Parous women perform less moderate to vigorous physical activity than their nulliparous peers: a population-based study in Denmark.

OBJECTIVES: The World Health Organization (WHO) highlights parous women as a key population for monitoring trends of physical activity (PA). We aimed to estimate the proportion of Danish women non-adhering to WHO PA guidelines in parous women compared with nulliparous women and to describe leisure-time PA intensity in each of these groups. STUDY DESIGN: Cross-sectional study. METHODS: This population-based study builds on a sample of 27,668 women aged 16-40 years from the Danish National Health Survey 2021. These data were linked with childbirth data from the Danish National Birth Registry. The primary outcome was self-reported weekly hours of moderate to vigorous leisure-time PA (MVPA) dichotomized into: (i) adhering to WHO guidelines for MVPA or (ii) not adhering to WHO guidelines for MVPA. Binomial regression analysis was used to calculate prevalence proportions (PP) and prevalence proportion ratios (PPR). RESULTS: Of the 27,668 women, a total of 20,022 were included; 9338 (46.6%) parous women and 10,684 (53.4%) nulliparous women. The PP of women non-adhering to WHO PA guidelines was 63.8% (95% CI 62.9-64.8) for parous and 51.3% (95% CI 50.4-52.3) for nulliparous women, corresponding to a PPR of 1.24 (95% CI 1.21; 1.27). CONCLUSIONS: The proportion of parous women who did not adhere to WHO PA guidelines for MVPA was 24% higher than that of nulliparous women. This highlights parous women as a subgroup of the adult population at increased risk of non-adherence to WHO PA guidelines. These findings call for future research to inform new strategies aiming to promote PA in parous women.

Investigating the effect of graphene oxide in chitosan/alginate-based foams on the release and antifungal activity of clotrimazole in vitro.

Polyelectrolyte complexes (PECs) have been used as the matrix of solid foams for drug delivery. This study aimed at investigating the effect of graphene oxide (GO) and the composition of excipients in chitosan/alginate-based buccal foams on the clotrimazole release and antifungal activities. The investigation has been focused on the interactions of the drug with excipients in the foams, and the changes of ionization degree upon exposure to various media are discussed. The solid foams were prepared by mixing the excipients and clotrimazole via probe sonication, followed by a freeze-drying method. The pH values of the formulations were measured during the foam preparation process to estimate the ionization degree of clotrimazole and the other excipients. The foam matrix was the PECs between the cationic chitosan and anionic alginate. The mechanical strength of clotrimazole-loaded foams was lower than that of drug-free foams due to the positively charged clotrimazole interacting with the anionic alginate and interfering the PECs between chitosan and alginate. Addition of GO in the clotrimazole-loaded matrix made the foams mechanically stronger and contributed to a faster release of clotrimazole from the buccal foams by disrupting the electrostatic interactions between alginate and clotrimazole. However, addition of 1 wt% GO in the formulations didn't affect the antifungal activity of clotrimazole-loaded foams significantly. A lower amount GO in the formulation may be required for enhancing the antifungal effect, which should be further investigated in future.

Contaminating DNA in human saliva alters the detection of variants from whole genome sequencing.

Cells obtained from human saliva are commonly used as an alternative DNA source when blood is difficult or less convenient to collect. Although DNA extracted from saliva is considered to be of comparable quality to that derived from blood, recent studies have shown that non-human contaminating DNA derived from saliva can confound whole genome sequencing results. The most concerning complication is that non-human reads align to the human reference genome using standard methodology, which can critically affect the resulting variant genotypes identified in a genome. We identified clusters of anomalous variants in saliva DNA derived reads which aligned in an atypical manner. These reads had only short regions of identity to the human reference sequence, flanked by soft clipped sequence. Sequence comparisons of atypically aligning reads from eight human saliva-derived samples to RefSeq genomes revealed the majority to be of bacterial origin (63.46%). To partition the non-human reads during the alignment step, a decoy of the most prevalent bacterial genome sequences was designed and utilised. This reduced the number of atypically aligning reads when trialled on the eight saliva-derived samples by 44% and most importantly prevented the associated anomalous genotype calls. Saliva derived DNA is often contaminated by DNA from other species. This can lead to non-human reads aligning to the human reference genome using current alignment best-practices, impacting variant identification. This problem can be diminished by using a bacterial decoy in the alignment process.

Graphene oxide as a functional excipient in buccal films for delivery of clotrimazole: Effect of molecular interactions on drug release and antifungal activity in vitro.

Graphene oxide (GO) is an amphiphilic, high surface area material with great potential as a functional excipient in drug delivery. The present study aimed at incorporating GO in buccal polyelectrolyte films for delivery of antifungal drugs and investigating the effect of GO on the film properties and drug release profiles, as well as antifungal activities. Mucoadhesive excipients chitosan and alginate were selected to form polyelectrolyte films with the antifungal drug clotrimazole. The buccal formulations were prepared by mixing the excipients and clotrimazole via probe sonication, followed by film casting and drying. Inclusion of GO in the formulations increased clotrimazole release from the films in vitro (pH 6.8), possibly due to GO altering the electrostatic interactions between chitosan and alginate. An increase of in vitro activity against Candida albicans was observed when 0.04 wt% GO was added in the formulation containing clotrimazole. However, when the GO amount increased to 0.09 wt%, the films had similar antifungal ability to the films with 0.04 wt% GO, suggesting that the electrostatic and hydrophobic interactions between GO and clotrimazole also affects the antifungal effect of clotrimazole. In summary, GO has a great potential as a functional excipient for delivery of antifungal drugs.

Penetrating Traumatic Brain Injury Triggers Dysregulation of Cathepsin B Protein Levels Independent of Cysteine Protease Activity in Brain and Cerebral Spinal Fluid.

Cathepsin B (CatB), a lysosomal cysteine protease, is important to brain function and may have dual utility as a peripheral biomarker of moderate-severe traumatic brain injury (TBI). The present study determined levels of pro- and mature (mat) CatB protein as well as cysteine protease activity within the frontal cortex (FC; proximal injury site), hippocampus (HC; distal injury site), and cerebral spinal fluid (CSF) collected 1-7 days after craniotomy and penetrating ballistic-like brain injury (PBBI) in rats. Values were compared with naïve controls. Further, the utility of CatB protein as a translational biomarker was determined in CSF derived from patients with severe TBI. Craniotomy increased matCatB levels in the FC and HC, and led to elevation of HC activity at day 7. PBBI caused an even greater elevation in matCatB within the FC and HC within 3-7 days. After PBBI, cysteine protease activity peaked at 3 days in the FC and was elevated at 1 day and 7 days, but not 3 days, in the HC. In rat CSF, proCatB, matCatB, and cysteine protease activity peaked at 3 days after craniotomy and PBBI. Addition of CA-074, a CatB-specific inhibitor, confirmed that protease activity was due to active matCatB in rat brain tissues and CSF at all time-points. In patients, CatB protein was detectable from 6 h through 10 days after TBI. Notably, CatB levels were significantly higher in CSF collected within 3 days after TBI compared with non-TBI controls. Collectively, this work indicates that CatB and its cysteine protease activity may serve as collective molecular signatures of TBI progression that differentially vary within both proximal and distal brain regions. CatB and its protease activity may have utility as a surrogate, translational biomarker of acute-subacute TBI.

Shed-MEDS: pilot of a patient-centered deprescribing framework reduces medications in hospitalized older adults being transferred to inpatient postacute care.

BACKGROUND: Polypharmacy is common in hospitalized older adults. Deprescribing interventions are not well described in the acute-care setting. The objective of this study was to describe a hospital-based, patient-centered deprescribing protocol (Shed-MEDS) and report pilot results. METHODS: This was a pilot study set in one academic medical center in the United States. Participants consisted of a convenience sample of 40 Medicare-eligible, hospitalized patients with at least five prescribed medications. A deprescribing protocol (Shed-MEDS) was implemented among 20 intervention and 20 usual care control patients during their hospital stay. The primary outcome was the total number of medications deprescribed from hospital enrollment. Deprescribed was defined as medication termination or dose reduction. Enrollment medications reflected all prehospital medications and active in-hospital medications. Baseline characteristics and outcomes were compared between the intervention and usual care groups using simple logistic or linear regression for categorical and continuous measures, respectively. RESULTS: There was no significant difference between groups in mean age, sex or Charlson comorbidity index. The intervention and control groups had a comparable number of medications at enrollment, 25.2 (±6.3) and 23.4 (±3.8), respectively. The number of prehospital medications in each group was 13.3 (±4.6) and 15.3 (±4.6), respectively. The Shed-MEDS protocol compared with usual care significantly increased the mean number of deprescribed medications at hospital discharge and reduced the total medication burden by 11.6 versus 9.1 (p = 0.032) medications. The deprescribing intervention was associated with a difference of 4.6 [95% confidence interval (CI) 2.5-6.7, p < 0.001] in deprescribed medications and a 0.5 point reduction (95% CI -0.01 to 1.1) in the drug burden index. CONCLUSIONS: A hospital-based, patient-centered deprescribing intervention is feasible and may reduce the medication burden in older adults.

Potentially Avoidable Readmissions of Patients Discharged to Post-Acute Care: Perspectives of Hospital and Skilled Nursing Facility Staff.

BACKGROUND: Hospital readmissions from skilled nursing facilities (SNFs) are common. Previous research has not examined how assessments of avoidable readmissions differ between hospital and SNF perspectives. OBJECTIVES: To determine the percentage of readmissions from post-acute care that are considered potentially avoidable from hospital and SNF perspectives. DESIGN: Prospective cohort study. SETTING: One academic medical center and 23 SNFs. PARTICIPANTS: We included patients from a quality improvement trial aimed at reducing hospital readmissions among patients discharged to SNFs. We included Medicare patients who were discharged to one of 23 regional SNFs between January 2013 and January 2015, and readmitted to the hospital within 30 days. MEASUREMENTS: Hospital-based physicians and SNF-based staff performed structured root-cause analyses (RCA) on a sample of readmissions from a participating SNF to the index hospital. RCAs reported avoidability and factors contributing to readmissions. RESULTS: The 30-day unplanned readmission rate to the index hospital from SNFs was 14.5% (262 hospital readmissions of 1,808 discharges). Of the readmissions, 120 had RCA from both the hospital and SNF. The percentage of readmissions rated as potentially avoidable was 30.0% and 13.3% according to hospital and SNF staff, respectively. Hospital and SNF ratings of potential avoidability agreed for 73.3% (88 of the 120 readmissions), but readmission factors varied between settings. Diagnostic problems and improved management of changes in conditions were the most common avoidable readmission factors by hospitals and SNFs, respectively. CONCLUSION: A substantial percentage of hospital readmissions from SNFs are rated as potentially avoidable. The ratings and factors underlying avoidability differ between hospital and SNF staff. These data support the need for joint accountability and collaboration for future readmission reduction efforts between hospitals and their SNF partners.

Preventability of Hospital Readmissions From Skilled Nursing Facilities: A Consumer Perspective.

Purpose of the Study: A structured interview was conducted with Medicare patients readmitted to a private, tertiary teaching hospital from skilled nursing facilities (SNFs) to assess their perspectives of readmission preventability and their role in the readmission. Design and Methods: Data were collected at Vanderbilt University Medical Center using a 6-item interview administered at the bedside to Medicare beneficiaries with unplanned hospital readmissions from 23 SNFs within 60 days of a previous hospital discharge. Mixed analytical methods were applied, including a content analysis that evaluated factors contributing to hospital readmission as perceived by consumers. Results: Among 208 attempted interviews, 156 were completed, of which 53 (34%) respondents rated their readmission as preventable. 28.3% of the 53 consumers attributed the readmission to hospital factors, 52.8% attributed it to the SNF, and 18.9% believed both sites could have prevented the readmission. The primary driver of the readmission was a family member/caregiver in 31 cases and the patient in 24 of the 156 cases, amounting to 55 (35.3%) consumer-driven readmissions. Contributing factors included: premature hospital discharge (16.3%); poor discharge planning (16.3%); a clinical issue not resolved in the hospital (14.3%); inadequate treatment at the SNF (69.4%); improper medication management at the SNF (20.4%); and poor decision-making regarding the transfer (14.3%). Conclusions and Implications: Interviewing readmitted patients provides information relevant to reducing readmissions that may otherwise be omitted from hospital and SNF records. Consumers identified quality issues at both the hospital and SNF and perceived themselves as initiating a significant number of readmissions.

Stability of Geriatric Syndromes in Hospitalized Medicare Beneficiaries Discharged to Skilled Nursing Facilities.

OBJECTIVES: To assess multiple geriatric syndromes in a sample of older hospitalized adults discharged to skilled nursing facilities (SNFs) and subsequently to home to determine the prevalence and stability of each geriatric syndrome at the point of these care transitions. DESIGN: Descriptive, prospective study. SETTING: One large university-affiliated hospital and four area SNFs. PARTICIPANTS: Fifty-eight hospitalized Medicare beneficiaries discharged to SNFs (N = 58). MEASUREMENTS: Research personnel conducted standardized assessments of the following geriatric syndromes at hospital discharge and 2 weeks after SNF discharge to home: cognitive impairment, depression, incontinence, unintentional weight loss, loss of appetite, pain, pressure ulcers, history of falls, mobility impairment, and polypharmacy. RESULTS: The average number of geriatric syndromes per participant was 4.4 ± 1.2 at hospital discharge and 3.8 ± 1.5 after SNF discharge. There was low to moderate stability for most syndromes. On average, participants had 2.9 syndromes that persisted across both care settings, 1.4 syndromes that resolved, and 0.7 new syndromes that developed between hospital and SNF discharge. CONCLUSION: Geriatric syndromes were prevalent at the point of each care transition but also reflected significant within-individual variability. These findings suggest that multiple geriatric syndromes present during a hospital stay are not transient and that most syndromes are not resolved before SNF discharge. These results underscore the importance of conducting standardized screening assessments at the point of each care transition and effectively communicating this information to the next provider to support the management of geriatric conditions.

Medications associated with geriatric syndromes and their prevalence in older hospitalized adults discharged to skilled nursing facilities.

BACKGROUND: More than half of the hospitalized older adults discharged to skilled nursing facilities (SNFs) have more than 3 geriatric syndromes. Pharmacotherapy may be contributing to geriatric syndromes in this population. OBJECTIVES: Develop a list of medications associated with geriatric syndromes and describe their prevalence in patients discharged from acute care to SNFs. DESIGN: Literature review and multidisciplinary expert panel discussion, followed by cross-sectional analysis. SETTING: Academic medical center in the United States PARTICIPANTS: One hundred fifty-four hospitalized Medicare beneficiaries discharged to SNFs. MEASUREMENTS: Development of a list of medications that are associated with 6 geriatric syndromes. Prevalence of the medications associated with geriatric syndromes was examined in the hospital discharge sample. RESULTS: A list of 513 medications was developed as potentially contributing to 6 geriatric syndromes: cognitive impairment, delirium, falls, reduced appetite or weight loss, urinary incontinence, and depression. Medications included 18 categories. Antiepileptics were associated with all syndromes, whereas antipsychotics, antidepressants, antiparkinsonism, and opioid agonists were associated with 5 geriatric syndromes. In the prevalence sample, patients were discharged to SNFs with an overall average of 14.0 (±4.7) medications, including an average of 5.9 (±2.2) medications that could contribute to geriatric syndromes, with falls having the most associated medications at discharge at 5.5 (±2.2). CONCLUSIONS: Many commonly prescribed medications are associated with geriatric syndromes. Over 40% of all medications ordered upon discharge to SNFs were associated with geriatric syndromes and could be contributing to the high prevalence of geriatric syndromes experienced by this population. Journal of Hospital Medicine 2016;11:694-700. © 2016 Society of Hospital Medicine.

Geriatric Syndromes in Hospitalized Older Adults Discharged to Skilled Nursing Facilities.

OBJECTIVES: To determine the prevalence, recognition, co-occurrence, and recent onset of geriatric syndromes in individuals transferred from the hospital to a skilled nursing facility (SNF). DESIGN: Quality improvement project. SETTING: Acute care academic medical center and 23 regional partner SNFs. PARTICIPANTS: Medicare beneficiaries hospitalized between January 2013 and April 2014 and referred to SNFs (N = 686). MEASUREMENTS: Project staff measured nine geriatric syndromes: weight loss, lack of appetite, incontinence, and pain (standardized interview); depression (Geriatric Depression Scale); delirium (Brief Confusion Assessment Method); cognitive impairment (Brief Interview for Mental Status); and falls and pressure ulcers (hospital medical record using hospital-implemented screening tools). Estimated prevalence, new-onset prevalence, and common coexisting clusters were determined. The extent to which treating physicians commonly recognized syndromes and communicated them to SNFs in hospital discharge documentation was evaluated. RESULTS: Geriatric syndromes were prevalent in more than 90% of hospitalized adults referred to SNFs; 55% met criteria for three or more coexisting syndromes. The most-prevalent syndromes were falls (39%), incontinence (39%), loss of appetite (37%), and weight loss (33%). In individuals who met criteria for three or more syndromes, the most common triad clusters were nutritional syndromes (weight loss, loss of appetite), incontinence, and depression. Treating hospital physicians commonly did not recognize and document geriatric syndromes in discharge summaries, missing 33% to 95% of syndromes present according to research personnel. CONCLUSION: Geriatric syndromes in hospitalized older adults transferred to SNFs are prevalent and commonly coexist, with the most frequent clusters including nutritional syndromes, depression, and incontinence. Despite the high prevalence, this clinical information is rarely communicated to SNFs on discharge.

Effect of a local anesthetic lozenge in relief of symptoms in burning mouth syndrome.

OBJECTIVE: Patients with burning mouth syndrome (BMS) often represent a clinical challenge as available agents for symptomatic treatment are few and often ineffective. The aim was to evaluate the effect of a bupivacaine lozenge on oral mucosal pain, xerostomia, and taste alterations in patients with BMS. METHODS: Eighteen patients (4 men and 14 women) aged 39-71 years with BMS were included in this randomized, double-blinded, placebo-controlled, crossover trial. Lozenges (containing bupivacaine or placebo) were administrated three times a day for 2 weeks for two separate treatment periods. Assessment of oral mucosal pain, xerostomia, and taste alterations was performed in a patient diary on a visual analog scale (ranging from 0 to 100 mm) before and after the lozenge was dissolved. RESULTS: The bupivacaine lozenge significantly reduced the burning oral pain (P < 0.001), increased the sense of taste disturbances (P < 0.001), and had no impact on xerostomia, when adjusted for the treatment period. CONCLUSIONS: Our results indicate that the bupivacaine lozenge offers a novel therapeutic modality to patients with BMS, although without alleviating effect on the associated symptoms, taste alterations, and xerostomia.

Reproducibility and responsiveness of a Danish Pedi-IKDC subjective knee form for children with knee disorders.

The modified International Knee Documentation Committee Subjective Knee Form (Pedi-IKDC) is a widely used patient-reported tool ranging on a scale from 0 to 100. We aimed to translate Pedi-IKDC into Danish and assess its reproducibility and responsiveness in children with knee disorders. The translation complied with the international guidelines. Reproducibility was assessed in 53 children (15 years) responding Pedi-IKDC at baseline and after 3-14 days. For analysis of responsiveness, 94 children (15 years) responded Pedi-IKDC again after 3 months. Test-retest reliability was excellent. Intraclass correlation coefficient was 0.9, standard error of measurement was 4.1 points, and smallest detectable change (SDC) was 11.3 points. Evaluating responsiveness as a large effect was found in children reporting improvement compared with children reporting deterioration. The change score was correlated to the external anchor Global Rating Scale consisting of 15 answers from -7 "A very great deal worse" to +7 "A very great deal better," with a Spearmen's rho of 0.45 (P > 0.001). The minimal clinically important changes was 12.0. In conclusion, excellent test-retest reproducibility was found at group level, but at individual level the SDC was high. The Pedi-IKDC showed adequate responsiveness and is suitable for assessing improvement or deterioration in children with knee disorders.

Pain and Satisfaction With Pain Management Among Older Patients During the Transition From Acute to Skilled Nursing Care.

PURPOSE: Approximately 20% of hospitalized Medicare beneficiaries are discharged from the hospital to skilled nursing facilities (SNFs); and up to 23% of SNF patients return to the hospital within 30 days of hospital discharge, with pain as one of the most common symptoms precipitating hospital readmission. We sought to examine the prevalence of moderate to severe pain at hospital discharge to SNF, the incidence of new moderate to severe pain (relative to prehospitalization), and satisfaction with pain management among older acute care patients discharged to SNF. DESIGN AND METHODS: Structured patient interviews were conducted with 188 Medicare beneficiaries discharged to 23 area SNFs from an academic medical center. Pain level (0-10) and satisfaction with pain management were assessed upon hospital admission, discharge, and within 1 week after transition to SNF. RESULTS: There was a high prevalence of moderate to severe pain at each time point including prehospital (51%), hospital discharge (38%), and following SNF admission (53%). Twenty-eight percent of participants reported new moderate to severe pain at hospital discharge, whereas 44% reported new moderate to severe pain following SNF admission. Most participants reported being "satisfied" with their pain treatment, even in the context of moderate to severe pain. IMPLICATIONS: Moderate to severe pain is a common problem among hospitalized older adults discharged to SNF and continues during their SNF stay. Pain assessment and management should involve a specific, planned process between hospital and SNF clinicians at the point of care transition, even if patients express "satisfaction" with current pain management.

Cathepsin B is a New Drug Target for Traumatic Brain Injury Therapeutics: Evidence for E64d as a Promising Lead Drug Candidate.

There is currently no therapeutic drug treatment for traumatic brain injury (TBI) despite decades of experimental clinical trials. This may be because the mechanistic pathways for improving TBI outcomes have yet to be identified and exploited. As such, there remains a need to seek out new molecular targets and their drug candidates to find new treatments for TBI. This review presents supporting evidence for cathepsin B, a cysteine protease, as a potentially important drug target for TBI. Cathepsin B expression is greatly up-regulated in TBI animal models, as well as in trauma patients. Importantly, knockout of the cathepsin B gene in TBI mice results in substantial improvements of TBI-caused deficits in behavior, pathology, and biomarkers, as well as improvements in related injury models. During the process of TBI-induced injury, cathepsin B likely escapes the lysosome, its normal subcellular location, into the cytoplasm or extracellular matrix (ECM) where the unleashed proteolytic power causes destruction via necrotic, apoptotic, autophagic, and activated glia-induced cell death, together with ECM breakdown and inflammation. Significantly, chemical inhibitors of cathepsin B are effective for improving deficits in TBI and related injuries including ischemia, cerebral bleeding, cerebral aneurysm, edema, pain, infection, rheumatoid arthritis, epilepsy, Huntington's disease, multiple sclerosis, and Alzheimer's disease. The inhibitor E64d is unique among cathepsin B inhibitors in being the only compound to have demonstrated oral efficacy in a TBI model and prior safe use in man and as such it is an excellent tool compound for preclinical testing and clinical compound development. These data support the conclusion that drug development of cathepsin B inhibitors for TBI treatment should be accelerated.

Otolith shape: a population marker for Atlantic herring Clupea harengus.

Otolith shape variation of seven Atlantic herring Clupea harengus populations from Canada, the Faroe Islands, Iceland, Ireland, Norway and Scotland, U.K., covering a large area of the species' distribution, was studied in order to see if otolith shape can be used to discriminate between populations. The otolith shape was obtained using quantitative shape analysis, transformed with Wavelet and analysed with multivariate methods. Significant differences were detected among the seven populations, which could be traced to three morphological structures in the otoliths. The differentiation in otolith shape between populations was not only correlated with their spawning time, indicating a strong environmental effect, but could also be due to differing life-history strategies. A model based on the shape differences discriminates with 94% accuracy between Icelandic summer spawners and Norwegian spring spawners, which are known to mix at feeding grounds. This study shows that otolith shape could become an accurate marker for C. harengus population discrimination.

Clinical evaluation of the safety and efficacy of 10% imidacloprid + 2.5% moxidectin topical solution for the treatment of ear mite (Otodectes cynotis) infestations in dogs.

A clinical field investigation was conducted to evaluate the safety and efficacy of 10% imidacloprid/2.5% moxidectin for the treatment of ear mites (Otodectes cynotis) in dogs. The study was a multi-centered, blinded, positive controlled, randomized clinical trial conducted under field conditions with privately owned pets. A total of 17 veterinary clinics enrolled cases for the study. An otoscopic examination was performed to confirm the presence of O. cynotis residing in the ear of the dog prior to enrollment. A single-dog household was enrolled in the study if the dog had 5 or more ear mites and an acceptable physical examination. A multi-dog household was eligible if at least one dog in the household had 5 or more mites and all dogs in the household had acceptable physical exams and met the inclusion criteria. Qualified households were randomly assigned to treatments to receive either 10% imidacloprid+2.5% moxidectin topical solution or topical selamectin solution (positive control product) according to a pre-designated enrollment ratio of 2:1, respectively. If more than one dog in a multiple dog household had adequate numbers of ear mites, one dog was randomly selected to represent the household for efficacy evaluation prior to treatment. Treatments were administered twice per label and dose banding directions for each product approximately 28 days apart (Days 0 and 28), by the dog's owner at the study site. All dogs in a household were treated on the same day and with the same product. The owners completed a post-treatment observation form one day after each treatment. Post-treatment otoscopic examinations were performed by the investigators or attending veterinarian on Days 28 and 56. Physical examinations were performed on Days 0 and 56. One hundred and four (104) households were evaluated for efficacy on SD 28, and 102 households were evaluated for efficacy on SD 56. The dogs' ages ranged from 2 months to 16 years. A total of 247 dogs were evaluated for safety. Percent efficacy was based on the percentage of dogs cleared of ear mites. Mite clearance on Day 28 was 71% for the imidacloprid+moxidectin group and 69% for the selamectin group. Mite clearance on Day 56 was 82% for the imidacloprid+moxidectin group and 74% for the selamectin group. No serious adverse events associated with either product were observed during the study. The study demonstrated that 10% imidacloprid+2.5% moxidectin applied using two topical treatments, 28 days apart, was safe and achieved similar efficacy against O. cynotis as selamectin treatments applied and evaluated under the same conditions.

Daytime spikes in dopaminergic activity drive rapid mood-cycling in mice.

Disruptions in circadian rhythms and dopaminergic activity are involved in the pathophysiology of bipolar disorder, though their interaction remains unclear. Moreover, a lack of animal models that display spontaneous cycling between mood states has hindered our mechanistic understanding of mood switching. Here, we find that mice with a mutation in the circadian Clock gene (ClockΔ19) exhibit rapid mood-cycling, with a profound manic-like phenotype emerging during the day following a period of euthymia at night. Mood-cycling coincides with abnormal daytime spikes in ventral tegmental area (VTA) dopaminergic activity, tyrosine hydroxylase (TH) levels and dopamine synthesis. To determine the significance of daytime increases in VTA dopamine activity to manic behaviors, we developed a novel optogenetic stimulation paradigm that produces a sustained increase in dopamine neuronal activity and find that this induces a manic-like behavioral state. Time-dependent dampening of TH activity during the day reverses manic-related behaviors in ClockΔ19 mice. Finally, we show that CLOCK acts as a negative regulator of TH transcription, revealing a novel molecular mechanism underlying cyclic changes in mood-related behavior. Taken together, these studies have identified a mechanistic connection between circadian gene disruption and the precipitation of manic episodes in bipolar disorder.

Conducted vasoreactivity: the dynamical point of view.

Conducted vasodilation is part of the physiological response to increasing metabolic demand of the tissue. Similar responses can be elicited by focal electrical or chemical stimulation. Some evidence suggests an endothelial pathway for nondecremental transmission of hyperpolarizing pulses. However, the underlying mechanisms are debated. Here, we focus on dynamical aspects of the problem hypothesizing the existence of a bistability-powered mechanism for regenerative pulse transmission along the endothelium. Bistability implies that the cell can have two different stable resting potentials and can switch between those states following an appropriate stimulus. Bistability is possible if the current-voltage curve is N shaped instead of monotonically increasing. Specifically, the presence of an inwardly rectifying potassium current may provide the endothelial cell with such properties. We provide a theoretical analysis as well as numerical simulations of both single- and multiunit bistable systems mimicking endothelial cells to investigate the self-consistence and stability of the proposed mechanism. We find that the individual cell may switch readily between two stable potentials. An array of coupled cells, however, as found in the vascular wall, requires a certain adaptation of the membrane currents after a switch, in order to switch back. Although the formulation is generic, we suggest a combination of specific membrane currents that could underlie the phenomenon.