Development and Validation of the Nonalcoholic Fatty Liver Disease Familial Risk Score to Detect Advanced Fibrosis: A Prospective, Multicenter Study.

BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD)-related fibrosis is heritable, but it is unclear how family history may be used to identify first-degree relatives with advanced fibrosis. We aimed to develop and validate a simple risk score to identify first-degree relatives of probands who have undergone assessment of liver fibrosis who are at higher risk of NAFLD with advanced fibrosis. METHODS: This prospective, cross-sectional, familial study consisted of a derivation cohort from San Diego, California, and a validation cohort from Helsinki, Finland. This study included consecutive adult probands (n = 242) with NAFLD and advanced fibrosis, NAFLD without advanced fibrosis, and non-NAFLD, with at least 1 of their first-degree relatives. All included probands and first-degree relatives underwent evaluation of liver fibrosis, the majority by magnetic resonance elastography. RESULTS: A total of 396 first-degree relatives (64% male) were included. The median age and body mass index were 47 years (interquartile range, 32-62 y) and 27.6 kg/m2 (interquartile range, 24.1-32.5 kg/m2), respectively. Age (1 point), type 2 diabetes (1 point), obesity (2 points), and proband with NAFLD and advanced fibrosis (2 points) were predictors of advanced fibrosis among first-degree relatives in the derivation cohort (n = 220) and formed the NAFLD Familial Risk Score. The area under the receiver operator characteristic curve of the NAFLD Familial Risk Score for detecting advanced fibrosis was 0.94 in the validation cohort (n = 176). The NAFLD Familial Risk Score outperformed the Fibrosis-4 index in the validation cohort (area under the receiver operator characteristic curve, 0.94 vs 0.70; P = .02). CONCLUSIONS: The NAFLD Familial Risk Score is a simple and accurate clinical tool to identify advanced fibrosis in first-degree relatives. These data may have implications for surveillance in NAFLD.

HIV self-testing acceptability among injured persons seeking emergency care in Nairobi, Kenya.

BACKGROUND: Emergency department-based HIV self-testing (ED-HIVST) could increase HIV-testing services to high-risk, under-reached populations. OBJECTIVES: This study sought to understand the injury patient acceptability of ED-HIVST. METHODS: Injury patients presenting to the Kenyatta National Hospital Accident and Emergency Department were enrolled from March to May 2021. Likert item data on HIVST assessing domains of general acceptability, personal acceptability, and acceptability to distribute to social and/or sexual networks were collected. Ordinal regression was performed yielding adjusted odds ratios (aOR) to identify characteristics associated with high HIVST acceptability across domains. RESULTS: Of 600 participants, 88.7% were male, and the median age was 29. Half reported having primary care providers (PCPs) and 86.2% reported prior HIV testing. For each Likert item, an average of 63.5% of the participants reported they 'Agree Completely' with positive statements about ED-HIVST in general, for themselves, and for others. In adjusted analysis for general acceptability, those <25 (aOR = 1.67, 95%CI:1.36-2.08) and with prior HIV testing (aOR = 1.68, 95%CI:1.27-2.21) had greater odds of agreeing completely. For personal acceptability, those with a PCP (aOR = 3.31, 95%CI:2.72-4.03) and prior HIV testing (aOR = 1.83, 95%CI:1.41-2.38) had greater odds of agreeing completely. For distribution acceptability, participants with a PCP (aOR = 2.42, 95%CI:2.01-2.92) and prior HIV testing (aOR = 1.79, 95%CI: 1.38-2.33) had greater odds of agreeing completely. CONCLUSIONS: ED-HIVST is perceived as highly acceptable, and young people with prior testing and PCPs had significantly greater favourability. These data provide a foundation for ED-HIVST programme development in Kenya.

Risk of advanced fibrosis in first-degree relatives of patients with nonalcoholic fatty liver disease.

BACKGROUNDA pilot, single-center study showed that first-degree relatives of probands with nonalcoholic fatty liver disease (NAFLD) cirrhosis have a high risk of advanced fibrosis. We aimed to validate these findings using 2 independent cohorts from the US and Europe.METHODSThis prospective study included probands with NAFLD with advanced fibrosis, NAFLD without advanced fibrosis, and non-NAFLD, with at least 1 first-degree relative. A total of 396 first-degree relatives - 220 in a derivation cohort and 176 in a validation cohort - were enrolled in the study, and liver fibrosis was evaluated using magnetic resonance elastography and other noninvasive imaging modalities. The primary outcome was prevalence of advanced fibrosis in first-degree relatives.RESULTSPrevalence of advanced fibrosis in first-degree relatives of probands with NAFLD with advanced fibrosis, NAFLD without advanced fibrosis, and non-NAFLD was 15.6%, 5.9%, and 1.3%, respectively (P = 0.002), in the derivation cohort, and 14.0%, 2.6%, and 1.3%, respectively (P = 0.004), in the validation cohort. In multivariable-adjusted logistic regression models, age of ≥50 years (adjusted OR [aOR]: 2.63, 95% CI 1.0-6.7), male sex (aOR: 3.79, 95% CI 1.6-9.2), diabetes mellitus (aOR: 3.37, 95% CI 1.3-9), and a first-degree relative with NAFLD with advanced fibrosis (aOR: 11.8, 95% CI 2.5-57) were significant predictors of presence of advanced fibrosis (all P < 0.05).CONCLUSIONFirst-degree relatives of probands with NAFLD with advanced fibrosis have significantly increased risk of advanced fibrosis. Routine screening should be done in the first-degree relatives of patients with advanced fibrosis.FUNDINGSupported by NCATS (5UL1TR001442), NIDDK (U01DK061734, U01DK130190, R01DK106419, R01DK121378, R01DK124318, P30DK120515, K23DK119460), NHLBI (P01HL147835), and NIAAA (U01AA029019); Academy of Finland grant 309263; the Novo Nordisk, EVO, and Sigrid Jusélius Foundations; and the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement 777377. This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation program and the EFPIA.

Intestinal microbiota signatures of clinical response and immune-related adverse events in melanoma patients treated with anti-PD-1.

Ample evidence indicates that the gut microbiome is a tumor-extrinsic factor associated with antitumor response to anti-programmed cell death protein-1 (PD-1) therapy, but inconsistencies exist between published microbial signatures associated with clinical outcomes. To resolve this, we evaluated a new melanoma cohort, along with four published datasets. Time-to-event analysis showed that baseline microbiota composition was optimally associated with clinical outcome at approximately 1 year after initiation of treatment. Meta-analysis and other bioinformatic analyses of the combined data show that bacteria associated with favorable response are confined within the Actinobacteria phylum and the Lachnospiraceae/Ruminococcaceae families of Firmicutes. Conversely, Gram-negative bacteria were associated with an inflammatory host intestinal gene signature, increased blood neutrophil-to-lymphocyte ratio, and unfavorable outcome. Two microbial signatures, enriched for Lachnospiraceae spp. and Streptococcaceae spp., were associated with favorable and unfavorable clinical response, respectively, and with distinct immune-related adverse effects. Despite between-cohort heterogeneity, optimized all-minus-one supervised learning algorithms trained on batch-corrected microbiome data consistently predicted outcomes to programmed cell death protein-1 therapy in all cohorts. Gut microbial communities (microbiotypes) with nonuniform geographical distribution were associated with favorable and unfavorable outcomes, contributing to discrepancies between cohorts. Our findings shed new light on the complex interaction between the gut microbiome and response to cancer immunotherapy, providing a roadmap for future studies.

Comparative efficacy of an optimal exam between ultrasound versus abbreviated MRI for HCC screening in NAFLD cirrhosis: A prospective study.

BACKGROUND: Retrospective studies report that visualisation of the liver may be severely limited using ultrasound (US), potentially contributing to diminished sensitivity for detection of hepatocellular carcinoma (HCC) among patients with nonalcoholic fatty liver disease (NAFLD) and cirrhosis, but there are limited prospective data. AIMS: To compare liver visualisation scores prospectively for US and abbreviated hepatobiliary phase (HBP) magnetic resonance imaging (AMRI) in a cohort of participants with NAFLD cirrhosis and a clinical indication for HCC surveillance. METHODS: This prospective multicenter study included 54 consecutive participants (67% women) with NAFLD cirrhosis who underwent contemporaneous US as well as HBP-AMRI with gadoxetic acid. Primary outcome was the proportion of imaging examinations with severe limitations in liver visualisation (visualisation score C) compared head-to-head between US and AMRI. RESULTS: The mean (± standard deviation) age was 63.3 years (±8.4) and body mass index was 32.0 kg/m2 (±6.0). Nineteen participants (35%) had severe visualisation limitations on US, compared with 10 (19%) with AMRI, p < 0.0001. Nine (17%) participants had <90% of the liver visualised on US, compared with only 1 (2%) participant with AMRI, p < 0.0001. Obesity was a strong and independent predictor for severe visualisation limitation on US (OR 5.1, CI 1.1-23.1, p = 0.03), after adjustment for age, sex and ethnicity. CONCLUSION: More than one-third of participants with NAFLD cirrhosis had severe visualisation limitations on US for HCC screening, compared with one-sixth on AMRI. US adequacy should be reported in all clinical studies and when suboptimal then AMRI may be considered for HCC screening.

MEF2 is a key regulator of cognitive potential and confers resilience to neurodegeneration.

Recent increases in human longevity have been accompanied by a rise in the incidence of dementia, highlighting the need to preserve cognitive function in an aging population. A small percentage of individuals with pathological hallmarks of neurodegenerative disease are able to maintain normal cognition. Although the molecular mechanisms that govern this neuroprotection remain unknown, individuals that exhibit cognitive resilience (CgR) represent a unique source of therapeutic insight. For both humans and animal models, living in an enriched, cognitively stimulating environment is the most effective known inducer of CgR. To understand potential drivers of this phenomenon, we began by profiling the molecular changes that arise from environmental enrichment in mice, which led to the identification of MEF2 transcription factors (TFs). We next turned to repositories of human clinical and brain transcriptomic data, where we found that the MEF2 transcriptional network was overrepresented among genes that are most predictive of end-stage cognition. Through single-nucleus RNA sequencing of cortical tissue from resilient and nonresilient individuals, we further confirmed up-regulation of MEF2C in resilient individuals to a subpopulation of excitatory neurons. Last, to determine the causal impact of MEF2 on cognition in the context of neurodegeneration, we overexpressed Mef2a/c in the PS19 mouse model of tauopathy and found that this was sufficient to improve cognitive flexibility and reduce hyperexcitability. Overall, our findings reveal a previously unappreciated role for MEF2 TFs in promoting CgR, highlighting their potential as biomarkers or therapeutic targets for neurodegeneration and healthy aging.

Fecal microbiota transplant overcomes resistance to anti-PD-1 therapy in melanoma patients.

Anti-programmed cell death protein 1 (PD-1) therapy provides long-term clinical benefits to patients with advanced melanoma. The composition of the gut microbiota correlates with anti-PD-1 efficacy in preclinical models and cancer patients. To investigate whether resistance to anti-PD-1 can be overcome by changing the gut microbiota, this clinical trial evaluated the safety and efficacy of responder-derived fecal microbiota transplantation (FMT) together with anti-PD-1 in patients with PD-1-refractory melanoma. This combination was well tolerated, provided clinical benefit in 6 of 15 patients, and induced rapid and durable microbiota perturbation. Responders exhibited increased abundance of taxa that were previously shown to be associated with response to anti-PD-1, increased CD8+ T cell activation, and decreased frequency of interleukin-8-expressing myeloid cells. Responders had distinct proteomic and metabolomic signatures, and transkingdom network analyses confirmed that the gut microbiome regulated these changes. Collectively, our findings show that FMT and anti-PD-1 changed the gut microbiome and reprogrammed the tumor microenvironment to overcome resistance to anti-PD-1 in a subset of PD-1 advanced melanoma.

Health inequalities in timely antenatal care: audit of pre- and post-referral delays in antenatal bookings in London 2015-16.

BACKGROUND: Antenatal booking has potential to reduce infant and maternal health inequalities; yet, those most in need are least likely to access timely care. This audit describes late referral and antenatal booking across London in 2015-16, according to maternal characteristics. METHODS: Referral < 8 weeks' gestation, booking < 2 weeks after referral and booking < 10 weeks' gestation were audited against maternal and referral characteristics. RESULTS: Of 122 275 antenatal bookings, 27.1% were before 10 weeks' gestation and 72.8% by 12 + 6 weeks. Characteristics associated with late booking were living in more deprived areas, age < 20 years, higher parity, Black or Minority ethnicity (particularly Bangladeshi or Black African), birth in Somalia, Jewish religion, first language other than English, unemployment of self or partner, lack of social support, or single parent families. Women living in more deprived areas, with first language other than English, of Jewish religion, Black and Minority ethnicity or who were unemployed, waited longer from referral to booking, despite later referral. CONCLUSIONS: Post-referral delays can compound late referral for some women, exacerbating health inequalities, but should be amenable to provider interventions. Different patterns of pre- and post-referral delay suggest that a tailored approach is needed to address inequalities in access to antenatal care.

Multi-sensory Gamma Stimulation Ameliorates Alzheimer's-Associated Pathology and Improves Cognition.

We previously reported that inducing gamma oscillations with a non-invasive light flicker (gamma entrainment using sensory stimulus or GENUS) impacted pathology in the visual cortex of Alzheimer's disease mouse models. Here, we designed auditory tone stimulation that drove gamma frequency neural activity in auditory cortex (AC) and hippocampal CA1. Seven days of auditory GENUS improved spatial and recognition memory and reduced amyloid in AC and hippocampus of 5XFAD mice. Changes in activation responses were evident in microglia, astrocytes, and vasculature. Auditory GENUS also reduced phosphorylated tau in the P301S tauopathy model. Furthermore, combined auditory and visual GENUS, but not either alone, produced microglial-clustering responses, and decreased amyloid in medial prefrontal cortex. Whole brain analysis using SHIELD revealed widespread reduction of amyloid plaques throughout neocortex after multi-sensory GENUS. Thus, GENUS can be achieved through multiple sensory modalities with wide-ranging effects across multiple brain areas to improve cognitive function.

Inhibition of p25/Cdk5 Attenuates Tauopathy in Mouse and iPSC Models of Frontotemporal Dementia.

Increased p25, a proteolytic fragment of the regulatory subunit p35, is known to induce aberrant activity of cyclin-dependent kinase 5 (Cdk5), which is associated with neurodegenerative disorders, including Alzheimer's disease. Previously, we showed that replacing endogenous p35 with the noncleavable mutant p35 (Δp35) attenuated amyloidosis and improved cognitive function in a familial Alzheimer's disease mouse model. Here, to address the role of p25/Cdk5 in tauopathy, we generated double-transgenic mice by crossing mice overexpressing mutant human tau (P301S) with Δp35KI mice. We observed significant reduction of phosphorylated tau and its seeding activity in the brain of double transgenic mice compared with the P301S mice. Furthermore, synaptic loss and impaired LTP at hippocampal CA3 region of P301S mice were attenuated by blocking p25 generation. To further validate the role of p25/Cdk5 in tauopathy, we used frontotemporal dementia patient-derived induced pluripotent stem cells (iPSCs) carrying the Tau P301L mutation and generated P301L:Δp35KI isogenic iPSC lines using CRISPR/Cas9 genome editing. We created cerebral organoids from the isogenic iPSCs and found that blockade of p25 generation reduced levels of phosphorylated tau and increased expression of synaptophysin. Together, these data demonstrate a crucial role for p25/Cdk5 in mediating tau-associated pathology and suggest that inhibition of this kinase can remedy neurodegenerative processes in the presence of pathogenic tau mutation.SIGNIFICANCE STATEMENT Accumulation of p25 results in aberrant Cdk5 activation and induction of numerous pathological phenotypes, such as neuroinflammation, synaptic loss, Aß accumulation, and tau hyperphosphorylation. However, it was not clear whether p25/Cdk5 activity is necessary for the progression of these pathological changes. We recently developed the Δp35KI transgenic mouse that is deficient in p25 generation and Cdk5 hyperactivation. In this study, we used this mouse model to elucidate the role of p25/Cdk5 in FTD mutant tau-mediated pathology. We also used a frontotemporal dementia patient-derived induced pluripotent stem cell carrying the Tau P301L mutation and generated isogenic lines in which p35 is replaced with noncleavable mutant Δp35. Our data suggest that p25/Cdk5 plays an important role in tauopathy in both mouse and human model systems.

MethyLock: DNA Demethylation Is the Epigenetic Key to Axon Regeneration.

In this issue of Neuron, Weng et al. (2017) reveal a role for active DNA demethylation in allowing axon regeneration to occur in the mature nervous system following axonal injury.

Efficacy of Low-dose (2 millicurie) versus Standard-dose (4 millicurie) Radioiodine Treatment for Cats with Mild-to-Moderate Hyperthyroidism.

BACKGROUND: Radioiodine (131 I) is effective treatment for hyperthyroidism in cats, but optimal dose to restore euthyroidism without inducing hypothyroidism is unclear. Treatment-induced hypothyroidism can lead to azotemia and reduced duration of survival. OBJECTIVE: To compare efficacy and short-term outcomes of low-dose 131 I versus higher, standard-dose 131 I as treatment for hyperthyroidism. ANIMALS: A total of 189 client-owned cats undergoing 131 I treatment for mild-to-moderate hyperthyroidism (serum T4 ≥ 4.0 µg/dL and <13.0 µg/dL). METHODS: Prospective, nonrandomized, cohort study comparing treatment with either low-dose (2 mCi, n = 150) or standard-dose (4 mCi, n = 39) 131 I. Serum T4 , thyroid-stimulating hormone (TSH), and creatinine concentrations were measured after 1, 3, and 6 months to determine persistent hyperthyroidism, overt hypothyroidism (low T4 , high TSH), subclinical hypothyroidism (normal T4 , high TSH), and azotemia. RESULTS: There was no significant difference in prevalence of cats with persistent hyperthyroidism between standard- and low-dose treatment groups at 3 (0% versus 5.3%; P = .34) and 6 (0% versus 3.3%; P = .51) months. Overt (18% versus 1%; P = .0005) or subclinical (46% versus 21%; P = .004) hypothyroidism was more common in cats at 6 months after standard-dose 131 I. No difference in incidence of azotemia existed between groups, but cats treated with standard-dose 131 I had higher creatinine concentrations (P < .05) and higher percent rises in creatinine (P < .0001). CONCLUSIONS AND CLINICAL IMPORTANCE: Low-dose 131 I is safe and effective for cats with mild-to-moderate hyperthyroidism, as evidenced by a cure rate of >95% with reduced frequency of iatrogenic hypothyroidism and azotemia.

Circumstances, Descriptive Characteristics, and Pathologic Findings in Dogs Suspected of Starving.

The authors reviewed the case circumstances, population characteristics, gross, and histopathologic findings in 40 cases of emaciated dogs with a suspected diagnosis of starvation. The dogs' estimated age ranged from 3 months to geriatric. Nineteen breeds were represented, including small-breed (n = 11), large-breed (n = 13), and pit bull-type (n = 16) dogs. The median body condition score was 1 out of 9 (Purina scale). Various diseases were identified as the cause of death in 7 dogs, while the cause of death in the other 33 dogs was starvation due to exogenous causes (SEC). Circumstances associated exclusively with SEC included being found in a vacated residence and death during temperature extremes or severe weather. Dogs with SEC did not differ significantly from diseased dogs in body condition score, sex, neuter status, or breed category (small, large, or pit bull type). Gross findings associated exclusively with SEC included severe hair matting and traumatic injuries. Diseased dogs had an empty stomach significantly more often than SEC dogs, which frequently had food and/or foreign material in the stomach. In 5 of the 7 cases where disease was the cause of death, disease involved the gastrointestinal tract. Gross and histopathologic changes commonly found in SEC and diseased dogs included the following: gross loss of muscle mass and absence of subcuticular fat; serous atrophy of omental, perirenal, epicardial, and bone marrow fat; atrophy of the liver, skin, thyroid gland, and testicle; gastric mucosal petechiae and ecchymoses; melena; and splenic hemosiderophages.

Free thyroxine concentrations by equilibrium dialysis and chemiluminescent immunoassays in 13 hypothyroid dogs positive for thyroglobulin antibody.

OBJECTIVE: To determine if concentrations of free thyroxine (FT4) measured by semi-automated chemiluminescent immunoassay (CLIA) correspond to FT4 determined by equilibrium dialysis (ED) in hypothyroid dogs positive for thyroglobulin antibody (TGA). ANIMALS: Thirteen TGA-positive dogs classified as hypothyroid based on subnormal FT4 concentrations by ED. METHODS: Qualitative assessment of canine TGA was performed using an enzyme-linked immunosorbent assay. Serum total thyroxine and total triiodothyronine concentrations were measured by radioimmunoassay. Serum FT4 concentration was determined by ED, and also by semi-automated CLIA for human FT4 (FT4h) and veterinary FT4 (FT4v). Canine thyroid stimulating hormone concentration was measured by semi-automated CLIA. RESULTS: Each dog's comprehensive thyroid profile supported a diagnosis of hypothyroidism. For detection of hypothyroidism, sensitivities of CLIA for FT4h and FT4v were 62% (95% CI, 32-85%) and 75% (95% CI, 36-96%), respectively, compared to FT4 by ED. Five of 13 (38%) dogs had FT4h and 2 of 8 (25%) dogs had FT4v concentrations by CLIA that were increased or within the reference range. Percentage of false-negative test results for FT4 by CLIA compared to ED was significantly (P < .0001 for FT4h and P < .001for FT4v) higher than the hypothesized false-negative rate of 0%. CONCLUSIONS AND CLINICAL IMPORTANCE: Caution should be exercised in screening dogs for hypothyroidism using FT4 measured by CLIA alone. Some (25-38%) TGA-positive hypothyroid dogs had FT4 concentrations determined by CLIA that did not support a diagnosis of hypothyroidism.

Distinct tau prion strains propagate in cells and mice and define different tauopathies.

Prion-like propagation of tau aggregation might underlie the stereotyped progression of neurodegenerative tauopathies. True prions stably maintain unique conformations ("strains") in vivo that link structure to patterns of pathology. We now find that tau meets this criterion. Stably expressed tau repeat domain indefinitely propagates distinct amyloid conformations in a clonal fashion in culture. Reintroduction of tau from these lines into naive cells reestablishes identical clones. We produced two strains in vitro that induce distinct pathologies in vivo as determined by successive inoculations into three generations of transgenic mice. Immunopurified tau from these mice recreates the original strains in culture. We used the cell system to isolate tau strains from 29 patients with 5 different tauopathies, finding that different diseases are associated with different sets of strains. Tau thus demonstrates essential characteristics of a prion. This might explain the phenotypic diversity of tauopathies and could enable more effective diagnosis and therapy.

Carbon substitution for oxygen in silicates in planetary interiors.

Amorphous silicon oxycarbide polymer-derived ceramics (PDCs), synthesized from organometallic precursors, contain carbon- and silica-rich nanodomains, the latter with extensive substitution of carbon for oxygen, linking Si-centered SiO(x)C(4-x) tetrahedra. Calorimetric studies demonstrated these PDCs to be thermodynamically more stable than a mixture of SiO2, C, and silicon carbide. Here, we show by multinuclear NMR spectroscopy that substitution of C for O is also attained in PDCs with depolymerized silica-rich domains containing lithium, associated with SiO(x)C(4-x) tetrahedra with nonbridging oxygen. We suggest that significant (several percent) substitution of C for O could occur in more complex geological silicate melts/glasses in contact with graphite at moderate pressure and high temperature and may be thermodynamically far more accessible than C for Si substitution. Carbon incorporation will change the local structure and may affect physical properties, such as viscosity. Analogous carbon substitution at grain boundaries, at defect sites, or as equilibrium states in nominally acarbonaceous crystalline silicates, even if present at levels at 10-100 ppm, might form an extensive and hitherto hidden reservoir of carbon in the lower crust and mantle.

TOF-Watch(R) monitor: failure to calculate the train-of-four ratio in the absence of baseline calibration in anaesthetized dogs.

BACKGROUND: TOF-Watch(®) monitors are designed to display train-of-four (TOF) count when neuromuscular block is intense, and to display TOF ratio when it is less intense. In dogs recovering from non-depolarizing neuromuscular block, when all four twitches are easily visible and apparently of similar magnitude, TOF-Watch(®) monitors often display TOF counts and not TOF ratios, as would be expected. We have never encountered this problem when the monitor was calibrated before neuromuscular blocking agent administration. METHODS: Fourteen healthy female dogs undergoing ovariohysterectomy were investigated. Recovery from neuromuscular block was assessed with a calibrated TOF-Watch SX(®) monitor. When the TOF ratio returned to 90%, the TOF-Watch SX(®) was replaced with an uncalibrated TOF-Watch(®) monitor. The output obtained from the uncalibrated TOF-Watch(®) was compared with that of the calibrated device. RESULTS: The median TOF ratio measured by the calibrated TOF-Watch SX(®) unit at recovery was 91 (86-100)% (n=14). The uncalibrated TOF-Watch(®) monitor displayed TOF counts in six dogs [2 (0, 4)] and TOF ratios in the remaining eight dogs [91 (79, 98)%], that is, the uncalibrated device failed to display appropriately >40% of the time. CONCLUSIONS: TOF-Watch(®) monitors must be calibrated before neuromuscular blocking agents are administered to dogs. When these devices are not so calibrated, they default to a reference value for twitch magnitude that was defined in healthy adult people. Even though neuromuscular transmission was restored in these dogs, we surmise that they did not achieve the default reference value, causing the monitor to display TOF counts rather than TOF ratios.

Use of group-randomized trials in pet population research.

Communities invest considerable resources to address the animal welfare and public health concerns resulting from unwanted pet animals. Traditionally, research in this area has enumerated the pet-owning population, described pet population dynamics in individual communities, and estimated national euthanasia figures. Recent research has investigated the human-animal bond and explored the community implications of managed feral cat colonies. These reports have utilized traditional epidemiologic study designs to generate observational data to describe populations and measure associations. However, rigorous scientific evaluations of potential interventions at the group level have been lacking. Group-randomized trials have been used extensively in public health research to evaluate interventions that change a population's behavior, not just the behavior of selected individuals. We briefly describe the strengths and limitations of group-randomized trials as they are used to evaluate interventions that promote social and behavioral changes in the human public health field. We extend these examples to suggest the appropriate application of group-randomized trials for pet population dynamics research.