Search

Denosumab is a fully human mAb that binds receptor activator of NFκB ligand (RANKL). It is routinely administered to patients with cancer to reduce the incidence of new bone metastasis. RANK-RANKL interactions regulate bone turnover by controlling osteoclast recruitment, development, and activity. However, these interactions also can regulate immune cells including dendritic cells and medullary thymic epithelial cells. Inhibition of the latter results in reduced thymic negative selection of T cells and could enhance the generation of tumor-specific T cells. We examined whether administering denosumab could modify modulate circulating immune cells in patients with cancer. Blood was collected from 23 patients with prostate cancer and 3 patients with renal cell carcinoma, all of whom had advanced disease and were receiving denosumab, prior to and during denosumab treatment. Using high-dimensional mass cytometry, we found that denosumab treatment by itself induced modest effects on circulating immune cell frequency and activation. We also found minimal changes in the circulating T-cell repertoire and the frequency of new thymic emigrants with denosumab treatment. However, when we stratified patients by whether they were receiving chemotherapy and/or steroids, patients receiving these concomitant treatments showed significantly greater immune modulation, including an increase in the frequency of natural killer cells early and classical monocytes later. We also saw broad induction of CTLA-4 and TIM3 expression in circulating lymphocytes and some monocyte populations. These findings suggest that denosumab treatment by itself has modest immunomodulatory effects, but when combined with conventional cancer treatments, can lead to the induction of immunologic checkpoints. See related Spotlight by Nasrollahi and Davar, p. 383.

CRISPR genome editing approaches theoretically enable researchers to define the function of each human gene in specific cell types, but challenges remain to efficiently perform genetic perturbations in relevant models. In this work, we develop a library cloning protocol that increases sgRNA uniformity and greatly reduces bias in existing genome-wide libraries. We demonstrate that our libraries can achieve equivalent or better statistical power compared to previously reported screens using an order of magnitude fewer cells. This improved cloning protocol enables genome-scale CRISPR screens in technically challenging cell models and screen formats.

To maximise the benefits of HIV self-testing (HIVST), it is critical to support self-testers in the testing process and ensure that they access appropriate prevention and care. To summarise systems and tools supporting HIVST (hereafter, 'support systems') and categorise them for future analysis, we synthesised the global data on HIVST support systems and proposed a typology. We searched five databases for articles reporting on one or more HIVST support systems and included 314 publications from 224 studies. Across 189 studies, there were 539 reports of systems supporting HIVST use; while across 115 studies, there were 171 reports of systems supporting result interpretation. Most commonly, these were pictorial instructions, followed by in-person demonstrations and in-person assistance while self-testing or reading self-test results. Less commonly, virtual interventions were also identified, including online video conferencing and smartphone apps. Smartphone-based automated result readers have been used in the USA, China, and South Africa. Across 173 studies, there were 987 reports of systems supporting post-test linkage to care; most commonly, these were in-person referrals/counselling, written referrals, and phone helplines. In the USA, Bluetooth beacons have been trialled to monitor self-test use and facilitate follow-up. We found that, globally, HIVST support systems use a range of methods, including static media, virtual tools, and in-person engagement. In-person and printed approaches were more common than virtual tools. Other considerations, such as linguistic and cultural appropriateness, may also be important in the development of effective HIVST programs. The success of HIV self-testing requires the user to accurately use the self-test, interpret the result, and be linked to relevant follow-up services. We summarised the systems and tools that have been used to support users through the self-testing process ('support systems'), and found a diverse range of support systems, including pictorial instructions, in-person support, and virtual tools. We have developed a typology to categorise these support systems, which can be used as a framework for further research. [ABSTRACT FROM AUTHOR]

Background: Approximately 20–50% of adolescent and young adult-aged childhood cancer survivors (AYA-CCS) experience sexual dysfunction (SD), although this healthcare need is widely underrecognized. Previous research from both AYA-CCS patients and their providers report that SD needs are unaddressed despite patient desires for SD discussions to be incorporated as part of their care. Patients and providers agree that standardized use of a patient-reported outcome measure may facilitate SD discussions; an SD screening approach was developed with patient and provider input. This study will measure the effectiveness of a standardized SD screening intervention and assess implementation outcomes and multilevel barriers and facilitators to guide future research. Methods: This multi-site, mixed methods, type 1 effectiveness-implementation hybrid trial will be evaluated using a pre-post design (NCT05524610). The trial will enroll 86 AYA-CCS (ages 15–39) from two cancer centers in the United States. The SD intervention consists of core fundamental functions with a "menu" of intervention options to allow for flexibility in delivery and tailoring in variable contexts. Effectiveness of the intervention on facilitating SD communication will be measured through patient surveys and clinical data; multivariable logistic regression will be used for the binary outcome of self-reported SD screening, controlling for patient-level predictors. Implementation outcomes will be assessed using mixed methods (electronic health record abstraction, patient and provider surveys, and provider interviews. Quantitative and qualitative findings will be merged using a joint display to understand factors affecting intervention success. Implications: Identification and treatment of SD in AYA-CCS is an important and challenging quality of life concern. The type 1 hybrid design will facilitate rapid translation from research to practice by testing the effects of the intervention while simultaneously identifying multilevel barriers and facilitators to real-world implementation. This approach will inform future testing and dissemination of the SD screening intervention. [ABSTRACT FROM AUTHOR]

We examined combinations of nine sexual activities that occurred during a sex episode with a recent male partner among men who have sex with men (MSM) who attended an urban sexual health clinic from April-2017 to September-2017. We collected the following sexual activities: tongue-kissing, penises touching, using saliva during mutual masturbation, performed rimming, received rimming, performed fellatio, received fellatio, insertive anal sex, and receptive anal sex. During a single-sex episode, the most common combinations of sexual activities involved all nine activities (10.6%, 166/1542). We assessed the agreement between any two sexual activities that occurred together during a sex episode. Agreement was highest for receiving rimming and receptive anal sex (kappa = 0.40; 95% CI: 0.35, 0.45), and performing rimming and insertive anal sex (kappa = 0.38; 95% CI: 0.33, 0.42). Agreement was lowest for insertive anal sex and receiving fellatio (kappa = −0.01; 95% CI: −0.05, 0.03), and receptive anal sex and insertive anal sex (kappa = −0.08; 95% CI: −0.13, 0.03). The sexual activities that occur between men are correlated with one another and this will influence transmission between anatomical sites. [ABSTRACT FROM AUTHOR]

Background: There are limited studies examining the early experiences of adolescent men who have sex with men (MSM), and the magnitude of changes in sexual practice among adolescent MSM is unclear. Therefore, we compared the sexual practice and trajectory among adolescent men who are MSM aged 16–20 years in two cohorts, 5 years apart in Melbourne, Australia. Methods: A total of 200 self-identified same-sex attracted men aged 16–20 years were recruited in each of HYPER1 (2010–2012) and HYPER2 (2017–2018) using similar methodology. Men completed a questionnaire about their sexual practices. Men were also asked to report the age of first sex with different sexual activities with men and women. Results: Compared to HYPER1, the median age at first sex with men was slightly increased in HYPER2: receiving oral sex (17.2 years in HYPER2 vs 16.5 years in HYPER1), performing oral sex (17.3 years vs 16.4 years), receptive anal sex (18 years vs 17.0 years) and insertive anal sex (18 years vs 17.3 years). Similar patterns were also observed in sexual practice with women: performing oral sex (17.0 years in HYPER2 vs 16.8 years in HYPER1), receiving oral sex (17.0 years vs 16.3 years) and vaginal sex (17.0 years vs 16.7 years). Conclusions: In general, there was a small delay in first-sex activity among adolescent MSM between two cohorts 5 years apart. Most adolescent MSM started their sexual practices before the age of 18 years and have engaged in activities that are at risk of HIV and STI. Health education and promotion, including regular sexual health check-ups, are important for HIV and STI prevention and intervention in this population. This study documents adolescent men who have sex with men aged between 16 and 20 years and assesses the magnitude of change in sexual practice and trajectory in this population. Compared to an earlier study cohort, the median age at first sex was slightly increased in this cohort and there was a small delay in first-sex activity. This study elicits evidence of changes in sexual practice which could translate into targeted sexually transmitted infections prevention strategies. [ABSTRACT FROM AUTHOR]

This article, titled "Lessons From the COVID-19 Pandemic: Updating Our Approach to Masking in Health Care Facilities," discusses the importance of wearing masks in healthcare settings to reduce the transmission of COVID-19 and other respiratory viruses. The authors recommend the use of respirators for the highest level of protection, but acknowledge that in situations where respirators are not feasible, universal wearing of surgical masks can still be effective. They also emphasize the need for a comprehensive approach to reduce viral transmission, including measures such as ventilation, vaccination, sick leave policies, and symptom screening. The authors of the article are Eric J. Chow, John B. Lynch, Danielle M. Zerr, Francis X. Riedo, Mary Fairchok, Steven A. Pergam, Christopher S. Baliga, John Pauk, James Lewis, and Jeffrey S. Duchin. [Extracted from the article]

Background: Siblings of children with cancer may experience adverse household economic consequences, but their financial outcomes in adulthood are unknown. Methods: A total of 880 siblings (aged 18–64 years) of adult‐aged childhood cancer survivors were surveyed to estimate the prevalence of financial hardship by three established domains (behavioral, material, and psychological). For individual financial hardship items matching the contemporaneous National Health Interview Survey or Behavioral Risk Factor Surveillance System, siblings were compared with the general population by calculating adjusted prevalence odds ratios (ORs) to sample‐weighted responses. Multivariable logistic regression models examined associations between sibling characteristics and each hardship domain and between sibling hardship and survivors' cancer/treatment characteristics. Results: Behavioral, material, and psychological hardship was reported by 24%, 35%, and 28%, respectively. Compared with national survey respondents, siblings were more likely to report worries about medical bills (OR, 1.14; 95% confidence interval [CI], 1.06–1.22), difficulty affording nutritious foods (OR, 1.79; 95% CI, 1.54–2.07), and forgoing needed medical care (OR, 1.38; 95% CI, 1.10–1.73), prescription medications (OR, 2.52; 95% CI, 1.99–3.20), and dental care (OR, 1.34; 95% CI, 1.15–1.57) because of cost. Sibling characteristics associated with reporting financial hardship in one or more domains included female sex, older age, chronic health conditions, lower income, not having health insurance, high out‐of‐pocket medical expenditures, and nonmedical/nonhome debt. No survivor cancer/treatment characteristics were associated with sibling financial hardship. Conclusions: Adult siblings of childhood cancer survivors were more likely to experience financial hardship compared with the general population. Childhood cancer may adversely affect entire households, with potentially lasting implications. Adult siblings of long‐term childhood cancer survivors may experience greater aspects of financial hardship compared with the general population. A childhood cancer diagnosis and treatment may adversely affect entire households, with potentially lasting implications. [ABSTRACT FROM AUTHOR]

Background: Early during the COVID-19 pandemic, it was important to better understand transmission dynamics of SARS-CoV-2, the virus that causes COVID-19. Household contacts of infected individuals are particularly at risk for infection, but delays in contact tracing, delays in testing contacts, and isolation and quarantine posed challenges to accurately capturing secondary household cases. Methods: In this study, 346 households in the Seattle region were provided with respiratory specimen collection kits and remotely monitored using web-based surveys for respiratory illness symptoms weekly between October 1, 2020, and June 20, 2021. Symptomatic participants collected respiratory specimens at symptom onset and mailed specimens to the central laboratory in Seattle. Specimens were tested for SARS-CoV-2 using RT-PCR with whole genome sequencing attempted when positive. SARS-CoV-2-infected individuals were notified, and their household contacts submitted specimens every 2 days for 14 days. Results: In total, 1371 participants collected 2029 specimens that were tested; 16 individuals (1.2%) within 6 households tested positive for SARS-CoV-2 during the study period. Full genome sequences were generated from 11 individuals within 4 households. Very little genetic variation was found among SARS-CoV-2 viruses sequenced from different individuals in the same household, supporting transmission within the household. Conclusions: This study indicates web-based surveillance of respiratory symptoms, combined with rapid and longitudinal specimen collection and remote contact tracing, provides a viable strategy to monitor households and detect household transmission of SARS-CoV-2. Trial registration identifier: NCT04141930, Date of registration 28/10/2019. [ABSTRACT FROM AUTHOR]

Background We have previously developed an artificial intelligence–based risk assessment tool to identify the individual risk of HIV and sexually transmitted infections (STIs) in a sexual health clinical setting. Based on this tool, this study aims to determine the optimal risk score thresholds to identify individuals at high risk for HIV/STIs. Methods Using 2008–2022 data from 216 252 HIV, 227 995 syphilis, 262 599 gonorrhea, and 320 355 chlamydia consultations at a sexual health center, we applied MySTIRisk machine learning models to estimate infection risk scores. Optimal cutoffs for determining high-risk individuals were determined using Youden's index. Results The HIV risk score cutoff for high risk was 0.56, with 86.0% sensitivity (95% CI, 82.9%–88.7%) and 65.6% specificity (95% CI, 65.4%–65.8%). Thirty-five percent of participants were classified as high risk, which accounted for 86% of HIV cases. The corresponding cutoffs were 0.49 for syphilis (sensitivity, 77.6%; 95% CI, 76.2%–78.9%; specificity, 78.1%; 95% CI, 77.9%–78.3%), 0.52 for gonorrhea (sensitivity, 78.3%; 95% CI, 77.6%–78.9%; specificity, 71.9%; 95% CI, 71.7%–72.0%), and 0.47 for chlamydia (sensitivity, 68.8%; 95% CI, 68.3%–69.4%; specificity, 63.7%; 95% CI, 63.5%–63.8%). High-risk groups identified using these thresholds accounted for 78% of syphilis, 78% of gonorrhea, and 69% of chlamydia cases. The odds of positivity were significantly higher in the high-risk group than otherwise across all infections: 11.4 (95% CI, 9.3–14.8) times for HIV, 12.3 (95% CI, 11.4–13.3) for syphilis, 9.2 (95% CI, 8.8–9.6) for gonorrhea, and 3.9 (95% CI, 3.8–4.0) for chlamydia. Conclusions Risk scores generated by the AI-based risk assessment tool MySTIRisk , together with Youden's index, are effective in determining high-risk subgroups for HIV/STIs. The thresholds can aid targeted HIV/STI screening and prevention. [ABSTRACT FROM AUTHOR]