A novel murine model of pulmonary fibrosis: the role of platelets in chronic changes induced by bleomycin.

Idiopathic pulmonary fibrosis (IPF) is a disease that causes scarring and destruction of lung tissue that is ultimately fatal. There is a need to develop improved treatments for IPF. One problem with identifying novel treatments of IPF is the poor predictability of current preclinical models. Few model investigate lung function changes, rather relying on histological changes which doesn't adequately reflect the complete clinical situation. The aim of this study was to establish a novel model of pulmonary fibrosis where we could investigate changes in lung function, and histology. We have also utilised this model to investigate the role of platelets in pulmonary fibrosis as platelets have been recognised as having a broader role than just facilitating haemostasis. Lung fibrosis was induced in male C57BL6/J mice by intranasal bleomycin on Days 0, 1, 2, 5, 6 and 7. Platelets were depleted by twice-weekly administration of anti-platelet antibodies. On Day 35 mice were assessed by examining lung function, platelet infiltration into lung tissues and bronchoalveolar lavage fluid (BAL), levels of BAL Tissue growth factor (TGF)-ß levels, and the degree of fibrosis evaluated histologically. Repeated bleomycin administration caused loss of lung function associated with fibrosis assessed histologically. Platelet depletion resulted in a reduction in fibrosis and modest inhibition of lung function changes. We have established a novel model of pulmonary fibrosis that is associated with a decline in lung function similar to the clinical setting. Furthermore, platelet depletion resulted in a less severe fibrosis suggesting that targeting platelets maybe worth further investigation.

Incremental utility of an extended stroop task for identifying subtle differences in cognitive performance among healthy older adults.

The Stroop Color and Word Test is a test of processing speed, response inhibition, and executive functioning (EF). This project examined whether extending the Stroop Color-Word trial beyond the standard time limit could more accurately assess performance on EF measures. Cognitively healthy older individuals (n = 198) enrolled in a study of cardiovascular health completed the Stroop as part of a neuropsychological battery. Two scores were computed for the Color-Word trial: the number of items completed within the first 45 seconds (traditional Color-Word score) and the speed of page completion beyond the first 45 seconds (Stroop-Extended score). Criterion measures included the Trail-Making Test Part B (TMT-B), Digit Span Backward, Symbol Digit Modalities Test, Short Category Test, and measures of verbal fluency. Results from hierarchical linear regression analyses indicated that the extended Stroop score accounted for small but statistically significant variance in TMT-B (additional 2.6%) and Digit Span Backwards (additional 2.6%) beyond the standard Color-Word score. These findings suggest that extending the Stroop Color-Word trial beyond the first 45 seconds provides a limited increase in predictive power within a healthy sample with restricted range of performance. The extended Stroop requires additional examination in heterogeneous samples, including clinical populations, to determine its predictive utility.

Reliability and validity of the Conners' Continuous Performance Test.

The Conners' Continuous Performance Test-Second Edition (CCPT-2) is a widely used measure of attention and impulsivity, however, only a minimal amount is known about its reliability. To clarify the psychometric properties of the CCPT-2, we assessed its performance stability and related it to criterion measures. A total of 91 undergraduate students completed the CCPT-2, the State-Trait Personality Inventory (STPI), and reported on sleep during two sessions approximately one week apart. They completed the Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A) at session one and the Stroop Color and Word Test at session two. Findings indicated that the CCPT-2 had strong internal consistency, adequate test-retest reliability for commission errors and response time, poor test-retest reliability for omission errors, and practice effects for omission and commission errors. The CCPT-2 was largely unrelated to the BRIEF-A, Stroop Color and Word Test, and the STPI. More sleep was related to a quicker response time and more commission errors on the CCPT-2, and the BRIEF-A's Behavior Regulation Index was positively related to commission errors. Relative to the omission error component of the CCPT-2, commission errors and response time may be useful and stable measures of sustained attention and impulsivity.

Interactive Relations Across Dimensions of Interpersonal-Level Discrimination and Depressive Symptoms to Carotid Intimal-Medial Thickening in African Americans.

OBJECTIVE: This study aimed to examine within-race interactions of multiple dimensions of self-reported discrimination with depressive symptoms in relation to carotid intimal-medial thickness (IMT), a subclinical marker of atherosclerosis prospectively implicated in stroke incidence, in middle-aged to older African American and white adults. METHODS: Participants were a socioeconomically diverse group of 1941 African Americans (56.5%) and whites from the Healthy Aging in Neighborhoods of Diversity across the Life Span study (30-64 years old, 47% men, 45.2% with household income <125% federal poverty threshold) who underwent carotid IMT measurement. Discrimination was assessed across four dimensions (everyday, frequency across various social statuses, racial, and lifetime burden). The Center for Epidemiologic Studies Depression scale was used to assess depressive symptoms. RESULTS: In cross-sectional hierarchical regression analyses, two interactions were observed in African Americans: more frequent discrimination across various social statuses (b < 0.001, p = .006) and a higher lifetime discrimination burden (b < 0.001, p = .02) were each related to thicker carotid IMT in those with greater depressive symptoms. No significant findings were observed within whites. CONCLUSIONS: Among African Americans, those reporting high levels of discrimination and depressive symptoms have increased carotid atherosclerosis and may be at greater risk for clinical end points compared with those reporting one or neither of these risk factors. Findings suggest that assessment of interactive relationships among social and psychological factors may elucidate novel pathways for cardiovascular disease, including stroke, among African Americans.

Fecal microbiota transplantation for recurrent Clostridioides difficile infection.

PURPOSE: Randomized controlled trials investigating the efficacy and safety of fecal microbiota transplantation (FMT) for recurrent Clostridioides difficile infection (CDI) are reviewed, and practical issues for pharmacists to consider are discussed. SUMMARY: Eight randomized controlled trials evaluating the use of FMT for recurrent CDI were analyzed. The trials varied in the type of sample (fresh, frozen, lyophilized), route of administration (nasogastric tube, colonoscopy, enema, oral), and comparator agent (different type of FMT, vancomycin). Efficacy rates ranged from 43.8% to 96.2% with FMT, and safety data were relatively similar. With these favorable data, pharmacists are likely to be involved at multiple steps in the delivery of FMT to patients with recurrent CDI, including the procurement, documentation, and administration of various products and patient education. CONCLUSION: FMT is an option for recurrent CDI that is supported by findings of randomized controlled trials, although a preferred method for the delivery remains to be defined. Pharmacists can play an important role in the successful management of patients with recurrent CDI who may benefit from FMT.

Use of animal models in IPF research.

Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease with a poor prognosis and limited treatment options. Many compounds have shown efficacy in preclinical models of this condition, but only pirfenidone and nintedanib have been approved for clinical use. It is widely accepted that the current animal models of IPF need to be improved and in this review we have critically evaluated the current state of play of preclinical models of IPF and discuss the challenges facing this field. The popular model of a single intratracheal (I.T.) administration of bleomycin could be adapted to provide a more progressive fibrosis as is thought to occur in humans. Furthermore, currently the majority of new drugs are investigated in preclinical models of IPF are dosed using a prophylactic dosing regimen, whereas patients are almost always treated after the fibrosis is well established. Using a therapeutic dosing regimen in preclinical models would be a better way to establish potential efficacy of new drugs. The most popular endpoints examined in pre-clinical models of IPF are histological scoring and lung collagen content. However in IPF patients imaging and lung function tests are more commonly used as end points. We propose that examining more clinically relevant endpoints in pre-clinical models could also provide give a better indication of a compound's potential efficacy on endpoints measured in patients.

Augmented reality fluoroscopy simulation of the guide-wire insertion in DHS surgery: A proof of concept study.

BACKGROUND: Hip fractures contribute to a significant clinical burden globally with over 1.6 million cases per annum and up to 30% mortality rate within the first year. Insertion of a dynamic hip screw (DHS) is a frequently performed procedure to treat extracapsular neck of femur fractures. Poorly performed DHS fixation of extracapsular neck of femur fractures can result in poor mobilisation, chronic pain, and increased cut-out rate requiring revision surgery. A realistic, affordable, and portable fluoroscopic simulation system can improve performance metrics in trainees, including the tip-apex distance (the only clinically validated outcome), and improve outcomes. METHOD: We developed a digital fluoroscopic imaging simulator using orthogonal cameras to track coloured markers attached to the guide-wire which created a virtual overlay on fluoroscopic images of the hip. To test the accuracy with which the augmented reality system could track a guide-wire, a standard workshop femur was used to calibrate the system with a positional marker fixed to indicate the apex; this allowed for comparison between guide-wire tip-apex distance (TAD) calculated by the system to be compared to that physically measured. Tests were undertaken to determine: (1) how well the apex could be targeted; (2) the accuracy of the calculated TAD. (3) The number of iterations through the algorithm giving the optimal accuracy-time relationship. RESULTS: The calculated TAD was found to have an average root mean square error of 4.2 mm. The accuracy of the algorithm was shown to increase with the number of iterations up to 20 beyond which the error asymptotically converged to an error of 2 mm. CONCLUSION: This work demonstrates a novel augmented reality simulation of guide-wire insertion in DHS surgery. To our knowledge this has not been previously achieved. In contrast to virtual reality, augmented reality is able to simulate fluoroscopy while allowing the trainee to interact with real instrumentation and performing the procedure on workshop bone models.

Pigmented villonodular synovitis of the knee: A retrospective analysis of 214 cases at a UK tertiary referral centre.

AIMS: Pigmented villonodular synovitis (PVNS) is a rare, locally aggressive and potentially recurrent synovial disease. We present the largest single-centre experience of knee PVNS. Our aim was to evaluate our tertiary hospital's experience in the management of knee PVNS. PATIENTS AND METHODS: Retrospective data collection of consecutive cases of knee PVNS from 2002 to 2015. RESULTS: In total, 214 cases of knee PVNS were identified which represented 53.4% of all PVNS (12.1% were recurrent at presentation). 100 were localised PVNS (LPVNS), 114 diffuse PVNS (DPVNS) and two malignant PVNS. Knee PVNS was more likely to occur in females with a mean age of 39. Following surgery, 47.6% had recurrence with DPVNS as opposed to 8.6% with LPVNS. In LPVNS, there was no significant difference in recurrence between open and arthroscopic synovectomy (8.7% vs 9.1%, P>0.05). However, in DPVNS, there was a significantly higher risk of recurrence with arthroscopic compared to open synovectomy (83.3% vs 44.8%, RR=1.86 95% CI 1.32-2.62, P=0.0004). CONCLUSION: PVNS can be difficult to treat. We found no difference in local recurrence rates between open and arthroscopic treatment of LPVNS but significantly increased rates of recurrence for DPVNS following arthroscopic treatment. We would therefore recommend open synovectomy for DPVNS.

Distributions of Subclinical Cardiovascular Disease in a Socioeconomically and Racially Diverse Sample.

BACKGROUND AND PURPOSE: Differential subgroup vulnerability to subclinical cardiovascular disease is likely, and yet few, if any, studies have addressed interactive relations of age, sex, race, and socioeconomic status (SES) to these conditions to examine nuances of known health disparities. We examined distributions of carotid atherosclerosis and arterial stiffness in a socioeconomically diverse, biracial, urban sample. METHODS: Participants (n=2270) in the population-based HANDLS study (Healthy Aging in Neighborhoods of Diversity Across the Life Span; 30-64 years old, 44% men, 57% African American, 39% with household income <125% federal poverty threshold) underwent carotid intimal medial thickness (IMT) and pulse wave velocity assessment. RESULTS: In cross-sectional hierarchical regression analyses, interactive race×SES effects were identified for IMT and pulse wave velocity, such that high SES African Americans had significantly thicker IMTs and faster pulse wave velocities than all other subgroups (ie, low SES African Americans, low SES whites, and high SES whites). A race×sex effect was also identified for IMT, such that the IMT discrepancy between white men and women was more pronounced than the discrepancy between African American men and women. Finally, an SES×sex effect indicated that while IMTs of high SES and low SES men did not significantly differ, high SES women had marginally thicker IMTs than low SES women. CONCLUSIONS: High SES African Americans may be particularly vulnerable to subclinical cardiovascular diseases, placing them at enhanced risk for clinical cardiovascular diseases, including stroke. These findings suggest that male sex, low SES, and African American ancestry may represent imprecise generalizations as risk factors for subclinical cardiovascular disease.

Nonlinear associations between plasma cholesterol levels and neuropsychological function.

OBJECTIVE: Although both high and low levels of total and low-density lipoprotein (LDL) cholesterol have been associated with poor neuropsychological function, little research has examined nonlinear effects. We examined quadratic relations of cholesterol to performance on a comprehensive neuropsychological battery. METHOD: Participants were 190 older adults (53% men, ages 54-83) free of major medical, neurologic, and psychiatric disease. Measures of fasting plasma total and high-density lipoprotein (HDL) cholesterol were assayed, and LDL cholesterol was calculated. Participants completed neuropsychological measures of attention, executive function, memory, visuospatial judgment, and manual speed and dexterity. Multiple regression analyses examined cholesterol levels as quadratic predictors of each measure of cognitive performance, with age (dichotomized as <70 vs. 70+) as an effect modifier. RESULTS: A significant quadratic effect of Total Cholesterol² × Age was identified for Logical Memory II (b = -.0013, p = .039), such that the 70+ group performed best at high and low levels of total cholesterol than at midrange total cholesterol (U-shaped) and the <70 group performed worse at high and low levels of total cholesterol than at midrange total cholesterol (inverted U shape). Similarly, significant U- and J-shaped effects of LDL Cholesterol² × Age were identified for Visual Reproduction II (b = -.0020, p = .026) and log of the Trail Making Test, Part B (b = .0001, p = .044). Quadratic associations between HDL cholesterol and cognitive performance were nonsignificant. CONCLUSIONS: Results indicate differential associations between cholesterol and neuropsychological function across different ages and domains of function. High and low total and LDL cholesterol may confer both risk and benefit for suboptimal cognitive function at different ages. (PsycINFO Database Record

Relations of blood pressure and head injury to regional cerebral blood flow.

Hypertension confers increased risk for cognitive decline, dementia, and cerebrovascular disease. These associations have been attributed, in part, to cerebral hypoperfusion. Here we posit that relations of higher blood pressure to lower levels of cerebral perfusion may be potentiated by a prior head injury. Participants were 87 community-dwelling older adults - 69% men, 90% white, mean age=66.9years, 27.6% with a history of mild traumatic brain injury (mTBI) defined as a loss of consciousness ≤30min resulting from an injury to the head, and free of major medical (other than hypertension), neurological or psychiatric comorbidities. All engaged in clinical assessment of systolic and diastolic blood pressure (SBP, DBP) and single photon emission computed tomography (SPECT). Computerized coding of the SPECT images yielded relative ratios of blood flow in left and right cortical and select subcortical regions. Cerebellum served as the denominator. Sex-stratified multiple regression analyses, adjusted for age, education, race, alcohol consumption, smoking status, and depressive symptomatology, revealed significant interactions of blood pressure and head injury to cerebral blood flow in men only. Specifically, among men with a history of head injury, higher systolic blood pressure was associated with lower levels of perfusion in the left orbital (ß=-3.21, p=0.024) and left dorsolateral (ß=-2.61, p=0.042) prefrontal cortex, and left temporal cortex (ß=-3.36, p=0.014); higher diastolic blood pressure was marginally associated with lower levels of perfusion in the left dorsolateral prefrontal cortex (ß=-2.79, p=0.051). Results indicate that men with a history of head injury may be particularly vulnerable to the impact of higher blood pressure on cerebral perfusion in left anterior cortical regions, thus potentially enhancing risk for adverse brain and neurocognitive outcomes.

Subclinical carotid atherosclerosis and neurocognitive function in an urban population.

BACKGROUND AND AIMS: Examine age, sex, race, and socioeconomic status as modifiers of the association between carotid intimal medial thickness (IMT) and neurocognitive performance in a socioeconomically diverse, biracial, urban, adult population. METHODS: Participants were 1712 community-dwelling adults (45% men, 56% African-American, 38% below poverty threshold, aged 30-64 years) enrolled in the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study. Participants underwent initial carotid ultrasonography followed by cognitive testing on up to two occasions over 4 years. Mixed-effects regression analyses were adjusted for demographic, behavioral, and biomedical covariates. RESULTS: Significant cross-sectional IMT × race × poverty interactions were identified for measures of delayed recall memory, auditory-verbal attention, and working memory. An IMT × race interaction also appeared for auditory-verbal learning. Higher IMT was generally associated with worse cognitive performance, but the disadvantage was most pronounced among those with higher socioeconomic status and white participants. No longitudinal associations were identified. CONCLUSIONS: Carotid IMT-cognition associations differed as a function of race and socioeconomic status and were most compelling for measures of attention, executive function, and memory. These findings highlight the possibility that subclinical atherosclerosis may be differentially informative as a predictor of cognitive performance among varied demographic subgroups.

Metal-on-polyethylene versus metal-on-metal bearing surfaces in total hip arthroplasty: a prospective randomised study investigating metal ion levels and chromosomal aberrations in peripheral lymphocytes.

The long term biological effects of wear products following total hip arthroplasty (THA) are unclear. However, the indications for THA are expanding, with increasingly younger patients undergoing the procedure. This prospective, randomised study compared two groups of patients undergoing THA after being randomised to receive one of two different bearing surfaces: metal-on-polyethylene (MoP) n = 22 and metal-on-metal (MoM) n = 23. We investigated the relationship between three variables: bearing surface (MoP vs MoM), whole blood levels of chromium (Cr) and cobalt (Co) and chromosomal aberrations in peripheral lymphocyte pre-operatively and at one, two and five years post-surgery. Our results demonstrated significantly higher mean cobalt and chromium (Co and Cr) blood levels in the MoM group at all follow-up points following surgery (p < 0.01), but there were no significant differences in the chromosomal aberration indices between MoM and MoP at two or five years (two years: p = 0.56, p = 0.08, p = 0.91, p = 0.51 and five years: p = 0.086, p = 0.73, p = 0.06, p = 0.34) for translocations, breaks, loss and gain of chromosomes respectively. Regression analysis showed a strong linear relationship between Cr levels and the total chromosomal aberration indices in the MoM group (R(2) = 0.90016), but this was not as strong for Co (R(2) = 0.68991). In the MoP group, the analysis revealed a poor relationship between Cr levels and the total chromosomal aberration indices (R(2) = 0.23908) but a slightly stronger relationship for Co (R(2) = 0.64292). Across both groups, Spearman's correlation detected no overall association between Co and Cr levels and each of the studied chromosomal aberrations. There remains no clear indication which THA bearing couple is the most biocompatible, especially in young active patients. While THA continues to be very successful at alleviating pain and restoring function, the long-term biological implications of the procedure still require further scrutiny.

Renal function and long-term decline in cognitive function: the Baltimore Longitudinal Study of Aging.

BACKGROUND: Renal disease has been associated with greater risk of dementia and greater cognitive impairment. However, the relationship of lower renal function with long-term decline in specific domains of cognitive function remains unclear among community-dwelling, non-demented individuals. METHODS: Stroke- and dementia-free participants (n = 2,116) were enrolled in the Baltimore Longitudinal Study of Aging, a community-based, prospective, longitudinal study. Renal function was estimated by the inverse of serum creatinine adjusted for age, sex and race and (in sensitivity analyses) estimated glomerular filtration rate (eGFR) using the MDRD formula. Outcome measures were changes in scores on 6 cognitive tests encompassing a range of cognitive functions, measured at 2-year intervals. Mixed-effects regression models examined the longitudinal relations of renal function with cognitive functions after adjusting for demographics, comorbidity and other potential confounders. RESULTS: Mean age at initial testing was 53.9 years (SD 17.1), and 94 participants (4.4%) had an eGFR <60 ml/min/1.73 m(2) and 18.5% had at least one comorbidity. With increasing age, longitudinal increases in creatinine concentrations were associated with more rapid decline in performance on several cognitive measures, including the learning slope of the California Verbal Learning Test, a test of verbal learning (p < 0.01), and the Benton Visual Retention Test, a test of visual memory (p < 0.01). Associations were similar for changes in eGFRMDRD, which was also associated with the rate of decline in verbal memory. CONCLUSION: In a community-based adult population, declines in renal function independently associated with greater long-term declines in visual memory and verbal memory and learning.

Revision cartilage cell transplantation for failed autologous chondrocyte transplantation in chronic osteochondral defects of the knee.

The management of failed autologous chondrocyte implantation (ACI) and matrix-assisted autologous chondrocyte implantation (MACI) for the treatment of symptomatic osteochondral defects in the knee represents a major challenge. Patients are young, active and usually unsuitable for prosthetic replacement. This study reports the results in patients who underwent revision cartilage transplantation of their original ACI/MACI graft for clinical or graft-related failure. We assessed 22 patients (12 men and 10 women) with a mean age of 37.4 years (18 to 48) at a mean of 5.4 years (1.3 to 10.9). The mean period between primary and revision grafting was 46.1 months (7 to 89). The mean defect size was 446.6 mm(2) (150 to 875) and they were located on 11 medial and two lateral femoral condyles, eight patellae and one trochlea. The mean modified Cincinnati knee score improved from 40.5 (16 to 77) pre-operatively to 64.9 (8 to 94) at their most recent review (p < 0.001). The visual analogue pain score improved from 6.1 (3 to 9) to 4.7 (0 to 10) (p = 0.042). A total of 14 patients (63%) reported an 'excellent' (n = 6) or 'good' (n = 8) clinical outcome, 5 'fair' and one 'poor' outcome. Two patients underwent patellofemoral joint replacement. This study demonstrates that revision cartilage transplantation after primary ACI and MACI can yield acceptable functional results and continue to preserve the joint.

Nonlinear longitudinal trajectories of cholesterol and neuropsychological function.

OBJECTIVE: Prior literature has identified inconsistent longitudinal associations between total cholesterol and cognitive decline. The authors examined prospective nonlinear relations of coincident trajectories of total cholesterol and cognitive function among persons free of stroke, dementia, and other neurological disease. METHOD: Up to 1,601 participants from the Baltimore Longitudinal Study of Aging (aged 19-93, 51% male, 75% White) underwent fasting cholesterol measurement and neuropsychological assessment on up to 12 occasions (M = 3.2, SD = 2.1) over up to 19 years (M = 6.4, SD = 5.3) of follow-up. Mixed-effects regression analyses were adjusted for age, sex, race, education, systolic blood pressure, body mass index, cardiovascular disease, lipid-lowering medication use, smoking, alcohol use, and depressive symptoms. RESULTS: Analyses revealed significant longitudinal associations between quadratic total cholesterol and performance on measures of global mental status, verbal learning, executive function, and language (all ps < .05). In general, higher total cholesterol was associated with poorer middle-aged or young-old (60-69 years) cognitive performance, but better old-old (80-89 years) cognitive performance. Linear models also revealed an association between lower total cholesterol and accelerated decline in visual memory performance. CONCLUSIONS: Overall, results indicate nonlinear longitudinal relations of total cholesterol to cognitive decline. Whereas higher cholesterol levels were associated with cognitive decline in the middle-aged or young-old, lower cholesterol levels were related to cognitive decline among old-old participants.

Cardiorespiratory fitness and accelerated cognitive decline with aging.

BACKGROUND: Growing evidence suggests that self-reported physical activity accounts for variability in cognitive function among older adults, and aerobic intervention may improve cognitive function in this population. However, much less is known about the longitudinal association between direct measures of cardiorespiratory fitness and cognitive function across the life span. The present study examined the prospective association between symptom-limited maximal oxygen consumption (VO2max) and longitudinal performance on a comprehensive neuropsychological battery. METHODS: Up to 1,400 participants aged 19-94 years underwent initial VO2max assessment and completed subsequent tests of memory, attention, perceptuomotor speed, language, and executive function, in addition to cognitive screening measures, on up to six occasions (mean, M = 2; standard deviation, SD = 1) for up to 18 years (M = 7, SD = 3). Mixed-effects regression models were adjusted for demographic, biomedical, and behavioral confounders. RESULTS: Analyses revealed significant longitudinal associations between baseline VO2max and trajectory of performance on multiple measures of verbal and visual memory, as well as on a cognitive screening test (all ps < .05). Individuals with lower VO2max demonstrated accelerated trajectories of cognitive decline over time. CONCLUSIONS: Baseline cardiorespiratory fitness is related to longitudinal neuropsychological performance, and memory appears to be a particularly vulnerable domain. Evidence that aerobic fitness is associated with accelerated cognitive decline emphasizes the possible importance of behavioral interventions to optimize cognitive aging over time.