Efficacy and Safety of Sarilumab in Hospitalized Patients With Coronavirus Disease 2019: A Randomized Clinical Trial.

BACKGROUND: Open-label platform trials and a prospective meta-analysis suggest efficacy of anti-interleukin (IL)-6R therapies in hospitalized patients with coronavirus disease 2019 (COVID-19) receiving corticosteroids. This study evaluated the efficacy and safety of sarilumab, an anti-IL-6R monoclonal antibody, in the treatment of hospitalized patients with COVID-19. METHODS: In this adaptive, phase 2/3, randomized, double-blind, placebo-controlled trial, adults hospitalized with COVID-19 received intravenous sarilumab 400 mg or placebo. The phase 3 primary analysis population included patients with critical COVID-19 receiving mechanical ventilation (MV). The primary outcome was proportion of patients with ≥1-point improvement in clinical status from baseline to day 22. RESULTS: There were 457 and 1365 patients randomized and treated in phases 2 and 3, respectively. In phase 3, patients with critical COVID-19 receiving MV (n = 298; 28.2% on corticosteroids), the proportion with ≥1-point improvement in clinical status (alive, not receiving MV) at day 22 was 43.2% for sarilumab and 35.5% for placebo (risk difference, +7.5%; 95% confidence interval [CI], -7.4 to 21.3; P =.3261), a relative risk improvement of 21.7%. In post hoc analyses pooling phase 2 and 3 critical patients receiving MV, the hazard ratio for death for sarilumab vs placebo was 0.76 (95% CI, .51 to 1.13) overall and 0.49 (95% CI, .25 to .94) in patients receiving corticosteroids at baseline. CONCLUSIONS: This study did not establish the efficacy of sarilumab in hospitalized patients with severe/critical COVID-19. Post hoc analyses were consistent with other studies that found a benefit of sarilumab in patients receiving corticosteroids. CLINICAL TRIALS REGISTRATION: NCT04315298.

A Phase 1 study of RO6870810, a novel bromodomain and extra-terminal protein inhibitor, in patients with NUT carcinoma, other solid tumours, or diffuse large B-cell lymphoma.

BACKGROUND: Bromodomain and extra-terminal (BET) proteins are epigenetic readers that can drive carcinogenesis and therapy resistance. RO6870810 is a novel, small-molecule BET inhibitor. METHODS: We conducted a Phase 1 study of RO6870810 administered subcutaneously for 21 or 14 days of 28- or 21-day cycles, respectively, in patients with the nuclear protein of the testis carcinoma (NC), other solid tumours, or diffuse large B-cell lymphoma (DLBCL) with MYC deregulation. RESULTS: Fatigue (42%), decreased appetite (35%) and injection-site erythema (35%) were the most common treatment-related adverse events. Pharmacokinetic parameters demonstrated linearity over the dose range tested and support once-daily dosing. Pharmacodynamic assessments demonstrated sustained decreases in CD11b levels in peripheral blood mononuclear cells. Objective response rates were 25% (2/8), 2% (1/47) and 11% (2/19) for patients with NC, other solid tumours and DLBCL, respectively. Responding tumours had evidence of deregulated MYC expression. CONCLUSIONS: This trial establishes the safety, favourable pharmacokinetics, evidence of target engagement and preliminary single-agent activity of RO6870810. Responses in patients with NC, other solid tumours and DLBCL provide proof-of-principle for BET inhibition in MYC-driven cancers. The results support further exploration of RO6870810 as monotherapy and in combinations. CLINICAL TRIALS REGISTRATION: NCT01987362.

Sex-specific patterns of senescence in Nazca boobies linked to mating system.

Under life-history theories of ageing, increased senescence should follow relatively high reproductive effort. This expectation has rarely been tested against senescence varying between and within the two sexes, although such an approach may clarify the origins of sex-specific ageing in the context of a given mating system. Nazca boobies (Sula granti; a seabird) practise serial monogamy and biparental care. A male-biased population sex ratio results in earlier and more frequent breeding by females. Based on sex-specific reproductive schedules, females were expected to show faster age-related decline for survival and reproduction. Within each sex, high reproductive effort in early life was expected to reduce late-life performance and accelerate senescence. Longitudinal data were used to (a) evaluate the sex specificity of reproductive and actuarial senescence and then (b) test for early-/late-life fitness trade-offs within each sex. Within-sex analyses inform an interpretation of sex differences in senescence based on costs of reproduction. Analyses incorporated individual heterogeneity in breeding performance and cohort-level differences in early-adult environments. Females showed marginally more intense actuarial senescence and stronger age-related declines for fledging success. The opposite pattern (earlier and faster male senescence) was found for breeding probability. Individual reproductive effort in early life positively predicted late-life reproductive performance in both sexes and thus did not support a causal link between early-reproduction/late-life fitness trade-offs and sex differences in ageing. A high-quality diet in early adulthood reduced late-life survival (females) and accelerated senescence for fledging success (males). This study documents clear variation in ageing patterns-by sex, early-adult environment and early-adult reproductive effort-with implications for the role mating systems and early-life environments play in determining ageing patterns. Absent evidence for a disposable soma mechanism, patterns of sex differences in senescence may result from age- and condition-dependent mate choice interacting with this population's male-biased sex ratio and mate rotation.

Randomized controlled trial of danoprevir plus peginterferon alfa-2a and ribavirin in treatment-naïve patients with hepatitis C virus genotype 1 infection.

BACKGROUND & AIMS: The combination of a hepatitis C virus (HCV) protease inhibitor, peginterferon, and ribavirin is the standard of care for patients with HCV genotype 1 infection. We report the efficacy and safety of response-guided therapy with danoprevir (a potent second-generation protease inhibitor), peginterferon alfa-2a (40 KD), and ribavirin in these patients. METHODS: Treatment-naïve patients (N = 237) were randomly assigned to groups given 12 weeks of danoprevir (300 mg every 8 hours; 600 mg every 12 hours, and 900 mg every 12 hours) or placebo plus peginterferon alfa-2a and ribavirin, followed by peginterferon alfa-2a and ribavirin. Patients given danoprevir who had an extended rapid virologic response (eRVR4-20: HCV RNA <15 IU/mL during weeks 4-20) stopped therapy at week 24; those without an eRVR4-20 continued therapy to 48 weeks. Patients who were given placebo received 48 weeks of peginterferon alfa-2a and ribavirin. The primary efficacy end point was sustained virologic response (SVR: HCV RNA <15 IU/mL after 24 weeks without treatment). RESULTS: Rates of SVR were higher among patients given danoprevir 300 mg (68%), 600 mg (85%), and 900 mg (76%) than placebo (42%) (95% confidence interval: 26%-59%). Seventy-nine percent of patients given danoprevir 600 mg had an eRVR4-20; among these, 96% had an SVR. Serious adverse events were reported in 7% to 8% of patients given danoprevir and 19% given placebo. Four patients given danoprevir (1 patient in the 600-mg group and 3 in the 900-mg group) had reversible, grade 4 increases in alanine aminotransferase, which led to early discontinuation of the 900-mg arm of the study. CONCLUSIONS: The combination of danoprevir, peginterferon alfa-2a, and ribavirin leads to high rates of SVR in patients with HCV genotype 1 infection, but high doses of danoprevir can lead to grade 4 increases in alanine aminotransferase. Studies of lower doses of danoprevir with ritonavir, to reduce overall danoprevir exposure while maintaining potent antiviral activity, are underway; Clinicaltrials.gov number, NCT00963885.

Age effects on Nazca booby foraging performance are largely constant across variation in the marine environment: Results from a 5-year study in Galápagos.

Foraging outcomes dictate the nutritional resources available to an organism and may vary with intrinsic factors, like age. Thus, understanding how age affects foraging performance, alone or in interaction with extrinsic factors (like environmental quality), improves our understanding of aging processes in the wild. We examined how foraging traits, measured across five breeding seasons, change with age, environmental variation, and their interaction in Nazca boobies (Sula granti), a pelagic seabird in Galápagos. We evaluated the hypotheses that (1) foraging performance is better in middle-aged birds than in young ones, and that (2) foraging performance is better in middle-aged birds than in old ones. Furthermore, favorable environmental conditions will either (3) attenuate age differences in foraging performance (by relieving constraints on young, inexperienced and old, senescent age classes), or (4) accentuate age differences (if middle-aged birds can exploit abundant resources better than other age classes can). Incubating birds tagged with GPS loggers (N = 815) provided data on foraging performance (e.g., total distance traveled, mass gained) to evaluate interactions between age and environmental variation (e.g., sea surface temperature). Poor environmental conditions associated with the cool phase of the El Niño-Southern Oscillation increased foraging effort, including foraging distance and duration, for example. Across age classes, foraging boobies responded similarly to environmental variation except for female mass gain rate: age-related declines in mass gain rate were reduced under favorable environmental conditions. Birds of different ages also searched in somewhat distinct areas in the poor conditions of 2016, but not in other years. In several foraging traits, including foraging duration and distance, female boobies showed predicted early-life improvement and late-life decline, following the established pattern for reproductive traits in this species. Thus, deficits in resource acquisition (this study) may contribute to the poor survival and reproductive outcomes previously observed in old Nazca boobies, particularly in females.

Los resultados del forrajeo determinan los recursos nutricionales disponibles de un organismo, los cuales pueden variar por factores intrínsecos, como la edad. Por lo tanto, el entendimiento de cómo la edad afecta el rendimiento de forrajeo, sola o en interacción con factores extrínsecos (como la calidad ambiental), mejora nuestro entendimiento de los procesos del envejecimiento en la naturaleza. Nosotros examinamos como las características de forrajeo, a lo largo de cinco temporadas reproductivas, cambian con la edad, la variabilidad ambiental y sus interacciones en el Piquero de Nazca (Sula granti), un ave marina pelágica en las Islas Galápagos. Evaluamos las hipótesis que (1) el desempeño de búsqueda de alimentación es mejor en aves adultas que en las jóvenes, y que (2) este desempeño es mejor en aves adultas que en las viejas. Además, las condiciones ambientales favorables (3) atenuaran las diferencias de edades en el rendimiento de forrajeo (aliviando las restricciones en los jóvenes, inexpertos, y viejos), o (4) acentuaran las diferencias de edad (sí los adultos pueden explotar recursos abundantes de mejor forma que otros grupos etarios). Colocamos dispositivos GPS en aves incubadoras (N = 815), para colectar datos sobre el rendimiento del forrajeo (p. ej. distancia total de viaje, incremento de peso) para evaluar las interacciones entre edad y la variación ambiental (p. ej. temperatura superficial del mar). Las condiciones ambientales adversas relacionadas a la fase fría de El Niño Oscilación del Sur incrementaron el esfuerzo de forrajeo (la distancia de forrajeo y su duración, por ejemplo). En todos los grupos etarios, los piqueros respondieron de forma similar a la variación ambiental, excepto la tasa de ganancia de peso de las hembras. Las reducciones relacionadas a la edad en la tasa de ganancia de peso fueron menores durante condiciones ambientales favorables. Las aves de diferentes grupos etarios buscaron alimento en zonas levemente diferentes durante las condiciones adversas de 2016, pero no en otros años. En varias características de forrajeo, incluyendo la duración y la distancia, las hembras mostraron un esperado mejoramiento en los primeros años y un declive en su vida tardía, mostrando el patrón establecido en rasgos reproductivos en esta especie. Por lo tanto, el déficit en la adquisición de recursos (este estudio), puede contribuir a la reducida supervivencia y los resultados reproductivos previamente observados en piqueros de Nazca viejos, especialmente en las hembras.

Breeding responses to environmental variation are age- and trait-dependent in female Nazca boobies.

Age and environment are important determinants of reproductive parameters in long-lived organisms. These factors may interact to determine breeding responses to environmental change, yet few studies have examined the environmental dependence of aging patterns across the entire life span. We do so, using a 20-yr longitudinal data set of reproductive phenotypes in long-lived female Nazca boobies (Sula granti), a monogamous seabird breeding in the eastern tropical Pacific. Young and old females may suffer from inexperience and senescence, respectively, and/or practice reproductive restraint. Breeding performance (for breeding participation, breeding date, clutch size, egg volume, and offspring production) was expected to be lower in these age classes, particularly under environmental challenge, in comparison with middle-aged breeders. Sea surface temperature anomalies (SSTA) represented interannual variation in the El Niño-Southern Oscillation (ENSO) and were one proxy for environmental quality (a population count of clutch initiations was a second). Although only females lay eggs, both sexes care for eggs and nestlings, and the male partner's age, alone or in interaction with female age, was evaluated as a predictor of breeding performance. Middle-aged females performed better than young and old birds for all reproductive traits. Pairing with a young male delayed breeding (particularly for old females) and reduced clutch size, and pairing with an old male reduced offspring production. Challenging environments increased age effects on breeding probability and breeding date across young to middle ages and for offspring production across middle to old ages. However, important exceptions to the predicted patterns for clutch size and fledging success across young to middle ages suggested that trade-offs between fitness components may complicate patterns of trait expression across the life span. Relationships between breeding participation, environment, and individual quality and/or experience in young females may also contribute to unexpected patterns for clutch size and fledging success, traits expressed only in breeders. Finally, independent of age, breeding responses of female Nazca boobies to the ENSO did not follow expectations derived from oceanic forcing of primary productivity. During El Niño-like conditions, egg-laying traits (clutch size, breeding date) improved, but offspring production declined, whereas La Niña-like conditions were "poor" environments throughout the breeding cycle.

Effects of age, sex, and ENSO phase on foraging and flight performance in Nazca boobies.

Age-related changes in survival and reproduction are common in seabirds; however, the underlying causes remain elusive. A lack of experience for young individuals, and a decline in foraging performance for old birds, could underlie age-related variation in reproduction because reproductive success is connected closely to provisioning offspring. For seabirds, flapping flight during foraging trips is physiologically costly; inexperience or senescent decline in performance of this demanding activity might cap delivery of food to the nest, providing a proximate explanation for poor breeding success in young and old age, respectively. We evaluated the hypothesis that young and old Nazca boobies (Sula granti), a Galápagos seabird, demonstrate deficits in foraging outcomes and flight performance. We tagged incubating male and female adults across the life span with both accelerometer and GPS loggers during the incubation periods of two breeding seasons (years), during the 2015 El Niño and the following weak La Niña. We tested the ability of age, sex, and environment to explain variation in foraging outcomes (e.g., mass gained) and flight variables (e.g., wingbeat frequency). Consistent with senescence, old birds gained less mass while foraging than middle-aged individuals, a marginal effect, and achieved a slower airspeed late in a foraging trip. Contrary to expectations, young birds showed no deficit in foraging outcomes or flight performance, except for airspeed (contingent on environment). Young birds flew slower than middle-aged birds in 2015, but faster than middle-aged birds in 2016. Wingbeat frequency, flap-glide ratio, and body displacement (approximating wingbeat strength) failed to predict airspeed and were unaffected by age. Sex influenced nearly all aspects of performance. Environment affected flight performance and foraging outcomes. Boobies' foraging outcomes were better during the extreme 2015 El Niño than during the 2016 weak La Niña, a surprising result given the negative effects tropical seabirds often experience during extreme El Niños.

Phase 1b study of the BET protein inhibitor RO6870810 with venetoclax and rituximab in patients with diffuse large B-cell lymphoma.

Bromodomain and extraterminal (BET) proteins are transcriptional activators for multiple oncogenic processes in diffuse large B-cell lymphoma (DLBCL), including MYC, BCL2, E2F, and toll-like receptor signaling. We report results of a phase 1b dose-escalation study of the novel, subcutaneous BET inhibitor RO6870810 (RO) combined with the BCL-2 inhibitor venetoclax, and rituximab, in recurrent/refractory DLBCL. RO was delivered for 14 days of a 21-day cycle, whereas venetoclax was delivered continuously. A 3 + 3 escalation design was used to determine the safety of the RO+venetoclax doublet; rituximab was added in later cohorts. Thirty-nine patients were treated with a median of 2.8 cycles (range, 1-11). Dose-limiting toxicities included grade 3 febrile neutropenia, grade 4 diarrhea, and hypomagnesemia for the doublet; and grade 3 hyperbilirubinemia and grade 4 diarrhea when rituximab was added. The doublet maximum tolerated dose (MTD) was determined to be 0.65 mg/kg RO+600 mg venetoclax; for RO+venetoclax+rituximab, the MTDs were 0.45 mg/kg, 600 mg, and 375 mg/m2, respectively. The most frequent grade 3 and 4 adverse events were neutropenia (28%) and anemia and thrombocytopenia (23% each). Responses were seen in all cohorts and molecular subtypes. Sustained decreases in CD11b on monocytes indicated pharmacodynamic activity of RO. Overall response rate according to modified Lugano criteria was 38.5%; 48% of responses lasted for ≥180 days. Complete response was observed in 8 patients (20.5%). Optimization of the treatment schedule and a better understanding of predictors of response would be needed to support broader clinical use. This trial is registered on www.clinicaltrials.gov as NCT03255096.

Safety and efficacy of a double-boosted protease inhibitor combination, saquinavir and lopinavir/ritonavir, in pretreated children at 96 weeks.

BACKGROUND: This study aimed to assess the long-term efficacy, safety and use of therapeutic drug monitoring (TDM) of a double-boosted protease inhibitor (PI) combination, saquinavir (SQV) and lopinavir/ritonavir (LPV/r), in Thai HIV type-1 (HIV-1)-infected children who had failed on reverse transcriptase inhibitors. METHODS: In total, 50 children from two sites in Thailand were treated with standard dosing of SQV and LPV/r. CD4(+) T-cell count and percentage, viral load (VL; HIV-1 RNA), minimum plasma drug concentrations (C(min)) and drug safety laboratory evaluations were monitored. Virological failure was defined as having two consecutive VL measures >400 copies/ml after week 12. An intention-to-treat analysis was performed. RESULTS: Baseline data were a median age of 9.3 years (interquartile range [IQR] 7.1-11.2), VL 4.8 log(10) copies/ml (IQR 4.5-5.1) and CD4(+) T-cell percentage 7% (IQR 3.0-9.5). CDC classifications were N=4%, A=14%, B=68% and C=14% of participants. Median CD4(+) T-cell percentage and CD4(+) T-cell count increase were 14% (IQR 7-19) and 558 cells/mm(3) (IQR 308-782), respectively (both P<0.001). Overall, 37 (74%) children achieved VL<50 copies/ml with significant differences between sites (90% versus 63%). Over 96 weeks, 10 patients had virological failure. Total cholesterol and high-density lipoprotein increased significantly over time, whereas the triglycerides and low-density lipoprotein did not. Approximately 50% of participants reported no change in body shape, and 33%, 43% and 39% reported fatter arms, face and abdomen, respectively. LPV and SQV C(min) were high and stable over time. CONCLUSIONS: Double-boosted SQV+LPV/r was an effective and safe alternative for a second-line regimen in children. Hypercholesterolaemia needs close follow-up. On the basis of the TDM results, PI dose reduction in this population should be considered.

Adherence to enfuvirtide and its impact on treatment efficacy.

High adherence rates to antiretroviral (ARV) therapy are associated with increased durability of viral suppression and decreased rates of drug resistance. The requirement of twice-daily subcutaneous self-administration of enfuvirtide (ENF) has raised concerns about adherence. This study assesses adherence to ENF and an optimized background (OB) of ARVs and its impact on virological and immunological responses during the TORO trials. Eighty-eight percent of patients in the OB arm reported > or = 85% adherence versus 87% of patients in the ENF + OB arm. Higher overall adherence was associated with improved virological and immunological response in both treatment arms at 48 weeks. In patients with > or = 85% adherence, 33% of patients in the ENF + OB arm achieved HIV-1 RNA < 400 copies/ml, versus 13% in the OB arm (p < 0.0001). Similarly, patients with > or = 85% adherence in the ENF + OB arm achieved a mean increase in CD4 cell count of 104 cells/mm(3) compared with 58 cells/mm(3) for patients in the OB arm (p < 0.001). None of the demographic factors explored (age, gender, race) or baseline characteristics (CD4 count, viral load, or baseline sensitivity score) was significant in predicting adherence to ENF when analyzed by multiple regression. Importantly, a history of intravenous drug use (IDU) was not associated with a significant decrease in adherence (mean adherence for IDU 96% versus mean adherence for non-IDU 96%; p = 0.825). Adherence was high in patients receiving the self-injectable ARV enfuvirtide. In addition, the inclusion of ENF did not negatively impact adherence to the ARV regimen as a whole.

Efficacy and safety of 48 weeks of enfuvirtide 180 mg once-daily dosing versus 90 mg twice-daily dosing in HIV-infected patients.

PURPOSE: To evaluate the safety and antiviral activity of once-daily (qd) enfuvirtide (ENF) compared with twice daily (bid) ENF. METHOD: T20-401 was a phase 2, open-label, randomized, 48-week pilot study comparing ENF 180 mg qd versus ENF 90 mg bid, added to an optimized background (OB) regimen. Patients were randomized 1:1 to receive ENF 180 mg qd given as two 90-mg injections (n = 30) or one 90-mg injection bid (n = 31), plus OB. The primary efficacy endpoint was the proportion of patients achieving a HIV-1 RNA viral load <400 copies/mL. Adherence, pharmacokinetics, safety, and tolerability parameters, including injection site reactions (ISRs), were compared between treatment arms. RESULTS: At Week 48, 23.3% of patients on once daily versus 22.6% on twice daily (p = .969) reached <400 copies/mL and 13.3% and 22.6% (p = .323), respectively, reached <50 copies/mL. The proportion reporting 1 adverse event or ISRs was comparable between arms, despite an increased incidence of grade 4 erythema (13% vs. 0%), induration (33% vs. 12%), and ecchymosis (7% vs. 0%) on twice daily versus once daily. ENF adherence (95% of prescribed doses) was higher on once daily (80.0%) versus twice daily (58.1%). CONCLUSION: The antiviral efficacy, safety, and tolerability of 180 mg ENF qd appeared comparable with that of 90 mg ENF bid at Week 48, although the study was not powered to demonstrate the noninferiority of once daily versus twice daily.

Decadal-scale variation in diet forecasts persistently poor breeding under ocean warming in a tropical seabird.

Climate change effects on population dynamics of natural populations are well documented at higher latitudes, where relatively rapid warming illuminates cause-effect relationships, but not in the tropics and especially the marine tropics, where warming has been slow. Here we forecast the indirect effect of ocean warming on a top predator, Nazca boobies in the equatorial Galápagos Islands, where rising water temperature is expected to exceed the upper thermal tolerance of a key prey item in the future, severely reducing its availability within the boobies' foraging envelope. From 1983 to 1997 boobies ate mostly sardines, a densely aggregated, highly nutritious food. From 1997 until the present, flying fish, a lower quality food, replaced sardines. Breeding success under the poor diet fell dramatically, causing the population growth rate to fall below 1, indicating a shrinking population. Population growth may not recover: rapid future warming is predicted around Galápagos, usually exceeding the upper lethal temperature and maximum spawning temperature of sardines within 100 years, displacing them permanently from the boobies' island-constrained foraging range. This provides rare evidence of the effect of ocean warming on a tropical marine vertebrate.

Avian Pox Discovered in the Critically Endangered Waved Albatross (Phoebastria irrorata) from the Galápagos Islands, Ecuador.

The Waved Albatross (Phoebastria irrorata) is a critically endangered seabird in a rapidly shrinking population in the Galápagos Islands, Ecuador. The introduction of novel pathogens and parasites poses a threat to population persistence. Monitoring disease prevalence and guarding against the spread of such agents in endemic taxa are conservation priorities for the Galápagos, where recent increases in the prevalence of avian pox may have contributed to population declines and range contractions in other bird species. During November 2013-January 2014, we identified 14 Waved Albatross nestlings at our study site on Española Island with avian pox-like lesions and clinical signs. Other seabirds, landbirds, and adult Waved Albatrosses were apparently unaffected. Histopathology of tissue samples from five infected nestlings revealed inclusion bodies in all samples, consistent with avipoxvirus infection. We documented higher mortality (6 of 14 nestlings) in affected nestlings than in unaffected young in this small outbreak of avian pox, the first report of its kind in the world's only tropical albatross.

Arts, Science, Engineering and Medicine Collaborate to Educate Public on Bioenergetics.

Mitochondrial dysfunction has correlated with a rise in energy deficiency disorders (EDD). The EDDs include mitochondrial disorders, obesity, metabolic disorders, cardiovascular and neurodegenerative disorders. Many individuals in our communities are at high risk of developing these disorders, yet are unaware of it. Our goal was to increase public awareness of mitochondrial health, whilst providing students with an innovative educational experience. We designed a 'Bioenergetics exhibition' by introducing Arts into traditional STEM (Science, Technology, Engineering & Mathematics) disciplines to create a new STEAM-(Health) initiative. Results indicated ~120,000 guests visited the exhibition, including many school-aged children, teachers and families. Comparative analysis of random first-time vs. repeat visitor surveys demonstrated a statistically significant (8.25% at p-value = 0.006) increase in knowledge of mitochondrial disease and bioenergetics. Our findings clearly support the power of the STEAM-H initiative in creatively communicating the complex science to a broader community.

Acquired tricuspid valve stenosis associated with two ventricular endocardial pacing leads in a dog.

Acquired tricuspid valve stenosis (TVS) is a rare complication of endocardial pacing lead implantation in humans that has only been described once previously in the veterinary literature in a dog with excessive lead redundancy. A 12 yr old terrier presented with right-sided congestive heart failure 6 mo after implantation of a second ventricular endocardial pacing lead. The second lead was placed due to malfunction of the first lead, which demonstrated abnormally low impedance. Transthoracic echocardiography identified hyperechoic tissue associated with the pacing leads as they crossed the tricuspid valve annulus as well as a stenotic tricuspid inflow pattern via spectral Doppler interrogation. Medical management was ultimately unsuccessful and the dog was euthanized 6 wk after TVS was diagnosed. The authors report the first canine case of acquired TVS associated with two ventricular endocardial pacing leads.

Yawning, acute stressors, and arousal reduction in Nazca booby adults and nestlings.

Yawning is a familiar and phylogenetically widespread phenomenon, but no consensus exists regarding its functional significance. We tested the hypothesis that yawning communicates to others a transition from a state of physiological and/or psychological arousal (for example, due to action of a stressor) to a more relaxed state. This arousal reduction hypothesis predicts little yawning during arousal and more yawning (above baseline) during and after down-regulation of arousal. Experimental capture-restraint tests with wild adult Nazca boobies (Sula granti), a seabird, increased yawning frequency after release from restraint, but yawning was almost absent during tests. Natural maltreatment by non-parental adults also increased yawning by nestlings, but only after the maltreatment ended and the adult left. CORT (corticosterone) was a logical a priori element of the stress response affecting the stressor-yawning relationship under the arousal reduction hypothesis, and cannot be excluded as such for adults in capture-restraint tests but is apparently unimportant for nestlings being maltreated by adults. The arousal reduction hypothesis unites formerly disparate results on yawning: its socially contagious nature in some taxa, its clear pharmacological connection to the stress response, and its temporal linkage to transitions in arousal between consciousness and sleep.

Left atrial rupture secondary to myxomatous mitral valve disease in 11 dogs.

The purpose of this retrospective study was to evaluate the long-term outcome in dogs with left atrial rupture secondary to myxomatous mitral valve disease. Eleven client-owned dogs met the inclusion criteria for the study. Median age was 11.6 yr (range, 8.3-17.8 yr), and median weight was 5.8 kg (range, 3.8-15.2 kg). Of the 11 dogs, 10 survived the initial 24 hr after diagnosis and 5 of the dogs were still alive at the conclusion of data collection. The median survival of all dogs was 203 days. Dogs with no previous history of congestive heart failure (CHF) at the time of diagnosis had a significantly longer median survival time (345 days) compared with dogs with a previous history of CHF (160 days, P = 0.0038). Outcome of dogs with myxomatous mitral valve disease presenting with left atria rupture was more favorable than previously reported, and dogs without previous CHF survived the longest.

Methicillin-resistant Staphylococcus infections.

Methicillin-resistant Staphylococcus aureus infection is currently the most common skin infection identified in human emergency rooms, and the development of methicillin resistance is increasing in veterinary medicine. This article reviews the current knowledge about methicillin-resistant Staphylococcus infections in human medicine as well as the limited information available in veterinary medicine, including options for diagnosis, treatment, and prevention.

Nosocomial infections.

Nosocomial infections (NIs) are infections acquired during hospitalization. They are characterized by a high incidence of antimicrobial resistance. The most common NIs are pneumonia and urinary tract, surgical site, and bloodstream infections. Hand hygiene has demonstrated efficacy in reducing NIs.

Therapeutic options for immune-mediated thrombocytopenia.

OBJECTIVE: To review the therapeutic options for immune-mediated thrombocytopenia (IMT). DATA SOURCES: Original research publications and review articles using the PubMed search engine for the phrases "immune-mediated thrombocytopenia" or "immune thrombocytopenic purpura" or "immune thormbocytopenia." VETERINARY AND HUMAN DATA SYNTHESIS: There are a number of therapeutic options for adult-onset immune thrombocytopenia in human medicine with demonstrated efficacy in clinical studies although corticosteroids and immunoglobulin therapy remain the first-line medical treatments. Thrombopoietin receptor agonist therapy and, to a lesser extent, rituximab have shown great promise in initial clinical trials and may become standard of care in human medicine for the management of IMT. Therapeutic options in veterinary medicine are less diverse and only vincristine and human intravenous immunoglobulin therapies have been evaluated in controlled clinical studies. CONCLUSIONS: There are a number of therapeutic options in the management of IMT veterinary medicine, most of which have not been investigated in clinical studies. Further research is warranted to best identify the optimal treatment strategy for IMT in veterinary patients.