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Min Yang,1 Jingdong Chao,2 Mirko Fillbrunn,1 Usha G Mallya,3 Min-Jung Wang,1 Leigh Franke,1 Lauren Cohn,4,5 Siddhesh Kamat2 1Analysis Group, Inc, Boston, MA, USA; 2Regeneron Pharmaceuticals, Inc, Tarrytown, NY, USA; 3Sanofi, Boston, MA, USA; 4Section of Pulmonary, Critical Care and Sleep Medicine, Yale School of Medicine, New Haven, CT, USA; 5VA Connecticut Healthcare System, West Haven, CT, USACorrespondence: Min Yang, Analysis Group, Inc, 111 Huntington Avenue, Fourteenth Floor, Boston, MA, 02199, USA, Tel +1-617-425-8487, Fax +1-617-425-8001, Email Min.Yang@analysisgroup.comPurpose: Multiple biologics are available for moderate to severe asthma. Given the important relationship between patient engagement in healthcare decision-making and health outcomes, patient preference is an increasingly important consideration. This study elicited patients’ preferences for attributes of biologic therapies for moderate to severe asthma.Patient and Methods: A discrete choice experiment (DCE) questionnaire was designed to collect data from an existing survey panel of adults with moderate to severe asthma in the United States. Patients were asked to select their preferred hypothetical treatment from profiles with varying attributes related to efficacy, safety, and administration convenience. Conditional logit regression models were used to quantify patient preferences.Results: Of 301 eligible patients who completed the survey, the mean age was 46.7± 15.1 years and 71.8% were female. Patients had asthma for 22.5± 16.3 years on average, and most (97.3%) had experienced ≥ 1 asthma attack in the past 12 months. Among treatment attributes examined, patients most valued the absence of a black box warning for the risk of a life-threatening allergic reaction, effectiveness of reducing severe asthma exacerbations, and improvement in lung function (all p < 0.001). Home administration setting for subcutaneous injections (vs doctor’s office/clinic) (p = 0.009) and ability of a biologic to treat additional chronic condition(s) (p < 0.05) were also considered important. Dosing frequency and type of injection device were not significant factors.Conclusion: Patients with moderate to severe asthma valued efficacy and safety over convenience attributes when selecting biologic treatments. Awareness of these preferences can facilitate patient-physician shared decision-making when managing moderate to severe asthma in clinical practice.Keywords: asthma, patient preference, biologic, treatment

Julius I Ejiofor, Lawrence Cohn,† Tsuyoshi Kaneko Division of Cardiac Surgery, Brigham and Women’s Hospital, Boston, MA, USA †Lawrence Cohn passed away on January 9, 2016 Abstract: Since the first mitral valvuloplasty in 1923, the technique of mitral valvuloplasty has matured over the years and now has become the first-line treatment, especially in patients with myxomatous mitral regurgitation (MR). We have highlighted some of the major problems that are encountered with the various etiologies of MR. We believe that repair is always the optimal surgical procedure for any of the above etiologies if it is consistent with a long-term result. However, replacement has shown to be a safer procedure in some instances such as severe functional MR or destructive endocarditis. Keywords: mitral regurgitation, mitral valvuloplasty, systolic anterior motion, functional mitral regurgitation, rheumatic valve disease

Background: A higher prevalence of methicillin-resistant Staphylococcus aureus (MRSA) colonization is reported in healthcare workers compared with nonhealthcare workers. Hypothesis: The prevalence of MRSA colonization differed in people and pets in households with healthcare workers as compared with households without healthcare workers. Subjects: A person and 1 dog or cat from 586 households defined as either a nonhealthcare (n = 213), veterinary healthcare (n = 211), or human healthcare (n = 162) worker household. Methods: Prospective cross-sectional study. Samples from humans and pets were cultured in vitro. Staphylococcus aureus was identified as methicillin sensitive (MSSA) or MRSA with mecA polymerase chain reaction. Pulsed-field gel electrophoresis and spa-typing were used to characterize relatedness of S. aureus and MRSA and assign USA types. Results: The prevalence of MSSA and MRSA in humans was 21.5% (126/586) and 5.63% (33/586), respectively, and 7.85% (46/586) and 3.41% (20/586), respectively, in pets. There were no differences in prevalences of either MSSA or MRSA between household types. The proportion of MRSA among all S. aureus isolates in humans and pets was 20.8% (33/159) and 30.3% (20/66), respectively. In <1.0% (4/586) of households, the same strain of MRSA was found in both a person and a pet. Conclusions and Clinical Importance: There were no differences in the prevalences of MSSA or MRSA between healthcare worker and nonhealthcare worker households. Pets and people colonized with S. aureus were as likely to be colonized with MRSA. Colonization of a person and their pet with the same strain of MRSA was rare. [ABSTRACT FROM AUTHOR]

Defects in nuclear morphology often correlate with the onset of disease, including cancer, progeria, cardiomyopathy, and muscular dystrophy. However, the mechanism by which a cell controls its nuclear shape is unknown. Here, we use adhesive micropatterned surfaces to control the overall shape of fibroblasts and find that the shape of the nucleus is tightly regulated by the underlying cell adhesion geometry. We found that this regulation occurs through a dome-like actin cap that covers the top of the nucleus. This cap is composed of contractile actin filament bundles containing phosphorylated myosin, which form a highly organized, dynamic, and oriented structure in a wide variety of cells. The perinuclear actin cap is specifically disorganized or eliminated by inhibition of actomyosin contractility and rupture of the LINC complexes, which connect the nucleus to the actin cap. The organization of this actin cap and its nuclear shape-determining function are disrupted in cells from mouse models of accelerated aging (progeria) and muscular dystrophy with distorted nuclei caused by alterations of A-type lamins. These results highlight the interplay between cell shape, nuclear shape, and cell adhesion mediated by the perinuclear actin cap. [ABSTRACT FROM AUTHOR]

Cognitive decline in Alzheimer's disease (AD) involves pathological accumulation of synaptotoxic amyloid-β (Aβ) oligomers and hyperphosphorylated tau. Because recent evidence indicates that glycogen synthase kinase 3β (GSK3β) activity regulates these neurotoxic pathways, we developed an AD therapeutic strategy to target GSK3β. The strategy involves the use of copper-bis(thiosemicarbazonoto) complexes to increase intracellular copper bioavailability and inhibit GSK3β through activation of an Akt signaling pathway. Our lead compound Cu[supII](gtsm) significantly inhibited GSK3β in the brains of APP/PSi transgenic AD model mice. Cu[supII](gtsm) also decreased the abundance of Aβ trimers and phosphorylated tau, and restored performance of AD mice in the Y-maze test to levels expected for cognitively normal animals. Improvement in the Y-maze correlated directly with decreased Aβ trimer levels. This study demonstrates that increasing intracellular copper bioavailability can restore cognitive function by inhibiting the accumulation of neurotoxic Aβ trimers and phosphorylated tau. [ABSTRACT FROM AUTHOR]

Background: Inhaled glucocorticoids reduce airway inflammation while minimizing systemic effects in several species. Hypothesis: Inhaled fluticasone suppresses the hypothalamic–pituitary–adrenal axis (HPAA), modifies immune function, and induces clinical signs to a lesser extent than PO-administered prednisone in dogs. Animals: Seven healthy adult pet dogs. Methods: Dogs were randomized to 1 of 3 treatment groups in a crossover design: fluticasone propionate (220 μg actuation of a metered dose inhaler delivered via a spacer and mask, q12h), placebo (spacer and mask alone, q12h), or prednisone (1 mg/kg PO q24h). Each treatment was administered for 3 weeks followed by a 4-week washout. Appetite, attitude, and water consumption were recorded during the last week of each treatment period. Urine cortisol : creatinine ratios, ACTH stimulation tests, white blood cell counts, lymphocyte phenotype, and serum IgM and IgA concentrations were recorded at each baseline and after the last day of each treatment. Clinical observations were expressed descriptively. Friedman's test was applied to all data comparisons. Pairwise comparisons were made with a mixed model analysis when data were normally distributed, whereas signed rank tests were used otherwise (significance P-value <.01). Results: Appetite and water consumption increased during prednisone treatment. Peak serum cortisol concentrations post-ACTH were significantly decreased in prednisone- and fluticasone-treated dogs compared with placebo (prednisone > fluticasone). Serum IgM concentrations were significantly decreased in dogs treated with prednisone. Conclusions and Clinical Importance: As used, fluticasone suppresses the HPAA to a lesser extent than prednisone and may avert systemic signs associated with PO-administered glucocorticoids in dogs. [ABSTRACT FROM AUTHOR]

The past decade has seen a complete rethinking of the traditional view of the nuclear envelope as simply a passive enclosure for the chromosomes. The convergence of several lines of clinical and basic research has revealed additional roles in both signaling and mitotic progression. It is becoming apparent that the nuclear envelope defines not only nuclear organization but also that of the cytoskeleton and, in this way, integrates both nuclear and cytoplasmic architecture. [ABSTRACT FROM AUTHOR]

Zmpste24 is a metalloproteinase required for the processing of prelamin A to lamin A, a structural component of the nuclear lamina. Zmpste24 deficiency results in the accumulation of prelamin A within cells, a complete loss of mature lamin A, and misshapen nuclear envelopes. Zmpste24-deficient (Zmpste24-/-) mice exhibit retarded growth, alopecia, micrognathia, dental abnormalities, osteolytic lesions in bones, and osteoporosis, which are phenotypes shared with Hutchinson-Gilford progeria syndrome, a human disease caused by the synthesis of a mutant prelamin A that cannot undergo processing to lamin A. Zmpste24-/- mice also develop muscle weakness. We hypothesized that prelamin A might be toxic and that its accumulation in Zmpste24-/- mice is responsible for all of the disease phenotypes. We further hypothesized that Zmpste24-/- mice with half-normal levels of prelamin A (Zmpste24-/+ mice with one Lmna knockout allele) would be subjected to less toxicity and be protected from disease. Thus, we bred and analyzed Zmpste24-/-Lmna+/- mice. As expected, prelamin A levels in Zmpste24-/-Lmna+/- cells were significantly reduced. Zmpste24-/-Lmna+/- mice were entirely normal, lacking all disease phenotypes, and misshapen nuclei were less frequent in Zmpste24-/-Lmna+/- cells than in Zmpste24-/-cells. These data suggest that prelamin A is toxic and that reducing its levels by as little as 50% provides striking protection from disease. [ABSTRACT FROM AUTHOR]

The retinoblastoma protein (pRB) is a critical regulator of cell proliferation and differentiation and an important tumor suppressor. In the G1 phase of the cell cycle, pRB localizes to perinucleolar sites associated with lamin A/C intranuclear foci. Here, we examine pRB function in cells lacking lamin A/C, finding that pRB levels are dramatically decreased and that the remaining pRB is mislocalized. We demonstrate that A-type lamins protect pRB from proteasomal degradation. Both pRB levels and localization are restored upon reintroduction of lamin A. Lmna-/- cells resemble Rb-/- cells, exhibiting altered cell-cycle properties and reduced capacity to undergo cell-cycle arrest in response to DNA damage. These findings establish a functional link between a core nuclear structural component and an important cell-cycle regulator. They further raise the possibility that altered pRB function may be a contributing factor in dystrophic syndromes arising from LMNA mutation. [ABSTRACT FROM AUTHOR]

Focuses on the causes of immigration to the United States. Information on male occupations for the purpose of inferring the causes; Estimates used to show English and Irish immigrants.

Discusses findings which identify a function for differential splicing in the regulation of transcription factor activity, particularly murine transcription factor E3 (mTFE3). Description of a naturally occurring splice product of MTFE3 messenger RNA (mRNA); Cotransfection of cells; How trans-dominant negative modulation of mTFE3 activity occurred.