Nevin Manimala

Arkh Patol. 2023;85(2):5-12. doi: 10.17116/patol2023850215.

ABSTRACT

OBJECTIVE: To study the somatic mutational status of the FGFR3 gene in urothelial bladder cancer (BC) and evaluate its relationship with the clinical and morphological characteristics of the tumor, deficiency of the DNA mismatch repair (dMMR), PD-L1 tumor status, and immunohistochemical (IHC) expression of the p16 protein.

MATERIAL AND METHODS: Surgical material of 40 patients with BC, on which the mutational status of the FGFR3 gene was studied using the molecular genetic method, as well as the MMR status, PD-L1 and p16 expression by the IHC method.

RESULTS: FGFR3 mutations, such as G370C, S249C, S371C/Y373C, R248C, were detected in 35.0% of the studied BC samples. FGFR3 status did not depend on the gender and age of patients, as well as on the degree of tumor lymphoid infiltration (TILs). Statistically significant differences were found in the analysis of FGFR3 status depending on the histological structure and degree of tumor differentiation, as well as on the pT stage. The FGFR3 status of BC was not associated with the IHC expression of the studied proteins of the MMR system, as well as with the PD-L1 status. Higher levels of PD-L1 expression were demonstrated by BC tumor cells, in which no aberrations in FGFR3 were detected. There was no significant association between p16 status and the presence of FGFR3 mutations, but for FGFR3-positive carcinomas, the basal pattern of p16 staining by IHC was noted.

CONCLUSION: A positive somatic mutational status of the FGFR3 gene was statistically significantly more common in the group of papillary low-grade non-muscle-invasive BC, demonstrating basal p16 IHC staining. In the study sample, there was no statistically significant relationship between the FGFR3 status of BC and gender and age differences, TILs, MMR status, PD-L1 status (SP142 and 22C3), and p16 status. The results of the study indicate the need to determine the FGFR3 status in patients with BC for further prescription of personalized therapy.

PMID:37053347 | DOI:10.17116/patol2023850215

J Clin Invest. 2023 Apr 27:e167339. doi: 10.1172/JCI167339. Online ahead of print.

ABSTRACT

BACKGOUND: Basic immune processes exhibit circadian rhythms, but it is unclear if rhythms exist in clinical endpoints like vaccine protection. Here, we examined associations between Coronavirus Infectious Disease 2019 (COVID-19) vaccination timing and effectiveness.

METHODS: We retrospectively analyzed a large Israeli cohort with timestamped COVID-19 vaccinations (n=1,515,754 patients over 12 years-old, 99.2% receiving BNT162b2). Endpoints included COVID-19 breakthrough infection, COVID-19 associated emergency department (ED) visits, and hospitalizations. Our main comparison was between patients vaccinated during morning (8:00-11:59), afternoon (12:00-15:59), or evening hours (16:00-19:59). We employed Cox regression to adjust for differences in age, sex, and co-morbidities.

RESULTS: Breakthrough infections differed based on vaccination time, with lowest rates associated with late morning to early afternoon, and highest rates with evening vaccination. Vaccination timing remained significant after adjustment for patient age, sex, and co-morbidities. Results were consistent in patients who received the basic two-dose series and who received booster doses. The relationship between COVID-19 immunization time and breakthrough infections was sinusoidal, consistent with a biological rhythm that modifies vaccine effectiveness by 8.6-25%. The benefits of daytime vaccination were concentrated in younger (<20 years old) and older patients (>50 years old). COVID-19 related hospitalizations varied significantly with the timing of the second booster dose, an intervention reserved for older and immunosuppressed patients (HR=0.64 morning vs. evening, 0.43-0.97 95% CI, p=0.038).

CONCLUSION: We report a significant association between the time of COVID-19 vaccination and its effectiveness. This has implications for mass vaccination programs.

FUNDING: National Institutes of Health.

PMID:37053011 | DOI:10.1172/JCI167339

J Med Internet Res. 2023 Apr 13;25:e44131. doi: 10.2196/44131.

ABSTRACT

BACKGROUND: Work stress places a heavy economic and disease burden on society. Recent technological advances include digital health interventions for helping employees prevent and manage their stress at work effectively. Although such digital solutions come with an array of ethical risks, especially if they involve biomedical big data, the incorporation of employees’ values in their design and deployment has been widely overlooked.

OBJECTIVE: To bridge this gap, we used the value sensitive design (VSD) framework to identify relevant values concerning a digital stress management intervention (dSMI) at the workplace, assess how users comprehend these values, and derive specific requirements for an ethics-informed design of dSMIs. VSD is a theoretically grounded framework that front-loads ethics by accounting for values throughout the design process of a technology.

METHODS: We conducted a literature search to identify relevant values of dSMIs at the workplace. To understand how potential users comprehend these values and derive design requirements, we conducted a web-based study that contained closed and open questions with employees of a Swiss company, allowing both quantitative and qualitative analyses.

RESULTS: The values health and well-being, privacy, autonomy, accountability, and identity were identified through our literature search. Statistical analysis of 170 responses from the web-based study revealed that the intention to use and perceived usefulness of a dSMI were moderate to high. Employees’ moderate to high health and well-being concerns included worries that a dSMI would not be effective or would even amplify their stress levels. Privacy concerns were also rated on the higher end of the score range, whereas concerns regarding autonomy, accountability, and identity were rated lower. Moreover, a personalized dSMI with a monitoring system involving a machine learning-based analysis of data led to significantly higher privacy (P=.009) and accountability concerns (P=.04) than a dSMI without a monitoring system. In addition, integrability, user-friendliness, and digital independence emerged as novel values from the qualitative analysis of 85 text responses.

CONCLUSIONS: Although most surveyed employees were willing to use a dSMI at the workplace, there were considerable health and well-being concerns with regard to effectiveness and problem perpetuation. For a minority of employees who value digital independence, a nondigital offer might be more suitable. In terms of the type of dSMI, privacy and accountability concerns must be particularly well addressed if a machine learning-based monitoring component is included. To help mitigate these concerns, we propose specific requirements to support the VSD of a dSMI at the workplace. The results of this work and our research protocol will inform future research on VSD-based interventions and further advance the integration of ethics in digital health.

PMID:37052996 | DOI:10.2196/44131

JMIR Form Res. 2023 Apr 13;7:e40671. doi: 10.2196/40671.

ABSTRACT

BACKGROUND: An increase in depression, anxiety, and stress symptoms worldwide, attributed to the COVID-19 pandemic, has been reported. If not treated, it may negatively affect a person’s everyday life by altering physical and social well-being and productivity and increasing expenditure on health care. Cognitive behavioral therapy (CBT)-based interventions are gaining popularity as a means to reduce stress and alleviate anxiety and depression symptoms. Moreover, CBT delivered through a mobile app has the same elements as traditional CBT training (eg, guided discovery). However, unlike conventional training, users of mobile apps are allowed to tailor their own experience at their own speed and schedule.

OBJECTIVE: This study aims to analyze Sensa users’ retrospective data and explore the dose-duration effect to find the optimal usage time when the user showed results.

METHODS: The study cohort comprised 381 consecutive community-based nonclinical users who started using Sensa between October 2021 and March 2022. All users included in the study took the Depression Anxiety Stress Scale-21 (DASS-21) assessment at least 2 times. Other parameters from the database containing all self-reported data were gender, number of active days, total time of use, and age. The primary outcome of the study was a change in the DASS-21 score. Statistical analyses were performed using GraphPad Prism (version 9, GraphPad Software). In addition, a logistic regression model was created to predict how the obtained independent parameters influenced the DASS-21 score.

RESULTS: The main finding of our study was that the majority of participants who started using Sensa were experiencing depression, anxiety, and stress symptoms (92.13%, 80.05%, and 87.93%, respectively). There was a statistically significant decrease of the DASS-21 subdomain scores after the use of the application (anxiety: mean 7.25, SD 4.03 vs mean 6.12, SD 4.00; P=.001; depression: mean 11.05, SD 4.26 vs mean 9.01, SD 4.77; P=.001; stress: mean 11.42, SD 3.44 vs mean 9.96, SD 3.65; P<.001). Finally, the logistic regression model showed that users who were using the app for more than 24 days and had at least 12 active days during that time had 3.463 (95% CI 1.142-11.93) and 2.644 (95% CI 1.024-7.127) times higher chances to reduce their DASS-21 subdomain scores of depression and anxiety, respectively.

CONCLUSIONS: Using the Sensa mobile app was related to decreased depression, anxiety, and stress symptoms.

PMID:37052990 | DOI:10.2196/40671

Altern Ther Health Med. 2023 Apr 14:AT7435. Online ahead of print.

ABSTRACT

CONTEXT: With the development of the Chinese economy, people’s quality of life has improved, obesity caused by excessive nutrition has increased among teenagers, and the age of patients with obesity-induced hypertension has become younger and younger.

OBJECTIVE: The study intended to analyze the factors affecting hypertension in adolescents to find methods to effectively prevent and treat hypertension in that age group.

DESIGN: The research team designed a prospective controlled study.

SETTING: The study took place at the First People’s Hospital of Nantong in Nantong, Jiangsu, China from 2020 to 2022 years.

PARTICIPANTS: Participants were 1000 students in Grades 7 to 9 at the Si’an middle school in Nantong, China.

INTERVENTION: From the 1000 participants, among of them 500 cases of hypertension. The research team (n = 500) participants who were obese and hypertensive and assigned them to the hypertension group, the control group (n = 500) participants with normal weights and no hypertension assigned them to a control group. Participants with obesity-induced hypertension received a comprehensive intervention.

OUTCOME MEASURES: The research team used a questionnaire and a physical examination to collect data about participants’ ages, heights, weights, demographic characteristics, waist circumferences, hip circumferences, and knowledge of hypertension and blood pressure and analyzed the relationships between those factors. The team measured blood pressure, blood lipids, blood glucose, and body mass index at baseline and postintervention.

RESULTS: Significant differences existed between the hypertension and control groups at general data: (1) weight-63.49 ± 13.22 kg and 52.59 ± 10.21 kg, respectively (P = .000); (2) waist circumference-75.44 ± 10.92 cm and 68.73 ± 8.15 cm, respectively (P = .001); (3) hip circumference-92.10 ± 7.98 cm and 85.95 ± 7.91 cm, respectively (P = .000); (4) body mass index (BMI)-22.12 ± 4.02 kg/m2 and 19.58 ± 3.34 kg/m2, respectively (P = .002); (5) waist-hip ratio-0.83 ± 0.08 and 0.81 ± 0.07, respectively (P = .003); and (6) waist-to-height ratio-0.46 ± 0.07 and 0.44 ± 0.06, respectively (P = .000). Only age (p=0.006), hip circumference(p=0.000), and BMI (P = .000) were significantly and positively correlated with hypertension. The regression coefficients for age, hip circumference, and BMI were 0.182, 0.062 and 0.096, respectively. The changes in the hypertension group’s mean systolic blood pressure (SBP), diastolic blood pressure (DBP), BMI, body fat, trunk fat, abdominal fat, upper-limb fat, and lower-limb fat between baseline and postintervention were statistically significant. Significant decreases in the hypertension group’s triglycerides, total cholesterol, and glycated albumin had occurred between baseline and postintervention (all P < .01), and that group’s glucagon (P = .011) had significantly increased. No significant changes had occurred in that group’s blood glucose, glycated hemoglobin, insulin, and insulin resistance index between baseline and postintervention (P < .05).

CONCLUSIONS: Obesity increases the risk of hypertension, and comprehensive interventions can effectively prevent and treat adolescent hypertension.

PMID:37052969

Lancet Oncol. 2023 Mar;24(3):286-296. doi: 10.1016/S1470-2045(23)00016-5. Epub 2023 Feb 14.

ABSTRACT

BACKGROUND: Adding immunotherapy to first-line chemotherapy might improve outcomes for patients with advanced or recurrent endometrial cancer. We aimed to compare carboplatin and paclitaxel versus avelumab plus carboplatin and paclitaxel as first-line treatment with avelumab given concurrent to chemotherapy and as maintenance after the end of chemotherapy.

METHODS: MITO END-3 is an open-label, randomised, controlled, phase 2 trial conducted at 31 cancer institutes, hospitals, and universities in Italy. Eligible patients were aged 18 years or older with histologically confirmed advanced (FIGO stage III-IV) or recurrent endometrial cancer, an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, and no previous systemic anticancer therapy as primary treatment for advanced or metastatic disease. Participants were randomly assigned (1:1) using a computerised minimisation procedure stratified by centre, histology, and stage at study entry, to either receive carboplatin (area under the curve [AUC] 5 mg/mL × min) and paclitaxel (175 mg/m²; standard group) intravenously every 3 weeks for six to eight cycles or avelumab (10 mg/kg intravenously) added to carboplatin and paclitaxel (experimental group) every 3 weeks and then every 2 weeks as a single maintenance treatment after the end of chemotherapy until disease progression or unacceptable toxicity. Patients, treating clinicians, and those assessing radiological examinations were not masked to study treatment. The primary endpoint was investigator-assessed progression-free survival, measured in the intention-to-treat (ITT) population. Patients who received at least one dose of study drug were included in the safety analysis. Experimental group superiority was tested with 80% power and one-tailed α 0·20. This trial is registered with ClinicalTrials.gov (NCT03503786) and EudraCT (2016-004403-31).

FINDINGS: From April 9, 2018, to May 13, 2021, 166 women were assessed for eligibility and 39 were excluded. 125 eligible patients were randomly assigned to receive carboplatin and paclitaxel (n=62) or avelumab plus carboplatin and paclitaxel (n=63) and included in the ITT population. The median follow-up was 23·3 months (IQR 13·2-29·6) and was similar between the two groups. 91 progression-free survival events were reported, with 49 events in 62 patients in the standard group and 42 events in 63 patients in the experimental group. The median progression-free survival was 9·9 months (95% CI 6·7-12·1) in the standard group and 9·6 months (7·2-17·7) in the experimental group (HR of progression or death 0·78 [60% CI 0·65-0·93]; one-tailed p=0·085). Serious adverse events were reported more frequently in the experimental group (24 vs seven events in the standard group); neutrophil count decrease was the most frequent grade 3-4 adverse event (19 [31%] of 61 patients in the experimental group vs 26 [43%] of 61 patients in the standard group). Two deaths occurred in the experimental group during treatment (one respiratory failure following severe myositis [possibly related to treatment] and one cardiac arrest [not related to treatment]).

INTERPRETATION: Adding avelumab to first-line chemotherapy deserves further testing in patients with advanced or recurrent endometrial cancer, although consideration of mismatch repair status is warranted.

FUNDING: Pfizer.

PMID:37052965 | DOI:10.1016/S1470-2045(23)00016-5

Invest Ophthalmol Vis Sci. 2023 Apr 3;64(4):15. doi: 10.1167/iovs.64.4.15.

ABSTRACT

PURPOSE: To determine if macular reticular pseudodrusen (RPD) were associated with markers of impaired macular choroidal perfusion, we investigated measurements of macular choriocapillaris (CC) flow deficits (FDs), CC thickness, and mean choroidal thickness (MCT) in eyes with macular RPD compared with normal eyes and eyes with soft drusen.

METHODS: Eyes with intermediate age-related macular degeneration (iAMD) and normal eyes underwent 6 × 6 mm swept-source optical coherence tomography angiography (SS-OCTA) imaging to diagnose macular RPD, occupying over 25% of the fovea-centered 5 mm diameter circle, and measure outer retinal layer (ORL) thickness, CC FDs, CC thickness, MCT, and choroidal vascularity index (CVI) using previously published strategies within the same fovea-centered 5 mm circle.

RESULTS: Ninety eyes were included; 30 normal eyes, 30 eyes with soft drusen, and 30 eyes with macular RPD. The RPD eyes showed higher macular CC FDs than normal eyes (P < 0.001) and soft drusen eyes (P = 0.019). Macular CC thickness was decreased in RPD eyes compared with normal eyes (P < 0.001) and soft drusen eyes (P = 0.016). Macular MCT in RPD eyes was thinner than normal eyes (P = 0.005) and soft drusen eyes (P < 0.001). No statistically and clinically significant differences were found in the ORL thickness and CVI measurements between RPD eyes and the other two groups (all P > 0.05).

CONCLUSIONS: Eyes with macular RPD had decreased macular CC perfusion, decreased CC thickness, and decreased MCT measurements compared with normal and soft drusen eyes, suggesting that RPD may result from impaired choroidal perfusion.

PMID:37052925 | DOI:10.1167/iovs.64.4.15

J Autism Dev Disord. 2023 Apr 13. doi: 10.1007/s10803-023-05977-w. Online ahead of print.

ABSTRACT

The Repetitive Behaviours Questionnaire for Adults (RBQ-2A) measures two factors of restricted and repetitive behaviours (RRBs) associated with autism. However, the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) provides four criteria for RRBs: repetitive motor behaviours, insistence on sameness, restricted interests, and interest in sensory aspects of the environment (or atypical sensitivity). The current paper aimed to examine whether the RBQ-2A is a psychometrically sound measure of these four factors. Study 1 had university students (N = 368) complete the RBQ-2A and other related measures online and revealed that the RBQ-2A can assess the factors highlighted in the DSM-5 and that these four factors comprise a general RRB construct. Study 2 had individuals disclosing a diagnosis of autism (N = 283) complete the RBQ-2A and other related measures online and supported that this four-factor structure provided good psychometric properties. While the current paper provides findings for an online autistic population, further research is needed to generalize these findings to autistic individuals less likely to partake in online studies (e.g., those with intellectual or language disabilities). Overall, the results suggest that the RBQ-2A reliably and validly assesses RRBs.

PMID:37052863 | DOI:10.1007/s10803-023-05977-w

J Magn Reson Imaging. 2023 Apr 13. doi: 10.1002/jmri.28734. Online ahead of print.

ABSTRACT

BACKGROUND: Papilledema is thought to be the hallmark sign of increased intracranial pressure (ICP). Distension of the subarachnoid space within the optic nerve sheath is also commonly reported in MR studies as an indirect sign of increased ICP.

HYPOTHESIS: General anesthesia and positive pressure ventilation might result in changes in optic sheath diameter (OSD) observed on clinical brain MRI.

STUDY TYPE: Retrospective.

POPULATION: One hundred forty-five patients (154 MRI scans, 7.3 years ± 5.1); 97 studies in the anesthesia group (4.4 years ± 3.4) of which 22 had papilledema, and 57 in the non-anesthesia group (12.3 years ± 3.2), of which 28 had papilledema.

FIELD STRENGTH/SEQUENCE: 1.5T or 3.0T volumetric T2 images. T2 images were obtained from different vendors.

ASSESSMENT: OSD, optic nerve diameter (OND), and peri-optic cerebrospinal fluid (CSF) were measured manually on T2-weighted MR images for various population subgroups (with and without anesthesia; with or without papilledema). The correlation between these measurements and the clinical diagnosis of papilledema was evaluated via receiver operating characteristic (ROC) analysis.

STATISTICAL TESTS: Chi-square test; Mann-Whitney Test; Spearman’s test and ROCs; Interclass correlation coefficient, P = 0.05.

RESULTS: General anesthesia resulted in significantly larger mean OSD in patients with or without papilledema (7.3 ± 1.0 mm vs. 6.1 ± 1.1 mm and 6.7 ± 1.0 mm vs. 5.4 ± 0.9 mm, respectively). In the non-anesthesia group, the average OSD values (6.1 ± 1.1 mm) were significantly higher in papilledema patients compared to non-papilledema patients (5.4 ± 0.9 mm), with larger peri-optic CSF rim (1.6 ± 0.4 mm vs. 1.3 ± 0.3 mm). In the anesthesia group, OND was significantly larger in papilledema patients (3.4 ± 0.4 mm vs. 3.1 ± 0.5 mm), though the average peri-optic CSF rim did not reach a significance in papilledema compared with non-papilledema patients (2.0 ± 0.3 mm vs. 1.8 ± 0.4 mm, P = 0.06). In patients with general anesthesia, peri-optic CSF rim had a limited correlation with increased ICP.

DATA CONCLUSION: In the pediatric population, imaging findings of increased OSD on brain MRI might be related to general anesthesia rather than increased ICP. The interpretation of optic nerve sheath distention should be reported cautiously in conjunction with anesthesia status, especially in the pediatric population.

EVIDENCE LEVEL: 4 Technical Efficacy: 5.

PMID:37052820 | DOI:10.1002/jmri.28734

3D Print Med. 2023 Apr 13;9(1):10. doi: 10.1186/s41205-023-00176-w.

ABSTRACT

BACKGROUND: 3D (three-dimensional) printing has been adopted by the medical community in several ways, procedure planning being one example. This application of technology has been adopted by several subspecialties including interventional radiology, however the planning of transjugular intrahepatic portosystemic shunt (TIPS) placement has not yet been described. The impact of a 3D printed model on procedural measures such as procedure time, radiation exposure, intravascular contrast dosage, fluoroscopy time, and provider confidence has also not been reported.

METHODS: This pilot study utilized a quasi-experimental design including patients who underwent TIPS. For the control group, retrospective data was collected on patients who received a TIPS prior to Oct 1, 2020. For the experimental group, patient-specific 3D printed models were integrated in the care of patients that received TIPS between Oct 1, 2020 and April 15, 2021. Data was collected on patient demographics and procedural measures. The interventionalists were surveyed on their confidence level and model usage following each procedure in the experimental group.

RESULTS: 3D printed models were created for six TIPS. Procedure time (p = 0.93), fluoroscopy time (p = 0.26), and intravascular contrast dosage (p = 0.75) did not have significant difference between groups. Mean radiation exposure was 808.8 mGy in the group with a model compared to 1731.7 mGy without, however this was also not statistically significant (p = 0.09). Out of 11 survey responses from interventionists, 10 reported “increased” or “significantly increased” confidence after reviewing the 3D printed model and all responded that the models were a valuable tool for trainees.

CONCLUSIONS: 3D printed models of patient anatomy can consistently be made using consumer-level, desktop 3D printing technology. This study was not adequately powered to measure the impact that including 3D printed models in the planning of TIPS procedures may have on procedural measures. The majority of interventionists reported that patient-specific models were valuable tools for teaching trainees and that confidence levels increased as a result of model inclusion in procedure planning.

PMID:37052816 | DOI:10.1186/s41205-023-00176-w