Distal forearm fractures are the most common pediatric fractures. This study aimed to investigate the effectiveness of below-elbow cast treatment for displaced distal forearm fractures in children compared to above-elbow cast through meta-analysis of randomized controlled trials.Several databases from January 1, 2000 until October 1, 2021 were searched for randomized controlled trials that assessed below versus above-elbow cast treatment of displaced distal forearm fractures in pediatric patients. The main meta-analysis comparison was based on the relative risk of loss of fracture reduction between children undergoing below versus above-elbow cast treatment. Other outcome measures including re-manipulation and cast-related complications were also investigated.Nine studies were eligible of the 156 articles identified, with a total of 1049 children. Analysis was undertaken for all included studies with a sensitivity analysis conducted for studies with high quality. In the sensitivity analysis, the relative risks of loss of fracture reduction  and re-manipulation  between the below and above-elbow cast groups were in favor of below-elbow cast and statistically significant. Cast-related complications were in favor of below-elbow cast but did not attain statistical significance . Loss of fracture reduction was noted in 28.9% of patients treated with above-elbow cast and 21.5% in below-elbow cast. Re-manipulation was attempted in 48.1% versus 53.8% of children who lost fracture reduction in the below-elbow cast and above-elbow cast groups, respectively.Below-elbow cast treatment was favored, with statistical significance, in terms of loss of fracture reduction and re-manipulation, and was not associated with a higher risk of cast-related complications. The accumulative evidence currently does not support above-elbow cast treatment and below-elbow cast treatment should be the mainstay for displaced distal forearm fractures in children.Level I, meta-analysis of therapeutic level I studies. These fractures represent 40% of all fractures in children and adolescents. AEC controls both elbow and forearm range of motion by neutralizing muscles forces that originate above the elbow and is thought to reduce the risk of displacement and loss of reduction of such fractures.7 Whereas, BEC has been proposed as a valid alternative that is easier to apply, allows better hand function, and minimize elbow stiffness.9 However, in children with either BEC or AEC treatment, the initial reduction is not always successful, and loss of fracture reduction (25%–39%) and re-manipulation during the first few weeks are frequent complications.11Displaced distal forearm fractures are generally reduced in emergency settings under conscious sedation and stabilized in a cast. Immobilization of such fractures in children is usually managed with either above-elbow cast (AEC) or below-elbow cast (BEC). published a meta-analysis more than 10 years ago that included three randomized controlled trials (RCTs). An update of the meta-analysis was further published in 2012, which included an additional two RCTs.15 Due to heterogeneity, the meta-analysis failed to generate robust conclusions and hence has provoked additional RCTs to answer this question. Since the updated meta-analysis, four additional recent RCTs1619 with larger sample sizes have been published.Several published studies have compared different outcome measures for BEC and AEC treatment. While this is not the first meta-analysis to report on BEC versus AEC treatment for displaced distal forearm fractures in pediatric patients, we decided to perform this meta-analysis because of the inconsistent results regarding the direction and scale of differences in the studies that reflect the existing uncertainties. Hendrickx et al.Currently, there is no clear consensus regarding the treatment of displaced distal forearm fractures in children. This meta-analysis aimed to evaluate the effectiveness of BEC treatment for displaced distal forearm fractures in pediatric patients compared to AEC. Analysis of outcomes included loss of fracture reduction, re-manipulation, and cast-related complications. We hypothesized that BEC treatment would have similar rates of loss of fracture reduction, re-manipulation, and cast-related complications compared to AEC.21This meta-analysis was conducted with strict adherence to the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).PubMed/MEDLINE, Web of Science, Cochrane Library, and Google Scholar were searched from January 1, 2000 until October 1, 2021. We used the following keywords:  and (“long” or “below”) and (“Short” or “below”) and (“Pediatrics” or “children”) and “Randomized.” Articles were confined to RCTs of children. Two authors independently screened the titles and abstracts, and a full-text review was conducted for eligible studies.Inclusion criteria were RCTs that compared BEC to AEC treatment of displaced distal forearm fractures  in the pediatric population (age < 16 years) and reported the rates of loss of fracture reduction, re-manipulation, and cast-related complications. The exclusion criteria entailed non-comparative studies, published studies in languages other than English, studies that included surgical management of distal forearm fractures in pediatric patients, and studies that included dislocation of the distal radial-ulna joint, radial head fractures, or isolated distal ulna fractures.Two authors independently collected data from the selected studies using a spreadsheet with a standardized approach. The collected items were as follows: study characteristics , number of patients undergoing BEC versus AEC treatment, sample size, age of children, bone involvement, follow-up duration, loss of follow-up, displacement criteria, loss of fracture reduction rate, re-manipulation rate, and cast-related complications.23 This tool comprises five domains as follows: randomization, adherence to treatment, missing outcomes, bias measurement, and bias reporting. Two authors assessed the methodological quality of the included studies with this tool independently, and where disagreement existed, a consensus was reached.The revised Cochrane risk-of-bias tool for randomized trials (RoB 2) was utilized to conduct the qualitative assessment.I2 statistic. This elucidates the variability percentage in effect estimates that is owed to heterogeneity instead of chance.Using a random-effects model, studies and constructed Forest plots were pooled. The random-effects model identifies articles as a sample of all potential articles and incorporates a between-article random-effect element to allow for between-study heterogeneity. We attained the rates of loss of fracture reduction, re-manipulation, and cast-related complications for each study. Between-study heterogeneity was quantified using the 19The main meta-analytic comparison was based on the rate of loss of fracture reduction in children who were treated with BEC versus those in AEC. The rates of re-manipulation and cast-related complications were also compared. Overall relative risks (RRs) were calculated. The RRs (risk ratios) were calculated as the effect size metric and pooled using the Mantel–Haenszel method without continuity correction. τ2 was estimated using the Paule–Mandel estimator. τ and τ2 confidence intervals were estimated using the Q-profile method. The Hartung–Knapp adjustment was utilized for random-effects model. Continuity correction of 0.5 in studies with zero cell frequencies . Sensitivity analysis was conducted with the exclusion of studies associated with high risk of bias.16 with children elder than 12 years of age would affect the results on the basis that these studies had adolescent patients compared with other studies with children younger than 12 years of age. Egger’s test with funnel plot was performed for our primary outcome, the risk of loss of fracture reduction. RStudio (2021.09.0 + 351 “Ghost Orchid” Release) was used for all statistical analyses.Another sensitivity analysis was conducted to evaluate if excluding articles1424 One publication reported the long-term follow-up of the same study as the original RCT. The kappa statistics for interobserver agreement on study eligibility was 1.0. The detailed selection process (PRISMA diagram) is shown in The literature search yielded 390 publications. After screening using titles and abstracts, 156 articles were left for full-text review. After applying eligibility criteria, nine articles remained for the analysis addressing BEC versus AEC treatment of displaced distal forearm fractures in pediatric patients.1424 The mean age of all children was 8.4 years. Cast application time ranged from 4 to 6 weeks, whereas follow-up duration ranged from 6 weeks to 8 months. Some studies did not report all basic demographics, which limited grouped statistics. Eight out of the nine studies reported loss of fracture reduction rates. Memon et al. described only the mean loss of fracture reduction for each group, resulting in an incapability to pool data for the meta-analysis. Sensitivity analysis was conducted and excluded studies with high risk of bias . Seven of the studies reported re-manipulation rates and a total of five studies reported cast-related complications. Treatment protocols of the included studies in our meta-analysis are summarized in 1424 A total of 106 out of 493 children in BEC group (21.5%) and 145 out of 501 children in AEC group (28.9%) had a loss of fracture reduction. The random-effects model meta-analysis of the eight RCTs concluded an overall RR of 0.74  = 0.49, 1.13, p = 0.07, I2 = 47%), which proposed a lower rate of loss of fracture reduction in children who had BEC treatment, but this difference did not reach a statistical significance (p = 0.14). However, sensitivity analysis following exclusion of studies with high risk of bias  showed that loss of fracture reduction was in favor of BEC with statistical significance   . Egger’s1424 Fifty-one children (12.6%) from the BEC group and 78 patients (18.9%) from the AEC underwent re-manipulation. The overall RR was 0.66 . Furthermore, sensitivity analysis following exclusion of two studies with high risk of bias19 showed that re-manipulation was in favor of BEC with statistical significance   .24 Forty out of 202 children (19.8%) had cast-related complications in the BEC group compared to 64 out of 209 children in AEC group (30.6%). Analysis of cast-related complication rate demonstrated that BEC treatment was associated with a pooled RR of 0.59 . This was also not statistically significant. Sensitivity analysis following exclusion of one study with high risk of bias failed to show a statistical difference between both groups  for loss of fracture reduction in favor of BEC treatment, but this did not reach a statistical significance (p = 0.51). The other outcome results and overall RRs altered only minimally.Further sensitivity analysis with the exclusion of the studies with patients older than 12 years of age2629 In a survey, Laaksonen et al. reported possible overtreatment and practice variation for treatment of completely displaced distal radius fractures in pediatric patients. In this survey, the majority of surgeons (84% of 213 participating surgeons) chose an AEC to immobilize distal forearm fractures, although earlier reports showed that AEC does not retain the alignment of displaced distal forearm fractures in children any better than BEC.The most important findings of this meta-analysis were the statistically significant difference of the sensitivity analysis of high-quality studies in the reported outcomes of displaced distal forearm fractures in children who underwent BEC compared to AEC treatment in terms of loss of fracture reduction and re-manipulation. The meta-analysis also suggests a treatment effect favoring BEC with regard to plaster-related complications as well; however, this lacked statistical significance. The relatively small sample sizes and article heterogeneity further confounded the capability to notice a benefit. This heterogeneity can be noticed in the inclusion criteria, the frequency and duration of follow-up, and the reported outcomes including loss of fracture reduction and re-manipulation in the included studies. Other outcomes, such as joint range of motion, functional outcomes, and return to normal activities, were not pooled due to the variability in time points and outcome measures. The rationale behind this meta-analysis was that there is a significant lack of agreement on the indications of cast type application regarding the treatment of displaced distal forearm fractures in pediatric patients.All included studies explicitly mentioned that the fractures were displaced. Several questions arise as to how best to define a loss of fracture reduction and the need for re-manipulation and at what specific time point. In our analysis, we took the number of loss of fracture reduction and the need for re-manipulation as specified by the authors. We excluded studies with high risk of bias and children more than 12 years of age in our sensitivity analyses. This was based on analyzing high-quality studies and considering that adolescent fractures might be treated as adult injuries that require surgical treatment to achieve and maintain fracture reduction. Hafeez et al. showed in their subgroup analyses adjusting for age group (4–8 or 9–12 years) and involvement of bone  significantly lowered the rate of loss of fracture reduction in the BEC group that was evident in the 4–8 years group, 9–12 years group, and both forearm bone group. Webb et al. suggested that AEC treatment was technically more difficult to apply which resulted in poor molding around the forearm and associated with loss of fracture reduction. The long-term study of Colaris et al. described no statistically significant differences between both groups at 7-year follow-up.Loss of fracture reduction is the most common complication after closed reduction and cast immobilization in the management of displaced distal forearm fractures in children. only a very small number of children underwent re-manipulation despite meeting the criteria of loss of fracture reduction. The authors suggested that this was due to the assumption that forearm fractures in children have the capability to remodel with growth which will lead to a final satisfactory outcome. Similarly, Webb et al. reported that none of the patients who lost fracture reduction in both groups underwent re-manipulation and concluded that loss of reduction in this population has minimal clinical relevance due to excellent remodeling potential. Furthermore, Seiler et al. stated that the confidence in a satisfactory outcome might explain the low rate of re-manipulation in their study due to the high remodeling potential.Re-manipulation was performed with varying reported rates between the studies. Indications for re-manipulation after loss of fracture reduction were not clearly reported in all studies. In the study of Bohm et al.,The limitations of this meta-analysis include the low number of available RCTs , the lack of ability to pool all available data and studies with differences in time points and reported outcome measures, the unknown bias in the primary studies, and the inclusion of articles published only in English. Hence, the simplest method is to evaluate trials on specific domains of quality that are most relevant to the control of bias for that particular study.Review of quality demonstrated methodological limitations in most of the included studies, with poor quality of reporting in three studies compared to the others. Studies of low quality have been shown to overestimate the treatment effect compared with high-quality trials.1424 had specified criteria for loss of fracture reduction, these criteria were not adjusted for age, except in the studies of Colaris et al. and Seiler et al. In addition, we could not specify the exact reason for the decision of re-manipulation of fracture(s) as not all of the fractures that lost reduction were re-manipulated. We contacted the corresponding authors of all the studies to provide us with indications of re-manipulation to avoid underestimating the actual number of fractures that required re-manipulation.Another limitation was the lack of a standard definition of loss of fracture reduction between studies. Although most of the studiesOur results are compatible with the literature in that any comparative treatment effect is likely to be minor, and reproducing this study designs with higher power may only serve to render a clinically insignificant difference statistically significant. Further attention should be oriented at good methodological-quality articles with adequate follow-up, and priority should be linked to specific patient-centered outcome measures. Finally, our meta-analysis demonstrated that BEC treatment is a safe and effective alternative to AEC treatment of displaced distal forearm fractures in children. It was evident that BEC treatment does not lead to increased loss of fracture reduction and re-manipulation rates and plaster-related complications and should be the mainstay for displaced distal forearm fractures in children.


Anas platyrhynchos) exhibits effective anti-subsidence properties when walking on soft ground. To investigate the effects of quartz sand particle size and thickness on joint angles and the movement patterns of webbed feet, we created a testing substrate with quartz sand and utilized high-speed cameras and kinematic analysis tools for data acquisition. Mallards mainly adjusted the tarsometatarso-phalangeal joint (TMTPJ) during touch-down and lift-off stages in response to increasing particle size or enhanced ground roughness. Conversely, adjustments to the intertarsal joint (ITJ) predominantly took place during mid-stance. Conversely, mallards predominantly adjusted the ITJ during touch-down and lift-off when coping with increased quartz sand thickness, with TMTPJ adjustments mainly occurring at touch-down. As quartz sand particle size increased, the TMTPJ angle increased, the ITJ angle decreased, toe closure advanced, and the duty factor decreased throughout the entire stride cycle. In contrast, increasing quartz sand thickness led to more delayed TMTPJ adjustments, slower webbed foot closure, and an increased duty factor throughout the stride cycle. Mallards modify their leg posture to notably decrease the touch-down foot angle upon encountering sandy terrain. This action subsequently forms a depression beneath their feet, contributing to sand consolidation and limiting flow. During the stance phase, the mallard's weight is distributed across the webbed foot, generating minimal pressure and preventing significant subsidence while walking on sandy ground.The webbed foot structure of mallards  angle and the webbed foot kinematics of mallard. AnimalMallards, as semi-aquatic birds, retain the ability to walk on land and frequently inhabit tidal flats, river bays, and similar environments. Their webbed feet readily adapt to both walking and swimming on soft terrain. Current research indicates that the coexistence of toes and webbing in mallard feet plays a crucial role in walking on sandy surfaces. However, specific adaptations in movement posture that the concurrent toes and webbing make to counteract sinking on soft ground have yet to be investigated. Additionally, the role of webbed feet compared to non-webbed birds such as pheasants warrants further investigation.To explore the kinematics and inverse dynamics of reindeer front and rear hooves, Caretta caretta) on solid and sandy terrains using high-speed cameras and fluidized beds. They observed that the webbed feet did not slip during locomotion on either surface, primarily due to the formation of a hardened area behind the webbed feet that restricts sliding. The kinematic characteristics of animals on sandy terrain have been determined by the aforementioned researchers.Consequently, in this study, four adult male mallards were chosen as research subjects, and two distinct substrates (fine quartz sand and coarse quartz sand) were utilized to construct loose, soft ground with varying thicknesses , with solid ground serving as the control group. Simi-Motion kinematic software was employed to track and analyze the instantaneous and continuous alterations in the primary joint angles of the tarsometatarso-phalangeal joint (TMTPJ), intertarsal joint (ITJ), and the webbed foot motion pattern. This allowed for a deeper understanding of the effects of particle size, thickness, and substrate composition on the webbed foot motion patterns of mallards. By studying the kinematic parameters, the effects of mallards’ foot structure and webbing on reducing ground pressure and improving anti-subsidence ability were clarified.The vertical height difference between marker points 7 and 4 was greater on solid ground (quartz sand thickness of 0 cm) than on soft ground. Upon conducting a significance analysis, a notable difference was observed between solid ground and soft ground across all six conditions . This fiP=0.02995) and lift-off (P=0.00321). In P=0.02739).As shown in In summary, quartz sand particle size significantly affected TMTPJ at touch-down and lift-off, and ITJ at mid-stance. Increasing quartz sand particle size decreased the TMTPJ angle at touch-down and the ITJ angle at mid-stance, while increasing the TMTPJ angle at lift-off. This indicates that the mallard responded to the gradually increasing particle size or rough substrate by adjusting the TMTPJ primarily at touch-down and lift-off, with no significant postural change in the TMTPJ at mid-stance. Concurrently, the increase in particle size impacted the ITJ at mid-stance and lift-off, without significantly affecting ITJ posture at touch-down. Quartz sand thickness significantly influenced TMTPJ at touch-down and ITJ at touch-down and lift-off, with an increase in quartz sand thickness augmenting the angle. The mallard primarily adjusted the ITJ at touch-down and lift-off in response to increasing quartz sand thickness, while no significant postural change occurred in the ITJ at mid-stance. For the TMTPJ, the posture was mainly adjusted at touch-down, with no significant alterations in the TMTPJ at mid-stance or lift-off.The continuous alteration pattern of TMTPJ under various substrates throughout a complete stride cycle is demonstrated in The continuous variation of α joint angle under different substrates during a complete stride cycle is presented in The continuous variation of α joint angle and β joint angle at 2 cm, 4 cm, and 6 cm thicknesses of fine and coarse quartz sand during a complete stride cycle was investigated, as shown in When walking on soft substrates such as sand, intertidal, or muddy areas, the mallard's anti-sink function is achieved through the coordinated action of the TMTPJ and ITJ. However, at different stages of the stance phase, the mallard relies on the TMTPJ and ITJ differently. The adjustments of the TMTPJ and ITJ are subtle, with the ITJ primarily adjusted during lift-off. For beach surfaces where grain size transitions from fine to coarse, the mallard predominantly adjusts the TMTPJ at touch-down, the ITJ at mid-stance, and both the TMTPJ and ITJ in tandem at lift-off.Regarding mallard locomotion on coarse- and fine-quartz sand, the duty factor diminishes with increasing quartz sand size , Fig. 3 The three anteriorly oriented toes  of the mallard are positioned horizontally for the majority of their length upon contact with a solid surface. During the later stages of the stance phase, these toes exhibit a smooth upward and forward rolling motion, lifting sequentially from the proximal to the distal end. The longest toe (third toe) rotates around the toe tip and seamlessly transitions into the swing phase without sliding backward. Mallard locomotion on soft quartz sand involves initial contact with the toenail, which remains approximately parallel to the substrate, followed by full palm contact with minimal sinking. The most notable difference from solid ground locomotion is that the toe tips pierce the substrate downward before lifting and sweeping backward and upward during withdrawal. When walking on soft ground, guineafowl immediately sink into the substrate upon foot contact, while knee height is reduced . In contThe papillae of the ostrich foot provide stable frictional properties, and the irregular surface of its toes expands on the ground contact area . The antThe ostrich's smaller touchdown angle on loose sand generates more robust reaction forces to support its body weight. The third toe bones sequentially detach from the ground, and the supplementary force exerted by the third toe not only enlarges the contact surface but also compacts the sand beneath it. During locomotion on loose sand, the intrusion of the third toe tip into the sand is noted in the stomping phase, while the fourth toe bears a comparatively reduced load ,b. The mAn increase in quartz sand particle size results in a decrease in the TMTPJ angle at touch-down, an increase in the angle at lift-off, and a decrease in the ITJ angle at mid-stance. This leads to an augmentation in the TMTPJ angle and a reduction in the ITJ angle throughout the stride cycle in mallards, culminating in a more pronounced closure of the toes and a corresponding decline in the duty factor. Conversely, an increase in quartz sand thickness elevates the TMTPJ angle at touch-down and the ITJ angle at both touch-down and lift-off. This induces a more delayed adjustment of the TMTPJ in mallards throughout the stride cycle, resulting in a more sluggish closure of the toes and an increased duty factor. To mitigate the sinking effect of sandy terrain, mallards adjust their leg posture, significantly reducing their touchdown foot angle. Qualitatively, the initial contact of the toes with the ground involves penetration into the sand, followed by webbed contact that restricts further toe subsidence and consolidates the sand between the toes. This generates less pressure on the sandy ground, and the foot's structural characteristics provide a natural advantage for mallard locomotion across sand and loose ground. This study underscores the challenges animals face when walking on various substrates and how joint function adapts accordingly.Four 24-month-old free-ranging male mallards were selected from a specialized farm in Zhejiang Province, China, for this experiment, with a mean body weight of 1275±43.30 g (expressed as mean±s.d.). During the trial, the subjects were housed in custom-made duck enclosures and provided with ample water and food to ensure optimal living conditions. Ethical approval was granted by the Animal Experimental Ethical Inspection of Jilin University (reference No. SY202206100). Following the experiment, all mallards remained healthy and were returned to the farm.To facilitate acclimatization during the formal trial, the mallards underwent a 2-week exercise training regimen on a sandy surface, lasting approximately 30 min, four times per week. To prevent mallards from flying away during the trial and to clearly capture the marker points with the high-speed camera, select feathers on the mallards' wings were trimmed without hindering hindlimb locomotion. Black markers were utilized to darken the joints as marker points, enabling more natural mallard toe locomotion while obtaining clear and precise video footage of the joints for efficient processing.The test site was selected within a well-ventilated and sanitary laboratory. Coarse quartz sand (particle size range 0.5-1.0 mm) and fine quartz sand (particle size range 0.12-0.25 mm) were employed in the study. Quartz sand of varying thicknesses was manually prepared on a horizontal runway , with thicknesses of 2 cm, 4 cm, and 6 cm, respectively. A solid surface served as the reference control, totaling seven experimental conditions. During quartz sand preparation, sand was evenly distributed on the horizontal surface, leveled with a brush, and thickness was measured using a straight steel rule to ensure compliance with specifications. Mallards were guided to walk at a consistent, uniform speed on the various substrates of the track using food incentives and a duck lead rope. A minimum of nine effective trials was conducted for each mallard on each substrate. The test was terminated immediately if a mallard exhibited reluctance to locomotion.A 3D capture system necessitates recording the same motion simultaneously from at least two different angles (>60°) to reconstruct the 3D spatial position. Consequently, two high-speed cameras  were utilized for 120 Hz/s video recording, positioned at the right front and right side of the sports field, respectively. It was ensured that the mallard in motion was captured within the field of view of both cameras, as depicted in The locomotion of the toes of the mallard was primarily completed by the second toe, the third toe and the fourth toe. Thus, the joint points on the three toes of the right foot of the mallard were marked B: the seVideos of the four mallards exhibiting uniform motion speed and optimal condition were selected and imported into Simi-Motion kinematics software  for tracking analysis. A minimum of three complete stride cycles for each condition per mallard were processed, totaling 12 strides. Spatiotemporal parameters  and joint angles of the mallard's motion were obtained through 3D space recovery and calculation using Simi-Motion software. The TMTPJ and ITJ angles were analyzed at right foot touch-down (0%), mid-stance (50%), and lift-off (100%). The α joint angle between the second and third toes and the β joint angle between the third and fourth toes were defined, and the continuous variation patterns of α and β joint angles concerning quartz sand particle size and thickness were analyzed.Exported data were compiled in Excel , and Bessel curves in Origin Pro 2023  were employed to graph the continuous changes in TMTPJ, ITJ, α, and β joint angles. Box plots were utilized to graph the instantaneous changes in TMTPJ and ITJ angles. The results and patterns of the instantaneous and continuous joint angles of the mallards were analyzed. Additionally, the vertical height difference between marker points 7 and 4 on the mallard's third toe at touch-down was represented in a box plot to measure the effect of ground softness on the angle of ground contact, as the third toe touches the ground first and is approximately parallel to the forward direction.F-tests in Origin Pro were conducted, with results corrected using the Bonferroni test. One-way ANOVA tests were performed to assess the variability of each of the four mallards under each condition. The impact of quartz sand particle size and thickness on toe and web locomotion posture was evaluated by two-way ANOVA. Results were considered statistically significant if P<0.05.To investigate the significant differences in quartz sand particle size and thickness on the mallard's joint angles, 10.1242/biolopen.060012_sup1Supplementary informationClick here for additional data file.


Mass vaccination has been a key strategy in effectively containing global COVID-19 pandemic that posed unprecedented social and economic challenges to many countries. However, vaccination rates vary across space and socio-economic factors, and are likely to depend on the accessibility to vaccination services, which is under-researched in literature. This study aims to empirically identify the spatially heterogeneous relationship between COVID-19 vaccination rates and socio-economic factors in England.We investigated the percentage of over-18 fully vaccinated people at the small-area level across England up to 18 November 2021. We used multiscale geographically weighted regression (MGWR) to model the spatially heterogeneous relationship between vaccination rates and socio-economic determinants, including ethnic, age, economic, and accessibility factors.This study indicates that the selected MGWR model can explain 83.2% of the total variance of vaccination rates. The variables exhibiting a positive association with vaccination rates in most areas include proportion of population over 40, car ownership, average household income, and spatial accessibility to vaccination. In contrast, population under 40, less deprived population, and black or mixed ethnicity are negatively associated with the vaccination rates.Our findings indicate the importance of improving the spatial accessibility to vaccinations in developing regions and among specific population groups in order to promote COVID-19 vaccination.The online version contains supplementary material available at 10.1186/s12889-023-15801-w. The Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has been a global pandemic that poses unprecedented health, social, and economic challenges .Vaccine hesitancy has been one of the primary threats to global health, even before the COVID-19 pandemic. The World Health Organisation (WHO) formally defines vaccine hesitancy as ‘delay in acceptance or refusal of vaccine despite the availability of vaccine services’ . EmpiricExisting studies have examined the socio-economic environment and spatial patterns of COVID-19 vaccination rates in different countries, revealing the significant association between socioeconomic determinants and vaccination rates. Soares et al.  identifiThe COVID-19 vaccines have been deployed since the early stage of the pandemic and at scale in the UK. In December 2020, UK regulators issued emergency-use authorisation for COVID-19 vaccines from Pfizer and BioNTech, and later AstraZeneca . In the This study makes contributions to the literature and policy in the following ways: first, it presents the first spatial model of the COVID-19 vaccination rates at the Middle Layer Super Output Areas (MSOA) level in England. Second, in a pioneering move, this study considers the role of spatial accessibility to vaccination sites as a factor influencing vaccine uptake rates, in conjunction with a range of socio-economic variables. Third, the findings can inform public health policymakers to develop tailored strategies to increase uptake of COVID-19 vaccines and adjust local vaccination policy.Figure We collected the MSOA-level weekly number of vaccination uptake by age groups in England from the National Health Services (NHS) England , which sWe used the MSOA from the 2011 UK census as the spatial analytical unit, which is a geographic area designed to improve the reporting of small area statistics in England and Wales. By definition, each MSOA has an average population of 7,500 residents or 4,000 households. England is divided into 6,791 MSOAs.The most recent MSOA-level demographic information for England is the resident population data from 2019 mid-year estimates , which iCar ownership (i.e. the proportion of households having at least one car or van) is used as a measure of local travel accessibility . This vaWe used the 2019 English Index of Multiple Deprivation (IMD)  as a meaThe travel duration between each pair of MSOA centroids and vaccination sites is required for computing the spatial accessibility to vaccination. As regions differ considerably regarding travel modes, we used the weighted-mean travel duration that combines driving and public transport, using the regional-level travel mode proportion as the weight. The proportion of driving and public transport in nine regions was derived from . DetailsN = 2,868) in England were retrieved from the NHS England [N = 108), hospital hubs (N = 230), and local vaccination services (N = 2530). The local vaccination services include pharmacies and GP-led vaccination services. Although mobile units were in operation as another type of vaccination services, the locations of these units are not publicly available and therefore they were excluded herein. The original vaccination site data contain address and postcode , which were geocoded into WGS-84 coordinates of  using the Geocoding API from Google Maps Platform [The addresses of publicly accessible SARS-CoV-2 vaccination sites  method as the baseline, geographically weighted regression (GWR), and multiscale GWR (MGWR). We will calibrate these models and evaluate their accuracy in explaining the variance of COVID-19 vaccination uptake rates in England.The OLS method fits a global linear model between the dependent and independent variables. When this method is applied in spatial analysis, it is limiting as it assumes that the relationship between dependent and independent variables is spatially homogeneous, which is not true in every spatial context. To relax this assumption, the GWR provides an alternative method to examine the spatial variations in local parameter estimates. More details about GWR is available in Additional file To overcome the GWR drawbacks, Fotheringham et al.  proposedmgwr [The dependent and independent variables were transformed to standardised z-score (with zero mean and unit standard deviation) before being used for modelling. The data standardisation serves two purposes: first, it allows for scale-free bandwidths that are comparable across variables; second, it reduces the computational complexity of GWR and MGWR. We used the Python package mgwr  for buil2 (Adj. R2), Akaike Information Criterion (AIC), residual sum of square (RSS), log likelihood, and Moran’s I. A larger adjusted R2 is desirable, as it indicates that the model can explain a larger variance of the vaccine uptake rates. On the other hand, a smaller AIC or a smaller RSS is preferred. A smaller AIC implies a more parsimonious model, and a smaller RSS implies that the model explains a larger variance of the vaccine uptake rates (which is similar to a larger adjusted R2). In addition, a larger log likelihood means that the model is more likely to be true given the data distribution. Moreover, the Moran’s I statistic is used to test whether the model’s residuals are spatially autocorrelated.We evaluated the performance of models using a combination of criteria: Adjusted RThe MSOA-level accessibility to vaccination sites was computed using the Extended Two-step Floating Catchment Area Method (E2SFCA) via the Python library ‘access’ . More dep-value < 0.01 , while MGWR produces a random distribution of residuals (p > 0.05). This indicates that MGWR effectively mitigates the spatial autocorrelation or clustering of residuals of the COVID-19 vaccination rates.In comparison with OLS, both the GWR and MGWR achieve better fits with improved adjusted R2, and the local models can explain 84% (from GWR) or 83% (from MGWR) of the variance of the COVID-19 vaccination rates. In terms of AIC, the MGWR is more parsimonious than OLS and GWR. On the other hand, GWR achieves the lowest residual sum of squares (RSS), which is followed by MGWR and OLS. Regarding the spatial distribution of residuals, both OLS and GWR produce a spatially clustered pattern of residuals that is statistically significant  was excluded from the model in order to mitigate multicollinearity between variables. Therefore, the parameter estimate shown in Fig. Our findings regarding how ethnicity is related with vaccination are largely consistent with reported vaccination rates (from 8 December 2020 to 15 May 2021) by socio-demographic groups among people over 40 in England , althougThe parameter estimates of age groups are illustrated in Fig. The parameter estimates of the economic, accessibility, and deprivation variables are demonstrated in Fig. The accessibility measure to vaccination services exhibits a positive association with vaccination rates, although at a less intensive level. This finding confirms the importance of improving the accessibility to vaccination services . In contThis study has several limitations, which has introduced potential bias in the current research and opens avenues for future research. First, other important determinants of vaccine uptake, including education levels and trust in government, were not assessed in this analysis. The absence of these variables might lead to the underfitting of regression models in some areas. Second, the accessibility measurement to the COVID-19 vaccination would be more accurate if the data of the mobile units for vaccination is available. Third, the dynamics of vaccination uptake is not considered in this study. Future research could build spatio-temporal models to simultaneously account for the spatial heterogeneity and evolution of the vaccination uptake, which could inform region-specific and population-group-specific policies in different stages of the mass vaccination.In this study, we used multiscale geographically weighted regression models to reveal that the spatial disparity of COVID-19 vaccination uptake rates in England is strongly associated with socio-economic-demographic variables. Moreover, this relationship exhibits considerable spatial heterogeneity and local effects. Overall, the younger groups  are associated with lower vaccination rates than the elderly, whilst higher car ownership or better accessibility to vaccination services lead to higher vaccination uptake rates. On the other hand, the more deprived areas are found to be related to a higher vaccination rate than the less deprived. It is worth noting that the sign and multitude of the relationship likely vary geographically, such as the ‘Asian’ ethnicity and age 50–59.To our best knowledge, there has been a lack of small-area spatial modelling of COVID-19 vaccination in the UK. For this reason, this quantitative study will serve to support public health management in developing regional-specific policies for maximising vaccination uptake in the ongoing COVID-19 vaccination and other mass vaccination programmes.Additional file 1.


Renal cell carcinoma (RCC) accounts for 4.1% of all new cancers, with a median age at diagnosis of 64 years. Approximately 85% of kidney tumors are RCC , and 70% of these have a clear cell histology (ccRCC)  in term of prognosis. The pooled results showed a significant impact of PSM during PN in term of risk of recurrence  and risk of metastasis (OR 4.63). However, PSM did not affect the risk of all-causes or cancer-specific death. Therefore, the study supports close monitoring for patients with PSM after PN.For selected patients with limited disease, partial nephrectomy (PN) is an option to treat RCC with oncological outcome comparable to radical nephrectomy. In their meta-analysis, Wang et al. analysed the impact in survival of different histologies (clear and non-clear cell) in RCC with TT. The presence of thrombosis was more common in papillary RCC (pRCC); the oncological outcomes  were worse for this subgroup of patients. Moreover, histology is independently associated to worst OS and PFS and strict follow-up should be followed for pRCC patients with TT.From a surgical perspective, tumor thrombus (TT) is often associated to primary RCC. In a mono-institutional cohort, Tyrosine kinase inhibitors (TKIs) such as Sunitinib or Pazopanib have been widely used in first-line treatment. Immunotherapy has provided a revolution in treatment options and recently, combination therapy ICI (Immune checkpoint inhibitors) -TKI and ICI-ICI have demonstrated remarkable efficacy in patients with mRCC. Tumour histology and risk stratification of patients is important in therapy selection.Dong et al., the authors investigated the expression profile of TFE3 of in 796 patients with RCC and the clinicopathological features as well as prognosis of TFE3-positive RCC. 91  patients were TFE3 positivity expression and only 31  of the patients were diagnosed with Xp11.2 translocation RCC. In this study, nuclear TFE3 expression is not specific to the Xp11.2 translocation RCC. Moreover, the positive TFE3 expression is associated with tumour progression and poor prognosis in patients with RCC irrespective of the presence of TFE3 translocation.In the paper by Qin et al., they conduced a Bayesian network meta-regression analysis to provide a head-to-head comparison of first line therapeutic immune checkpoint inhibitors (ICI) and tyrosine kinase inhibitor (TKI) combinations for metastatic renal cell carcinoma. After analysing a total of 22 randomised clinical trials (RCTS) the combination Lenvatinib-Pembrolizumab shows dominance of progression free survival (PFS) and Pembrolizumab-Axitinib shows superiority in overall survival (OS). After meta-regression analysis, for hazard ratio (HR) of PFS, Lenvatinib-Pembrolizumab shows advantages; for HRs of OS, Pembrolizumab-Axitinib demonstrates superiority; for objective response rate (ORR), Lenvatinib-Pembrolizumab provides better results. About tolerability, the combination Atezolizumab-Bevacizumab is better. The authors conclude that Pembrolizumab-Axitinib should be recommended as the optimal therapy for the first line treatment of mRCC thanks to the lower toxicity and the higher quality of life.In the paper by Boutros et al. reported two cases of patients with muscle enzyme elevation in association with hypothyroidism during treatment with Pembrolizumab-Axitinib for mRCC. The myopathy rapidly resolved after hormone replacement therapy with levothyroxine. This adverse event is rare and in the differential diagnosis with immune-related myositis which has different pathogenesis and course.Although the adverse events of both drug classes of combination therapy are now well-known, it may be difficult to recognise which drug is related to a particular adverse event. Wang et al. the role of Glutamate dehydrogenase 1 (GLUD1), which plays a critical role in the malignancy of diverse tumors. They found that GLUD1 has a novel tumor-suppressing role of GLUD1 in ccRCC, different from that in other tumors, and these results provide a theoretical basis for GLUD1 as a therapeutic target and prognostic marker in renal cancer.In a changing scenario with new multiple combinations of drugs effective for RCC, other mechanisms of action are desirable. In summary, in the ever-changing scenario of first line treatment for RCC, this collection highlights the significance of appropriate surgery and pathological reports, to ensure adequate follow-up to patients with a greater risk of relapse. Moreover, it is of crucial significance the appropriate choice of the first line therapy among all the different approved treatments, to maximise patients’ benefit. Finally, identifying biomarkers or possible targets for new drugs development is critical to find out treatment strategies for RCC patients.MV, MM, RS drafted, reviewed, edited, finalized the manuscript. All authors contributed to the article and approved the submitted version.


Are community-level factors and state-level gun laws associated with rates of firearm-related deaths in children and adolescents?In this cross-sectional study including 5813 youths aged 10 to 19 years who died of an assault-related firearm injury, death rates increased in a stepwise fashion with increasing community-level social vulnerability; this trend persisted among all types of state gun laws. States with restrictive gun laws had lower rates of assault-related firearm deaths among youths; however, youths from socially vulnerable communities were disproportionately impacted across the spectrum of state gun laws.These findings suggest that legislation may not be sufficient to solve the problem of assault-related firearm deaths among children and adolescents. Firearm-related injuries are the leading cause of death among children and adolescents in the US. For youths aged 10 to 19 years, 64% of firearm-related deaths are due to assault. Understanding the association between the rate of death due to assault-related firearm injury and both community-level vulnerability and state-level gun laws may inform prevention efforts and public health policy.To assess the rate of death due to assault-related firearm injury stratified by community-level social vulnerability and state-level gun laws in a national cohort of youths aged 10 to 19 years.This national cross-sectional study used the Gun Violence Archive to identify all assault-related firearm deaths among youths aged 10 to 19 years occurring in the US between January 1, 2020, and June 30, 2022.Census tract–level social vulnerability  and state-level gun laws .Youth death rate (per 100 000 person-years) due to assault-related firearm injury.Among 5813 youths aged 10 to 19 years who died of an assault-related firearm injury over the 2.5-year study period, the mean (SD) age was 17.1 (1.9) years, and 4979 (85.7%) were male. The death rate per 100 000 person-years in the low SVI cohort was 1.2 compared with 2.5 in the moderate SVI cohort, 5.2 in the high SVI cohort, and 13.3 in the very high SVI cohort. The mortality rate ratio of the very high SVI cohort compared with the low SVI cohort was 11.43 . When further stratifying deaths by the Giffords Law Center state-level gun law scorecard rating, the stepwise increase in death rate (per 100 000 person-years) with increasing SVI persisted, regardless of whether the Census tract was in a state with restrictive gun laws (0.83 in the low SVI cohort vs 10.11 in the very high SVI cohort), moderate gun laws (0.81 in the low SVI cohort vs 13.18 in the very high SVI cohort), or permissive gun laws (1.68 in the low SVI cohort vs 16.03 in the very high SVI cohort). The death rate per 100 000 person-years was higher for each SVI category in states with permissive compared with restrictive gun laws .In this study, socially vulnerable communities in the US experienced a disproportionate number of assault-related firearm deaths among youths. Although stricter gun laws were associated with lower death rates in all communities, these gun laws did not equalize the consequences on a relative scale, and disadvantaged communities remained disproportionately impacted. While legislation is necessary, it may not be sufficient to solve the problem of assault-related firearm deaths among children and adolescents. This cross-sectional study assesses the rate of death due to assault-related firearm injury stratified by community-level social vulnerability and state-level gun laws in a national cohort of US youths aged 10 to 19 years. Higher social vulnerability has also been correlated with higher overall injury-related fatality rates.5 To our knowledge, the association between community-level social vulnerability and assault-related firearm deaths among youths on a national level has not been previously reported. This lack of research is at least partly because access to detailed data on locations of firearm-related deaths at a national level is limited. The Gun Violence Archive (GVA) maintains an online archive of firearm-related violence incidents detailing the precise locations of firearm-related injuries and deaths, presenting an opportunity to evaluate this association.6Social vulnerability indices (SVIs), which measure socioeconomic and population characteristics of discrete geographic regions, are emerging as a useful collective measure of social and societal determinants of health. Previous studies7; similarly, findings from a systematic review8 suggest that in certain nations, the simultaneous implementation of laws targeting multiple firearm restrictions is associated with a reduction in firearm-related deaths. However, it is not understood whether the strength of state-level gun laws has differential consequences for the rate of firearm-related violence in communities with different levels of social vulnerability and disadvantage. We sought to assess the rate of death due to assault-related firearm injury stratified by community-level social vulnerability and state-level gun laws in a national cohort of youths aged 10 to 19 years.In the US, states with more restrictive gun laws have been reported to have lower rates of firearm-related violence9 The study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline for cross-sectional studies.This study used publicly available deidentified data and did not require institutional review board approval per guidelines on human participant research from the University of Washington.6 The GVA records of gun violence deaths have been correlated (r = 0.95) with firearm-related deaths reported by the Centers for Disease Control and Prevention,10 confirming GVA records to be a reliable source of assault-related firearm deaths. Incidents with no identifiable address and deaths related to suicide were excluded.The GVA was used to identify all assault-related firearm deaths among youths aged 10 to 19 years occurring between January 1, 2020, and June 30, 2022. The GVA is a nonpartisan nonprofit organization dedicated to maintaining an online archive of gun violence incidents collected from more than 7500 commercial, governmental, law enforcement, and media sources. It provides near real-time data that capture details surrounding each incident, including date, street location, age, sex, and intention .11; this SVI provides a comprehensive ranking of the relative vulnerability of every US Census tract, with higher values indicating greater vulnerability. The SVI captures the potential negative consequences for the community due to the aggregate of demographic and social factors in 4 domains: (1) socioeconomic status, (2) household composition and disability, (3) racial and ethnic minority status and language, and (4) housing type and transportation. The Census tract of each incident was determined by converting the incident addresses provided in the GVA to geographic coordinates, which were then matched to Census tract–level geographic identifiers using the Census geocoder.12 The geographic identifiers were then linked to the Census tract–level SVI using the 2018 Census tract rankings. Youths were categorized into the following quartiles based on composite SVI: low SVI (<25th percentile), moderate SVI (25th-50th percentile), high SVI (51st-75th percentile), and very high SVI (>75th percentile). Data on youth race and ethnicity categories were not collected because this information is not available through the GVA.Social vulnerability was determined using the SVI developed by the Centers for Disease Control and Prevention13 and used for population adjustment. The Giffords Law Center  2020 and 2021 gun law scorecard  was used to classify Census tracts by state as having restrictive (A and B ratings), moderate (C rating), or permissive (D and F ratings) firearm laws.14Population estimates of youths aged 10 to 19 years by Census tract in 2020 were obtained from the Surveillance, Epidemiology, and End Results Program (SEER) databaseP = .05.Estimated death rates by SVI category were calculated using the total number of deaths in each SVI category (extracted from the GVA) and per 100 000 person-years from the 2020 SEER population estimates within each SVI category across the 2.5-year study period. Crude mortality rate ratios were calculated, with the low SVI category as the reference group. A similar model was used to estimate the death rates and mortality rate ratios across the SVI categories and Gifford scorecard ratings. All Census tracts were included to estimate person-years regardless of whether the tract had any deaths reported. A Poisson regression model was used to test the interaction between SVI category and Giffords state-level gun law scorecard rating. The linear plots and their slopes were estimated from linear regression analysis of death rates per 100 000 person-years over incident month and year. Changes in death rates over time were assessed using the Mann-Kendall trend test and the Theil-Sen median slope estimator. All analyses were performed using Stata software, version 15/IC (StataCorp LLC). The threshold for statistical significance was 2-tailed We used the GVA to identify 6154 youths aged 10 to 19 years who died due to an assault-related firearm injury between January 2020 and June 2022. After excluding youths who died of suicide (n = 248), incidents without an address (n = 85), and incidents in Census tracts without SVI data (n = 8), 5813 individuals were included in the SVI analysis. For analyses related to Giffords gun law scorecard ratings, an additional 61 deaths due to incidents occurring in an area without a Giffords scorecard rating  were excluded, leaving 5752 youths included.P < .001). Trends in other SVI communities were not statistically significant due to seasonal variation in the number of deaths over the 2.5-year study period; however, a steady increase in the number of deaths over time was seen in all SVI communities with positive slopes in the linear regression model for each SVI category  age was 17.1 (1.9) years; 4979 (85.7%) were male and 834 (14.3%) were female. Using SEER population estimates, the total population of youths aged 10 to 19 years in each SVI quartile was similar . The totcategory .P = .009).Stratifying the overall cohort by Giffords gun law scorecard rating, the death rate per 100 000 person-years for Census tracts in states with restrictive gun laws (Giffords A and B ratings) was 4.21 compared with 4.95 for Census tracts in states with moderate gun laws (Giffords C rating) and 7.04 for Census tracts in states with permissive gun laws (Giffords D and F ratings). The mortality rate ratios were 1.17  for Census tracts in states with moderate gun laws and 1.67  for Census tracts in states with permissive gun laws compared with Census tracts in states with restrictive gun laws. Population-adjusted death rates and mortality rate ratios stratified by Giffords state-level gun law scorecard rating and composite SVI quartile are shown in This national cross-sectional study found that Census tracts with higher levels of social vulnerability experienced a disproportionate number of assault-related firearm deaths among youths. Communities with very high social vulnerability had an 11-fold higher death rate than communities with low social vulnerability. Although the assault-related firearm death rate among youths was higher overall in states with permissive compared with restrictive gun laws, the increase in death rate with increasing social vulnerability persisted, regardless of restrictive, moderate, or permissive gun laws.16 Previous studies have described higher numbers of firearm injury-related emergency department visits,4 increased urban firearm violence,16 and increased fatal police shootings17 with increased community-level social vulnerability. There is likely a complex array of social phenomena that contribute to these associations. Children and adolescents living in disadvantaged communities are often exposed to lack of economic resources and opportunity, reduced social investment, lack of safe and green spaces, and high levels of community disorganization.21 These community-level factors combined with individual- and family-level instability can disrupt normal parent-child relationships and contribute to high-risk behaviors in youths.22 The combination of a lack of opportunity and hopelessness may be a common pathway to high-risk behaviors and violence. Our study revealed that these same disadvantaged communities experienced a disproportionate number of assault-related firearm deaths among youths.Our findings on the association between community-level social vulnerability and assault-related firearm deaths among youths add to the growing body of literature focusing on the troubling associations between neighborhood disadvantage, lack of opportunity, and violence.8 suggested that very few of the existing state-specific firearm laws are associated with reductions in firearm-related mortality; however, this finding must be interpreted with caution because there are limited high-quality studies on the association between firearm legislation and injury, limiting our understanding of the true impact of specific firearm legislation.23 Notably, some firearm laws, specifically those focused on the purchase, access, and use of firearms, have been associated with reductions in firearm-related mortality.8 Our results suggest that legislation alone, although important, will not address the problem of gun violence in the US and needs to be accompanied by genuine, deep, and long-term investment in historically marginalized communities to reduce inequities.To our knowledge, this study is one of the first to describe assault-related firearm deaths among youths by both community-level vulnerability and state-level gun laws. We found the strength of a state’s gun laws to be associated with the rate of assault-related firearm deaths among youths; specifically, stricter gun laws were associated with a lower rate of assault-related firearm deaths. However, these gun laws did not seem to equalize the consequences on a relative scale, as community-level disadvantage was associated with a disproportionate number of assault-related firearm deaths among youths across the spectrum of state gun laws. Our findings suggest that more restrictive firearm laws are unlikely by themselves to reduce the disparities observed in firearm death rates among youths across communities. A previous systematic review6 and detailed demographic data are not available. Third, the GVA records the incident address, and our results describe only the association between the community-level vulnerability of the incident location and youth death related to firearm violence, which may be different from the vulnerability of the community of residence. Fourth, the death rates were calculated using the most up-to-date population estimates available from the SEER database. These SEER database population estimates were for 2020 and were used for the study period extending from January 2020 to June 2022. Changes in the total population of youths aged 10 to 19 years that may have occurred during the study period could not be accounted for. Fifth, this is a national cross-sectional study based on US data; thus, the results are not generalizable to other countries.This study has limitations. First, this is an ecological study, and measures of exposure are based on the mean in the population; thus, our results do not necessarily apply at the individual level. Second, we used the GVA to identify all assault-related firearm deaths among youths. Although the GVA is a rigorously maintained online archive of gun violence–related incidents, there is the potential for both missed events and misclassification,This cross-sectional study of youths who died of assault-related firearm injury found that socially vulnerable communities in the US experience a disproportionate number of assault-related firearm deaths among youths. Although stricter state-level gun laws were associated with decreases in death rates in all communities, the rates in disadvantaged communities remained disproportionately higher, regardless of the strength of the gun laws. Thoughtful and sincere investment in the most disadvantaged communities with the aim of creating opportunity and building community health and safety should be considered an important public health strategy to successfully reduce youth gun violence.


Objectives: To examine birth cohort differences in depressive symptoms and life satisfaction in older men and women and the mechanisms underpinning the possible cohort differences. Methods: Two independent cohorts of Finnish men and women aged 75 and 80 were assessed in 1989–1990 (n = 617) and 2017–2018 (n = 794). They reported their depressive symptoms (CES-D), current life satisfaction, and evaluation of life until now. Results: The later-born cohort reported fewer depressive symptoms (8.6 ± 7.1 vs. 13.9 ± 8.3) and the differences were similar for the subdomains of depressive symptoms. The later-born cohort was more often mostly satisfied with life until now (90 vs. 70%) but not with the current life than the earlier-born cohort. Better self-rated health and education of the later-born cohort partly explain the cohort differences. Discussion: Older people in Finland report fewer depressive symptoms and they are more satisfied with their past life compared to their counterparts assessed 28 years ago. In the Evergreen II study, the corresponding proportions were 43% (n = 794) and 40% (n = 726) of the eligible participants (n = 1835)  . All whoAll participants in the Evergreen I and II studies signed an informed consent, and the research ethical principles required at the time were followed. The Evergreen II study was approved by the ethical committee of the Central Finland Hospital .Our earlier analyses indicated that non-participants in earlier and later cohorts were comparable . Poor seDepressive symptoms were assessed by the Center for the Epidemiological Studies Depression Scale (CES-D) ( (CES-D) . ParticiLife satisfaction was studied using two questions. The current situation was rated with the question “Are you happy and satisfied with your life?” with response options No (=1); Yes, occasionally (=2); and Yes, usually (=3). The satisfaction during the life course was asked with the question “How would you evaluate your life until now?” with response options Mostly unsatisfactory (=1), Occasionally unsatisfactory (=2), and Mostly satisfactory (=3). Due to a low number of replies (<2%) in the lowest categories, the two most negative categories were combined for the analysis of both items.The analyses were not adjusted for any confounders. The age and sex groups were similar, and differences between cohorts in other variables were more likely to be factors contributing to the cohort differences than confounders. To study these factors, correlates of depressive symptoms and life satisfaction that differed between the cohorts were chosen for the analyses.Social resources were assessed by marital status (married vs. not married), social contacts, and loneliness. Social contacts were assessed with three questions asking the frequency to meet (a) children or other relatives, (b) close friends, and (c) other acquaintances with a response scale from I do not have any (=0) to every day (=5). The sum score from the three items was calculated. Loneliness was assessed with a single item: “How often do you feel lonely?” with a response scale of very rarely/never (=1), rarely (=2), often (=3), and almost always (=4) . The catFunctional capacity measures were available for 81% of Evergreen I and 91% for Evergreen II samples, who took part also in physical and cognitive tests. Maximum walking speed was assessed using a ten-meter test in the laboratory corridor. Participants were instructed to walk as fast as possible, and the time was taken with a hand-held stopwatch. Cognitive functioning was assessed using the Digit Symbol coding task from Wechsler Adult Intelligence Scale-Revised . In the To compare the earlier and current same-age cohorts, t-tests for continuous and chi-square tests for categorical variables were used.The factors underlying the cohort differences were tested with a set of regression models. Linear regression for CES-D and its four dimensions and binary logistic regression for two life satisfaction items were used. The first model included only the birth cohort as an independent variable. Then several models were run adding covariates one at a time to see which of them attenuates the cohort differences. Finally, models including all five covariates simultaneously were estimated. For linear regression models, the change (%) in regression coefficients between models was calculated to present how much covariate(s) explained from the potential cohort difference. A similar procedure was used in additional analyses for the smaller laboratory sample to see whether walking speed and cognitive functioning attenuate the cohort differences.khb version .11 . The strongest explanatory variable of cohort differences was the higher self-rated health in the later-born cohort, which explained 36–49% of the cohort differences in depressive symptoms. Among men, the higher education in the later-born cohorts explained 19–23% of the difference. Controlling simultaneously for education, marital status, social contacts, loneliness, and self-rated health attenuated the associations between birth cohort and depressive symptoms for 30% in women, 54% in 75-year-old men, and 43% in 80-year-old men, but the associations remained statistically significant. The results for CES-D subscales were similar to those for the total CES-D scale: the more favorable values of the later-born cohorts in the CES-D subscales were explained by their more favorable values in self-rated health and in men in education. The association between birth cohorts and CES-D subscales of depressed affect, lack of positive affect, and interpersonal problems remained statistically significant after all covariates were added in the models. The cohort differences in the somatic symptoms subscale were attenuated after adjusting the models for self-rated health.The results of regression analyses are shown in The birth cohort difference in current life satisfaction among 80-year-old men favored the earlier-born cohort which coincided with their slightly less frequent reports of loneliness . The advThe associations between birth cohort and life satisfaction until now were statistically significantly attenuated after adjusting the models for self-rated health in both men and women and both age groups, and among 75-year-old women also after adjusting the model for education  and 5: tSupplementary Tables S3–S6). The cohort differences in mental well-being favoring the later-born cohort remained statistically significant after adjusting the models for cognitive functioning and walking speed.The additional analyses conducted among those who took part also in the laboratory tests are shown in supplementary materials , the Civil War (1918), the Winter War (1939–40), the Continuation War (1941–1944), and the Lapland War (1944–1945), and thus lived through an epoch with several episodes of hardship beyond control. The later-born cohorts were born during wartime, but they grow up during the period of rapid development and the occurrence of many social reforms in Finland. In all, their circumstances have been more foreseeable than the earlier cohort’s. However, it is not possible to separate the effects of birth cohort and period from each other and it is likely that many societal changes have produced both period effects affecting all age groups simultaneously as well as cohort effects affecting specific age cohorts .Better self-rated health in the later-born cohorts partly explained the cohort differences in depressive symptoms , and in satisfaction with the past life. In addition, higher education in the later-born cohorts partly explained the cohort differences. However, most of the cohort differences were not completely explained by the covariates included in the present study. Previous studies have shown that later-born cohorts report more internal control beliefs, less external control beliefs , and perA major strength of this study is the use of identical methods 28 years apart. Participant recruitment, mental well-being questionnaires, and questions and performance assessments were comparable between cohorts. This is one of the first studies focusing on mental well-being in relatively old age and including both negative (depressive symptoms) and positive (life satisfaction) aspects of mental well-being in the same study. In addition, this study contributes to the literature by investigating not only the cohort differences but also the underlying factors behind these differences.Some limitations should be kept in mind when considering the findings of this study. The participation rate was lower in the later than in the earlier cohort study, which may suggest that the later cohort may be more selected, and the results can be partly explained by selection bias. However, it should be taken into account that the earlier cohort was already more selected. Around 60% of the Finnish people born in 1914 were alive at age 75, while the corresponding proportion for people born in 1942–1943 was 76% . The corTo conclude, this study provides evidence for improved mental well-being in the more recent birth cohorts of 75- and 80-year-old Finnish adults. Better self-rated health and higher education of the later-born cohort explained the cohort differences only partly. While satisfaction with the past life and the lack of depressive symptoms are important outcomes as such, they are also important resources to function in society and daily life. Moreover, both positive feelings and the lack of depressive symptoms predict longevity, better health, and better functioning . Future Click here for additional data file.Supplemental Material for Cohort Differences in Depressive Symptoms and Life Satisfaction in 75- and 80-Year-Olds: A Comparison of Two Cohorts 28 Years Apart by Tiia Kekäläinen, Kaisa Koivunen, Katja Pynnönen, Erja Portegijs, and Taina Rantanen in Journal of Aging and Health.


The COVID-19 pandemic has affected a significant number of pregnant women worldwide, but studies on immune responses have presented conflicting results. This study aims to systematically review cytokine profiles in pregnant women with SARS-CoV-2 infection and their infants to evaluate immune responses and potential transplacental transfer of cytokines.A comprehensive search of 4 databases was conducted to identify relevant studies. Inclusion criteria included studies measuring individual cytokines in pregnant women and/or their neonates. Studies were evaluated for quality, and data were extracted for analysis. Meta-analyses were performed using the random-effects model.n = 339) compared to SARS-CoV-2 negative pregnant women (n = 409). Subset analysis of maternal samples (n = 183) collected during the acute phase of COVID-19 infection showed elevated CXCL10 and IFN-γ. No significant differences in cytokine levels were found between cord blood samples collected from infants born to mothers with (n = 97) and without (n = 190) COVID-19 during gestation. Subset analysis of cord blood samples collected during the acute phase of maternal infection was limited by insufficient data. The heterogeneity among the studies was substantial.Seventeen studies met the inclusion criteria, including data from 748 pregnant women and 287 infants. More than three of these studies evaluated data of 20 cytokines in maternal serum, and data of 10 cytokines was available from cord blood samples. Only the serum level of CXCL10 was significantly up-regulated in SARS-CoV-2 positive pregnant women (The findings suggest that maternal cytokines responses to SARS-CoV-2 infection during pregnancy are not significantly dysregulated, except for CXCL10 and IFN-γ during the acute phase of illness. No evidence of increased cytokine levels in cord blood samples was observed, although this could be impacted by the time period between initial maternal infection and cord blood collection. These results provide some reassurance to parents and healthcare providers but should be interpreted cautiously due to study variations and limitations. Pregnancy involves changes in the immune system of women to ensure tolerance of the fetus, which may make pregnant women more vulnerable to any infection. COVID-19 has a significant negative impact on pregnancy. Compared with non-pregnant women of a similar age, pregnant women are at a higher risk of developing severe COVID-19, requiring intensive care unit admission, mechanical ventilation or extracorporeal membrane oxygenation support, and even death . AdditioCurrent data suggests that vertical transmission of the SARS-CoV-2 virus to the fetus is relatively rare . HoweverThere exist various plausible mechanisms through which maternal infection with SARS-CoV-2 could impact the developing fetal brain. In addition to immune factors, non-immune mediated effects could potentially impact fetal brain development, such as direct viral infection of fetal neurological cells through transmission across the placenta and compromised placental function, which can lead to adverse pregnancy outcomes and an elevated risk of neurological harm, such as fetal growth restriction, premature birth, or placental abruption. Recent investigations, involving both human subjects and animals, into the consequences of maternal immune activation resulting from viral and bacterial infections during pregnancy have underscored the role of maternal cytokines in potentially contributing to the pathogenesis of preterm birth and negative neurodevelopmental outcomes in the offspring , 22–24. Our study adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for systematic reviews . In collThe following inclusion criteria were applied to select articles for this systematic review and meta-analysis: all studies that evaluated the measurement of individual cytokines in pregnant women and/or their neonates were included. For the control group, data on individual cytokine measurements from healthy pregnant women and their neonates were collected from the same selected studies. We only included studies evaluating maternal serum samples or cord blood samples. We considered studies of any design and from any period since the outbreak of SARS-COV2 commenced as eligible for inclusion. We established exclusion criteria, which entailed the removal of case reports pertaining to individual patient, literature reviews, studies involving nonhuman subjects, editorials, comments, and expert opinions from our analyses. The full texts of potentially relevant studies were carefully reviewed to determine their eligibility based on the inclusion and exclusion criteria. The final list of included studies was identified through consensus among the reviewers.The reviewers then independently extracted data from the included studies. The extracted details included baseline information on the study population, the number of patients in each study group, the measured immunological indicators, and the methods used for testing. These details are presented in We collected the number of participants, the mean and standard deviation (SD) values for immune mediators from serum samples of pregnant women with and without COVID-19, as well as from cord blood samples of infants born to mothers with and without COVID-19 during pregnancy. We conducted a subset analysis of maternal serum samples collected within 2 weeks of COVID-19 diagnosis to capture acute and ongoing infection. COVID-19 infection was confirmed through a positive nasopharyngeal RT-PCR test result at any time during pregnancy in all studies. The control cohort comprised women with documented negative COVID-19 nasal swabs throughout their pregnancy. Women who received the COVID-19 vaccine were excluded from both the study and control cohorts. In cases where mean and SD data were not directly reported, we applied a previously established method to convert median and interquartile range (IQR) values to mean and SD. For articles presenting immunological signatures in figures, we extracted data by measuring the pixel positions of the electronic figures and calculating the actual values. For box plots, medians and ranges were used to derive means and SDs, while scatter plots provided individual values for the computation of means and SDs.2 statistic. Publication bias was assessed using funnel plots and the Begg and Egger tests. All analyses were performed in Stata v.17.1 .Random effects meta-analyses were performed for all immune mediators separately for mothers and infants and for subgroups. Forest plots were generated to illustrate the differences between the two groups. Due to potential variations in cytokine testing methods across studies, which can affect the pooling of means and differences for effect estimation, we calculated a dimensionless effect measure from each study for pooling purposes. The standardized mean difference (SMD) was computed using the means and SDs and used as the effect size. Heterogeneity was assessed using the IA detailed flow diagram illustrating the study selection process and the number of studies selected is presented in n = 339) documented to have COVID-19 infection during pregnancy and 54% (n = 409) without documented COVID-19 infection. In all included reports, the study and control cohorts were matched for maternal age. The studies also included data from 287 infants, with 34% (n = 97) born to mothers with COVID-19 infection during pregnancy and 66% (n = 190) born to mothers without COVID-19 infection. More than three of these studies evaluated data on 20 cytokines in maternal serum, and data on 10 cytokines was available from cord blood samples. A comprehensive overview of the characteristics of the included studies for each immune mediator including baseline information, number of patients in each study group, measured immunological indicators and their outcome reporting measures, were extracted and summarized in The articles included data from 748 pregnant women, with 46%  were included. This subset analysis included data on 10 cytokines from maternal serum of 183 pregnant women with active COVID-19 infection and 214 pregnant women without COVID-19 infection. The study and control groups were age matched in all the included studies in the subset analysis as well. However, only 1 report   had gest2 statistic for majority of the cytokines was >95%, indicating significant heterogeneity among the studies. In the subset analysis, which included serum samples from COVID-19 positive women during the acute phase of illness, significant heterogeneity was also observed for most cytokines, except for IFN-γ, IL-1β, and IL-17 (When comparing COVID-19 positive pregnant women to COVID-19 negative pregnant women, we found that only the serum level of CXCL10 was significantly up-regulated in the COVID-19 positive group . The I2 nd IL-17 . In the nd IL-17 . There wnd IL-17 , 35 thatDysregulation of the maternal immune system during pregnancy have been associated with negative pregnancy outcomes, including miscarriage, impaired fetal growth, and premature birth, which could have lasting impacts on the health of the newborns , 44. AmiSystematic reviews of immune signatures secondary to COVID-19 infection in the general population have consistently reported significant elevation of cytokines like IL-6 and TNFa in severe cases –49. In oAnother factor impacting the measured cytokine levels is the timing of sample collection in relation to active infection. Our results did show an elevation of maternal serum levels of CXCL10 and IFN-γ during the acute phase of COVID-19 infection. CXCL10, a chemokine involved in immune cell recruitment, and IFN-γ, a pro-inflammatory cytokine, play pivotal roles in orchestrating the body's defense against viral infections. However, exaggerated immune responses may disrupt the intra-uterine environment during critical periods of development, posing potential complications for the fetus. Thus, the timing of infection during pregnancy may drive the eventual fetal outcomes. Longitudinal studies tracking these serum levels across the course of infection, as well as larger cohorts assessing the correlation between timing of COVID-19 infection during pregnancy, as well as disease severity with maternal-fetal outcomes, can provide deeper insights.While the overall results of this meta-analysis are reassuring, they should be interpreted with caution. The included studies exhibited significant variation in terms of the timing of sample collection in relation to the onset of infection and the methods used to measure cytokine levels. Studies comparing available cytokine panels have demonstrated substantial variability in the sensitivity and specificity of these panels for detecting serum cytokine levels –52. AddiThis systematic review and meta-analysis of cytokine levels shows no evidence of an exacerbated or dysregulated cytokines response to SARS-CoV-2 infection in the pregnant mothers and their newborns. However, it is important to acknowledge both the strengths and limitations of this review and meta-analysis, considering the rapidly evolving nature of the literature in this field. On one hand, our study results can provide reassurance to pregnant individuals and healthcare providers caring for infants born during the COVID-19 pandemic. On the other hand, it is crucial to emphasize that our analyses should be regarded as hypothesis-generating rather than hypothesis-testing. Further research is needed to corroborate these findings and provide a more comprehensive understanding of the immune response during pregnancy in the context of SARS-CoV-2 infection. Continued monitoring and investigation of immune markers and their impact on pregnancy outcomes are warranted to inform clinical decision-making and optimize care for pregnant individuals and their infants.