This report describes the synthesis of a range of chiral polycyclic molecules (tricyclic to pentacyclic) from achiral polyene precursors by enantioselective proton-initiated polycyclization promoted by the 1:1 complex of o,o'-dichloro-BINOL and SbCl(5). Excellent yields (ca. 90% per ring formed) and enantioselectivety (20:1 to 50:1) were obtained. The process is practical as well as efficient, because the chiral ligand is both readily prepared from R,R- or S,S-BINOL and easily recovered from the reaction mixture by extraction.

The purpose of this study was to investigate the effects of stressful life events (SLE) on medication adherence (3 days, 30 days) as mediated by sense of coherence (SOC), self-compassion (SCS), and engagement with the healthcare provider (eHCP) and whether this differed by international site. Data were obtained from a cross-sectional sample of 2082 HIV positive adults between September 2009 and January 2011 from sites in Canada, China, Namibia, Puerto Rico, Thailand, and US. Statistical tests to explore the effects of stressful life events on antiretroviral medication adherence included descriptive statistics, multivariate analysis of variance, analysis of variance with Bonferroni post-hoc analysis, and path analysis. An examination by international site of the relationships between SLE, SCS, SOC, and eHCP with adherence (3 days and 30 days) indicated these combined variables were related to adherence whether 3 days or 30 days to different degrees at the various sites. SLE, SCS, SOC, and eHCP were significant predictors of adherence past 3 days for the United States (p = < 0.001), Canada (p = 0.006), and Namibia (p = 0.019). The combined independent variables were significant predictors of adherence past 30 days only in the United States and Canada. Engagement with the provider was a significant correlate for antiretroviral adherence in most, but not all, of these countries. Thus, the importance of eHCP cannot be overstated. Nonetheless, our findings need to be accompanied by the caveat that research on variables of interest, while enriched by a sample obtained from international sites, may not have the same relationships in each country.

Isothermal titration calorimetry (ITC) is a traditional and powerful method for studying the linkage of ligand binding to proton uptake or release. The theoretical framework has been developed for more than two decades and numerous applications have appeared. In the current work, we explored strategic aspects of experimental design. To this end, we simulated families of ITC data sets that embed different strategies with regard to the number of experiments, range of experimental pH, buffer ionization enthalpy, and temperature. We then re-analyzed the families of data sets in the context of global analysis, employing a proton linkage binding model implemented in the global data analysis platform SEDPHAT, and examined the information content of all data sets by a detailed statistical error analysis of the parameter estimates. In particular, we studied the impact of different assumptions about the knowledge of the exact concentrations of the components, which in practice presents an experimental limitation for many systems. For example, the uncertainty in concentration may reflect imperfectly known extinction coefficients and stock concentrations or may account for different extents of partial inactivation when working with proteins at different pH values. Our results show that the global analysis can yield reliable estimates of the thermodynamic parameters for intrinsic binding and protonation, and that in the context of the global analysis the exact molecular component concentrations may not be required. Additionally, a comparison of data from different experimental strategies illustrates the benefit of conducting experiments at a range of temperatures.

PURPOSE: To present a new measurement instrument, the Effectiveness of Treatment Apnea-Hypopnea Index (ET-AHI), which the authors developed to determine an estimate of the therapeutic control of obstructive sleep apnea (OSA). MATERIALS AND METHODS: The authors retrospectively evaluated a cohort of patients with OSA who initially attempted to use continuous positive airway pressure (CPAP) therapy and subsequently underwent maxillomandibular advancement (MMA) surgery. The ET-AHI calculations were performed to estimate the level of CPAP adherence that would be necessary to achieve equivalence with the MMA surgical result and to reach effective AHIs of 5 and 15. RESULTS: The sample was composed of 37 adult patients (mean age, 44.2 ± 9.0 yr; 73% men) with moderate to severe OSA (baseline AHI, 56.3 ± 22.6). CPAP therapy was highly efficacious (CPAP titration AHI, 4.3 ± 5.9), but no patient could adequately adhere to treatment. MMA produced a significant decrease in OSA (AHI after MMA, 11.6 ± 7.4). The ET-AHI calculations predicted that an 86% adherence rate with CPAP would be necessary to achieve equivalence with MMA, whereas adherence rates of 99% and 79% may be required to achieve effective AHIs of 5 and 15, respectively. CONCLUSIONS: The ET-AHI has the potential to significantly affect the care of patients with OSA because it may provide the treating clinician with a valuable tool to estimate the control of OSA for any therapeutic intervention. How closely the ET-AHI predicts the true effective AHI in the home setting requires further validation.

Rising incidence of type 2 diabetes (DM) in Korean immigrants has highlighted the need for better prevention efforts. Health literacy is an important predictor in the utilization of preventative health measures, however little is known about health literacy in Korean immigrants. This study examined DM risk factors in a sample of 145 at-risk Korean immigrants, their level of health literacy, and associations between health literacy and DM risk factors. Findings indicated a high prevalence of DM risk factors and a low level of health literacy in the sample. Health literacy was correlated with English proficiency, acculturation, and lower waist to hip ratios among all participants, and with lower blood glucose levels among highly acculturated participants. Korean immigrants who are less acculturated may have lower health literacy than those who are more acculturated. Thus, linguistically and culturally sensitive health education should be incorporated into diabetes prevention efforts.

The histone methyltransferase WHSC1 (also known as MMSET) is overexpressed in multiple myeloma (MM) as a result of the t(4;14) chromosomal translocation and in a broad variety of other cancers by unclear mechanisms. Overexpression of WHSC1 did not transform wild-type or tumor-prone primary hematopoietic cells. We found that ACA11, an orphan box H/ACA class small nucleolar RNA (snoRNA) encoded within an intron of WHSC1, was highly expressed in t(4;14)-positive MM and other cancers. ACA11 localized to nucleoli and bound what we believe to be a novel small nuclear ribonucleoprotein (snRNP) complex composed of several proteins involved in postsplicing intron complexes. RNA targets of this uncharacterized snRNP included snoRNA intermediates hosted within ribosomal protein (RP) genes, and an RP gene signature was strongly associated with t(4;14) in patients with MM. Expression of ACA11 was sufficient to downregulate RP genes and other snoRNAs implicated in the control of oxidative stress. ACA11 suppressed oxidative stress, afforded resistance to chemotherapy, and increased the proliferation of MM cells, demonstrating that ACA11 is a critical target of the t(4;14) translocation in MM and suggesting an oncogenic role in other cancers as well.

BACKGROUND: Acute coronary syndromes (ACS; myocardial infarction or unstable angina) can induce posttraumatic stress disorder (PTSD), and ACS-induced PTSD may increase patients' risk for subsequent cardiac events and mortality. OBJECTIVE: To determine the prevalence of PTSD induced by ACS and to quantify the association between ACS-induced PTSD and adverse clinical outcomes using systematic review and meta-analysis. DATA SOURCES: Articles were identified by searching Ovid MEDLINE, PsycINFO, and Scopus, and through manual search of reference lists. METHODOLOGY/PRINCIPAL FINDINGS: Observational cohort studies that assessed PTSD with specific reference to an ACS event at least 1 month prior. We extracted estimates of the prevalence of ACS-induced PTSD and associations with clinical outcomes, as well as study characteristics. We identified 56 potentially relevant articles, 24 of which met our criteria (N = 2383). Meta-analysis yielded an aggregated prevalence estimate of 12% (95% confidence interval [CI], 9%-16%) for clinically significant symptoms of ACS-induced PTSD in a random effects model. Individual study prevalence estimates varied widely (0%-32%), with significant heterogeneity in estimates explained by the use of a screening instrument (prevalence estimate was 16% [95% CI, 13%-20%] in 16 studies) vs a clinical diagnostic interview (prevalence estimate was 4% [95% CI, 3%-5%] in 8 studies). The aggregated point estimate for the magnitude of the relationship between ACS-induced PTSD and clinical outcomes (ie, mortality and/or ACS recurrence) across the 3 studies that met our criteria (N = 609) suggested a doubling of risk (risk ratio, 2.00; 95% CI, 1.69-2.37) in ACS patients with clinically significant PTSD symptoms relative to patients without PTSD symptoms. CONCLUSIONS/SIGNIFICANCE: This meta-analysis suggests that clinically significant PTSD symptoms induced by ACS are moderately prevalent and are associated with increased risk for recurrent cardiac events and mortality. Further tests of the association of ACS-induced PTSD and clinical outcomes are needed.

Efficacy endpoints for previous registrational trials of antimicrobials for acute bacterial skin and skin structure infections (ABSSSIs) and community-acquired bacterial pneumonia (CABP) were based on nonstandardized, clinician-based observations and decisions, as well as on patient reports. More quantifiable, reproducible, and externally verifiable endpoints could improve the design of future noninferiority trials. At the request of the Food and Drug Administration, the Foundation for the National Institutes of Health convened a broadly representative scientific project team to evaluate potential endpoints for such registrational trials. Review of historical and modern data led to the conclusion that antimicrobial treatment effects are most apparent early in therapy; later outcomes provide important supportive information. Although evidence is incomplete, early response endpoints can anchor noninferiority hypotheses in ABSSSI and CABP registrational trials, thereby allowing evidence-based drug development to continue. Further research is underway to establish which short- and long-term outcomes are well-defined, reliable, and reflective of how patients feel, function, or survive.

PURPOSE: Acquired perineal hernias through the reconstructed pelvic floor can complicate radical pelvic operations including abdominoperineal resection of rectum. Operative intervention is indicated for symptomatic hernias. There is a lack of consensus as to the best operative technique. Here we present a novel method for repairing perineal herniation using saline-filled tissue expanders. METHODS: Perineal hernia repair may be affected either via an abdominal or via a perineal approach. After adhesiolysis to remove small bowel from the pelvis, a Natrelle™ 150SH tissue expander (Allergan Inc., California, USA) or Siltex™ Round Becker (Mentor Medical Systems, Holland) of appropriate size is inserted in the pelvis and the button placed in a subcutaneous pocket in the perineal skin. The tissue expander is then filled with saline until it fills the true anatomical pelvis without bladder compression. The volume may be increased or decreased postoperatively by accessing the subcutaneous button. RESULTS: We have performed this procedure in three patients with some success, all of whom have experienced symptomatic relief. The tissue expander may subsequently be removed without recurrence of symptoms, due to the fibrous capsule which forms. One patient required re-operation to elevate a herniating tissue expander. The tissue expander was removed earlier than anticipated to avoid deep pelvic infection in another. CONCLUSION: Our early experience suggests that using saline-filled tissue expanders to fill dead space in the pelvis after radical surgery may prove to be a valuable approach to perineal herniation, particularly if adjuvant radiotherapy is planned.

Covalent attachment of poly(ethylene glycol) (PEG) to therapeutic proteins has been used to prolong in vivo exposure of therapeutic proteins. We have examined pharmacokinetic, biodistribution, and biophysical profiles of three different tumor necrosis factor alpha (TNF) Nanobody-40 kDa PEG conjugates: linear 1 × 40 KDa, branched 2 × 20 kDa, and 4 × 10 kDa conjugates. In accord with earlier reports, the superior PK profile was observed for the branched versus linear PEG conjugates, while all three conjugates had similar potency in a cell-based assay. Our results also indicate that (i) a superior PK profile of branched versus linear PEGs is likely to hold across species, (ii) for a given PEG size, the extent of PEG branching affects the PK profile, and (iii) tissue penetration may differ between linear and branched PEG conjugates in a tissue-specific manner. Biophysical analysis (R(g)/R(h) ratio) demonstrated that among the three protein-PEG conjugates the linear PEG conjugate had the most extended time-average conformation and the most exposed surface charges. We hypothesized that these biophysical characteristics of the linear PEG conjugate accounts for relatively less optimal masking of sites involved in elimination of the PEGylated Nanobodies (e.g., intracellular uptake and proteolysis), leading to lower in vivo exposure compared to the branched PEG conjugates. However, additional studies are needed to test this hypothesis.