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Background Over-/undertreatment are pervasive in older adults with cancer, and challenges arise in applying the principles of bioethics: beneficence, nonmaleficence, justice, and patient autonomy. The objective of this study was to determine whether these ethical principles relate to over-/undertreatment for older adults, and how tensions among the principles may contribute. Methods We conducted a modified Delphi study with 13 experts in biomedical ethics for iterative rounds of data collection. In the first round, we presented via electronic questionnaire our previously published definitions of over-/undertreatment in older adults with cancer. We then asked which ethical principles related to each definition, followed by how over-/undertreatment might arise from conflicts among different ethical principles. Consensus for each question was defined as ≥ 75% of experts answering “agree” or “strongly agree”. The second round consisted of a virtual discussion with nine of the panel experts led by a qualitative researcher to summarize round one results and review questions that did not reach consensus, followed by a second questionnaire including those questions. Findings Experts reached consensus that beneficence, non-maleficence, and autonomy were related to over-/undertreatment in older adults with cancer. Consensus was reached (92%) that overtreatment can occur when oncologists overemphasize beneficence valuing the potential benefit of cancer treatments, while underemphasizing non-maleficence with respect to treatment toxicities. Consensus was also reached (85%) that undertreatment reflects a lack of justice in equitable consideration of cancer treatments that could provide similar net benefits in older adults compared to younger adults. Lastly, consensus was reached that, in most cases, it is unethical to make a treatment recommendation without (1) formal assessment of patient frailty (e.g., via a geriatric assessment) or (2) the opportunity for the patient to share their values, goals, and preferences. Interpretation Our findings elucidate the ethical principles underpinning over- and undertreatment in older adults with cancer.

BACKGROUNDDisease due to dengue viruses is a growing global health threat, causing 100-400 million cases annually. An ideal dengue vaccine should demonstrate durable protection against all 4 serotypes in phase III efficacy trials, however the lack of circulating serotypes may lead to incomplete efficacy data. Controlled human infection models help downselect vaccine candidates and supply critical data to supplement efficacy trials. We evaluated the efficacy of a leading live-attenuated tetravalent dengue vaccine candidate, TV005, against infection with a newly established dengue serotype 3 or an established serotype 2 challenge virus.METHODSTwo randomized, controlled clinical trials were performed. In study 1, a total of 42 participants received TV005 or placebo (n = 21 each), and 6 months later, all were challenged with dengue 2 virus (rDEN2Δ30) at a dose of 103 PFU. In study 2, a total of 23 participants received TV005 and 20 received placebo, and 6 months later, all were challenged with 104 PFU dengue 3 virus (rDEN3Δ30). The study participants were closely monitored for safety, viremia, and immunologic responses. Infection, measured by post-challenge viremia, and the occurrence of rash and neutropenia were the primary endpoints. Secondary endpoints included safety, immunologic, and virologic profiles following vaccination with TV005 and subsequent challenge with the rDEN2Δ30 or rDEN3Δ30 strain.RESULTSTV005 was well tolerated and protected all vaccinated volunteers from viremia with DENV2 or DENV3 (none infected in either group). Placebo recipients had post-challenge viremia (100% in study 1, 85% in study 2), and all experienced rash following challenge with either serotype.CONCLUSIONSTV005 is a leading tetravalent dengue vaccine candidate that fully protected against infection with DENV2 and DENV3 in an established controlled human infection model.TRIAL REGISTRATIONClinicalTrials.gov NCT02317900 and NCT02873260.FUNDINGIntramural Research Program, NIH (contract HHSN272200900010C).

Individuals are exposed to a large number of diverse environmental chemicals simultaneously and the evaluation of multiple chemical exposures is important for identifying cancer risk factors. The measurement of a large number of chemicals (the exposome) in epidemiologic studies is allowing for a more comprehensive assessment of cancer risk factors than was done in earlier studies that focused on only a few chemicals. Empirical evidence from epidemiologic studies shows that chemicals from different chemical classes have different magnitudes and directions of association with cancers. Given increasing data availability, there is a need for the development and assessment of statistical methods to model environmental cancer risk that considers a large number of diverse chemicals with different effects for different chemical classes. The method of grouped weighted quantile sum (GWQS) regression allows for multiple groups of chemicals to be considered in the model such that different magnitudes and directions of associations are possible for each group of chemicals. In this paper, we assessed the ability of GWQS regression to estimate exposure effects for multiple chemical groups and correctly identify important chemicals in each group using a simulation study. We compared the performance of GWQS regression with WQS regression, the least absolute shrinkage and selection operator (lasso), and the group lasso in estimating exposure effects and identifying important chemicals. The simulation study results demonstrate that GWQS is an effective method for modeling exposure to multiple groups of chemicals and compares favorably with other methods used in mixture analysis. As an application, we used GWQS regression in the California Childhood Leukemia Study (CCLS), a population-based case-control study of childhood leukemia in California to estimate exposure effects for many chemical classes while also adjusting for demographic factors. The CCLS analysis found evidence of a positive association between exposure to the herbicide dacthal and an increased risk of childhood leukemia.

Morbidity and mortality from dengue virus (DENV) is rapidly growing in the large populations of south Asia. Few formal evaluations of candidate dengue vaccine candidates have been undertaken in India, Pakistan, or Bangladesh. Tetravalent vaccines must be tested for safety and immunogenicity in all age groups and in those previously exposed and naive to DENV infections. TV005 is a live, attenuated tetravalent dengue vaccine. We evaluated the safety and immunogenicity of a single dose of TV005 across age groups in dengue-endemic Bangladesh. We performed a randomised, placebo-controlled age de-escalating clinical trial of TV005 at a single clinical site in dengue-endemic Dhaka, Bangladesh, following a technology transfer from the USA. Healthy (as determined by history, clinical examination, and safety laboratory test results) volunteers aged 1–50 years were randomly assigned 3:1 (stratified by four age groups) to receive a single dose of TV005 vaccine or placebo. Participants were followed up for 3 years. The study was double blind and was unmasked at day 180; outcome assessors, clinic staff, and volunteers remained blind throughout. Primary outcomes were safety, evaluated per-protocol as proportion of volunteers with solicited related adverse events of any severity through 28 days post dosing, and post-vaccination seropositivity by day 180 using serotype-specific neutralising antibodies (PRNT50 ≥10). Secondary outcomes included viremia, impact of past dengue exposure, and durability of antibody responses. This study is registered with Clinicaltrials.gov, NCT02678455, and is complete. Between March 13, 2016, and Feb 14, 2017, 192 volunteers were enrolled into four age groups (adults [18–50 years; 20 male and 28 female], adolescents [11–17 years; 27 male and 21 female], children [5–10 years; 15 male and 33 female], and young children [1–4 years; 29 male and 19 female]) with 48 participant per group. All participants were Bangladeshi. Vaccination was well tolerated and most adverse events were mild. Rash was the most common vaccine-associated solicited adverse event, in 37 (26%) of 144 vaccine recipients versus six (12%) of 48 placebo recipients; followed by fever in seven (5% of 144) and arthralgias in seven (6% of 108), which were only observed in vaccine recipients. Post-vaccine, volunteers of all ages (n=142) were seropositive to most serotypes with 118 (83%) seropositive to DENV 1, 141 (99%) to DENV 2, 137 (96%) to DENV 3, and 124 (87%) to DENV 4, overall by day 180. Post-vaccination, viraemia was not consistently found and antibody titres were higher (10–15-fold for DENV 1–3 and 1·6-fold for DENV 4) in individuals with past dengue exposure compared with the dengue-naive participants (DENV 1 mean 480 [SD 4·0] vs 32 [2·4], DENV 2 1042 [3·2] vs 105 [3·1], DENV 3 1406 [2·8] vs 129 [4·7], and DENV 4 105 [3·3] vs 65 [3·1], respectively). Antibody titres to all serotypes remained stable in most adults (63–86%) after 3 years of follow-up. However, as expected for individuals without past exposure to dengue, titres for DENV 1, 3, and 4 waned by 3 years in the youngest (1–4 year old) cohort (69% seropositive for DENV 2 and 22–28% seropositive for DENV 1, 3, and 4). With 3 years of follow-up, the single-dose tetravalent dengue vaccine, TV005, was well tolerated and immunogenic for all four serotypes in young children to adults, including individuals with no previous dengue exposure. National Institutes of Health–National Institute of Allergy and Infectious Diseases Intramural Research Program and Johns Hopkins University. For the Bangla translation of the abstract see Supplementary Materials section.

Social prescription programs represent a viable solution to linking primary care patients to nonmedical community resources for improving patient well-being. However, their success depends on the integration of patient needs with local resources. This integration could be accelerated by digital tools that use expressive ontology to organize knowledge resources, thus enabling the seamless navigation of diverse community interventions and services tailored to the needs of individual users. This infrastructure bears particular relevance for older adults, who experience a range of social needs that impact their health, including social isolation and loneliness. An essential first step in enabling knowledge mobilization and the successful implementation of social prescription initiatives to meet the social needs of older adults is to incorporate the evidence-based academic literature on what works, with on-the-ground solutions in the community. This study aims to integrate scientific evidence with on-the-ground knowledge to build a comprehensive list of intervention terms and keywords related to reducing social isolation and loneliness in older adults. A meta-review was conducted using a search strategy combining terms related to older adult population, social isolation and loneliness, and study types relevant to reviews using 5 databases. Review extraction included intervention characteristics, outcomes (social [eg, loneliness, social isolation, and social support] or mental health [eg, psychological well-being, depression, and anxiety]), and effectiveness (reported as consistent, mixed, or not supported). Terms related to identified intervention types were extracted from the reviewed literature as well as descriptions of corresponding community services in Montréal, Canada, available from web-based regional, municipal, and community data sources. The meta-review identified 11 intervention types addressing social isolation and loneliness in older adults by either increasing social interactions, providing instrumental support, promoting mental and physical well-being, or providing home and community care. Group-based social activities, support groups with educational elements, recreational activities, and training or use of information and communication technologies were the most effective in improving outcomes. Examples of most intervention types were found in community data sources. Terms derived from the literature that were the most commonly congruent with those describing existing community services were related to telehealth, recreational activities, and psychological therapy. However, several discrepancies were observed between review-based terms and those addressing the available services. A range of interventions found to be effective at addressing social isolation and loneliness or their impact on mental health were identified from the literature, and many of these interventions were represented in services available to older residents in Montréal, Canada. However, different terms were occasionally used to describe or categorize similar services across data sources. Establishing an efficient means of identifying and structuring such sources is important to facilitate referrals and help-seeking behaviors of older adults and for strategic planning of resources.

Background. The 4 serotypes of dengue virus, DENV-1-4, are the leading cause of arboviral disease globally. The ideal dengue vaccine would provide protection against all serotypes after a single dose. Methods. Two randomized, placebo-controlled trials were performed with 168 flavivirus-naive adults to demonstrate the safety and immunogenicity of a live attenuated tetravalent dengue vaccine (TV003), compared with those of a second tetravalent vaccine with an enhanced DENV-2 component (TV005), and to evaluate the benefit of a booster dose at 6 months. Safety data, viremia, and neutralizing antibody titers were evaluated. Results. A single dose of TV005 elicited a tetravalent response in 90% of vaccinees by 3 months after vaccination and a trivalent response in 98%. Compared with TV003, the higher-dose DENV-2 component increased the observed frequency of immunogenicity to DENV-2 in the TV005 trial. Both the first and second doses were well tolerated. Neither vaccine viremia, rash, nor a significant antibody boost were observed following a second dose. Conclusions. A single subcutaneous dose of TV005 dengue vaccine is safe and induces a tetravalent antibody response at an unprecedented frequency among vaccinees. A second dose has limited benefit and appears to be unnecessary. Studies to confirm these findings and assess vaccine efficacy will now move to populations in regions where DENV transmission is endemic. Clinical Trials Registration. NCT01072786. and NCT01436422.

The objectives of this study were to estimate the prevalence of fecal incontinence (FI) in older women and examine associations between potential risk factors and prevalent FI. We conducted a cross-sectional study of prevalent FI in 64,559 women, aged 62-87 years, in the Nurses' Health Study. Since 1976, participants provided information on health and lifestyle on mailed biennial questionnaires. Data on FI were collected in 2008. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for FI were calculated using logistic regression models. The reported prevalence of liquid or solid stool incontinence at least monthly increased from 9% in women aged 62 to 64 years to 17% in women aged 85 to 87 years. Prevalent FI was 50% less common in black women compared with white women (6% vs. 12%, respectively). Other variables associated with increased odds of FI at least monthly were pregnancy, higher body mass index (BMI), lower physical activity, functional limitations, current cigarette smoking, type 2 diabetes, high blood pressure, and neurologic disease. Urinary incontinence (UI) was a strong correlate of FI, with 63% of women with FI reporting UI at least monthly compared with 45% of women in the whole study population. FI is a common condition among older women, and often co-occurs with UI. Potentially modifiable risk factors include BMI, physical activity, and cigarette smoking.

There has been a growing interest in the literature on multiple environmental risk factors for diseases and an increasing emphasis on assessing multiple environmental exposures simultaneously in epidemiologic studies of cancer. One method used to analyze exposure to multiple chemical exposures is weighted quantile sum (WQS) regression. While WQS regression has been demonstrated to have good sensitivity and specificity when identifying important exposures, it has limitations including a two-step model fitting process that decreases power and model stability and a requirement that all exposures in the weighted index have associations in the same direction with the outcome, which is not realistic when chemicals in different classes have different directions and magnitude of association with a health outcome. Grouped WQS (GWQS) was proposed to allow for multiple groups of chemicals in the model where different magnitude and direction of associations are possible for each group. However, GWQS shares the limitation of WQS of a two-step estimation process and splitting of data into training and validation sets. In this paper, we propose a Bayesian group index model to avoid the estimation limitation of GWQS while having multiple exposure indices in the model. To evaluate the performance of the Bayesian group index model, we conducted a simulation study with several different exposure scenarios. We also applied the Bayesian group index method to analyze childhood leukemia risk in the California Childhood Leukemia Study (CCLS). The results showed that the Bayesian group index model had slightly better power for exposure effects and specificity and sensitivity in identifying important chemical exposure components compared with the existing frequentist method, particularly for small sample sizes. In the application to the CCLS, we found a significant negative association for insecticides, with the most important chemical being carbaryl. In addition, for children who were born and raised in the home where dust samples were taken, there was a significant positive association for herbicides with dacthal being the most important exposure. In conclusion, our approach of the Bayesian group index model appears able to make a substantial contribution to the field of environmental epidemiology.

Abstract Background Adjuvant 5-FU monotherapy was previously the standard treatment for stage II/III rectal cancer. This study compared adjuvant FOLFIRI, FOLFOX, and 5-FU/LV. Methods Eligible patients had T3-T4 N0 or Tany N1-3 rectal adenocarcinoma ≤12 cm from the anal verge and received pre-operative or postoperative 5-FU chemoradiotherapy (CRT). Patients were randomized to adjuvant FOLFIRI (8 cycles), FOLFOX (8 cycles), or 5-FU/LV weekly (6/8 weeks; 3 cycles). The trial planned to enroll 3,150 patients but was closed early following activation of an alternative adjuvant rectal cancer study including bevacizumab (E5204). The primary endpoint was overall survival (OS); secondary endpoints included disease-free survival (DFS), sphincter preservation, tolerability, and quality of life (QOL). Results The trial enrolled 225 patients (179 randomized) before early closure. Grade 3/4 toxicity occurred in 59%, with neutropenia, leukopenia, and diarrhea being the most common. At a median follow-up of 9.7 years, no significant OS or DFS differences were observed. The rate of sphincter preservation was numerically higher with FOLFIRI and FOLFOX versus 5-FU/LV, but the difference was not statistically significant. Conclusion FOLFOX and FOLFIRI can be safely administered after CRT in rectal cancer patients safely with expected toxicities. Due to early trial closure and small sample size, the survival analysis was underpowered to detect a significant difference between regimens. ClinicalTrials.gov identifier NCT00068692

Background The opioid epidemic continues to be associated with high numbers of fatalities in the USA and other countries, driven mainly by the inclusion of potent synthetic opioids in street drugs. Drug checking by means of various technologies is being increasingly implemented as a harm reduction strategy to inform users about constituent drugs in their street samples. We assessed how valued drug checking services (DCS) would be for opioid street drug users given the ubiquity of fentanyl and related analogs in the drug supply, the information they would most value from drug checking, and compared expected versus actual constituent drugs in collected samples. Methods A convenience sample of opioid street drug users ( N  = 118) was recruited from two syringe service exchange programs in Chicago between 2021 and 2022. We administered brief surveys asking about overdose history, whether fentanyl was their preferred opioid, and interest in DCS. We also collected drug samples and asked participants what drug(s) they expected were in the sample. Provided samples were analyzed using LC–MS technology and the results compared to their expected drugs. Results Participants reported an average of 4.4 lifetime overdoses (SD = 4.8, range = 0–20) and 1.1 (SD = 1.8, range = 0–10) past-year overdoses. A majority (92.1%) believed they had recently used drugs containing fentanyl whether intentionally or unintentionally. Opinions about the desirability of fentanyl were mixed with 56.1% indicating they did not and 38.0% indicating they did prefer fentanyl over other opioids, mainly heroin. Attitudes toward DCS indicated a general but not uniform receptiveness with a majority indicating interest in DCS though sizeable minorities believed DCS was “too much trouble” (25.2%) or there was “no point” in testing (35.4%). Participants were especially inaccurate identifying common cutting agents and potentiating drugs such as diphenhydramine in their samples (sensitivity = .17). Conclusions Results affirmed street drug users remain interested in using DCS to monitor their drugs and such services should be more widely available. Advanced checking technologies that provide information on the relative quantities and the different drugs present in a given sample available at point-of-care, would be most valuable but remain challenging to implement.