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Background: Even if robotic assisted total knee arthroplasty (RATKA) is a widely used technique, there is still a gap of knowledge about whether this technology is effective in improving the patient utility. This measure is of paramount importance for conducting cost effectiveness analysis. The aim of this study was to compare the utility measure derived from self-reported outcomes questionnaires in patients who underwent RATKA compared to patients who underwent the manual surgery. Methods: We compared 72 patients operated with a robotic technique with 70 operated with traditional technique. The utility data were collected with the WOMAC (Western Ontario and McMaster University Osteoarthritis index) self-administrated questionnaire that investigates pain, stiffness and functionality of the patients, an then mapped to a utility value through a validated transforming function. We performed three surveys: the first one before the intervention (t0), the second one 1 year after the surgery (t1) and the third one at the 2 year follow up (t2). Results: we observed higher utility values in both groups. In detail, the mean utility score in the RATKA group increased from 0.37 to 0.71 (t1) and 0.78 (t2), while in the conventional group it increased from 0.41 to 0.78 (t1) and 0.78 (t2). The fixed effect coefficients of t1 and t2 were found to be 0.37 and 0.363 (p < 0.001 for both). The coefficient of the robotic technique, along with its interaction with the t1 and t2 time effect was non-significant. Conclusions: Even if at t1 the utility of patient who underwent RATKA were lower, at longer follow up (t2) we found no significant difference compared to traditional technique, leaving the superiority of robotic assisted technique yet to be proved. Our results may be useful for calculating the gained or lost Quality Adjusted Life Years (QALYs), so that the health care system (or an insurance company) could make an appropriate decision whether to fund the robotic approach or not, after a careful assessment of the incremental costs incurred. [ABSTRACT FROM AUTHOR]

Background: Football, as the most popular sport worldwide, has long been under suspicion of causing varus knee alignment as early as adolescence. However, no causal relationship has yet been found. The first step to do so would be to determine the prevalence of lower leg malalignment among male junior football players depending on age, performance level and the number of active seasons played. Methods: Leg axis alignment in frontal plane was determined in male junior football players of different age levels between 7 and 18 years by measuring the intercondylar/intermalleolar distance (ICD/IMD) in an upright position. In addition to anthropometric data, multiple sport-specific data such as the start of their football career or training time per week were collected by means of questionnaires (clinical trial registration number: DRKS00020446). Results: 207 male junior football players were included in this survey. The mean age was 12.8 years. Within the group of 15 to 18 year olds, the prevalence of varus knee malalignment was highest at just under a third (32.1%). In the subpopulation that played actively for more than ten seasons, 28.9% showed varus leg axis. Regarding performance level, the highest IMD/ICD values and highest prevalence of varus alignment were found among football players who play on a semi-professional level (16.7%), compared to amateur (11.4%) and high-performance levels (2.8%). Conclusions: Further research is necessary to investigate if this high prevalence of varus knee in children of a higher age and higher playing levels is due to the selection bias of football players with varus knee or a real development of varus knee in individuals. [ABSTRACT FROM AUTHOR]

Background/Objectives: The increase in digital tools in early childhood education highlights the need for evidence-based assessments that support cognitive development and align with educational requirements and technological advances. This study contributes to the evaluation of the Bilingual English Language Learner Assessment (BELLA), designed to enhance early learning through curriculum-aligned tasks in preschool-aged children. Methods: Data were collected from 17 schools, including 506 preschool children, using a mixed-model approach to assess BELLA's capacity to appraise early numeracy, literacy, science, and social/emotional development. Analyses included a three-way ANOVA to examine the effects of sex, age, and sub-domain on pass rates and mixed-effects models to evaluate interactions between age and domain. Results: The results indicated a significant effect of age on performance across all domains, with older children demonstrating higher pass rates (p < 0.0001). No significant gender bias was detected. The interaction between age and domain was also significant (p < 0.0001), suggesting domain-specific age-related performance trends, which aligns with internal validity requirements. Conclusion: These findings position BELLA within the growing body of literature on digital media use in early childhood assessment and education, highlighting its potential as a curriculum-compliant digital assessment tool that evaluates and supports cognitive development without a gender bias. This study contributes to the field by providing empirical evidence of BELLA's effectiveness and suggesting future research directions, including the exploration of its bilingual (and potentially multilingual) applications and external validation against existing evidence-based assessments. [ABSTRACT FROM AUTHOR]

Previous studies have explored use of smart glasses in telemedicine, but no study has investigated its use in teleradiography. The purpose of this study was to implement a six-month pilot program for Western Australian X-ray operators (XROs) to use smart glasses to obtain assisted reality support in their radiography practice from their supervising radiographers, and evaluate its effectiveness in terms of XROs' competence improvement and equipment usability. Pretest–posttest design with evaluation of the XROs' competence (including their X-ray image quality) and smart glasses usability by XROs in two remote centers and their supervising radiographers from two sites before and after the program using four questionnaire sets and X-ray image quality review was employed in this experimental study. Paired t-test was used for comparing mean values of the pre- and post-intervention pairs of 11-point scale questionnaire and image quality review items to determine any XROs' radiography competence improvements. Content analysis was used to analyze open questions about the equipment usability. Our study's findings based on 13 participants (11 XROs and 2 supervising radiographers) and 2053 X-ray images show that the assisted reality support helped to improve the XROs' radiography competence (specifically X-ray image quality), with mean post-intervention competence values of 6.16–7.39 (out of 10) and statistical significances (p < 0.001–0.05), and the equipment was considered effective for this purpose but not easy to use. [ABSTRACT FROM AUTHOR]

Objective: This cross-sectional, case-control study aimed to explore the psychodynamic characteristics that influenced adolescents' mental health during the COVID-19 pandemic. Methods: Personality structure impairments, psychodynamic conflicts, defense styles, and mental health issues were examined using the OPD-Structure- and Conflict-Questionnaires, the Defense Style Questionnaire, and the Patient Health Questionnaire in adolescents before (n = 288) and after (n = 451) the COVID-19 pandemic in Germany. Results: Adolescents with mental health issues exhibited greater impairments in personality structure, more immature defense styles, and higher levels of psychodynamic conflicts both before and after the pandemic onset. Comparisons between pre-pandemic and pandemic samples indicated a lower level of the conflict of taking care of oneself versus being cared for in passive mode among adolescents during the pandemic. In-depth analysis of adolescents with mental health issues from the pandemic group revealed significant associations between personality structure impairments and a maladaptive defense style with somatoform, depressive, anxiety, eating, and alcohol use disorders. Conclusion: The findings provide clinically relevant insights into the psychodynamic factors that contributed to the psychological vulnerability of adolescents during the COVID-19 pandemic. These insights can guide the development of targeted psychodynamic interventions to support adolescents' mental health in similar future crises. [ABSTRACT FROM AUTHOR]

(1) Background: The surgical procedure to create an arteriovenous fistula (AVF) can be performed in either an ambulatory or in-patient hospital setting, depending on the case's complexity, the anesthesia type used, and the patient's comorbidities. The main scope of this study is to assess the cost-effectiveness and clinical implications of surgically creating an AVF in both ambulatory and in-hospital settings. (2) Methods: We conducted a retrospective observational study, in which we initially enrolled all patients with end-stage kidney disease (ESKD) admitted to the Vascular Surgery Department, Emergency County Hospital of Targu Mures, Romania, to surgically create an AVF for dialysis, between January 2020 and December 2022. The primary endpoint of this study is to assess the cost-effectiveness of surgically creating an AVF in an ambulatory vs. in-hospital setting by comparing the costs required for the two types of admissions. Further, the 116 patients enrolled in this study were divided into two groups based on their preference for hospitalization: out-patients and in-patients. (3) Results: Regarding in-patient comorbidities, there was a higher prevalence of peripheral artery disease (PAD) (p = 0.006), malignancy (p = 0.020), and previous myocardial infarction (p = 0.012). In addition, active smoking (p = 0.006) and obesity (p = 0.018) were more frequent among these patients. Regarding the laboratory data, the in-patients had lower levels of white blood cells (WBC) (p = 0.004), neutrophils count (p = 0.025), lymphocytes (p = 0.034), and monocytes (p = 0.032), but there were no differences between the two groups regarding the systemic inflammatory biomarkers or the AVF type. Additionally, we did not register any difference regarding the outcomes: local complications (p = 0.588), maturation failure (p = 0.267), and primary patency (p = 0.834). In our subsequent analysis, we discovered no significant difference between the hospitalization type chosen by patients regarding AVF primary patency failure (p = 0.195). We found no significant association between the hospitalization type and the recorded outcomes (all ps > 0.05) in both multivariate linear regression and Cox proportional hazard analysis. (4) Conclusions: In conclusion, there are no significant differences in the clinical implications, short-term and long-term complications of AVF for out-patient and in-patient admissions. Additionally, we found no variation in the costs associated with laboratory tests and surgical supplies for an AVF creation. Therefore, it is safe to perform ambulatory AVFs, which can reduce the risk of hospital-acquired infections and provide greater comfort to the patient. [ABSTRACT FROM AUTHOR]

Spinal disorders are some of the most prevalent health concerns, especially among students. Based on student demographics, this cross-sectional study evaluated the correlation between functional tests (FTs) and spinal range of motion (ROM). This study included 206 students (age = 19.85 ± 1.80 years) from the Vasile Alecsandri University of Bacău. Participants' assessments were conducted using the following tests: (i) Ott, (ii) Schober, (iii) Stibor, (iv) finger-to-floor distance, (v) lateral flexion of the cervical and lumbar spine, and (vi) flexion of the cervical spine. Correlation analyses were evaluated using the Spearman correlation coefficient analysis. The results indicated a very strong relationship between lateral flexion of the lumbar spine on the left (LFLSL) and right (LFLSR) for all departments (r = 0.85 to 0.97, p < 0.05). There was a stronger relationship between FT results and spinal ROM for physical-education-department students compared to students from other departments (n = 17, r = −0.38 to 0.93, p < 0.05). There was no statistically significant correlation between FTs and spinal ROM based on age (p > 0.05). The study results provide evidence of the primary risk factors that predispose students to postural deviations. Practitioners and physiotherapists can utilize these values as a reference for potential therapeutic interventions. [ABSTRACT FROM AUTHOR]

Women are at increased risk of trauma exposure and of experiencing prolonged posttraumatic stress. Maternal trauma exposure and associated impairment may adversely impact mother–infant interaction quality, which may in turn be associated with infant temperament difficulties. More research is needed to identify which maternal trauma predictors are most robustly related to infant temperament outcomes. The present study aimed to address this gap by examining maternal sensitivity as a mediator of relations between maternal trauma and infant temperament in a longitudinal study of a rural cohort of mother–infant dyads. Mediation via maternal sensitivity was not supported in any of the primary analyses. Greater maternal trauma exposure was found to predict greater infant regulation behavior, a finding that was in opposition to expected results and which may be explained by protective factors found within the sample. The present sample was skewed toward married, educated women who reported high social support satisfaction and low trauma-associated impairment. The findings elucidate protective factors that may mitigate adverse outcomes for both mothers and infants. Future research models should include additional maternal trauma variables (e.g., recency, type, revictimization/polyvictimization), in utero maternal cortisol exposure, maternal insensitivity/ambiguous response patterns during caregiver tasks, and analysis of the IBQ-R subscales. [ABSTRACT FROM AUTHOR]

Diet diversity becomes especially relevant during adolescence to satisfy the adequate micronutrient intake. Diet diversity (DD) and micronutrient probability of adequacy (PA) were studied in 818 Costa Rican (CR) and 1202 Mexican (MX) adolescents aged 13–18 years. DD was compared using the Minimum Dietary Diversity (MDD) score. Receiver-operating characteristic (ROC) curves were employed to identify the optimal MDD for each sample from the respective countries. The mean MDD for the overall CR sample was 4.17 ± 1.43 points, and for the MX sample, the mean MDD was 4.68 ± 1.48 points. The proportion of adolescents with a DD was significantly higher in Costa Rica than in Mexico (66.5% vs. 55.6%; p < 0.0001). Also, DD was higher in rural Costa Rican adolescents, while no difference was found in the MX adolescents by area of residence. CR adolescents reported significantly higher PA than MX participants for 6 of the 11 micronutrients assessed. The calcium PA in MX adolescents was significantly higher than in the CR sample (MX: 0.84 vs. CR: 0.03; p < 0.0001), while low PA was obtained for iron in both countries (CR: 0.01 vs. MX: 0.07; p < 0.0001). In Costa Rica and Mexico, nutritional interventions and assessing the compliance of food-fortifying programs are needed to improve the PA of diverse micronutrients. [ABSTRACT FROM AUTHOR]

Second-hand smoke (SHS) has adverse effects for pregnant women and foetuses. This controlled and randomized clinical trial evaluated the efficacy of a comic booklet intervention in promoting SHS avoidance among pregnant women and appropriate smoking behaviours among their male partners. We allocated 140 couples to the experimental group (EG), who received the comic booklet and a reminder sticker, and 146 couples to the control group (CG), who received usual care. The primary outcomes were women's self-reported SHS exposure and their male partners' smoking behaviours. Secondary outcomes included knowledge and awareness of SHS. Independent t-tests revealed that three months post-intervention, more male partners in the EG had appropriate self-reported smoking behaviours with a small effect size (Cohen's d = 0.35, 95% CI [0.08, 0.62], p-value = 0.01). Significantly more pregnant women in the EG recognised their partners' appropriate smoking behaviours with a nearly middle effect size (Cohen's d = 0.43, 95% CI [0.16, 0.70], p-value ≤ 0.01). Cues to action showed a significant difference between groups with a small effect size (Cohen's d = 0.36, 95% CI [0.09, 0.63], p-value = 0.01), as evaluated by male partners. These findings suggest that the comic booklet intervention might be effective against SHS exposure by providing several cues to action through knowledge and awareness of SHS. [ABSTRACT FROM AUTHOR]

Existing research concerning the effects of the sitting birth position during the second stage of labour on maternal and neonatal outcomes remains controversial, and there is a lack of studies to explore its effect on the childbirth experience. The objective of this study is to explore whether the sitting birth position would influence maternal and neonatal outcomes, as well as the childbirth experience. The prospective cohort design was conducted in the study from February to June 2023, a total of 222 women (including primiparous women and multiparous women) were enrolled in our study, and they were divided into the sitting position cohort (n = 106) or the lithotomy position cohort (n = 116). The pre-designed questionnaire and Childbirth Experience Questionnaire (CEQ) were used for data collection during hospitalisation. Chi-square, Fisher's exact test, t-tests, or the Mann–Whitney U test were utilised to assess differences between groups. Multivariate linear regression and logistic regression were employed to control possible confounders. The study found that primiparous women in the sitting position cohort had a shorter duration of the second stage of labour, higher spontaneous vaginal birth rates, lower episiotomy rates, and a better childbirth experience (p < 0.01). After adjusting for confounding factors through multiple linear and logistic regression analyses, the results remained consistent with those reported above. No neonate in each cohort had Apgar scores at 1 min and 5 min postpartum less than 7 or a Cord artery pH less than 7.00, regardless of parity. Based on the findings, we recommend that women could take the sitting birth position into account when giving birth for a positive childbirth experience, especially for primiparous women. The study could also serve as a reference for healthcare providers in the management of childbirth positions and the development of high-quality maternal care. [ABSTRACT FROM AUTHOR]

Psychosocial correlates are one of the crucial determinants for the uptake of colorectal cancer (CRC) screening by the pre-eligible population. The present study aimed to identify the psychosocial correlates of colorectal cancer screening and determine their associated factors among the Saudi population in the Najran region, Saudi Arabia. Using a validated questionnaire, we assessed five constructs of psychosocial correlates of CRC screening among 790 participants aged 45 years and above. The five constructs were salience and coherence, cancer worries, perceived susceptibility, response efficacy, and social influence. Of the studied population, less than 50% agreed with most of the five constructs' statements, and 27.5% preferred to follow their family members' advice. Significantly higher mean scores (±SD) were identified for the male gender (7.38 ± 2.15, p = 0.027) and participants working in government sectors (7.60 ± 2.03, p = 0.027) in the cancer worries construct, while the mean (±SD) scores of perceived susceptibility were significantly higher among married participants (14.38 ± 4.10, p = 0.023) and smokers (14.95 ± 3.92, p = 0.041). Our survey results could help policymakers to implement focused health education programs for the pre-eligible population on the importance of the uptake of CRC screening. Furthermore, it is recommended to carry out exploratory mixed-method surveys in other regions of Saudi Arabia to understand the region's specific psychosocial correlates towards CRC screening. [ABSTRACT FROM AUTHOR]

Laptop use appears to contribute to poor working postures and neck pain among university students. Postural braces have the potential to improve upper back/neck posture and therefore might have a role as an ergonomic aid for this population. Therefore, the purpose of this study was to assess the short-term effects of scapular bracing on pain, fatigue, cervicothoracic posture, and the activity of the neck and upper-back muscles in healthy college students. A randomized controlled crossover trial was conducted to evaluate the self-reported pain and fatigue, the amplitude and median frequency of surface electromyography in neck extensors, upper trapezius, and lower trapezius, as well as the neck and shoulder sagittal alignment (measured by inertial sensors and digital photographs) during a 30-min typing task in a sample of young, healthy university students with or without a scapular brace. The brace condition resulted in significantly smaller levels of bilateral trapezius muscle activity (p < 0.01). Rounded shoulder posture was slightly better in the brace condition, but these differences were not significant (p > 0.05). There were no significant immediate differences in pain or fatigue scores, neck alignment, or the electromyographic activity of the other muscles tested between brace and non-brace conditions (all p > 0.05). However, bracing appears to immediately reduce the electromyographic activity of the lower trapezius muscles (p < 0.05). These findings shed some light on the possible advantages of scapular bracing for enhancing laptop ergonomics in this group of individuals. Future studies are warranted to evaluate the effects of different types of braces, the importance of matching the brace to the user, and the short- and long-term effects of brace use on computer posture and muscle activity. [ABSTRACT FROM AUTHOR]

Identifying mental distress is a complex task, particularly when individuals experience physical symptoms. Traditional self-report questionnaires that detect psychiatric symptoms using emotional words may not work for these individuals. Consequently, there is a need for a screening tool that can identify both the physical and mental symptoms of mental distress in individuals without a clinical diagnosis. Our study aimed to develop and validate a scale that measures mental distress by measuring the extent of brain overwork, which can be extrapolated as the burden of mental distress. In this population-based cross-sectional study, we recruited a total of 739 adults aged 16–65 years from 64 sampling centers of a cohort in Mongolia to validate a 10-item self-report questionnaire. Internal consistency was measured using McDonald's ω coefficient. Test–retest reliability was analyzed using intraclass correlation coefficients. Construct and convergent validities were examined using principal component analysis (PCA) and confirmatory factor analysis (CFA). The Hospital Anxiety and Depression Scale (HADS) and the abbreviated version of World Health Organization Quality of Life (WHOQOL-BREF) were used to evaluate criterion validity. Among the participants, 70.9% were women, 22% held a bachelor's degree or higher, 38.8% were employed, and 66% were married. The overall McDonald's ω coefficient was 0.861, demonstrating evidence of excellent internal consistency. The total intraclass correlation coefficient of the test–retest analysis was 0.75, indicating moderate external reliability. PCA and CFA established a three-domain structure that provided an excellent fit to the data (RMSEA = 0.033, TLI = 0.984, CFI = 0.989, χ2 = 58, p = 0.003). This 10-item scale, the Brain Overwork Scale (BOS-10), determines mental distress in three dimensions: excessive thinking, hypersensitivity, and restless behavior. All the items had higher item-total correlations with their corresponding domain than they did with the other domains, and correlations between the domain scores had a range of 0.547–0.615. BOS-10 correlated with HADS, whereas it was inversely correlated with WHOQOL-BREF. In conclusion, the results suggest that BOS-10 is a valid and reliable instrument for assessing mental distress in the general population. The scale screens for mental distress that is characterized by subjective symptoms such as excessive thinking, hypersensitivity, and restless behavior. The current findings also demonstrate that the BOS-10 is quantitative, simple, and applicable for large group testing. This scale may be useful for identifying at-risk individuals who may require further evaluation and treatment for mental distress. [ABSTRACT FROM AUTHOR]

There has been no research on the trends in early sexual initiation associated with socio-environmental factors in Korea. This study aimed to examine the trends of early sexual initiation with various socio-environmental factors among adolescents. The Korea Youth Risk Behavior Web-based Survey data were used, and two pooled datasets extracted from the 2006–2008 and 2014–2016 waves were conducted and compared. In this study, early sexual initiation was defined as sexual intercourse at the age of 13 years or younger. The weighted percentage and 95% confidence interval reporting early sexual initiation were estimated, and multiple logistic regression was performed for each subgroup of socio-environmental variables with the 2006–2008 pooled data as a reference. Regardless of sex, the weighted percentage of adolescents with sexual experience who reported early sexual initiation increased in 2014–2016 with statistical significance in most cases. Moreover, the possibility of experiencing early sexual intercourse overtime was more prominent among girls than boys. While indifference to adolescent sexual behavior continues, more adolescents become involved in early sexual initiation. Socio-environmental considerations, such as the establishment of safe environments for adolescents' sexual activity, along with systematized monitoring mechanisms, should be administered. [ABSTRACT FROM AUTHOR]

Simple Summary: The number of pigmented moles is the most important risk factor for melanoma. This "real world" study conducted in 25 Australian childcare centers is the first to show it is possible to prevent a significant proportion of pigmented moles in young Caucasian children by dressing them in UPF 30-50+ clothing that covers at least half their body on a daily basis. Regularly wearing this clothing for 3.5 years was sufficient to prevent almost one-quarter of the pigmented moles that young children developed on their skin. This should, by implication, reduce their risk of developing melanoma in the future. Primary health care providers should stress the importance of garment coverage when recommending sun protection for children and should lobby for all sun-protective clothing standards to assess and report garment coverage, in addition to the transmission of ultraviolet radiation through the fabric (reported as UPF), on clothing labels and packaging for children's clothing, including school uniforms. Numerous pigmented moles are associated with sun exposure and melanomarisk. This cluster randomized controlled trial aimed to determine if sun-protective clothing could prevent a significant proportion of the moles developing in young children (ACTRN12617000621314; Australian New Zealand Clinical Trials Registry. Twenty-five childcare centers in Townsville (19.25° S), Australia, were matched on shade provision and socioeconomic status. One center from each pair was randomized to the intervention arm and the other to the control arm. Children at 13 intervention centers wore study garments and legionnaire hats at childcare and received sun-protective swimwear and hats for home use, while children at the 12 control centers did not. The 1–35-month-old children (334 intervention; 210 control) were examined for moles at baseline (1999–2002) and were re-examined annually for up to 4 years. Both groups were similar at baseline. Children at intervention centers acquired fewer new moles overall (median 12.5 versus 16, p = 0.02; 0.46 versus 0.68 moles/month, p = 0.001) and fewer new moles on clothing-protected skin (6 vs. 8; p = 0.021 adjusted for confounding and cluster sampling) than controls. Intervention children had 24.3% fewer new moles overall (26.5 versus 35) and 31.6% (13 versus 19) fewer moles on clothing-protected skin than controls after 3.5 years. Sunlight's influence on nevogenesis is mitigated when children regularly wear UPF 30-50+ clothing covering half their body, implying that increased clothing cover reduces melanoma risk. Sun-protective clothing standards should mandate reporting of the percentage of garment coverage for childrenswear. [ABSTRACT FROM AUTHOR]

Simple Summary: There is a wide range of choices for combining PD-1/PD-L1 checkpoint inhibitors with other measures in treating tumors, but certain choices of regimens are still controversial. We aimed to investigate the therapeutic efficacy and potential side effects of combination therapy with anti-PD-1/PD-L1 compared to anti-PD-1/PD-L1 monotherapy. Meanwhile, we also explored whether different combination strategies would yield consistent efficacy across different types of tumors. Our study can provide important and useful information for clinicians and encourage the enrollment of more clinical trials for anti-PD-1/PD-L1 combination therapy. Objective: In recent years, the anti-programmed cell death protein-1 and its ligand (PD-1/PD-L1) or combination therapies have been recommended as an alternative emerging choice of treatment for oncology patients. However, the efficacy and adverse events of different combination strategies for the treatment of tumors remain controversial. Methods: PubMed, Embase, Cochrane Library, the American Society of Clinical Oncology (ASCO), and the European Society of Medicine Oncology (ESMO) were searched from database inception until 16 February 2022. The endpoints of objective response rate (ORR), disease control rate (DCR), overall survival (OS), progression-free survival (PFS), and adverse events (AEs) were analyzed from different treatment schemes and tumor types. The protocol was registered in PROSPERO (CRD42022328927). Results: This meta-analysis included forty-eight eligible studies. Combination therapy has improved ORR (RR = 1.40, p < 0.001), DCR (RR = 1.22, p < 0.001), and PFS (the median survival ratio (MSR) was estimated to be 1.475 p < 0.001) compared to anti-PD-1/PD-L1 but had no significant benefit on OS (MSR was estimated to be 1.086 p = 0.117). Besides, combination treatment strategies are more toxic in any grade AEs (RR = 1.13, p < 0.001) and grade 3–5 AEs (RR = 1.81, p < 0.001). Conclusions: Treatment with PD-1/PD-L1 inhibitors in combination with other antitumor therapies improve patients' ORR, DCR, and PFS compared to anti-PD-1/PD-L1. However, it is regrettable that there is no benefit to OS and an increased risk of AEs in combinatorial therapies. [ABSTRACT FROM AUTHOR]

Simple Summary: Different cells present in the tumor microenvironment can deeply influence both cancer spreading and the success of therapy in solid tumors, including colorectal carcinoma (CRC). In particular, tumor-associated fibroblasts (TAF) exert potent immunosuppressive effects leading to the impairment of anti-tumor surveillance and interfering with the function of therapeutic antibodies. Herein, we show that CRC-derived TAF can be turned by zoledronic acid (ZA), in soluble form or as antibody-drug conjugate (ADC), into efficient stimulators of anti-tumor lymphocytes. The ADC, made of the anti-EGFR cetuximab (Cet), used in CRC therapy, and ZA (Cet-ZA) can induce the proliferation of lymphocytes that become able to kill both tumor cells and TAF. The double result is a direct anti-cancer effect and the neutralization of the inhibitory activity exerted by its stroma. The major advantage of the Cet-ZA ADC formulation is the precise delivery of ZA to EGFR+ cells, targeting TAF (potentially immunosuppressive), besides CRC cells. Tumor-associated fibroblasts (TAF) exert immunosuppressive effects in colorectal carcinoma (CRC), impairing the recognition of tumor cells by effector lymphocytes, including Vδ2 T cells. Herein, we show that CRC-derived TAF can be turned by zoledronic acid (ZA), in soluble form or as antibody-drug conjugate (ADC), into efficient stimulators of Vδ2 T cells. CRC-TAF, obtained from patients, express the epidermal growth factor receptor (EGFR) and the butyrophilin family members BTN3A1/BTN2A1. These butyrophilins mediate the presentation of the phosphoantigens, accumulated in the cells due to ZA effect, to Vδ2 T cells. CRC-TAF exposed to soluble ZA acquired the ability to trigger the proliferation of Vδ2 T cells, in part represented by effector memory cells lacking CD45RA and CD27. In turn, expanded Vδ2 T cells exerted relevant cytotoxic activity towards CRC cells and CRC-TAF when primed with soluble ZA. Of note, also the ADC made of the anti-EGFR cetuximab (Cet) and ZA (Cet-ZA), that we recently described, induced the proliferation of anti-tumor Vδ2 T lymphocytes and their activation against CRC-TAF. These findings indicate that ZA can educate TAF to stimulate effector memory Vδ2 T cells; the Cet-ZA ADC formulation can lead to the precise delivery of ZA to EGFR+ cells, with a double targeting of TAF and tumor cells. [ABSTRACT FROM AUTHOR]

Simple Summary: Sodium butyrate (NaB) is a short-chain fatty acid produced by intestinal microbial fermentation of dietary fiber. It has been shown to be effective in inhibiting colorectal cancer (CRC), but the mechanism is not known. We verified the ability of NaB to induce ferroptosis and the effect on relevant genotypes in normal intestinal cells and colorectal tumor cells, respectively. Moreover, better inhibition of tumor cells was observed when NaB was combined with Erastin (a ferroptosis-positive drug), suggesting that NaB combined with Erastin might have a stronger anti-CRC effect. Colorectal cancer (CRC) is one of the most common malignancies, and effective treatment and prevention methods are lacking. Sodium butyrate (NaB) is a short-chain fatty acid produced by intestinal microbial fermentation of dietary fiber. It has been shown to be effective in inhibiting CRC, but the mechanism is not known. Methods: Human normal intestinal epithelial cell line FHT and colorectal tumor cell line HCT-116 were treated with NaB alone or in combination with different programmed cell death inhibitors. Cell activity was then assessed with MTT assays and PI staining; ferroptosis with Fe2+, glutathione (GSH), and lipid peroxidation assays; signaling pathway screening with PCR arrays; and CD44, SCL7A11, and GPX4 expression with Western blotting. A CD44-overexpressing HCT-116 cell line was constructed to determine the effect of the overexpression of CD44 on NaB-induced ferroptosis. The synergistic effect of co-treatment with NaB and Erastin was assessed by isobolographic analysis. Results: NaB induced apoptosis and ferroptosis in HCT-116 cells but only induced low-level apoptosis in FHC cells. Moreover, NaB significantly increased intracellular Fe2+ and promoted GSH depletion and lipid peroxidation in HCT-116 cells. Ferroptosis-related qPCR array analysis identified CD44/SLC7A11 as a potential effector molecular of NaB-induced ferroptosis. NaB significantly inhibited the expression of CD44 and SLC7A11 in mouse CRC tissues. A CD44 overexpressed HCT-116 cell line was used to verify that CD44/SLC7A11 was a key signaling pathway that NaB-induced GSH depletion, lipid peroxidation accumulation, and ferroptosis in HCT-116 cells. Examination of whether NaB can increase the effect of ferroptosis agents showed that NaB, in combination with Erastin, a ferroptosis inducer, further promoted HCT-116 cell death and increased changes of ferroptosis markers. Conclusions: Our results suggest that NaB induces ferroptosis in CRC cells through the CD44/SLC7A11 signaling pathway and has synergistic effects with Erastin. These results may provide new insights into CRC prevention and the combined use of NaB and ferroptosis-inducing agents. [ABSTRACT FROM AUTHOR]

Simple Summary: We have recently reported that the cytosolic C-terminal domain (CTD) of the tumour suppressor PTCH1, the Hedgehog proteins receptor, interacts with the autophagy-related protein ATG101 and impairs autophagic flux. In this study, we identified the interaction region and found that it is absent in a subset of colorectal, stomach and endometrial cancers. We demonstrated that truncation mutants lack the ability to constraint autophagy, resulting in a proliferative advantage and reduced sensitivity to autophagy inducers or glycolysis inhibitors in cell lines harbouring endogenous PTCH1 CTD mutations compared to isogenic cells expressing wild-type PTCH1. In summary, this study highlights the importance of the PTCH1-ATG101 interaction in the regulation of basal and stimulated autophagy and the metabolic flexibility in cancer cells. The Hedgehog receptor, Patched1 (PTCH1), is a well-known tumour suppressor. While the tumour suppressor's activity is mostly ascribed to its function as a repressor of the canonical Smoothened/Gli pathway, its C-terminal domain (CTD) was reported to have additional non-canonical functions. One of them is the reduction of autophagic flux through direct interaction with the Unc-51, like the autophagy activating kinase (ULK) complex subunit autophagy-related protein-101 (ATG101). With the aim of investigating whether this function of PTCH1 is important in cancer cell fitness, we first identified frameshift mutations in the CTD of PTCH1 in cancer databases. We demonstrated that those mutations disrupt PTCH1 interaction with ATG101 and increase autophagic flux. Using deletion mutants of the PTCH1 CTD in co-immunoprecipitation studies, we established that the 1309–1447 region is necessary and sufficient for interaction with ATG101. We next showed that the three most common PTCH1 CTD mutations in endometrial, stomach and colon adenocarcinomas that cause frameshifts at S1203, R1308 and Y1316 lack the ability to interact with ATG101 and limit autophagic flux, determined by bafilomycin A1-sensitive accumulation of the autophagy markers LC3BII and p62. We next engineered PTCH1 indel mutations at S1223 by CRISPR/Cas9 in SW620 colon cancer cells. Comparison of two independent clones harbouring PTCH1 S1223fs mutations to their isogenic parental cell lines expressing wild-type PTCH1 showed a significant increase in basal and rapamycin-stimulated autophagic flux, as predicted by loss of ATG101 interaction. Furthermore, the PTCH1 CTD mutant cells displayed increased proliferation in the presence of rapamycin and reduced sensitivity to glycolysis inhibitors. Our findings suggest that loss of the PTCH1-ATG101 interaction by mutations in the CTD of PTCH1 in cancer might confer a selective advantage by stimulating autophagy and facilitating adaptation to nutrient deprivation conditions. [ABSTRACT FROM AUTHOR]

Simple Summary: We assessed whether anti-VEGF therapy increases the risk of thromboembolic events or major adverse cardiovascular events (MACEs) in patients with colorectal cancer based on real-world evidence. Patients with advanced colorectal cancer who had previously received anti-VEGF therapy did not increase the risk of thromboembolic events and major cardiovascular events more than patients without anti-VEGF therapy in Taiwan. Antivascular endothelial growth factor (anti-VEGF) therapy has been a standard treatment for patients with metastatic colorectal cancer. However, the risk of thromboembolic events and cardiovascular events associated with this therapy remains controversial. We assessed whether anti-VEGF therapy increases the risk of thromboembolic events or major adverse cardiovascular events (MACEs) in patients with colorectal cancer based on real-world evidence. This retrospective cohort study was designed using linked 2009–2016 nationwide databases, including the Taiwan Cancer Registry, the National Health Insurance Research Database, and Taiwan's National Death Index. In total, 189,708 patients newly diagnosed as having advanced colorectal cancer from 2009 to 2016 were identified and categorized into the anti-VEGF and comparator groups through age, sex, clinical stage, and diagnosis date (within 180 days) matching. Propensity score matching was further performed to balance the baseline characteristics between the two groups. The Kaplan–Meier method was used to create the cumulative incidence curves of thromboembolic events and MACEs, and log-rank tests were used to compare the differences in Kaplan–Meier curves. Competing hazard ratios (HRs) for thromboembolic events and MACEs were estimated using the Fine–Gray method when considering the competing event of death. Statistical analysis was performed using two-tailed tests with a significance level of 0.05. In total, 4635 patients were included in both the anti-VEGF group and comparator group. The risk of thromboembolic events and MACEs did not differ significantly between the two groups. After propensity score matching, the adjusted HR for MACEs or thromboembolic events was 1.040, which for MACEs was 0.989, and that for thromboembolic events was 1.028. The competing HR for MACEs or thromboembolic events was 0.921, which for MACEs, was 0.862, and that for thromboembolic events was 0.908. In conclusion, patients with advanced colorectal cancer who received anti-VEGF therapy did not exhibit significantly higher risks of thromboembolic events and MACEs than those without anti-VEGF therapy. Our study provides real-world evidence regarding the safety of anti-VEGF therapy in Asian patients with advanced colorectal cancer. [ABSTRACT FROM AUTHOR]

A "Workcation" (combining work and vacation) has become increasingly common. Traditionally, the workcation focus has been on productivity; however, data showing associations between workcations and improvements in employees' health are lacking. Therefore, this study examines the effects of a workcation on blood pressure, arterial stiffness, heart rate, autonomic nervous system function, and physical activity. Twenty healthy employees participating in a five-day workcation project at a large private company agreed to participate in this study. Data on arterial stiffness, heart rate, autonomic nerve activity, and physical activity were collected before, during, and after the workcation. Arterial stiffness, blood pressure, and heart rate significantly decreased (p < 0.05); meanwhile, physical activity levels and parasympathetic function during sleep significantly increased during the workcation (p < 0.05). Thus, a workcation implies a new way of working that improves employees' cardiovascular indices and parasympathetic function during sleep. [ABSTRACT FROM AUTHOR]

Acute SARS-CoV-2 infections in children and adolescents are usually mild. However, they can suffer from ongoing symptoms, generally referred to as long COVID. Sleep disorders are one of the most frequent complaints in long COVID although precise data are missing. We assessed the sleep behavior of children and adolescents who presented at our outpatient clinic between January 2021 and May 2022 with the Children's Sleep Habits Questionnaire (CSHQ-DE). We compared the sleep behavior at three different time points: pre-COVID-19; post-COVID-19 at the initial presentation; and post-COVID-19 at re-presentation. Data from 45 patients were analyzed. Of those, 64% were female and the median age was 10 years (range: 0–18 years). Asymptomatic or mild COVID-19 disease was experienced in 89% of patients; 11% experienced moderate disease. The initial presentation occurred at a median of 20.4 weeks (6 weeks–14 months) after the infection. The CSHQ-DE score increased significantly from pre-COVID-19 (45.82 ± 8.7 points) to post-COVID-19 (49.40 ± 8.3 points; p ≤ 0.01). The score then normalized at re-presentation (46.98 ± 7.8; p = 0.1). The greatest changes were seen in the CSHQ-DE subscale score "daytime sleepiness". Our data showed that children and adolescents with long COVID often suffer from sleep disturbances. For most children and adolescents, these sleep disorders decreased over time without any further medical intervention aside from a basic sleep consultation. [ABSTRACT FROM AUTHOR]

Adolescents diagnosed with Restrictive Eating Disorders (REDs) are at risk for alexithymia. REDs patients' families show dysfunctional interactive patterns, and childhood family environment influences alexithymia development. We aimed to assess the relationship between family dysfunctional interactive patterns and patients' alexithymia in a sample of adolescents diagnosed with REDs. Forty-five patients and their parents were enrolled. They participated in the clinical version of the Lausanne Triadic Play (LTPc), a standardized observational procedure to assess family functioning. We used the self-report questionnaire Toronto Alexithymia Scale (TAS-20) to assess patients' alexithymia. The TAS-20 provides a multi-factorial measure of patients' alexithymia: Difficulty in Identifying Feelings, DIF; Difficulty in Describing Feelings, DDF; Externally-oriented Thinking, EOT) and a total (TOT) score. DDF and EOT scores were significantly higher than DIF score. Patients' families showed dysfunctional interactive patterns, with a predominance of collusive alliance. Patients from families characterized by collusive alliance had higher TOT scores compared to counterparts from families exhibiting a different interactive dysfunctional pattern. In families characterized by a collusive triadic alliance, the dysfunctional interactive pattern was linked with the risk of alexithymia in patients with REDs. Assessment of family relationships should be included in the routine consultation with adolescent patients affected by REDs. [ABSTRACT FROM AUTHOR]

Mesenchymal cells employ actin-based membrane protrusions called podosomes and invadopodia for cross-tissue migration during normal human development such as embryogenesis and angiogenesis, and in diseases such as atherosclerosis plaque formation and cancer cell metastasis. The Akt isoforms, downstream effectors of phosphatidylinositol 3 kinase (PI3K), play crucial roles in cell migration and invasion, but their involvement in podosome formation and cell invasion is not known. In this study, we have used Akt1 and/or Akt2 knockout mouse embryonic fibroblasts and Akt3-targeted shRNA to determine the roles of the three Akt isoforms in Src and phorbol ester-induced podosome formation, and extracellular matrix (ECM) digestion. We found that deletion or knockdown of Akt1 significantly reduces Src-induced formation of podosomes and rosettes, and ECM digestion, while suppression of Akt2 has little effect. In contrast, Akt3 knockdown by shRNA increases Src-induced podosome/rosette formation and ECM invasion. These data suggest that Akt1 promotes, while Akt3 suppresses, podosome formation induced by Src, and Akt2 appears to play an insignificant role. Interestingly, both Akt1 and Akt3 suppress, while Akt2 enhances, phorbol ester-induced podosome formation. These data show that Akt1, Akt2 and Akt3 play different roles in podosome formation and ECM invasion induced by Src or phorbol ester, thus underscoring the importance of cell context in the roles of Akt isoforms in cell invasion. [ABSTRACT FROM AUTHOR]

Chronic inflammation plays a key tumor-promoting role in lung cancer. Our previous studies in mice demonstrated that neutrophils are critical mediators of tumor promotion in methylcholanthrene (MCA)-initiated, butylated hydroxytoluene (BHT)-promoted lung carcinogenesis. In the present study we investigated the role of neutrophil myeloperoxidase (MPO) activity in this inflammation promoted model. Increased levels of MPO protein and activity were present in the lungs of mice administered BHT. Treatment of mice with N-acetyl lysyltyrosylcysteine amide (KYC), a novel tripeptide inhibitor of MPO, during the inflammatory stage reduced tumor burden. In a separate tumor model, KYC treatment of a Lewis Lung Carcinoma (LLC) tumor graft in mice had no effect on tumor growth, however, mice genetically deficient in MPO had significantly reduced LLC tumor growth. Our observations suggest that MPO catalytic activity is critical during the early stages of tumor development. However, during the later stages of tumor progression, MPO expression independent of catalytic activity appears to be required. Our studies advocate for the use of MPO inhibitors in a lung cancer prevention setting. [ABSTRACT FROM AUTHOR]

Hereditary Tyrosinemia type 1 (HT1) is a metabolic liver disease caused by genetic defects of fumarylacetoacetate hydrolase (FAH), an enzyme necessary to complete the breakdown of tyrosine. The severe hepatic dysfunction caused by the lack of this enzyme is prevented by the therapeutic use of NTBC (2-[2-nitro-4-(trifluoromethyl)benzoyl] cyclohexane-1,3-dione). However despite the treatment, chronic hepatopathy and development of hepatocellular carcinoma (HCC) are still observed in some HT1 patients. Growing evidence show the important role of heat shock proteins (HSPs) in many cellular processes and their involvement in pathological diseases including cancer. Their survival-promoting effect by modulation of the apoptotic machinery is often correlated with poor prognosis and resistance to therapy in a number of cancers. Here, we sought to gain insight into the pathophysiological mechanisms associated with liver dysfunction and tumor development in a murine model of HT1. Differential gene expression patterns in livers of mice under HT1 stress, induced by drug retrieval, have shown deregulation of stress and cell death resistance genes. Among them, genes coding for HSPB and HSPA members, and for anti-apoptotic BCL-2 related mitochondrial proteins were associated with the hepatocarcinogenetic process. Our data highlight the variation of stress pathways related to HT1 hepatocarcinogenesis suggesting the role of HSPs in rendering tyrosinemia-affected liver susceptible to the development of HCC. [ABSTRACT FROM AUTHOR]