Patient-reported experiences with refractory or unexplained chronic cough: a qualitative analysis.

BACKGROUND: Chronic cough, defined as a cough lasting 8 or more weeks, affects up to 10% of adults. Refractory chronic cough (RCC) is a cough that is uncontrolled despite comprehensive investigation and treatment of comorbid conditions while unexplained chronic cough (UCC) is a cough with no identifiable cause despite extensive evaluation of comorbid conditions. RCC and UCC are often poorly controlled. Understanding individuals' lived experience of the symptoms and impacts of these conditions may guide therapeutic strategies. OBJECTIVES: The primary objectives of this study were to assess respondents' perceptions of the key symptoms of RCC and UCC and the impacts of RCC and UCC and their symptoms on well-being, health-related quality of life, work productivity, and social relationships. DESIGN: Qualitative study. METHODS: This study enrolled 30 adults with physician-diagnosed RCC or UCC. Two trained qualitative researchers conducted individual, in-depth telephone interviews using a semi-structured interview guide. Interviews were audio-recorded, transcribed, coded, and systematically analyzed to identify content themes. RESULTS: A total of 15 respondents with RCC and 15 with UCC were included in the study. Many respondents had RCC or UCC for a long duration (median 9 years, range: 0-24). Half of the respondents reported having a coughing episode at least once daily. Only 40% of respondents reported that medication had improved their symptoms. In over half of the respondents, RCC or UCC hindered communication, caused embarrassment, frustration, and worry, and lowered quality of life. Perceptions of meaningful treatment benefits in RCC or UCC varied widely across respondents. CONCLUSION: RCC and UCC remained poorly managed in many individuals and were associated with a wide range of symptoms and cough triggers that hindered daily activities and reduced emotional well-being. Understanding individuals' lived experiences may inform the development of RCC and UCC therapeutic strategies.

Patient-reported experiences with refractory or unexplained chronic cough: a qualitative analysisChronic cough, particularly refractory and unexplained chronic cough, remain poorly managed in many individuals and are associated with a wide range of symptoms and cough triggers that hinder daily activities and reduce emotional well-being. Currently there are no US Food and Drug Administration-approved treatments for refractory or unexplained chronic cough. Understanding the experience and treatment preferences of individuals with these conditions may help inform the development of new therapies and clarify the potential impact of such therapies on the lives of individuals with chronic cough. Using in-depth interviews, the present study comprehensively evaluated individuals' experience with refractory or unexplained chronic cough and treatment priorities, a research area that has not been well-studied. This study detailed broad-ranging physical, behavioral, and emotional impacts of chronic cough, which hindered individuals' social well-being.

Dairy cattle welfare - the relative effect of legislation, industry standards and labelled niche production in five European countries.

The only common European Union (EU) legislation set up specifically to ensure the welfare of dairy cattle is for calves. As a consequence, there is wide diversity in how dairy cattle welfare is ensured in EU countries. A few countries have legal requirements for dairy cattle welfare, while in others, it is left to industry standards or niche production requirements, typically linked to various premium labels. In this paper, we compared animal welfare provisions in dairy cattle production across five countries with different combinations of legislative and other approaches: Denmark, Germany, the Netherlands, Sweden, and the United Kingdom. Firstly, we aimed to map the diversity of animal welfare initiatives. Secondly, we used the Benchmark method of expert valuations and weightings of the relative importance of individual welfare provisions. We found that Denmark and Sweden have the highest level of dairy cattle welfare provisions as measured by the Benchmark method, partly due to high legislative welfare requirements, followed by the United Kingdom, which has an extensive industry standard with very high uptake. Germany and the Netherlands, on the other hand, have lower levels of documented welfare provisions, and correspondingly a Benchmark score closer to a baseline defined by legal requirements at EU level. We also found differences in what elements of animal welfare were focussed on. Some initiatives emphasised fulfilling the social needs of cattle, while others focused more on space and freedom to move. Also, the countries with the highest Benchmark score had a relatively high level of production of organic and other specialty dairy products. We found the effect of national legislation or ambitious industry standards on dairy cattle welfare to be much larger than previous studies have found in either pigs or poultry. At a time when the EU is considering stepping up its efforts to improve animal welfare in terms of common minimum standards, the results of this study could have important policy implications. The diversity in the level of dairy cattle welfare standards found across countries may speak in favour of having shared minimum standards, both at EU level and globally. However, even among countries with a similar Benchmark score, we found a difference in the kinds of welfare provisions at work, which may make full harmonisation of standards more challenging.

Patterns of Cough Medication Prescribing among Patients with Chronic Cough in Florida: 2012-2021.

Among patients with chronic cough (CC) in the 2012-2021 statewide OneFlorida Clinical Research Consortium database, we examined trends in cough medication (CM) prescribing prevalence over time in repeated cross-sectional analyses and identified distinct CM utilization trajectories using group-based trajectory modeling (GBTM) in a retrospective cohort study. Among eligible adults (≥18 years) without cancer/benign respiratory tumor diagnoses, we identified CC patients and non-CC patients with any cough-related diagnosis. In the GBTM analysis, we calculated the number of monthly prescriptions for any CMs (excluding gabapentinoids) during the 12 months from the first qualifying cough event to identify distinct utilization trajectories. From 2012 to 2021, benzonatate (9.6% to 26.1%), dextromethorphan (5.2% to 8.6%), and gabapentinoid (5.3% to 14.4%) use increased among CC patients, while opioid antitussive use increased from 2012 to 2015 and decreased thereafter (8.4% in 2012, 14.7% in 2015, 6.7% in 2021; all p < 0.001). Of 15,566 CC patients and 655,250 non-CC patients identified in the GBTM analysis, CC patients had substantial burdens of respiratory/non-respiratory comorbidities and healthcare service and concomitant medication use compared to non-CC patients. Among CC patients, GBTM identified three distinct CM utilization trajectories: (1) no CM use (n = 11,222; 72.1%); (2) declining CM use (n = 4105; 26.4%); and (3) chronic CM use (n = 239; 1.5%). CC patients in Florida had limited CM use with increasing trends in use of benzonatate, dextromethorphan, and gabapentinoids and a decreasing trend in opioid antitussive use. CC patients, particularly with chronic prescription CM use, experienced substantial disease burden.

Efficacy and Safety of Eliapixant in Refractory Chronic Cough: The Randomized, Placebo-Controlled Phase 2b PAGANINI Study.

INTRODUCTION: The PAGANINI study evaluated the efficacy and safety of the selective P2X3 antagonist eliapixant in patients with refractory chronic cough (RCC). METHODS: PAGANINI was a randomized, double-blind, parallel-group, placebo-controlled, multicenter, dose-finding, phase 2b study. Adults with RCC lasting ≥ 12 months and cough severity ≥ 40 mm on a visual analog scale at screening were enrolled. Participants were randomized 1:1:1:1 to twice-daily 25 mg, 75 mg, or 150 mg oral eliapixant or placebo for 12 weeks. The primary endpoint was change from baseline in 24-h cough count after 12 weeks of intervention. RESULTS: Overall, 310 participants were randomized to twice-daily eliapixant 25 mg (n = 75), 75 mg (n = 78), 150 mg (n = 80), or placebo (n = 77). A statistically significant dose-response signal with eliapixant was detected for the primary endpoint (all dose-response models, adjusted p < 0.1; one-sided). Adverse events (AEs) were reported in 39 (51%) participants with placebo and 43-51 (57-65%) participants receiving eliapixant. The most common AE was dysgeusia, occurring in 1% (n = 1) of the placebo group and 1-16% (n = 1-13) of the eliapixant groups in a dose-related manner. One case of a moderate drug-induced liver injury occurred in a participant receiving 150 mg twice-daily eliapixant. CONCLUSION: Eliapixant demonstrated efficacy and a favorable taste tolerability profile in RCC. However, a drug-induced liver injury contributed to intensified liver monitoring in clinical trials with eliapixant and discontinuation of the entire development program in all indications by Bayer AG. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT04562155; registered September 18, 2020.

Evaluation of Cough Medication Use Patterns in Ambulatory Care Settings in the United States: 2003-2018.

Using 2003−2018 National Ambulatory Medical Care Survey data for office-based visits and 2003−2018 National Hospital Ambulatory Medical Care Survey data for emergency department (ED) visits, we conducted cross-sectional analyses to examine cough medication (CM) use trends in the United States (US) ambulatory care settings. We included adult (≥18 years) patient visits with respiratory-infection-related or non-infection-related cough as reason-for-visit or diagnosis without malignant cancer or benign respiratory tumor diagnoses. Using multivariable logistic regressions, we examined opioid antitussive, benzonatate, dextromethorphan-containing antitussive, and gabapentinoid use trends. From 2003−2005 to 2015−2018, opioid antitussive use decreased in office-based visits (8.8% to 6.4%, Ptrend = 0.03) but remained stable in ED visits (6.3% to 5.9%, Ptrend = 0.99). In both settings, hydrocodone-containing antitussive use declined over 50%. Benzonatate use more than tripled (office-based:1.6% to 4.8%; ED:1.5% to 8.0%; both Ptrend < 0.001). Dextromethorphan-containing antitussive use increased in ED visits (1.8% to 2.6%, Ptrend = 0.003) but stayed unchanged in office-based visits (3.8% to 2.7%; Ptrend = 0.60). Gabapentinoid use doubled in office-based visits (1.1% in 2006−2008 to 2.4% in 2015−2018, Ptrend < 0.001) but was negligible in ED visits. In US office-based and ED ambulatory care settings, hydrocodone-containing antitussive use substantially declined from 2003 to 2018, while benzonatate use more than tripled, and dextromethorphan-containing antitussive and gabapentinoid use remained low (<3%).

Implementation of less-invasive surfactant administration in a Canadian neonatal intensive care unit.

BACKGROUND: Less-invasive surfactant administration (LISA) is a recent technique used extensively in Europe but rarely used in North America. The aim of this study was to describe our experience following LISA implementation using poractant in a Canadian neonatal intensive care (NICU). METHODS: A retrospective analysis was conducted from June 2017 to April 2021 of LISA procedures in preterm infants. Data were collected on patient characteristics, outcomes following LISA, laryngoscopy, and adverse events. The primary outcome was the rate of successful LISA procedures. SETTING: Level IIIa academic NICU. RESULTS: LISA was successful in 93 of 101 infants (92%). Median gestational age was 30.9 weeks (interquartile range [IQR]: 29.4-33.0). All infants received atropine and fentanyl premedication. Eight LISA procedures were unsuccessful: five because of thoracic rigidity and three because of inability to expose the vocal cords. In the 93 successful procedures, a second dose of surfactant was needed for 15 of 93 infants (16.1%), either by repeated LISA (7/15; 7.5%) or by endotracheal intubation (8/15; 8.6%). In 63.4% of successful procedures, one laryngoscopy attempt was made. The median duration of laryngoscopy attempts was 60 s (IQR: 52-110). Two types of catheters were used: the multi-access catheter (MAC) or the Angiocath in 67% and 33% of procedures, respectively. One infant had bradycardia and 30.6% had profound desaturation of <75%. CONCLUSION: LISA with poractant alfa was implemented in a Canadian NICU with a high degree of procedural success. Fentanyl may lead to more adverse events with a risk of interrupting LISA and may not be the ideal agent for this procedure. These results may encourage wider dissemination of LISA in North America.

Characterization of Patients With Refractory or Unexplained Chronic Cough Participating in a Phase 2 Clinical Trial of the P2X3-Receptor Antagonist Gefapixant.

PURPOSE: This analysis assesses clinical characteristics of patients with refractory chronic cough (RCC) or unexplained chronic cough (UCC) enrolled in a phase 2 study to better understand this patient population. METHODS: Patients with RCC/UCC lasting for ≥ 1 year and cough severity visual analog scale (VAS) score of > 40 mm at screening were eligible. Demographics, clinical characteristics, and medical history were collected at baseline. Cough-related measures included cough severity VAS, Cough Severity Diary (CSD), Leicester Cough Questionnaire (LCQ), and a structured cough-trigger questionnaire. Medication history included all medications 30 days before screening and chronic cough treatments within 1 year before screening. Data were summarized using descriptive statistics. RESULTS: Patients (N = 253; female, 76%; mean age, 60 years) had severe (mean cough severity VAS, 57.5 mm) and long-lasting (median duration, 11 years) cough. The most burdensome self-reported aspects included psychological and social factors (LCQ) and cough frequency and intensity (CSD). Patient-reported triggers were consistent with cough hypersensitivity (e.g., 95% to 96% reported irritation or tickle in throat). Common reported comorbidities included gastroesophageal reflux disease (GERD; 56%), allergic rhinitis (47%), and asthma (30%); 12% of patients had been diagnosed with all 3 conditions. The most common prior medications included inhaled or oral steroids (21%), antihistamines (15%), and antacids (15%). CONCLUSION: Patients with RCC/UCC had severe, long-lasting, and burdensome cough with clinical features of cough hypersensitivity. Many patients had been diagnosed with GERD, allergic rhinitis, and asthma but had a persistent cough despite treatment of these conditions. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02612610; registered November 20, 2015.

Gefapixant, a P2X3 receptor antagonist, for the treatment of refractory or unexplained chronic cough: a randomised, double-blind, controlled, parallel-group, phase 2b trial.

BACKGROUND: Gefapixant is a P2X3 receptor antagonist that has shown promise for the treatment of refractory and unexplained chronic cough. The aim of this study was to evaluate the efficacy of gefapixant compared with placebo after 12 weeks of treatment for refractory chronic cough or unexplained chronic cough. METHODS: We did a 12-week, phase 2b, randomised, double-blind, placebo-controlled study in patients with refractory chronic cough or unexplained chronic cough aged 18-80 years who were recruited from 44 primarily outpatient pulmonologist or allergist sites in the UK and the USA. Eligible patients had refractory or unexplained chronic cough lasting 1 year or longer, no radiographic chest abnormality, and 40 mm or more on a 100-mm cough severity visual analogue scale at enrolment. Patients were randomly assigned to receive placebo or one of three doses (7·5 mg, 20 mg, or 50 mg) of oral gefapixant twice daily, every day, for 84 days; visits to investigative sites were on days 1, 28, 42, 56, 70, 84, and 85. The randomisation schedule was computer generated using a permuted block algorithm by Advance Research Associates (Santa Clara, CA, USA). Patients and all personnel involved in the conduct and interpretation of the study were masked to treatment assignment. The primary endpoint was placebo-adjusted change from baseline in awake cough frequency after 12 weeks, assessed in the full analysis set, which is a subset of the intention-to-treat population. Adverse events were monitored and safety was evaluated in all patients receiving one or more doses of study drug. This trial is registered with ClinicalTrials.gov, NCT02612610. FINDINGS: Between Dec 21, 2015, and July 26, 2016, 253 patients were randomly assigned to placebo (n=63), gefapixant 7·5 mg (n=64), gefapixant 20 mg (n=63), or gefapixant 50 mg (n=63) twice daily. The mean age of patients was 60·2 (SD 9·9) years and 193 (76%) were women. At 12 weeks, patients' geometric mean awake cough frequency was 18·2 coughs per h (geometric SD 3·1) with placebo, and 14·5 coughs per h (3·7) with 7·5 mg, 12·0 coughs per h (4·2) with 20 mg, and 11·3 coughs per h (2·8) with 50 mg gefapixant. Estimated percentage change relative to placebo was -22·0% (-41·8 to 4·6; p=0·097) with 7·5 mg, -22·2% (-42·0 to 4·3; p=0·093) with 20 mg, and -37·0% (95% CI -53·3 to -14·9; p=0·0027) with 50 mg gefapixant. Dysgeusia was the most common adverse event, occurring in three (5%) patients given placebo, six (10%) given 7·5 mg gefapixant, 21 (33%) given 20 mg gefapixant, and 30 (48%) given 50 mg gefapixant. INTERPRETATION: Targeting purinergic receptor P2X3 with gefapixant at a dose of 50 mg twice daily significantly reduced cough frequency in patients with refractory chronic cough or unexplained chronic cough after 12 weeks of treatment compared with placebo. Further development of gefapixant is warranted for the treatment of chronic cough. FUNDING: Afferent Pharmaceuticals (acquired by Merck & Co., Inc., Kenilworth, NJ, USA).

Gefapixant in two randomised dose-escalation studies in chronic cough.

BACKGROUND AND OBJECTIVES: Gefapixant has previously demonstrated efficacy in the treatment of refractory chronic cough at a high daily dose. The current investigations explore efficacy and tolerability of gefapixant, a P2X3 receptor antagonist, for the treatment of chronic cough using a dose-escalation approach. MATERIALS AND METHODS: Two randomised, double-blind, placebo-controlled, crossover, dose-escalation studies recruited participants with refractory chronic cough. Patients were assigned to receive ascending doses of gefapixant (study 1: 50-200 mg, study 2: 7.5-50 mg) or placebo for 16 days, then crossed-over after washout. The primary end-point was awake cough frequency assessed using a 24-h ambulatory cough monitor at baseline and on day 4 of each dose. Patient-reported outcomes included a cough severity visual analogue scale and the cough severity diary. RESULTS: In clinical studies, gefapixant doses ≥30 mg produced maximal improvements in cough frequency compared with placebo (p<0.05); reported cough severity measures improved at similar doses. Taste disturbance exhibited a different relationship with dose, apparently maximal at doses ≥150 mg. CONCLUSIONS: P2X3 antagonism with gefapixant demonstrates anti-tussive efficacy and improved tolerability at lower doses than previously investigated. Studies of longer duration are warranted.

Short communication: Detection of lameness in dairy cows using a grooming device.

Lameness in dairy cattle is a common welfare problem with significant economic implications. All too often, appropriate treatment is delayed or neglected due to insufficient detection of lame cows. Brush usage is considered a low-resilience activity; that is, one that typically decreases when energy resources are limited or when the cost involved in the activity increases, such as during sickness and stress. The aim of this study was to determine the association between brush usage and different degrees of lameness. Locomotion scores of 209 lactating Holstein dairy cows were collected individually once a week for 14 consecutive weeks, using a 5-point visual assessment scoring system (1 = nonlame, 2 = uneven gait, 3 = mild lameness, 4 = lameness, 5 = severe lameness). Daily brush usage was collected automatically from 3 cowsheds of similar size and structure located on a commercial dairy farm. In each of the 3 cowsheds, 2 brushes were installed, one next to the feed bunk, and the other away from the feed bunk (on the opposite side of the cowshed). Linear and generalized linear mixed-effects models were used to evaluate the association between locomotion scores and daily measures of brush usage. We found a significant interaction between locomotion score and brush location (near to/distant from feed bunk) on the daily proportion of cows using the brush at least once and on daily duration of brush usage. Specifically, we showed that lame and severely lame cows did not use brushes that were installed away from the feed bunk but continued to use brushes that were installed next to the feed bunk. Brush usage by cows with uneven gait (locomotion score 2) or with mild lameness (locomotion score 3) did not differ from that of nonlame cows (locomotion score 1). The results of this study suggest that monitoring of daily usage of brushes located away from the feed bunk could be a useful method for detecting lameness and severe lameness in dairy cows. However, the use of this method to detect mild lameness or cases of abnormal gait is, at this stage, less promising.

Short communication: Detection and monitoring of metritis in dairy cows using an automated grooming device.

Metritis, a prevalent disease on dairy farms, is negatively associated with reproduction, milk production, and the welfare of cows. The objective of this study was to evaluate the efficacy of monitoring low-resilience activities (i.e., behaviors that typically decrease when energy resources are limited or when the cost involved in the activity increases; e.g., brush usage) in the early detection of metritis. Data on daily brush usage (i.e., proportion of cows using the brush and the duration of usage) were collected from 28 metritic and 60 control cows 28 d postpartum using an automated monitoring system developed for the purpose of this study. During the first week following partum (before clinical diagnosis), we found no differences in brush usage between sick and control cows. However, 8 to 21 d postpartum (the week of clinical diagnosis and the first week of medical treatment), a lower proportion of metritic cows used the brush compared with control cows (0.49 compared with 0.64, respectively, at brushes installed away from the feed bunk). In addition, the daily duration of brush usage was 50% lower among cows diagnosed with metritis compared with control cows 8 to 28 d postpartum (44 s/d compared with 88 s/d, respectively). The results of this study suggest that on-farm monitoring of low-resilience behaviors, combined with existing systems that monitor core behaviors (e.g., activity and rumination), may serve as an improved method for detecting events that compromise the welfare of animals. The slow recovery of low-resilience behaviors following medical treatment (wk 4) might serve as a particularly useful indicator of progress of recovery from disease.

Formal evaluation of PYNK: Breast Cancer Program for Young Women-the patient perspective.

PURPOSE: The aim of the present study was to assess patient satisfaction with pynk: Breast Cancer Program for Young Women so as to determine how the program might be improved and to provide feedback to donors. METHODS: All pynk patients who had consented to have their information entered in our database and who supplied us with their e-mail address were invited to complete a 58-item online questionnaire consisting of multiple choice and open-ended questions. Domains included demographics, provision of written and spoken information, support, infertility risk, research awareness, attitudes toward discharge, and general feedback. RESULTS: Of 120 pynk patients approached, 61 (51%) participated. More than 90% were satisfied or very satisfied with the timing, usefulness, and clarity of spoken and written information given, and 69% found the service and support provided by the nurse navigator to be the most helpful component of the program. Of those who had received systemic therapy, 93% recalled a health care provider initiating a discussion of the risk of treatment-related infertility, and 67% were referred to a fertility clinic. On the negative side, 11%-27% were unaware of various services provided by pynk, and 11% were unaware of pynk's ongoing research. One third of patients were unhappy or ambivalent about the prospect of discharge from the program. CONCLUSIONS: Patient satisfaction with this novel program for young women with breast cancer is high. This study highlights the critical role that the nurse navigator plays in patient support and dissemination of information. In contrast to other reported surveys of young cancer patients, pynk patients are routinely given the opportunity to undergo fertility preservation.

Invited review: Environmental enrichment of dairy cows and calves in indoor housing.

In recent years, an increasing number of farmers are choosing to keep their cows indoors throughout the year. Indoor housing of cows allows farmers to provide high-yielding individuals with a nutritionally balanced diet fit for their needs, and it has important welfare benefits for both cows and their calves, such as protection from predators, parasites, and exposure to extreme weather conditions. However, it also confronts cows and calves with a wide range of environmental challenges. These include abiotic environmental sources of stress (e.g., exposure to loud and aversive sound) and confinement-specific stressors (e.g., restricted movement and maintenance in abnormal social groups). Cows and calves that live indoors are also faced with the challenge of occupying long periods with a limited range of possible behavioral patterns. Environmental enrichment can improve biological functioning (measured as increased lifetime reproductive success, increased inclusive fitness, or a correlate of these such as improved health), help animals to cope with stressors in their surroundings, reduce frustration, increase the fulfillment of behavioral needs, and promote more positive affective states. Here, we review recent findings on the effect of social, occupational, physical, sensory, and nutritional enrichment on dairy cows and calves, and we assess the appropriateness and practicality of implementing different enrichment practices on commercial dairy farms. Some of the enrichment methods reviewed here may also be applied to those more extensive cattle-raising systems, where similar challenges occur.

Neuroprotective potential of pleiotrophin overexpression in the striatonigral pathway compared with overexpression in both the striatonigral and nigrostriatal pathways.

Intrastriatal injection of recombinant adeno-associated viral vector serotype 2/1 (rAAV2/1) to overexpress the neurotrophic factor pleiotrophin (PTN) provides neuroprotection for tyrosine hydroxylase immunoreactive (THir) neurons in the substantia nigra pars compacta (SNpc), increases THir neurite density in the striatum (ST) and reverses functional deficits in forepaw use following 6-hydroxydopamine (6-OHDA) toxic insult. Glial cell line-derived neurotrophic factor (GDNF) gene transfer studies suggest that optimal neuroprotection is dependent on the site of nigrostriatal overexpression. The present study was conducted to determine whether enhanced neuroprotection could be accomplished via simultaneous rAAV2/1 PTN injections into the ST and SN compared with ST injections alone. Rats were unilaterally injected in the ST alone or injected in both the ST and SN with rAAV2/1 expressing either PTN or control vector. Four weeks later, all rats received intrastriatal injections of 6-OHDA. Rats were euthanized 6 or 16 weeks relative to 6-OHDA injection. A novel selective total enumeration method to estimate nigral THir neuron survival was validated to maintain the accuracy of stereological assessment. Long-term nigrostriatal neuroprotection and functional benefits were only observed in rats in which rAAV2/1 PTN was injected into the ST alone. Results suggest that superior preservation of the nigrostriatal system is provided by PTN overexpression delivered to the ST and restricted to the ST and SN pars reticulata and is not improved with overexpression of PTN within SNpc neurons.

The effect of food location, heat load, and intrusive medical procedures on brushing activity in dairy cows.

Animals allocate time and effort to a range of core (e.g., sleeping, feeding, drinking) and "luxury" (e.g., playing, exploring) activities. A luxury activity is characterized by low resilience and, as such, will be reduced when time or energy resources are limited, including under conditions of stress or discomfort. One seemingly luxurious activity available to cows on an increasing number of dairy farms is rubbing against an automated brush. The current study examined the effect of distance from food, heat load, and an intrusive medical procedure (i.e., artificial insemination and transrectal pregnancy examination) on the resilience of brush usage. The probability of using the brush decreased significantly when food was located distantly from the brush (mean=0.53) compared with days when food was located closer to the brush (mean=0.81). Brush usage also decreased at high temperature and humidity levels, with an average decrease of 0.062 brushing events for an increase of 1 temperature-humidity index unit (95% confidence interval=-0.93-0.030). In addition, a significant reduction of approximately 50% in brushing activity was observed on days of artificial insemination compared with the preceding 3d and the following 3d. These findings show that brush usage is a low resilience activity that reduces under a range of conditions. It may thus have the potential to be used as an indicator of a range of health and welfare problems in cows. Further research should be conducted to assess the sensitivity and specificity of this suggested tool and its possible contribution to the early detection of morbidity.

Imaging of an atypical large perineal cyst diagnosed during pregnancy.

Perineal cysts are quite frequent, almost 2% of women developing symptoms related to Bartholin or Gartner cysts. In most cases these cysts derive from embryological remnants or ectopic tissue, or form as epithelial inclusion cysts. These structures are usually asymptomatic unless they are complicated by infection. We report the sonographic and magnetic resonance imaging characteristics of a large perineal cyst diagnosed during the first trimester of an uncomplicated pregnancy, followed by conservative management during pregnancy and surgical excision in the puerperium.

BDNF tagging polymorphisms and haplotype analysis in sporadic Parkinson's disease in diverse ethnic groups.

Experimental and clinical data suggest that genetic variations in brain-derived neurotrophic factor (BDNF) gene may affect risk for Parkinson's disease (PD). We performed a case-control association analysis of BDNF in three independent Caucasian cohorts (Greek, North American, and Finnish) of PD using eight tagging SNPs and five constructed haplotypes. No statistically significant differences in genotype and allele frequencies were found between cases and controls in all series. A relatively rare BDNF haplotype showed a trend towards association in the Greek (p=0.02) and the Finnish (p=0.03) series (this haplotype was not detected in the North American series). However, given the large number of comparisons these associations are considered non-significant. In conclusion, our results do not provide statistically significant evidence that common genetic variability in BDNF would associate with the risk for PD in the Caucasian populations studied here.

LRRK2 mutations in a clinic-based cohort of Parkinson's disease.

In the last decade, major breakthroughs in the understanding of genetic contributions to Parkinson's disease (PD) have been achieved. Recently, mutations in LRRK2, encoding dardarin, have been found to be responsible for an autosomal dominant parkinsonism (OMIM 607060). We screened 311 subjects (cases: n = 202, controls: n = 109) for the three previously reported LRRK2 mutations. Our investigation revealed a sporadic case of PD with a heterozygous mutation G2019S (c.6055G>A). Here, we present the clinical phenotype of this patient and discuss the implications of genetic testing for the G2019S mutation in patients with sporadic PD.

RNA knockdown as a potential therapeutic strategy in Parkinson's disease.

Parkinson's disease is a prevalent progressive degenerative disorder of the elderly. There is a current need for novel therapeutic strategies because the standard levodopa pharmacotherapy is only temporarily efficacious. Recently, there have been some high-profile successful preclinical results obtained in animal models of neurological disorders using small interfering RNAs delivered by viral vectors. RNA interference can theoretically be applied to Parkinson's disease since over-expression of various proteins is known to kill the dopamine neurons of the substantia nigra in animal models and in familial forms of Parkinson's disease. Potential RNA interfering strategies and caveats are discussed in this review.