Behavioural digital biomarkers enable real-time monitoring of patient-reported outcomes: a substudy of the multicenter, prospective observational SafeHeart study.

INTRODUCTION: Patient-reported outcome measures (PROMs) serve multiple purposes, including shared decision-making and patient communication, treatment monitoring and health-technology assessment. Patient monitoring using PROMs is constrained by recall and non-response bias, respondent burden and missing data. We evaluated the potential of behavioural digital biomarkers obtained from a wearable accelerometer to achieve personalised predictions of PROMs. METHODS: Data from the multicenter, prospective SafeHeart study conducted at Amsterdam University Medical Center in the Netherlands and Copenhagen University Hospital, Rigshospitalet in Copenhagen, Denmark, was used. The study enrolled patients with an implantable cardioverter defibrillator (ICD) between May 2021 and September 2022 who then wore wearable devices with raw acceleration output to capture digital biomarkers reflecting physical behaviour. To collect PROMs, patients received the KCCQ and EQ5D-5 L questionnaire at two instances; baseline and after 6 months. Multivariable Tobit regression models were used to explore associations between digital biomarkers and PROMs, specifically whether digital biomarkers could enable PROM prediction. RESULTS: The study population consisted of 303 patients (mean age 62.9 ± 10.9 years, 81.2% male). Digital biomarkers showed significant correlations to patient-reported physical and social limitations, severity and frequency of symptoms and quality of life. Prospective validation of the Tobit models indicated moderate correlations between the observed and predicted scores for KCCQ (concordance correlation coefficient (CCC) = 0.49, mean difference: 1.07 points) and EQ5D-5 L (CCC = 0.38, mean difference 0.02 points). CONCLUSION: Wearable digital biomarkers correlate with PROMs, and may be leveraged for real-time prediction. These findings hold promise for monitoring of PROMs through wearable accelerometers.

Monobody adapter for functional antibody display on nanoparticles for adaptable targeted delivery applications.

Vascular endothelial cells (ECs) play a central role in the pathophysiology of many diseases. The use of targeted nanoparticles (NPs) to deliver therapeutics to ECs could dramatically improve efficacy by providing elevated and sustained intracellular drug levels. However, achieving sufficient levels of NP targeting in human settings remains elusive. Here, we overcome this barrier by engineering a monobody adapter that presents antibodies on the NP surface in a manner that fully preserves their antigen-binding function. This system improves targeting efficacy in cultured ECs under flow by >1000-fold over conventional antibody immobilization using amine coupling and enables robust delivery of NPs to the ECs of human kidneys undergoing ex vivo perfusion, a clinical setting used for organ transplant. Our monobody adapter also enables a simple plug-and-play capacity that facilitates the evaluation of a diverse array of targeted NPs. This technology has the potential to simplify and possibly accelerate both the development and clinical translation of EC-targeted nanomedicines.

Vibrational properties of anhydrous and partially hydrated uranyl fluoride.

Uranyl fluoride (UO2F2) is a hygroscopic powder with two main structural phases: an anhydrous crystal and a partially hydrated crystal of the same R3¯m symmetry. The formally closed-shell electron structure of anhydrous UO2F2 is amenable to density functional theory calculations. We use density functional perturbation theory (DFPT) to calculate the vibrational frequencies of the anhydrous crystal structure and employ complementary inelastic neutron scattering and temperature-dependent Raman scattering to validate those frequencies. As a model closed-shell actinide, we investigated the effect of LDA, GGA, and non-local vdW functionals as well as the spherically averaged Hubbard +U correction on vibrational frequencies, electronic structure, and geometry of anhydrous UO2F2. A particular choice of Ueff=5.5 eV yields the correct U-Oyl bond distance and vibrational frequencies for the characteristic Eg and A1g modes that are within the resolution of experiment. Inelastic neutron scattering and Raman scattering suggest a degree of water coupling to the lattice vibrations in the more experimentally accessible partially hydrated UO2F2 system, with the symmetric stretching vibration shifted approximately 47 cm-1 lower in energy compared to the anhydrous structure. Evidence of water interaction with the uranyl ion is present from a two-peak decomposition of the uranyl stretching vibration in the Raman spectra and anion-hydrogen stretching vibrations in the inelastic neutron scattering spectra. A first-order dehydration phase transition temperature is definitively identified to be 125 °C using temperature-dependent Raman scattering.

Development of an ELISA for the Pharmacokinetic Evaluation of a Murine Anti CD66 Monoclonal Antibody in Human Serum.

An enzyme-linked immunosorbent assay (ELISA) was needed to assist in the pharmacokinetic evaluation of the murine antibody conjugate CHX A" DTPA Besilesomab in serum samples in a clinical trial . A search failed to locate a validated assay that quantified murine antibodies in human serum so the purpose of this article was to develop a robust assay, validated against current guidelines. A detailed method for an ELISA to measure a murine antibody in human serum is described. The assay was validated as fit for purpose against the target values of coefficient of variation < 20% and accuracy ± 20%.

An alternative marker for the effectiveness of water fluoridation: hospital extraction rates for dental decay, a two-region study.

BACKGROUND: Contemporary evidence for the effectiveness of water fluoridation schemes in the U.K. is sparse. The utility of routinely collected data in providing evidence warrants further research. OBJECTIVES: To examine inpatient hospital episodes statistics for dental extractions as an alternative population marker for the effectiveness of water fluoridation by comparing hospital admissions between two major strategic health authority (SHA) areas, the West Midlands SHA-largely fluoridated--and the North West SHA--largely unfluoridated. METHOD: Hospital episodes statistics (HES) were interrogated to provide data on admissions for simple and surgical dental extractions, which had a primary diagnostic code of either dental caries or diseases of pulp and periapical tissues for financial years 2006/7, 2007/8 and 2008/9. Data was aggregated by SHA area and quinary age group. Directly standardised rates (DSR) of admissions purchased for each primary care trust (PCT) were calculated and ranked by index of multiple deprivation (IMD). RESULTS: A significant difference in DSRs of admission between PCTs in the West Midlands and North West was observed (Mann-Whitney U test [p <0.0001]) irrespective of IMD ranking. The difference in rates between the two most deprived PCTs was 27-fold. CONCLUSIONS: After ranking by IMD, DSRs of hospital admissions for the extraction of decayed or pulpally/periapically involved teeth is lower in areas with a fluoridated water supply. The analysis of routinely collected HES data may help identify the impact of water fluoridation schemes.

Occupational hazard: radiation exposure for the urologist--developing a reference standard.

INTRODUCTION: To date, there is a paucity of literature offering practicing urologists a reference for the amount of radiation exposure received while surgically managing urolithiasis. This study examines the cumulative radiation exposure of an urologist over 9 months. MATERIALS AND METHODS: We present a case series of fluoroscopic exposures of an experienced stone surgeon operating at an academic comprehensive stone center between April and December 2011. Radiation exposure measurements were determined by a thermoluminescent dosimeter worn on the outside of the surgeon's thyroid shield. Estimations of radiation exposure (mrem) per month were charted with fluoroscopy times, using scatter plots to estimate Spearman's rank correlation coefficients. RESULTS: The total 9-month radiation exposure was 87 mrems for deep dose equivalent (DDE), 293 mrem for lens dose equivalent (LDE), and 282 mrem for shallow dose equivalent (SDE). Total fluoroscopy time was 252.44 minutes for 64 ureteroscopies (URSs), 29 percutaneous nephrolithtomies (PNLs), 20 cystoscopies with ureteral stent placements, 9 shock wave lithotripsies (SWLs), 9 retrograde pyelograms (RPGs), 2 endoureterotomies, and 1 ureteral balloon dilation. Spearman's rank correlation coefficients examining the association between fluoroscopy time and radiation exposure were not significant for DDE (p = 0.6, Spearman's rho = 0.2), LDE (p = 0.6, Spearman's rho = 0.2), or SDE (p = 0.6, Spearman's rho = 0.2). CONCLUSIONS: Over a 9-month period, total radiation exposures were well below annual accepted limits (DDE 5000 mrem, LDE 15,000 mrem and SDE 50,000 mrem). Although fluoroscopy time did not correlate with radiation exposure, future prospective studies can account for co-variates such as patient obesity and urologist distance from radiation source.

Development and evaluation of a driving observation schedule (DOS) to study everyday driving performance of older drivers.

This paper describes the development and evaluation of an on-road procedure, the Driving Observation Schedule (DOS), for monitoring individual driving behavior. DOS was developed for use in the Candrive/Ozcandrive five-year prospective study of older drivers. Key features included observations in drivers' own vehicles, in familiar environments chosen by the driver, with start/end points at their own homes. Participants were 33 drivers aged 75+ years, who drove their selected route with observations recorded during intersection negotiation, lane-changing, merging, low speed maneuvers and maneuver-free driving. Driving behaviors were scored by a specialist occupational therapy driving assessor and another trained observer. Drivers also completed a post-drive survey about the acceptability of DOS. Vehicle position, speed, distance and specific roadways traveled were recorded by an in-vehicle device installed in the participant's vehicle; this device was also used to monitor participants' driving over several months, allowing comparison of DOS trips with their everyday driving. Inter-rater reliability and DOS feasibility, acceptability and ecological validity are reported here. On average, drivers completed the DOS trip in 30.48min (SD=7.99). Inter-rater reliability measures indicated strong agreement between the trained and the expert observers: intra-class correlations (ICC)=0.905, CI 95% 0.747-0.965, p<0.0001; Pearson product correlation, r (18)=.83, p<0.05. Standard error of the measurement (SEM), method error (ME) and coefficient of variation (CV) measures were consistently small (3.0, 2.9 & 3.3%, respectively). Most participants reported being 'completely at ease' (82%) with the driving task and 'highly familiar with the route' (97%). Vehicle data showed that DOS trips were similar to participants' everyday driving trips in roads used, roadway speed limits, drivers' average speed and speed limit compliance. In summary, preliminary findings suggest that DOS can be scored reliably, is of feasible duration, is acceptable to drivers and representative of everyday driving. Pending further research with a larger sample and other observers, DOS holds promise as a means of quantifying and monitoring changes in older drivers' performance in environments typical of their everyday driving.

Epistaxis in racehorses: risk factors and effects on career.

OBJECTIVE: To profile Thoroughbreds that incurred a ban under Australian Rule of Racing 53A on New South Wales racetracks between August 1999 and July 2008, determine the effect on their careers and identify the factors that predict whether these horses would race again or experience a recurrence of epistaxis. METHODS: Differences between horses that did or did not return to racing and did or did not suffer recurrent epistaxis were determined. Backwards stepwise logistic regression was used to identify variables predicting a return to racing and recurrence of epistaxis. RESULTS: The mean (± SD) age at the first episode of epistaxis was 4.90 ± 1.28 years. Males that bled were older, had more career starts and were more likely to race again than females. Horses that were retired from racing after the first episode of epistaxis were older than horses that continued to race. Variables that were significant predictors of retirement were: age at the first episode of epistaxis, sex, percentage of winning starts before the first episode of epistaxis, percentage of placed starts before the first episode of epistaxis and number of starts in the preparation before the first episode of epistaxis. The significant predictors of recurrence of epistaxis were: change in distance between previous start and start at which the second episode occurred and a change in percentage of winning starts, although the odds ratios were low (0.98-0.99). CONCLUSIONS: Females experience epistaxis at a younger age than males. No readily applicable predictors of the recurrence of epistaxis were identified.

Occupational Hazard: Radiation Exposure for the Urologist – Developing a Reference Standard

Introduction To date, there is a paucity of literature offering practicing urologists a reference for the amount of radiation exposure received while surgically managing urolithiasis. This study examines the cumulative radiation exposure of an urologist over 9 months. Materials and Methods We present a case series of fluoroscopic exposures of an experienced stone surgeon operating at an academic comprehensive stone center between April and December 2011. Radiation exposure measurements were determined by a thermoluminescent dosimeter worn on the outside of the surgeon's thyroid shield. Estimations of radiation exposure (mrem) per month were charted with fluoroscopy times, using scatter plots to estimate Spearman's rank correlation coefficients. Results The total 9-month radiation exposure was 87 mrems for deep dose equivalent (DDE), 293 mrem for lens dose equivalent (LDE), and 282 mrem for shallow dose equivalent (SDE). Total fluoroscopy time was 252.44 minutes for 64 ureteroscopies (URSs), 29 percutaneous nephrolithtomies (PNLs), 20 cystoscopies with ureteral stent placements, 9 shock wave lithotripsies (SWLs), 9 retrograde pyelograms (RPGs), 2 endoureterotomies, and 1 ureteral balloon dilation. Spearman's rank correlation coefficients examining the association between fluoroscopy time and radiation exposure were not significant for DDE (p = 0.6, Spearman's rho = 0.2), LDE (p = 0.6, Spearman's rho = 0.2), or SDE (p = 0.6, Spearman's rho = 0.2). Conclusions Over a 9-month period, total radiation exposures were well below annual accepted limits (DDE 5000 mrem, LDE 15,000 mrem and SDE 50,000 mrem). Although fluoroscopy time did not correlate with radiation exposure, future prospective studies can account for co-variates such as patient obesity and urologist distance from radiation source. .

Is there a differential in the dental health of new recruits to the British Armed Forces? A pilot study.

BACKGROUND AND AIM: Figures from the British Defence Dental Services reveal that serving personnel in the British Army have a persistently lower level of dental fitness than those in the Royal Navy or the Royal Air Force. No research had been undertaken to ascertain if this reflects the oral health of recruits joining each Service. This study aimed to pilot a process for collecting dental and sociodemographic data from new recruits to each Service and examine the null hypothesis that no differences in dental health existed. METHOD: Diagnostic criteria were developed, a sample size calculated and data collected at the initial training establishments of each Service. RESULTS: Data for 432 participants were entered into the analysis. Recruits in the Army sample had a significantly greater prevalence of dental decay and greater treatment resource need than either of the other two Services. Army recruits had a mean number of 2.59 (2.08, 3.09) decayed teeth per recruit, compared to 1.93 (1.49, 2.39 p <0.01) in Royal Navy recruits and 1.26 (0.98, 1.53 p <0.001) in Royal Air Force recruits. Among Army recruits 62.7% were from the two most deprived quintiles of the Index of Multiple Deprivation compared to 42.5% of Royal Naval recruits and 36.6% of Royal Air Force recruits. CONCLUSION: A significant difference in dental health between recruits to each Service does exist and is a likely to be a reflection of the sociodemographic background from which they are drawn.

Summary of: third molar-related morbidity in deployed Service personnel.

INTRODUCTION: The minimisation of disease and non-battle injury (DNBI) is essential for maintaining efficiency in a fighting force. Third molar-related morbidity is a common cause of DNBI. With extended lines of communication in current military deployments, travelling for dental care is often subject to significant danger. MATERIAL AND METHODS: Military dental officers in Afghanistan and Iraq recorded data on patients presenting with third molar pathology. Related previous history was obtained from the individual and from the military dental records. RESULTS: Three hundred and three individuals presented during the 23 month study period; 27.7% were unable to access care immediately, most commonly citing work pressure or lack of safe transport. Of those needing to travel, 70% were moved by helicopter. Pericoronitis was diagnosed in 84.4% of cases, 20.6% of these teeth being extracted; 53.5% of patients reported no prior symptoms, 22.7% with two or more episodes. There was documented evidence in military dental records of previous problems in 29.2% of cases. 11.3% had previously been listed for extraction of the presenting tooth. DISCUSSION: Dental treatment for troops in combat situations is fraught with difficulty. Special consideration must be given to the management of third molars in military personnel.

A prospective longitudinal study to assess psychological changes following anterior cruciate ligament reconstruction surgery.

OBJECTIVE: To determine whether the psychological characteristics of athletes who have undergone an anterior cruciate ligament (ACL) reconstruction change during rehabilitation are related to returning to competitive sport. DESIGN: Prospective longitudinal study. METHOD: 87 athletes completed the Emotional Response of Athletes to Injury Questionnaire (ERAIQ) and the ACL Return to Sport after Injury scale (ACL-RSI) at 3, 6 and 12 months following ACL reconstruction surgery. Physical outcome measures were also taken at each time point. RESULTS: At 12 months 44 (51%) participants had returned to competitive sport and 43 (49%) participants had not returned. There were no differences in physical recovery or scores on the ERAIQ between the two groups. Participants who had returned to competitive sport at 12 months, however, scored significantly higher on the ACL-RSI scale (reflecting a more positive psychological response about sport participation) at both 6 and 12 months than participants who had not returned to competitive sport. CONCLUSIONS: During rehabilitation there are significant psychological differences regarding sport resumption between athletes who do, and do not, resume competitive sport 12 months following ACL reconstruction. These differences occur as early as 6 months postoperatively and highlight the importance of addressing all aspects of an athlete's recovery in order to help facilitate the athlete returning to sport.

The distribution of general dental practitioners with NHS contract numbers in relation to the distance of their practices from the seven dental undergraduate teaching hospitals in England outside London.

OBJECTIVE: To examine whether the presence of a dental school acts as an influence on the number of dentists practicing in the surrounding area. RESEARCH DESIGN: The project used Geographical Information Systems (GIS) mapping techniques, along with data on the location of NHS dentists, to plot dentist to population rates at selected distances from dental undergraduate teaching hospitals in England. A GIS map of dentist to population rates was then constructed for each of the dental schools and the rate patterns examined and compared. RESULTS: With the exception of Liverpool, the maps demonstrated higher than average rates up to two miles, and up to five miles for Manchester, from the location of the dental school before falling and then varying around the England and Wales average. No clear pattern emerged between dental schools, and no two schools produced a similar 'footprint'. CONCLUSIONS: Within the constraints of the current study, it appears that for graduates from the seven dental undergraduate teaching hospitals in England outside London, who work as general dental practitioners with NHS contracts, factors other than the distance of a practice from their place of training appear to have a greater influence on their choice of geographical location where they work, than its distance from a dental hospital.

Effects of pore structure and molecular size on diffusion in chromatographic adsorbents.

Two computational approaches, namely Brownian dynamics and network modeling, are presented for predicting effective diffusion coefficients of probes of different sizes in three chromatographic adsorbents, the structural properties of which were determined previously using electron tomography. Three-dimensional reconstructions of the adsorbents provide detailed, explicit characteristics of the pore network, so that no assumptions have to be made regarding pore properties such as connectivity, pore radius and pore length. The diffusivity predictions obtained from the two modeling approaches were compared to experimental diffusivities measured for dextran and protein probes. Both computational methods captured the same qualitative results, while their predictive capabilities varied among adsorbents.

Attitudes and opinions of NHS general dental practitioners towards clinical governance.

AIM: To assess the attitudes and opinions of NHS general dental practitioners towards clinical governance. DESIGN: This was a questionnaire based study, sent to NHS principal dentists within the West Midlands area. METHOD: A Likert scale questionnaire was developed, consisting of 26 statements in four subject areas. It was internally and externally validated, and sent to 208 practices within four geographic areas. RESULTS: A total of 150 questionnaires were returned; a response rate of 72%. For each question, no significant difference was found between areas. The cost and time involved with clinical governance emerged as the most important issues, with many respondents considering that costs of implementation might make more dentists leave the NHS. Dentists were largely positive about the principles of clinical governance and evidence based practice, but were concerned about the possibility of increasing complaints and some doubted that it would result in improved patient care. Many respondents claimed to be still confused about clinical governance and the majority considered that more guidance should be available to assist with development within dental practice. CONCLUSIONS: This survey showed that some problems exist around the introduction of clinical governance within NHS general dental practice.

Identification of an invasion regulatory domain within the core protein of syndecan-1.

Among the four members of the syndecan family there exists a high level of divergence in the ectodomain core protein sequence. This has led to speculation that these core proteins bear important functional domains. However, there is little information regarding these functions, and thus far, the biological activity of syndecans has been attributed largely to their heparan sulfate chains. We have previously demonstrated that cell surface syndecan-1 inhibits invasion of tumor cells into three-dimensional gels composed of type I collagen. Inhibition of invasion is dependent on the syndecan heparan sulfate chains, but a role for the syndecan-1 ectodomain core protein was also indicated. To more closely examine this possibility and to map the regions of the ectodomain essential for syndecan-1-mediated inhibition of invasion, a panel of syndecan-1 mutational constructs was generated, and each construct was transfected individually into myeloma tumor cells. The anti-invasive effect of syndecan-1 is dramatically reduced by deletion of an ectodomain region close to the plasma membrane. Further mutational analysis identified a stretch of 5 hydrophobic amino acids, AVAAV (amino acids 222-226), critical for syndecan-1-mediated inhibition of cell invasion. This invasion regulatory domain is 26 amino acids from the start of the transmembrane domain. Importantly, this domain is functionally specific because its mutation does not affect syndecan-1-mediated cell binding to collagen, syndecan-1-mediated cell spreading, or targeting of syndecan-1 to specific cell surface domains. This invasion regulatory domain may play an important role in inhibiting tumor cell invasion, thus explaining the observed loss of syndecan-1 in some highly invasive cancers.

Heparan sulfate regulates targeting of syndecan-1 to a functional domain on the cell surface.

In polarized B lymphoid cells, syndecan-1 is targeted specifically to a discrete membrane domain termed the uropod that is located at the cell's trailing edge. Within this functional domain, syndecan-1 promotes cell-cell adhesion and concentration of heparin binding growth factors. The present study reveals the surprising finding that targeting of syndecan-1 to uropods is mediated by its heparan sulfate chains and that targeting is regulated by cell surface events rather than solely by intracellular mechanisms. The addition of exogenous heparin or the treatment of polarized cells with heparitinase initiates a rapid and dramatic redistribution of uropod syndecan-1 over the entire cell surface, and a mutated syndecan-1 lacking heparan sulfate chains fails to concentrate within uropods. Interestingly, the heparan sulfate-bearing proteoglycans glypican-1 and beta glycan fail to concentrate in uropods, indicating that targeting may require heparan sulfate structural motifs unique to syndecan-1 or that the core protein of syndecan-1 participates in specific interactions that promote heparan sulfate-mediated targeting. These findings suggest functional specificity for syndecan-1 within uropods and, in addition, reveal a novel mechanism for the targeting of molecules to discrete membrane subcellular domains via heparan sulfate.

Soluble syndecan-1 promotes growth of myeloma tumors in vivo.

Syndecan-1 (CD138) is a transmembrane heparan sulfate-bearing proteoglycan expressed by most myeloma plasma cells that regulates adhesion, migration, and growth factor activity. In patients with myeloma, shed syndecan-1 accumulates in the bone marrow, and high levels of syndecan-1 in the serum are an indicator of poor prognosis. To test the effect of soluble syndecan-1 on tumor cell growth and dissemination, ARH-77 B-lymphoid cells were engineered to produce a soluble form of syndecan-1. Controls included vector only (neo)-transfected cells and cells transfected with full-length syndecan-1 complementary DNA that codes for the cell surface form of syndecan-1. Assays reveal that all 3 transfectants have similar growth rates in vitro, but cells expressing soluble syndecan-1 are hyperinvasive in collagen gels relative to controls. When injected into the marrow of human bones that were implanted in severe combined immunodeficient mice, tumors formed by cells expressing soluble syndecan-1 grow faster than tumors formed by neo-transfected cells or by cells expressing cell surface syndecan-1. In addition, cells bearing cell surface syndecan-1 exhibit a diminished capacity to establish tumors within the mice as compared with both neo- and soluble syndecan-1-transfected cells. Tumor cell dissemination to a contralateral human bone is detected significantly more often in the tumors producing soluble syndecan-1 than in controls. Thus, high levels of soluble syndecan-1 present in patients with myeloma may contribute directly to the growth and dissemination of the malignant cells and thus to poor prognosis.