Publications

Ozone is an important constituent of ambient air pollution and represents a major public health concern. Oxidative injury due to ozone inhalation causes the generation of reactive oxygen species and can be genotoxic. To determine whether ozone exposure causes genetic damage in peripheral blood lymphocytes, we used a well-validated cytokinesis-block micronucleus Cytome assay. Frequencies of micronuclei (MN) and nucleoplasmic bridges (NB) were used as indicators of cytogenetic damage. Samples were obtained from 22 non-smoking healthy subjects immediately before and 24-hr after controlled 4-hr exposures to filtered air, 100 ppb, and 200 ppb ozone while exercising in a repeated-measure study design. Inhalation of ozone at different exposure levels was associated with a significant dose-dependent increase in MN frequency (P < 0.0001) and in the number of cells with more than one MN per cell (P <  .0005). Inhalation of ozone also caused an increase in the number of apoptotic cells (P = 0.002). Airway neutrophilia was associated with an increase in MN frequency (P = 0.033) independent of the direct effects of ozone exposure (P < 0.0001). We also observed significant increases in both MN and NB frequencies after exercise in filtered air, suggesting that physical activity is also an important inducer of oxidative stress. These results corroborate our previous findings that cytogenetic damage is associated with ozone exposure, and show that damage is dose-dependent. Further study of ozone-induced cytogenetic damage in airway epithelial cells could provide evidence for the role of oxidative injury in lung carcinogenesis, and help to address the potential public health implications of exposures to oxidant environments.

UNLABELLED

Interindividual variability exists in persistent breast pain following breast cancer surgery. Recently, we used growth mixture modeling to identify 3 subgroups of women (N = 398) with distinct persistent breast pain trajectories (ie, mild, moderate, severe) over 6 months following surgery. The purposes of this study were to identify demographic and clinical characteristics that differed among the breast pain classes and, using linear mixed effects modeling, to examine how changes over time and in sensitivity in the breast scar area, pain qualities, pain interference, and hand and arm function differed among these classes. Several demographic and clinical characteristics differentiated the breast pain classes. Of note, 60 to 80% of breast scar sites tested were much less sensitive than the unaffected breast. Significant group effects were observed for pain qualities and interference scores, such that, on average, women in the severe pain class reported higher scores than women in the moderate pain class. In addition, women in the moderate pain class reported higher scores than women in the mild pain class. Compared to women in the mild pain class, women in the severe pain class had significantly impaired grip strength, and women in the moderate and severe pain classes had impaired flexion and abduction.

PERSPECTIVE

Subgroups of women with persistent postsurgical breast pain differed primarily with respect to the severity rather than the nature or underlying mechanisms of breast pain. Pervasive sensory loss and the association between persistent breast pain and sustained interference with function suggest the need for long-term clinical follow-up.

UNLABELLED

Persistent pain following breast cancer surgery is well documented. However, it is not well characterized in terms of the anatomic site affected (ie, breast, arm). In 2 separate growth mixture modeling analyses, we identified subgroups of women (N = 398) with distinct breast pain and arm pain trajectories. The fact that these latent classes differed by anatomic site, types of tissue affected, and neural innervation patterns suggests the need for separate evaluations of these distinct persistent pain conditions. The purposes of this companion study were to identify demographic and clinical characteristics that differed between the 2 arm pain classes and determine if differences existed over time in sensitivity in the upper inner arm and axillary lymph node dissection sites, pain qualities, pain interference, and hand and arm function, as well as to compare findings with persistent breast pain. Higher occurrence rates for depression and lymphedema were found in the moderate arm pain class. Regardless of pain group membership, sensory loss was observed in the upper inner arm and axillary lymph node dissection site. Arm pain was described similarly to neuropathic pain and interfered with daily functioning. Persistent arm pain was associated with sustained impairments in shoulder mobility.

PERSPECTIVE

For persistent breast and arm pain, changes in sensation following breast cancer surgery were notable. Persistent arm pain was associated with sustained interference with daily functioning and upper body mobility impairments. Long-term management of persistent pain following breast cancer surgery is warranted to improve the quality of survivorship for these women.

BACKGROUND

Among HIV-infected women, perinatal depression compromises clinical, maternal, and child health outcomes. Antiretroviral therapy (ART) is associated with lower depression symptom severity but the uniformity of effect through pregnancy and postpartum periods is unknown.

METHODS

We analyzed prospective data from 447 HIV-infected women (18-49 years) initiating ART in rural Uganda (2005-2012). Participants completed blood work and comprehensive questionnaires quarterly. Pregnancy status was assessed by self-report. Analysis time periods were defined as currently pregnant, postpartum (0-12 months post-pregnancy outcome), or non-pregnancy-related. Depression symptom severity was measured using a modified Hopkins Symptom Checklist 15, with scores ranging from 1 to 4. Probable depression was defined as >1.75. Linear regression with generalized estimating equations was used to compare mean depression scores over the 3 periods.

RESULTS

At enrollment, median age was 32 years (interquartile range: 27-37), median CD4 count was 160 cells per cubic millimeter (interquartile range: 95-245), and mean depression score was 1.75 (s = 0.58) (39% with probable depression). Over 4.1 median years of follow-up, 104 women experienced 151 pregnancies. Mean depression scores did not differ across the time periods (P = 0.75). Multivariable models yielded similar findings. Increasing time on ART, viral suppression, better physical health, and "never married" were independently associated with lower mean depression scores. Findings were consistent when assessing probable depression.

CONCLUSIONS

Although the lack of association between depression and perinatal periods is reassuring, high depression prevalence at treatment initiation and continued incidence across pregnancy and non-pregnancy-related periods of follow-up highlight the critical need for mental health services for HIV-infected women to optimize both maternal and perinatal health.

BACKGROUND

Alcohol consumption among HIV-infected patients may accelerate HIV disease progression or reduce antiretroviral therapy adherence. Self-reported alcohol use is frequently under-reported due to social desirability and recall bias. The aim of this study was to compare self-reported alcohol consumption to phosphatidylethanol (PEth), a biomarker of alcohol consumption, and to estimate the correlation between multiple measures of self-reported alcohol consumption with PEth.

METHODS

The Uganda AIDS Rural Treatment Outcomes (UARTO) cohort is located in southwestern Uganda and follows patients on ART to measure treatment outcomes. Patients complete standardized questionnaires quarterly including questions on demographics, health status and alcohol consumption. Baseline dried blood spots (DBS) were collected and retrieved to measure PEth.

RESULTS

One hundred fifty samples were tested, and 56 (37.3%) were PEth positive (≥8 ng/mL). Of those, 51.7% did not report alcohol use in the past month. Men were more likely to under-report compared to women, OR 2.9, 95% CI = 1.26, 6.65) and those in the higher economic asset categories were less likely to under-report compared to those in the lowest category (OR = 0.41 95% CI: 0.17, 0.94). Among self-reported drinkers (n = 31), PEth was highly correlated with the total number of drinking days in the last 30 (Spearman R = 0.73, p<0.001).

CONCLUSIONS

Approximately half of HIV infected patients initiating ART and consuming alcohol under-report their use of alcohol. Given the high prevalence, clinicians should assess all patients for alcohol use with more attention to males and those in lower economic asset categories who deny alcohol use. Among those reporting current drinking, self-reported drinking days is a useful quantitative measure.

The pharmacokinetic and pharmacodynamic disciplines address pharmacological traits, including efficacy and adverse events. Pharmacogenomics studies have identified pervasive genetic effects on treatment outcomes, resulting in the development of genetic biomarkers for optimization of drug therapy. Pharmacogenomics-based tests are already being applied in clinical decision making. However, despite substantial progress in identifying the genetic etiology of pharmacological response, current biomarker panels still largely rely on single gene tests with a large portion of the genetic effects remaining to be discovered. Future research must account for the combined effects of multiple genetic variants, incorporate pathway-based approaches, explore gene-gene interactions and nonprotein coding functional genetic variants, extend studies across ancestral populations, and prioritize laboratory characterization of molecular mechanisms. Because genetic factors can play a key role in drug response, accurate biomarker tests capturing the main genetic factors determining treatment outcomes have substantial potential for improving individual clinical care.

CYP3A4 is an abundant and catalytically dominant human liver endoplasmic reticulum-anchored cytochrome P450 enzyme engaged in the biotransformation of endo- and xenobiotics, including >50% of clinically relevant drugs. Alterations of CYP3A4 protein turnover can influence clinically relevant drug metabolism and bioavailability and drug-drug interactions. This CYP3A4 turnover involves endoplasmic reticulum-associated degradation via the ubiquitin (Ub)-dependent 26 S proteasomal system that relies on two highly complementary E2 Ub-conjugating-E3 Ub-ligase (UBC7-gp78 and UbcH5a-C terminus of Hsc70-interacting protein (CHIP)-Hsc70-Hsp40) complexes, as well as protein kinases (PK) A and C. We have documented that CYP3A4 Ser/Thr phosphorylation (Ser(P)/Thr(P)) by PKA and/or PKC accelerates/enhances its Lys ubiquitination by either of these E2-E3 systems. Intriguingly, CYP3A4 Ser(P)/Thr(P) and ubiquitinated Lys residues reside within the cytosol-accessible surface loop and/or conformationally assembled acidic Asp/Glu clusters, leading us to propose that such post-translational Ser/Thr protein phosphorylation primes CYP3A4 for ubiquitination. Herein, this possibility was examined through various complementary approaches, including site-directed mutagenesis, chemical cross-linking, peptide mapping, and LC-MS/MS analyses. Our findings reveal that such CYP3A4 Asp/Glu/Ser(P)/Thr(P) surface clusters are indeed important for its intermolecular electrostatic interactions with each of these E2-E3 subcomponents. By imparting additional negative charge to these Asp/Glu clusters, such Ser/Thr phosphorylation would generate P450 phosphodegrons for molecular recognition by the E2-E3 complexes, thereby controlling the timing of CYP3A4 ubiquitination and endoplasmic reticulum-associated degradation. Although the importance of phosphodegrons in the CHIP targeting of its substrates is known, to our knowledge this is the first example of phosphodegron involvement in gp78-substrate recruitment, an important step in CYP3A4 proteasomal degradation.

BACKGROUND

The number of older jail inmates in poor health is increasing rapidly. Among older adults, pain is common and leads to greater acute care use. In jail, pain management is complicated by concerns about misuse and diversion. A lack of data about the prevalence and management of pain in older jail inmates limits our ability to develop optimal palliative care strategies for this population.

OBJECTIVE

To describe the prevalence of and factors associated with pain and analgesic use in a population of older jail inmates.

DESIGN

Cross-sectional study. χ(2) tests assessed association between characteristics, pain, and analgesic use.

SETTING/SUBJECTS

Two hundred ten jail inmates age 55 or older.

MEASUREMENTS

"Severe frequent pain" defined as "severe or very severe" pain experienced "frequently or constantly" using the validated Memorial Symptom Assessment Scale. Medical conditions, substance use, and analgesic treatment determined through self-report and jail medical records.

RESULTS

Participants' mean age was 59 years; 69% had multimorbidity; 75% reported any pain; 39% reported severe frequent pain. Report of severe frequent pain was associated with multimorbidity, functional impairment, and pre-jail acute care use (p<0.05), but not with substance use (57% versus 56%, p=0.89). Within a week of their interview, most participants with severe frequent pain had received an analgesic (87%) and many received an opioid (70%).

CONCLUSION

High rates of pain in a rapidly growing population of older jail inmates with multimorbidity and functional impairment suggest that jails are an important site for assessing symptom burden and developing appropriate palliative care interventions.

UNLABELLED

Article-at-a-Glance Background: Care transitions across health care settings are common and can result in adverse outcomes for older adults. Few studies have examined health care professionals' perspectives on important process measures or pay-for-performance (P4P) strategies related to transitional care. A study was conducted to characterize health care professionals' perspectives on (1) successful transitional care of older adults (age 65 years and older), (2) suggestions for improvement, and (3) P4P strategies related to transitional care.

METHODS

In a qualitative study, one-hour semistructured in-depth interviews were conducted in an acute care hospital, a skilled nursing facility, two community-based primary care practices, and one home health care agency with 20 health care professionals (18 physicians and 2 home health care administrators) with direct experience in care transitions of older adults and who were likely to be affected by P4P strategies.

RESULTS

Findings were organized into three thematic domains: (1) components and markers of effective transitional care, (2) difficulties in design and implementation of P4P strategies, and (3) health care professionals' concerns and unmet needs related to delivering optimal care during transitions. A conceptual framework was developed on the basis of the findings to guide design and implementation of P4P strategies for improving transitional care.

CONCLUSION

In characterizing health care professionals' perspectives, specific care processes to target, challenges to address in the design of P4P strategies, and unmet needs to consider regarding education and feedback for health care professionals were described. Future investigations could evaluate whether performance targets, educational interventions, and implementation strategies based on this conceptual framework improve quality of transitional care.