Factors Associated With a Higher Risk of Undiagnosed Prediabetes in a Community-Dwelling Medicare Population.

OBJECTIVE: To identify characteristics in an ambulatory Medicare population that are significantly more likely to be associated with a high risk of undiagnosed prediabetes.
DESIGN: Cross-sectional study.
SETTING: Fourteen health clinics targeting Medicare beneficiaries were held throughout northern and central California during the fall of 2017.
PATIENTS, PARTICIPANTS: Noninstitutionalized Medicare beneficiaries receiving medication therapy management services without self-reported diabetes.
INTERVENTIONS: Beneficiaries were screened for their risk of type 2 diabetes mellitus (T2DM) through the use of the American Diabetes Association (ADA) risk assessment (score of ≥ 5 indicates increased risk of developing type 2 diabetes) by pharmacy students. For this study, patients with a score of ≥ 5 were considered to be at high risk for undiagnosed prediabetes.
MAIN OUTCOME MEASURE(S): Characteristics significantly more likely to be identified in patients at high risk for undiagnosed prediabetes.
RESULTS: A total of 683 Medicare beneficiaries without self-reported diabetes completed the ADA risk assessment, with 457 (66.9%) receiving a score of 5 or more. In those, the presence of hyperlipidemia, hypertension, obesity, coronary heart disease, and use of aspirin were all characteristics researchers identified as significantly more likely to be found in this group. In contrast, those of Asian race or who took dietary supplements were significantly less likely to score 5 or higher in the questionnaire.
CONCLUSION: Identification of older adults at higher risk for undiagnosed prediabetes through the use of appropriate screening tools allows for targeted preventive interventions, potentially lowering risk of developing T2DM for selected patients.

Interactions between multiple genetic determinants in the 5' UTR and VP1 capsid control pathogenesis of chronic post-viral myopathy caused by coxsackievirus B1.

Mice infected with coxsackievirus B1 Tucson (CVB1(T)) develop chronic, post-viral myopathy (PVM) with clinical manifestations of hind limb muscle weakness and myositis. The objective of the current study was to establish the genetic basis of myopathogenicity in CVB1(T). Using a reverse genetics approach, full attenuation of PVM could only be achieved by simultaneously mutating four sites located at C706U in the 5' untranslated region (5' UTR) and at Y87F, V136A, and T276A in the VP1 capsid. Engineering these four myopathic determinants into an amyopathic CVB1(T) variant restored the ability to cause PVM. Moreover, these same four determinants controlled PVM expression in a second strain of mice, indicating that the underlying mechanism is operational in mice of different genetic backgrounds. Modeling studies predict that C706U alters both local and long range pairing in the 5' UTR, and that VP1 determinants are located on the capsid surface. However, these differences did not affect viral titers, temperature stability, pH stability, or the antibody response to virus. These studies demonstrate that PVM develops from a complex interplay between viral determinants in the 5' UTR and VP1 capsid and have uncovered intriguing similarities between genetic determinants that cause PVM and those involved in pathogenesis of other enteroviruses.

Membrane cytosolic translocation of verotoxin A1 subunit in target cells.

In sensitive cells, verotoxin 1 (VT1) utilizes a globotriaosylceramide receptor-dependent retrograde transport pathway from the cell surface to the Golgi/endoplasmic reticulum (ER). The VT1 A subunit (VTA) is an RNA glycanase. Although translocation of VTA from the ER to the cytosol is considered the route for protein synthesis inhibition, cell-based evidence is lacking. A dual-fluorescent-labelled VT1 holotoxin was constructed to simultaneously monitor VTA and VT1 B subunit (VTB) intracellular transport. By confocal microscopy, VTA/VTB subunits remained associated throughout the retrograde transport pathway without cytosolic staining. However, in [125I]VT1-treated cells, the selective cytosolic translocation (4 %) of the activated form of VTA, VTA1, was demonstrated for the first time by monitoring [125I]VTA1 release after plasma membrane permeabilization by streptolysin O (SLO). Lactacystin, a proteasome inhibitor, increased cytosolic VTA1 and enhanced VT1 cytotoxicity. VT1 ER arrival coincided with cytosolic VTA1 detection. Brefeldin A and 16 degrees C, conditions which inhibit VT1 retrograde transport to the Golgi/ER, prevented VTA1 cytosolic translocation; however, these treatments did not completely prevent VT1-induced protein synthesis inhibition. Thus, efficient cytosolic translocation of VTA1 requires transport to the Golgi/ER, but alternative minor escape pathways for protein synthesis inhibition may operate when transport to the Golgi/ER is prevented. Inhibition of protein synthesis was time and dose dependent, and not necessarily a valid index of subsequent cytopathology. Only protein synthesis inhibition following >3 h VT1 exposure correlated with eventual cell cytotoxicity. Extrapolation of translocated cytosolic VTA1 values indicates that about one molecule of translocated VTA1 per cell is sufficient to inhibit protein synthesis and kill a cell.

Coxsackievirus myocarditis: interplay between virus and host in the pathogenesis of heart disease.

Coxsackievirus (CVB) infection is a significant cause of myocarditis and dilated cardiomyopathy (DCM). Heart disease may be caused by direct cytopathic effects of the virus, a pathologic immune response to persistent virus, or autoimmunity triggered by the viral infection. CVB interacts with its host at multiple stages during disease development. Signaling through viral receptors may alter the intracellular environment in addition to facilitating virus entry. Viral genetic determinants that encode cardiovirulence have been mapped and may change depending on the nutritional status of the host. Virus persistence is directly associated with pathology, and recent work demonstrates that CVB evolves into a slowly replicating form capable of establishing a low-grade infection in the heart. The innate immune response to CVB has taken on increasing importance because of its role in shaping the development of the adaptive immune response that is responsible for cardiac pathology. Studies of T cell responsiveness and the development of autoimmunity at the molecular level are beginning to clarify the mechanisms through which CVB infection causes inflammatory heart disease.

Multiple viral determinants mediate myopathogenicity in coxsackievirus B1-induced chronic inflammatory myopathy.

Mice infected with myopathic coxsackievirus B1 Tucson (CVB1(T)) develop chronic inflammatory myopathy (CIM) consisting of hind limb weakness and inflammation. Amyopathic virus variants are infectious but attenuated for CIM. In this report, viral clones, chimeras, and sequencing were used to identify viral determinants of CIM. Chimeras identified several regions involved in CIM and localized a weakness determinant to nucleotides 2493 to 3200 of VP1. Sequencing of multiple clones and viruses identified five candidate determinants that were strictly conserved in myopathic viruses with one located in the 5' untranslated region (UTR), three in the VP1 capsid, and one in the 3C protease. Taken together, these studies implicate Tyr-87 and/or Val-136 as candidate determinants of weakness. They also indicate that there are at least two determinants of inflammation and one additional determinant of weakness encoded by myopathic CVB1(T).

Coxsackievirus B1-induced chronic inflammatory myopathy: differences in induction of autoantibodies to muscle and nuclear antigens by cloned myopathic and amyopathic viruses.

Infection of susceptible strains of mice with the myopathic Tucson strain of coxsackievirus B1 (CVB1(T)) leads to the development of chronic inflammatory myopathy (CIM). The underlying mechanism of CIM appears to be immunopathic, but it is not known whether autoimmunity is involved. The objectives of this study were to determine whether autoantibodies are produced and whether they correlate with the pathology of CIM. Mice were infected with either a myopathic (MP1.23 or MP1.24) or an amyopathic (AMP2.17) CVB1(T) cloned virus. The two myopathic (MP) viruses cause CIM, whereas the amyopathic (AMP) virus, derived from a variant of the same parent, causes the same acute disease but does not cause CIM. Antimuscle IgG was found in 51% of MP1.23-infected and 58% of MP1.24-infected mice but in just 18% of mice infected with AMP2.17 and in 10% of controls (MP vs AMP: chi(2), P < or =.006). Several staining patterns were observed, indicating that autoantibodies of multiple specificities were produced. Antinuclear antibodies were found in 57% of MP1.23-infected and 27% of MP1.24-infected mice but were rare in mice infected with AMP2.17 (0%) or in controls (4%) (MP vs AMP: chi(2), P < or =.01). Antiviral-antibody titers were higher with MP virus than with AMP virus (ANOVA, P <.001). A trend toward an association between antiviral antibody or autoantibodies and the presence or severity of clinical measures of CIM was noted but was not significant. These data suggest that the autoantibodies do not mediate muscle disease but are an independent manifestation of an immunopathic response induced by infection with MP but not AMP CVB1(T).

Controlled breaks as a fatigue countermeasure on the flight deck.

BACKGROUND: A major challenge for flight crews is the need to maintain vigilance during long, highly automated nighttime flights. No system currently exists to assist in managing alertness, and countermeasure options are limited. Surveys reveal many pilots use breaks as an in-flight countermeasure, but there have been no controlled studies of their effectiveness. HYPOTHESIS: We hypothesized that brief, regular breaks could improve alertness and performance during an overnight flight. METHOD: A 6-h, uneventful, nighttime flight in a Boeing 747-400 flight simulator was flown by fourteen two-man crews. The 14 subjects in the treatment group received 5 short breaks spaced hourly during cruise; the 14 subjects in the control group received 1 break in the middle of cruise. Continuous EEG/EOG, subjective sleepiness, and psychomotor vigilance performance data were collected. RESULTS: During the latter part of the night, the treatment group showed significant reductions for 15 min post-break in slow eye movements, theta-band activity, and unintended sleep episodes compared with the control group. The treatment group reported significantly greater subjective alertness for up to 25 min post-break, with strongest effects near the time of the circadian trough. There was no evidence of objective vigilance performance improvement at 15-25 min post-break, with expected performance deterioration occurring due to elevated sleep drive and circadian time. CONCLUSIONS: The physiological and subjective data indicate the breaks reduced nighttime sleepiness for at least 15 min post-break and may have masked sleepiness for up to 25 min, suggesting the potential usefulness of short-duration breaks as an in-flight fatigue countermeasure.