Impact of immunotherapy time-of-day infusion on survival and immunologic correlates in patients with metastatic renal cell carcinoma: a multicenter cohort analysis.

BACKGROUND: Recent studies have demonstrated that earlier time-of-day infusion of immune checkpoint inhibitors (ICIs) is associated with longer progression-free survival (PFS) and overall survival (OS) among patients with metastatic melanoma and non-small cell lung cancer. These data are in line with growing preclinical evidence that the adaptive immune response may be more effectively stimulated earlier in the day. We sought to determine the impact of time-of-day ICI infusions on outcomes among patients with metastatic renal cell carcinoma (mRCC). METHODS: The treatment records of all patients with stage IV RCC who began ICI therapy within a multicenter academic hospital system between 2015 and 2020 were reviewed. The associations between the proportion of ICI infusions administered prior to noon (denoting morning infusions) and PFS and OS were evaluated using univariate and multivariable Cox proportional hazards regression. RESULTS: In this study, 201 patients with mRCC (28% women) received ICIs and were followed over a median of 18 months (IQR 5-30). The median age at the time of ICI initiation was 63 years (IQR 56-70). 101 patients (50%) received ≥20% of their ICI infusions prior to noon (Group A) and 100 patients (50%) received <20% of infusions prior to noon (Group B). Across the two comparison groups, initial ICI agents consisted of nivolumab (58%), nivolumab plus ipilimumab (34%), and pembrolizumab (8%). On univariate analysis, patients in Group A had longer PFS and OS compared with those in Group B (PFS HR 0.67, 95% CI 0.48 to 0.94, Punivar=0.020; OS HR 0.57, 95% CI 0.34 to 0.95, Punivar=0.033). These significant findings persisted following multivariable adjustment for age, sex, performance status, International Metastatic RCC Database Consortium risk score, pretreatment lactate dehydrogenase, histology, and presence of bone, brain, and liver metastases (PFS HR 0.70, 95% CI 0.50 to 0.98, Pmultivar=0.040; OS HR 0.57, 95% CI 0.33 to 0.98, Pmultivar=0.043). CONCLUSIONS: Patients with mRCC may benefit from earlier time-of-day receipt of ICIs. Our findings are consistent with established mechanisms of chrono-immunology, as well as with preceding analogous studies in melanoma and lung cancer. Additional prospective randomized trials are warranted.

Radiation and anti-PD-L1 synergize by stimulating a stem-like T cell population in the tumor-draining lymph node.

Radiotherapy (RT) and anti-PD-L1 synergize to enhance local and distant (abscopal) tumor control. However, clinical results in humans have been variable. With the goal of improving clinical outcomes, we investigated the underlying synergistic mechanism focusing on a CD8+ PD-1+ Tcf-1+ stem-like T cell subset in the tumor-draining lymph node (TdLN). Using murine melanoma models, we found that RT + anti-PD-L1 induces a novel differentiation program in the TdLN stem-like population which leads to their expansion and differentiation into effector cells within the tumor. Our data indicate that optimal synergy between RT + anti-PD-L1 is dependent on the TdLN stem-like T cell population as either blockade of TdLN egress or specific stem-like T cell depletion reduced tumor control. Together, these data demonstrate a multistep stimulation of stem-like T cells following combination therapy which is initiated in the TdLN and completed in the tumor.

SAMHD1 expression contributes to doxorubicin resistance and predicts survival outcomes in diffuse large B-cell lymphoma patients.

Diffuse large B-cell lymphoma (DLBCL) is a commonly diagnosed, aggressive non-Hodgkin's lymphoma. While R-CHOP chemoimmunotherapy is potentially curative, about 40% of DLBCL patients will fail, highlighting the need to identify biomarkers to optimize management. SAMHD1 has a dNTPase-independent role in promoting resection to facilitate DNA double-strand break (DSB) repair by homologous recombination. We evaluated the relationship of SAMHD1 levels with sensitivity to DSB-sensitizing agents in DLBCL cells and the association of SAMHD1 expression with clinical outcomes in 79 DLBCL patients treated with definitive therapy and an independent cohort dataset of 234 DLBCL patients. Low SAMHD1 expression, Vpx-mediated, or siRNA-mediated degradation/depletion in DLBCL cells was associated with greater sensitivity to doxorubicin and PARP inhibitors. On Kaplan-Meier log-rank survival analysis, low SAMHD1 expression was associated with improved overall survival (OS), which on subset analysis remained significant only in patients with advanced stage (III-IV) and moderate to high risk (2-5 International Prognostic Index (IPI)). The association of low SAMHD1 expression with improved OS remained significant on multivariate analysis independent of other adverse factors, including IPI, and was validated in an independent cohort. Our findings suggest that SAMHD1 expression mediates doxorubicin resistance and may be an important prognostic biomarker in advanced, higher-risk DLBCL patients.

Development of chitosan biopolymer by chemically modified orange peel for safranin O dye removal: A sustainable adsorbent and adsorption modeling using RSM-BBD.

This study aimed to develop a biocomposite (hereinafter, CHI/OP-H2SO4) via the functionalization of chitosan (CHI) biopolymer by chemically modified orange peel (OP-H2SO4). The physicochemical characteristics of CHI/OP-H2SO4 were studied using methods such as pHpzc, XRD, FTIR, BET, and FESEM-EDX. The efficacy of the CHI/OP-H2SO4 biocomposite in removing cationic dye (safranin O, SAF-O) from aqueous solutions was assessed. The Box-Behnken Design (BBD) based on response surface methodology (RSM) was employed to optimize the adsorption performance of CHI/OP-H2SO4, considering factors such as A: CHI/OP-H2SO4 dose (0.02-0.08 g), B: pH (4-10), and C: time (10-60 min). The pseudo-first-order and Freundlich isotherm models align well with the experimental data of SAF-O adsorption by CHI/OP-H2SO4. The excellent adsorption capacity for CHI/OP-H2SO4 was recorded (321.2 mg/g). The notable adsorption of SAF-O onto CHI/OP-H2SO4 is attributed primarily to electrostatic forces between the acidic groups of CHI/OP-H2SO4 and the SAF-O cation, along with H-bonding, and n-π interactions. By transforming waste materials into valuable resources, this approach not only mitigates environmental impact but also produces a promising and sustainable adsorbent for the removal of cationic dyes, exemplified here by the effective removal of SAF-O dye.

Chitosan/functionalized fruit stones as a highly efficient adsorbent biomaterial for adsorption of brilliant green dye: Comprehensive characterization and statistical optimization.

In this research, a highly efficient adsorbent biomaterial (hereinafter, CTS/PPS-HS) of chitosan/functionalized fruit stones (peach and plum) with H2SO4 was produced for the adsorption of brilliant green (BG) dye from aquatic systems. The developed biomaterial was characterized by several techniques like SEM-EDX, FTIR, XRD, BET, and pHpzc. To systematically optimize the adsorption performance of CTS/PPS-HS, the Box-Behnken design (BBD) based on response surface methodology (RSM) was attained. The factors considered for optimization included A: CTS/PPS-HS dosage (0.02-0.08 g), B: pH (4-10), and C: removal time (10-60 min). The pseudo-first-order and Langmuir isotherm models exhibited excellent agreement with the experimental results of BG adsorption by CTS/PPS-HS. The outstanding adsorption capacity (409.63 mg/g) of CTS/PPS-HS was obtained. The remarkable adsorption of BG onto CTS/PPS-HS can be primarily attributed to electrostatic forces between the acidic sites of CTS/PPS-HS and the BG cations, accompanied by interactions such as π-π, Yoshida H-bonding, n-π, and H-bond interactions. The current data underscores the significant potential inherent in combining biomass with CTS polymer to create an exceptionally effective adsorbent biomaterial tailored for the elimination of cationic dyes.

Total scalp irradiation: A study comparing multiple types of bolus and VMAT optimization techniques.

PURPOSE: To investigate bolus design and VMAT optimization settings for total scalp irradiation. METHODS: Three silicone bolus designs (flat, hat, and custom) from .decimal were evaluated for adherence to five anthropomorphic head phantoms. Flat bolus was cut from a silicone sheet. Generic hat bolus resembles an elongated swim cap while custom bolus is manufactured by injecting silicone into a 3D printed mold. Bolus placement time was recorded. Air gaps between bolus and scalp were quantified on CT images. The dosimetric effect of air gaps on target coverage was evaluated in a treatment planning study where the scalp was planned to 60 Gy in 30 fractions. A noncoplanar VMAT technique based on gEUD penalties was investigated that explored the full range of gEUD alpha values to determine which settings achieve sufficient target coverage while minimizing brain dose. ANOVA and the t-test were used to evaluate statistically significant differences (threshold = 0.05). RESULTS: The flat bolus took 32 ± 5.9 min to construct and place, which was significantly longer (p < 0.001) compared with 0.67 ± 0.2 min for the generic hat bolus or 0.53 ± 0.10 min for the custom bolus. The air gap volumes were 38 ± 9.3 cc, 32 ± 14 cc, and 17 ± 7.0 cc for the flat, hat, and custom boluses, respectively. While the air gap differences between the flat and custom boluses were significant (p = 0.011), there were no significant dosimetric differences in PTV coverage at V57Gy or V60Gy. In the VMAT optimization study, a gEUD alpha of 2 was found to minimize the mean brain dose. CONCLUSIONS: Two challenging aspects of total scalp irradiation were investigated: bolus design and plan optimization. Results from this study show opportunities to shorten bolus fabrication time during simulation and create high quality treatment plans using a straightforward VMAT template with simple optimization settings.

Effect of Number of Tests on the Mechanical Characteristics of Agave sisalana Yarns for Composites Structures: Statistical Approach.

A designer of sustainable biocomposite structures and natural ropes needs to have a high confidence interval (95% CI) for mechanical characteristics data of performance materials, yet qualities for plant-based fibers are very diverse. A comprehensive study of the elements that enhance the performance of biocomposites or sustainable ropes created from vegetable fibers is necessary. The current study included five groups with varying numbers (N) of tests of 20, 40, 60, 80, and 100 on the mechanical characteristics at room temperatures. The purpose of this study was to determine how changing N affects the mechanical properties of sisal yarn. These properties include its strength, Young's modulus, and deformation at rupture. A significance testing program including more than 100 tests was performed. Owing to the heterogeneity of the plant yarn, each group received more than 20 samples at a gauge length (GL) of 100 mm. The tensile strength characteristics of sisal yarns produced a wide range of findings, as is common for natural fibers, necessitating a statistical analysis. Its dispersion was explored and measured using the statistical methods. The Weibull distribution with two parameters and a prediction model with a 95% confidence level for maximum likelihood (ML) and least squares (LS) were used to investigate and quantify its dispersion.

Effect of Fiber Loading on Thermal Properties of Cellulosic Washingtonia Reinforced HDPE Biocomposites.

In this research work, we aim to study the effect of the incorporation of vegetable fiber reinforcement on the thermo-mechanical and dynamic properties of a composite formed by a polymeric matrix reinforced with cellulosic fibers with the various Washingtonia fiber (WF) loadings (0%, 10%, 20%, and 30% by wt%) as reinforced material in high-density polyethylene (HDPE) Biocomposites to evaluate the optimum fiber loading of biocomposites. In addition, several characterization techniques (i.e., thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), dynamic mechanical analysis (DMA), and thermal mechanical analysis (TMA)) were used to better understand the characteristics of the new composites prepared. With these techniques, we managed to verify the rigidity and thermal stability of the composites so elaborated, as well as the success of the polymer and the structural homogeneity of the obtained biocomposites. Hence, the biocomposite with the best ratio (HDPE/20WF) showed a loss modulus (E″) of 224 MPa, a storage modulus (E') of 2079 MPa, and a damping factor (Tanδ) of 0.270 to the glass transition (Tg) of 145 °C. In addition, thermomechanical analysis (TMA) of the biocomposite samples exhibited marginally higher Ts compared to the HDPE matrix. The best results were recorded with biocomposites with 20% WF, which showed better thermal properties. This composite material can be used as insulation in construction materials (buildings, false ceilings, walls, etc.).

Enhanced Open-Hole Strength and Toughness of Sandwich Carbon-Kevlar Woven Composite Laminates.

Fiber-reinforced plastic composites are sensitive to holes, as they cut the main load-carrying member in the composite (fibers) and they induce out-of-plane stresses. In this study, we demonstrated notch sensitivity enhancement in a hybrid carbon/epoxy (CFRP) composite with a Kevlar core sandwich compared to monotonic CFRP and Kevlar composites. Open-hole tensile samples were cut using waterjet cutting at different width to diameter ratios and tested under tensile loading. We performed an open-hole tension (OHT) test to characterize the notch sensitivity of the composites via the comparison of the open-hole tensile strength and strain as well as the damage propagation (as monitored via CT scan). The results showed that hybrid laminate has lower notch sensitivity than CFRP and KFRP laminates because the strength reduction rate with hole size was lower. Moreover, this laminate showed no reduction in the failure strain by increasing the hole size up to 12 mm. At w/d = 6, the lowest drop in strength showed by the hybrid laminate was 65.4%, followed by the CFRP and KFRP laminates with 63.5% and 56.1%, respectively. For the specific strength, the hybrid laminate showed a 7% and 9% higher value as compared with CFRP and KFRP laminates, respectively. The enhancement in notch sensitivity was due to its progressive damage mode, which was initiated via delamination at the Kevlar-carbon interface, followed by matrix cracking and fiber breakage in the core layers. Finally, matrix cracking and fiber breakage occurred in the CFRP face sheet layers. The specific strength (normalized strength and strain to density) and strain were larger for the hybrid than the CFRP and KFRP laminates due to the lower density of Kevlar fibers and the progressive damage modes which delayed the final failure of the hybrid composite.

Immune niches in brain metastases contain TCF1+ stem-like T cells, are associated with disease control and are modulated by preoperative SRS.

The CD8+ T-cell response is prognostic for survival outcomes in several tumor types. However, whether this extends to tumors in the brain, an organ with barriers to T cell entry, remains unclear. Here, we analyzed immune infiltration in 67 brain metastasis (BrM) and found high frequencies of PD1+ TCF1+ stem-like CD8+ T-cells and TCF1- effector-like cells. Importantly, the stem-like cells aggregate with antigen presenting cells in immune niches, and niches were prognostic for local disease control. Standard of care for BrM is resection followed by stereotactic radiosurgery (SRS), so to determine SRS's impact on the BrM immune response, we examined 76 BrM treated with pre-operative SRS (pSRS). pSRS acutely reduced CD8+ T cells at 3 days. However, CD8+ T cells rebounded by day 6, driven by increased frequency of effector-like cells. This suggests that the immune response in BrM can be regenerated rapidly, likely by the local TCF1+ stem-like population.

Low-dose radiotherapy for COVID-19 pneumonia and cancer: summary of a recent symposium and future perspectives.

The lessons learned from the Coronavirus Disease 2019 (COVID-19) pandemic are numerous. Low dose radiotherapy (LDRT) was used in the pre-antibiotic era as treatment for bacterially/virally associated pneumonia. Motivated in part by these historic clinical and radiobiological data, LDRT for treatment of COVID-19-associated pneumonia was proposed in early 2020. Although there is a large body of epidemiological and experimental data pointing to effects such as cancer at low doses, there is some evidence of beneficial health effects at low doses. It has been hypothesized that low dose radiation could be combined with immune checkpoint therapy to treat cancer. We shall review here some of these old radiobiological and epidemiological data, as well as the newer data on low dose radiation and stimulated immune response and other relevant emerging data. The paper includes a summary of several oral presentations given in a Symposium on "Low dose RT for COVID and other inflammatory diseases" as part of the 67th Annual Meeting of the Radiation Research Society, held virtually 3-6 October 2021.

Clinical Presentation and Outcome Differences Between Black Patients and Patients of Other Races and Ethnicities With Mycosis Fungoides and Sézary Syndrome.

Importance: Mycosis fungoides and Sézary syndrome (MF/SS) has an increased incidence in Black patients, but clinical characteristics, treatments, and outcomes have been poorly characterized. Objective: To assess racial differences in presentation and outcome and identify drivers for racial disparities in MF/SS. Design, Setting, and Participants: A retrospective cohort analysis was conducted of 566 patients with MF/SS diagnosed from 1990 to 2020 and seen at the Winship Cancer Institute of Emory University and Grady Memorial Hospital, both in Atlanta, Georgia. Self-reported race and ethnicity were obtained from patient medical records and analyzed as 2 groups: non-Hispanic Black (Black) and all other races and ethnicities, including Asian, Hispanic, White, and unknown/undeclared (non-Black). Main Outcomes and Measures: Univariate and multivariable models and Kaplan-Meier assessments were analyzed for overall survival and time to next treatment. The primary outcome was to assess differences in overall survival by racial and ethnic group. The hypotheses were formulated prior to data collection. Results: Of the 566 patients with MF/SS identified (mean [SD] age 55 [16.4] years; 270 (47.7%) female), 257 were Black and 309 were non-Black. Black race was associated with increased rates of progression to a higher TNMB stage (39.8% in Black patients vs 29.1% in non-Black patients; P < .001) but not survival. Black patients were younger and had increased female predominance, higher TNMB stage, higher tumor stage, nodal involvement, and higher lactate dehydrogenase level compared with non-Black patients with MF/SS. Hypopigmented MF (HMF) was found in 62 patients, who were mostly Black (n = 59). Hypopigmented MF was significantly associated with survival on univariate and multivariable models, with 10-year survival of 100% in patients with HMF compared with 51.8% in patients without HMF. Black race was only associated with inferior outcomes after excluding patients with HMF who were younger than 60 years (hazard ratio [HR], 1.61; 95% CI, 1.02-2.55; P = .04), but not in patients older than 60 years (HR, 1.20; 95% CI, 0.80-1.81; P = .37). On multivariate analysis, among the cohort without HMF who were younger than 60 years, Black race remained statistically significant when controlling for cancer stage and large-cell transformation (HR, 1.27; 95% CI, 1.08-2.87; P = .43). Conclusions and Relevance: In this cohort study, Black patients with MF/SS showed distinct clinical presentations and patterns of progression with heterogeneous outcomes depending on age at presentation and presence of HMF.

From best practice to next practice: implementing Comprehensive School Health in rural and remote northern communities. / D'une pratique exemplaire à la pratique subséquente : mise en œuvre de l'Approche globale de la santé en milieu scolaire dans les collectivités rurales et éloignées du Nord.

INTRODUCTION: Northern communities in Canada experience a disproportionate burden of chronic diseases including mental illness. To mitigate the growing health inequalities, an ongoing Comprehensive School Health program promoting healthy lifestyle behaviours and mental health and well-being was expanded to rural and remote northern communities. We report on the program's impact on knowledge, attitudes, lifestyle behaviours (healthy eating, physical activity, screen time), weight status and the mental health and well-being of elementary school students during the first four years of implementation. METHODS: Following a repeated cross-sectional design, we surveyed 440, 352 and 384 Grade 4 to 6 students (9-12 years old) from eight schools in 2016, 2018 and 2020/21, respectively. Students were approximately equally represented by girls and boys. RESULTS: Between 2016 and 2018, students reported modest increases in vegetable and fruit consumption and dietary variety; declines in screen time; no changes in physical activity; and declines in attitudes toward healthy lifestyle and in mental health and well-being. Between 2018 and 2020/21, lifestyle behaviours deteriorated substantially, while attitudes and mental health and well-being continued to decline. CONCLUSION: A program that was successful in socioeconomically disadvantaged urban neighbourhoods had a favourable, though modest, impact on selected lifestyle behaviours, but not on attitudes and mental health and well-being, in rural and remote northern communities. In light of cultural differences and logistical challenges in Canada's North, systematic and proactive adaptations to local contexts, increased intensity, and longer program delivery are essential to facilitate sustainable improvements in lifestyle behaviours and mental health and well-being.

Kinetics and Adsorption Isotherms of Amine-Functionalized Magnesium Ferrite Produced Using Sol-Gel Method for Treatment of Heavy Metals in Wastewater.

This study is focused on the kinetics and adsorption isotherms of amine-functionalized magnesium ferrite (MgFe2O4) for treating the heavy metals in wastewater. A sol-gel route was adopted to produce MgFe2O4 nanoparticles. The surfaces of the MgFe2O4 nanoparticles were functionalized using primary amine (ethanolamine). The surface morphology, phase formation, and functionality of the MgFe2O4 nano-adsorbents were studied using the SEM, UV-visible, FTIR, and TGA techniques. The characterized nanoparticles were tested on their ability to adsorb the Pb2+, Cu2+, and Zn2+ ions from the wastewater. The kinetic parameters and adsorption isotherms for the adsorption of the metal ions by the amine-functionalized MgFe2O4 were obtained using the pseudo-first-order, pseudo-second-order, Langmuir, and Freundlich models. The pseudo-second order and Langmuir models best described the adsorption kinetics and isotherms, implying strong chemisorption via the formation of coordinative bonds between the amine groups and metal ions. The Langmuir equation revealed the highest adsorption capacity of 0.7 mmol/g for the amine-functionalized MgFe2O4 nano-adsorbents. The adsorption capacity of the nanoadsorbent also changed with the calcination temperature. The MgFe2O4 sample, calcined at 500 °C, removed the most of the Pb2+ (73%), Cu2+ (59%), and Zn2+ (62%) ions from the water.

Gold Nanorods for Doxorubicin Delivery: Numerical Analysis of Electric Field Enhancement, Optical Properties and Drug Loading/Releasing Efficiency.

The optical properties and electric field enhancement of gold nanorods for different cases were investigated in this study. The numerical analysis was carried out to understand the functionality and working of gold nanorods, while the experimental portion of the work was focused on the efficiency of gold nanorods for targeted drug delivery. COMSOL Multiphysics was used for numerical analysis. The theoretical results suggest the use of gold nanorods (AuNRs) for anticancer applications. The resonance peaks for gold nanorods of 10 nm diameter were observed at 560 nm. The resonance peaks shifted towards longer wavelengths with an increase in nanorod size. The resonance peaks showed a shift of 140 nm with a change in nanorod length from 25 to 45 nm. On the experimental side, 22 nm, 35 nm and 47 nm long gold nanorods were produced using the seed-mediated growth method. The surface morphology of the nanorods, as well as their optical characteristics, were characterized. Later, gold nanorods were applied to the targeted delivery of the doxorubicin drug. Gold nanorods showed better efficiency for doxorubicin drug loading time, release time, loading temperature, and release temperature. These results reveal that AuNRs@DA possess good ability to load and deliver the drug directly to the tumorous cells since these cells show high temperature and acidity.

Clinical Correlation between Acute Exudative Polymorphous Paraneoplastic Vitelliform Maculopathy and Metastatic Melanoma Disease Activity: A 48-month Longitudinal Case Report.

PURPOSE: Longitudinal evaluation of acute exudative polymorphous paraneoplastic vitelliform maculopathy (AEPPVM) following diagnosis and treatment of metastatic melanoma. METHODS: Case report of a 47-year-old male with unknown primary metastatic melanoma and AEPPVM monitored before and during melanoma treatment using clinical exam, retinal imaging, and electroretinograms (ERG). Genetic testing and autoantibody panels were performed. RESULTS: He presented within a month of metastatic melanoma diagnosis with numerous bilateral vitelliform lesions in the posterior pole, consistent with AEPPVM. Metastatic disease was treated with immunotherapy, radiosurgery, and radiation over 48 months. Maculopathy and metastatic disease improved and worsened in parallel. Genetic testing was negative for bestrophin-1. An autoantibody panel was positive for anti-recoverin and transducin-α. CONCLUSION: AEPPVM is an uncommon paraneoplastic retinopathy found in patients with metastatic malignancy. To our knowledge, this is the first report demonstrating a temporal association between metastatic disease activity and quantifiable changes in retinal imaging over a 4-year period.

Perceived changes in lifestyle behaviours and in mental health and wellbeing of elementary school children during the first COVID-19 lockdown in Canada.

OBJECTIVES: The closure of schools to prevent the spread of COVID-19 prompted concerns of deteriorating lifestyle behaviours, mental health, and wellbeing of children, particularly those in socioeconomically disadvantaged settings. We assessed changes in lifestyle behaviours (physical activity, screen time, eating habits and bed/wake-up times), mental health and wellbeing during the first lockdown in Spring 2020 as perceived by school children from disadvantaged settings, and examined determinants of these changes. STUDY DESIGN: Cross-sectional study. METHODS: We surveyed 1095 grade 4 to 6 students (age 9-12 years) from 20 schools in socioeconomically disadvantaged communities in northern Canada. Students reported on changes in lifestyle behaviours, mental health and wellbeing during the lockdown. Determinants of these perceived changes were examined in multivariable regression models. RESULTS: A majority of students reported declines in physical activity, having late bed/wake-up times, and modest improvements in mental health and wellbeing. Many students reported increases rather than decreases in screen time and snacking. Positive attitudes toward being active, eating healthy, going to sleep on time and being healthy were strongly associated with maintaining healthy lifestyle behaviours during the lockdown. Positive attitudes toward active and healthy living and healthy lifestyle behaviours were associated with maintaining positive mental health and wellbeing during the lockdown. CONCLUSIONS: The considerable changes in lifestyle behaviors, superimposed on the pre-existing burden of unhealthy lifestyle behaviours, put this generation of children at increased risk for future chronic disease. Findings call for effective health promotion of active and healthy lifestyles to benefit both physical and mental health.

Effect of immunotherapy time-of-day infusion on overall survival among patients with advanced melanoma in the USA (MEMOIR): a propensity score-matched analysis of a single-centre, longitudinal study.

BACKGROUND: The dependence of the adaptive immune system on circadian rhythm is an emerging field of study with potential therapeutic implications. We aimed to determine whether specific time-of-day patterns of immune checkpoint inhibitor infusions might alter melanoma treatment efficacy. METHODS: Melanoma Outcomes Following Immunotherapy (MEMOIR) is a longitudinal study of all patients with melanoma who received ipilimumab, nivolumab, or pembrolizumab, or a combination of these at a single tertiary cancer centre (Winship Cancer Institute of Emory University, Atlanta, GA, USA). For this analysis, we collected deidentified participant-level data from the MEMOIR database for adults (age ≥18 years) diagnosed with stage IV melanoma between 2012 and 2020. Those who received fewer than four infusions were excluded. Standard of care doses were used, with modifications at the treating physicians' discretion. The primary outcome was overall survival, defined as death from any cause and indexed from date of first infusion of immune checkpoint inhibitor. We calculated the association between overall survival and proportion of infusions of immune checkpoint inhibitors received after 1630 h (a composite time cutoff derived from seminal studies of the immune-circadian rhythm to represent onset of evening) using Cox regression and propensity score-matching on age, Eastern Cooperative Oncology Group performance status, serum lactate dehydrogenase concentration, and receipt of corticosteroids and radiotherapy. Treatment-related adverse events that led to change or discontinuation of immune checkpoint inhibitors were also assessed. FINDINGS: Between Jan 1, 2012, and Dec 31, 2020, 481 patients with melanoma received treatment with immune checkpoint inhibitors at the study centre, of whom 299 had stage IV disease and were included in this study; median follow-up was 27 months (IQR 14 to 47). In the complete unmatched sample, 102 (34%) patients were female and 197 (66%) were male, with a median age of 61 years (IQR 51 to 72). Every additional 20% of infusions of immune checkpoint inhibitors received after 1630 h (among all infusions received by a patient) conferred an overall survival hazard ratio (HR) of 1·31 (95% CI 1·00 to 1·71; p=0·046). A propensity score-matched analysis of patients who did (n=73) and did not (n=73) receive at least 20% of their infusions of immune checkpoint inhibitors after 1630 h (54 [37%] of 146 patients were women and 92 [63%] were men, with a median age of 58 years [IQR 48 to 68]) showed that having at least 20% of infusions in the evening was associated with shorter overall survival (median 4·8 years [95% CI 3·9 to not estimable] vs not reached; HR 2·04 [1·04 to 4·00; p=0·038]). This result remained robust to multivariable proportional hazards adjustment with (HR 1·80 [1·08 to 2·98; p=0·023]) and without (2·16 [1·10 to 4·25; p=0·025]) inclusion of the complete unmatched study sample. The most common adverse events were colitis (54 [18%] of 299 patients), hepatitis (27 [9%]), and hypophysitis (15 [5%]), and there were no treatment-related deaths. INTERPRETATION: Our findings are in line with an increasing body of evidence that adaptive immune responses are less robust when initially stimulated in the evening than if stimulated in the daytime. Although prospective studies of the timing of immune checkpoint inhibitor infusions are warranted, efforts towards scheduling infusions before mid-afternoon could be considered in the multidisciplinary management of advanced melanoma. FUNDING: National Institutes of Health, American Society for Radiation Oncology and Melanoma Research Alliance, and Winship Cancer Institute.