The development of biomedical interventions to reduce acquisition of HIV-1 infection remains a global priority, however their potential effectiveness is challenged by very high HIV-1 envelope ...diversity. Two large prophylactic trials in high incidence, clade C epidemic regions in southern Africa are imminent; passive administration of the monoclonal antibody VRC01, and active immunization with a clade C modified RV144-like vaccines. We have created a large representative panel of C clade viruses to enable assessment of antibody responses to vaccines and natural infection in Southern Africa, and we investigated the genotypic and neutralization properties of recently transmitted clade C viruses to determine how viral diversity impacted antibody recognition. We further explore the implications of these findings for the potential effectiveness of these trials. A panel of 200 HIV-1 Envelope pseudoviruses was constructed from clade C viruses collected within the first 100 days following infection. Viruses collected pre-seroconversion were significantly more resistant to serum neutralization compared to post-seroconversion viruses (p = 0.001). Over 13 years of the study as the epidemic matured, HIV-1 diversified (p = 0.0009) and became more neutralization resistant to monoclonal antibodies VRC01, PG9 and 4E10. When tested at therapeutic levels (10ug/ml), VRC01 only neutralized 80% of viruses in the panel, although it did exhibit potent neutralization activity against sensitive viruses (IC50 titres of 0.42 μg/ml). The Gp120 amino acid similarity between the clade C panel and candidate C-clade vaccine protein boosts (Ce1086 and TV1) was 77%, which is 8% more distant than between CRF01_AE viruses and the RV144 CRF01_AE immunogen. Furthermore, two vaccine signature sites, K169 in V2 and I307 in V3, associated with reduced infection risk in RV144, occurred less frequently in clade C panel viruses than in CRF01_AE viruses from Thailand. Increased resistance of pre-seroconversion viruses and evidence of antigenic drift highlights the value of using panels of very recently transmitted viruses and suggests that interventions may need to be modified over time to track the changing epidemic. Furthermore, high divergence such as that observed in the older clade C epidemic in southern Africa may impact vaccine efficacy, although the correlates of infection risk are yet to be defined in the clade C setting. Findings from this study of acute/early clade C viruses will aid vaccine development, and enable identification of new broad and potent antibodies to combat the HIV-1 C-clade epidemic in southern Africa.
Background. Defining mucosal immune responses and inflammation to candidate human immunodeficiency virus type 1 (HIV-1) vaccines represents a current research priority for the HIV-1 vaccine field. In ...particular, it is unclear whether intramuscular immunization can elicit immune responses at mucosal surfaces in humans. Methods. In this double-blind, randomized, placebo-controlled clinical trial, we evaluated systemic and mucosal immune responses to a candidate adenovirus serotype 26 (Ad26) vectored HIV-1 envelop (Env) vaccine in baseline Ad26-seronegative and Ad26-seropositive healthy volunteers. Systematic mucosal sampling with rectal Weck-Cel sponges and rectal biopsies were performed. Results. Intramuscular immunization elicited both systemic and mucosal Env-specific humoral and cellular immune responses in the majority of subjects. Individuals with preexisting Ad26-specific neutralizing antibodies had vaccine-elicited immune responses comparable to those of subjects who were Ad26 seronegative. We also observed no increase in activated total or vector-specific mucosal CD4⁺ T lymphocytes following vaccination by either histopathology or flow cytometry. Conclusions. These data demonstrate that a single intramuscular administration of this Ad26-vectored HIV-1 Env vaccine elicited both systemic and mucosal immune responses in humans. Induction of antigen-specific humoral and cellular mucosal immunity was not accompanied by a detectable increase in mucosal inflammation.
Background. We report the first-in-human safety and immunogenicity assessment of a prototype hexon chimeric adenovirus (Ad) serotype 5 (Ad5) vector containing the hexon hypervariable regions of Ad ...serotype 48 (Ad48) and expressing human immunodeficiency virus (HIV) type 1 EnvA. Methods. Forty-eight Ad5 and Ad48 seronegative, HIV-uninfected subjects were enrolled in a randomized, double-blind, placebo-controlled, dose escalation phase 1 study. Four groups of 12 subjects received 10⁹ to 10¹¹ viral particles (vp) of the Ad5HVR48. EnvA. 01 vaccine (n = 10 per group) or placebo (n = 2 per group) at week 0 or weeks 0, 4, and 24. Safety and immunogenicity were assessed. Results. Self-limited reactogenicity was observed after the initial immunization in the highest (10¹¹ vp) dose group. Responses in vaccinées included Ad48 neutralizing antibody (nAb) titers higher than Ad5 nAb titers, EnvA-specific enzyme-linked immunosorbent assay titers, and EnvA-specific enzyme-linked immunospot assay responses, and these responses generally persisted at week 52. At week 28 in the 10⁹, 10¹⁰, and 10¹¹ vp 3-dose groups, geometric mean EnvA enzyme-linked immunosorbent assay titers were 5721, 10 929, and 3420, respectively, and Ad48 nAb titers were a median of 1.7-fold higher than for Ad5. Conclusions. Ad5HVR48.ENVA.01 was safe, well tolerated, and immunogenic at all doses tested. Vector-elicited nAb responses were greater for Ad48 than Ad5, confirming that Ad-specific nAbs in humans are primarily, but not exclusively, directed against the hexon hypervariable regions. Clinical Trials Registration. NCT00695877.
A number of potent broadly neutralizing antibodies against HIV-1 have recently been identified that target epitopes on the viral envelope that contain N-linked glycans. It remains unknown how ...frequently glycan-dependent neutralizing antibodies generally arise during the course of natural infection or whether particular glycosylation sites are preferentially targeted. We tested sera with a broad range of neutralization activity from individuals infected with HIV-1 clades B or C against panels of HIV-1 Env pseudoviruses that lacked specific glycans in the outer domain glycan cluster (ODGC) or inner domain glycan cluster (IDGC) to determine the presence of glycan-dependent neutralizing antibodies. Overall, 54% of individuals were observed to have neutralizing antibodies targeting these glycan regions. Glycan-specific neutralizing antibodies were readily detected in sera that were selected for having broad, moderate, or weak neutralization potency and breadth. Our results demonstrate that glycan-specific neutralizing antibodies arise with appreciable frequency in individuals chronically infected with HIV-1 clades B and C. Antibody responses that commonly occur during natural infection may be more feasible to induce by vaccination; thus glycan-specific neutralizing antibodies may be desirable responses to elicit with candidate HIV-1 vaccines.
To develop guideline recommendations concerning optimal neoadjuvant therapy for breast cancer.
ASCO convened an Expert Panel to conduct a systematic review of the literature on neoadjuvant therapy ...for breast cancer and provide recommended care options.
A total of 41 articles met eligibility criteria and form the evidentiary basis for the guideline recommendations.
Patients undergoing neoadjuvant therapy should be managed by a multidisciplinary care team. Appropriate candidates for neoadjuvant therapy include patients with inflammatory breast cancer and those in whom residual disease may prompt a change in therapy. Neoadjuvant therapy can also be used to reduce the extent of local therapy or reduce delays in initiating therapy. Although tumor histology, grade, stage, and estrogen, progesterone, and human epidermal growth factor receptor 2 (HER2) expression should routinely be used to guide clinical decisions, there is insufficient evidence to support the use of other markers or genomic profiles. Patients with triple-negative breast cancer (TNBC) who have clinically node-positive and/or at least T1c disease should be offered an anthracycline- and taxane-containing regimen; those with cT1a or cT1bN0 TNBC should not routinely be offered neoadjuvant therapy. Carboplatin may be offered to patients with TNBC to increase pathologic complete response. There is currently insufficient evidence to support adding immune checkpoint inhibitors to standard chemotherapy. In patients with hormone receptor (HR)-positive (HR-positive), HER2-negative tumors, neoadjuvant chemotherapy can be used when a treatment decision can be made without surgical information. Among postmenopausal patients with HR-positive, HER2-negative disease, hormone therapy can be used to downstage disease. Patients with node-positive or high-risk node-negative, HER2-positive disease should be offered neoadjuvant therapy in combination with anti-HER2-positive therapy. Patients with T1aN0 and T1bN0, HER2-positive disease should not be routinely offered neoadjuvant therapy.Additional information is available at www.asco.org/breast-cancer-guidelines.
Accelerometer-based technologies can be utilized for precision monitoring of feeding behaviors, but limited information is available regarding the impact of varying environmental conditions on sensor ...performance. The objective of this study was to determine if a commercially available ear-tag sensor (CM; CowManager SensOor, Agis Automatisering BV) could accurately quantify eating and rumination time under heat stress conditions. Data obtained from CM sensors was compared with data collected using an automated gold standard (RW; Rumiwatch System; Itin+Hoch). Automated measurements were obtained from 2 experiments in which cattle were exposed to heat stress conditions. In the principal study (Experiment 1), 3428 h of data were collected from 9 Holstein × Angus steers (470.9 ± 23.9 kg) subjected to either thermoneutral (TN; 21.0°C; 64.0% humidity; temperature-humidity index THI = 67; 12- and 12-h light and dark cycle; n = 1714 h), or heat stress conditions (HS; cyclical daily temperatures to mimic diurnal patterns; 0800 – 2000 h: 33.6°C, 40.0% RH, THI: 83.5; 2000 – 0800 h: 23.2°C, 70.0% RH; THI: 70.3; n = 1714 h). Data (n = 719 h) from 6 Holstein x Angus steers (487.9 ± 9.1 kg) were obtained from a subsequent experiment (Experiment 2) to confirm consistency of ear-tag accelerometer performance under elevated THI (HS conditions as described above). In Experiment 1, CM was capable of quantifying rumination time with high accuracy under TN conditions (concordance correlation coefficient CCC: 0.75 – 0.81). Overall, agreement between CM and the automated gold standard declined 6 – 7% during HS, which was most apparent later in the day when cattle had been subjected to HS for multiple hours (moderate agreement; CCC: 0.68). Accuracy for rumination time was also only moderate for data collected during Experiment 2 (CCC: 0.55 – 0.61). In contrast, CM reported total eating (eating with the head down + head up while masticating) time with moderate accuracy for TN (CCC: 0.53 – 0.54), only achieved negligible to low accuracy during HS (CCC: 0.39 – 0.44 Experiment 1 and 0.17 – 0.34 Experiment 2). Sensor performance did improve when CM eating time was compared specifically to the time spent with the head down reported by RW; HS still negatively influenced sensor performance, however, with high agreement during TN (CCC: 0.72 – 0.73) but low to moderate agreement during HS (CCC: 0.65 – 0.69 Experiment 1 and 0.40 – 0.58 Experiment 2). Results of this study suggest accuracy of ear-tag accelerometers may be impaired when cattle are subjected to heat stress.
This meta-analysis examined the effects of mindfulness-based interventions (MBIs) on stress, psychological symptoms, and biomarkers of disease among people living with HIV/AIDS (PLWHA). Comprehensive ...searches identified 16 studies that met the inclusion criteria (
N
= 1059
; M
age = 42 years; 20% women). Participants had been living with HIV for an average of 8 years (range = < 1–20 years); 65% were currently on antiretroviral therapy. Between-group analyses indicated that depressive symptoms were reduced among participants receiving the MBIs compared to controls (
d
+ = 0.37, 95% CI 0.03, 0.71). Within-group analyses showed reductions in psychological symptoms (i.e., less anxiety, fewer depressive symptoms) and improved quality of life over time among MBI participants (
d
+s = 0.40–0.85). No significant changes were observed for immunological outcomes (i.e., CD4 counts) between- or within-groups. MBIs may be a promising approach for reducing psychological symptoms and improving quality of life among PLWHA. Studies using stronger designs (i.e., randomized controlled trials) with larger sample sizes and longer follow-ups are needed to clarify the potential benefits of MBIs for PLWHA.
Abstract
Background
Individuals with cardiovascular disease (CVD) report psychological distress and poor physical functioning and may benefit from mindfulness training.
Purpose
To examine the effects ...of mindfulness-based interventions (MBIs) on psychological and physiological measures in adults with CVD using meta-analysis.
Methods
Comprehensive searches identified studies that (a) evaluated MBIs in adults with CVD or who had experienced a cardiac event, (b) included a comparison condition, and (c) assessed psychological (e.g., anxiety and depression) or physiological (e.g., systolic or diastolic blood pressure BP) outcomes. Independent raters coded methodological (e.g., design and quality) and intervention features (e.g., intervention content) as potential moderators. Weighted mean effect sizes (d+), using full information maximum likelihood estimation, were calculated.
Results
Of the 1,507 records reviewed, 16 studies met inclusion criteria (N = 1,476; M age = 56 years; 40% women). Compared to controls, participants who received an MBI reported greater improvements in psychological outcomes (i.e., anxiety, depression, distress, and perceived stress: d+s = 0.49 to 0.64). MBI recipients also reduced their systolic (d+ = 0.89, 95% confidence interval CI = 0.26, 1.51; k = 7) but not diastolic (d+ = 0.07, 95% CI = −0.47, 0.60; k = 6) BP relative to controls.
Conclusions
MBIs demonstrated favorable effects on psychological and physiological outcomes among adults with CVD. Future research should investigate if such benefits lead to improvements in disease outcomes in studies with longer follow-ups.
Mindfulness-based interventions improved psychological and physiological outcomes among adults with cardiovascular disease but the long-term benefits could not be established.
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•Eating time showed very high agreement for noseband sensors and visual observations.•Rumination time showed very high agreement for noseband sensors and visual observations.•Noseband ...sensor accuracy was robust to heat stress conditions.
Precision monitoring of feeding behaviors can aid in dairy herd management. Noseband sensors (RumiWatch System RW; Itin + Hoch GmbH) have been established as an automated gold standard for evaluating precision technologies in grazing cows, but more advanced algorithms have not been validated in confinement settings. Additionally, little is known regarding effects of environmental conditions on sensor performance. Therefore, accuracy of RW in quantifying eating and rumination time in confinement was evaluated using 2 versions of the analysis software algorithms (RW Converter V.7.3.2 and V.7.3.36) under thermoneutral (TN; 21.0°C, 64.0% relative humidity RH, temperature-humidity index THI = 67) and heat stress conditions (HS; cyclical daily temperatures to mimic diurnal patterns; 0700–1900 h: 33.6°C, 40.0% RH, THI = 83.5; 1900–0700 h: 23.2°C, 70.0% RH; THI = 70.3). Nine individually housed Holstein × Simmental cross steers were fitted with RW noseband sensors. Agreement for eating time reported by RW and visual observations (1-min scan sampling) was very high in TN regardless of software version (concordance correlation coefficient CCC: V.7.3.2 = 0.91; V.7.3.36 = 0.94), and remained high to very high (CCC: V.7.3.2 = 0.89; V.7.3.36 = 0.95) during HS. Agreement for rumination time was very high regardless of software version in both TN (CCC: V.7.3.2 = 0.93; V.7.3.36 = 0.99) and HS (CCC: V.7.3.2 = 0.91; V.7.3.36 = 0.99). Overall, RW accurately quantified eating and ruminating time in confined cattle, and noseband sensors retained accuracy during heat stress. These results indicate RW may serve as a benchmark for future precision technology validations in dairy cattle managed in confinement systems.
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