Publications

BACKGROUND AND PURPOSE

Established risk factors do not fully identify patients at risk for recurrent stroke. The SPARCL trial (Stroke Prevention by Aggressive Reduction in Cholesterol Levels) evaluated the effect of atorvastatin on stroke risk in patients with a recent stroke or transient ischemic attack and no known coronary heart disease. This analysis explored the relationships between 13 plasma biomarkers assessed at trial enrollment and the occurrence of outcome strokes.

METHODS

We conducted a case-cohort study of 2176 participants; 562 had outcome strokes and 1614 were selected randomly from those without outcome strokes. Time to stroke was evaluated by Cox proportional hazards models.

RESULTS

There was no association between time to stroke and lipoprotein-associated phospholipase A, monocyte chemoattractant protein-1, resistin, matrix metalloproteinase-9, N-terminal fragment of pro-B-type natriuretic peptide, soluble vascular cell adhesion molecule-1, soluble intercellular adhesion molecule-1, or soluble CD40 ligand. In adjusted analyses, osteopontin (hazard ratio per SD change, 1.362; <0.0001), neopterin (hazard ratio, 1.137; =0.0107), myeloperoxidase (hazard ratio, 1.177; =0.0022), and adiponectin (hazard ratio, 1.207; =0.0013) were independently associated with outcome strokes. After adjustment for the Stroke Prognostic Instrument-II and treatment, osteopontin, neopterin, and myeloperoxidase remained independently associated with outcome strokes. The addition of these 3 biomarkers to Stroke Prognostic Instrument-II increased the area under the receiver operating characteristic curve by 0.023 (=0.015) and yielded a continuous net reclassification improvement (29.1%; <0.0001) and an integrated discrimination improvement (42.3%; <0.0001).

CONCLUSIONS

Osteopontin, neopterin, and myeloperoxidase were independently associated with the risk of recurrent stroke and improved risk classification when added to a clinical risk algorithm.

CLINICAL TRIAL REGISTRATION

URL: http://www.clinicaltrials.gov. Unique Identifier: NCT00147602.

We examined the relationship between the tobacco industry and the journal Regulatory Toxicology and Pharmacology (RTP) using the Truth Tobacco Industry Documents Library and internet sources. We determined the funding relationships, and categorised the conclusions of all 52 RTP papers on tobacco or nicotine between January 2013 and June 2015, as "positive", "negative" or "neutral" for the tobacco industry. RTP's editor, 57% (4/7) of associate editors and 37% (14/38) of editorial board members had worked or consulted for tobacco companies. Almost all (96%, 50/52) of the papers had authors with tobacco industry ties. Seventy-six percent (38/50) of these papers drew conclusions positive for industry; none drew negative conclusions. The two papers by authors not related to the tobacco industry reached conclusions negative to the industry (p < .001). These results call into question the confidence that members of the scientific community and tobacco product regulators worldwide can have in the conclusions of papers published in RTP.

BACKGROUND

It is unknown if extremely early initiation of antiretroviral therapy (ART) may lead to long-term ART-free HIV remission or cure. As a result, we studied 2 individuals recruited from a pre-exposure prophylaxis (PrEP) program who started prophylactic ART an estimated 10 days (Participant A; 54-year-old male) and 12 days (Participant B; 31-year-old male) after infection with peak plasma HIV RNA of 220 copies/mL and 3,343 copies/mL, respectively. Extensive testing of blood and tissue for HIV persistence was performed, and PrEP Participant A underwent analytical treatment interruption (ATI) following 32 weeks of continuous ART.

METHODS AND FINDINGS

Colorectal and lymph node tissues, bone marrow, cerebral spinal fluid (CSF), plasma, and very large numbers of peripheral blood mononuclear cells (PBMCs) were obtained longitudinally from both participants and were studied for HIV persistence in several laboratories using molecular and culture-based detection methods, including a murine viral outgrowth assay (mVOA). Both participants initiated PrEP with tenofovir/emtricitabine during very early Fiebig stage I (detectable plasma HIV-1 RNA, antibody negative) followed by 4-drug ART intensification. Following peak viral loads, both participants experienced full suppression of HIV-1 plasma viremia. Over the following 2 years, no further HIV could be detected in blood or tissue from PrEP Participant A despite extensive sampling from ileum, rectum, lymph nodes, bone marrow, CSF, circulating CD4+ T cell subsets, and plasma. No HIV was detected from tissues obtained from PrEP Participant B, but low-level HIV RNA or DNA was intermittently detected from various CD4+ T cell subsets. Over 500 million CD4+ T cells were assayed from both participants in a humanized mouse outgrowth assay. Three of 8 mice infused with CD4+ T cells from PrEP Participant B developed viremia (50 million input cells/surviving mouse), but only 1 of 10 mice infused with CD4+ T cells from PrEP Participant A (53 million input cells/mouse) experienced very low level viremia (201 copies/mL); sequence confirmation was unsuccessful. PrEP Participant A stopped ART and remained aviremic for 7.4 months, rebounding with HIV RNA of 36 copies/mL that rose to 59,805 copies/mL 6 days later. ART was restarted promptly. Rebound plasma HIV sequences were identical to those obtained during acute infection by single-genome sequencing. Mathematical modeling predicted that the latent reservoir size was approximately 200 cells prior to ATI and that only around 1% of individuals with a similar HIV burden may achieve lifelong ART-free remission. Furthermore, we observed that lymphocytes expressing the tumor marker CD30 increased in frequency weeks to months prior to detectable HIV-1 RNA in plasma. This study was limited by the small sample size, which was a result of the rarity of individuals presenting during hyperacute infection.

CONCLUSIONS

We report HIV relapse despite initiation of ART at one of the earliest stages of acute HIV infection possible. Near complete or complete loss of detectable HIV in blood and tissues did not lead to indefinite ART-free HIV remission. However, the small numbers of latently infected cells in individuals treated during hyperacute infection may be associated with prolonged ART-free remission.

PURPOSE

The purpose of this study was to evaluate for differences in demographic, clinical, and pain characteristics, as well as measures of sensation, balance, perceived stress, symptom burden, and quality of life (QOL) among survivors who received neurotoxic chemotherapy (CTX) and who reported only chemotherapy-induced neuropathy (CIN, n = 217), CIN and hearing loss (CIN/HL, n = 69), or CIN, hearing loss, and tinnitus (CIN/HL/TIN, n = 85). We hypothesized that as the number of neurotoxicities increased, survivors would have worse outcomes.

METHODS

Survivors were recruited from throughout the San Francisco Bay area. Survivors completed self-report questionnaires for pain and other symptoms, stress and QOL. Objective measures were assessed at an in person visit.

RESULTS

Compared to survivors with only CIN, survivors with all three neurotoxicities were less likely to be female and less likely to report child care responsibilities. In addition, survivors with all three neurtoxicities had higher worst pain scores, greater loss of protective sensation, and worse timed get up and go scores. These survivors reported higher state anxiety and depression and poorer QOL. For some outcomes (e.g., longer duration of CIN, self-reported balance problems), significantly worse outcomes were found for the survivors with CIN/HL and CIN/HL/TIN compared to those with only CIN.

CONCLUSIONS

Our findings suggest that compared to survivors with only CIN, survivors with CIN/HL/TIN are at increased risk for the most severe symptom burden, significant problems associated with sensory loss and changes in balance, as well as significant decrements in all aspects of QOL.