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Simple Summary: The prognosis of PCa at diagnosis is assessed by classification systems that aim to group homogenous sets of patients. However, great heterogeneity exists within these risk groups, in terms of prognostic factors and treatment options. The aim of this study was to assess the prognostic impact and predictors of adverse tumor grade in very favorable low- and intermediate-risk prostate cancer patients treated with robot-assisted radical prostatectomy at a high-volume tertiary referral center. Objectives: To assess the prognostic impact and predictors of adverse tumor grade in very favorable low- and intermediate-risk prostate cancer (PCa) patients treated with robot-assisted radical prostatectomy (RARP). Methods: Data of low- and intermediate PCa risk-class patients were retrieved from a prospectively maintained institutional database. Adverse tumor grade was defined as pathology ISUP grade group > 2. Disease progression was defined as a biochemical recurrence event and/or local recurrence and/or distant metastases. Associations were assessed by Cox's proportional hazards and logistic regression model. Results: Between January 2013 and October 2020, the study evaluated a population of 289 patients, including 178 low-risk cases (61.1%) and 111 intermediate-risk subjects (38.4%); unfavorable tumor grade was detected in 82 cases (28.4%). PCa progression, which occurred in 29 patients (10%), was independently predicted by adverse tumor grade and biopsy ISUP grade group 2, with the former showing stronger associations (hazard ratio, HR = 4.478; 95% CI: 1.840–10.895; p = 0.001) than the latter (HR = 2.336; 95% CI: 1.057–5.164; p = 0.036). Older age and biopsy ISUP grade group 2 were independent clinical predictors of adverse tumor grade, associated with larger tumors that eventually presented non-organ-confined disease. Conclusions: In a very favorable PCa patient population, adverse tumor grade was an unfavorable prognostic factor for disease progression. Active surveillance in very favorable intermediate-risk patients is still a hazard, so molecular and genetic testing of biopsy specimens is needed. [ABSTRACT FROM AUTHOR]

BACKGROUND: Uranium exposure remains an important environmental legacy and physiological health concern, with hundreds of abandoned uranium mines located in the Southwestern United States largely impacting underserved indigenous communities. The negative effects of heavy metals on barrier permeability and inhibition of intestinal epithelial healing have been described; however, transcriptomic changes within the intestinal epithelial cells and impacts on lineage differentiation are largely unknown. OBJECTIVES: Herein, we sought to determine the molecular and cellular changes that occur in the colon in response to uranium bearing dust (UBD) exposure. METHODS: Human colonoids from three biologically distinct donors were acutely exposed to UBD then digested for single cell RNA sequencing to define the molecular changes that occur to specific identities of colonic epithelial cells. Validation in colonoids was assessed using morphological and imaging techniques. RESULTS: Human colonoids acutely exposed to UBD exhibited disrupted proliferation and hyperplastic differentiation of the secretory lineage cell, enteroendocrine cells (EEC). Single-cell RNA sequencing also showed more EEC subtypes present in UBD-exposed colonoids. DISCUSSION: These findings highlight the significance of crypt-based proliferative cells and secretory cell differentiation using human colonoids to model major colonic responses to uranium-bearing particulate dust exposure. [ABSTRACT FROM AUTHOR]

Introduction: Healthcare workforce diversity is essential for increasing access and reducing racial/ethnic health disparities. We examined the growth and trends in physician assistant/associate (PA) workforce demographic composition by initial year of certification. Methods: Drawing on data from the National Commission on Certification of Physician Assistants, we aggregated gender, age (1975-2020), race/ethnicity, and underrepresented in medicine (URiM) (2000-2020). Descriptive statistics of demographics were calculated by the initial certification year and assessed for trends using the Cochran-Armitage test. Results: Analyses revealed an 11.7% annual growth rate in PAs earning initial certification and a change in gender composition (23.9% to 74.2% female) from 1975 to 2020. Between 2000 and 2020, we observed significant increases (all p<0.001) in the proportions of PAs who self-identify as Asian (5.7 percentage points), Hispanic/Latino(a) (3.5 percentage points), and multiracial (2.4 percentage points). However, there was a decline (all p<0.001) in the proportions of PAs who self-identify as Black/African American (1.2 percentage points), American Indian/Alaska Native (0.1 percentage points), Native Hawaiian/Pacific Islander (0.1 percentage points), and other race (1.1 percentage points). Trend analyses revealed that the proportion of PAs identifying as URiM decreased over the past 21 years. Conclusion: Ongoing assessment of the PA workforce demographics is essential to track the progress and effectiveness of diversification initiatives. [ABSTRACT FROM AUTHOR]

Background: Misconceptions about male nurses not only exacerbate the gender imbalance in the nursing profession but also negatively impact male nurses embarking on their careers. Currently, no tool exists to measure the gender biases toward males in nursing among nursing students in China. Consequently, the primary objective of this study is to assess the validity and reliability of the Chinese translation of the Gender Misconceptions of Men in Nursing (GEMINI) scale among nursing students. Methods: This cross-sectional study involved 1,102 nursing students from China who participated online. We utilized the Brislin translation technique with a forward-backward approach. To determine the factor structure within the Men in Nursing Gender Misconceptions Scale's Chinese version, both exploratory (EFA) and confirmatory factor analysis (CFA) were applied. The scale's internal consistency was measured through the Cronbach's alpha coefficient, corrected item-total correlation, and a retest reliability assessment. Results: The scale showed a content validity index of 0.938 and a retest reliability of 0.844. EFA indicated a two-factor structure for the translated instrument. CFA revealed a chi-square/degree of freedom of 3.837, an incremental fit index (IFI) of 0.952, a goodness-of-fit index (GFI) of 0.910, a comparative fit index (CFI) of 0.952, and an RMSEA of 0.073, all of which were within acceptable limits. The scale's Cronbach's α was 0.953, and the corrected item-total correlations ranged between 0.539 and 0.838. Gender-based misconceptions about men in nursing among students appeared to be influenced by their gender and whether they considered a nursing program as their first choice when applying for a major. Misconceptions about male nurses are greater among men and those who do not consider nursing programs as their first choice when applying for a major. Conclusions: The Chinese adaptation of the GEMINI scale showcased high reliability and validity. It stands as a potential instrument to gauge gender misconceptions concerning male nurses among Chinese nursing students. [ABSTRACT FROM AUTHOR]

Objective The objective of this study was to describe the utilization of physical therapist and occupational therapist services after rotator cuff repair (RCR) and examine variation in rehabilitation characteristics by profession. Methods This retrospective cohort study used the IBM MarketScan Commercial Claims and Encounters database. Eligible patients were 18 to 64 years old and had undergone outpatient RCR between 2017 and 2020. Physical therapist and occupational therapist services were identified using evaluation and treatment codes with profession-specific modifiers ("GP" or "GO"). Factors predicting utilization of formal rehabilitation and physical therapist versus occupational therapist services were examined; and univariable and multivariable analyses of days to initiate therapy, number of visits, and episode length by profession were completed. Results Among 53,497 patients with an RCR, 81.2% initiated formal rehabilitation (93.8% physical therapist, 5.2% occupational therapist, 1.0% both services). Patients in the Northeast and West (vs the South) were less likely to receive rehabilitation (odds ratio [OR] = 0.67 to 0.70) and less likely to receive occupational therapist services (OR = 0.39). Patients living in the Midwest (versus the South) were less likely to receive rehabilitation (OR = 0.79) but more likely to receive occupational therapist services (OR = 1.51). Similarly, those living in a rural (versus urban) area were less likely to utilize rehabilitation (OR = 0.89) but more likely to receive occupational therapist services (OR = 2.21). Additionally, receiving occupational therapist instead of physical therapist services was associated with decreased therapist visits (−16.89%), days to initiate therapy (−13.43%), and episode length (−13.78%). Conclusion Most patients in our commercially insured cohort utilized rehabilitation services, with a small percentage receiving occupational therapist services. We identified profession-specific variation in utilization characteristics that warrants further examination to understand predictors and associated outcomes. Impact Variation in rehabilitation utilization after RCR, including profession-specific and regional differences, may indicate opportunities to improve standardization and quality of care. [ABSTRACT FROM AUTHOR]

AIM The aim of this study was to evaluate the effects of a virtual mindfulness meditation intervention on stress and anxiety levels of 145 nursing students. BACKGROUND Because of the twin demands of classroom and clinical workloads, nursing students experience greater amounts of stress and anxiety than the average college student. Mindfulness meditation is a promisingmethod to alleviate stress and anxiety. METHOD A pretest-posttest randomized controlled design was used. Participants received either weekly mindfulness meditation recordings or recordings on nursing information. Participants completed the Perceived Stress Scale and the Generalized Anxiety Disorder-7 Scale. RESULTS A two-way mixed analysis of variance and follow-up simple main effects tests revealed that participants in the experimental group, who received meditation recordings, experienced significantly lower levels of stress and anxiety on posttest surveys than the control group. CONCLUSION Mindfulness meditation can reduce stress and anxiety levels in nursing students. This can improve students' overall mental and physical well-being. [ABSTRACT FROM AUTHOR]

Background: Alexithymia is the inability to identify and describe one's own emotions. Adolescents who suffer from Restrictive Eating Disorders (REDs) show a higher prevalence of alexithymia than the general population. Methods: The study explored the correlation between levels of alexithymia in mothers, fathers, and adolescents affected by REDs and patients' ability to recognize their emotions. The study also aimed to evaluate if patients' emotional distress can significantly impact the severity of their disorder and functioning measured by the Clinical Global Impression Scale - Severity (CGI-S) and the Children's Global Assessment Scale (CGAS). We enrolled 67 families of adolescents affected by REDs. Parents and patients' levels of alexithymia were assessed through the Toronto Alexithymia Scale (TAS-20). Spearman's correlation shows a statistically significant correlation between mothers and patients' levels of alexithymia. Results: Our findings also suggest that fathers and mothers' TAS scores correlate with each other. However, there is no statistically significant relationship between the influence of the TAS scores of fathers and sons/daughters. Conclusions: In conclusion, mothers' level of alexithymia could influence both fathers and patients' difficulty in identifying and describing their own emotions. This relationship can be investigated further when considering externally oriented thinking. However, the severity of the disease and overall functioning do not appear to be affected by patients' levels of alexithymia. [ABSTRACT FROM AUTHOR]

Simple Summary: In Sri Lanka, the authors are encouraging a cost-effective way to reduce the number of people developing oral cancer, which is a common cancer among men. The authors wanted to find out how well dentists can find signs of oral cancer and potential problems in their patients, and they did this by asking dentists questions in an online survey. Surprisingly, most of the dentists thought it would be better to only check people who are at a higher risk for oral cancer instead of checking everyone. Only about two thirds of the dentists regularly look for signs of oral cancer when people come for dental check-ups. The authors found that these dentists, on average, had noticed about 34 patients with concerning signs in the past year. Almost all the dentists believed that they needed more training to spot these problems. So, while opportunistic screening at the dentist's office is good, dental professionals also need to focus on other ways to prevent oral cancer, like checking high-risk groups and giving dentists more confidence to spot potential issues. In Sri Lanka, opportunistic screening is encouraged as a cost-effective tool to bring down the prevalence of oral cancer, which is the most common cancer among males. The objectives of the study were to determine the practices, attitudes, and level of competency of dental surgeons regarding the early detection of oral cancer and oral potentially malignant disorders (OPMDs) through opportunistic screening. A prospective study was conducted online via a Google form using a pretested, self-administered questionnaire of 22 close-ended questions and 3 open-ended questions. Out of the 137 dental surgeons who responded, 88% (121/137) of the participants believed that screening high-risk target groups would be more effective in the early detection of oral cancer rather than opportunistic screening. Only 64% (88/137) of the participants frequently check for oral cancer and OPMDs when patients visit for dental treatment. Participants recalled an average of 34 patients (4628/137) with clinically suspicious lesions being diagnosed during examination at general dental practice during the past year, and 98% (134/137) of the participants believed that they should receive additional training in order to identify and diagnose clinically suspicious OPMDs and oral cancer. Opportunistic screening in general dental practice as an oral-cancer prevention strategy is appreciable, but due emphasis should be given to other prevention strategies such as population screening and screening high-risk target groups. The level of confidence of general dental practitioners in the early detection of oral cancer has to be raised in order to achieve higher standards in oral cancer prevention through opportunistic screening. [ABSTRACT FROM AUTHOR]

BACKGROUND: Climate change scenarios illustrate various pathways in terms of global warming ranging from “sustainable development” (Shared Socioeconomic Pathway SSP1-1.9), the best-case scenario, to ‘fossil-fueled development’ (SSP5-8.5), the worst-case scenario. OBJECTIVES: We examined the extent to which increase in daily average urban summer temperature is associated with future cause-specific mortality and projected heat-related mortality burden for the current warming trend and these two scenarios. METHODS: We did an observational cohort study of 363,754 participants living in six cities in Finland. Using residential addresses, participants were linked to daily temperature records and electronic death records from national registries during summers (1 May to 30 September) 2000 to 2018. For each day of observation, heat index (average daily air temperature weighted by humidity) for the preceding 7 d was calculated for participants’ residential area using a geographic grid at a spatial resolution of 1 km × 1 km. We examined associations of the summer heat index with risk of death by cause for all participants adjusting for a wide range of individual-level covariates and in subsidiary analyses using case-crossover design, computed the related period population attributable fraction (PAF), and projected change in PAF from summers 2000–2018 compared with those in 2030–2050. RESULTS: During a cohort total exposure period of 582,111,979 summer days (3,880,746 person-summers), we recorded 4,094 deaths, including 949 from cardiovascular disease. The multivariable-adjusted rate ratio (RR) for high (≥21°C) vs. reference (14-15°C) heat index was 1.70 (95% CI: 1.28, 2.27) for cardiovascular mortality, but it did not reach statistical significance for noncardiovascular deaths, RR=1.14 (95% CI: 0.96, 1.36), a finding replicated in case-crossover analysis. According to projections for 2030-2050, PAF of summertime cardiovascular mortality attributable to high heat will be 4.4% (1.8%-7.3%) under the sustainable development scenario, but 7.6% (3.2%-12.3%) under the fossil-fueled development scenario. In the six cities, the estimated annual number of summertime heat-related cardiovascular deaths under the two scenarios will be 174 and 298 for a total population of 1,759,468 people. DISCUSSION: The increase in average urban summer temperature will raise heat-related cardiovascular mortality burden. The estimated magnitude of this burden is >1.5 times greater if future climate change is driven by fossil fuels rather than sustainable development. [ABSTRACT FROM AUTHOR]

Background: Diabetic neovascular glaucoma is a secondary glaucoma that may require immediate correction of elevated intraocular pressure to control pain and protect the optic nerve. While there is a seasonal trend to glucose levels, it is unknown if a seasonal trend exists for diabetic neovascular glaucoma. Objective: This study evaluates the incidence of urgent glaucoma tube shunt implantation in diabetic neovascular glaucoma in a tertiary academic referral center in Southern California. Methods: Electronic medical records were queried for urgent glaucoma tube shunt surgery from 2014 to 2021. The number of cases were separated by month of occurrence, and average hemoglobin A1c values were calculated per month. Data were analyzed via ANOVA tests and one-tailed t-tests. Results: A total of 127 cases were identified. The months of March and April contained the most cases averaging 3 and 2.75 cases, respectively. April had statistically significant higher case numbers than that of other months (P =.041). ANOVA tests excluding April showed no statistically significant difference between the remaining months (P =.901). Average hemoglobin A1c values were highest in the months of April and March at 9.8 and 9.6%, respectively. Conclusion: Emergency glaucoma tube shunt surgery for diabetic neovascular glaucoma occurs most frequently in April. This observation may provide insight into disease prevention through diabetes management and help improve surgical operations such that staffing and resources are allocated accordingly. [ABSTRACT FROM AUTHOR]

Background: Our aim was to determine whether child attachment to parents, parent attachment style, and morning cortisol levels were related to diabetes outcomes measured by average glycated hemoglobin (HbA1c), HbA1c variability over 4 years and time in range (TIR) in children with type 1 diabetes (T1D). Research design and methods: 101 children with T1D and one of their parents were assessed at baseline for child attachment (Child Attachment Interview; CAI) and parent attachment (Relationship Structures Questionnaire; ECR-RS). Serum samples were collected for cortisol measurements before the interviews. HbA1c levels were measured during a 4-year follow-up period at regular 3-monthly visits, and data for TIR were exported from blood glucose measuring devices. Multivariate linear regression models were constructed to identify independent predictors of glycemic outcomes. Results: More girls than boys exhibited secure attachment to their mothers. The results of the regression models showed that securely attached girls (CAI) had higher average HbA1c than did insecurely attached girls (B = −0.64, p = 0.03). In boys, the more insecure the parent's attachment style, the worse the child's glycemic outcome: the higher the average Hb1Ac (B = 0.51, p = 0.005), the higher the HbA1c variability (B = 0.017, p = 0.011), and the lower the TIR (B = −8.543, p = 0.002). Conclusions: Attachment in close relationships is associated with glycemic outcomes in children with T1D, and we observed significant differences between sexes. A sex- and attachment-specific approach is recommended when treating children with less favorable glycemic outcomes. Special attention and tailored support should be offered to securely attached girls in transferring responsibility for diabetes care and at least to male children of insecurely attached parents to prevent suboptimal glycemic control. Further studies in larger samples and more daily cortisol measurements may help us better understand the links between stress response, attachment and T1D. [ABSTRACT FROM AUTHOR]

Patellofemoral pain (PFP) is a common source of knee pain in active individuals, accounting for a large number of knee injuries examined in sports medicine clinics. As a chronic condition, PFP can affect mental health. However, this effect has not yet been studied in individuals with PFP. To determine how subjective physical and mental health measures in individuals with PFP differed from those measures in pain-free individuals. Case-control study. Laboratory. Volunteers for the study were 30 people with PFP (19 women, 11 men; age = 20.23 ± 3.32 years, height = 166.69 ± 6.41 cm, mass = 69.55 ± 13.15 kg) and 30 matched pain-free individuals (19 women, 11 men; age = 20.33 ± 3.37 years, height = 169.31 ± 9.30 cm, mass = 64.02 ± 11.00 kg). Current and worst pain levels in the past 24 hours were determined using a visual analog scale (VAS). The Anterior Knee Pain Scale, Fear Avoidance Belief Questionnaire, and Lower Extremity Functional Scale were administered. Physical and mental health measures were obtained using a modified 12-item Short Form Health Survey. Scores for 2 subscales on the modified Short Form-12 were weighted and calculated: physical component and mental component. Independent t tests were calculated to compare variables between groups. Coefficient correlations were used to measure the associations between the variables. Individuals with PFP reported lower levels of physical (pain free: 56.13 ± 1.63, PFP: 50.54 ± 7.10, P <.001) and mental (pain-free: 53.32 ± 4.71, PFP: 48.64 ± 10.53, P =.03) health. In the PFP group, we found moderate negative correlations between the VAS score for current pain and mental health (r = −0.52, P <.01) and between the VAS score for worst pain in the past 24 hours and mental health (r = −0.46, P =.01) and between activity limitations in individuals with PFP and fear avoidance beliefs (r = −0.61, P <.01). Our results should encourage clinicians, especially musculoskeletal rehabilitation professionals, to acknowledge the importance of a whole-person approach when treating or planning rehabilitation programs for individuals with PFP. [ABSTRACT FROM AUTHOR]

Sense of belongingness in the academic environment has been associated with positive student outcomes and increased student success. To cultivate belongingness, graduate nursing students were invited to participate in a virtual fitness challenge. Sense of belongingness was measured through pre-(n = 103) and post-intervention (n = 64) surveys with three subscales: other students, faculty, and the university. Students reported improved sense of belongingness following the intervention for all subscales, with statistically significant improvements related to other students (p = .007) and the university (p = .023). A virtual fitness challenge may improve sense of belongingness among graduate nursing students. [ABSTRACT FROM AUTHOR]

INTRODUCTION The use of e-cigarettes has steadily increased, and vocational students are one primary target of e-cigarette marketing. This cross-sectional survey research aimed to explore e-cigarette use and examine the factors associated with it. METHODS Multistage cluster random sampling was employed to select 1536 students in vocational education institutions. A self-administered questionnaire was used to collect the data from September to December 2019. Multinomial logistic regression analysis was used to obtain the adjusted odds ratio (AOR) to determine the associated factors of e-cigarette use. RESULTS Altogether, 28.7% of the subjects were currently e-cigarette users, 7.4% used e-cigarettes only, and 21.3% were dual users. Various factors were found to be significantly associated with e-cigarette use by 43.7%. Those consisted of sex (male) (AOR=2.183; 95% CI: 1.510-3.157), grade point average (GPA) of <2.5 (AOR=2.363; 95% CI: 1.502-3.717), having neutral attitudes toward e-cigarette use (AOR=2.676; 95% CI: 1.499-4.779) and positive attitudes toward e-cigarette use (AOR=4.171; 95% CI: 2.250-7.734), moderate level of perceived behavioral control on e-cigarette use (AOR=3.520; 95% CI: 2.287-5.418) and low level of perceived behavioral control on e-cigarettes use (AOR=4.959; 95% CI: 3.274-7.511), moderate price of e-cigarettes (AOR=1.436; 95% CI: 1.009-2.044), and e-cigarette use of their parents (AOR=1.827; 95% CI: 1.137-2.938), close friends (AOR=4.327; 95% CI: 2.954-6.338) and idols (AOR=4.604; 95% CI: 1.844-11.497). CONCLUSIONS Students should be encouraged to develop negative attitudes toward e-cigarette use and increase their self-confidence to control the use of e-cigarettes. This can be achieved by regularly distributing information on the product's risks. Moreover, students can find inspiration and guidance from peers, close friends, or their idols, who will act as positive role models and inspire them not to initiate e-cigarette use. [ABSTRACT FROM AUTHOR]

BACKGROUND: Newborns can be exposed to inorganic arsenic (iAs) through contaminated drinking water, formula, and other infant foods. Epidemiological studies have demonstrated a positive association between urinary iAs levels and the risk of developing nonalcoholic fatty liver disease (NAFLD) among U.S. adolescents and adults. OBJECTIVES: The present study examined how oral iAs administration to neonatal mice impacts the intestinal tract, which acts as an early mediator for NAFLD. METHODS: Neonatal mice were treated with a single dose of iAs via oral gavage. Effects on the small intestine were determined by histological examination, RNA sequencing, and biochemical analysis. Serum lipid profiling was analyzed by fast protein liquid chromatography (FPLC), and hepatosteatosis was characterized histologically and biochemically. Liver X receptor-alpha (LXRα) knockout (퐿푥푟α-/-) mice and liver-specific activating transcription factor 4 (ATF4)-deficient (퐴푡푓 4Δ퐻푒푝) mice were used to define their roles in iAs-induced effects during the neonatal stage. RESULTS: Neonatal mice exposed to iAs via oral gavage exhibited accumulation of dietary fat in enterocytes, with higher levels of enterocyte triglycerides and free fatty acids. These mice also showed accelerated enterocyte maturation and a longer small intestine. This was accompanied by higher levels of liver-derived very low-density lipoprotein and low-density lipoprotein triglycerides, and a lower level of high-density lipoprotein cholesterol in the serum. Mice exposed during the neonatal period to oral iAs also developed hepatosteatosis. Compared with the control group, iAs-induced fat accumulation in enterocytes became more significant in neonatal 퐿푥푟α-/- mice, accompanied by accelerated intestinal growth, hypertriglyceridemia, and hepatosteatosis. In contrast, regardless of enterocyte fat accumulation, hepatosteatosis was largely reduced in iAs-treated neonatal 퐴푡푓 4Δ퐻푒푝 mice. CONCLUSION: Exposure to iAs in neonatal mice resulted in excessive accumulation of fat in enterocytes, disrupting lipid homeostasis in the serum and liver, revealing the importance of the gut–liver axis and endoplasmic reticulum stress in mediating iAs-induced NAFLD at an early age. [ABSTRACT FROM AUTHOR]

Objective The role of inspiratory muscle performance in functional performance in patients with coronavirus disease 2019 (COVID-19) is poorly understood. The purpose of this study was to perform a longitudinal examination of inspiratory and functional performance from intensive care unit (ICU) discharge (ICUD) to hospital discharge (HD) and symptoms at HD and 1 month after HD in patients with COVID-19. Methods Thirty patients (19 men, 11 women) with COVID-19 were included. Examination of inspiratory muscle performance at ICUD and HD was performed with an electronic manometer, which provided the maximal inspiratory pressure (MIP) and several other inspiratory measures. Examination of dyspnea and functional performance was performed at ICUD and HD with the Modified Borg Dyspnea Scale and the 1-minute sit-to-stand test (1MSST), respectively. Results The mean age was 71 (SD = 11) years, the mean length of ICU stay was 9 (SD = 6) days, and the mean length of hospital stay was 26 (SD = 16) days. Most of the patients were diagnosed with severe COVID-19 (76.7%) and had a mean Charlson Comorbidity Index of 4.4 (SD = 1.9), reflecting high comorbidity. The mean MIP of the entire cohort increased minimally from ICUD to HD (from 36 [SD = 21] to 40 [SD = 20] cm H2O), reflecting predicted values for men and women at ICUD and HD of 46 (25%) to 51 (23%) and 37 (24%) to 37 (20%), respectively. The 1MSTS score increased significantly from ICUD to HD (9.9 [SD = 7.1] vs 17.7 [SD = 11.1]) for the entire cohort but remained far below population-based reference values (2.5th percentile) for the majority of patients at ICUD and HD. At ICUD, MIP was found to be a significant predictor of a favorable change in 1MSTS performance (β = 0.308; odds ratio = 1.36) at HD. Conclusion A significant reduction in inspiratory and functional performance exists in patients with COVID-19 at both ICUD and HD, with a greater MIP at ICUD being a significant predictor of a greater 1MSTS score at HD. Impact This study shows that inspiratory muscle training may be an important adjunct after COVID-19. [ABSTRACT FROM AUTHOR]

BACKGROUND: Previous studies aiming at relating exposure to phenols and phthalates with child social behavior characterized exposure using one or a few spot urine samples, resulting in substantial exposure misclassification. Moreover, early infancy exposure was rarely studied. OBJECTIVES: We aimed to examine the associations of phthalates and phenols with child social behavior in a cohort with improved exposure assessment and to a priori identify the chemicals supported by a higher weight of evidence. METHODS: Among 406 mother-child pairs from the French Assessment of Air Pollution exposure during Pregnancy and Effect on Health (SEPAGES) cohort, 25 phenols/phthalate metabolites were measured in within-subject pools of repeated urine samples collected at the second and third pregnancy trimesters (∼21 samples/trimester) and at 2 months and 1-year of age (∼7 samples/period). Social behavior was parent-reported at 3 years of age of the child using the Social Responsiveness Scale (SRS). A structured literature review of the animal and human evidence was performed to prioritize the measured phthalates/phenols based on their likelihood to affect social behavior. Both adjusted linear regression and Bayesian Weighted Quantile Sum (BWQS) regression models were fitted. False discovery rate (FDR) correction was applied only to nonprioritized chemicals. RESULTS: Prioritized compounds included bisphenol A, bisphenol S, triclosan (TCS), diethyl-hexyl phthalate (RDEHP), mono-ethyl phthalate (MEP), mono-n-butyl phthalate (MnBP), and mono-benzyl phthalate (MBzP). With the exception of bisphenols, which showed a mixed pattern of positive and negative associations in pregnant mothers and neonates, few prenatal associations were observed. Most associations were observed with prioritized chemicals measured in 1-y-old infants: Each doubling in urinary TCS (β=0.78; 95% CI: 0.00, 1.55) and MEP (β=0.92; 95% CI: -0.11, 1.96) concentrations were associated with worse total SRS scores, whereas MnBP and RDEHP were associated with worse Social Awareness (β=0.25; 95% CI: 0.01, 0.50) and Social Communication (β=0.43; 95% CI: -0.02, 0.89) scores, respectively. BWQS also suggested worse total SRS [Beta 1=1.38; 95% credible interval (CrI): -0.18, 2.97], Social Awareness (Beta 1=0.37; 95% CrI: 0.06, 0.70), and Social Communication (Beta 1=0.91; 95% CrI: 0.31, 1.53) scores per quartile increase in the mixture of prioritized compounds assessed in 1-y-old infants. The few associations observed with nonprioritized chemicals did not remain after FDR correction, with the exception of benzophenone-3 exposure in 1-y-old infants, which was suggestively associated with worse Social Communication scores (corrected 푝=0.07). DISCUSSION: The literature search allowed us to adapt our statistical analysis according to the weight of evidence and create a corpus of experimental and epidemiological knowledge to better interpret our findings. Early infancy appears to be a sensitive exposure window that should be further investigated. [ABSTRACT FROM AUTHOR]

Objective: The risk of malignancy in pediatric thyroid nodules is higher compared to the risk in adults. Our aim was to investigate the clinical, radiological, and histopathological characteristics of pediatric thyroid nodules. Materials and Methods: The data of 132 children and adolescents who had thyroid nodules were collected retrospectively from medical records. Results: The mean age of the patients was 12.07 ± 4.08 years and 67% were female. Fine-needle aspiration biopsy was performed in 86 patients (65%) and the results were as follows: benign in 53.4% (n = 46), atypia or follicular lesion of undetermined significance in 3.5% (n = 3), suspicious for follicular neoplasia in 2.3% (n = 2), and malignancy in 32.5% (n = 28). The overall malignancy rate was 22.7% (n = 30). Malignancy was detected after surgery in 2 thyroid nodules belonging to the atypia or follicular lesion of undetermined significance category. Malignancy was detected in 7 patients who had autoimmune thyroiditis and in 1 patient who had congenital dyshormonogenesis. The malignancy rate of the nodules in the patients, who had autoimmune thyroiditis, was found to be 13.4%. Mixed echogenicity, microcalcifications, nodules larger than 10 mm, abnormal lymph nodes, and irregular borders were more common in the malignant group. The nodule size, abnormal lymph nodes, and irregular borders were found to be significant in terms of predicting malignancy. Conclusion: We found malignancy in 22.7% of the thyroid nodules, and the malignancy rate of nodules in the patients, who had autoimmune thyroiditis, was 13.4%. The nodule size, abnormal lymph nodes, and irregular nodule borders emerged as the most significant risk factors for malignancy. [ABSTRACT FROM AUTHOR]

This retrospective analysis examined the association between change in A1C and professional continuous glucose monitoring (p-CGM) use in patients with type 2 diabetes and poor glycemic control who were not using insulin. Data from 15,481 eligible patients (p-CGM users n = 707 and p-CGM nonusers n = 14,774) showed a greater decrease in A1C from baseline to the end of follow-up for p-CGM users, and differences favored p-CGM users regardless of whether they started insulin therapy during the follow-up period. These findings suggest that people with type 2 diabetes who have poor glycemic control using multiple noninsulin therapies may benefit from p-CGM, which can reduce A1C over a 6-month period compared with usual care. [ABSTRACT FROM AUTHOR]

Background: The Apolipoprotein E (ApoE) polymorphism plays an important role in the pathophysiology of end-stage renal disease (ESRD). Additionally, ApoE may contribute to the progression of oxidative stress. Thus, this study aimed to determine the ApoE gene polymorphism and evaluate the malondialdehyde (MDA) level in ESRD patients and healthy individuals. Methods: The present cross-sectional study was conducted at 2010 at Kermanshah University of Medical Sciences (Kermanshah, Iran). The study population comprised ESRD patients (n=136) and healthy individuals (n=137). The MDA level was assessed using high-performance liquid chromatography (HPLC), and the frequencies of ApoE gene alleles were analyzed using restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR). The data were analyzed using Statistical Package for Social Sciences (SPSS), version 13. The significant differences of ApoE genotypes in case and control groups were assessed using Pearson's Chi square tests, and two-tailed Student's tests. A logistic regression model was used to calculate the odd ratio. P<0.05 was considered statistically significant. Results: According to the results, ESRD patients had a higher frequency of the E2/E3 genotype than the healthy group (P<0.001). The results indicated that E3/E4 genotype frequency in the patients' group was higher than that of the control group (P=0.026). Furthermore, the E3/E2 (OR=5.7, 95% CI=2.68-12.14) (P<0.001) and E3/E4 (OR=1.57, 95% CI=1.05-2.34) (P=0.029) genotypes were found to increase the risk of ESRD. Moreover, the MDA level in ESRD patients was higher than the healthy individuals (P<0.001). The patients with E3/E2 (P<0.001) and E3/E4 (P<0.001) genotypes had a higher level of MDA than the control group. Conclusion: According to the findings, patients with ESRD had higher genotypes of E3/E2 and E3/E4, which suggests a higher risk of developing ESRD. [ABSTRACT FROM AUTHOR]

BACKGROUND: Consumption of an organic diet reduces exposure to a range of agricultural pesticides. Only three studies have examined the effect of an organic diet intervention on exposure to the herbicide glyphosate, the most heavily used agricultural chemical in the world. Despite its widespread use, the primary sources of glyphosate exposure in humans are poorly understood. OBJECTIVE: Our objective was to examine the effect of an organic diet intervention on urinary glyphosate concentrations among pregnant individuals. METHODS: We conducted a 2-wk randomized crossover trial in which 39 pregnant participants living near (≤0.5 km) and far (>0.5 km) from agricultural fields received a 1-wk supply of conventional groceries and 1 wk of organic groceries, randomized to order. We collected daily first morning void urine samples and analyzed composite samples from each week for glyphosate. We examined differences in urinary glyphosate concentrations between the conventional week and the organic week among all participants and stratified by residential proximity to an agricultural field. RESULTS: Median specific gravity-adjusted glyphosate concentrations were 0.19 μg/L and 0.16 μg/L during the conventional and organic weeks, respectively. We observed modest decreases in urinary glyphosate concentrations from the conventional to organic week among far-field participants, but no difference among near-field participants. In secondary analyses excluding participants who did not meet a priori criteria of compliance with the intervention, we observed significant decreases in urinary glyphosate concentrations, particularly among far-field participants (푝< 0.01-0.02, depending on exclusion criteria). DISCUSSION: This trial is the first to examine the effect of an organic diet intervention on glyphosate among people living near and far from agricultural fields. Our results suggest that diet is an important contributor to glyphosate exposure in people living >0.5 km from agricultural fields; for people living near crops, agriculture may be a dominant exposure source during the pesticide spray season. [ABSTRACT FROM AUTHOR]

OBJECTIVES: Incidental small renal masses (SRMs) now account for the majority of new diagnoses of renal cancers. Although there are established management guidelines, referral and management patterns can vary. We aimed to explore identification, practice patterns, and management of identified SRMs in an integrated health system. STUDY DESIGN: Retrospective analysis. METHODS: We identified patients with a newly diagnosed SRM measuring 3 cm or less from January 1, 2013, to December 31, 2017, at Kaiser Permanente Southern California. These patients were flagged at the time of radiographic identification to ensure adequate notification of findings. Diagnostic modality, referral, and treatment patterns were analyzed. RESULTS: Of 519 patients with SRMs, 65% were found on abdominal CT and 22% on renal/abdominal ultrasounds. Within 6 months, 70% of patients consulted with a urologist. Initial management patterns were as follows: active surveillance (60%), partial/radical nephrectomy (18%), and ablation (4%). Among 312 patients on surveillance, 14% eventually received treatment. The majority of patients (69.4%) did not receive guideline-recommended chest imaging for initial staging. Urologist visit within 6 months of SRM diagnosis was associated with increased adherence to staging (P = .003) and subsequent surveillance imaging (P < .001). CONCLUSIONS: In this contemporary analysis of an integrated health system's experience, referral to a urologist was associated with guideline-concordant staging and surveillance imaging. Frequent utilization of active surveillance with a low rate of progression to active treatment was noted in both groups. These findings shed light on care patterns upstream of urologic evaluation and support the need for clinical pathways to be implemented at the time of radiologic diagnosis. [ABSTRACT FROM AUTHOR]

Simple Summary: No measures of the changes occurring in the liver in the case of outflow deprivation during hepatectomies are available. This study investigated four indexes obtained using hyperspectral imaging in a pig model, measured in different liver lobes, before and after hepatic vein occlusion. The variations of StO2% and deoxy-Hb were considerably good markers of venous liver congestion. Introduction. The changes occurring in the liver in cases of outflow deprivation have rarely been investigated, and no measurements of this phenomenon are available. This investigation explored outflow occlusion in a pig model using a hyperspectral camera. Methods. Six pigs were enrolled. The right hepatic vein was clamped for 30 min. The oxygen saturation (StO2%), deoxygenated hemoglobin level (de-Hb), near-infrared perfusion (NIR), and total hemoglobin index (THI) were investigated at different time points in four perfused lobes using a hyperspectral camera measuring light absorbance between 500 nm and 995 nm. Differences among lobes at different time points were estimated by mixed-effect linear regression. Results. StO2% decreased over time in the right lateral lobe (RLL, totally occluded) when compared to the left lateral (LLL, outflow preserved) and the right medial (RML, partially occluded) lobes (p < 0.05). De-Hb significantly increased after clamping in RLL when compared to RML and LLL (p < 0.05). RML was further analyzed considering the right portion (totally occluded) and the left portion of the lobe (with an autonomous draining vein). StO2% decreased and de-Hb increased more smoothly when compared to the totally occluded RLL (p < 0.05). Conclusions. The variations of StO2% and deoxy-Hb could be considered good markers of venous liver congestion. [ABSTRACT FROM AUTHOR]

Consumption of unhealthy commercial foods and beverages (UCFB) is common among infants and young children living in low- and middle-income countries. Such foods can displace other nutritious foods, however, there is limited evidence on how this consumption tracks across time. This study assessed and tracked UCFB consumption of children living in rural/peri-urban Cambodia during the complementary feeding period, identified UCFB consumption patterns of these children, and explored the association between UCFB consumption and growth. A 6-month longitudinal cohort study was implemented among 567 caregivers of children aged 10-14 months at recruitment. UCFB consumption was estimated each month via a telephone-administered 7-day food frequency questionnaire, and UCFB consumption patterns were identified based on changes in this frequency of consumption over time. The majority of children either maintained (45.7%, n = 246) or developed (43.5%, n = 234) an unhealthy consumption pattern and only 10.8% (n = 58) of children maintained/transitioned into a healthy consumption pattern. High consumers of UCFB at 10-14 months had a 4.7 (CI: 4.7 [3.1-7.2]) times odds of being high consumers of UCFB at 15-19 months (p < 0.001). There was a trend of lower length- for-age z-scores (LAZ) among children maintaining or developing an unhealthy consumption pattern (~-0. SD LAZ) compared to children maintaining/transitioning into a healthy consumption pattern, however, this association was not statistically significant. Findings indicate that high UCFB consumption begins during infancy and tracks into early childhood. National policies and programmes centred on early interventions addressing the use of UCFB for infant and young child feeding are needed. [ABSTRACT FROM AUTHOR]

Trauma anesthesia care can be among the most challenging situations anesthesia providers may encounter. The challenges encountered are helped by providing anesthesia providers on forward-deployed surgical teams with the best equipment available that meets the limitations of light weight, easily movable, and not reliant on electrical supply. This study assesses three questions derived out of the recent formation and equipping of the U.S. Army's Forward Resuscitative and Surgical Detachment. The highly advanced field transport ventilator, the Hamilton-T1 is being used by the detachments' anesthetists with the Universal Portable Anesthesia, Complete (UPAC) draw-over vaporizer. However, no literature supports best use practices regarding use in a push- or pull-through configuration, adding supplemental oxygen, and the impact on the ventilator from contamination with inhaled anesthetics. Utilizing a human patient simulator, these questions were examined in a quasiexperimental and descriptive manner, using the Hamilton-T1 and UPAC vaporizer in multiple configurations. The findings support the efficacy of both push- and pull-through configurations, offer options for the most efficacious use of oxygen, and appear to show no adverse effects from anesthetic vapor entering the ventilator's compression mechanism. [ABSTRACT FROM AUTHOR]

Background: Social housing tenants are at greater risk of engaging in unhealthy behaviours than the general population. Housing association employees are in an ideal position to contribute positively to their tenants' health. 'New Home, New You' (NHNY) is a joint venture between a social housing association, a city council and a community healthcare provider in the South West of England. It was designed with the aim of improving the health and well‐being of social housing tenants. Objectives: The aim of this retrospective evaluation was to establish whether social housing tenants were benefiting from this health‐related behavioural intervention in terms of their mental well‐being and health‐related behaviours. Methods: This was a mixed‐methods evaluation. The outcome evaluation was a secondary analysis of quantitative data collected during the NHNY project. The process of delivering and receiving the intervention was evaluated using qualitative, semi‐structured interviews with housing officers and tenants who had participated in the programme. The development of the intervention was evaluated through a focus group and additional semistructured interviews with key stakeholders. Quantitative data were analysed using the Statistical Package for the Social Sciences. Qualitative interviews were analysed using thematic analysis. Results: Six key stakeholders and a total of seven housing officers from several teams and seven tenants were interviewed. Of the 1016 tenants who were invited to participate in NHNY, 226 enroled in the programme. For participating tenants, the scope for health‐related behaviour change was greatest in relation to eating and smoking. Small positive statistically significant changes in mental health were found between the 6‐ and 12‐month mean score and between the baseline and the 12‐month score. Conclusions: The findings indicate that NHNY may have been beneficial for some participating tenants. Housing officers can have a significant role in promoting health messages and embedding behaviour change among their tenants. Although the programme was implemented as a service improvement rather than a controlled trial and focused on a particular intervention and geographical area, other housing associations may find this evaluation useful for considering whether to adopt some of the principles applied in NHNY in other settings. Patient or Public Contribution: A social housing tenant representative provided input on the methodology and methods used to evaluate NHNY, as well as the information sheet. [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]

Hip strength may influence the energy flow through the kinematic chain during baseball pitching, affecting athlete performance as well as the risk for injury. To identify associations between hip strength and pitching biomechanics in adolescent baseball pitchers during 3 key events of the pitching cycle. Cross-sectional study. Biomechanics laboratory. A total of 26 adolescent male baseball pitchers (age = 16.1 ± 0.8 years, height = 184.29 ± 5.5 cm, mass = 77.5 ± 8.5 kg). The main outcome measure was hip strength (external rotation, internal rotation, flexion, abduction, adduction, and extension). After strength measurements were acquired, motion capture was used to obtain a full-body biomechanical analysis at 3 events during the pitching cycle (foot contact, maximal external rotation, and ball release). We then evaluated these values for associations between hip strength and pitching biomechanics. Scatterplots were examined for linearity to identify an appropriate correlation test. The associations were linear; thus, 2-tailed Pearson correlation coefficients were used to determine correlations between biomechanical metrics. An α level of.01 was chosen. Ten strong correlations were found between pitching biomechanics and hip strength: 8 correlations between hip strength and kinematics at key points during the pitch and 2 correlations of hip strength with peak elbow-varus torque. Several correlations were noted between lower extremity strength and pitching biomechanics. This information provides data that may be used to improve performance or reduce injury (or both) in pitchers. Increased hip strength in adolescent pitchers may both improve performance and decrease the risk of injury. [ABSTRACT FROM AUTHOR]

Objective: To evaluate and compare the costal cartilage lateral crural strut graft's (LCSG) ability to support a weak lateral crus in patients with external nasal valve dysfunction (EVD) undergoing primary versus revision functional rhinoplasty. Methods: This is a prospective cohort study of 26 patients (mean [SD]: 40.23 [6.75] years of age; 10 [38%] females) with clinically diagnosed EVD, who underwent primary versus revision functional rhinoplasty with the use of a costal cartilage LCSG (10 [38%] primary functional rhinoplasty patients and the 16 [62%] revision patients). Preoperative and 12-month postoperative subjective and objective functional measurements along with statistical analysis were performed. Results: While all baseline demographic and preoperative functional measurement scores were similar between the 2 groups, the primary cohort's preoperative scores were higher overall. Follow-up was a mean of 14.58 months. The primary group demonstrated a greater difference in score improvement postoperatively in all categories. All patients had significantly improved visual analog scale (VAS), Nasal Obstruction Symptom Evaluation Scale, 22-Item Sinonasal Outcome Test, and nasal peak inspiratory flow (NPIF) scores. When comparing the overall score outcome and surgical efficacy of the LCSG, both groups had near equal final score outcomes with the exception of VASL and NPIF. Conclusion: The LCSG is a viable and versatile option in the management of EVD for both primary and revision rhinoplasty patients. [ABSTRACT FROM AUTHOR]

Background: To investigate venous thromboembolism (VTE) in hospitalized patients with severe high altitude pulmonary edema (HAPE), we performed a single center retrospective study to evaluate its clinical characteristics, prognosis, and potential thromboprophylaxis strategies in a large referral and treatment center in plateau regions. Methods: We studied a total of 18 patients with severe HAPE from January 1, 2012 to December 31, 2021. Demographic and clinical data, laboratory data, including ultrasound scans of the lower extremities and cardiac ultrasound, and computed tomographic pulmonary angiography (CTPA) variables were obtained, and comparisons were made between groups with and without VTE. Results: Of the 18 patients hospitalized with severe HAPE (age 43 (range, 34–54) years, 14 [77.8%] men), 7 patients developed VTE (38.9%), including 5 with deep vein thrombosis (DVT) and pulmonary embolism (PE), 2 of whom had DVT only. Eighteen patients are all firstly rapid ascent to high altitudes which the mean altitude was 3700 m (3656–4050 m). Compared with patients who did not have VTE, patients with VTE had a longer time in hospital (13 [11, 19] versus 9 [7, 12]; P = 0.027), respiratory failure (6 [85.7%] versus 2 [18.2%]; P = 0.013), the shortened APTT (21.50 [19.00, 27.50] versus 26.30 [24.80, 30.10]; P = 0.044) and the higher level of D-dimer (7.81 [4.62, 9.60] versus 2.90 [1.75, 3.37]; P = 0.003). The proportion of thromboprophylaxis is too low in our cohort which 2 of 18 (11.1%) patients were given VTE prophylaxis. There was no statistically significant difference between the VTE and non-VTE groups (0 [0.0%] versus 2 [18.2%]; P = 0.497). Conclusions: The prevalence of VTE is high in hospitalized patients with severe high altitude pulmonary edema (HAPE). Prophylaxis for venous thromboembolism may be protective in severe HAPE patients after admission. Our data seem to suggest that VTE is probably an additional prognostic factors in patients with severe HAPE. [ABSTRACT FROM AUTHOR]

Background: New daily persistent headache (NPDH) is a rare primary headache that is highly disabling. The pathophysiology of NDPH is still unclear, and we aimed to reveal the underlying mechanism of NDPH through functional magnetic resonance imaging (fMRI) analysis. Methods: In this cross-sectional study, thirty patients with NDPH and 30 healthy controls (HCs) were recruited. The blood oxygen level-dependent (BOLD) sequences of all participants were obtained using the GE 3.0 T system. We performed ReHo, ALFF (conventional band: 0.01–0.08 Hz, slow-5: 0.01–0.027 Hz, slow-4: 0.027–0.073 Hz) and seed-based to the whole brain functional connectivity (FC) analysis in the NDPH and HC groups. The sex difference analysis of ReHo, ALFF, and FC values was conducted in the NDPH group. We also conducted Pearson's correlation analysis between ReHo, ALFF, FC values and clinical characteristics (pain intensity, disease duration, HIT-6, GAD-7, PHQ-9, and PSQI scores). Results: Both increased ReHo (PFWE-corr = 0.012) and ALFF values (0.01–0.08 Hz, PFWE-corr = 0.009; 0.027–0.073 Hz, PFWE-corr =0.044) of the left middle occipital gyrus (MOG_L) were found in the NDPH group compared to the HC group. There was no significant difference in FC maps between the two groups. Compared to the HC group, no difference was found in ReHo (p = 0.284), ALFF (p = 0.246), and FC (p = 0.118) z scores of the MOG_L in the NDPH group. There was also no sex difference in ReHo (p = 0.288), ALFF (p = 0.859), or FC z score (p = 0.118) of the MOG_L in patients with NDPH. There was no correlation between ReHo, ALFF, FC z scores and clinical characteristics after Bonferroni correction (p < 0.05/18). Conclusions: Patients with NDPH may have abnormal activation of the visual system. Abnormal visual activation may occur mainly in higher frequency band of the classical band. No sex differences in brain activity were found in patients with NDPH. [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]

Background: Attention deficit hyperactivity disorder (ADHD) is a prevalent child neurodevelopmental disorder that is treated in clinics and in schools. Previous trials suggested that our brain–computer interface (BCI)-based attention training program could improve ADHD symptoms. We have since developed a tablet version of the training program which can be paired with wireless EEG headsets. In this trial, we investigated the feasibility of delivering this tablet-based BCI intervention at home. Methods: Twenty children diagnosed with ADHD, who did not receive any medication for the preceding month, were randomised to receive the 8-week tablet-based BCI intervention either in the clinic or at home. Those in the home intervention group received instructions before commencing the program and got reminders if they were lagging on the training sessions. The ADHD Rating Scale was completed by a blinded clinician at baseline and at week 8. Adverse events were monitored during any contact with the child throughout the trial and at week 8. Results: Children in both groups could complete the tablet-based intervention easily on their own with minimal support from the clinic therapist or their parents (at home). The intervention was safe with few reported adverse effects. Clinician-rated inattentive symptoms on the ADHD-Rating Scale reduced by 3.2 (SD 6.20) and 3.9 (SD 5.08) for the home-based and clinic-based groups respectively, suggesting that home-based intervention was comparable to clinic-based intervention. Conclusions: This trial demonstrated that the tablet version of our BCI-based attention training program can be safely delivered to children in the comfort of their own home. Trial registration This trial is registered at clinicaltrials.gov as NCT01344044 [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]

Introduction: This study aimed to investigate the incidence of rheumatoid arthritis (RA) flare-ups following immunization with the Sinopharm COVID-19 inactivated virus-based vaccine. Methods: We conducted a retrospective observational study at the Rheumatology Clinic of Imam Hossein Hospital, incorporating 200 RA patients in remission undergoing non-biologic Disease-Modifying Antirheumatic Drugs (DMARDs) treatments. A rheumatologist confirmed a flare-up based on patients complain of arthralgia and joint stiffness and complete examination of joints over a three-month period following vaccination. Results: Twelve percent of all included patients experienced symptom recurrence. The average age of patients with flare-ups was significantly higher, but no gender-based differences were observed (p<0.001 and p=0.071, respectively). The second vaccine dose resulted in a higher number of symptom flares compared to the first dose (9.30% vs. 3.0%, p < 0.001). No significant differences were observed between patients experiencing flare-ups after the first dose and the second dose in terms of the number of involved joints (p=0.321) and the time gap from vaccination to symptom recurrence (p=0.526). No patients required hospitalization, and prednisolone dosage adjustments effectively managed symptoms. Conclusion: The occurrence of flare-ups was relatively low after the Sinopharm COVID-19 vaccination in RA patients undergoing treatment with DMARDs during remission. The majority of these flares were mild and no hospitalizations were required. [ABSTRACT FROM AUTHOR]

Objective: to investigate the factors associated with extubation failure of patients in the intensive care unit. Method: unpaired, longitudinal, retrospective and quantitative case-control with the participation of 480 patients through clinical parameters for ventilator weaning. Data were analyzed by: Fisher's exact test or the chi-square test; unpaired two-tailed Student's t test; and Mann-Whitney test. Significant P values lower than or equal to 0.05 were admitted. Results: of the patients, 415 (86.5%) were successful and 65 (13.5%) failed. Success group: the most negative fluid balance, APACHE II in 20 (14-25), weak cough in 58 (13.9%). Failure group: the most positive fluid balance, APACHE II in 23 (19-29), weak cough in 31 (47.7%), abundant amount of pulmonary secretions in 47.7%. Conclusion: positive fluid balance and the presence of inefficient cough or inability to clear the airway were predictors of extubation failure. [ABSTRACT FROM AUTHOR]

Purpose: Heparin-based regimens are recommended for anticoagulation in hospitalized patients with COVID-19 though a study reported similar mortality with apixaban in critically ill hospitalized COVID-19 patients. Our pilot study sought to determine the differences in all-cause mortality, venous thromboembolism (VTE), and bleeding events between apixaban and therapeutic heparin-based regimens in hospitalized non-critically ill COVID-19 patients. Methods: We conducted a retrospective analysis of non-critically ill COVID-19 patients aged ≥ 18 years admitted to 3 campuses of Montefiore Medical Center during the first (March 2020 to May 2020) and second (January 2021 to February 2021) COVID-19 surges, who received within 48 hours of admission and continued for ≥72 hours a therapeutic dose of low-molecular-weight heparin (LMWH), unfractionated heparin (UFH), or any apixaban dose for VTE prophylaxis. Outcomes data analyzed included mortality, suspected or imaging-confirmed VTE, and bleeding using a defined criteria. Results: Overall, 162 patients met eligibility for analysis. Baseline characteristics were similar between the 2 groups except liver and renal functions. Mortality occurred in 10 (13.3%) patients on apixaban and 23 (26.4%) patients on a heparin-based regimen (P =.059). Confirmed VTE events were not different between the groups (8% vs 13.8%, P =.359), but higher incidence of bleeding occurred in heparin-based group (4% vs 52.9%, P <.001). Conclusion: There were no differences in mortality or confirmed VTE between apixaban and heparin-based regimens except for more bleeding events with the heparins. This study highlights the utility of apixaban in COVID-19. [ABSTRACT FROM AUTHOR]

Background: Flipped learning excessively boosts the conceptual understanding of students through the reversed arrangement of pre-learning and in classroom learning events and challenges students to independently achieve learning objectives. Using a gamification method in flipped classrooms can help students stay motivated and achieve their goals. Methods: This study adopted a randomized controlled study design with a pre-test and post-test and involved 128 nursing students at Mansoura University. This study randomly divided the students into the study and control groups. Data were collected at three time points using six tools. In the intervention group, Moodle was gamified for 6 weeks. Results: A significant difference in the students' self-confidence (p = 0.021), skills knowledge (p < 0.001), intensity of preparation (p < 0.001), and motivation (p < 0.001) was observed between the two groups; however, no difference in the students' skills performance (p = 0.163) was observed between the two groups after using gamified flipped classrooms. Conclusions: Compared with the traditional flipped classrooms, gamified flipped classrooms improved nursing students' motivation, intensity of preparation, skills knowledge, and self-confidence during laboratory clinical practice. Thus, gamification is a learning approach that can be implemented in conjunction with the flipped classroom model to motivate students to participate in the learning process. Trial registration. Prospectively registered with ClinicalTrials.gov on 26/04/2021; registration number NCT04859192. [ABSTRACT FROM AUTHOR]

Background: Adjuvant chemotherapy (ACT) is considered for high‐risk patients in stage IB lung adenocarcinoma (LUAD). However, these risk factors are recognized as negative prognostic factors, not as predictors of ACT efficacy. This study aimed to analyze the efficacy of ACT in stage IB patients by retrospectively examining patients who had recurrence. Methods: We reviewed 1399 patients with stage IB (American Joint Committee on Cancer 7th edition) LUAD from 2012 to 2017 in our institution and found 147 patients with recurrence. The last follow‐up date was December 30, 2021. One‐to‐one propensity‐score matching (PSM) was used to reduce the potential selection bias. Results: Fifty‐five (37.4%) patients had received ACT and 92 (62.6%) had not (non‐ACT). Patients with ACT were younger (p < 0.001), had larger tumors (p < 0.001) and more lymphovascular invasion (p = 0.02), and seemed to have less distant recurrence (p = 0.001). After PSM, 110 patients were matched and baseline characteristics were balanced. ACT was not associated with improved disease‐free survival (DFS) after matching (mDFS = 23.5 m for ACT vs. 29.5 m for non‐ACT, p = 0.13). ACT failed to prolong DFS of patients in the extracranial recurrence subgroup and EGFR mutation subgroups, and was even associated with shorter DFS in intracranial relapsed patients (mDFS = 30.3 m vs. 33.5 m, p = 0.083) and patients with tumor ≤30 mm (mDFS = 21.9 m vs. 30.8 m, p = 0.076). Conclusion: In patients who were destined to develop recurrence after completely resected stage IB LUAD, ACT might not be associated with improved DFS. Further large multicenter studies are warranted to validate these findings. [ABSTRACT FROM AUTHOR]

Background: Effective team leadership and good activation criteria can effectively initiate rapid response system (RRS) to reduce hospital mortality and improve quality of life. The first reaction time of nurses plays an important role in the rescue process. To construct a nurse-led (nurse-led RRS) and activation criteria and then to conduct a pragmatic evaluation of the nurse-led RRS. Methods: We used literature review and the Delphi method to construct a nurse-led RRS and activation criteria based on the theory of "rapid response system planning." Then, we conducted a quasi-experimental study to verify the nurse-led RRS. The control group patients were admitted from August to October 2020 and performed traditional rescue procedures. The intervention group patients were admitted from August to October 2021 and implemented nurse-led RRS. The primary outcome was success rate of rescue. Setting: Emergency department, Gansu Province, China. Results: The nurse-led RRS and activation criteria include 4 level 1 indicators, 14 level 2 indicators, and 88 level 3 indicators. There were 203 patients who met the inclusion criteria to verify the nurse-led RRS. The results showed that success rate of rescue in intervention group (86.55%) was significantly higher than that in control group (66.5%), the rate of cardiac arrest in intervention group (33.61%) was significantly lower than that in control group (72.62%), the effective rescue time of intervention group (46.98 ± 12.01 min) was shorter than that of control group (58.67 ± 13.73 min), and the difference was statistically significant (P < 0.05). The rate of unplanned ICU admissions in intervention group (42.85%) was lower than that in control group (44.04%), but the difference was not statistically significant (P > 0.05). Conclusions: The nurse-led RRS and activation criteria can improve the success rate of rescue, reduce the rate of cardiac arrest, shorten the effective time of rescue, effectively improve the rescue efficiency of patients. [ABSTRACT FROM AUTHOR]

Objective The prognostic markers of hepatocellular carcinoma (HCC) patients with bone metastasis are of great significance for the design of treatment strategy, the maintenance of life quality of the patients, and the improvement of cancer prognosis. MicroRNA-149 (miR-149) rs2292832 C/T polymorphism in HCC patients has been reported to be associated with the risk of HCC, but whether it can predict the prognosis of HCC patients with bone metastasis remains unclear. The goal of our study was to examine the prognostic impact of miR-149 rs2292832 C/T polymorphism on HCC patients with bone metastasis. Methods A total of 67 cases of HCC patients with bone metastasis (BC group) and 73 cases of HCC patients without bone metastasis (NC group) were included in this study. The miR-149 levels in blood leukocytes and tumor tissues were determined by qRT-PCR. Genotyping analysis of miR-149 rs2292832 was performed using polymerase chain reaction (PCR)-restriction fragment length polymorphism assay. Results The blood leukocyte miR-149 levels were significantly decreased in HCC patients, compared with the healthy controls, and they were significantly decreased in the BC patients, compared with the NC cases. BC patients carrying miR-149 rs2292832 CC+CT phenotype have a better overall survival (OS) rate, whereas no significant correlation was found between miR-149 rs2292832 CC+CT phenotype and the OS rate in NC group. The miR-149 rs2292832 CC+CT phenotype was correlated with certain bone turnover markers and bone metabolism markers but was not correlated with receptor activator of nuclear factor-kappaB ligand (RANKL) expression. Meanwhile, the combination of miR-149 rs2292832 CC+CT phenotype and RANKL expression could improve the prognosis assessment of HCC patients with bone metastasis. Conclusion miR-149 rs2292832 polymorphism might be a novel prognostic biomarker for HCC patients with bone metastasis. A follow-up study with a larger cohort from a multicenter should be performed to test our conclusions. [ABSTRACT FROM AUTHOR]

Introduction: Older adults with Alzheimer's disease (AD) experience drastic changes in their physical and mental abilities. AD patients became heavily dependent on their caregivers for everyday functions, which have significant implications not only for them but also for their caregivers. So, many AD caregivers experienced an increased level of depression and anxiety symptoms, lower perceived control, and higher burden compared to non-AD caregivers. Therefore, psychological first aid (PFA) and educational interventions are designed to enable those caregivers to meet the daily requirements of their patient care and to cope with its challenges. Aim: Determine the effect of psychological first aid program on stress level and psychological well-being among caregivers of older adults with Alzheimer's disease. Design: One group pre-test post-test was followed. Subjects: A convenience sample of one hundred (100) caregivers of older adults with AD. Setting: All online groups concerned with the care of Alzheimer's disease patients on Facebook. Tools: Socio-demographic and clinical data of older adults with Alzheimer's disease and their caregivers' questionnaire, Alzheimer's disease knowledge scale, Kingston caregiver stress scale, and authentic identity measures (AIM) scale of psychological well-being Results: The psychological first aid program has highly statistically significant effect on the AD caregivers' knowledge, stress level and psychological well-being as (t=-30.707, P = 0.000, t = 8.500, P = 0.000 & t= -4.763, P = 0.000 respectively). Conclusion: Psychological first aid program is considered an effective intervention in decreasing the AD caregivers' stress and increasing their psychological wellbeing and knowledge regarding delivering care for AD patients. [ABSTRACT FROM AUTHOR]

In a prospective cohort study, stools from children <3 years with and without diarrhea who were Clostridioides difficile nucleic acid amplification test-positive underwent ultrasensitive and quantitative toxin measurement. Among 37 cases and 46 controls, toxin concentration distributions overlapped substantially. Toxin concentration alone does not distinguish C. difficile infection from colonization in young children. [ABSTRACT FROM AUTHOR]

Simple Summary: Resistance to standard therapies impose a huge challenge on the treatment for glioblastoma multiforme (GBM), which is often considered as a cell intrinsic property of either GBM or, more significantly, of GBM stem-like cells. Tumor-associated macrophages and microglia (TAMs) take up the majority of the immune population in the tumor microenvironment of GBM and potentially participating in modulating therapy responses. However, little is known about the mechanisms underlying the effect of TAMs on temozolomide (TMZ) induced chemoresistance. Members of the metzincin superfamily such as Matrix Metalloproteases (MMPs) and A Disintegrin and Metalloprotease (ADAM) proteases are important participants in the process of intercellular communications in the tumor microenvironment. Herein, we revealed a novel concept of an intra-tumoral ADAM8 mediated malignant positive feedback loop constituted by the intimate interaction of tumor associated macrophages (TAMs) and GBM cells under TMZ treatment. These findings provide a convincing example and further support the notion that the tumor microenvironment, in addition to GBM cells and GBM stem-like cells, should be considered as an essential modulator of therapy in GBM. In conclusion, our study provides a rational basis for TAM sparing ADAM8-targeting in GBM to optimize standard chemotherapy. Standard chemotherapy of Glioblastoma multiforme (GBM) using temozolomide (TMZ) frequently fails due to acquired chemoresistance. Tumor-associated macrophages and microglia (TAMs) as major immune cell population in the tumor microenvironment are potential modulators of TMZ response. However; little is known about how TAMs participate in TMZ induced chemoresistance. Members of the metzincin superfamily such as Matrix Metalloproteases (MMPs) and A Disintegrin and Metalloprotease (ADAM) proteases are important mediators of cellular communication in the tumor microenvironment. A qPCR screening was performed to identify potential targets within the ADAM and MMP family members in GBM cells. In co-culture with macrophages ADAM8 was the only signature gene up-regulated in GBM cells induced by macrophages under TMZ treatment. The relationship between ADAM8 expression and TAM infiltration in GBM was determined in a patient cohort by qPCR; IF; and IHC staining and TCGA data analysis. Moreover; RNA-seq was carried out to identify the potential targets regulated by ADAM8. CCL2 expression levels were determined by qPCR; Western blot; IF; and ELISA. Utilizing qPCR; IF; and IHC staining; we observed a positive relationship between ADAM8 expression and TAMs infiltration level in GBM patient tissues. Furthermore; ADAM8 induced TAMs recruitment in vitro and in vivo. Mechanistically; we revealed that ADAM8 activated HB-EGF/EGFR signaling and subsequently up-regulated production of CCL2 in GBM cells in the presence of TMZ treatment; promoting TAMs recruitment; which further induced ADAM8 expression in GBM cells to mediate TMZ chemoresistance. Thus; we revealed an ADAM8 dependent positive feedback loop between TAMs and GBM cells under TMZ treatment which involves CCL2 and EGFR signaling to cause TMZ resistance in GBM. [ABSTRACT FROM AUTHOR]

Simple Summary: The application of IL-2 for treating cancer is limited owing to its toxicity and short half-life. Its high binding ability to IL-2 receptor α expands immunosuppressive Treg cells, which represents an undesirable toxicity in cancer immunotherapy. Moreover, its small molecular size is the reason for its short half-life. We solved these problems by using a covalent modification strategy of IL-2 variant IL-2K35C with fatty acid by maleimide chemistry, namely, IL-2K35C-moFA. The experiments performed in vitro and in vivo proved that IL-2K35C-moFA is a novel immunotherapeutic agent with the potential to selectively stimulate CD8+ T cells and NK cells. Compared to IL-2WT, IL-2K35C-moFA showed a specifically reduced potency for the stimulation of Treg cells. Our results also showed that fatty acid conjugation appears to be effective in half-life extension. The combination of selective lymphocyte expansion and its long half-life means IL-2K35C-moFA should be evaluated as a potential human immunotherapeutic in the future. Human interleukin 2 (IL-2) has shown impressive results as a therapeutic agent for cancer. However, IL-2-based cancer therapy is limited by strong Treg amplification owing to its high binding affinity to IL-2 receptor α (IL-2Rα) and its short half-life owing to its small molecular size. In this study, we solved these problems using a covalent modification strategy of the IL-2 variant, i.e., substituting cysteine (C) for lysine (K) at position 35, using octadecanedicarboxylic acid through maleimide chemistry, creating IL-2K35C-moFA. IL-2K35C-moFA was equipotent to human IL-2 wild type (IL-2WT) in activating tumor-killing CD8+ memory effector T cells (CD8+ T) and NK cells bearing the intermediate affinity IL-2 receptors, and less potent than IL-2WT on CTLL-2 cells bearing the high-affinity IL-2 receptors. Moreover, it was shown to support the preferential activation of IL-2 receptor β (IL-2Rβ) over IL-2Rα because of the mutation and fatty acid conjugation. In a B16F10 murine tumor model, IL-2K35C-moFA showed efficacy as a single dose and provided durable immunity for 1 week. Our results support the further evaluation of IL-2K35C-moFA as a novel cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Simple Summary: Multiple myeloma (MM) is characterized by the presence of systemic clinical manifestations. Among them, pneumonia accounts for a significant cause of morbidity and mortality, highlighting an urgent need to explore possible susceptibility and potential mechanisms of pneumonia in MM. Recently, the gut–lung axis has emphasized the relevance of gut microbiota and pneumonia, indicating that the compromised function of gut microbiota may be susceptible to pneumonia. It has been previously shown that intestinal Klebsiella pneumonia enriches in MM patients and promotes MM progression in our previous work. In addition, host metabolism has been identified as a key regulator of MM. However, what role the altered gut microbiota plays in MM with pneumonia remains unknown. In this study, we explored the association between gut microbiota and MM with pneumonia. This is the first study to identify and elucidate the function of gut microbiota involved in MM with pneumonia. Pneumonia accounts for a significant cause of morbidity and mortality in multiple myeloma (MM) patients. It has been previously shown that intestinal Klebsiella pneumonia (K. pneumonia) enriches in MM and promotes MM progression. However, what role the altered gut microbiota plays in MM with pneumonia remains unknown. Here, we show that intestinal K. pneumonia is significantly enriched in MM with pneumonia. This enriched intestinal K. pneumonia links to the incidence of pneumonia in MM, and intestinal colonization of K. pneumonia contributes to pneumonia in a 5TGM1 MM mice model. Further targeted metabolomic assays reveal the elevated level of glutamine, which is consistently increased with the enrichment of K. pneumonia in MM mice and patients, is synthesized by K. pneumonia, and leads to the elevated secretion of TNF-α in the lung normal fibroblast cells for the higher incidence of pneumonia. Inhibiting glutamine synthesis by establishing glnA-mutated K. pneumonia alleviates the incidence of pneumonia in the 5TGM1 MM mice model. Overall, our work proposes that intestinal K. pneumonia indirectly contributes to pneumonia in MM by synthesizing glutamine. Altogether, we unveil a gut–lung axis in MM with pneumonia and establish a novel mechanism and a possible intervention strategy for MM with pneumonia. [ABSTRACT FROM AUTHOR]

Simple Summary: This work focuses on the peculiar contribution made by molecular dynamics simulation and in silico tools, in the choice of an effective second line therapy for a BRAF-mutated melanoma patient who developed resistance to the undergoing targeted therapy with BRAF/MEK inhibitors. Among the MEK inhibitors, we identified a drug alternative to trametinib, able to block the target even in the presence of a damaging mutation, and supported these findings, gathered by an in silico approach, with a liquid biopsy tracking of the response to treatment. The evolution of the disease, before and after the therapy change, was followed by analysis of the circulating tumor DNA and circulating melanoma cells. The systemic treatment of metastatic melanoma has radically changed, due to an improvement in the understanding of its genetic landscape and the advent of targeted therapy. However, the response to BRAF/MEK inhibitors is transitory, and big efforts were made to identify the mechanisms underlying the resistance. We exploited a combined approach, encompassing liquid biopsy analysis and molecular dynamics simulation, for tracking tumor evolution, and in parallel defining the best treatment option. The samples at different time points were collected from a BRAF-mutant melanoma patient who developed an early resistance to dabrafenib/trametinib. The analysis of the circulating tumor DNA (ctDNA) identified the MEK1 p.P124L mutation that confers resistance to trametinib. With an in silico modeling, we identified cobimetinib as an alternative MEK inhibitor, and consequently suggested a therapy switch to vemurafenib/cobimetinib. The patient response was followed by ctDNA tracking and circulating melanoma cell (CMC) count. The cobimetinib administration led to an important reduction in the BRAF p.V600E and MEK1 p.P124L allele fractions and in the CMC number, features suggestive of a putative response. In summary, this study emphasizes the usefulness of a liquid biopsy-based approach combined with in silico simulation, to track real-time tumor evolution while assessing the best treatment option. [ABSTRACT FROM AUTHOR]

Simple Summary: Epigenetic modification plays an important regulatory role in breast cancer progression. However, the relationship between epigenetic modification with tumor metabolism has not yet been fully elucidated. PDK1, as a key enzyme in glucose metabolism, mediates multiple tumors development. But, the mechanism of epigenetic modification in regulating PDK1 remains unclear in breast cancer. Here, we demonstrated that HDAC2 and EZH2 upregulated PDK1 expression through inhibiting miR-148a. Importantly, miR-148a targeting PDK1 regulated breast cancer cells glycolysis, invasion, epithelial-mesenchymal transition (EMT) and Adriamycin resistance. Our results suggested that the HDAC2/EZH2/miR-148a/PDK1 axis may be a promising potential therapeutic strategy. Background: Breast cancer has one of highest morbidity and mortality rates for women. Abnormalities regarding epigenetics modification and pyruvate dehydrogenase kinase 1 (PDK1)-induced unusual metabolism contribute to breast cancer progression and chemotherapy resistance. However, the role and mechanism of epigenetic change in regulating PDK1 in breast cancer remains to be elucidated. Methods: Gene set enrichment analysis (GSEA) and Pearson's correlation analysis were performed to analyze the relationship between histone deacetylase 2 (HDAC2), enhancer of zeste homologue 2 (EZH2), and PDK1 in database and human breast cancer tissues. Dual luciferase reporters were used to test the regulation between PDK1 and miR-148a. HDAC2 and EZH2 were found to regulate miR-148a expression through Western blotting assays, qRT-PCR and co-immunoprecipitation assays. The effects of PDK1 and miR-148a in breast cancer were investigated by immunofluorescence (IF) assay, Transwell assay and flow cytometry assay. The roles of miR-148a/PDK1 in tumor growth were investigated in vivo. Results: We found that PDK1 expression was upregulated by epigenetic alterations mediated by HDAC2 and EZH2. At the post-transcriptional level, PDK1 was a new direct target of miR-148a and was upregulated in breast cancer cells due to miR-148a suppression. PDK1 overexpression partly reversed the biological function of miR-148a—including miR-148a's ability to increase cell sensitivity to Adriamycin (ADR) treatment—inhibiting cell glycolysis, invasion and epithelial–mesenchymal transition (EMT), and inducing apoptosis and repressing tumor growth. Furthermore, we identified a novel mechanism: DNMT1 directly bound to EZH2 and recruited EZH2 and HDAC2 complexes to the promoter region of miR-148a, leading to miR-148a downregulation. In breast cancer tissues, HDAC2 and EZH2 protein expression levels also were inversely correlated with levels of miR-148a expression. Conclusion: Our study found a new regulatory mechanism in which EZH2 and HDAC2 mediate PDK1 upregulation by silencing miR-148a expression to regulate cancer development and Adriamycin resistance. These new findings suggest that the HDAC2/EZH2/miR-148a/PDK1 axis is a novel mechanism for regulating cancer development and is a potentially promising target for therapeutic options in the future. [ABSTRACT FROM AUTHOR]