Evaluation of mobility recovery after hip fracture: a scoping review of randomized controlled studies.

Few older adults regain their pre-fracture mobility after a hip fracture. Intervention studies evaluating effects on gait typically use short clinical tests or in-lab parameters that are often limited to gait speed only. Measurements of mobility in daily life settings exist and should be considered to a greater extent than today. Less than half of hip fracture patients regain their pre-fracture mobility. Mobility recovery is closely linked to health status and quality of life, but there is no comprehensive overview of how gait has been evaluated in intervention studies on hip fracture patients. The purpose was to identify what gait parameters have been used in randomized controlled trials to assess intervention effects on older people's mobility recovery after hip fracture. This scoping review is a secondary paper that identified relevant peer-reviewed and grey literature from 11 databases. After abstract and full-text screening, 24 papers from the original review and 8 from an updated search and manual screening were included. Records were eligible if they included gait parameters in RCTs on hip fracture patients. We included 32 papers from 29 trials (2754 unique participants). Gait parameters were primary endpoint in six studies only. Gait was predominantly evaluated as short walking, with gait speed being most frequently studied. Only five studies reported gait parameters from wearable sensors. Evidence on mobility improvement after interventions in hip fracture patients is largely limited to gait speed as assessed in a controlled setting. The transition from traditional clinical and in-lab to out-of-lab gait assessment is needed to assess effects of interventions on mobility recovery after hip fracture at higher granularity in all aspects of patients' lives, so that optimal care pathways can be defined.

Human genomics of the humoral immune response against polyomaviruses.

Human polyomaviruses are widespread in humans and can cause severe disease in immunocompromised individuals. To identify human genetic determinants of the humoral immune response against polyomaviruses, we performed genome-wide association studies and meta-analyses of qualitative and quantitative immunoglobulin G responses against BK polyomavirus (BKPyV), JC polyomavirus (JCPyV), Merkel cellpolyomavirus (MCPyV), WU polyomavirus (WUPyV), and human polyomavirus 6 (HPyV6) in 15,660 individuals of European ancestry from three independent studies. We observed significant associations for all tested viruses: JCPyV, HPyV6, and MCPyV associated with human leukocyte antigen class II variation, BKPyV and JCPyV with variants in FUT2, responsible for secretor status, MCPyV with variants in STING1, involved in interferon induction, and WUPyV with a functional variant in MUC1, previously associated with risk for gastric cancer. These results provide insights into the genetic control of a family of very prevalent human viruses, highlighting genes and pathways that play a modulating role in human humoral immunity.

Epstein-Barr virus infection after adolescence and human herpesvirus 6A as risk factors for multiple sclerosis.

BACKGROUND AND PURPOSE: Infections with human herpesvirus 6A (HHV-6A) and Epstein-Barr virus (EBV) have been linked to multiple sclerosis (MS) development. For EBV, late infection has been proposed as a risk factor, but serological support is lacking. The objective of this study was to investigate how age affects the EBV and HHV-6A associated risks of developing MS. METHODS: In this nested case-control study, Swedish biobanks were accessed to find pre-symptomatically collected blood samples from 670 individuals who later developed relapsing MS and 670 matched controls. A bead-based multiplex assay was used to determine serological response against EBV and HHV-6A. Conditional logistic regression was used to calculate odds ratios and 95% confidence intervals. RESULTS: Seropositivity against EBV exhibited a pattern where associations switched from a decreased risk of developing MS in the group below 20 years of age to an increased risk amongst individuals aged 20-29 and 30-39 years (p for trend 0.020). The age of transition was estimated to be 18.8 years. In contrast, HHV-6A was associated with increased MS risk in all age groups (total cohort odds ratio 2.1, 95% confidence interval 1.6-2.7). CONCLUSIONS: This study suggests EBV infection after adolescence and age independent HHV-6A infection as risk factors for MS.

Timing of HPV16-E6 antibody seroconversion before OPSCC: findings from the HPVC3 consortium.

BACKGROUND: Human papillomavirus type 16 (HPV16)-E6 antibodies are detectable in peripheral blood before diagnosis in the majority of HPV16-driven oropharyngeal squamous cell carcinoma (OPSCC), but the timing of seroconversion is unknown. PATIENTS AND METHODS: We formed the HPV Cancer Cohort Consortium which comprises nine population cohorts from Europe, North America and Australia. In total, 743 incident OPSCC cases and 5814 controls provided at least one pre-diagnostic blood sample, including 111 cases with multiple samples. Median time between first blood collection and OPSCC diagnosis was 11.4 years (IQR = 6-11 years, range = 0-40 years). Antibodies against HPV16-E6 were measured by multiplex serology (GST fusion protein based Luminex assay). RESULTS: HPV16-E6 seropositivity was present in 0.4% of controls (22/5814; 95% CI 0.2% to 0.6%) and 26.2% (195/743; 95% CI 23.1% to 29.6%) of OPSCC cases. HPV16-E6 seropositivity increased the odds of OPSCC 98.2-fold (95% CI 62.1-155.4) in whites and 17.2-fold (95% CI 1.7-170.5) in blacks. Seropositivity in cases was more frequent in recent calendar periods, ranging from 21.9% pre-1996 to 68.4% in 2005 onwards, in those with blood collection near diagnosis (lead time <5 years). HPV16-E6 seropositivity increased with lead time: 0.0%, 13.5%, 23.7%, and 38.9% with lead times of >30 years (N = 24), 20-30 years (N = 148), 10-20 years (N = 228), and <10 years (N = 301 cases) (p-trend < 0.001). Of the 47 HPV16-E6 seropositive cases with serially-collected blood samples, 17 cases seroconverted during follow-up, with timing ranging from 6 to 28 years before diagnosis. For the remaining 30 cases, robust seropositivity was observed up to 25 years before diagnosis. CONCLUSIONS: The immune response to HPV16-driven tumorigenesis is most often detectable several decades before OPSCC diagnosis. HPV16-E6 seropositive individuals face increased risk of OPSCC over several decades.

Development and validation of HIV-1 Multiplex Serology.

By inducing immunosuppression in infected patients, human immunodeficiency virus-1 (HIV-1) generates a favorable environment for opportunistic infections and the development of several human cancers. In order to detect individual serum or plasma HIV-1 antibody status for epidemiological studies, high-throughput HIV-1 Multiplex Serology was developed. Seven HIV-1 antigens were recombinantly expressed in E. coli as N-terminal glutathione-S-transferase (GST) fusion proteins that are bound to glutathione-coupled sets of beads with distinct fluorescent color. Combining all bead sets in a suspension array allowed for simultaneous detection of antibodies targeting structural, regulatory and accessory proteins expressed during HIV-1 infection. HIV-1 Multiplex Serology was validated with 244 reference sera whose HIV-1 serostatus had been pre-determined by screening microparticle immunoassay and confirmatory line immunoassay. The multifunctional protein GAG emerged as an excellent marker to determine HIV-1 serostatus with a specificity of 99% (95% CI 96%-100%) and sensitivity of 100% (95% CI 88%-100%). Seropositivity for multiple HIV-1 antigens appeared to be characteristic for HIV-1 infected individuals (median number of antigens recognized in reference assay positive sera: 4; median number of antigens recognized in reference assay negative sera: 0), indicating a broad immune response targeting also regulatory and accessory proteins which may be useful for the identification of antibody patterns specific for infection-associated disease stages. HIV-1 Multiplex Serology performs similarly to conventional HIV-1 serology but eliminates the need for a two-step screening approach with subsequent confirmation assay. Thus, this high-throughput method will facilitate large-scale epidemiological studies of the role of HIV-1 in cancer development.

Fluctuations-induced coexistence in public goods dynamics.

Cooperative interactions between individuals in a population and their stability properties are central to population dynamics and evolution. We introduce a generic class of nonlinear dynamical systems describing such interactions between producers and non-producers of a rapidly equilibrating common resource extracted from a finite environment. In the deterministic mean field approximation, fast-growing non-producers drive the entire population to extinction. However, the presence of arbitrarily small perturbations destabilizes this fixed point into a stochastic attractor where both phenotypes can survive. Phase space arguments and moment closure are used to characterize the attractor and show that its properties are not determined by the noise amplitude or boundary conditions, but rather it is stabilized by the stochastic nonlinear dynamics. Spatial Monte Carlo simulations with demographic fluctuations and diffusion illustrate a similar effect, supporting the validity of the two-dimensional stochastic differential equation as an approximation. The functional distribution of the noise emerges as the main factor determining the dynamical outcome. Noise resulting from diffusion between different regions, or additive noise, induce coexistence while multiplicative or local demographic noise do not alter the outcome of deterministic dynamics. The results are discussed in a general context of the effect of noise on phase space structure.

Transients and tradeoffs of phenotypic switching in a fluctuating limited environment.

Phenotypic variability in a microorganism population is thought to be advantageous in fluctuating environments, however much remains unknown about the precise conditions for this advantage to hold. In particular competition for a growth-limiting resource and the dynamics of that resource in the environment modify the tradeoff between different effects of variability. Here we investigate theoretically a model system for variable populations under competition for a flowing resource that governs growth (chemostat model) and changes with time. This environment generally induces density-dependent selection among competing sub-populations. We characterize quantitatively the transient dynamics in this system, and find that equilibration between total population density and environment can occur separately and with a distinct timescale from equilibration between competing sub-populations. We analyze quantitatively the two opposing effects of heterogeneity--transient response to change, and fitness at equilibrium--and find the optimal strategy in a fluctuating environment. We characterize the phase diagram of the system in term of its optimal strategy and find it to be strongly dependent on the typical timescale of the environment and weakly dependent on the internal parameters of the population.

Investigation of the content and of the distribution of chemical elements in human nails by SRXRF.

The purpose of this investigation is to analyze 20 nails in individuals (and several persons) for the definition of how chemical elements distribute from nail to nail. The aim was to determine whether it will be rightful to take only one nail for the elemental analysis for the diagnostic of human state in future or not? Another purpose of the research is to analyze the elemental content of nails in temporal dynamic (in several persons). Analytical determinations of 20 nails of nine donors (healthy persons), nails of both hands and both feet were carried out. The analysis was performed by SRXRF. Symmetry of the elemental distribution in nails of right and left hands and right and left feet was found. The analysis of the distribution of chemical elements on the total area of a nail (55 points) was performed. The nail cutaway reflects adequately the distribution of several chemical elements over the nail plate area. In this study the elemental concentrations in nails of three donors in a 6-month period was determined. This study found the content of the chemical elements in donors' nails changes with time, individually.

Primary neuroendocrine carcinoma of inguinal lymph node.

Ninety-seven percent of neuroendocrine carcinomas are located in the gastrointestinal tract or in the bronchopulmonary tree. Inguinal lymph nodes as the primary tumor site for neuroendocrine carcinoma represent a very unusual location, and have only been described in 2 patient series in the literature. A 64-year-old, previously healthy, Caucasian female presented with a 2-month history of an enlarged inguinal lymph node on the right side. The removed lymph node showed histological and immunohistochemical characteristics of neuroendocrine differentiation (positive for synaptophysin, cytokeratin 20, neuron-specific enolase and chromogranin A). Although extensive investigations including repeated CT and NMR scans, classical endoscopy, wireless capsule endoscopy of the small intestine, octreotide- and MIBG scintigraphy were performed, no other primary tumor was found. Furthermore, there was no evidence of Merkel cell carcinoma on dermatological examinations. A possible explanation for the presence of neuroendocrine carcinomas within the lymph nodes is malignant transformation of preexisting intranodal epithelial nests, which have previously been described in lymph nodes located close to the salivary glands, thyroid gland, breast tissue and pancreas. Since the surgical removal of the affected lymph node, the patient has now been disease-free for 42 months. We therefore consider our case to represent a primary undifferentiated neuroendocrine carcinoma in an inguinal lymph node.

Quantification, localization, and expression of IGF-I and TGF-beta1 during growth factor-stimulated fracture healing.

Because of the increasing interest on stimulating fracture healing, knowledge about the role and chronology of growth factors during the healing process is important. The purpose of this study was to quantify the protein concentration of IGF-I and TGF-beta1 during rat tibial fracture healing 5, 10, and 15 days after fracture using ELISA methods and to analyze the distribution of the proteins and the related mRNA expression in the fracture callus by immunohistochemistry and in situ hybridization. The following three groups were analyzed: Fractured tibiae intramedullary stabilized with K-wires coated with IGF-I and TGF-beta1 compared with fractures stabilized with uncoated K-wires and unfractured tibiae. The weight of the callus increased during the healing process in both experimental groups. The protein concentration of IGF-I and TGF-beta1 in the fracture callus showed significant changes between the investigated time points and treatment groups compared with the unfractured tibia. IGF-I increased with healing time whereas TGF-beta1 revealed a constantly elevated level at the investigated time points. Mesenchymal cells, osteoblasts, osteocytes, proliferating and immature chondrocytes, and osteoclasts expressed both growth factors. No differences in the expression and localization pattern of the growth factors were detectable among the groups. Using the different methods for quantification and visualization of the growth factors, no differences (except the increased IGF-I concentration at day 15 in the growth factor group) were seen between the normal and the growth factor-stimulated fracture healing as an indication for physiological healing after exogenous growth factor treatment.

[Special aspects of implant-associated infection in orthopedic surgery. From the pathophysiology to custom-tailored prevention strategies]. / Besonderheiten der implantatassoziierten Infektion in der orthopädischen Chirurgie. Von der Pathophysiologie zu massgeschneiderten Präventionsstrategien.

One of the most important risk factors in orthopedic surgery is implant-associated infection. Adhesion and colonization mediated implant infections are extremely resistant to antibiotics and host defences and frequently persist until the biomaterial or foreign body is removed, which is standard therapy. Tissue damage caused by surgery and foreign body implantation increases the susceptibility to infections, activates host defences and stimulates the generation of inflammatory mediators including radicals that are further aggravated by bacterial activity and toxins. Nearly one third of implant-related infections can be prevented by strictly following established infection control guidelines. However, a significant number of implant-associated infections remains. The escape of bacteria from host defence and antibiotic therapy makes the development of infection-resistant materials as anti-microbial drug delivery systems feasible. This concept consists of the sustained delivery of antimicrobial drugs into the local microenvironment of implants avoiding systemic side effects exceeding usual systemic concentrations by magnitudes of order.

Synergy in a neural code.

We show that the information carried by compound events in neural spike trains-patterns of spikes across time or across a population of cells-can be measured, independent of assumptions about what these patterns might represent. By comparing the information carried by a compound pattern with the information carried independently by its parts, we directly measure the synergy among these parts. We illustrate the use of these methods by applying them to experiments on the motion-sensitive neuron H1 of the fly's visual system, where we confirm that two spikes close together in time carry far more than twice the information carried by a single spike. We analyze the sources of this synergy and provide evidence that pairs of spikes close together in time may be especially important patterns in the code of H1.

Adaptive rescaling maximizes information transmission.

Adaptation is a widespread phenomenon in nervous systems, providing flexibility to function under varying external conditions. Here, we relate an adaptive property of a sensory system directly to its function as a carrier of information about input signals. We show that the input/output relation of a sensory system in a dynamic environment changes with the statistical properties of the environment. Specifically, when the dynamic range of inputs changes, the input/output relation rescales so as to match the dynamic range of responses to that of the inputs. We give direct evidence that the scaling of the input/output relation is set to maximize information transmission for each distribution of signals. This adaptive behavior should be particularly useful in dealing with the intermittent statistics of natural signals.

[Efficacy of Doppler color echography in the diagnosis of caverno-venous leakage in the impotent patient]. / Efficacité de l'échographie Doppler couleur dans le diagnostic des fruites caverno-veineuses chez le patient impuissant.

Duplex sonography is now the gold standard for the non-invasive study of cavernous arteries. Many authors consider that this technique allows for the exploration of the veno-occlusive system and can detect venous leakage. The most common criteria is an end diastolic velocity > 5 cm/s, measured in the cavernous arteries. In a retrospective study, 34 impotent patients were reviewed. All of them were explored both by doppler sonography and pharmacocavernosometry to assess the efficacy of duplex sonography in detecting venous leakage. The data show that the doppler detects venous leakage in only 41%. The specificity and the sensitivity are both 50% which is clearly disappointing. Therefore, in our experience, duplex sonography is not a reliable technique to detect venous leakage. We consider that the best method is still pharmacocavernosometry.

Characterization of the binding of [125I]L-735,286: a new nonpeptide angiotensin II AT1 receptor radioligand.

[125I]L-735,286, a new potent and AT1-selective nonpeptide angiotensin II receptor radioligand, bound saturably to whole adrenal membranes. Scatchard and Hill plot analysis indicates a single class of high affinity (Kd = 0.5 nM) binding sites. The potencies of various angiotensin II agonists and antagonists in displacing specific [125I]L-735,286 binding are in good agreement with their potencies in displacing the binding of [125I]Sar1,Ile8-AII to adrenal AT1 receptors. The AT2 selective ligand, PD121981 had no effect on specific [125I]L-735,286 binding. In autoradiographic studies using rat kidney slices, specific labeling of [125I]L-735,286 was abolished by coincubation with saralasin. Collectively, the data indicated that [125I]L-735,286 represents a new, potent nonpeptide antagonist radioligand suitable for the study of angiotensin II AT1 receptors.

Receptor binding radiotracers for the angiotensin II receptor: radioiodinated [Sar1, Ile8]Angiotensin II.

The potential for imaging the angiotensin II receptor was evaluated using the radioiodinated peptide antagonist [125I][Sar1, Ile8)angiotensin II. The radioligand provides a receptor-mediated signal in several tissues in rat (kidneys, adrenal and liver). The receptor-mediated signal of 3% ID/g kidney cortex should be sufficient to permit imaging, at least via SPECT. The radiotracer is sensitive to reductions in receptor concentration and can be used to define in vivo dose-occupancy curves of angiotensin II receptor ligands. Receptor-mediated images of [123I][Sar1, Ile8]angiotensin II were obtained in the rat kidney and Rhesus monkey liver.