Cancer survival varies by socioeconomic status in Japan. We examined the extent to which survival disparities are explained by factors relevant to cancer control measures .N = 376,077) were classified into quartiles using the Area Deprivation Index (ADI). Trends in inequalities were assessed for potentially associated factors: early‐stage detection, treatment modality, and utilization of ACH (for first contact/diagnosis/treatment). 3‐year all‐cause survival was computed by the ADI quartile. Multivariable Cox regression models were used to assess survival disparities and their trends through a series of adjustment for the potentially associated factors.From the Osaka Cancer Registry, patients diagnosed with solid malignant tumors during 2005–2014 and aged 15–84 years ; receipt of surgery (58.1% vs. 64.1%); and utilization of ACH (83.5% vs. 88.4%). While rate differences decreased for receipt of surgery and utilization of ACH  over time, it remained unchanged for early‐stage detection. During 2012–2014, the most deprived ADI quartile had lower 3‐year survival than the least deprived (59.0% vs. 69.4%) and higher mortality : this attenuated with additional adjustment for stage at diagnosis (HR = 1.23); treatment modality (HR = 1.20); and utilization of ACH (HR = 1.19)Despite improvements in equalizing access to quality cancer care during 2005–2014, survival disparities remained. Interventions to reduce inequalities in early‐stage detection could ameliorate such gaps. Cancer staging in this study was based on the summary stating system in Surveillance, Epidemiology, and End Results (SEER) program.2.3.3Other characteristics assessed in this study included calendar year of diagnosis, sex, age , and cancer site.2.4p < 0.05. Analyses on inequality indicators were conducted using the software HD*Calc and Joinpoint, both developed by the U.S. National Cancer Institute.We used the ADI quartile of the Osaka general population to classify the study cohort into four groups . Descriptive analysis was conducted by cross‐tabulating the ADI quartile and demographic or clinical characteristics. To investigate inequalities by ADI quartile in early‐stage detection, treatment modality, and utilization of ACH, we calculated absolute indicators (rate difference and between‐group variance) and relative indicators of inequalities (rate ratio and index of disparity) within each of the calendar years during 2005–2014. Annual Percent Change (APC) was computed to examine the trends for the respective indicators with the statistical significance threshold set at p < 0.05). We calculated Cramer's V to check for correlations among the independent variables and confirmed that none of the assessed variables were strongly correlated (i.e. >0.5). Cox‐Snell residual test was used to assess the goodness of fit. The Proportional hazards assumption was checked by using statistical tests and graphical diagnostics based on the scaled Schoenfeld residuals and supported by a non‐significant relationship between residuals and time.And 3‐year all‐cause survival was estimated by cohort analysis for the following diagnostic periods: 2005–2007, 2008–2011, and 2012–2014. We did not examine cause‐specific or relative survival because information on cause of death was not collected in the OCR and reference mortality data by ADI quartile were not available. Hazard ratios (HRs) were computed by Cox proportional hazard models adjusted for calendar year, sex, age, and cancer site to compare 3‐year all‐cause mortality by ADI quartile. To test trends in survival disparities during 2005–2014, a variable representing the interaction between ADI quartile and calendar year was included in Cox proportional hazard models. The direction of trend was determined according to the interaction coefficient (>1 as widening: <1 as narrowing). Statistical significance of the interaction term was assessed using likelihood ratio tests . The base model (Model 1) estimated the HRs by ADI quartile adjusted for calendar year, sex, age, and cancer site. Additional adjustments were made sequentially for the stage at diagnosis (Model 2), treatment modality (Model 3), and utilization of ACH (Model 4). We also fitted separate models to decompose the explanatory effect of each of the three potentially associated factors. Survival analyses were conducted using the survival package of R version 4.0.3.This study was approved by the Institutional Review Board of Osaka International Cancer Institute . We obtained the dataset with no personally identifiable information from the OCR and independently processed it in accordance with the Act on Promotion of Cancer Registries. The OCR data are not publicly accessible and are available only on request due to privacy and ethical restrictions.3Table p < 0.05). Disparities significantly narrowed among individuals diagnosed with liver cancer and laryngeal cancer (both p < 0.05).Table Table Similarly, during 2005–2007, HRs in Q2, Q3, and Q4 was reduced through a series of adjustment. Notably, more apparent reduction was observed for 2005–2007 compared to that for 2012–2014 when the model was adjusted for utilization of ACH; from Model 3 to Model 4, HRs decreased from 1.08 (95% CI = 1.04–1.11) to 1.07 (95% CI = 1.03–1.10) in Q2: 1.13 (95% CI = 1.10–1.16) to 1.10 (95% CI = 1.07–1.13) in Q3: and 1.19 (95% CI = 1.16–1.23) to 1.14 (95% CI = 1.11–1.17) in Q4. Looking at the trends in survival disparity, a significant increase was observed during 2005–2014 when the model was adjusted for all the potentially associated factors assessed (Model 4). Decomposed effects of each of the factors are presented in Table p < 0.05). For early‐stage detection, significant trends were not observed for any of the four inequality indicators assessed.Table 4This is the first study to investigate socioeconomic disparities in cancer care and survival in Japan in relation to factors that can be addressed through cancer control measures. During 2005–2014, there was a socioeconomic gradient in early‐stage detection, receipt of surgery, and utilization of ACH with lower rates in more deprived ADI quartiles. While absolute inequalities decreased for receipt of surgery and utilization of ACH over the 10 years, it remained unchanged for early‐stage detection. During 2012–2014, the most deprived ADI quartile had a 10.4 percentage points lower 3‐year survival than the least deprived ADI quartile (59.0% vs. 69.4%) which corresponded with a 32% higher mortality hazard (HR = 1.32) after adjusting for case‐mix. This differential decreased to HR = 1.19 when additional adjustment was made for the stage at diagnosis, treatment modality, and utilization of ACH, suggesting that stage at diagnosis was the most influential explanatory factor. While these findings demonstrate progress toward equalization of access to quality cancer care, survival disparities did not narrow over the 10 years. Furthermore, the need to strengthen certain domains of cancer control, such as the reduction of inequalities in early‐stage detection, is highlighted.During 2005–2014, a majority of patients utilized ACHs in all ADI quartiles, and inequalities in utilization of ACH attenuated. The greatest increase in the ACH utilization rate was seen in the most deprived ADI quartile from 75.4% in 2005 to 84.3% in 2014. This indicates that the current centralization scheme may have been especially effective to connect individuals living in deprived neighborhoods to ACHs who would otherwise not attend those facilities. Furthermore, in the series of adjustment, disparities in cancer survival during 2012–2014 scarcely changed when the model was adjusted for utilization of ACH, while an apparent reduction was seen in the same analysis for 2005–2007. This is likely due to the progress that had been made during 2005–2014 in equalizing access to ACHs which might have achieved a near‐optimal level by 2014.Decreased inequality was also seen for receipt of surgery, but not for radiotherapy or chemotherapy. While radiotherapy and chemotherapy can be used for either curative or palliative purposes, surgery plays a vital role in radical treatment for solid tumors.Consistent with findings from the previous studies,It is important to note that, even after controlling for the stage at diagnosis and the other associated factors, disparities in cancer survival remained statistically significant, and there was a widening trend during 2005–2014. Possible explanations for the remaining disparities are as follows. First, patients' survival used as an end‐point reflects all‐cause death which might have resulted in overestimation of disparities in cancer survival. It is well‐documented that individuals in lower SES have a heavier burden of morbidities and shorter life expectancy than those in higher SES.Our study is subject to several limitations. First, we used ADI, area‐based ecological information of residents' SES. Individuals may have been misclassified as the inferences at the area level do not directly transfer to individuals. However, given that cancer control measures are often implemented at the local or regional levels, it is reasonable to use an area‐based ecological indicator as a tool for assessing cancer disparities. Second, the HRs assessed by Cox proportional hazard models should be interpreted with caution as we were unable to adjust for all potential confounders  that are not collected by the OCR. Third, we excluded invalid registrations  from the analysis which may have resulted in biased cohort characteristics. However, the DCO rate of our study cohort was 6.3%, which met the international standard for completeness (DCO <10%),5During 2005–2014, there was a socioeconomic gradient in 3‐year survival of cancer patients with lower survival probabilities in more deprived ADI quartiles, while inequalities in receipt of surgery and utilization of ACH attenuated over the 10 years. The most deprived ADI quartile had 1.32 times higher 3‐year mortality hazard during 2012–2014 compared to the least deprived ADI quartile. This disparity was reduced to 1.19 times when adjusted for early stage detection, treatment modality, and utilization of ACH, suggesting that stage at diagnosis was the most influential factor to describe survival disparities. Continued implementation of a structural approach to intervening in the medical care provision system, in combination with the individual‐ or community‐based interventions to narrow inequalities in early‐stage detection, could help reduce survival disparities among cancer patients.Takahiro Tabuchi: Conceptualization ; data curation ; methodology ; supervision ; validation ; visualization ; writing – review and editing . Tomoki Nakaya: Conceptualization ; data curation ; formal analysis ; methodology ; validation ; writing – review and editing . Toshitaka Morishima: Data curation ; investigation ; project administration ; resources ; validation ; writing – review and editing . Kayo Nakata: Data curation ; investigation ; project administration ; resources ; validation ; writing – review and editing . Yoshihiro Kuwabara: Data curation ; investigation ; project administration ; resources ; validation ; writing – review and editing . Mari Kajiwara Saito: Data curation ; investigation ; project administration ; resources ; validation ; writing – review and editing . Chaochen Ma: Data curation ; investigation ; resources ; validation ; writing – review and editing . Isao Miyashiro: Data curation ; investigation ; project administration ; resources ; validation ; writing – review and editing .This work was supported by JSPS KAKENHI Grant (JP22K10548) and Health, Labor and Welfare Sciences Research Grant (H30‐Gantaisaku‐Ippan‐009).The authors have no conflicts of interest to disclose.This study was approved by the Institutional Review Board of Osaka International Cancer Institute .Appendix S1:Click here for additional data file.


Observational studies have shown an association between COVID‐19 and epilepsy. However, causality remains unproven. This study aimed to investigate the causative effect of genetically predicted COVID‐19 phenotypes on epilepsy risk using a two‐sample Mendelian randomization (MR) analysis.We retrieved summary‐level datasets for three COVID‐19 phenotypes  and epilepsy from the genome‐wide association studies conducted by the COVID‐19 Host Genetics Initiative (COVID‐19 HGI) and International League Against Epilepsy (ILAE) consortium, respectively. To analyze the final results, nine MR analytic methods were utilized. The inverse‐variance weighted (IVW) method was chosen as the primary approach for data analysis to evaluate the potential causal effect. Other MR analytic methods  were used as a supplement to IVW to ensure the robustness of the results.p = 0.92; COVID‐19 hospitalization: OR = 1.00, 95% CI = 0.96–1.04, p = 0.95; COVID‐19 severity: OR = 0.99, 95% CI = 0.96–1.01, p = 0.25]. Other MR complementary methods revealed consistent results. Additionally, no evidence for heterogeneity and horizontal pleiotropy was found.The IVW approach demonstrated no causal association between any genetically predicted COVID‐19 phenotype and the risk of epilepsy [COVID‐19 susceptibility: odds ratio (OR) = 0.99, 95% confidence interval (CI) = 0.86–1.14, This MR study revealed no genetically predicted causal relationship between COVID‐19 phenotypes and epilepsy. Mendelian randomization (MR) was used to investigate the causal relationship between genetically predicted COVID‐19 phenotypes and epilepsy.This two‐sample MR study did not show a causal relationship between COVID‐19 and epilepsy.COVID‐19 may not be a risk factor for epilepsy.1Since the start of the pandemic, severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), the causative agent of coronavirus disease 2019 (COVID‐19), has been associated with a large number of infections and deaths, representing a major threat to human health and public safety.About 65–70 million people throughout the world suffer from epilepsy, a neurological illness marked by recurring seizures.Mendelian randomization (MR) is an epidemiological method which utilizes genetic variants as instrumental variables (IVs) to examine the causative association between exposures and outcomes.22.1Single nucleotide polymorphisms (SNPs) were chosen from the Genome‐Wide Association Study (GWAS) datasets as the IVs for COVID‐19.2.2www.covid19hg.org, Release 7). RNA RT‐PCR or serologic testing was used as the diagnostic approach for COVID‐19, while patient self‐reported infections and electronic health records were also considered. The susceptibility phenotype was compared between COVID‐19 cases and controls without history of SARS‐CoV‐2 infection. The hospitalization phenotype compared COVID‐19‐hospitalized patients to controls who were not admitted for COVID‐19 or to patients without COVID‐19. The severity phenotype was determined by comparing dead or respiratory‐assisted hospitalized patients with COVID‐19 to individuals that did not have COVID‐19 and others who had the disease but did not have a severe status. Table Exposure data were obtained from the latest GWAS summary statistics of the COVID‐19 Host Genetics Initiative (COVID‐19 HGI), which includes the susceptibility, hospitalization, and severity of COVID‐19GWAS summary statistics of the outcome for all epilepsy were obtained from the International League Against Epilepsy (ILAE) consortium Table .16 Morp < 5E‐08) and had a minor allele frequency (MAF) > 0.01. Then, we performed a clumping process  based on the European 1000 Genomes dataset.r2 ≥ 0.8) were obtained from an online website (snipa.helmholtz‐muenchen.de/snipa3/). Moreover, the MR Steiger filtering test was used to identify and remove SNPs that imply reverse directional causality.p < 5E‐08), we searched for the phenotypes associated with variants in Phenoscanner V2.To select valid IVs, we first identified SNPs which were genome‐wide significant  was considered significant. MR analyses were performed with the TwoSampleMR and MR‐PRESSO packages in R software (version 4.1.3), while genetic correlation was calculated with LDSC V1.0.1 ,3The results of MR Steiger filtering tests are presented in Table p = 0.92; COVID‐19 hospitalization: OR = 1.00, 95%CI = 0.96–1.04, p = 0.95; COVID‐19 severity: OR = 0.99, 95%CI = 0.96–1.01, p = 0.25; Figure In the IVW‐fe model, we observed no causal correlation between genetically predicted COVID‐19 phenotypes and epilepsy risk (COVID‐19 susceptibility: odds ratio (OR) = 0.99, 95% confidence interval (CI) = 0.86–1.14, The Cochran's Q test demonstrated a low degree of heterogeneity among the IVs Table . Using t4The causal effect of the genetically predicted COVID‐19 phenotypes on epilepsy risk was estimated in this study using up to nine MR analytic approaches. The results demonstrated no causative link between genetically predicted COVID‐19 phenotypes and the risk of epilepsy, which was also confirmed by multiple sensitivity analyses. Since SARS‐CoV‐2 infection is associated with a range of neurological sequelae, understanding the casual relationship between COVID‐19 and epilepsy is of great importance for managing this event.Although some investigations showed a higher risk of epilepsy and seizures post‐COVID‐19, there are multiple probable explanations for this inconsistency. First, certain studies were conducted with both seizures and epilepsy as the outcome.Mechanistically, seizures and epilepsy may be a direct result of viral invasion of the central nervous system or an indirect result mediated by the host's immune response.On the other hand, the brains of SARS‐CoV‐2 infected hamsters and patients who died from COVID‐19 exhibited increased blood–brain barrier permeability, expression of interleukin (IL)‐1β and IL‐6, microglial activation, and decreased hippocampal neurogenesis.The main advantage of this study is that potential biases, like reverse causality and residual confounders, were reduced by MR analysis compared to traditionally designed observational studies. Secondly, using multiple sensitivity analyses, the robustness of our findings was evaluated with no evidence of heterogeneity or horizontal pleiotropy. The findings of MR Steiger test and Phenoscanner V2 also showed no pleiotropic SNPs. Consequently, the risk of pleiotropic effects in this study was limited.However, several limitations should be considered. First, the population in this study mainly consisted of Europeans. Therefore, the current conclusions should be carefully interpreted, particularly for non‐European populations. Second, the ability to discern weaker causal links is compromised by the relatively small variance explained by the IVs of the exposures. The correlation between COVID‐19 and epilepsy might become significant in future GWAS summary statistics with larger sample sizes. Third, some cases of COVID‐19 were identified through self‐reporting, which may induce measurement bias. Fourth, the risk of epilepsy in relation to the infection with SARS‐CoV‐2 variants and vaccination could not be investigated due to the limitation of COVID‐19 GWAS data. Fifth, COVID‐19 hospitalization and severity phenotypes might be influenced by factors such as medical conditions in each country that could not be taken into account in the MR analysis. In addition, Due to the linear effect assumption in the MR analysis, we were unable to assess nonlinear associations between COVID‐19 exposures and the risk of epilepsy. Finally, even though this study indicates that COVID‐19 exposures are not causally associated with epilepsy, it is important to note that the MR analysis is an unvalidated prediction. Therefore, further investigation and validation is still warranted.5In summary, this two‐sample MR investigation did not show the genetically predicted causal association between COVID‐19 phenotypes and an increased risk of epilepsy in the European population. Future MR studies based on larger sample sizes of GWAS data require additional research on this topic.Study conception, design, and draft preparation: Z.H. and Y.L.; Data collection and analyses: Z.H., Y.L., and S.L.; Supervision of the study and revision of the manuscript: J.L.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.All datasets utilized in this work are publicly available, and their original studies already obtained patients' permissions and ethical approval. No further informed consent or ethical permit was required.Figure S1.Click here for additional data file.Table S1.Click here for additional data file.Table S2.Click here for additional data file.Table S3.Click here for additional data file.Appendix S1–S3:Click here for additional data file.


Plectranthus amboinicus essential oil (PAE) and rosemary  essential oil (ROE) as feed additives on performance, antioxidant activity, intestinal microbiota, intestinal morphology, immune response, and plasma biochemistry using 320 unsexed 1‐day‐old Ross 308 broiler chickens. The chickens were assigned randomly into four treatments containing eight replicates with 10 chickens each. Treatment diets included a basal diet as a control group, 100 mg/kg PAE, 200 mg/kg PAE, and 100 mg/kg ROE. ROE affected the growth performance in the starter phase by improving (p = .01) the feed conversion ratio (FCR) compared with the control diet. Glutathione peroxidase (GPx) and superoxide dismutase (SOD) activity in the plasma were elevated (p < .0001) by both feed additives. Supplementation of additives could increase (p < .006) total antioxidant capacity (TAC). Furthermore, malondialdehyde (MDA) values in the breast (p < .0001) and thigh (p < .001) for all supplemented diets were less than the control group. The essential oils (EOs) reduced (p < .005) coliform counts in the ileum and increased (p = .029) lactic acid bacteria counts. In addition, villus height (VH) and crypt depth (CD) increased, whereas the density of goblet cells decreased in the small intestine when feed additives were included. Also, the antibody titers against sheep red blood cells (SRBC) and Newcastle disease virus (NDV) were increased (p < .0001) by EOs. Plasma total protein (p = .04) and globulin (p = .02) were increased, and cholesterol was reduced (p = .002) by supplemented diets. Our study revealed that PAE could effectively improve the antioxidant activity, intestinal microbiota population, intestinal morphology, immune response, and plasma biochemistry parameters in broiler chickens.This work aimed to assess the effects of  Plectranthus amboinicus and Rosemary EOs increased the activity of plasma antioxidant enzymes, decreased MDA in meat, improved intestinal microbiota and morphology, improved humoral immunity, as well as, reduced plasma cholesterol, and increased plasma protein in broiler chicken.Our study showed  The temperature of the oven was programmed to increase from 60 to 250°C at a rate of 4°C per minute. It was ultimately held for 10 min; at a transfer line temperature of 250°C. The carrier gas was helium with a split ratio of 1/50 at a 1.1 mL/min flow rate. Over 35–465 amu (atomic mass units) the mass spectrometer was scanned via the quadrupole, with an ionizing voltage of 70 eV and an ionization current of 150 mA. The constituents were identified based on their retention indices by comparison of the mass spectra with those reported in the studies and Willey (Chem Station data system) libraries  using 320 unsexed 1‐day‐old broiler chickens . The chickens were randomly allocated into four treatments with eight replicates of 10 chickens each. The treatments were the basal diet as the control group, basal diet +100 mg/kg PAE, basal diet +200 mg/kg PAE, and basal diet +100 mg/kg ROE. Table 2.4The weight gain and feed intake were assayed per pen at the end of each week for the broiler chickens. Then, the average daily feed intake (ADFI), average daily gain (ADG), and the ratio of those as FCR were calculated for the different phases of starter, grower, and finisher. Chick mortality was reported and considered in calculations for all treatments.2.53+ to Fe2+ by antioxidants present in the sample, with the absorbance monitored at 593 nm  was drawn using heparinized syringes via the jugular vein. The blood plasma was separated to assay the activity of antioxidant enzymes using SOD and GPx commercial kits  according to the manufacturer's instructions. Inhibition of pyrogallol autoxidation and decrease in the absorbance at 405 nm were used to detect SOD activity. GPx activity was determined by monitoring the level of the consumption of NADPH with decreasing absorbance at 340 nm. The measurement of TAC was conducted by the ferric reducing ability of plasma (FRAP) assay. This assay is based on the reduction of Fe2.6At day 42, after slaughter, the breast and thigh meat of eight chickens per treatment were removed and used for the lipid oxidation assay. Measuring MDA was performed as a secondary oxidation product based on the thiobarbituric acid method as explained by Botsoglou et al. .2.71 to 108 in sterile phosphate‐buffered saline (PBS). Agar media, plate count agar, MacConkey agar, and MRS agar were used to enumerate total aerobic, coliform, and lactic acid bacteria, respectively. Each duplicate sample dilution was inoculated on agar plates and incubated at 37°C for 24 h before counting. The counts were stated as log10 CFU/g.At day 42, eight chickens were slaughtered from each treatment. The small intestine  was dissected to assess the numeral of total aerobic, coliform, and lactic acid bacteria. Immediately postmortem, the small intestine was longitudinally opened. A sterile knife was used to scrape the digestive contents and mucosal surface, and the ileal contents were then transferred using aseptic technique into sterile tubes. One gram of the homogenized ileal content was diluted from 102.8At the end of the experimental period, eight chickens per treatment were randomly selected and slaughtered to prepare tissue samples from the small intestine. The small intestine was removed, and 2 cm sections of the duodenum, jejunum (between the entry of the bile duct and Meckel's diverticulum), and ileum were excised, rinsed, and stabilized using physiological serum in 10% saline‐formalin solution for 24 h. Tissue was dehydrated, clarified, and embedded in paraffin in order before cutting into 5‐μm‐thick sections using a rotary microtome. After mounting on glass slides, the sections were stained with both hematoxylin–eosin and alcian blue. The determination of villus height, crypt depth, and the density of goblet cells (per 100 μm villus height) was conducted with an Olympus light microscope using imaging software (Dino Capture 2.0). At last, the ratio of villus length to crypt depth (VH/CD) was calculated.2.9At day 9, two chickens per pen were subcutaneously vaccinated (0.2 mL per chicken) with inactivated bivalent NDV and H9N2 avian influenza virus (AIV) vaccines. At day 19, the blood of these chickens was drawn using heparinized syringes to assess the antibody titers for AIV and NDV. A hemagglutination inhibition assay to assess antibody titers was conducted on the collected blood plasma. In addition, at day 28, 0.1 mL of 5% SRBC in sterile PBS was injected into the breast muscle of two chickens per pen. A booster injection was also given per chicken at day 35 to measure the secondary anti‐SRBC antibody response. After 7 days, the blood of each chicken receiving the SRBC was drawn with heparinized syringes, and the plasma was assayed for anti‐SRBC antibody titers via a microhemagglutination test using 96‐well microplates. The assessment methods were carried out according to Sedaghat and Karimi Torshizi .2.10At day 42, eight chickens were slaughtered from each treatment, and the spleen and bursa were removed and quickly weighed after slaughtering. Then, their relative weight percent was determined.2.11g at room temperature to separate the plasma. The plasma samples were stored at −20°C in Eppendorf tubes until further analysis. Plasma biochemistry measures, such as total protein, uric acid, albumin, globulin, cholesterol, triglycerides, and glucose, were spectrophotometrically analyzed with analytical kits (Pars Azmun Company) and a microplate reader . Ultimately, the ratio of albumin to globulin was determined.Blood samples were randomly collected from two chickens per pen using heparinized syringes via the jugular vein. Then, the samples were centrifuged within 20 min at 1000 × 2.12This work was performed in a completely randomized design. The obtained data were exposed to ANOVA via the SAS software  GLM Proc. The statistical significance was compared among the means at a 95% significance level through Duncan's multiple‐range test. Results are presented as the mean value.33.1p = .01) in FCR for the ROE treatment compared to the control group  by both feed additives compared to the control, except 200 mg/kg PAE which showed no significant effect on GPx. In addition, supplemented diets had increased (p = .006) TAC. Moreover, all the supplemented diets reduced MDA in both breast (p < .0001) and thigh (p < .001) when compared to the control group  coliform counts. Moreover, both EOs increased (p = .029) lactic acid bacteria counts in the ileum  VH in the duodenum and that all the supplemented EOs increased (p < .041) VH in the jejunum. Also, VH (p = .023) was increased by 200 mg/kg PAE in the ileum. The ratio of VH to CD was not significant in the different parts of the intestine. Furthermore, the CD was increased (p = .022), and the density of goblet cells was decreased (p = .046) by ROE and 200 mg/kg PAE in the ileum (Table This study showed that PAE increased p < .03 VH in th3.5p < .0001) with feed additives. Total anti‐SRBC antibody titers in supplemented diets were higher (p < .0001) when compared to the control group  in birds fed 200 mg/kg PAE. The globulin also was increased (p = .02) by all the feed additive treatments. In addition, cholesterol levels were lowered (p = .002) by EOs. The other parameters measured were not statistically different from the control group.In the current study Table , the tot4There have been several factors postulated as being involved in improving health and performance traits by EOs in animals  can function synergistically to neutralize oxidative stress and recycle endogenous antioxidants ; data curation ; formal analysis ; investigation ; methodology ; validation ; visualization ; writing – original draft ; writing – review and editing . Farid Shariatmadari: Conceptualization ; funding acquisition ; methodology ; project administration ; resources ; supervision ; validation ; writing – review and editing . Mohammad Amir Karimi Torshizi: Conceptualization ; formal analysis ; methodology ; software ; validation ; visualization ; writing – review and editing . Hamed Ahmadi: Conceptualization ; data curation ; methodology ; project administration ; validation ; visualization . Dawn V Scholey: Writing – review and editing .The authors declare that they do not have any conflict of interest.The study protocol was evaluated and accepted by the Tarbiat Modares University's Ethics Committee for animal use.


There is no well‐established late‐line treatment for advanced nonsquamous non‐small cell lung cancer (NSCLC). Therefore, we retrospectively determined the efficacy and safety of platinum rechallenge with paclitaxel‐carboplatin and bevacizumab in patients with nonsquamous NSCLC as a late‐line therapy in a clinical setting.Thirty patients with nonsquamous NSCLC who received paclitaxel‐carboplatin with bevacizumab therapy as a late‐line treatment at Sendai Kousei Hospital  between December 2011 and December 2021 were enrolled into the study. The efficacy and safety of this treatment were evaluated. The patients were further categorized into responders and nonresponders, and predictive factors of treatment response were estimated.p = 0.012). No fatal adverse events were reported.The median progression‐free survival (PFS) was 6.3  months, and the median overall survival (OS) was 11.8  months. There were no significant differences in PFS and OS between patients with and those without epidermal growth factor receptor mutations. In the univariate analyses of this study, responders were younger than nonresponders (With the increase in the number of treatment options in recent years, the sequence of treatments and overall therapeutic strategy are becoming increasingly important. Thus, platinum rechallenge with paclitaxel‐carboplatin and bevacizumab, a late‐line treatment for patients with nonsquamous NSCLC, may be an effective therapeutic option. Thirty patients with nonsquamous non‐small cell lung cancer who received paclitaxel‐carboplatin with bevacizumab therapy as a late‐line treatment were retrospectively evaluated.The median progression‐free survival was 6.3 months.Paclitaxel‐carboplatin with bevacizumab as a late‐line therapy may be an effective therapeutic option. Lung cancer remains a leading cause of cancer‐related deaths worldwide.Above all, ICIs have become standard treatment options for NSCLC. In recent years, the life expectancy of patients with NSCLC has increased.Paclitaxel‐carboplatin with bevacizumab as the first‐line therapy for patients with nonsquamous NSCLC has significant survival benefits.2 body surface area) and carboplatin  plus bevacizumab (15 mg/kg) intravenously every 3 weeks for 4–6 cycles, followed by bevacizumab monotherapy every 3 weeks, with reference to the ECOG 4599 trial.This was a retrospective study of patients with nonsquamous NSCLC treated with paclitaxel‐carboplatin and bevacizumab as a late‐line therapy at Sendai Kousei Hospital  between December 2011 and December 2021. The data cutoff time was December 31, 2021. Patients were selected based on the following criteria: (1) pathologically proven stage IIIB–IV nonsquamous NSCLC, based on the tumor‐node‐metastasis (TNM) staging system (seventh edition),This study was conducted according to the Helsinki Declaration and the study protocol was approved by the institutional review board of Sendai Kousei Hospital (IRB no.2‐37). Informed consent was obtained using the opt‐out method on the website of our institution. Those who opted out were excluded.Objective tumor response to chemotherapy was assessed by computed tomography at 8–9‐week intervals. Two pulmonary physicians (an attending physician and an investigator) evaluated objective tumor response using the RECIST guidelines, version 1.1.p < 0.05, based on two‐tailed tests, were considered statistically significant. We estimated the time to events using the Kaplan‐Meier method. The hazard ratio was calculated using the Cox proportional hazards model.All statistical analyses were performed with EZR , a graphical user interface for R .Thirty patients with nonsquamous NSCLC treated with paclitaxel‐carboplatin and bevacizumab at Sendai Kousei Hospital  between December 2011 and December 2021 were enrolled in this study. Patient characteristics and comparisons between patients are summarized in Table p = 0.93 and 0.98, respectively).At data cutoff, the median follow‐up was 11.2  months. Overall, 26 patients (86.7%) were treated with four or more courses of chemotherapy. Four patients were still undergoing treatment. The median PFS was 6.3  months and the median OS was 11.8 . The Kaplan Meier curves for PFS and OS are shown in Figure AEs of any grade were observed in 30 patients (100%) and severe AEs (grade ≥3) were observed in 21 patients (70.0%). The AE categories are shown in Table p = 0.012).Table Platinum rechallenge with paclitaxel‐carboplatin and bevacizumab as a late‐line therapy is effective for most patients with nonsquamous NSCLC and the associated AEs are tolerable.Asahina et al. reported that 38.4% of patients with advanced NSCLC who received first‐line chemotherapy could receive third‐line chemotherapy.Data on platinum rechallenge in patients with NSCLC are limited. In a pooled analysis,In the present study, the median OS and median PFS in patients with nonsquamous NSCLC following paclitaxel‐carboplatin with bevacizumab treatment as the late‐line therapy were 11.8 and 6.3 months, respectively. The ORR in these patients was 66.7%. The ECOG 4599 trial, a randomized phase 3 study involving patients with advanced nonsquamous NSCLC who had not previously undergone chemotherapy, compared paclitaxel and carboplatin alone with paclitaxel and carboplatin plus bevacizumab. In the paclitaxel and carboplatin plus bevacizumab group, the median survival was 12.3 months and the median PFS was 6.2 months. The ORR in these patients was 35%. Thus, the median OS and median PFS reported in our study were not considerably inferior to those in the previous study, even though our study included only patients on third‐line therapy or later. Moreover, the ORR in this study (66.7%) was higher than that reported in the previous study.In previous large clinical randomized trials of docetaxel plus ramucirumab therapy, docetaxel monotherapy, pemetrexed monotherapy, and tegafur/gimeracil/oteracil therapy (the S‐1 regimen), the median PFS and OS of second‐ or third‐line therapy for NSCLC were 2.9–4.5 and 7.5–12.8 months, respectively.In this study, as more than 80% of patients had received docetaxel as prior therapy, it was difficult to compare the difference in response between patients with and without previous docetaxel treatment. However, the 6.3‐month PFS and 66.7% ORR are still noteworthy and this regimen is promising.Efficacy, PFS, and OS were not significantly different between patients with and those without an EGFR mutation. Therefore, paclitaxel‐carboplatin with bevacizumab as a late‐line therapy has the same effect regardless of the presence or absence of EGFR mutations.In the ECOG 4599 trial, 25.5% of the patients treated with paclitaxel and carboplatin plus bevacizumab experienced neutropenia of grade 4. In the present study, the frequency of neutropenia (26.7%) was almost the same. Furthermore, most of the patients (86.7%) were treated with up to four courses of therapy, suggesting that these AEs were manageable.p = 0.012). There was no significant difference between responders and nonresponders in terms of prior treatment with ICI or EGFR TKIs. Further research is needed and there is a possibility that this treatment may be more appropriate for younger patients.In the univariate analysis of this study, responders were significant younger than nonresponders (There were some limitations in the present study. First, this was a retrospective study performed in a single institution using a small number of patients. In general, a small number of patients were in good general condition after second‐ or later‐line treatments. The patients of this study had good performance status. However, they had already been heavily treated, and their prognosis was not very good, with a few treatment options left as a late‐line treatment. Second, observer bias cannot be ruled out. Third, previous medications may have altered the effectiveness and safety of this treatment. Finally, although only three patients had been treated with ICIs as a first‐line therapy, ICI were administered as a second‐ or late‐line therapy in most patients. Currently, more patients are treated with ICI monotherapy or ICI plus chemotherapy as the first‐line therapy; thus, the efficacy and safety of paclitaxel‐carboplatin with bevacizumab as a subsequent treatment to these therapies requires future consideration. As the number of treatment options has increased in recent years, the sequence of treatments and overall therapeutic strategy are becoming increasingly important. In this light, this platinum rechallenge with paclitaxel‐carboplatin and bevacizumab may be a promising treatment option.In conclusion, platinum rechallenge with paclitaxel‐carboplatin and bevacizumab as a late‐line therapy may be an effective option in patients with nonsquamous NSCLC, regardless of the presence or absence of EGFR mutations. Moreover, the AE associated with this treatment were tolerable. Further examinations such as prospective studies comparing this regimen with docetaxel or S‐1 are warranted.Jun Sugisaka: Conceptualization, investigation, formal analysis, writing–original draft, and writing–review and editing. Yukihiro Toi: Conceptualization, investigation, formal analysis, writing–original draft, and writing–review and editing. Yosuke Kawashima: Investigation, writing–original draft, and writing–review and editing. Yutaka Domeki: Investigation, writing–original draft, and writing–review and editing. Tomoiki Aiba: Investigation, writing–original draft, and writing–review and editing. Sachiko Kawana: Investigation, writing–original draft, and writing–review and editing. Atsushi Nakamura: Investigation, writing–original draft, and writing–review and editing. Shinsuke Yamanda: Investigation, writing–original draft, and writing–review and editing. Yuichiro Kimura: Investigation, writing–original draft, and writing–review and editing. Shunichi Sugawara: Conceptualization, methodology, formal analysis, writing–original draft, writing–review and editing, and project administration.This research received no specific grant from any funding agency in the public, commercial, or not‐for‐profit sectors.Shunichi Sugawara received honoraria from MSD, Ono Pharmaceutical, Bristol‐Myers Squibb, AstraZeneca, Chugai Pharma, Nippon Boehringer Ingelheim, Pfizer, Taiho Pharmaceutical, Eli Lilly and Company, Novartis, Kyowa Kirin, and Yakult Honsha. Yukihiro Toi received honoraria from MSD, Ono Pharmaceutical, AstraZeneca, Taiho Pharmaceutical, and Bristol‐Myers Squibb. Yosuke Kawashima received honoraria from Eli Lilly and Company and Taiho Pharmaceutical. Atsushi Nakamura received honoraria from Nippon Boehringer Ingelheim, Chugai Pharma, MSD, and AstraZeneca. Shinsuke Yamanda received honoraria from AstraZeneca, Taiho Pharmaceutical, Novartis, and GlaxoSmithKline. The other authors declare no conflicts of interest.


Atopic dermatitis (AD) is one of the most common inflammatory skin diseases. It is associated with significant itch and impaired quality of life. Systemic treatments are efficient but associated with side effects. Novel topical treatments with a favourable safety profile are needed. SNG100 is a novel composition of hydrocortisone 1% in a cream base comprising sulphated polysaccharide , a well‐known hydrating, moisturising and a skin barrier repairing agent.To assess the safety, usability and efficacy of SNG100 cream in patients aged ≥6 years with moderate AD.In this proof of concept phase I, double‐blind, randomised trial, participants received one of three treatments for 14 days: SNG100 twice daily (BID), hydrocortisone 1% BID or mometasone furoate once daily (QD). The primary endpoint was the safety and tolerability of SNG100 cream compared to hydrocortisone 1% and mometasone furoate. The secondary endpoint was the subject's usability of SNG100. Exploratory efficacy endpoints included percent change from baseline in SCOring AD (SCORAD), Eczema Area and Severity Index, Patient‐Oriented Eczema Measure, Dermatology Life Quality Index, pruritus Numerical Rating Score (NRS), peak pruritus‐NRS and Investigator's Global Assessment. Subjects were also followed up without any treatment for additional 14 days.Overall, 66 participants were screened, and 60 patients were randomised. SNG100 demonstrated a high safety profile, similar to marketed products hydrocortisone 1% and mometasone furoate 0.1%, with no unanticipated drug safety related events. SNG100 and mometasone furoate 0.1% cream achieved almost similar and statistically significant greater percentage reductions from baseline in SCORAD as compared to hydrocortisone 1% cream. SNG100 demonstrated significant improvement in NRS as compared to hydrocortisone 1% cream. Remarkably, SNG100 led to a lasting effect with only 29.4% of subjects returning to IGA3 during the follow‐up period compared to 50% and 38.9% in the hydrocortisone 1% and in mometasone furoate treatment arms, respectively.Topical SNG100 is an effective, safe, and well‐tolerated innovative treatment for moderate AD. Trial registration number: NCT04615962 . Safe and effective topical therapies to improve disease control and long‐term outcomes in atopic dermatitis (AD) are needed. This clinical trial demonstrates the safety, usability and efficacy of topical SNG100, a novel formulation of hydrocortisone 1% with sulphated polysaccharide , for moderate AD patients aged 6 years of age or older, as compared to low and mid‐potency corticosteroids, hydrocortisone 1% and mometasone furoate, respectively. What is already known about this topic?Safe and effective topical therapies to improve disease control and long‐term outcomes in atopic dermatitis (AD) are needed.Although novel topical therapies for AD are under development, topical corticosteroids still serve as first line agents; however, concerns about potential adverse effects limit the use of potent corticosteroids.SNG100 is a novel composition of hydrocortisone 1% with sulphated polysaccharide , a well‐known hydrating, moisturising and a skin barrier repair agent.What does this study add?This trial demonstrates the safety, usability and efficacy of topical SNG100 for moderate AD patients aged 6 years of age or older.SNG100 offers a novel alternative to current topical treatments for AD.1Atopic dermatitis (AD) is a common pruritic inflammatory skin disease affecting up to 10% of adults and 20% of children with considerable impact on patients and caregivers quality of life.Corticosteroids are available for treatment of AD by various routes of administration, including topical, oral, and intramuscular. Although systemic corticosteroids result in rapid improvement, their discontinuation results in recurrence of disease of greater severity, restricting their use. Topical corticosteroids (TCS) still represent the mainstay of treatment in mild‐to‐moderate AD but their long‐term use may result in a wide array of complications, especially in children.SNG100 is a novel formulation comprising the low‐potency corticosteroid hydrocortisone 1% in combination with sulphated polysaccharides (SPS) extracted from Porphyridium cruentum microalgae, an excellent gelling agent and stabiliser, with well‐known hydrating, moisturising and skin barrier repair capabilities.In the current randomised, double‐blinded study, we aimed to assess the safety, tolerability and efficacy of SNG100 in moderate AD patients as compared to marketed products hydrocortisone 1% and mometasone furoate 0.1%.22.1clinicaltrials.gov: NCT04615962). Participants were randomised at 5 sites in Israel between March 2020 and April 2022. The study included a screening visit, a 2‐week treatment period and a 2‐week follow‐up period  score of 3, Eczema Area and Severity Index (EASI) total score of 7.1–21 and scoring AD (SCORAD) of 26–50. Exclusion criteria included participants with AD restricted to face and scalp, unstable disease requiring consistent treatment with high potency TCS, active secondary infection, uncontrolled diabetes mellitus or autoimmune disease, pregnancy or breastfeeding. In addition, patients were required to discontinue topical medications, systemic treatments/phototherapy and biologics, 2 weeks, 4 weeks and 6 months prior to enrolment, respectively.2.3Participants were randomised to three treatment arms: SNG100 twice daily (BID) (containing 1.0% (w/w) of hydrocortisone in SNG cream vehicle comprising Porphyridium cruentum exopolysaccharides), hydrocortisone 1% cream BID  or mometasone furoate 0.1%  once daily (QD), for 14 days Figure . The amo2.4The primary endpoints were safety and tolerability, assessed by self‐reporting experience, measuring the incidence of treatment‐emergent adverse events (TEAEs) including serious AEs , assessing significant changes (based on physician assessment) in vital signs  and laboratory assessment . Adverse events were reported from screening until the end of the follow up period. The secondary endpoints were usability factors of SNG100 cream versus hydrocortisone 1% and mometasone furoate cream. Usability was evaluated by self‐completion of a 9 questions usability questionnaire completed at visit 3  versus commercial reference products (hydrocortisone 1% or mometasone furoate 0.1% cream), the total reduction and percentage change from baseline in EASI, SCORing AD (SCORAD), Investigator's Global Assessment (IGA), Patient‐Oriented Eczema Measure (POEM), Dermatology Life Quality Index (DLQI), Numerical Rating Score (NRS) and peak pruritus‐NRS, were assessed at screening and baseline (visits 1 and 2), days 7 and 14 of treatment (visits 3 and 4) and after 14 days follow up (visit 5) .As this was a phase 1 study, sample size determination was not planned to meet specific statistical significance and power requirements. Analyses were based on existing data without any imputations. The intent to treat set was used for safety while the Per Protocol set (PP) was used for efficacy evaluation. Continuous variables were summarised with mean and 95% confidence interval or median and interquartile range (IQR) and compared between study arms using Kruskal Wallis test followed by Dunn's post hoc test. Categorical variables were summarised using frequency and percentages and compared between study arms using Fisher exact test or Chi‐square test. The Friedman's paired test was used to compare each follow‐up time point to baseline within study arms. A general estimating equations (GEE) model was applied to estimate the EASI scores during repeated visits and to compare between 3 treatment arms, accounting for the within‐subject correlation and adjusting for age and gender. A 33.1In total, 66 subjects were screened out of whom 60 were enroled and randomised to treatment Figure . The mea3.2Overall, 5 participants experienced AEs during the study Table . In the 3.3Treatment with SNG100 resulted in excellent usability with an average usability score above 4, similar to hydrocortisone 1% Figure . In cont3.4Baseline IGA was 3 for all participants Table . On day p = 0.040) and hydrocortisone 1% cream   Table . No sign2) Table .Similar to EASI score, a statistically significant reduction in SCORAD score was observed in all treatment groups (best results achieved at visit 4) with no significant difference in SCORAD change observed between groups Table . A steadp < 0.01). There was no significant difference in percent of change from baseline of DLQI between groups at all visits . Similarly, also for PP‐NRS, SNG100 and mometasone furoate arms had significantly lower values as compared to hydrocortisone 1% . At visit 4, a significant change in mean pruritus NRS and PP‐NRS was noted , respectively.A significant reduction in pruritus NRS and PP‐NRS scores was noted in all arms, with best results achieved at visit 4. For pruritus NRS, SNG100 and mometasone furoate arms had significantly lower values as compared to hydrocortisone 1%  with 69% of patients demonstrating improvement of AD severity as compared to baseline. This is in contrast to only 54% and 42% of patients in the mometasone furoate and hydrocortisone 1% cream groups, respectively, demonstrating improvement in EASI score at visit 5. Similarly, clinically relevant reduction in average pruritus was observed as early as day 7 in the SNG100 group with further improvement at day 14  and persistent effect at 14 days follow‐up observed in 40% of patients .Although preliminary, these observations point to a possible long‐term immunomodulatory and anti‐pruritic effect of SNG100. Accordingly, SNG100 containing the low potency TCS hydrocortisone 1% may serve as an effective topical treatment for AD patients with very low risk for TCS‐associated cutaneous side effects and possible superior proactive and maintenance activity as compared to other currently available topical treatments for AD given its potential long‐term effect on the immune system. In addition, given the comparable non‐inferior efficacy of SNG100 to the mid‐potency corticosteroid mometasone furoate 0.1%, SNG100 can be safely applied on gentle skin surfaces with no risk of long term side effects given its low potency steroid content.SNG100 formulation was well‐tolerated with usability score similar to hydrocortisone 1% and superior to mometasone furoate 0.1% marketed products. In addition, only one reported case of AD worsening was observed with SNG100.A limitation of this study is its relatively small sample size. Given the known beneficial effect of TCS in AD, to detect significant differences between treatment arms, larger group sizes are needed. In addition, the treatment period spanned only 2 weeks. Formal efficacy assessment over a longer treatment and follow‐up periods would be required to confirm persistent efficacy and long‐term safety profile. This study's strengths included monotherapy without any rescue therapy providing added robustness to the results. In addition, the patient‐reported outcomes strongly supported the clinical improvement shown by objective measures with SNG100 treatment.In conclusion, the results of this study showed that SNG100 formulation is effective and well tolerated in moderate AD. Further studies are required to evaluate SNG100 safety and efficacy in a larger sample size and for a longer treatment period.L.S. has served as principal Investigator and/or sub‐Investigator for Eli Lilly, Abbvie, Pfizer, and has participated in advisory boards of Abbvie, Pfizer and Sanofi; S.G. has served as principal Investigator and/or sub‐Investigator for Eli Lilly, Abbvie, Pfizer and Amgene and also received honoraria and consultancy fees from Eli Lilly, Abbvie and Pfizer, Dexcel, Pierre Fabre and Padagis; R.D‐G. serves as consultant for Pfizer, Janssen, Sanofi, AbbVie, Novartis, La Roche‐Posay, Dexcel, Eli Lilly, Mii Labs and Padagis and served as principal Investigator and/or sub‐Investigator for Abbvie, Sanofi, Mii Labs and Regeneron; Y.R. serves as the CMO of Mii Labs, which develops SNG100, and has also received honoraria and consultancy fees from Eli Lilly, Abbvie, Novartis, Janssen, Neopharm, Giuliani S.p.A, Dexcel Pharma, Sanofi, Taro, Monasterium laboratories and Pfizer; E.S. serves as consultant for Pierre Fabre, Kamari, Biomx, Bayer, Amryt, Medison Pharma, Sol‐Gel, Krystal, BiondVax, Galmed, LaserTeam; I.Z., D.F. and O.Y.Z. work at Synergy dermatology Ltd.Liat Samuelov: Investigation (lead); methodology ; writing – original draft (lead). Avner Shemer: Investigation ; writing – review & editing (supporting). Shoshana Greenberger: Investigation ; writing – review & editing (supporting). Inbal Ziv: Conceptualization ; data curation ; formal analysis ; methodology ; resources ; validation ; writing – review & editing (supporting). Doron Friedman: Conceptualization (lead); data curation (lead); formal analysis (lead); funding acquisition (lead); investigation ; methodology (lead); resources (lead); validation (lead); writing – review & editing . Oron Yacoby‐Zeevi: Conceptualization ; data curation ; formal analysis ; methodology ; resources ; validation ; writing – review & editing (supporting). Roni Dodiuk‐Gad: Investigation ; writing – review & editing (supporting). Yuval Ramot: Investigation ; methodology ; writing – review & editing . Sari Murad: Investigation ; writing – review & editing (supporting). Eli Sprecher: Investigation (lead); methodology (lead); writing – original draft (lead).This study was conducted in compliance with the principles of the Declaration of Helsinki and the study protocol was reviewed and approved by Institutional Review boards at each participating centre.Supporting Information S1Click here for additional data file.Supporting Information S2Click here for additional data file.


Digital therapeutics are emerging as a new form of therapeutic interventions. Unlike conventional therapeutics, digital therapeutics deliver interventions directly to patients using an evidence‐based, clinically evaluated software to treat, manage, or prevent diseases. Digital therapeutics manifest in diverse forms such as web‐based applications, mobile applications on smart devices, virtual reality, and video games. As its own product category for FDA approval, digital therapeutics can function as stand‐alone treatments or in combination with conventional therapeutics to improve adherence and/or efficacy. Here, we review the clinical landscape of digital therapeutics. We summarize FDA‐approved products and their clinical use, overview >300 ongoing clinical trials, and discuss challenges for their clinical translation and strategies to overcome the same. According to the Digital Therapeutics Alliance, DTx are referred to as “evidence‐based, clinically evaluated software to treat, manage, and prevent a broad spectrum of diseases and disorders.”The FDA has recognized digital health and its relevance to patient health and opened the Digital Health Center of Excellence in 2020 to streamline the regulation process in accordance with its safety policies.2DTx employ technologies such as artificial intelligence (AI), data analytics and understanding of behavioral psychology to offer a new way for disease treatment, management, and prevention.The application of DTx for treating chronic diseases such as diabetes has been executed through web platforms,Other DTx treatments such as for treating viral diseases like oral hepatitis C therapies combine the use of medical devices , attention‐deficient hyperactivity disorder (ADHD), psychosis, and depression Table . These pOther FDA‐approved or EUA‐designated DTx for psychiatric disorders include EndeavorRx® for treating ADHD, Deprexis® for treating psychosis/depression, and SparkRx® for treating depression in adolescents Table . Endeave3.2ReSET™ and ReSET‐O™, developed by Pear Therapeutics, are the only FDA‐approved DTx for treating substance use disorders. These mobile applications are used in conjunction with buprenorphine and individual counseling to enhance the retention of patients with substance use disorders.3.3Two DTx products have been approved by FDA for managing neurological diseases Table , includi3.4Seven DTx products have been approved for treating Type I and/or Type II diabetes Table . Most of3.5In addition to the abovementioned products, the other FDA‐approved DTx products focus on treating orthopedic disorders , gastrointestinal diseases , cardiovascular diseases, respiratory disease , and cancer care Table . In part4clinicaltrials.gov to identify active clinical trials investigating DTx. The searches were conducted under “Other Terms” using the search terms “Digital Therapeutic OR Digital Therapy” and limited to “Interventional Studies ” under the “Study type” category. Trials with an active status including “Not yet recruiting”, “Recruiting”, “Enrolling by invitation”, and “Active, not recruiting” were included. Further selections were put in place as the clinical trials of interest were limited to the last 10 years. Initially, 456 clinical trials were identified. Trials that included the terms “digit”, “digital angiography”, or “digital” without the use of interactive software or not related to DTx were excluded. After screening, a total of 317 trials of interest were identified for further analysis. The data were collected in December 2022 and selected trials are shown in Table A search was conducted on n = 129, 40.6%), oncology , addiction , endocrinology , and neurology  diseases represent the major areas  of the identified trials focus on treating psychiatric disorders , the most common form of DTx was through web applications (69.2%) , many DTx came in the form of a mobile application (45.9%) followed by web‐based apps (43.24%) with devices, AI‐based and video game DTx being the least common  had a larger proportion of web‐based applications  Figure A. Convern Figure . Within n Figure B. Anxiets Figure  comprisis Figure C. These s Figure .4.2Within the oncology‐focused trials, DTx were tailored to be centered on patient support in the cancer recovery process within breast cancer and generalized cancers Figure ; these D4.3The addiction‐related trials mainly focus on three themes: opioid use disorder (OUD) (63.3%), smoking (23.3%), and alcohol abuse (13.3%) within its own category Figure . Similar4.4The neurological disease‐focused trials were more equal in spread; however, a large focus remained on Alzheimer's disease, dementia, autism, and migraine management Figure . More se4.5The endocrinology‐focused trials centered primarily on diabetes management with insulin titration‐related applications that allowed for patients to individualize their therapy Figure . Diabete4.6Other disease areas such as orthopedic, metabolism, respiratory, cardiovascular, musculoskeletal, gastroenterological, rheumatic, and dermatological diseases were also found in the identified DTx trials Table . The ortOther disease areas such as sexually transmitted disease (STD), rheumatic , speech therapy (dysarthria), dermatology, multiple indications, and geriatric and physical activity (exercise) are also present in the identified trials Table . STD‐rel5Despite its potential to alter the way modern medicine approaches therapeutics, clinical translation of DTx does face some pressing challenges. The concept of a “dose” and “exposure” to DTx is ambiguous and the definition of digital endpoints also poses an issue with determining when therapeutic effects are experienced by the patient.When examining the barriers that exist for the patient and the use of DTx, the concept of reimbursement as a prescribed therapeutic also hinders its potential. Healthcare professionals tend to be the largest factor in encouraging DTx use and ensuring adherence to their treatment among patients.The handling of patient‐sensitive healthcare data must be addressed as devices and applications are utilizing machine learning and algorithms to tailor patient care. When addressing psychiatric issues, patients are often encouraged to track patterns in cognitive dissonance in order to adapt behaviors. With the accessibilities of smartphones and smart watch incorporated technology, there can be concerns of maintaining ease of access to the patients while also ensuring the information's confidentiality. Compromises of patient care data have previously been addressed in the latest updated version for digital medicine devices in 2014 by the FDAOn a global perspective, the implementation of DTx will have a particular impact on the countries/areas with a low healthcare provider to patient ratio  where the healthcare system is already overburdened.6Overall, the potential for DTx remains huge. The ease of access of DTx is low risk to patients and is available in multiple platforms, which can extend care to a greater population. With its digital interface, DTx eliminates the need for face‐to‐face interactions necessary for therapeutic benefit; patients can access their needs through the comfort of their homes and can also be prescribed as a combinational therapy with counseling and/or drug medication regimes. Challenges and issues arise with the lack of proper regulatory infrastructure for such an emerging field. Reimbursement through insurance companies and also the lack of standardized cybersecurity features for DTx hinder its clinical translation. Similarly, patient metrics for successful treatment for psychiatric diseases often rely on a patient‐reported improvement scale that can differ among individuals and the need for a prescription also limits access across various socioeconomic classes. However, despite these challenges, it has been predicted that there will be a large increase in the number of individuals using DTx over time, with a market predicted value of an 865% increase from 2020 to 2025.Philana Phan: Data curation (lead); formal analysis (lead); methodology (lead); writing – original draft (lead); writing – review and editing . Samir Mitragotri: Conceptualization ; writing – review and editing . Zongmin Zhao: Conceptualization ; writing – original draft (supporting); writing – review and editing .The authors declare no conflicts of interest.https://www.webofscience.com/api/gateway/wos/peer-review/10.1002/btm2.10536.The peer review history for this article is available at Digital therapeutics are a new form of interventions that deliver treatments to patients through evidence‐based software. In this work, we provided a comprehensive review of the clinical landscape of digital therapeutics. Our discussions can help the field understand the opportunities and challenges associated with developing new and efficacious digital therapeutics, offering guidelines to facilitate their clinical translation.Figure S1: Subtypes of Web Applications Dtx used in the specific psychiatric disease‐focused clinical trials of (A) Insomnia, (B) Depression, and (C) Anxiety. The respective percentages of each type are delineated in the respective legends.Figure S2: Subtypes of Web Application Dtx used in the specific Oncological disease‐focused trials of (A) Breast cancer and (B) generalized Cancer. The respective percentages of each type are delineated in the respective legends.Figure S3: Subtypes of Web Application Dtx used in the specific Addiction disease‐focused clinical trials of (A) Opioid Use Disorder, (B) Smoking, and (C) Alcohol Abuse. The respective percentages of each type are shown in the respective legends.Click here for additional data file.


N = 412) in which we first assessed heterosexual men's motivation to protect traditional masculinity. Then, we informed them that men’s gender norms are becoming more feminine (feminization norm condition) or are remaining masculine in a traditional sense . In the third (baseline-control) condition, participants received no information about men’s gender norms. Finally, we assessed the extent to which participants endorsed gender-hierarchy-legitimizing ideologies, namely sexism (Study 1) and masculinist beliefs (Study 2). Results showed that men who were less motivated to protect traditional masculinity were less likely to endorse gender-hierarchy-legitimizing ideologies when exposed to the feminization and control conditions compared to the traditional norm condition. The implications of these findings for gender equality and gender relations are discussed.Contemporary evidence suggests that masculinity is changing, adopting perceived feminine traits in the process. Implications of this new masculine norm on gender relations remain unclear. Our research aims to better understand the influence of changing masculine norms on men’s endorsement of gender-hierarchy-legitimizing ideologies. Based on Precarious Manhood Theory and Social Role Theory, we conducted two quasi-experimental studies ( According to masculine ideology, masculinity is a cultural construct defined by a set of beliefs and expectations regarding how men should behave in a given time and culture , 75. TheAlthough traditional masculinity seems to remain the predominant masculinity ideology nowadays , or at lThe norms defining traditional masculinity are hegemonic, meaning that they legitimize and uphold men’s privileged status in society and male dominance over women and subordinated masculinities, such as gay and racialized men , 20. CenContexts characterized by prevailing traditional gender norms, and in particular traditional masculinity norms, are the least egalitarian with respect to gender relations e.g., , 76, 85), 8576, 8However, gender roles are being challenged, and traditional norms of masculinity  are giving way to more progressive and feminized norms of masculinity , 86. IndDespite the theoretical and practical relevance of social changes in gender norms for gender equality, research examining the consequences of the feminization of men’s gender norms on men’s attitudes and behaviors toward women are scarce, and results are mixed. Indeed, to date, research examining the consequences of the feminization of men’s gender norms has focused solely on men’s self-description , 10, 13 In order to anticipate the potential consequences of a feminization of men’s gender norms , we were informed by two theories in the domain of gender norms and behaviors: Social Role Theory  reduced their fear of being perceived as gay, their discomfort while imagining performing feminine behaviors , and thetraditional condition, we highlighted the normativity of the traditional traits and roles of masculinity among men, as well as the related strong gender differences. In the feminized condition, participants learned that men are becoming more feminine and that gender differences are blurring. The control condition did not include any information about the ingroup norm, which allowed us to determine where the baseline is located. Indeed, among past studies, only Bosson and Michniewicz , t(227) = 15.55, p < 0.001, η2p = 0.52. Overall, sexism increased as a function of men’s endorsement of traditional masculinity norms. This effect was qualified by a significant C1 × motivation to protect traditional masculinity interaction, B = 0.10, 95% CI = , t(227) = 2.44, p = 0.016, η2p = 0.03, while C2 × motivation to protect traditional masculinity interaction was not significant, B = 0.01, 95% CI = , t(227) = 0.34, p = 0.73. Looking at simple effects revealed that C1 was significant only among men who were less motivated to protect traditional masculinity (− 1SD), B = 0.15, 95% CI = , t(227) = 2.71, p < 0.01, η2p = 0.03, revealing that ambivalent sexism in the traditional condition (M = 3.67) was significantly higher compared to the feminization condition (M = 3.40) and marginally higher compared to the control condition  = 1.74, p = 0.08). The control and the feminization conditions did not differ from each other t(227) = − 1.01, p = 0.31  < − 1.41, ps > 0.160.Analyses revealed a significant main effect of motivation to protect traditional masculinity,  0.57], t27 = 15.5Results of Study 1 confirm our main prediction regarding a difference in sexism between the feminization and traditional norm conditions among men who were less motivated to protect traditional masculinity . Simple effects revealed that priming a traditional norm of masculinity increased sexism among less traditional participants, while the feminization condition did not decrease it. Although we did not anticipate this result, these effects are consistent with SRT. SRT suggest that the traditional gender role division is associated with the expectancy of women being more communal and empathic and men being more agentic and dominant. Highlighting a traditional norm of masculinity may have emphasized the traditional gender division and compelled less traditional men to conform to it. Consistent with this reasoning, past research  suggestsStudy 2 was designed to replicate the findings of Study 1 with a different dependent variable, i.e., masculinism. Masculinism is an ideology and set of beliefs supporting the idea that masculinity in crisis in the face of the challenge posed by feminist and LGTBI advances. This ideology is based on antifeminism and supports three basic beliefs. The first is gynocentrism, the belief that society privileges women and relegates men to a subordinate position. The second is male victimization, the self-perception that men are victims, and the third is the trivialization of violence against women . Recent n = 3). The final sample consisted of 179 heterosexual American men . A sensitivity power analysis conducted on G*Power for a multiple linear regression model with five predictors, assuming an α of 0.05 and a power of 0.80, revealed that our final sample afforded us enough power to detect a small effect size (f2 = 0.06). Participants identified as White (56.4%), Asian American (12.3%), Hispanic/Latino (12.3%), Native American (10.1%), and African American (7.8%).Based on recommendations to recruit at least 50 participants per experimental condition , 79, we Motivation to protect traditional masculinity was assessed in the same way as in Study 1 .Manipulation of the gender norm was induced as in Study 1, the only difference being that the study was presented as being conducted in a U.S. University to match participants’ national background.r(179) = 0.80, p < 0.001, suggesting that both subscales measure the same construct. Accordingly, all the items were averaged into a single score, wherein higher scores reflect a higher endorsement of masculinist beliefs . The scale has good reliability and predictive validity, and it has been shown to correlate with both hostile and benevolent sexism , t(173) = 8.80, p < 0.001, η2p = 0.31. Overall, men’s gender norms were perceived as becoming more feminine as endorsement of traditional masculinity norms increased. The main effect of C1 was also significant, B = 0.27, 95% CI = , t(173) = 2.64, p < 0.01, η2p = 0.04. As expected, acknowledgment that men’s gender norms are becoming more feminine was stronger in the feminization condition (M = 5.02) than in the traditional condition (M = 4.50), with the baseline-control condition (M = 4.62) lying between the two experimental conditions. No other effect reached significance, ts < 1.91, ps > 0.06. Simple effects revealed that the control condition did not differ from the traditional condition (t(173) = − 0.68, p = 0.50) but differed from the feminization condition (t(173) = 2.01, p = 0.04).The analysis revealed a significant main effect of motivation to protect traditional masculinity, B = 1.00, 95% CI = , t(173) = 14.63, p < 0.001, η2p = 0.55. Overall, endorsement of masculinist beliefs increased as endorsement of traditional masculinity norms increased. This effect was qualified by a significant C1 × motivation to protect traditional masculinity interaction, B = 0.17, 95% CI = , t(173) = 2.00, p = 0.047, η2p = 0.02, while the C2 × motivation to protect traditional masculinity interaction was not significant, B = 0.02, 95% CI = , t(173) = 0.25, p = 0.80. Simple effects revealed that C1 was significant only among less traditional men (− 1SD), B = 0.29, 95% CI = , t(173) = 2.45, p = 0.015, η2p = 0.03, so that masculinism was significantly higher in the traditional condition (M = 3.70) compared to the feminization (M = 3.12) and control conditions (M = 3.22). The control and feminization conditions did not differ from each other (t(173) = − 0.43, p = 0.67; see Fig. ts(227) < − 1.41, ps > 0.160.The analysis revealed a main effect of motivation to protect traditional masculinity, .14], t17 = 14.63,Results of Study 2 are consistent with those observed in Study 1 and confirm our main prediction regarding a significant difference between the feminization and traditional norms conditions among less traditional participants (H1). Again, simple effects revealed that priming a traditional norm of masculinity increased masculinism among less traditional participants, while the feminization condition did not decrease it. These findings provide further evidence that traditional norms may be onerous for less traditional men because they are compelled to conform to an ingroup norm that does not reflect their conception of masculinity, whereas more feminized norms liberate them from this ingroup conformity pressure (see ). FinallAcross two studies, we investigated the consequences of the feminization of men’s gender norms  on men’s gender-hierarchy-legitimizing ideologies. According to Precarious Manhood Theory , 88 and Both studies consistently supported H1 and showed that the feminization norm condition differed from the traditional norm condition among less traditional men. Interestingly, specific comparisons between the two experimental and the control conditions revealed that priming less traditional participants with a traditional norm of masculinity increased their legitimation of the gender hierarchy, while priming a feminization of men’s gender norms did not influence their legitimation of the gender hierarchy. Overall, these findings are consistent with SRT because the salience of traditional gender roles increases conformity to a traditional view of gender. Moreover, they denote the importance of considering a control condition in order to conclude on the directions of the observed effects. Indeed, based on these results, we could speculate that the traditional norm condition increases less traditional participants' perceptual salience of the intergroup context . Under sBoth studies consistently showed no evidence for a defensive reaction among more traditional men, which is at odds with H2. Contrary to our expectations based on PMT, exposure to information emphasizing the feminization of men’s norm did not increase more traditional men’s endorsement of gender-hierarchy-legitimizing ideologies. Indeed, and given the precarious status of masculinity, we would have expected the feminization of men’s norm to trigger defensive reactions among more traditional men to reaffirm the gender hierarchy blurred by the alleged feminization. Both studies, however, suggest that more traditional men may be already reaffirming intergroup differences regardless of the experimental condition. Indeed, in Study 1, we observed a lack of difference between the feminization and control conditions on the manipulation check measure suggesting that men perceive their gender group as becoming more feminine. Similarly, in Study 2, we observed a main effect of participants’ motivation to protect traditional masculinity on the manipulation check, suggesting that the more participants are motivated to protect traditional masculinity, the more they perceive their gender group as becoming more feminine. Thus, the findings on the manipulation check measures may inform on the absence of effects of our manipulated variable.Interestingly, the high scores on the gender-hierarchy-legitimizing ideologies in the three experimental conditions of both studies suggest that traditional men are motivated to reinforce the gender hierarchy regardless of information concerning gender boundaries. This may indicate, first, that traditional men may feel threatened by default and thus are more motivated to protect the gender hierarchy in all circumstances. Second, this may also indicate that previous research failed to detect men's motivation to maintain the gender hierarchy independently of male norms because it has focused solely on men's self-description or attitudes toward deviant ingroup members. Moreover, the content of traditional masculinity norms seemed to encourage the domination of men over women. This may then explain the higher levels of gender-hierarchy-legitimizing ideologies in the three experimental conditions and regardless of their content. Interestingly, this suggests that the mechanisms that operate in the two experimental conditions may differ. While the feminization of the men’s norm threatens distinctiveness, traditional masculinity simply makes the norm of dominance more salient and motivate traditional men to conform to it. More research on this topic is needed.The present research makes an important contribution to our understanding of the dynamic nature of gender norms and the consequences of the evolving role of men on gender relations. At the same time, some limitations need to be mentioned. First, in both studies, participants’ motivation to protect traditional masculinity was assessed at the beginning of the questionnaire, which could have activated a traditional masculinity mindset among participants and influenced the impact of the norm manipulation. However, in both studies, participants overall scored close to the middle of the scale, suggesting that some participants are relatively aligned with traditional masculinity norms, while others are relatively unaligned. Therefore, it is unclear whether assessing motivation to protect traditional masculinity can directly impact the manipulation of the norm in any way. Nevertheless, this potential limitation suggests the need for alternative methods to rule out the possibility that the present results were influenced by the activation of a traditional mindset. For instance, further research could operationalize motivation to protect traditional masculinity by using a false feedback paradigm . Beyond the theoretical interpretations for the absence of results, some methodological issues may also be accountable. Indeed, our dependent variables are meant to capture the need for differentiation by measuring participants’ attitudes toward the gender hierarchy. In this regard, Jetten et al.  observedOur experimental manipulation check may also raise concerns. Participants had to indicate whether, in their opinion, men’s ingroup norms have become more feminine, which might have highlighted the possibility that they were more or less in agreement with the information provided in their experimental condition. Indeed, manipulation checks can sometimes induce participants to counter-correct the experimental information, leading to unpredicted outcomes . HoweverMore broadly, our research was the first to demonstrate that a normative change in men’s gender norms may have deleterious consequences for outgroups  without the need for the outgroup itself to be responsible for this social change. However, as the masculinist movements suggest, some men may believe that men are becoming more feminine because of women or because of deviant ingroup members. For now, we cannot comment on the mechanisms behind these effects. Indeed, our results do not inform us whether the norm feminization is perceived as a change derived by ingroup members or outgroup members, and whether the perceived norm feminization is actually liberating for less traditional men and threatening for more traditional ones. In this regard, future research should build on our findings to investigate the motivations underlying the observed effects.Gender norms and gender-hierarchy-legitimizing ideologies are both among the most important factors predicting gender inequality , which rThe present findings highlight the importance of examining the evolving role of men with regard to gender relations and the maintenance of the gender hierarchy. Two studies showed that less traditional men are more accepting of ideologies that legitimize male dominance over women when confronted with traditional norms of masculinity. Conversely, more traditional men appear to be non-sensitive to information about changes in their gender norms while maintaining high levels of gender-hierarchy legitimization.