Chagas disease, caused by the protozoan parasite Trypanosoma cruzi is one of the most important neglected parasitic diseases in the Americas. Vaccines represent an attractive complementary strategy ...for the control of T. cruzi infection and pre-clinical studies in mice demonstrated that trypomastigote surface antigen (TSA-1) and the flagellar calcium-binding (Tc24) parasite antigens are promising candidates for vaccine development. We performed here the first evaluation of the safety and immunogenicity of two recombinant vaccine antigens (named TSA1-C4 and Tc24-C4) in naïve non-human primates. Three rhesus macaques received 3 doses of each recombinant protein, formulated with E6020 (Eisai Co., Ltd.), a novel Toll-like receptor-4 agonist, in a stable emulsion. All parameters from blood chemistry and blood cell counts were stable over the course of the study and unaffected by the vaccine. A specific IgG response against both antigens was detectable after the first vaccine dose, and increased with the second dose. After three vaccine doses, stimulation of PBMCs with a peptide pool derived from TSA1-C4 resulted in the induction of TSA1-C4-specific TNFα-, IL-2- and IFNγ-producing CD4+ in one or two animals while stimulation with a peptide pool derived from Tc24-C4 only activated IFNγ-producing CD4+T cells in one animal. In two animals there was also activation of TSA1-C4-specific IL2-producing CD8+ T cells. This is the first report of the immunogenicity of T. cruzi-derived recombinant antigens formulated as an emulsion with a TLR4 agonist in a non-human primate model. Our results strongly support the need for further evaluation of the preventive efficacy of this type of vaccine in non-human primates and explore the effect of the vaccine in a therapeutic model of naturally-infected Chagasic non-human primates, which would strengthen the rationale for the clinical development as a human vaccine against Chagas disease.
What can the stable isotope values of human and animal faeces tell us? This often under-appreciated waste product is gaining recognition across a variety of disciplines. Faecal isotopes provide a ...means of monitoring diet, resource partitioning, landscape use, tracking nutrient inputs and cycling, and reconstructing past climate and environment. Here, we review what faeces are composed of, their temporal resolution, and how these factors may be impacted by digestive physiology and efficiency. As faeces are often used to explore diet, we clarify how isotopic offsets between diet and faeces can be calculated, as well as some differences among commonly used calculations that can lead to confusion. Generally, faecal carbon isotope (δ
C) values are lower than those of the diet, while faecal nitrogen isotope values (δ
N) values are higher than in the diet. However, there is considerable variability both within and among species. We explore the role of study design and how limitations stemming from a variety of factors can affect both the reliability and interpretability of faecal isotope data sets. Finally, we summarise the various ways in which faecal isotopes have been applied to date and provide some suggestions for future research. Despite remaining challenges, faecal isotope data are poised to continue to contribute meaningfully to a variety of fields.
Clinical guidelines have recommended adjuvant chemotherapy (ACT) for patients with high-risk stage II colon cancer, although the survival benefit is unclear. ACT is also recommended for patients with ...stage III colon cancer to reduce the risk of recurrence and mortality. For stage II/III rectal cancer, however, the role of perioperative chemotherapy (PCT, adjuvant or neoadjuvant) remains controversial, resulting in substantial variation in its use in clinical practice.
To understand real-world use and predictors of ACT or PCT use and survival outcomes in 3 heterogeneous patient groups with colorectal cancer (CRC), and to inform the evidence gap between guideline-based care and clinical practice.
This retrospective cohort study included patients with an initial stage II/III CRC diagnosis between 2008 and 2013 identified from Kaiser Permanente Southern California electronic health record databases. Patients were eligible if they were aged 18-74 years at diagnosis and received primary curative surgery. We fitted mixed effects logistic regression models to evaluate predictors of ACT receipt and Cox proportional hazards models on propensity score-matched (PS-matched) samples to assess the association between ACT/PCT receipt and survival.
We included 1,690 patients with colon cancer (stage II: 820 and stage III: 870) and 587 patients with rectal cancer (stage II: 241 and stage III: 346). We found that 65% of patients with high-risk stage II colon cancer, 15% of those with stage III colon, and 15% of those with stage II/III rectal cancer did not receive ACT/PCT. Patients with stage II colon cancer with T4 stage (odds ratio OR = 5.79, 95% CI = 3.33 - 10.06) and a lower comorbidity score were more likely to receive ACT (high vs low Charlson score: OR = 0.69, 95% CI = 0.55 - 0.87). Patients with stage III rectal cancer were more likely to receive PCT than those with stage II disease (OR = 7.85, 95% CI = 2.07 - 29.74). Patients with another cancer diagnosis prior to CRC diagnosis were less likely to receive PCT (OR = 0.37, 95% CI = 0.16 - 0.85). ACT/PCT use was associated with improved overall survival among patients with high-risk stage II colon cancer (PS-matched hazard ratio HR = 0.42, 95% CI = 0.25 - 0.70) and those with stage III CRC (stage III colon: PS-matched HR = 0.3, 95% CI = 0.25 - 0.36; stage III rectal: PS-matched HR = 0.2, 95% CI = 0.13 - 0.31).
We found potential underuse of appropriate chemotherapy treatment in patients with high-risk stage II colon cancer and stage III CRC. Clinicians' and providers' decisions on ACT administration may not be fully guided by the risk of recurrence and 5-year survival benefits in stage II colon cancer.
This research was supported by the National Cancer Institute of the National Institutes of Health (NIH) (under R37-CA218413). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
Primary analyses of a study in young women aged 16–26 years showed efficacy of the nine-valent human papillomavirus (9vHPV; HPV 6, 11, 16, 18, 31, 33, 45, 52, and 58) vaccine against infections and ...disease related to HPV 31, 33, 45, 52, and 58, and non-inferior HPV 6, 11, 16, and 18 antibody responses when compared with quadrivalent HPV (qHPV; HPV 6, 11, 16, and 18) vaccine. We aimed to report efficacy of the 9vHPV vaccine for up to 6 years following first administration and antibody responses over 5 years.
We undertook this randomised, double-blind, efficacy, immunogenicity, and safety study of the 9vHPV vaccine study at 105 study sites in 18 countries. Women aged 16–26 years old who were healthy, with no history of abnormal cervical cytology, no previous abnormal cervical biopsy results, and no more than four lifetime sexual partners were randomly assigned (1:1) by central randomisation and block sizes of 2 and 2 to receive three intramuscular injections over 6 months of 9vHPV or qHPV (control) vaccine. All participants, study investigators, and study site personnel, laboratory staff, members of the sponsor's study team, and members of the adjudication pathology panel were masked to vaccination groups. The primary outcomes were incidence of high-grade cervical disease (cervical intraepithelial neoplasia grade 2 or 3, adenocarcinoma in situ, invasive cervical carcinoma), vulvar disease (vulvar intraepithelial neoplasia grade 2/3, vulvar cancer), and vaginal disease (vaginal intraepithelial neoplasia grade 2/3, vaginal cancer) related to HPV 31, 33, 45, 52, and 58 and non-inferiority (excluding a decrease of 1·5 times) of anti-HPV 6, 11, 16, and 18 geometric mean titres (GMT). Tissue samples were adjudicated for histopathology diagnosis and tested for HPV DNA. Serum antibody responses were assessed by competitive Luminex immunoassay. The primary evaluation of efficacy was a superiority analysis in the per-protocol efficacy population, supportive efficacy was analysed in the modified intention-to-treat population, and the primary evaluation of immunogenicity was a non-inferiority analysis. The trial is registered with ClinicalTrials.gov, number NCT00543543.
Between Sept 26, 2007, and Dec 18, 2009, we recruited and randomly assigned 14 215 participants to receive 9vHPV (n=7106) or qHPV (n=7109) vaccine. In the per-protocol population, the incidence of high-grade cervical, vulvar and vaginal disease related to HPV 31, 33, 45, 52, and 58 was 0·5 cases per 10 000 person-years in the 9vHPV and 19·0 cases per 10 000 person-years in the qHPV groups, representing 97·4% efficacy (95% CI 85·0–99·9). HPV 6, 11, 16, and 18 GMTs were non-inferior in the 9vHPV versus qHPV group from month 1 to 3 years after vaccination. No clinically meaningful differences in serious adverse events were noted between the study groups. 11 participants died during the study follow-up period (six in the 9vHPV vaccine group and five in the qHPV vaccine group); none of the deaths were considered vaccine-related.
The 9vHPV vaccine prevents infection, cytological abnormalities, high-grade lesions, and cervical procedures related to HPV 31, 33, 45, 52, and 58. Both the 9vHPV vaccine and qHPV vaccine had a similar immunogenicity profile with respect to HPV 6, 11, 16, and 18. Vaccine efficacy was sustained for up to 6 years. The 9vHPV vaccine could potentially provide broader coverage and prevent 90% of cervical cancer cases worldwide.
Merck & Co, Inc.
•Seasonal influenza A causes significant morbidity and mortality worldwide.•Annually influenza vaccines are on average only 40–60% effective.•Adjuvanted vaccines enhance and shape immune responses to ...vaccines.•Novel BECC TLR4 ligands adjuvant flu vaccines to induce a balanced Th1/Th2 response.•BECC adjuvants protect from homologous and heterologous flu infection in mice.
Influenza A virus (IAV) is a leading cause of respiratory disease worldwide often resulting in hospitalization or death. In this study, TLR4 immunostimulatory molecules, Bacterial Enzymatic Combinatorial Chemistry (BECC) 438 and BECC470 were found to be superior IAV vaccine adjuvants when compared to the classic adjuvant alhydrogel (alum) and Phosphorylated Hexa-Acyl Disaccharide (PHAD), a synthetic TLR4 agonist. BECC molecules allow for antigen sparing of a recombinant HA (rHA) protein, elicit a more balanced IgG1/IgG2a response, and were protective in a prime only dosing schedule. Importantly, BECC molecules afford protection from a heterologous IAV strain demonstrating that a cross-protective influenza vaccine is possible when the antigen is effectively adjuvanted.
Influenza A virus (IAV) is a leading cause of respiratory disease worldwide often resulting in severe morbidity and mortality. We have previously shown that the Bacterial Enzymatic Combinatorial ...Chemistry (BECC) adjuvants, BECC438 and BECC470, formulated with an influenza virus hemagglutinin (HA) protein vaccine, offer greater protection from influenza virus challenge in mouse respiratory models using adult mice than standard HA:adjuvant combinations. In this study, we determined that immunization with HA + BECC adjuvants also significantly broadened the epitopes targeted on HA as compared with other adjuvants, resulting in increased titers of antibodies directed against the highly conserved HA stalk domain. Importantly, we demonstrate that BECC470 combined with an influenza virus HA protein antigen in a prime-only immunization regimen was able to achieve complete protection from challenge in a ~ 12-month-old mouse aged model. Together, this demonstrates the heightened protection provided by the BECC470 adjuvant in an influenza virus vaccine model and shows the enhanced immune response, as compared to other adjuvants elicited by the formulation of HA with BECC470.
e13726 Background: Taxane-based chemotherapy is well-established as a backbone of treatment for patients with breast cancer. While highly effective, all taxanes are known to cause peripheral ...neuropathy, with a high prevalence in obese patients. Other risk factors to developing peripheral neuropathy include older age, smoking, and hyperglycemia. Prior studies have shown that obesity is more prevalent in Black women compared with other racial group in the United States. Obese women have higher body surface areas and thus, tend to receive higher doses of chemotherapy. The higher total doses of taxanes received by obese women puts them at higher risks for developing peripheral neuropathy. We sought to evaluate the racial and BMI differences in rates of neuropathy in patients with breast cancer receiving taxanes. Methods: We created a 2-year database (2021-2022) of women diagnosed with breast cancer who received a taxane across a single health system. Data collected included age at diagnosis, self-identified race, breast cancer subtype, BMI, type of taxane, neuropathy, smoking and diabetes. Stratification analysis was performed using SAS Software 9.4. Results: The rate of neuropathy was 65.2% in White patients and 71.01% in Black patients (p=0.4649). The risk ratio between Black patients with neuropathy to White patients with was 1.26, 95% Cl (0.73-2.17), p=0.6525. In the total cohort of patients, regardless of neuropathy, 60.6% of Black patients had a BMI >30 compared with only 39.5% of White patients. Of those who had neuropathy, obesity was present in 64% of White patients and 65% of Black patients. Conclusions: The data presented here suggest that in a population of breast cancer patients treated with taxanes, there was a trend towards increased neuropathy in Black patients, but no increase in neuropathy based on BMI. Black women were more obese, which suggests that they are at increased risk for developing neuropathy. Factors such as universal effects of chemotherapy across races, comorbid conditions and insufficient sample size could have masked potential significant differences. Further research is needed to understand the complex elements influencing treatment responses in a diverse population. Table: see text
Background
Despite significant investment in colorectal cancer (CRC) screening, 40% of US adults are not up-to-date. Commitment devices, which are psychologically tailored approaches to enforce ...health goals, may be an effective method to increase CRC screening.
Objective
Compare the effectiveness of a commitment device (patient self-ordering fecal immunochemical test (FIT) kits) to standard CRC screening outreach.
Design
A retrospective observational study.
Participants
Participants were > 49 years and < 75 years, had no history of CRC, and were eligible for CRC screening.
Intervention
An electronic screening reminder with an embedded order button allowed participants to order FIT kits directly from a patient portal. Those who used the order button were promptly sent a kit; those who did not were later mailed kits.
Main Measures
Primary outcome was completion of FIT kits. Secondary outcomes included number of days to completion, completion of follow-up for positive results, and CRC diagnosis; we also examined prior use of FIT kit. We used inverse probability of treatment weights to control for pretreatment imbalances.
Key Results
The cohort comprised 176,231 participants: 53% female; median age was 59; 11% were Asian, 21% Hispanic/Latino, 7% black, 51% White, 3% other/mixed race. Approximately 10% (
N
= 16,918) used the button. Using inverse probability of treatment weights, we found that those who used the button had 3.8 times the odds of completing a kit compared to participants who did not (odds ratio, 3.77; 95% confidence interval, 3.57–3.98). Within the button group, 63% of those eligible completed a FIT kit in the year prior to the button compared to 87% in the year after the button became available (
p
< 0.0001).
Conclusion
The ability to self-order screening kits may act as a commitment device that increases CRC screening. Scalable tools leveraging existing patient portals such as this can complement existing CRC outreach strategies.
This study aimed to determine the prevalence of osteoarthritis (OA) and associated clinical signs in young dogs. Owners of dogs aged 8 months-4 years from a single practice, were contacted in random ...order, to participate in a general health screen. Clinical and orthopedic examinations were performed. Each joint was scored for pain reactions (0-4). Orthogonal radiographs of all joints were made under sedation. Each joint was scored for radiographic OA (rOA) severity on an 11-point scale. Clinical OA (cOA) was defined as an overlap of rOA and joint pain in ≥ 1 joint. Owners completed OA questionnaires. The owners of 123 dogs agreed to participate. Overall, 39.8% (49/123) of dogs had rOA in ≥ 1 joint, and 16.3% (20/123) or 23.6% (29/123) dogs had cOA, depending on the cut-off value of joint pain; moderate (2), or mild (1), respectively. Owners of dogs with cOA observed signs of impairment in approximately 30% of cases. Only 2 dogs with cOA were receiving OA pain management. The most commonly affected joints in descending order of frequency were elbow, hip, tarsus, and stifle. Radiographically visible OA is common in young dogs, and 40-60% of dogs with rOA had cOA. However, OA-pain appears underdiagnosed and undertreated in young dogs.
Including race and ethnicity as a predictor in clinical risk prediction algorithms has received increased scrutiny, but there continues to be a lack of empirical studies addressing whether simply ...omitting race and ethnicity from the algorithms will ultimately affect decision-making for patients of minoritized racial and ethnic groups.
To examine whether including race and ethnicity as a predictor in a colorectal cancer recurrence risk algorithm is associated with racial bias, defined as racial and ethnic differences in model accuracy that could potentially lead to unequal treatment.
This retrospective prognostic study was conducted using data from a large integrated health care system in Southern California for patients with colorectal cancer who received primary treatment between 2008 and 2013 and follow-up until December 31, 2018. Data were analyzed from January 2021 to June 2022.
Four Cox proportional hazards regression prediction models were fitted to predict time from surveillance start to cancer recurrence: (1) a race-neutral model that explicitly excluded race and ethnicity as a predictor, (2) a race-sensitive model that included race and ethnicity, (3) a model with 2-way interactions between clinical predictors and race and ethnicity, and (4) separate models by race and ethnicity. Algorithmic fairness was assessed using model calibration, discriminative ability, false-positive and false-negative rates, positive predictive value (PPV), and negative predictive value (NPV).
The study cohort included 4230 patients (mean SD age, 65.3 12.5 years; 2034 48.1% female; 490 11.6% Asian, Hawaiian, or Pacific Islander; 554 13.1% Black or African American; 937 22.1% Hispanic; and 2249 53.1% non-Hispanic White). The race-neutral model had worse calibration, NPV, and false-negative rates among racial and ethnic minority subgroups than non-Hispanic White individuals (eg, false-negative rate for Hispanic patients: 12.0% 95% CI, 6.0%-18.6%; for non-Hispanic White patients: 3.1% 95% CI, 0.8%-6.2%). Adding race and ethnicity as a predictor improved algorithmic fairness in calibration slope, discriminative ability, PPV, and false-negative rates (eg, false-negative rate for Hispanic patients: 9.2% 95% CI, 3.9%-14.9%; for non-Hispanic White patients: 7.9% 95% CI, 4.3%-11.9%). Inclusion of race interaction terms or using race-stratified models did not improve model fairness, likely due to small sample sizes in subgroups.
In this prognostic study of the racial bias in a cancer recurrence risk algorithm, removing race and ethnicity as a predictor worsened algorithmic fairness in multiple measures, which could lead to inappropriate care recommendations for patients who belong to minoritized racial and ethnic groups. Clinical algorithm development should include evaluation of fairness criteria to understand the potential consequences of removing race and ethnicity for health inequities.
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