Target Delineation in Postoperative Radiation Therapy for Head and Neck Cancer After Flap Reconstruction.

Delineation of the clinical target volume (CTV) after resection of head and neck cancer can be challenging, especially after flap reconstruction. The main area of contention is whether the entire flap should be included in the CTV. Several case series have reported marginal misses and intraflap failures when the entire flap was not routinely included in the CTV. On the other hand, available data have not convincingly demonstrated a detriment to long-term outcomes using intensity modulated radiotherapy after flap reconstruction. On the contrary, postoperative radiation can facilitate epilation and mucosalization of the flap tissue, reduce flap bulk, and improve long-term esthetic and functional outcomes. Therefore, our standard practice is to include the entire flap in the CTV. In certain scenarios, we may allow for a lower dose to part of flap distant from the resection bed than the flap-tumor bed junction, where recurrences are most likely. We provide three case vignettes describing such scenarios where sparing part of the flap, and more importantly, the nearby uninvolved native tissue, from high-dose radiation may be justified.

Association of age at antiretroviral therapy initiation with CD4 +  : CD8 + ratio recovery among virally suppressed people with HIV.

OBJECTIVE: To investigate the association of age at antiretroviral therapy (ART) initiation with CD4 +  : CD8 + T-cell ratio in virally suppressed people with HIV on long-term ART, and to characterize potential CD4 +  : CD8 + ratio recovery in this population by age. DESIGN: A longitudinal study of people attending an HIV clinic at the Royal Free Hospital NHS Trust, London, who initiated ART between 2001 and 2015, and achieved and maintained HIV-1 viral suppression (viral load <1,000 copies/ml). The association of age group at ART initiation with CD4 +  : CD8 + ratio at 5 and 10 years was assessed. METHODS: Multivariable linear regression was used to investigate the relationship between age at ART initiation and log CD4 +  : CD8 + ratio, adjusting for demographic factors (gender/HIV transmission route, ethnicity), baseline CD4 + count and calendar year. RESULTS: The sample included 1859 people aged 20-78 (75% men, 56% white ethnicity). Overall, median CD4 +  : CD8 + T-cell ratio increased from 0.24 at baseline to 0.77 at year 5 and 0.88 at year 10. Ratios increased among all age groups in unadjusted and adjusted models but increased less among older ages (baseline ages 60-69 and 70-79). Median ratios at year 5 were 0.85, 0.80, 0.72, 0.76, 0.6, and 0.44, respectively, among people aged 20-29, 30-39, 40-49, 50-59, 60-69 and 70-79 years at baseline. CONCLUSION: In a virally suppressed London population, age had a substantial impact on CD4 +  : CD8 + ratio recovery, especially for those starting ART after age 60 years. Results may indicate the level of CD4 +  : CD8 + ratio recovery possible in an HIV-positive, virally suppressed, aging population.

Lifestyle management of hypertension: International Society of Hypertension position paper endorsed by the World Hypertension League and European Society of Hypertension.

Hypertension, defined as persistently elevated systolic blood pressure (SBP) >140 mmHg and/or diastolic blood pressure (DBP) at least 90 mmHg (International Society of Hypertension guidelines), affects over 1.5 billion people worldwide. Hypertension is associated with increased risk of cardiovascular disease (CVD) events (e.g. coronary heart disease, heart failure and stroke) and death. An international panel of experts convened by the International Society of Hypertension College of Experts compiled lifestyle management recommendations as first-line strategy to prevent and control hypertension in adulthood. We also recommend that lifestyle changes be continued even when blood pressure-lowering medications are prescribed. Specific recommendations based on literature evidence are summarized with advice to start these measures early in life, including maintaining a healthy body weight, increased levels of different types of physical activity, healthy eating and drinking, avoidance and cessation of smoking and alcohol use, management of stress and sleep levels. We also discuss the relevance of specific approaches including consumption of sodium, potassium, sugar, fibre, coffee, tea, intermittent fasting as well as integrated strategies to implement these recommendations using, for example, behaviour change-related technologies and digital tools.

Transforming global approaches to chronic disease prevention and management across the lifespan: integrating genomics, behavior change, and digital health solutions.

Chronic illnesses are a major threat to global population health through the lifespan into older age. Despite world-wide public health goals, there has been a steady increase in chronic and non-communicable diseases (e.g., cancer, cardiovascular and metabolic disorders) and strong growth in mental health disorders. In 2010, 67% of deaths worldwide were due to chronic diseases and this increased to 74% in 2019, with accelerated growth in the COVID-19 era and its aftermath. Aging and wellbeing across the lifespan are positively impacted by the presence of effective prevention and management of chronic illness that can enhance population health. This paper provides a short overview of the journey to this current situation followed by discussion of how we may better address what the World Health Organization has termed the "tsunami of chronic diseases." In this paper we advocate for the development, validation, and subsequent deployment of integrated: 1. Polygenic and multifactorial risk prediction tools to screen for those at future risk of chronic disease and those with undiagnosed chronic disease. 2. Advanced preventive, behavior change and chronic disease management to maximize population health and wellbeing. 3. Digital health systems to support greater efficiencies in population-scale health prevention and intervention programs. It is argued that each of these actions individually has an emerging evidence base. However, there has been limited research to date concerning the combined population-level health effects of their integration. We outline the conceptual framework within which we are planning and currently conducting studies to investigate the effects of their integration.

All-cause hospitalisation among people living with HIV according to gender, mode of HIV acquisition, ethnicity, and geographical origin in Europe and North America: findings from the ART-CC cohort collaboration.

BACKGROUND: Understanding demographic disparities in hospitalisation is crucial for the identification of vulnerable populations, interventions, and resource planning. METHODS: Data were from the Antiretroviral Therapy Cohort Collaboration (ART-CC) on people living with HIV in Europe and North America, followed up between January, 2007 and December, 2020. We investigated differences in all-cause hospitalisation according to gender and mode of HIV acquisition, ethnicity, and combined geographical origin and ethnicity, in people living with HIV on modern combination antiretroviral therapy (cART). Analyses were performed separately for European and North American cohorts. Hospitalisation rates were assessed using negative binomial multilevel regression, adjusted for age, time since cART intitiaion, and calendar year. FINDINGS: Among 23 594 people living with HIV in Europe and 9612 in North America, hospitalisation rates per 100 person-years were 16·2 (95% CI 16·0-16·4) and 13·1 (12·8-13·5). Compared with gay, bisexual, and other men who have sex with men, rates were higher for heterosexual men and women, and much higher for men and women who acquired HIV through injection drug use (adjusted incidence rate ratios ranged from 1·2 to 2·5 in Europe and from 1·2 to 3·3 in North America). In both regions, individuals with geographical origin other than the region of study generally had lower hospitalisation rates compared with those with geographical origin of the study country. In North America, Indigenous people and Black or African American individuals had higher rates than White individuals (adjusted incidence rate ratios 1·9 and 1·2), whereas Asian and Hispanic people living with HIV had somewhat lower rates. In Europe there was a lower rate in Asian individuals compared with White individuals. INTERPRETATION: Substantial disparities exist in all-cause hospitalisation between demographic groups of people living with HIV in the current cART era in high-income settings, highlighting the need for targeted support. FUNDING: Royal Free Charity and the National Institute on Alcohol Abuse and Alcoholism.

Retinopathy, Optic Neuropathy, and Cataract in Childhood Cancer Survivors Treated With Radiation Therapy: A PENTEC Comprehensive Review.

PURPOSE: Few reports describe the risks of late ocular toxicities after radiation therapy (RT) for childhood cancers despite their effect on quality of life. The Pediatric Normal Tissue Effects in the Clinic (PENTEC) ocular task force aims to quantify the radiation dose dependence of select late ocular adverse effects. Here, we report results concerning retinopathy, optic neuropathy, and cataract in childhood cancer survivors who received cranial RT. METHODS AND MATERIALS: A systematic literature search was performed using the PubMed, MEDLINE, and Cochrane Library databases for peer-reviewed studies published from 1980 to 2021 related to childhood cancer, RT, and ocular endpoints including dry eye, keratitis/corneal injury, conjunctival injury, cataract, retinopathy, and optic neuropathy. This initial search yielded abstracts for 2947 references, 269 of which were selected as potentially having useful outcomes and RT data. Data permitting, treatment and outcome data were used to generate normal tissue complication probability models. RESULTS: We identified sufficient RT data to generate normal tissue complication probability models for 3 endpoints: retinopathy, optic neuropathy, and cataract formation. Based on limited data, the model for development of retinopathy suggests 5% and 50% risk of toxicity at 42 and 62 Gy, respectively. The model for development of optic neuropathy suggests 5% and 50% risk of toxicity at 57 and 64 Gy, respectively. More extensive data were available to evaluate the risk of cataract, separated into self-reported versus ophthalmologist-diagnosed cataract. The models suggest 5% and 50% risk of self-reported cataract at 12 and >40 Gy, respectively, and 50% risk of ophthalmologist-diagnosed cataract at 9 Gy (>5% long-term risk at 0 Gy in patients treated with chemotherapy only). CONCLUSIONS: Radiation dose effects in the eye are inadequately studied in the pediatric population. Based on limited published data, this PENTEC comprehensive review establishes relationships between RT dose and subsequent risks of retinopathy, optic neuropathy, and cataract formation.

Switching it up: Activity diversity and cognitive functioning in later life.

Participating in a broad and balanced range of daily activities (i.e., activity diversity) has been associated with better cognitive functioning in later life. One possible explanation for this finding is that high levels of activity diversity are merely a proxy for being more physically active, a factor robustly linked to cognitive health. The present study examined whether activity diversity has a unique association with cognitive functioning beyond physical movement. Community-dwelling older adults (N = 252, Mage = 73.55 years, SD = 6.39) completed a cognitive battery and then responded to ecological momentary assessments of their participation in 10 common activity types (e.g., reading, chores, social visits) every 3 hr for 5-6 days. They also wore accelerometers to track daily physical movement. Multiple regression models revealed that greater diversity in daily activities was related to higher cognitive functioning even after adjusting for physical movement and other covariates such as education level. This study further clarifies the unique relationship of activity diversity, beyond physical movement, with cognition. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Methods for Embedding Cell-Free Protein Synthesis Reactions in Macro-Scale Hydrogels.

Synthetic gene networks provide a platform for scientists and engineers to design and build novel systems with functionality encoded at a genetic level. While the dominant paradigm for the deployment of gene networks is within a cellular chassis, synthetic gene networks may also be deployed in cell-free environments. Promising applications of cell-free gene networks include biosensors, as these devices have been demonstrated against biotic (Ebola, Zika, and SARS-CoV-2 viruses) and abiotic (heavy metals, sulfides, pesticides, and other organic contaminants) targets. Cell-free systems are typically deployed in liquid form within a reaction vessel. Being able to embed such reactions in a physical matrix, however, may facilitate their broader application in a wider set of environments. To this end, methods for embedding cell-free protein synthesis (CFPS) reactions in a variety of hydrogel matrices have been developed. One of the key properties of hydrogels conducive to this work is the high-water reconstitution capacity of hydrogel materials. Additionally, hydrogels possess physical and chemical characteristics that are functionally beneficial. Hydrogels can be freeze-dried for storage and rehydrated for use later. Two step-by-step protocols for the inclusion and assay of CFPS reactions in hydrogels are presented. First, a CFPS system can be incorporated into a hydrogel via rehydration with a cell lysate. The system within the hydrogel can then be induced or expressed constitutively for complete protein expression through the hydrogel. Second, cell lysate can be introduced to a hydrogel at the point of polymerization, and the entire system can be freeze-dried and rehydrated at a later point with an aqueous solution containing the inducer for the expression system encoded within the hydrogel. These methods have the potential to allow for cell-free gene networks that confer sensory capabilities to hydrogel materials, with the potential for deployment beyond the laboratory.

Feasibility of the Audio-Visual Assisted Therapeutic Ambience in Radiotherapy (AVATAR) System for Anesthesia Avoidance in Pediatric Patients: A Multicenter Trial.

PURPOSE: The Audio-Visual Assisted Therapeutic Ambience in Radiotherapy (AVATAR) system was the first published radiation therapy (RT)-compatible system to reduce the need for pediatric anesthesia through video-based distraction. We evaluated the feasibility of AVATAR implementation and effects on anesthesia use, quality of life, and anxiety in a multicenter pediatric trial. METHODS AND MATERIALS: Pediatric patients 3 to 10 years of age preparing to undergo RT at 10 institutions were prospectively enrolled. Children able to undergo at least 1 fraction of RT using AVATAR without anesthesia were considered successful (S). Patients requiring anesthesia for their entire treatment course were nonsuccessful (NS). The PedsQL3.0 Cancer Module (PedsQL) survey assessed quality of life and was administered to the patient and guardian at RT simulation, midway through RT, and at final treatment. The modified Yale Preoperative Anxiety Scale (mYPAS) assessed anxiety and was performed at the same 3 time points. Success was evaluated using the χ2 test. PedsQL and mYPAS scores were assessed using mixed effects models with time points evaluated as fixed effects and a random intercept on the subject. RESULTS: Eighty-one children were included; median age was 7 years. AVATAR was successful at all 10 institutions and with photon and proton RT. There were 63 (78%) S patients; anesthesia was avoided for a median of 20 fractions per patient. Success differed by age (P = .04) and private versus public insurance (P < .001). Both patient (P = .008) and parent (P = .006) PedsQL scores significantly improved over the course of RT for patients aged 5 to 7. Anxiety in the treatment room decreased for both S and NS patients over RT course (P < .001), by age (P < .001), and by S versus NS patients (P < .001). CONCLUSIONS: In this 10-center prospective trial, anesthesia avoidance with AVATAR was 78% in children aged 3 to 10 years, higher than among age-matched historical controls (49%; P < .001). AVATAR implementation is feasible across multiple institutions and should be further studied and made available to patients who may benefit from video-based distraction.

Loss of FoxOs in muscle increases strength and mitochondrial function during aging.

BACKGROUND: Muscle mitochondrial decline is associated with aging-related muscle weakness and insulin resistance. FoxO transcription factors are targets of insulin action and deletion of FoxOs improves mitochondrial function in diabetes. However, disruptions in proteostasis and autophagy are hallmarks of aging and the effect of chronic inhibition of FoxOs in aged muscle is unknown. This study investigated the role of FoxOs in regulating muscle strength and mitochondrial function with age. METHODS: We measured muscle strength, cross-sectional area, muscle fibre-type, markers of protein synthesis/degradation, central nuclei, glucose/insulin tolerance, and mitochondrial bioenergetics in 4.5-month (Young) and 22-24-month-old (Aged) muscle-specific FoxO1/3/4 triple KO (TKO) and littermate control (Ctrl) mice. RESULTS: Lean mass was increased in Aged TKO compared with both Aged Ctrl and younger groups by 26-33% (P < 0.01). Muscle strength, measured by max force of tibialis anterior (TA) contraction, was 20% lower in Aged Ctrl compared with Young Ctrls (P < 0.01) but was not decreased in Aged TKOs. Increased muscle strength in Young and Aged TKO was associated with 18-48% increased muscle weights compared with Ctrls (P < 0.01). Muscle cross-sectional analysis of TA, soleus, and plantaris revealed increases in fibre size distribution and a 2.5-10-fold increase in central nuclei in Young and Aged TKO mice, without histologic signs of muscle damage. Age-dependent increases in Gadd45a and Ube4a expression as well accumulation of K48 polyubiquitinated proteins were observed in quad and TA but were prevented by FoxO deletion. Young and Aged TKO muscle showed minimal changes in autophagy flux and no accumulation of autophagosomes compared with Ctrl groups. Increased strength in Young and Aged TKO was associated with a 10-20% increase in muscle mitochondrial respiration using glutamate/malate/succinate compared with controls (P < 0.05). OXPHOS subunit expression and complex I activity were decreased 16-34% in Aged Ctrl compared with Young Ctrl but were prevented in Aged TKO. Both Aged Ctrl and Aged TKO showed impaired glucose tolerance by 33% compared to young groups (P < 0.05) indicating improved strength and mitochondrial respiration are not due to improved glycemia. CONCLUSIONS: FoxO deletion increases muscle strength even during aging. Deletion of FoxOs maintains muscle strength in part by mild suppression of atrophic pathways, including inhibition of Gadd45a and Ube4a expression, without accumulation of autophagosomes in muscle. Deletion of FoxOs also improved mitochondrial function by maintenance of OXPHOS in both young and aged TKO.

Physical Activity and Daily Stress Processes in Older Adulthood.

OBJECTIVES: Older adults who are physically active report lower levels of stress. Less is known about the links between physical activity and exposure and reactivity to stressful events in daily life. The current study examined within-person associations between actigraphy-assessed daily physical activity and exposure and affective reactivity to naturally occurring interpersonal stressors. METHOD: Older adults (N = 180) from the Daily Experiences and Well-being Study completed ecological momentary assessments (EMAs) every 3 hr for 5-6 days where they reported negative affect throughout the day and interpersonal tensions at the end of the day. They also wore Actical accelerometers to capture physical activity. RESULTS: Older adults reported greater numbers of interpersonal stressors on days when they spent less time being sedentary and engaged in more light physical activity. On days when older adults experienced more interpersonal stressors, they reported higher levels of negative affect, but this association was attenuated when they were more physically active that day. DISCUSSION: Physical activity may bolster older adults' capabilities to manage affective responses to interpersonal stressors in a more successful way. These findings underscore the importance of assessing physical activity and stressful events in daily life and have implications for both physical and psychological well-being.

Kelp carbon sink potential decreases with warming due to accelerating decomposition.

Cycling of organic carbon in the ocean has the potential to mitigate or exacerbate global climate change, but major questions remain about the environmental controls on organic carbon flux in the coastal zone. Here, we used a field experiment distributed across 28° of latitude, and the entire range of 2 dominant kelp species in the northern hemisphere, to measure decomposition rates of kelp detritus on the seafloor in relation to local environmental factors. Detritus decomposition in both species were strongly related to ocean temperature and initial carbon content, with higher rates of biomass loss at lower latitudes with warmer temperatures. Our experiment showed slow overall decomposition and turnover of kelp detritus and modeling of coastal residence times at our study sites revealed that a significant portion of this production can remain intact long enough to reach deep marine sinks. The results suggest that decomposition of these kelp species could accelerate with ocean warming and that low-latitude kelp forests could experience the greatest increase in remineralization with a 9% to 42% reduced potential for transport to long-term ocean sinks under short-term (RCP4.5) and long-term (RCP8.5) warming scenarios. However, slow decomposition at high latitudes, where kelp abundance is predicted to expand, indicates potential for increasing kelp-carbon sinks in cooler (northern) regions. Our findings reveal an important latitudinal gradient in coastal ecosystem function that provides an improved capacity to predict the implications of ocean warming on carbon cycling. Broad-scale patterns in organic carbon decomposition revealed here can be used to identify hotspots of carbon sequestration potential and resolve relationships between carbon cycling processes and ocean climate at a global scale.

In Situ Assembly of Platinum(II)-Metallopeptide Nanostructures Disrupts Energy Homeostasis and Cellular Metabolism.

Nanostructure-based functions are omnipresent in nature and essential for the diversity of life. Unlike small molecules, which are often inhibitors of enzymes or biomimetics with established methods of elucidation, we show that functions of nanoscale structures in cells are complex and can implicate system-level effects such as the regulation of energy and redox homeostasis. Herein, we design a platinum(II)-containing tripeptide that assembles into intracellular fibrillar nanostructures upon molecular rearrangement in the presence of endogenous H2O2. The formed nanostructures blocked metabolic functions, including aerobic glycolysis and oxidative phosphorylation, thereby shutting down ATP production. As a consequence, ATP-dependent actin formation and glucose metabolite-dependent histone deacetylase activity are downregulated. We demonstrate that assembly-driven nanomaterials offer a rich avenue to achieve broad-spectrum bioactivities that could provide new opportunities in drug discovery.

Nanoscale patterning of polymers on DNA origami.

The combination of DNA-origami and synthetic polymers paves the way to a new class of structurally precise biohybrid nanomaterials for diverse applications. Herein, we introduce the grafting to method with high conversions (70-90%) under ambient conditions to generate DNA-polymer conjugates, which can hybridized precisely to DNA-origami architectures. We generated homo and block copolymers from three different polymer families (acrylates, methacrylates and acrylamides), coupled them to single stranded DNA (ssDNA) and pattern different DNA-origami architectures to demonstrate the formation of precise surface nanopatterns.

A B-cell or a key player? The different roles of B-cells and antibodies in melanoma.

The B-cell system plays an important role in the melanoma immune response; however, consensus has yet to be reached in many facets. Here, we comprehensively review human studies only, due to fundamental differences in the humoral response with animal models. Tumour-infiltrating B-cells are associated with contradictory prognostic values, reflecting a lack of agreement between studies on cell subset classification and differences in the markers used, particularly the common use of a single marker not differentiating multiple subsets. Tertiary lymphoid structures (TLS) organise T-cells and B-cells within tumours to generate a local anti-tumour response and TLS presence associates with improved survival in response to immune checkpoint blockade, in late-stage disease. Autoantibody production is increased in melanoma patients and has been proposed as biomarkers for diagnosis, prognosis and treatment/toxicity response; however, no consistent targets are yet identified. The function of antibodies in an anti-tumour response is determined by its isotype and subclass; IgG4 is immune-suppressive and robustly correlate with poor patient survival in melanoma. We conclude that the current B-cell literature needs careful interpretation based on the methods used and that we need a consensus of markers to define B-cells and associated lymphoid organs. Furthermore, future studies need to not only examine antibody targets, but also isotypes when considering functional roles.

Key reaction components affect the kinetics and performance robustness of cell-free protein synthesis reactions.

Cell-free protein synthesis (CFPS) reactions have grown in popularity with particular interest in applications such as gene construct prototyping, biosensor technologies and the production of proteins with novel chemistry. Work has frequently focussed on optimising CFPS protocols for improving protein yield, reducing cost, or developing streamlined production protocols. Here we describe a statistical Design of Experiments analysis of 20 components of a popular CFPS reaction buffer. We simultaneously identify factors and factor interactions that impact on protein yield, rate of reaction, lag time and reaction longevity. This systematic experimental approach enables the creation of a statistical model capturing multiple behaviours of CFPS reactions in response to components and their interactions. We show that a novel reaction buffer outperforms the reference reaction by 400% and importantly reduces failures in CFPS across batches of cell lysates, strains of E. coli, and in the synthesis of different proteins. Detailed and quantitative understanding of how reaction components affect kinetic responses and robustness is imperative for future deployment of cell-free technologies.

Does Diversity of Social Ties Really Matter More for Health and Leisure Activity than Number of Social Ties? Evidence from Later Adulthood.

OBJECTIVES: Claims that the diversity of social ties matters more for health than the sheer number of ties have largely gone untested. This study accordingly compared the unique associations of number versus diversity of social ties with key health-related outcomes: functional limitations and leisure activities. Additionally, positive and ambivalent ties were distinguished. METHODS: Social networks, health, and leisure activities were assessed in a national sample of older adults (N = 874; ages 65-91). RESULTS: Regression analyses revealed that number of ties related to each outcome at a magnitude comparable to, or exceeding, that of diversity in most models. For positive ties, number related more strongly than diversity to greater leisure activities. For ambivalent ties, number related more strongly than diversity to worse functional limitations. DISCUSSION: Contrary to prevailing views, diversity of ties is not necessarily more important than number of ties. Findings extend scientific understanding and approaches to interventions.