Study protocol: understanding the pathophysiologic mechanisms underlying delirium in older people undergoing hip fracture surgery.

BACKGROUND: Postoperative delirium (POD) is a common complication of older people undergoing hip fracture surgery, which negatively affects clinical- and healthcare-related outcomes. Unfortunately, POD pathophysiology is still largely unknown, despite previous studies showing that neuroinflammation, neuroendocrine dysfunction, increased reactive oxidative stress (ROS), and endothelial dysfunctions may be involved. There is also evidence that many of the pathophysiological mechanisms which are involved in delirium are involved in sarcopenia too. This article describes the protocol of a pilot study to evaluate the feasibility of a larger one that will explore the pathophysiological mechanisms correlating POD with sarcopenia. We will analyse whether various biomarkers reflecting neuroinflammation, ROS, neuroendocrine disorders, and microvasculature lesions will be simultaneously expressed in in the blood, cerebrospinal fluid (CSF), and muscles of patients developing POD. METHODS: Two centres will be involved in this study, each recruiting a convenient sample of ten older patients with hip fracture. All of them will undergo a baseline Comprehensive Geriatric Assessment, which will be used to construct a Rockwood-based Frailty Index (FI). Blood samples will be collected for each patient on the day of surgery and 1 day before. Additionally, CSF and muscle fragments will be taken and given to a biologist for subsequent analyses. The presence of POD will be assessed in each patient every morning until hospital discharge using the 4AT. Delirium subtypes and severity will be assessed using the Delirium Motor Subtype Scale-4 and the Delirium-O-Meter, respectively. We will also evaluate the patient's functional status at discharge, using the Cumulated Ambulation Score. DISCUSSION: This study will be the first to correlate biomarkers of blood, CSF, and muscle in older patients with hip fracture.

The Hybrid Subischial Socket for Persons With Transfemoral Amputation: Gait Parameters and Clinical Assessment of a Case Series.

BACKGROUND: The subischial socket interface design is a promising new shape of socket for persons with transfemoral amputation. Typically, the proximal trim line is located distal to the ischial tuberosity, improving comfort in prosthetic users without interfering with gait parameters compared to Ischial Containment Socket (ICS). No studies have investigated the performances of a subischial sockets with suction suspension system. A new subischial socket (Hybrid Subischial Socket - HySS) combined with a hypobaric passive suspension system has been recently developed. OBJECTIVE: To assess the effects of HySS in terms of comfort, hip range-of-motion and gait parameters. METHODOLOGY: Three persons with transfemoral amputation were tested first using their usual ICS and then after one month of continuous use of HySS. FINDINGS: The following parameters improved in all participants using HySS: 1) hip range-of-motion, 2) walking speed and distance, 3) Timed-Up-and-Go-Test time, 4) stride length, 5) double support duration, 6) peak value of hip extension during stance, 7) satisfaction with the prosthesis. CONCLUSION: These findings suggest that the use of HySS could allow improvements for prosthetic use.

A Literature Review of the Quality of Life, Health Status and Prosthesis Satisfaction in Older Patients With A Trans-tibial Amputation.

BACKGROUND: Several reviews have been published regarding quality of life (QoL) and Health Status (HS) in persons with lower limb amputation (LLA). However, little has been discussed in the literature with respect to older populations (i.e. age>60 years) with trans-tibial amputation. Furthermore, the perceived satisfaction with prosthesis is another important aspect for consideration in the amputees' life. OBJECTIVE: The purpose of this review was to evaluate the impact of trans-tibial amputation on the QoL, HS and prosthesis satisfaction, in order to determine the appropriate intervention to improve these aspects in older population of trans-tibial amputees (TTA). METHODS: Research articles, published between January 2000 to March 2019, were found using Scopus, PubMed and Google Scholar databases. The methodological quality of the selected articles was assessed using the Critical Review Form-Quantitative Studies checklist. RESULTS: Ten articles that met the inclusion criteria were selected. In these papers, we can summarize that people with trans-tibial amputation have a better QoL compared to those with above knee amputation. Moreover, physical functioning and mobility are the most influencing factors for QoL and HS in older people with lower limb amputation. Finally, the prosthesis weight reduction may improve satisfaction with the prosthetic limb. CONCLUSION: Efforts have to be made in order to improve mobility in older population with transtibial amputation for better QoL and HS. This can be accomplished by means of adequate rehabilitation, pain management and an accurate choice of appropriate prosthetic components. We observed that the quality of evidence in the literature available is inadequate and future research would benefit from more prospective observational cohort studies with appropriate inclusion criteria and larger sample sizes to better understand the QoL and HS in this population.

Which is the Best Way to Perform the Physiological Cost Index in Active Individuals With Unilateral Trans-Tibial Amputation?

BACKGROUND: Physiological Cost Index (PCI) is a simple method used to estimate energy expenditure during walking. It is based on a ratio between heart rate and self-selected walking speed. Previous studies reported that PCI is reliable in individuals with lower limb amputation but only if there is an important walking impairment. No previous studies have investigated the correlation of PCI with the Energy Cost Walking (ECW) in active individuals with traumatic unilateral trans-tibial amputation, considering that this particular category of amputees has an ECW quite similar to healthy individual without lower limb amputation. Moreover, it is important to determine if PCI is also correlated to ECW in the treadmill test so as to have an alternative to over-ground test. OBJECTIVES: The aim of this study was to evaluate the correlation between PCI and ECW in active individuals with traumatic trans-tibial amputation in different walking conditions. The secondary aim was to evaluate if this correlation permits to determine ECW from PCI values. METHODOLOGY: Ninety traumatic amputees were enrolled. Metabolic data, heart rate and walking speed for the calculation of ECW and for PCI were computed over-ground and on a treadmill with 0% and 12% slopes during a 6-minute walking test. FINDINGS: There is a significant correlation between ECW and PCI walking over-ground (p=0.003; R2=0.10) and on treadmill with 12% slopes (p=0.001; R2=0.11) but there is only a poor to moderate correlation around the trendline. No significant correlation was found walking on treadmill with 0% slope. The Bland-Altman plot analysis suggests that is not possible to evaluate ECW directly from PCI. CONCLUSIONS: PCI is a reliable alternative measure of energy expenditure during walking in active individuals with trans-tibial amputation when performing over-ground or at high intensity effort on treadmill. PCI is therefore useful only for monitoring a within subject assessment.

Improved recovery time and sensitivity to H2 and NH3 at room temperature with SnOx vertical nanopillars on ITO.

Nanostructured SnO2 is a promising material for the scalable production of portable gas sensors. To fully exploit their potential, these gas sensors need a faster recovery rate and higher sensitivity at room temperature than the current state of the art. Here we demonstrate a chemiresistive gas sensor based on vertical SnOx nanopillars, capable of sensing < 5 ppm of H2 at room temperature and 10 ppt at 230 °C. We test the sample both in vacuum and in air and observe an exceptional improvement in the performance compared to commercially available gas sensors. In particular, the recovery time for sensing NH3 at room temperature is more than one order of magnitude faster than a commercial SnO2 sensor. The sensor shows an unique combination of high sensitivity and fast recovery time, matching the requirements on materials expected to foster widespread use of portable and affordable gas sensors.

Muscle-specific Drp1 overexpression impairs skeletal muscle growth via translational attenuation.

Mitochondrial fission and fusion are essential processes in the maintenance of the skeletal muscle function. The contribution of these processes to muscle development has not been properly investigated in vivo because of the early lethality of the models generated so far. To define the role of mitochondrial fission in muscle development and repair, we have generated a transgenic mouse line that overexpresses the fission-inducing protein Drp1 specifically in skeletal muscle. These mice displayed a drastic impairment in postnatal muscle growth, with reorganisation of the mitochondrial network and reduction of mtDNA quantity, without the deficiency of mitochondrial bioenergetics. Importantly we found that Drp1 overexpression activates the stress-induced PKR/eIF2α/Fgf21 pathway thus leading to an attenuated protein synthesis and downregulation of the growth hormone pathway. These results reveal for the first time how mitochondrial network dynamics influence muscle growth and shed light on aspects of muscle physiology relevant in human muscle pathologies.

Vessel-associated myogenic precursors control macrophage activation and clearance of apoptotic cells.

Swift and regulated clearance of apoptotic cells prevents the accumulation of cell remnants in injured tissues and contributes to the shift of macrophages towards alternatively activated reparatory cells that sustain wound healing. Environmental signals, most of which are unknown, in turn control the efficiency of the clearance of apoptotic cells and as such determine whether tissues eventually heal. In this study we show that vessel-associated stem cells (mesoangioblasts) specifically modulate the expression of genes involved in the clearance of apoptotic cells and in macrophage alternative activation, including those of scavenger receptors and of molecules that bridge dying cells and phagocytes. Mesoangioblasts, but not immortalized myoblasts or neural precursor cells, enhance CD163 membrane expression in vitro as assessed by flow cytometry, indicating that the effect is specific. Mesoangioblasts transplanted in acutely or chronically injured skeletal muscles determine the expansion of the population of CD163(+) infiltrating macrophages and increase the extent of CD163 expression. Conversely, macrophages challenged with mesoangioblasts engulf significantly better apoptotic cells in vitro. Collectively, the data reveal a feed-forward loop between macrophages and vessel-associated stem cells, which has implications for the skeletal muscle homeostatic response to sterile injury and for diseases in which homeostasis is jeopardized, including muscle dystrophies and inflammatory myopathies.

Macrophages commit postnatal endothelium-derived progenitors to angiogenesis and restrict endothelial to mesenchymal transition during muscle regeneration.

The damage of the skeletal muscle prompts a complex and coordinated response that involves the interactions of many different cell populations and promotes inflammation, vascular remodeling and finally muscle regeneration. Muscle disorders exist in which the irreversible loss of tissue integrity and function is linked to defective neo-angiogenesis with persistence of tissue necrosis and inflammation. Here we show that macrophages (MPs) are necessary for efficient vascular remodeling in the injured muscle. In particular, MPs sustain the differentiation of endothelial-derived progenitors to contribute to neo-capillary formation, by secreting pro-angiogenic growth factors. When phagocyte infiltration is compromised endothelial-derived progenitors undergo a significant endothelial to mesenchymal transition (EndoMT), possibly triggered by the activation of transforming growth factor-ß/bone morphogenetic protein signaling, collagen accumulates and the muscle is replaced by fibrotic tissue. Our findings provide new insights in EndoMT in the adult skeletal muscle, and suggest that endothelial cells in the skeletal muscle may represent a new target for therapeutic intervention in fibrotic diseases.

Visit-to-visit systolic blood pressure variability and outcomes in hemodialysis.

Visit-to-visit blood pressure variability (VTV-BPV) is an independent risk factor for cardiovascular events and death in the general population. We sought to determine the association of VTV-BPV with outcomes in patients on hemodialysis, using data from a National Institutes of Health-sponsored randomized trial (the HEMO study). We used the coefficient of variation (CV) and the average real variability in systolic blood pressure (SBP) as metrics of VTV-BPV. In all, 1844 out of 1846 randomized subjects had at least three visits with SBP measurements and were included in the analysis. Median follow-up was 2.5 years (interquartile range 1.3-4.3 years), during which time there were 869 deaths from any cause and 408 (adjudicated) cardiovascular deaths. The mean pre-dialysis SBP CV was 9.9 ± 4.6%. In unadjusted models, we found a 31% higher risk of death from any cause per 10% increase in VTV-BPV. This association was attenuated after multivariable adjustment but remained statistically significant. Similarly, we found a 28% higher risk of cardiovascular death per 10% increase in VTV-BPV, which was attenuated and no longer statistically significant in fully adjusted models. The associations among VTV-BPV, death and cardiovascular death were modified by baseline SBP. In a diverse, well-dialyzed cohort of patients on maintenance hemodialysis, VTV-BPV, assessed using metrics of variability in pre-dialysis SBP, was associated with a higher risk of all-cause mortality and a trend toward higher risk of cardiovascular mortality, particularly in patients with a lower baseline SBP.

Residual limb wounds or ulcers heal in transtibial amputees using an active suction socket system. A randomized controlled study.

BACKGROUND: The factors that determine successful rehabilitation after lower limb amputation have been widely investigated in the literature, but little attention has been paid to the type of prosthesis and clinical state of the residual limb, particularly the presence of open ulcers. AIM: The aim of this study was to investigate the effects of a vacuum-assisted socket system (VASS) in a sample of trans-tibial amputees with wounds or ulcers on the stump and to evaluate prosthesis use as a primary outcome. Secondary outcome measures were mobility with the prosthesis, pain associated with prosthesis use, and wound/ulcer healing. STUDY DESIGN: Randomized controlled study. SETTING: Inpatient. POPULATION: Twenty dysvascular transtibial amputees suffering from ulcers due to prosthesis use or delayed wound healing post-amputation were enrolled. METHODS: Participants were separated into two groups: the experimental group was trained to use a VASS prosthesis in the presence of open ulcers/wounds on the stump; and the control group was trained to use a standard suction socket system prosthesis following ulcers/wounds healing. RESULTS: At the end of the 12-week rehabilitation program, all VASS users were able to walk independently with their prosthesis as reflected by a median Locomotor Capability Index (LCI) value of 42, whereas only five participants in the control group were able to walk independently with a median LCI value of 21. At the two-month follow-up, the participants used their VASS prostheses for 62 hours a week (median; range: 0-91), which was significantly longer than the control group using the standard prosthesis for 5 hours per week (range: 0-56, p=0.003). At the six-month follow-up, the difference between VASS-users (80, range: 0-112 hours a weeks) and control-users (59, range: 0-91) was no longer significant (p=0.191). Despite more intense use of the prosthesis, pain and wound healing did not significantly differ between the two groups. CONCLUSION: These results showed that the VASS prosthesis allowed early fitting with prompt ambulation recovery without inhibiting wound healing or increasing pain.

Necdin enhances muscle reconstitution of dystrophic muscle by vessel-associated progenitors, by promoting cell survival and myogenic differentiation.

Improving stem cell therapy is a major goal for the treatment of muscle diseases, where physiological muscle regeneration is progressively exhausted. Vessel-associated stem cells, such as mesoangioblasts (MABs), appear to be the most promising cell type for the cell therapy for muscular dystrophies and have been shown to significantly contribute to restoration of muscle structure and function in different muscular dystrophy models. Here, we report that melanoma antigen-encoding gene (MAGE) protein necdin enhances muscle differentiation and regeneration by MABs. When necdin is constitutively overexpressed, it accelerates their differentiation and fusion in vitro and it increases their efficacy in reconstituting regenerating myofibres in the α-sarcoglycan dystrophic mouse. Moreover, necdin enhances survival when MABs are exposed to cytotoxic stimuli that mimic the inflammatory dystrophic environment. Taken together, these data demonstrate that overexpression of necdin may be a crucial tool to boost therapeutic applications of MABs in dystrophic muscle.

Pericytes resident in postnatal skeletal muscle differentiate into muscle fibres and generate satellite cells.

Skeletal muscle fibres form by fusion of mesoderm progenitors called myoblasts. After birth, muscle fibres do not increase in number but continue to grow in size because of fusion of satellite cells, the postnatal myogenic cells, responsible for muscle growth and regeneration. Numerous studies suggest that, on transplantation, non-myogenic cells also may contribute to muscle regeneration. However, there is currently no evidence that such a contribution represents a natural developmental option of these non-myogenic cells, rather than a consequence of experimental manipulation resulting in cell fusion. Here we show that pericytes, transgenically labelled with an inducible Alkaline Phosphatase CreERT2, but not endothelial cells, fuse with developing myofibres and enter the satellite cell compartment during unperturbed postnatal development. This contribution increases significantly during acute injury or in chronically regenerating dystrophic muscle. These data show that pericytes, resident in small vessels of skeletal muscle, contribute to its growth and regeneration during postnatal life.

Benefits of double reading of screening mammograms: retrospective study on a consecutive series.

PURPOSE: The purpose of this study was to assess the performance of delayed second reading of screening mammograms when added to real-time reading plus immediate assessment. MATERIAL AND METHODS: The study setting was the mammography screening programme of an Italian Local Health Unit. Recall rate and cancer detection rate at first reading or informed second reading only were assessed in a cohort of 23,629 women aged 50-69 years screened during 2007-2008. Incremental recall rate, incremental cancer detection rate and incremental cost of second reading were determined. RESULTS: Recall rate was 13.0% at first and 2.7% at second reading (incremental recall rate +21.1%). Overall, recalls were more frequent in the younger decade and in the presence of denser breasts. Cancer detection rate was 7.06‰ (n=167) at first and 0.93‰ (n=22) at second reading (incremental cancer detection rate +13.1%). Compared with first reading, second reading detected more cancers depicted as isolated microcalcifications and distortions (40.9% vs. 16.2%, p=0.02) and at a lower stage (stage 0-I 81.8% vs. 69.5%, p=0.34). The cost of adding delayed second reading was + 3.65 per screened individual or 3,926.61 per incremental cancer detected. CONCLUSIONS: The study confirms the efficacy of second reading, even as an adjunct to real-time single reading plus immediate assessment. Incremental recall rate is acceptable in view of the incremental cancer detection rate, and both figures are within the range of literature reports on double-reading performance.

On the role of arbitration of discordant double readings of screening mammography: experience from two Italian programmes.

PURPOSE: The authors sought to assess the role of arbitration by a third reader of discordant double readings to reduce the rate of recalls to diagnostic assessment. MATERIALS AND METHODS: A consecutive series of 7,660 double readings of screening examinations were considered. Discordant recalls were arbitrated by an expert reader (negative/positive). Diagnostic assessment was performed irrespective of arbitration results, and its outcome was used as reference standard for the study purpose. Assuming that negative arbitration would deny recall, its impact was assessed in terms of reduced recall rate and reduced cancer detection rate. Cost analysis of introducing arbitration was performed according to these results. RESULTS: Recalls at double reading were 528 (6.8%), of which 230 (43.5%) were concordant and 298 (56.5%) were discordant. The latter underwent arbitration, which was negative in 216 (72.4%) and positive in 82 (27.6%) cases, respectively. Overall, 49 cancers were detected (6.39 ‰ screened, 9.2% recalled): 43 cancers were detected among concordant (5.6 ‰ screened, 18.6% concordant) and six among discordant recalls (0.7 ‰ screened, 2.0% discordant). Six cancers were observed among arbitrated cases: five (6%) in positive and one (4.6 ‰) in negative arbitrations. Negative arbitration would have spared 216 assessment procedures (2.8% absolute, 40.9% relative reduction of recall rate) while missing one cancer case (0.13 ‰ absolute, 2.0% relative reduction of cancer detection rate). Arbitration cost was 74 euro, whereas 216 spared assessment procedures would have cost 14,558.4-23,346 euro. CONCLUSIONS: Arbitration is a cost-effective procedure that could be employed as a first measure to counterbalance excess recall rate observed in a double-reading scenario.

A single-center experience of preemptive anticoagulation for patients with risk factors for allograft thrombosis in renal transplantation.

AIMS: to review our single-center experience of preemptive anticoagulation for the prevention of allograft thrombosis in patients with hypercoagulable states. MATERIAL AND METHODS: this is a retrospective cohort study. Included subjects were first-time kidney allograft recipients transplanted between 2003 and 2007 at a single center, with hypercoagulable states: prior venous thromboembolism, multiple vascular access thromboses, or identifiable thrombophilia. The predictor variable was preemptive anticoagulation and outcome variable was allograft thrombosis. Other risk factors for allograft thrombosis, characteristics of transplantation, and hemorrhagic complications were also examined. RESULTS: among this high-risk cohort (n = 48), 16 received preemptive anticoagulation and 32 did not. The anticoagulated group included significantly more subjects with identifiable thrombophilia (50.0% vs. 0%; p < 0.001). One subject (6.3%) in the anticoagulated group and 6 (18.8%) without anticoagulation developed allograft thrombosis (p = 0.40). A perinephric hematoma was observed in 5 (31.3%) and 2 (6.3%) with and without anticoagulation, respectively (p = 0.03). CONCLUSIONS: preemptive anticoagulation was associated with a non-significant trend towards decreased allograft thrombosis. It may be associated with increased risk of hemorrhage and should be considered cautiously in high-risk patients.

Nitric oxide inhibition of Drp1-mediated mitochondrial fission is critical for myogenic differentiation.

During myogenic differentiation the short mitochondria of myoblasts change into the extensively elongated network observed in myotubes. The functional relevance and the molecular mechanisms driving the formation of this mitochondrial network are unknown. We now show that mitochondrial elongation is required for myogenesis to occur and that this event depends on the cellular generation of nitric oxide (NO). Inhibition of NO synthesis in myogenic precursor cells leads to inhibition of mitochondrial elongation and of myogenic differentiation. This is due to the enhanced activity, translocation and docking of the pro-fission GTPase dynamin-related protein-1 (Drp1) to mitochondria, leading also to a latent mitochondrial dysfunction that increased sensitivity to apoptotic stimuli. These effects of NO inhibition were not observed in myogenic precursor cells containing a dominant-negative form of Drp1. Both NO-dependent repression of Drp1 action and maintenance of mitochondrial integrity and function were mediated through the soluble guanylate cyclase. These data uncover a novel level of regulation of differentiation linking mitochondrial morphology and function to myogenic differentiation.

Anatomical variants and anomalies of the coronary tree studied with MDCT coronary angiography.

Anomalies of the coronary arteries are congenital and in most of the cases asymptomatic, although they may present with severe symptoms such as angina pectoris or cardiac arrest. Multidetector CT coronary angiography (MDCT-CA) permits, through curved multiplanar reconstructions and three-dimensional reformatting, noninvasive visualisation of the coronary tree and its variants and anomalies, providing a more accurate alternative to conventional coronary angiography (CCA). The purpose of this pictorial essay is to describe the main variants and anomalies of the coronary arteries using MDCT imaging with multiplanar and three-dimensional reconstructions.

Influence of a cement industry on the fine and ultrafine particles composition in a rural area.

The cement industry of this work is located in the Fumane valley, in the north of Verona. The environmental impact of the air emissions from the plant was studied using different methods: the characterisation of the raw materials utilised in the production process and of the emissions from the chimney of the clinker kiln; the sampling of the air particles on filter in the region around the plant; the biomonitoring using transplanted mosses; the study of the air pollution dispersion using a model.

Choice strategy of different dose-saving protocols in 64-slice MDCT coronary angiography.

PURPOSE: Multidetector-row computed tomography coronary angiography (MDCT-CA) produces high-level radiation dose because of submillimetre slice thickness and short scan time. As a result, manufacturers have produced different dose-saving protocols that may, however, reduce image quality and thus diagnostic accuracy. The aim of our study was to assess the diagnostic quality of MDCT-CA using different dose-saving protocols. MATERIALS AND METHODS: Between April and August 2008, we examined 65 patients with 64-slice MDCT-CA: 6/65 using the step-and-shoot dose-saving protocol, 45/65 the cardiac dose right protocol and 14/65 using a standard protocol. Image quality was evaluated on a per-patient and per-segment basis, and the effective dose of each protocol was recorded. RESULTS: In the per-patient analysis, image quality was excellent in 100% of the step-and-shoot protocols, in 91.1% of the cardiac dose right protocols and in 85.8% of the standard protocols. Effective dose to the patient considering the whole study (i.e. scout, calcium score, triggering and MDCT-CA) was 20.49 mSv in the standard protocol, 14.8 mSv in the cardiac dose right protocol and 6.63 mSv in the step-and-shoot protocol. CONCLUSIONS: The radiologist should apply the appropriate protocol in relation to the clinical indications, type of patient and information required in order to spare as much dose as possible while maintaining high image quality.

Cardiac mesoangioblasts are committed, self-renewable progenitors, associated with small vessels of juvenile mouse ventricle.

Different cardiac stem/progenitor cells have been recently identified in the post-natal heart. We describe here the identification, clonal expansion and characterization of self-renewing progenitors that differ from those previously described for high spontaneous cardiac differentiation. Unique coexpression of endothelial and pericyte markers identify these cells as cardiac mesoangioblasts and allow prospective isolation and clonal expansion from the juvenile mouse ventricle. Cardiac mesoangioblasts express many cardiac transcription factors and spontaneously differentiate into beating cardiomyocytes that assemble mature sarcomeres and express typical cardiac ion channels. Cells similarly isolated from the atrium do not spontaneously differentiate. When injected into the ventricle after coronary artery ligation, cardiac mesoangioblasts efficiently generate new myocardium in the peripheral area of the necrotic zone, as they do when grafted in the embryonic chick heart. These data identify cardiac mesoangioblasts as committed progenitors, downstream of earlier stem/progenitor cells and suitable for the cell therapy of a subset of juvenile cardiac diseases.