Effect of gentle stroking and vocalization on behaviour, mucosal immunity and upper respiratory disease in anxious shelter cats

Emotional, behavioural, and health benefits of gentle stroking and vocalizations, otherwise known as gentling, have been documented for several species, but little is known about the effect of gentling on cats in stressful situations. In this study, 139 cats rated as anxious upon admission to an animal shelter were allocated to either a Gentled or Control group. Cats were gentled four times daily for 10min over a period of 10 days, with the aid of a tool for cats that were too aggressive to handle. The cats' mood, or persistent emotional state, was rated daily for 10 d as Anxious, Frustrated or Content. Gentled cats were less likely to have negatively valenced moods (Anxious or Frustrated) than Control cats (Incidence Rate Ratio [IRR]=0.61 CI 0.42-0.88, P=0.007). Total secretory immunoglobulin A (S-IgA) was quantified from faeces by enzyme-linked immunosorbent assay. Gentled cats had increased S-IgA (6.9±0.7logμg/g) compared to Control cats (5.9±0.5logμg/g) (

EFFICACY OF ALIROCUMAB IN 1,191 PATIENTS WITH A WIDE SPECTRUM OF MUTATIONS IN GENES CAUSATIVE FOR FAMILIAL HYPERCHOLESTEROLEMIA

Background Mutation(s) in genes involved in the low-density lipoprotein receptor (LDLR) pathway are typically the underlying cause of familial hypercholesterolemia. Objective The objective of the study was to examine the influence of genotype on treatment responses with alirocumab. Methods Patients from 6 trials (n = 1191, including 758 alirocumab-treated; Clinicaltrials.gov identifiers: NCT01266876; NCT01507831; NCT01623115; NCT01709500; NCT01617655; NCT01709513) were sequenced for mutations in LDLR , apolipoprotein B ( APOB ), proprotein convertase subtilisin/kexin type 9 ( PCSK9 ), LDLR adaptor protein 1, and signal-transducing adaptor protein 1 genes. New mutations were confirmed by Sanger sequencing. Results One or more specific gene mutations were found in 898 patients (75%): 387 and 437 patients had heterozygous LDLR defective and negative mutations, respectively; 46 had a heterozygous APOB -defective mutation; 8 patients had a heterozygous PCSK9 gain-of-function mutation; 293 (25%) had no identifiable mutation in the genes investigated. LDL cholesterol reductions at Week 24 were generally similar across genotypes: 48.3% (n = 131) and 54.3% (n = 89) in LDLR -defective heterozygotes with alirocumab 75 mg Q2W (with possible increase to 150 mg at Week 12) and 150 mg Q2W, respectively; 49.7% (n = 168) and 60.7% (n = 88) in LDLR -negative heterozygotes; 54.1% (n = 20) and 50.1% (n = 6) in APOB -defective heterozygotes; 60.5% (n = 5) and 94.0% (n = 1) in PCSK9 heterozygotes; and 44.9% (n = 85) and 55.4% (n = 69) in patients with no identified mutations. Overall rates of treatment-emergent adverse events were similar for alirocumab vs controls (placebo in 5 trials, ezetimibe control or atorvastatin calibrator arm in 1 trial), with only a higher rate of injection-site reactions with alirocumab. Conclusions In this large patient cohort, individuals with a wide spectrum of mutations in genes underlying familial hypercholesterolemia responded substantially and similarly to alirocumab treatment

Forced Abstinence from Cocaine Self-Administration is Associated with DNA Methylation Changes in Myelin Genes in the Corpus Callosum: a Preliminary Study

Background: Human cocaine abuse is associated with alterations in white matter integrity revealed upon brain imaging, an observation that is recapitulated in an animal model of continuous cocaine exposure. The mechanism through which cocaine may affect white matter is unknown and the present study tested the hypothesis that cocaine self-administration results in changes in DNA methylation that could result in altered expression of several myelin genes that could contribute to the effects of cocaine on white matter integrity. Methods: In the present study, we examined the impact of forced abstinence from cocaine self-administration on chromatin associated changes in white matter. To this end, rats were trained to self-administer cocaine (0.75 mg/kg/0.1 mL infusion) for 14 days followed by forced abstinence for 1 day (n = 6) or 30 days (n = 6) before sacrifice. Drug-free, sham surgery controls (n = 7) were paired with the experimental groups. Global DNA methylation and DNA methylation at specific CpG sites in the promoter regions ofmyelin basic protein (Mbp), proteolipid protein-1 (Plp1), and SRY-related HMG-box-10 (Sox10) genes were analyzed in DNA extracted from corpus callosum. Results: Significant differences in the overall methylation patterns of the Sox10 promoter region were observed in the corpus callosum of rats at 30 days of forced abstinence from cocaine self-administration relative to sham controls; the −189, −142, −93, and −62 CpG sites were significantly hypomethylated point-wise at this time point. After correction for multiple comparisons, no differences in global methylation or the methylation patterns of Mbp or Plp1 were found. Conclusion: Forced abstinence from cocaine self-administration was associated with differences in DNA methylation at specific CpG sites in the promoter region of the Sox10 gene in corpus callosum. These changes may be related to reductions in normal age related changes in DNA methylation and could be a factor in white matter alterations seen after withdrawal from repeated cocaine self-administration. Further research is warranted examining the effects of cocaine on DNA methylation in white matter

Alirocumab efficacy in patients with double heterozygous, compound heterozygous, or homozygous familial hypercholesterolemia

Background Mutations in the genes for the low-density lipoprotein receptor ( LDLR ), apolipoprotein B, and proprotein convertase subtilisin/kexin type 9 have been reported to cause heterozygous and homozygous familial hypercholesterolemia (FH). Objective The objective is to examine the influence of double heterozygous, compound heterozygous, or homozygous mutations underlying FH on the efficacy of alirocumab. Methods Patients from 6 alirocumab trials with elevated low-density lipoprotein cholesterol (LDL-C) and FH diagnosis were sequenced for mutations in the LDLR , apolipoprotein B, proprotein convertase subtilisin/kexin type 9, LDLR adaptor protein 1 ( LDLRAP1 ), and signal-transducing adaptor protein 1 genes. The efficacy of alirocumab was examined in patients who had double heterozygous, compound heterozygous, or homozygous mutations. Results Of 1191 patients sequenced, 20 patients were double heterozygotes (n = 7), compound heterozygotes (n = 10), or homozygotes (n = 3). Mean baseline LDL-C levels were similar between patients treated with alirocumab (n = 11; 198 mg/dL) vs placebo (n = 9; 189 mg/dL). All patients treated with alirocumab 75/150 or 150 mg every 2 weeks had an LDL-C reduction of ≥15% at either week 12 or 24. At week 12, 1 patient had an increase of 7.1% in LDL-C, whereas in others, LDL-C was reduced by 21.7% to 63.9% (corresponding to 39–114 mg/dL absolute reduction from baseline). At week 24, LDL-C was reduced in all patients by 8.8% to 65.1% (10–165 mg/dL absolute reduction from baseline). Alirocumab was generally well tolerated in the 6 trials. Conclusion Clinically meaningful LDL-C–lowering activity was observed in patients receiving alirocumab who were double heterozygous, compound heterozygous, or homozygous for genes that are causative for FH

Interactions between the adducin 2 gene and antihypertensive drug therapies in determining blood pressure in people with hypertension

<p>Abstract</p> <p>Background</p> <p>As part of the NHLBI Family Blood Pressure Program, the Genetic Epidemiology Network of Arteriopathy (GENOA) recruited 575 sibships (n = 1583 individuals) from Rochester, MN who had at least two hypertensive siblings diagnosed before age 60. Linkage analysis identified a region on chromosome 2 that was investigated using 70 single nucleotide polymorphisms (SNPs) typed in 7 positional candidate genes, including adducin 2 (<it>ADD2</it>).</p> <p>Method</p> <p>To investigate whether blood pressure (BP) levels in these hypertensives (n = 1133) were influenced by gene-by-drug interactions, we used cross-validation statistical methods (i.e., estimating a model for predicting BP levels in one subgroup and testing it in a different subgroup). These methods greatly reduced the chance of false positive findings.</p> <p>Results</p> <p>Eight SNPs in <it>ADD2 </it>were significantly associated with systolic BP in untreated hypertensives (p-value < 0.05). Moreover, we also identified SNPs associated with gene-by-drug interactions on systolic BP in drug-treated hypertensives. The TT genotype at SNP rs1541582 was associated with an average systolic BP of 133 mmHg in the beta-blocker subgroup and 148 mmHg in the diuretic subgroup after adjusting for overall mean differences among drug classes.</p> <p>Conclusion</p> <p>Our findings suggest that hypertension candidate gene variation may influence BP responses to specific antihypertensive drug therapies and measurement of genetic variation may assist in identifying subgroups of hypertensive patients who will benefit most from particular antihypertensive drug therapies.</p

The monoclonal antibody combination REGEN-COV protects against SARS-CoV-2 mutational escape in preclinical and human studies.

Monoclonal antibodies against SARS-CoV-2 are a clinically validated therapeutic option against COVID-19. Because rapidly emerging virus mutants are becoming the next major concern in the fight against the global pandemic, it is imperative that these therapeutic treatments provide coverage against circulating variants and do not contribute to development of treatment-induced emergent resistance. To this end, we investigated the sequence diversity of the spike protein and monitored emergence of virus variants in SARS-COV-2 isolates found in COVID-19 patients treated with the two-antibody combination REGEN-COV, as well as in preclinical in vitro studies using single, dual, or triple antibody combinations, and in hamster in vivo studies using REGEN-COV or single monoclonal antibody treatments. Our study demonstrates that the combination of non-competing antibodies in REGEN-COV provides protection against all current SARS-CoV-2 variants of concern/interest and also protects against emergence of new variants and their potential seeding into the population in a clinical setting

Descriptive epidemiology of upper respiratory disease and associated risk factors in cats in an animal shelter in coastal western Canada

We examined 250 cats at an animal shelter in the coastal temperate region of Canada to determine whether age, source, gender, and sterilization status influenced risk of shedding at intake, transmission of infection, and development of clinical upper respiratory disease (URD). On admission, 28% of the cats were positive for 1 or more infectious agent related to URD; 21% were carriers of Mycoplasma felis and 0.05). Viral and bacterial shedding increased by 9% and 11%, respectively, over 3 sampling times (days 1, 4, and 10). Over 40 days after admission, the cumulative probability of developing URD was 2.2 times greater for stray than owner-surrendered cats (P = 0.02) and 0.5 times as great for neutered cats as for intact cats (P = 0.03). Cats that were shedding at intake were 2.6 times more likely to develop URD than were non-carriers (

Corrigendum to “Efficacy of alirocumab in 1191 patients with a wide spectrum of mutations in genes causative for familial hypercholesterolemia” J Clin Lipidol 11 (2017) 1338-1346 (Journal of Clinical Lipidology (2017) 11(6) (1338–1346.e7), (S1933287417304415), (10.1016/j.jacl.2017.08.016))

The authors regret that the row labels for the following data in Table 1 were transposed: ApoB and non-HDL-C; and TG and Lp(a). The authors would like to apologise for any inconvenience caused

A pilot study of the Earable device to measure facial muscle and eye movement tasks among healthy volunteers

The Earable device is a behind-the-ear wearable originally developed to measure cognitive function. Since Earable measures electroencephalography (EEG), electromyography (EMG), and electrooculography (EOG), it may also have the potential to objectively quantify facial muscle and eye movement activities relevant in the assessment of neuromuscular disorders. As an initial step to developing a digital assessment in neuromuscular disorders, a pilot study was conducted to determine whether the Earable device could be utilized to objectively measure facial muscle and eye movements intended to be representative of Performance Outcome Assessments, (PerfOs) with tasks designed to model clinical PerfOs, referred to as mock-PerfO activities. The specific aims of this study were: To determine whether the Earable raw EMG, EOG, and EEG signals could be processed to extract features describing these waveforms; To determine Earable feature data quality, test re-test reliability, and statistical properties; To determine whether features derived from Earable could be used to determine the difference between various facial muscle and eye movement activities; and, To determine what features and feature types are important for mock-PerfO activity level classification. A total of N = 10 healthy volunteers participated in the study. Each study participant performed 16 mock-PerfOs activities, including talking, chewing, swallowing, eye closure, gazing in different directions, puffing cheeks, chewing an apple, and making various facial expressions. Each activity was repeated four times in the morning and four times at night. A total of 161 summary features were extracted from the EEG, EMG, and EOG bio-sensor data. Feature vectors were used as input to machine learning models to classify the mock-PerfO activities, and model performance was evaluated on a held-out test set. Additionally, a convolutional neural network (CNN) was used to classify low-level representations of the raw bio-sensor data for each task, and model performance was correspondingly evaluated and compared directly to feature classification performance. The model’s prediction accuracy on the Earable device’s classification ability was quantitatively assessed. Study results indicate that Earable can potentially quantify different aspects of facial and eye movements and may be used to differentiate mock-PerfO activities. Specially, Earable was found to differentiate talking, chewing, and swallowing tasks from other tasks with observed F1 scores >0.9. While EMG features contribute to classification accuracy for all tasks, EOG features are important for classifying gaze tasks. Finally, we found that analysis with summary features outperformed a CNN for activity classification. We believe Earable may be used to measure cranial muscle activity relevant for neuromuscular disorder assessment. Classification performance of mock-PerfO activities with summary features enables a strategy for detecting disease-specific signals relative to controls, as well as the monitoring of intra-subject treatment responses. Further testing is needed to evaluate the Earable device in clinical populations and clinical development settings. Author summary Many neuromuscular disorders impair function of cranial nerve enervated muscles. Clinical assessment of cranial muscle function has several limitations. Clinician rating of symptoms suffers from inter-rater variation, qualitative or semi-quantitative scoring, and limited ability to capture infrequent or fluctuating symptoms. Patient-reported outcomes are limited by recall bias and poor precision. Current tools to measure orofacial and oculomotor function are cumbersome, difficult to implement, and non-portable. Here, we show how Earable, a wearable device, can discriminate certain cranial muscle activities such as chewing, talking, and swallowing. We demonstrate using data from a pilot study how Earable can be used to measure features from EMG, EEG, and EOG waveforms from subjects wearing the device while performing mock Performance Outcome Assessments (PerfOs), utilized widely in clinical research. Our analysis pipeline provides a framework for how to computationally process and statistically rank features from the Earable device. Our results, conducted in a pilot study of healthy participants, enable a more comprehensive strategy for the design, development, and analysis of wearable sensor data for investigating clinical populations. Understanding how to derive clinically meaningful quantitative metrics from wearable sensor devices is required for the development of novel digital endpoints, a hallmark goal of clinical research