Symptom Attribution and Neuropsychological Outcomes Among Treatment-Seeking Veterans With a History of Traumatic Brain Injury.

OBJECTIVE: In this cross-sectional study, the authors aimed to examine relationships between illness perception, measured as symptom attribution, and neurobehavioral and neurocognitive outcomes among veterans with a history of traumatic brain injury (TBI). METHODS: This study included 55 treatment-seeking veterans (N=43 with adequate performance validity testing) with a remote history of TBI (80% with mild TBI). Veterans completed a clinical interview, self-report questionnaires, and a neuropsychological assessment. A modified version of the Neurobehavioral Symptom Inventory (NSI) was administered to assess neurobehavioral symptom endorsement and symptom attribution. Composite scores were calculated from standardized cognitive tests to assess specific aspects of objective cognitive functioning, including memory, executive functioning, attention and working memory, and processing speed. RESULTS: The symptoms most frequently attributed to TBI included forgetfulness, poor concentration, slowed thinking, and headaches. There was a significant positive association between symptom attribution and overall symptom endorsement (NSI total score) (r=0.675) and endorsement of specific symptom domains (NSI symptom domain scores) (r=0.506-0.674), indicating that greater attribution of symptoms to TBI was associated with greater symptom endorsement. Furthermore, linear regressions showed that symptom attribution was significantly associated with objective cognitive functioning, whereas symptom endorsement generally did not show this relationship. Specifically, greater attribution of symptoms to TBI was associated with worse executive functioning (ß=-0.34), attention and working memory (ß=-0.43), and processing speed (ß=-0.35). CONCLUSIONS: These findings suggest that veterans who routinely attribute neurobehavioral symptoms to their TBI are at greater risk of experiencing poor long-term outcomes, including elevated symptom endorsement and worse objective cognition. Although more research is needed to understand how illness perception influences outcomes in this population, these preliminary results highlight the importance of early psychoeducation regarding the anticipated course of recovery following TBI.

Real-world treatment sequencing and survival in previously treated advanced renal cell carcinoma patients receiving nivolumab monotherapy: a UK retrospective cohort study.

BACKGROUND: The CheckMate 025 trial established nivolumab monotherapy as one of the standards of care in previously treated advanced or metastatic renal cell carcinoma (aRCC). However, supporting real-world data is lacking. This study investigated characteristics, treatment sequences and clinical outcomes of patients who received nivolumab monotherapy for previously treated aRCC in the UK. METHODS: This was a retrospective cohort study of aRCC patients treated with nivolumab at second line or later (2L +) at 4 UK oncology centres. Eligible patients commenced nivolumab (index date) between 01 March 2016 and 30 June 2018 (index period). Study data were extracted from medical records using an electronic case report form. Data cut-off (end of follow-up) was 31 May 2019. RESULTS: In total, 151 patients were included with median follow-up of 15.2 months. Mean age was 66.9 years, male preponderance (72.2%), and mostly Eastern Cooperative Oncology Group performance status grade 0-1 (71.5%). Amongst 112 patients with a known International Metastatic RCC Database Consortium score, distribution between favourable, intermediate, and poor risk categories was 20.5%, 53.6%, and 25.9% respectively. The majority of patients (n = 109; 72.2%) received nivolumab at 2L, and these patients had a median overall survival (OS) of 23.0 months [95% confidence interval: 17.2, not reached]. All patients who received nivolumab at 2L had received TKIs at 1L. Amongst the 42 patients (27.8%) who received nivolumab in third line or later (3L +) the median OS was 12.4 months [95% CI: 8.8, 23.2]. The most common reasons for nivolumab discontinuation were disease progression (2L: 61.2%; 3L: 68.8%) and adverse events (2L: 34.7%; 3L: 28.1%). CONCLUSION: This study provides real-world evidence on the characteristics, treatment sequences, and outcomes of aRCC patients who received 2L + nivolumab monotherapy in the UK. Nivolumab-specific survival outcomes were similar to those achieved in the CheckMate 025 trial.

Unemployment Status Is Associated With Greater Cognitive Intraindividual Variability in Veterans With a History of Remote Mild TBI.

OBJECTIVE: To examine the association between employment status and neuropsychological functioning in veterans with a history of remote mild traumatic brain injury (mTBI) using 2 approaches to assess cognitive performance: (a) standard, traditional mean cognitive performance; and (b) across-test intraindividual variability (IIV). SETTING: Outpatient Veterans Affairs (VA) hospital. PARTICIPANTS: Eligibility criteria included veterans with a history of mTBI who performed adequately on performance validity tests. Participants (N = 75; 37 employed, 38 unemployed) were evaluated, on average, about 5.5 years after their most recent mTBI. DESIGN: Observational cohort study; all participants completed a clinical interview and a comprehensive neuropsychological assessment. MAIN MEASURES: Primary outcomes of interest included mean cognitive composite test scores and IIV scores on tasks of memory, attention/processing speed, and executive functioning. RESULTS: Logistic regression models showed that mean cognitive performance was not predictive of employment status; however, IIV indices were ( = 7.88, P = .048) and accounted for 13% of the variance. Greater memory-IIV was significantly associated with being unemployed (ß = -.16, SE = .07, P = .020, Exp(B) = 0.85; 95% CI, 0.74-0.98). CONCLUSION: These findings build upon prior work showing that IIV, or cognitive dispersion, is associated with important functional outcomes following mTBI, including employment status. Future studies are needed to verify these findings, but the present study suggests that IIV indices offer a clinically meaningful marker of cognitive functioning and should be considered when evaluating functional outcomes following head trauma.

Relationships between type of hoof lesion and behavioral signs of lameness in Holstein cows housed in Canadian tiestall facilities.

Although foot pain can affect gait, the presence of a hoof lesion may or may not cause the cow to show visible changes in their gait. This can be dependent on the type and severity of the lesion; for example, the presence of a sole ulcer (SU) has been associated with increased gait scores, whereas digital dermatitis (DD) and sole hemorrhage (SH) have not. In tiestall facilities, gait scoring can be difficult to perform. An alternative method, known as stall lameness scoring (SLS), allows observers to assess cattle for lameness while they remain in their stall. Lameness is determined based on behavioral changes in weight bearing and foot positioning, which include: shifting weight, resting a foot, standing on the edge of the stall, and uneven weight bearing when stepping side to side. The aim of this study was to examine relationships between hoof lesions and these behavioral indicators. A total of 557 observations of SLS and corresponding hoof trimming records, collected during routine trimming events on 7 tiestall herds, were obtained. Trimming was performed by 2 trained hoof trimmers with good agreement on lesion identification, based on quizzes taken at the beginning and mid-way through the study. To ensure trimming had no effect on the behavioral indicators observed, SLS was always performed by a trained observer before trimming. Behavioral indicators focused on the hind limbs only; therefore, the analysis was confined to hind limb lesions using logistic regression to detect the presence of hoof lesion based on observations made during SLS. Seventy-five percent of observed cows had no SLS behavioral indicators, whereas, 11, 12, and 1% had 1, 2, and 3 behavioral indicators, respectively. At least one hind limb lesion was noted during trimming in 19% of cows, with the most common lesions being DD (7%), SU (6%), and SH (4%). A cow that was observed resting one foot and bearing weight unevenly when moving side to side had higher odds of having a hind limb hoof lesion than a cow not displaying these behaviors. When looking at specific hoof lesions, a cow observed resting one limb and bearing weight unevenly had higher odds of having a SU compared with those not displaying these behaviors. A cow observed shifting their weight from one foot to another had higher odds of having SH, and a cow observed bearing weight unevenly had higher odds of DD. Behavioral indicators in weight bearing and foot positioning can help identify cows in tiestalls with hind limb hoof lesions. Producers could routinely observe their cattle for these indicators to assist in the identification of cows that may require treatment. This could help reduce the duration of clinical lameness through earlier intervention.

Self-efficacy and coping style in Iraq and Afghanistan-era veterans with and without mild traumatic brain injury and posttraumatic stress disorder.

OBJECTIVE: To examine self-efficacy and coping style in combat-exposed Veterans with and without mild traumatic brain injury (mTBI) history and posttraumatic stress disorder (PTSD). METHODS: Veterans (N = 81) were categorized into four groups: comorbid mTBI and PTSD (n = 23), PTSD-only (n = 16), mTBI-only (n = 25), and combat-exposed controls (n = 17). Outcomes included the Self-Efficacy for Symptom Management Scale and the Brief Coping Orientation to Problems Experienced. RESULTS: Significant group effects were found on self-efficacy and coping style, even when adjusting for total mTBIs and psychiatric comorbidities. Post-hoc analyses revealed that the comorbid and PTSD-only groups generally had lower self-efficacy than the mTBI-only and control groups and that the PTSD-only group used less action-focused coping than the mTBI-only and control groups. CONCLUSION: Our results suggest that self-efficacy and coping style vary as a function of mTBI history and PTSD status and that it may be important to integrate these malleable factors into interventions for this population.

[Standardized documentation of health-related quality of life in patients with psoriatic arthritis : Validation of the German version of the psoriatic arthritis quality of life (PsAQoL) questionnaire]. / Standardisierte Erfassung der gesundheitsbezogenen Lebensqualität bei Patienten mit Psoriasisarthritis : Validierung der deutschen Version des "Fragebogen zur Lebensqualität von Patienten mit Psoriasisarthritis (PsAQoL)".

BACKGROUND: The standardized assessment of health-related quality of life is becoming increasingly more important. The English questionnaire on psoriatic arthritis quality of life (PsAQoL) is a disease-specific instrument for measuring the quality of life of patients with psoriatic arthritis (PsA). The aim of the present study was to translate the PsAQoL into German and to validate the German version in a cohort of PsA patients recruited from routine care. METHOD: The translation and validation of the PsAQoL questionnaire was carried out in a stepwise procedure involving affected patients with PsA. After translation of the original English questionnaire the German version was evaluated in a field test. The psychometric features of the questionnaire were then examined in a PsA cohort from routine care. In addition to the construct and group validity, the reliability of the questionnaire was tested using test-retest reliability and internal consistency. The physical functioning was measured with the health assessment questionnaire (HAQ) and domains of the quality of life with the Nottingham health profile (NHP). RESULTS: In a field test with 10 patients the German version of the PsAQoL questionnaire proved to be relevant, easily understandable and feasible (processing time 4.7 ± 2.1 min). A total of 126 patients (37.3% male, age 55.6 ± 11.3 years) were included in the validation cohort. The PsAQoL showed moderate correlation with the HAQ (r = 0.65) and moderate to good correlation with the NHP (subdomains r = 0.58-0.75). The internal consistency was high (Cronbach's α 0.92) and reliability in patients with stable disease course was very good (Spearman correlation coefficient 0.94). The PsAQoL can differentiate between different patient groups. CONCLUSION: The German translation of the PsAQoL provides a valid disease-specific instrument for the standardized assessment of health-related quality of life in patients with PsA. The psychometric characteristics of this questionnaire are comparable with the original English version. The German PsAQoL can therefore be recommended for clinical and scientific application.

Prevalence of lameness and associated risk factors on dairy farms in the Maritime Provinces of Canada.

Lameness in dairy cattle is a major issue for the industry due to the effects on the welfare of the animal, the economic impact, and consumer perception. The aim of this study was to determine the prevalence of lameness and explore potential risk factors in the Maritime Provinces of Canada. Cows were scored for lameness and potential risk factors and were assessed in 46 freestall herds and 33 tiestall herds in Nova Scotia, New Brunswick, and Prince Edward Island. In freestall herds, lameness was assessed using the most common method, locomotion scoring. A cow with a gait score of ≥3 out of 5 was considered to be lame. In tiestall herds, lameness was assessed using an alternative method known as stall lameness scoring. This assessment consisted of observation of the cow for 4 behavioral changes: standing on the edge of the stall, shifting weight, resting a limb, and uneven weight bearing when moved side to side. A cow displaying 2 or more of these behaviors was considered to be lame. At the time of the assessment, other animal-, environmental-, and management-based measurements were collected. These measurements were used in multivariable logistic regression analysis to determine risk factors that were associated with lameness for both freestalls and tiestalls independently. The prevalence of lameness was 21% for freestall-housed cattle and 15% for tiestall-housed cattle. Of the 1,488 tiestall-housed cows that were assessed, 68% showed no behavioral changes, whereas 15, 15, 2, and <1% showed 1, 2, 3, or 4 changes, respectively. In freestalls, higher odds of lameness were seen when cows spent ≥3 h/d in the holding area for milking compared with those that spent <3 h/d. In tiestall herds, higher odds of lameness were seen when bedding material was wet compared with when it was dry. For both lactating cow facility types, housing the dry cows and heifers on a deep bedded pack compared with tiestalls or freestalls was associated with a decreased odds of lameness. There were also many cow-level variables associated with lameness, including parity, daily milk production, stage of production, body condition, and width at the tuber coxae (hook bones). If producers become aware of the risk factors associated with lameness, they can make informed decisions on where to implement changes to help reduce the level of lameness in their herd.

Prevalence of hock, knee, and neck skin lesions and associated risk factors in dairy herds in the Maritime Provinces of Canada.

Skin lesions are commonly seen in dairy herds and have been associated with animal-, environmental-, and management factors. These lesions are not only a welfare concern, but they also affect profitability. Three areas on the cattle were examined for skin lesions: the hock, knee, and neck. Previous Canadian studies estimating the prevalence of lesions and the risk factors associated with them have not included the Maritime Provinces. In this study, 73 herds in the Maritime Provinces were chosen voluntarily to participate, with both tiestalls (n = 33) and freestalls (n = 40) represented. Within each herd, 67 to 90% of the lactating cows were selected and assessed for potential animal-, environmental-, and management-based risk factors. If producers were aware of the potential risk factors, this could help them reduce the prevalence in their herd. Leg lesions were scored on a 4-point scale (0-3) based on hair loss, swelling, and scabs, with a lesion defined as a score of 2 or 3 on at least 1 hock or knee. Necks were scored on a 3-point scale (0-2), with a lesion defined as score 2. For freestalls, the prevalence (95% confidence interval) of hock lesions was 39% (29-49%), knee lesions was 14% (11-18%), and neck lesions was 1% (<1-2%). Similarly, for tiestalls the prevalence (95% confidence interval) of hock lesions was 39% (33-46%), knee lesions was 17% (13-22%), and neck lesions was 5% (3-8%). Due to differences in management and methods of assessment between facility types, tiestalls and freestalls were analyzed separately. Due to dichotomization of cows as having a skin lesion or not, random-effects multivariable logistic regression was used to determine the risk factors for each lesion and facility type. Several environmental-based measurements, such as the stall base, type and dryness of bedding, and type of milking parlor, were associated with leg lesions. An environmental-based measurement that was associated with neck lesions was the design of the feed rail barrier in freestalls and the dimensions of the tie rail in tiestalls. Animal-based risk factors, such as stage of lactation, parity, and body condition, were also associated with all 3 types of lesions. This study showed that lesions to the hock, knee, and neck were common in the Maritime Provinces of Canada. Although differences were seen between facility types, in general, the results suggest that improving stall design and management and feed bunk design would help producers reduce the number of skin lesions seen in dairy cattle.

Comparison of fecal pooling strategies for detection of Mycobacterium avium ssp. paratuberculosis in cattle.

In herds with typical moderate to low within-herd prevalence, testing for Mycobacterium avium ssp. paratuberculosis (MAP), the infectious agent of Johne's disease, will be more cost-effective if individual fecal samples are cultured in composite pools. However, sensitivity to classify a pool containing 1 or more positive individual samples as positive may depend on pool size and number of individual positive samples within a pool. Fecal samples collected from 994 dairy cows sampled at slaughter were cultured to detect MAP. Culturing was done both individually and as composite pooled samples using the TREK ESP Culture System II broth medium (Thermo Fisher Scientific, Trek Diagnostic Systems Inc., Cleveland, OH). Composite samples consisted of pools containing feces from 3, 5, 8, 10, or 15 cows. The number of individual fecal culture-positive cows within each pool ranged from 0 to 4. Culture of individual fecal samples detected MAP in 36 (3.6%) of the 994 cows. Individual samples that were detected within the first 50 d by TREK ESP Culture System II were more likely to lead to a positive pool result. In total, 840 pooled fecal samples were examined for presence of MAP, and of those, 272 pools actually contained feces from fecal culture-positive cows. The crude sensitivity (proportion of pools that contained at least 1 fecal-positive cow that tested positive) for pools of 3, 5, 8, 10, and 15 was 47, 67, 44, 59, and 39%, respectively. Across pools, an increase of the number of fecal culture-positive samples from 1 to 2 enhanced overall crude sensitivity from 44 to 71%. However, sensitivity did not further increase for pools with 3 or 4 fecal culture-positive samples (63 and 60%, respectively). Additionally, a simulation analysis assessing probability of pooled fecal samples being positive in herds of 50 and 100 cows was conducted. The simulation assumed that 1, 2, or 5 cows per herd were MAP fecal culture-positive and that pools of 5 and 10 were used. This low-prevalence herd simulation indicated that weighted mean herd probabilities of detecting a positive herd ranged between 52 and 99.3%, with the lowest probability for pools of 10 with 1 positive cow in the herd and the highest probability for pools of 5 with 5 positive cows in the herd. However, overall, pools of 5 and 10 had similar diagnostic capabilities, enabling cost savings by utilizing pools of 10.

Pulmonary outcomes following specialized respiratory management for acute cervical spinal cord injury: a retrospective analysis.

STUDY DESIGN: Retrospective analysis. OBJECTIVES: To identify multivariate interactions of respiratory function that are sensitive to spinal cord injury level and pharmacological treatment to promote strategies that increase successful liberation from mechanical ventilation. SETTING: United States regional spinal cord injury (SCI) treatment center. METHODS: Retrospective chart review of patients consecutively admitted to Santa Clara Valley Medical Center between May 2013 and December 2014 for ventilator weaning with C1-C5 American Spinal Injury Association Impairment Scale (AIS) A or B SCI, <3 months from injury and who had a tracheostomy in place. A nonlinear, categorical principal component analysis (NL-PCA) was performed to test the multivariate interaction of respiratory outcomes from patients (N=36) being weaned off ventilator support after acute SCI with (N=15) or without (N=21) theophylline treatment. RESULTS: In total, 36 patients met inclusion criteria (2 C1, 5 C2, 11 C3, 14 C4 and 4 C5). The NL-PCA returned three independent components that accounted for 95% of the variance in the data set. Multivariate general linear models hypothesis tests revealed a significant syndromic interaction between theophylline treatment and SCI level (Wilks' Lambda, P=0.028, F (12,64)=2.116, η2=0.256, 1-ß=0.838), with post hoc testing demonstrating a significant interaction on PC1, explained by a positive correlation between improved forced vital capacity and time it took to reach 16 h of ventilator-free breathing. Thirty-three patients (92%) achieved 16 h of ventilator-free breathing (VFB) and 30 patients (83%) achieved 24 h of VFB. CONCLUSIONS: We suspect that some portion of the high success rate of ventilator weaning may be attributable to theophylline use in higher cervical SCI, in addition to our aggressive regimen of high volume ventilation, medication optimization and pulmonary toilet (positive pressure treatments and mechanical insufflation-exsufflation).

Applying Rasch analysis to evaluate measurement equivalence of different administration formats of the Activity Limitation scale of the Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR).

BACKGROUND: Electronic formats of patient-reported outcome (PRO) measures are now routinely used in clinical research studies. When changing from a validated paper and pen to electronic administration it is necessary to establish their equivalence. This study reports on the value of Rasch analysis in this process. METHODS: Three groups of US pulmonary hypertension (PH) patients participated. The first completed an electronic version of the CAMPHOR Activity Limitation scale (e-sample) and this was compared with two pen and paper administrated samples (pp1 and pp2). The three databases were combined and analysed for fit to the Rasch model. Equivalence was evaluated by differential item functioning (DIF) analyses. RESULTS: The three datasets were matched randomly in terms of sample size (n = 147). Mean age (years) and percentage of male respondents were as follows: e-sample (51.7, 16.0 %); pp1 (50.0, 14.0 %); pp2 (55.5, 40.4 %). The combined dataset achieved fit to the Rasch model. Two items showed evidence of borderline DIF. Further analyses showed the inclusion of these items had little impact on Rasch estimates indicating the DIF identified was unimportant. CONCLUSIONS: Differences between the performance of the electronic and pen and paper administrations of the CAMPHOR Activity Limitation scale were minor. The results were successful in showing how the Rasch model can be used to determine the equivalence of alternative formats of PRO measures.

Comparing the impact of psoriasis and atopic dermatitis on quality of life: co-calibration of the PSORIQoL and QoLIAD.

BACKGROUND: Disease-specific patient-reported outcome (PRO) measures are designed to be highly relevant to one disease. It is widely believed that comparisons of outcomes between patients with different diseases are only possible using generic measures. The present study employs a novel method of using Rasch analysis to co-calibrate scores from different disease-specific PRO measures, allowing scores to be compared across diseases. METHODS: Psoriasis patients (n = 146, mean age = 44.4, males = 50 %) completed the Psoriasis Quality of Life scale (PSORIQoL) and atopic dermatitis patients (n = 146, mean age = 45.5, males = 50 %) the Quality of Life in Atopic Dermatitis scale (QoLIAD). Both measures employ the needs-based model of QoL, and they share five common items-providing a link between assessments. The groups were analysed separately, and then combined to test fit to the Rasch model. RESULTS: Both scales showed good fit to the Rasch model after minor adjustments (PSORIQoL: χ (2) p = 0.25; QoLIAD: χ (2) p = 0.51). For the combined dataset, one common item showing differential item functioning by disease was removed and fit to the Rasch model was achieved (χ (2) p = 0.08). The co-calibrated scale successfully distinguished between perceived severity groups (p < 0.001). CONCLUSIONS: It is possible to co-calibrate scores on the PSORIQoL and QoLIAD. This is one of the first studies in health research to demonstrate how Rasch analysis can be used to make comparisons across diseases using different disease-specific measures. Such an approach maintains the greater relevance and, consequently, accuracy associated with disease-specific measurement.

Evaluation of selective dry cow treatment following on-farm culture: Milk yield and somatic cell count in the subsequent lactation.

Compared with blanket dry cow therapy (DCT), the selective antimicrobial treatment of cows based upon on-farm culture results has the potential to reduce the amount of antimicrobials used in dairy production. The objective of the current study was to determine the effect of a Petrifilm (3M Canada, London, Ontario) on-farm culture-based selective DCT program on milk yield and somatic cell count (SCC) in the following lactation. A total of 729 low-SCC (<200,000 cells/mL) cows from 16 commercial dairy herds with a low bulk tank SCC (<250,000 cells/mL) were randomly assigned to receive either blanket DCT or Petrifilm-based selective DCT. Cows belonging to the blanket DCT group were infused with a commercial DCT product and an internal teat sealant (ITS) at drying off. Using composite milk samples collected on the day before drying off, cows in the selective DCT group were treated at drying off based on the results obtained by the Petrifilm on-farm culture system with DCT and ITS (Petrifilm culture positive) or ITS alone (Petrifilm culture negative). Milk test-day records for the following lactation were obtained from Dairy Herd Improvement for all cows enrolled in the trial. Repeated measures linear mixed models were used to assess the effect of study group (blanket or selective DCT) on test-day milk production and natural logarithm of SCC over the first 180 d of the subsequent lactation. According to the final multivariable models, when low-SCC cows were selectively treated with DCT at drying off based on results obtained using the Petrifilm on-farm culture system, no effect on milk production (least squares means for blanket DCT = 39.3 kg vs. selective DCT = 39.0 kg) or natural logarithm of SCC (least squares means for blanket DCT = 3.95 vs. selective DCT = 3.97) was observed in the subsequent lactation when compared with cows receiving blanket DCT. The results of this study indicate that selective DCT based on results obtained by the Petrifilm on-farm culture system enabled a reduction in the use of DCT without negatively affecting milk production and milk quality.

The RNA helicase RHAU (DHX36) unwinds a G4-quadruplex in human telomerase RNA and promotes the formation of the P1 helix template boundary.

Human telomerase RNA (hTR) contains several guanine tracts at its 5'-end that can form a G4-quadruplex structure. Previous evidence suggests that a G4-quadruplex within this region disrupts the formation of an important structure within hTR known as the P1 helix, a critical element in defining the template boundary for reverse transcription. RNA associated with AU-rich element (RHAU) is an RNA helicase that has specificity for DNA and RNA G4-quadruplexes. Two recent studies identify a specific interaction between hTR and RHAU. Herein, we confirm this interaction and identify the minimally interacting RNA fragments. We demonstrate the existence of multiple quadruplex structures within the 5' region of hTR and find that these regions parallel the minimal sequences capable of RHAU interaction. We confirm the importance of the RHAU-specific motif in the interaction with hTR and demonstrate that the helicase activity of RHAU is sufficient to unwind the quadruplex and promote an interaction with 25 internal nucleotides to form a stable P1 helix. Furthermore, we have found that a 5'-terminal quadruplex persists following P1 helix formation that retains affinity for RHAU. Finally, we have investigated the functional implications of this interaction and demonstrated a reduction in average telomere length following RHAU knockdown by small interfering RNA (siRNA).

Evaluation of milk ELISA for detection of Mycobacterium avium subspecies paratuberculosis in dairy herds and association with within-herd prevalence.

Cow-level milk ELISA results can be used to determine herd Mycobacterium avium ssp. paratuberculosis (MAP) status. Milk sample collection is minimally invasive and ELISA results can be obtained quickly and economically. The objectives were to evaluate the herd-level test characteristics of 3 commercial milk ELISA, and to determine the impact of within-herd MAP prevalence on the performance of the milk ELISA herd test. A total of 32 purposively selected herds with a median herd size of 66 milking cows were used in this 2-yr project. Fecal and milk samples were collected from all milking cows at 6-mo intervals. Fecal samples were pooled by cow age, with 5 cow samples per pool; individual fecal culture was completed on cow samples from positive pools. Herd MAP status was defined as MAP positive if, at any point during the longitudinal study, a pooled fecal culture from the herd was positive. Milk samples were analyzed using each of 3 commercial milk ELISA kits; a cow-level result from each ELISA was classified as positive following the respective manufacturer's recommended threshold for a positive result. Herd-level milk ELISA test characteristics were estimated using generalized estimating equations logistic models, which accounted for repeated measurements. Using a cutoff of 2% milk ELISA-positive cows, milk ELISA herd sensitivity relative to a herd MAP status based on all pooled fecal culture results collected during the study was as follows: ELISA A: 59% [95% confidence interval (CI): 36-78%), ELISA B: 56% (95% CI: 32-77%), and ELISA C: 63% (95% CI: 41-81%). Herd specificity for ELISA A, B, and C was 80% (95% CI: 71-88%), 96% (95% CI: 89-98%), and 92% (95% CI: 86-96%), respectively. The remainder of the analyses focused on results from ELISA B. Herd sensitivity of ELISA B increased as MAP prevalence increased. In herds with a mean MAP prevalence ≤5%, the herd sensitivity of the milk ELISA was low, ranging from 11% when MAP prevalence was 1%, to 62% when MAP prevalence was 5%. Categorical likelihood ratios based on milk ELISA within-herd prevalence predicted that herds with milk ELISA prevalence above 0 but <2% had a similar likelihood to be MAP positive or MAP negative, whereas herds with a milk ELISA prevalence between 2 and 4% were 3.7 times more likely to be MAP positive than MAP negative. All herds with a milk ELISA prevalence >4% were MAP positive. Although milk ELISA B worked well to establish herd MAP status in high-prevalence herds, interpretation was unreliable in MAP-negative and low-prevalence herds.

Evaluation of selective dry cow treatment following on-farm culture: risk of postcalving intramammary infection and clinical mastitis in the subsequent lactation.

The objective of the study was to evaluate the utility of a Petrifilm-based on-farm culture system when used to make selective antimicrobial treatment decisions on low somatic cell count cows (<200,000 cells/mL) at drying off. A total of 729 cows from 16 commercial dairy herds with a low bulk tank somatic cell count (<250,000 cells/mL) were randomly assigned to receive either blanket dry cow therapy (DCT) or Petrifilm-based selective DCT. Cows belonging to the blanket DCT group were infused with a commercial dry cow antimicrobial product and an internal teat sealant (ITS) at drying off. Using composite milk samples collected on the day before drying off, cows in the selective DCT group were treated at drying off based on the results obtained by the Petrifilm on-farm culture system with DCT + ITS (Petrifilm culture positive), or ITS alone (Petrifilm culture negative). Quarters of all cows were sampled for standard laboratory bacteriology on the day before drying off, at 3 to 4d in milk (DIM), at 5 to 18 DIM, and from the first case of clinical mastitis occurring within 120 DIM. Multilevel logistic regression was used to assess the effect of study group (blanket or selective DCT) and resulting dry cow treatment (DCT + ITS, or ITS alone) on the risk of intramammary infection (IMI) at calving and the risk of a first case of clinical mastitis between calving and 120 DIM. According to univariable analysis, no difference was observed between study groups with respect to quarter-level cure risk and new IMI risk over the dry period. Likewise, the risk of IMI at calving and the risk of clinical mastitis in the first 120 DIM was not different between quarters belonging to cows in the blanket DCT group and quarters belonging to cows in the selective DCT group. The results of this study indicate that selective DCT based on results obtained by the Petrifilm on-farm culture system achieved the same level of success with respect to treatment and prevention of IMI over the dry period as blanket DCT and did not affect the risk of clinical mastitis in the first 120 d of the subsequent lactation.

The "Lollypop" technique for polyethylene exchange in total ankle replacement.

UNLABELLED: We describe a simple technique for the removal of the polyethylene meniscus bearing surface in patients undergoing re-operation and meniscus bearing exchange following a previous total ankle replacement. LEVEL OF EVIDENCE: Level V.

Expression of MxA in esophageal cancer cell lines can influence sensitivity to chemotherapeutic agents but this does not require apoptosis.

Esophageal cancer is a poor prognosis cancer characterized by intrinsic or acquired resistance to chemotherapeutic agents. The primary determinants of treatment failure are unknown. Expression of an anti-viral protein, myxovirus resistance protein A (MxA) is de-regulated in many cancers, including esophageal cancer, and its activity has been linked to apoptosis. This study has assessed whether MxA expression can influence the response of esophageal cancer cells to the chemotherapeutic agents 5-fluorouracil (5-FU) or oxaliplatin. MxA protein was differentially expressed in a panel of five esophageal cancer cell lines. KYSE450 and KYSE140 cells did not express MxA and were apoptosis incompetent. FLO-1, KYSE270, and OE21 cells expressed MxA, were more drug-sensitive and were apoptosis competent. MxA was artificially overexpressed in cell lines with no endogenous expression (KYSE450 and KYSE140). This increased the resistance of KYSE450 but not KYSE140 cells. Both cell lines remained apoptosis incompetent. We then evaluated siRNA knockdown of MxA in FLO-1 cells and CRISPR knockout in OE21 cells. Knockdown of MxA significantly increased drug sensitivity and caspase-3 activation in FLO-1 cells. OE21-MX1KO cells were also more drug-sensitive, but in contrast to FLO-1 cells, caspase-3 activation was reduced. Collectively these data indicate that MxA can promote resistance to chemotherapy, but this does not always correspond with effects on apoptosis. Effects on apoptosis are cell line specific, suggesting that other co-operating pathways determine the overall impact of MxA. Importantly, in cancer cells that overexpress the protein, drug sensitivity can be improved by interfering with MxA.

Examining the role of depression on the relationship between performance-based and self-reported cognitive functioning after sport-related concussion.

OBJECTIVE: Little is known about the relationship between neuropsychological test performance, cognitive symptom reporting, and depressive symptoms after sport-related concussion. Accordingly, this cross-sectional study examined these relationships in collegiate athletes. It was hypothesized that depressive symptoms would moderate and mediate the relationship between performance-based and self-reported cognitive functioning after concussion. METHODS: After sustaining a sport-related concussion, 110 collegiate athletes completed a neuropsychological battery, the Post-Concussion Symptoms Scale, and the Beck Depression Inventory-Fast Screen. Neuropsychological test performance, depressive symptoms, and their interactions were entered into distinct hierarchical linear regression analyses with self-reported cognition as the dependent variable to assess moderation. Mediation was analyzed using the PROCESS macro with 5000 bootstrap samples and a 95% confidence interval. RESULTS: There was a significant interaction between the mean memory composite and depressive symptoms when predicting cognitive symptom reporting, p = 0.047. Simple effects tests revealed that for athletes who had a lower memory composite score, an increase in depressive symptoms led to an increase in self-reported cognitive dysfunction, p < 0.001, ηp2 = 0.11. Depressive symptoms partially mediated the relationship between the memory composite and cognitive symptom reporting, indirect effect = -0.26, 95%CI[-0.58,0.001], but this relationship was not found for any other neurocognitive domain. CONCLUSIONS: For tests of memory, depressive symptoms moderated and partially mediated the relationship between performance-based and self-reported cognitive functioning after sport-related concussion. Athletes reporting high depressive symptoms and cognitive dysfunction may need more comprehensive evaluations to inform return-to-play decisions, and depression could be a treatment target for athletes who report high levels of cognitive dysfunction after concussion.