia in cervical cancer

Background Locoregional hyperthermia combined with radiotherapy significantly improves locoregional control and overall survival for cervical tumors compared to radiotherapy alone. In this study biological modelling is applied to quantify the effect of radiosensitization for three cervical cancer patients to evaluate the improvement in equivalent dose for the combination treatment with radiotherapy and hyperthermia. Methods The Linear-Quadratic (LQ) model extended with temperature-dependent LQ-parameters α and β was used to model radiosensitization by hyperthermia and to calculate the conventional radiation dose that is equivalent in biological effect to the combined radiotherapy and hyperthermia treatment. External beam radiotherapy planning was performed based on a prescription dose of 46Gy in 23 fractions of 2Gy. Hyperthermia treatment using the AMC-4 system was simulated based on the actual optimized system settings used during treatment. Results The simulated hyperthermia treatments for the 3 patients yielded a T50 of 40.1 °C, 40.5 °C, 41.1 °C and a T90 of 39.2 °C, 39.7 °C, 40.4 °C, respectively. The combined radiotherapy and hyperthermia treatment resulted in a D95 of 52.5Gy, 55.5Gy, 56.9Gy in the GTV, a dose escalation of 7.3–11.9Gy compared to radiotherapy alone (D95 = 45.0–45.5Gy). Conclusions This study applied biological modelling to evaluate radiosensitization by hyperthermia as a radiation-dose escalation for cervical cancer patients. This model is very useful to compare the effectiveness of different treatment schedules for combined radiotherapy and hyperthermia treatments and to guide the design of clinical studies on dose escalation using hyperthermia in a multi-modality setting

Development of conjugated secondary antibodies for wildlife disease surveillance

Disease monitoring in free-ranging wildlife is a challenge and often relies on passive surveillance. Alternatively, proactive surveillance that relies on the detection of specific antibodies could give more reliable and timely insight into disease presence and prevalence in a population, especially if the evidence of disease occurs below detection thresholds for passive surveillance. Primary binding assays, like the indirect ELISA for antibody detection in wildlife, are hampered by a lack of species-specific conjugates. In this study, we developed anti-kudu (Tragelaphus strepsiceros) and anti-impala (Aepyceros melampus) immunoglobulin-specific conjugates in chickens and compared them to the binding of commercially available protein-G and protein-AG conjugates, using an ELISA-based avidity index. The conjugates were evaluated for cross-reaction with sera from other wild herbivores to assess future use in ELISAs. The developed conjugates had a high avidity of >70% against kudu and impala sera. The commercial conjugates (protein-G and protein-AG) had significantly low relative avidity (<20%) against these species. Eighteen other wildlife species demonstrated cross-reactivity with a mean relative avidity of >50% with the impala and kudu conjugates and <40% with the commercial conjugates. These results demonstrate that species-specific conjugates are important tools for the development and validation of immunoassays in wildlife and for the surveillance of zoonotic agents along the livestock-wildlife-human interface

Spin Transfer Measurements for (p,n) Reactions at Intermediate Energy

This research was sponsored by the National Science Foundation Grant NSF PHY 87-1440

Sources of variation in quality of South African beef: Case studies in relation to the red meat classification system

Abstract The South African classification system describes beef carcasses in regard to visual fat cover, conformation and age by dentition. Animal age provides a fairly accurate description of expected eating quality in regard to tenderness in an industry where other sources of variation in tenderness are limited. Since deregulation in the beef industry in the 90s many changes have occurred in all parts of the value chain. This paper presents a number of case studies that focussed on the sources of variation in meat quality, but in particular on sources of changes in meat tenderness over the past two decades. These sources include feeding regime, the use of beta agonists, post mortem ageing and electrical stimulation. In some studies these factors are integrated with age or interactions among two or more of these factors are investigated

A joint physics and radiobiology DREAM team vision - Towards better response prediction models to advance radiotherapy.

Radiotherapy developed empirically through experience balancing tumour control and normal tissue toxicities. Early simple mathematical models formalized this practical knowledge and enabled effective cancer treatment to date. Remarkable advances in technology, computing, and experimental biology now create opportunities to incorporate this knowledge into enhanced computational models. The ESTRO DREAM (Dose Response, Experiment, Analysis, Modelling) workshop brought together experts across disciplines to pursue the vision of personalized radiotherapy for optimal outcomes through advanced modelling. The ultimate vision is leveraging quantitative models dynamically during therapy to ultimately achieve truly adaptive and biologically guided radiotherapy at the population as well as individual patient-based levels. This requires the generation of models that inform response-based adaptations, individually optimized delivery and enable biological monitoring to provide decision support to clinicians. The goal is expanding to models that can drive the realization of personalized therapy for optimal outcomes. This position paper provides their propositions that describe how innovations in biology, physics, mathematics, and data science including AI could inform models and improve predictions. It consolidates the DREAM team's consensus on scientific priorities and organizational requirements. Scientifically, it stresses the need for rigorous, multifaceted model development, comprehensive validation and clinical applicability and significance. Organizationally, it reinforces the prerequisites of interdisciplinary research and collaboration between physicians, medical physicists, radiobiologists, and computational scientists throughout model development. Solely by a shared understanding of clinical needs, biological mechanisms, and computational methods, more informed models can be created. Future research environment and support must facilitate this integrative method of operation across multiple disciplines

Rotating Shallow Water Dynamics: Extra Invariant and the Formation of Zonal Jets

We show that rotating shallow water dynamics possesses an approximate (adiabatic-type) positive quadratic invariant, which exists not only at mid-latitudes (where its analogue in the quasigeostrophic equation has been previously investigated), but near the equator as well (where the quasigeostrophic equation is inapplicable). Deriving the extra invariant, we find "small denominators" of two kinds: (1) due to the triad resonances (as in the case of the quasigeostrophic equation) and (2) due to the equatorial limit, when the Rossby radius of deformation becomes infinite. We show that the "small denominators" of both kinds can be canceled. The presence of the extra invariant can lead to the generation of zonal jets. We find that this tendency should be especially pronounced near the equator. Similar invariant occurs in magnetically confined fusion plasmas and can lead to the emergence of zonal flows.Comment: 29 pages, 4 figure

Assessment of a viral load result-triggered automated differentiated service delivery model for people taking ART in Lesotho (the VITAL study): study protocol of a cluster-randomized trial

INTRODUCTION: To sustainably provide good quality care to increasing numbers of people living with HIV (PLHIV) receiving antiretroviral therapy (ART) in resource-limited settings, care delivery must shift from a "one-size-fits-all" approach to differentiated service delivery models. Such models should reallocate resources from PLHIV who are doing well to groups of PLHIV who may need more attention, such as those with treatment failure. The VIral load Triggered ART care Lesotho (VITAL) trial assesses a viral load (VL)-, participant's preference-informed, electronic health (eHealth)-supported, automated differentiated service delivery model (VITAL model). With VITAL, we aim to assess if the VITAL model is at least non-inferior to the standard of care in the proportion of participants engaged in care with viral suppression at 24 months follow-up and if it is cost-saving. METHODS: The VITAL trial is a pragmatic, multicenter, cluster-randomized, non-blinded, non-inferiority trial with 1:1 allocation conducted at 18 nurse-led, rural health facilities in two districts of northern Lesotho, enrolling adult PLHIV taking ART. In intervention clinics, providers are trained to implement the VITAL model and are guided by a clinical decision support tool, the VITALapp. VITAL differentiates care according to VL results, clinical characteristics, sub-population and participants' and health care providers' preferences. EXPECTED OUTCOMES: Evidence on the effect of differentiated service delivery for PLHIV on treatment outcomes is still limited. This pragmatic cluster-randomized trial will assess if the VITAL model is at least non-inferior to the standard of care and if it is cost saving. TRIAL REGISTRATION: The study has been registered with clinicaltrials.gov (Registration number NCT04527874; August 27, 2020)

Constraints on (2060) Chiron's size, shape, and surrounding material from the November 2018 and September 2019 stellar occultations

After the discovery of rings around the largest known Centaur object, (10199) Chariklo, we carried out observation campaigns of stellar occultations produced by the second-largest known Centaur object, (2060) Chiron, to better characterize its physical properties and presence of material on its surroundings. We predicted and successfully observed two stellar occultations by Chiron. These observations were used to constrain its size and shape by fitting elliptical limbs with equivalent surface radii in agreement with radiometric measurements. Constraints on the (2060) Chiron shape are reported for the first time. Assuming an equivalent radius of R$_{equiv}$ = 105$^{+6}_{-7}$ km, we obtained a semi-major axis of a = 126 $\pm$ 22 km. Considering Chiron's true rotational light curve amplitude and assuming it has a Jacobi equilibrium shape, we were able to derive a 3D shape with a semi-axis of a = 126 $\pm$ 22 km, b = 109 $\pm$ 19 km, and c = 68 $\pm$ 13 km, implying in a volume-equivalent radius of R$_{vol}$ = 98 $\pm$ 17 km, implying a density of 1119 $\pm$ 4 kg m$^{-3}$. We determined the physical properties of the 2011 secondary events around Chiron, which may then be directly compared with those of Chariklo rings, as the same method was used. Data obtained from SAAO in 2018 do not show unambiguous evidence of the proposed rings, mainly due to the large sampling time. Meanwhile, we discarded the possible presence of a permanent ring similar to (10199) Chariklo's C1R in optical depth and extension. Using the first multi-chord stellar occultation by (2060) Chiron and considering it to have a Jacobi equilibrium shape, we derived its 3D shape. New observations of a stellar occultation by (2060) Chiron are needed to further investigate the material's properties around Chiron, such as the occultation predicted for September 10, 2023