Classification of Parkinson's disease by deep learning on midbrain MRI.

Purpose: Susceptibility map weighted imaging (SMWI), based on quantitative susceptibility mapping (QSM), allows accurate nigrosome-1 (N1) evaluation and has been used to develop Parkinson's disease (PD) deep learning (DL) classification algorithms. Neuromelanin-sensitive (NMS) MRI could improve automated quantitative N1 analysis by revealing neuromelanin content. This study aimed to compare classification performance of four approaches to PD diagnosis: (1) N1 quantitative "QSM-NMS" composite marker, (2) DL model for N1 morphological abnormality using SMWI ("Heuron IPD"), (3) DL model for N1 volume using SMWI ("Heuron NI"), and (4) N1 SMWI neuroradiological evaluation. Method: PD patients (n = 82; aged 65 ± 9 years; 68% male) and healthy-controls (n = 107; 66 ± 7 years; 48% male) underwent 3 T midbrain MRI with T2*-SWI multi-echo-GRE (for QSM and SMWI), and NMS-MRI. AUC was used to compare diagnostic performance. We tested for correlation of each imaging measure with clinical parameters (severity, duration and levodopa dosing) by Spearman-Rho or Kendall-Tao-Beta correlation. Results: Classification performance was excellent for the QSM-NMS composite marker (AUC = 0.94), N1 SMWI abnormality (AUC = 0.92), N1 SMWI volume (AUC = 0.90), and neuroradiologist (AUC = 0.98). Reasons for misclassification were right-left asymmetry, through-plane re-slicing, pulsation artefacts, and thin N1. In the two DL models, all 18/189 (9.5%) cases misclassified by Heuron IPD were controls with normal N1 volumes. We found significant correlation of the SN QSM-NMS composite measure with levodopa dosing (rho = -0.303, p = 0.006). Conclusion: Our data demonstrate excellent performance of a quantitative QSM-NMS marker and automated DL PD classification algorithms based on midbrain MRI, while suggesting potential further improvements. Clinical utility is supported but requires validation in earlier stage PD cohorts.

Care of children with congenital rubella syndrome (CRS) in Indonesia.

INTRODUCTION: Congenital rubella syndrome (CRS) is associated with severe birth defects, that lead to disability in later life. Hence, early detection and intervention are needed to prevent permanent disability and mortality in children with CRS. We evaluated the time to diagnosis or correction intervention related to survival rate using survival analysis. METHODOLOGY: A retrospective cohort study was conducted to evaluate the follow-up of CRS-confirmed cases from 2011-2018 at a national referral hospital in Jakarta, Indonesia. Parents of eligible children who registered in the national CRS registry as laboratory-confirmed CRS cases were contacted through phone calls or home visits and interviewed about the current situation of their child's health. We also obtained clinical data from the medical records. RESULTS: Fifty children, age 4 to 14 years, identified with laboratory-confirmed CRS were included in this study. Half (54%) of these children were female. All were born from mothers with no previous rubella vaccination history. Ophthalmic abnormalities such as congenital cataracts (88%) were the most common birth defect. Multiple congenital abnormalities including congenital heart disease, ocular abnormalities, and auditory defects were identified in 52% of the children. Based on Kaplan-Meier analysis, 50% of children were diagnosed at four months. Ophthalmic corrections such as cataract surgery were performed earlier than heart or auditory correction, with 50% of children undergoing eye correction one month after the diagnosis. CONCLUSIONS: There is a vital need to implement CRS surveillance in Indonesia to know the burden of CRS and reinforce the preventive actions, including vaccination against rubella.

Protocol for establishing spontaneous metastasis in mice using a subcutaneous tumor model.

Recapitulating spontaneous metastasis in preclinical models is crucial for understanding mechanisms underlying cancer progression and testing effective therapeutic interventions. We present a protocol for establishing and characterizing the spontaneous metastasis model in mice. We describe steps for generating primary tumors, tumor resection, monitoring metastatic dissemination, and evaluating metastatic burden using histological and imaging techniques. This protocol provides a valuable tool for studying metastasis in vivo and testing therapeutic strategies aimed at preventing or targeting metastatic diseases. For complete details on the use and execution of this protocol, please refer to Liu et al.1.

Hybrid immunity augments cross-variant protection against COVID-19 among immunocompromised individuals.

BACKGROUND: Immunity to SARS-CoV-2 vaccination and infection differs considerably among individuals. We investigate the critical pathways that influence vaccine-induced cross-variant serological immunity among individuals at high-risk of COVID-19 complications. METHODS: Neutralizing antibodies to the wild-type SARS-CoV-2 virus and its variants (Beta, Gamma, Delta and Omicron) were analyzed in patients with autoimmune diseases, chronic comorbidities (multimorbidity), and healthy controls. Antibody levels were assessed at baseline and at different intervals up to 12 months following primary and booster vaccination with either BNT162b2 or mRNA-1273. Immunity induced by vaccination with and without infection (hybrid immunity) was compared with that of unvaccinated individuals with recent SARS-CoV-2 infection. Plasma cytokines were analyzed to investigate variations in antibody production following vaccination. RESULTS: Patients with autoimmune diseases (n = 137) produced lesser antibodies to the wild-type SARS-CoV-2 virus and its variants compared with those in the multimorbidity (n = 153) and healthy groups (n = 229); antibody levels were significantly lower in patients with neuromyelitis optica and those on prednisolone, mycophenolate or rituximab treatment. Multivariate logistic regression analysis identified neuromyelitis optica (odds ratio 8.20, 95% CI 1.68-39.9) and mycophenolate (13.69, 3.78-49.5) as significant predictors of a poorer antibody response to vaccination (i.e, neutralizing antibody <40%). Infected participants exhibited antibody levels that were 28.7% higher (95% CI 24.7-32.7) compared to non-infected participants six months after receiving a booster vaccination. Individuals infected during the Delta outbreak generated cross-protective neutralizing antibodies against the Omicron variant in quantities comparable to those observed after infection with the Omicron variant itself. In contrast, unvaccinated individuals recently infected with the wild-type (n = 2390) consistently displayed lower levels of neutralizing antibodies against both the wild-type virus and other variants. Pathway analyses suggested an inverse relationship between baseline T cell subsets and antibody production following vaccination. CONCLUSION: Hybrid immunity confers a robust protection against COVID-19 among immunocompromised individuals.

Knowledge, attitude, and practice of e-cigarette use among undergraduate students: A comparative study between China and Indonesia.

INTRODUCTION: The health risks associated with e-cigarettes are currently the focus of tobacco control efforts and public health initiatives. Given that China and Indonesia have the highest rates of adult smoking worldwide, it is imperative to gain a comprehensive understanding of e-cigarette prevalence among college students in these two nations. METHODS: From May to June 2023, a cross-sectional study was employed to conduct an online questionnaire survey among college students in three universities located in Kunming (China) and Jakarta (Indonesia), respectively. The chi-squared test was utilized to compare the rates/ratios, while binary logistic regression analysis was applied to examine the factors influencing e-cigarette knowledge, attitude, and practice. RESULTS: A total of 1327 individuals were included in the investigation. The proportion of Indonesian students (75.6%) with a high level of e-cigarette knowledge was lower than that observed among Chinese students (87.4%) (χ2=29.7, p<0.001). Additionally, the prevalence of e-cigarette use among Indonesian students (9.4%) was higher compared to their Chinese counterparts (3.0%) (χ2=22.32, p<0.001). Binary logistic regression analysis revealed that age, place of residence, studies, gender, and e-cigarette use by friends and family, significantly influenced knowledge levels and attitudes toward e-cigarettes in both countries (p<0.05). CONCLUSIONS: Despite the positive knowledge, attitudes, and practices towards e-cigarettes among undergraduate students in both countries, a notable knowledge gap exists concerning the harmful effects of e-cigarettes. Chinese students had better e-cigarette knowledge and demonstrated lower usage rates, suggesting that heightened awareness plays a favorable role in preventing e-cigarette use. Furthermore, it becomes imperative for policymakers and health educators to focus on specific factors, such as the influence of close friends and family members, as well as the area of residence.

Early Experience of Left Bundle Branch Pacing with Lumenless Lead in a Single Center: A Case Series.

Left bundle branch pacing (LBBP) has been subject to increasing interest over the last few years due to its capacity for physiological conduction and its advantages compared to His bundle pacing. His bundle pacing has certain limitations, such as a small pacing area for the His bundle, a high threshold that leads to battery depletion, a low R-wave amplitude that may result in atrial or His oversensing, and ventricular signal undersensing. In this case series, four patients (two female and two male) aged 62.2 ± 8.4 years old with symptomatic sick sinus disease and no scar tissue in the interventricular septum underwent LBBP. All LBBPs were done with standard LBBP using a lumenless SelectSecure 3830 lead (Medtronic®, Minneapolis, USA) with a fixed helix. The lead parameters showed a good R-wave amplitudes (13 ± 7.4 mV) and a low threshold  (0.77 ± 0.17 V @ 0.4 ms). All patients were discharged on the next day. During follow-up period of 13.3 ± 12.9 months, all patients were well and no complications were noted. In conclusion, LBBP may be as an alternative of novel conduction pacing techniques and can be done relatively easy and safe, even with limited experience center.

New model of sports tourism with sustainable tourism development to increase tourist arrivals in Central Aceh Regency, Indonesia.

Introduction: This study explores the development and implementation of a new sports tourism product called "Run H2O Ride" as a strategy for sustainable tourism in Indonesia. Methods: The research employs a research and development (R&D) methodology, focusing on identifying potential issues, conducting literature reviews, designing the product, validating the design, and undergoing product development. A combination of discussion group forums (FGD) and expert judgment decisions was used to design the new sport tourism model. Results: The effectiveness of the model was assessed through limited product tests, main product tests, and operational product tests involving respondents from the local community and tourists. The results indicate that the "Run H2O Ride" model has been well-received, with positive feedback on its suitability and effectiveness in attracting tourists and enhancing the local economy. Discussion: The study concludes by recommending further research to refine the model and emphasizes the importance of local government support and community participation in sustainable tourism development. Theoretical implications highlight the significance of sports tourism events in promoting tourism, while practical implications suggest alternative solutions for increasing tourist visits and improving destination image. Policy recommendations for local governments are proposed to adopt and implement sports tourism events, aligning with long-term development plans for regional tourism growth.

Unveiling the Influence of Osmotic Pretreatment on Dried Fruit Characteristics: A Meta-Analysis Approach.

Considering the diverse findings regarding the impact of osmotic pretreatment on the quality of dried products, it is important to determine whether osmotic pretreatment can either maintain or reduce the quality of fruit products. Thus, the present study aimed to scrutinize research regarding the influence of osmotic pretreatment on the qualities of dried fruits through meta-analysis. The Scopus database was used to search for relevant articles. Following the Preferred Reporting Items for Systematic Reviews and Meta-analyses protocol, 26 studies that met the criteria for meta-analysis were identified. The presentation included statistics (mean, standard deviation, sample size) and moderator variables (fruit types, osmotic agents, solution concentrations, drying methods, and drying temperatures). After pooling data using a random effects model, the OpenMEE software was used to conduct meta-analysis. The results showed that osmo-dried fruits had significantly decreased total color difference, titratable acidity, total flavonoid content, and vitamins B1 and B3 (P<0.05) and significantly increased ß-carotene and 2,2-diphenyl-1-picrylhydrazyl levels (P<0.05). Osmotic pretreatment did not affect total phenolic content and vitamin C. Subgroup analysis highlighted the influence of moderator variables on the quality of osmo-dried fruits, with each fruit responding differently to osmotic pretreatment. Moreover, using 10% sugar solution as an additive effectively enhanced the quality of dried fruits. In addition, osmotic dehydration can be combined with convective drying at a temperature of 60°C for optimal results in the drying process.

Effect of mobile app-based oral hygiene instructions on clinical parameters, oral bacterial diversity, and composition of subgingival microbiota in periodontitis patients.

Introduction: Oral hygiene instruction (OHI) is essential during periodontitis treatment. Various OHI approaches have been explored, including mobile apps. Objective: To evaluate the mobile app-based OHI's effect on periodontitis management by analyzing clinical parameters and subgingival microbiota. Methods: Forty-four periodontitis patients were randomly assigned into two groups. The test group (n = 22) received scaling and root planing (SRP), OHI, and mobile app-based OHI, whereas the control group (n = 22) received SRP and OHI. Full mouth plaque score (FMPS), bleeding on probing (BOP) and probing pocket depth at the sampling sites (site-PPD) were assessed at baseline, one- and three-month visits. The 16S rRNA next-generation sequencing (NGS) was used to analyze subgingival plaque samples. Results: Significant reduction in FMPS, BOP, and site-PPD at one- and three-month visits compared to baseline (p < 0.001) with no significant differences across groups (p > 0.05). In test groups, intra-group analysis showed better improvement in BOP and site-PPD (p < 0.05) than control. The diversity and composition of subgingival microbiota did not differ between groups or timepoints (p > 0.05). Conclusions: Mobile app-based OHI showed no superior effects on improving clinical parameters and subgingival microbiota compared to conventional OHI. Further investigation into its long-term impact on periodontitis treatment is needed.

Past and future land use change dynamics: assessing the impact of urban development on agricultural land in the Pantura Jabar region, Indonesia.

The conversion of large-scale agricultural land into urban areas poses a significant challenge to achieving national and global food security targets, as outlined in Sustainable Development Goal number 2, which aims to eradicate hunger. Indonesia has experienced a significant decline in rice field areas, with a reduction of approximately 650 thousand hectares within a year (2017-2018), the largest being in Java. Hence, this study aims to examine the impact of urban expansion on agricultural land in the north coast region of West Java Province from 2013 to 2020 and develop a predictive model for 2030 to support sustainable land use planning. The primary methods employed were random forest (RF) analysis using Google Earth Engine, intensity analysis, multilayer perceptron-neural network (MLP-NN), Markov chains-cellular automata (Markov-CA), and stakeholder interviews. The model also evaluated the influence of "distance to tollgates" as a previously unexplored driving factor in existing land use modeling studies. Landsat image classification results using the RF algorithm showed 87-88% accuracy. Cropland has historically been and is projected to remain the primary target for the expansion of built-up areas. Spatial planning irregularities were found in the growth of these areas that adversely affected farmers' socioeconomic and environmental conditions. Evaluation of land use models using MLP-NN and Markov-CA demonstrated an accuracy rate of 86.29-86.23%. The distance to tollgates factor significantly impacts the models, albeit less than population density. The 2030 intervention scenario, which implements a firm policy for sustainable agricultural land use, offers the potential to maintain the predicted cropland loss compared to business as usual.

Impact of Climate on Soil Organic Matter Composition in Soils of Tropical Volcanic Regions Revealed by EGA-MS and Py-GC/MS.

Soil organic matter (SOM) crucially influences the global carbon cycle, yet its molecular composition and determinants are understudied, especially for tropical volcanic regions. We investigated how SOM compounds change in response to climate, vegetation, soil horizon, and soil properties and the relationship between SOM composition and microbial decomposability in Tanzanian and Indonesian volcanic regions. We collected topsoil (0-15 cm) and subsoil (20-40 cm) horizons (n = 22; pH: 4.6-7.6; SOC: 10-152 g kg-1) with undisturbed vegetation and wide mean annual temperature and moisture ranges (14-26 °C; 800-3300 mm) across four elevational transects (340-2210 m asl.). Evolved gas analysis-mass spectrometry (EGA-MS) documented a simultaneous release of SOM compounds and clay mineral dehydroxylation. Subsequently applying double-shot pyrolysis-gas chromatography/mass spectrometry (Py-GC/MS) at 200 and 550 °C, we detailed the molecular composition of topsoil and subsoil SOM. A minor portion (2.7 ± 1.9%) of compounds desorbed at 200 °C, limiting its efficacy for investigating overall SOM characteristics. Pyrolyzed SOM closely aligns with the intermediate decomposable SOM pool, with most pyrolysates (550 °C) originating from this pool. Pyrolysates composition suggests tropical SOM is mainly microbial-derived and subsoil contains more degraded compounds. Higher litter inputs and attenuated SOM decomposition due to cooler temperatures and lower soil pH (<5.5) produce less-degraded SOM at higher elevations. Redundancy analyses revealed the crucial role of active Al/Fe (oxalate-extractable Al/Fe), abundant in low-temperature/high-moisture conditions, in stabilizing these less-degraded components. Our findings provide new insights into SOM molecular composition and its determinants, critical for understanding the carbon cycle in tropical ecosystems.

Validity of the Active Australia Survey in an Australian cardiac rehabilitation population.

OBJECTIVES: To examine the long-term validity of the Active Australia Survey in a cardiac rehabilitation population using accelerometry as the reference measure. DESIGN: Cohort validation study. METHODS: Cardiac rehabilitation participants with coronary heart disease were recruited to a prospective cohort study. Over 7-days, 61 participants wore an ActiGraph ActiSleep accelerometer (1-second epoch, 10-minute bout) and completed the self-administered Active Australia Survey at baseline, 6-weeks, 6 and 12-months. Total daily moderate-to-vigorous physical activity from both methods was compared using Bland-Altman plots and Spearman rank-order correlations. RESULTS: Participants tended to over-report moderate-to-vigorous physical activity, with more active participants more likely to over-report moderate-to-vigorous physical activity. There was a good level of agreement between the accelerometer 1-second epochs and Active Australia Survey at all time points (mean bias (ratio) 1.04, 1.16, 1.14, and 1.06, respectively), with weak-moderate correlations (ρ = 0.3-0.48). Conversely, there was a poor level of agreement between the accelerometer 10-minute bouts and Active Australia Survey at all time points (mean bias (ratio) 6.78, 9.09, 6.35, and 5.68, respectively), with weak-moderate correlations (ρ = 0.3-0.52). Agreement between the two measures did not improve over time for both 1-second and 10-minute bout accelerometry data. CONCLUSIONS: The Active Australia Survey may be an acceptable self-report measure of moderate-to-vigorous physical activity in cardiac rehabilitation attendees when capturing any time spent in moderate-to-vigorous physical activity. The Active Australia Survey may be useful to routinely monitor physical activity levels over-time in Australian cardiac rehabilitation programs at both individual and group levels. TRIAL REGISTRATION: Trial registration: Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12615000995572, http://www.ANZCTR.org.au/ACTRN12615000995572.aspx.

Parasitic pygopagus conjoined twins' incidental findings in the obstructed labor of an intrapartum dead baby that had undergone emergency C-section: rare case report in South Papua.

BACKGROUND: Conjoined twins (CT), which used to be historically defined as "monstrous human" and previously so-called Siamese twins in the early eighteenth century, are one of the very rare congenital malformations with an uncertain etiology and complex yet remain inconclusively debatable regarding its pathophysiological mechanisms of fusion and fission theories. Among all types of CT, parasitic CT, especially the pygopagus sub-type, is exceedingly rarer. To the best of the authors' knowledge, no parasitic CT had been reported in Papua, and this is the first finding in South Papua. CASE REPORT: Herein, a 30-year-old multigravida female with 37th-week gestation, previous twice spontaneous miscarriage, and non-adequate antenatal care history is presented with a chief complaint of painful construction and greenish fluid leakage from the vagina, with an examination that showed a cephalic presentation with a "peculiar" big mass at the upper uterus and complete cervical dilation toward second-stage inpartu. Vaginal delivery was performed with a complication of obstructed labor due to uncommon dystocia with a suspected "big mass" below the fetal buttocks and intrapartum dead. Intrapartum transabdominal ultrasound demonstrates a gross anatomically like an organ inside a fluid-filled mass with unidentified parts, leading to a suspected type of congenital malformation at the baby's sacral region. Emergency C-section was done with findings of parasitic pygopagus CT, showing an attachment of a large irregular fluid-filled mass-like incomplete twin (parasite) with palpable soft tissue and bony structure inside to the buttocks of a male autosite twin, and an additional third leg which happened to be an under-developed lower extremity with a sacrum-like structure. CONCLUSIONS: An obstetrician's routine ANC and critical radiological evaluation will increase the odds of identifying CT or other congenital malformations to provide better delivery planning or further management. Increasing maternal health knowledge in society, improving medical skills and knowledge levels for health providers, and advancing supporting facilities and specialists are future strategies for managing and preventing such cases in low-middle-income countries.

Metaphyseal trauma of the lower extremities in major orthopedic surgery as an independent risk factor for deep vein thrombosis.

PURPOSE: Major orthopedic surgeries of the lower extremities, which heavily injure the metaphyseal region, are strongly associated with the risk of developing deep vein thrombosis (DVT). This study aims to investigate the role of metaphyseal trauma as an independent risk factor for DVT. METHODS: Patients undergoing major orthopedic surgery of the hip and knee had their existing DVT risk factors recorded. Metaphyseal trauma was defined by the extent of bone injury during these surgeries. The samples were categorized into three surgery groups: total arthroplasty group (TA), hemiarthroplasty group (HA), and the open reduction internal fixation group (ORIF). Logistic regression test between significant existing risk factors and surgery groups determines the independent association between risk factors and DVT. RESULT: The study found a 24.8% incidence of asymptomatic DVT in patients undergoing major orthopedic surgeries, with the highest prevalence (37.2%) in TA, which had the largest extent of metaphyseal trauma and the least existing DVT risk factors. TA showed 6.2 OR and 95% CI (p = 0.036) compared to the other existing risk factor in relation to DVT incidence. CONCLUSION: Metaphyseal bone trauma in the hip and knee major orthopedic surgery is an independent risk factor for deep vein thrombosis.

Atypical twin-to-twin transfusion syndrome case managed in a single centre in Indonesia with fetoscopic laser photocoagulation and amniopatch: 'Case Report'.

Introduction and importance: The diagnostic criteria for Quintero staging in twin-to-twin transfusion syndrome (TTTS) are not applicable in all cases of TTTS, such as those in which the symptoms overlap with other monochorionic twin complications such as selective intrauterine growth restriction (sIUGR). Case presentation: A 25-year-old woman, G1P0A0, at 22-24 weeks' gestational age was diagnosed with TTTS, with no outstanding history of medication use during pregnancy, and no family history of genetic disorder or twin pregnancy. In the donor twin, persistently absent end-diastolic flow in the umbilical artery was observed using Doppler velocimetry. Polyhydramnios was observed in the recipient twins. The fetal weight discordance between the twins was 39%. After 2 weeks of follow-up, the authors performed fetoscopic laser photocoagulation and successfully ablated five vascular anastomoses and amnioreduction by 2.5 l. Five days after the laser surgery, the patient developed amniotic fluid leakage, and an amniopatch was performed. The authors did the caesarean section at 34 weeks because of severe preeclampsia, the donor and recipient birth weights were 1,120 g and 1,837 g, respectively (weight discordance 39%). The APGAR scores were 3/4 and 6/8, respectively. The donor twin died 6 days after delivery due to respiratory failure, and the recipient twin survived. Neonatal echocardiography of the surviving twin showed no tricuspid regurgitation. No long-term follow-up was performed. Clinical discussion: The traditional diagnostic criteria for TTTS stage 3 were not met and overlapped with the diagnostic criteria for sIUGR type 2. This is the first procedure reported in Indonesia for atypical TTTS with the outcome, one twin survived. Conclusion: Some TTTS cases do not meet traditional diagnostic criteria and overlap with other monochorionic twin complications.

Interventions for anxiety and depression in patients with atopic dermatitis: a systematic review and meta-analysis.

Atopic dermatitis (AD) is a chronic inflammatory skin disease that is associated with anxiety and depression. Few studies have addressed interventions for symptoms of anxiety and depression in this population. To determine the efficacy of interventions for anxiety and depression in patients with AD. PubMed, MEDLINE, EMBASE, and PsycINFO were searched from inception to November 2023. English-language studies published in peer-reviewed journals evaluating the effect of interventions on anxiety and/or depression using validated assessment tools on patients with AD were included. Titles, abstracts, and articles were screened by at least two independent reviewers. Of 1410 references that resulted in the initial search, 17 studies were included. Fourteen of these studies are randomized controlled trials, while the other 3 studies are prospective controlled trials with pre and post-test designs. Data were extracted using a standardized extraction form, and the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines were followed. To accommodate trials with multiple interventions (each compared to a control group), we conducted a mixed-effects meta-analysis with the trial as a random effect. Prespecified outcomes were changes in symptoms of anxiety and depression in patients with AD as evaluated using standardized assessment tools. Of the 17 studies included in this systematic review, 7 pharmacological intervention studies with 4723 participants examining 5 different medications were included in a meta-analysis. Of these studies, only 1 study evaluated medications prescribed to treat anxiety and/or depression; the rest evaluated medications prescribed to treat AD. Meta-analysis of all the pharmacological interventions resulted in significant improvement in anxiety, depression, and combined anxiety-depression scale scores (standardized mean difference [95% CI]: - 0.29 [- 0.49 to - 0.09], - 0.27 [- 0.45 to - 0.08], - 0.27 [- 0.45 to - 0.08]) respectively. The 10 non-pharmacological studies with 2058 participants showed general improvement in anxiety but not depression. A meta-analysis of the non-pharmacological interventions was not conducted due to variable approaches and limited data. Pharmacological interventions designed to improve AD were found to improve anxiety and depression in patients with moderate-severe disease. More comprehensive studies on non-pharmacological and pharmacological interventions that primarily target anxiety and depression are needed.

An Indocyanine Green-Based Nanoprobe for In Vivo Detection of Cellular Senescence.

There is an urgent need to improve conventional cancer-treatments by preventing detrimental side effects, cancer recurrence and metastases. Recent studies have shown that presence of senescent cells in tissues treated with chemo- or radiotherapy can be used to predict the effectiveness of cancer treatment. However, although the accumulation of senescent cells is one of the hallmarks of cancer, surprisingly little progress has been made in development of strategies for their detection in vivo. To address a lack of detection tools, we developed a biocompatible, injectable organic nanoprobe (NanoJagg), which is selectively taken up by senescent cells and accumulates in the lysosomes. The NanoJagg probe is obtained by self-assembly of indocyanine green (ICG) dimers using a scalable manufacturing process and characterized by a unique spectral signature suitable for both photoacoustic tomography (PAT) and fluorescence imaging. In vitro, ex vivo and in vivo studies all indicate that NanoJaggs are a clinically translatable probe for detection of senescence and their PAT signal makes them suitable for longitudinal monitoring of the senescence burden in solid tumors after chemotherapy or radiotherapy.

Developing insulin-like peptide 5-based antagonists for the G protein-coupled receptor, RXFP4.

Human insulin-like peptide 5 (INSL5) is a gut hormone produced by colonic L-cells, and its biological functions are mediated by Relaxin Family Peptide Receptor 4 (RXFP4). Our preliminary data indicated that RXFP4 agonists are potential drug leads for the treatment of constipation. More recently, we designed and developed a novel RXFP4 antagonist, A13-nR that was shown to block agonist-induced activity in cells and animal models. We showed that A13-nR was able to block agonist-induced increases in colon motility in mice of both genders that express the receptor, RXFP4. Our data also showed that colorectal propulsion induced by intracolonic administration of short-chain fatty acids was antagonized by A13-nR. Therefore, A13-nR is an important research tool and potential drug lead for the treatment of colon motility disorders, such as bacterial diarrhea. However, A13-nR acted as a partial agonist at high concentrations in vitro and demonstrated modest antagonist potency (∼35 nM). Consequently, the primary objective of this study is to pinpoint novel modifications to A13-nR that eliminate partial agonist effects while preserving or augmenting antagonist potency. In this work, we detail the creation of a series of A13-nR-modified analogues, among which analogues 3, 4, and 6 demonstrated significantly improved RXFP4 affinity (∼3 nM) with reduced partial agonist activity, enhanced antagonist potency (∼10 nM) and maximum agonist inhibition (∼80 %) when compared with A13-nR. These compounds have potential as candidates for further preclinical evaluations, marking a significant stride toward innovative therapeutics for colon motility disorders.

Enzalutamide induces cytotoxicity in desmoplastic small round cell tumor independent of the androgen receptor.

Desmoplastic Small Round Cell Tumor (DSRCT) is a rare, pediatric cancer caused by the EWSR1::WT1 fusion protein. DSRCT predominantly occurs in males, which comprise 80-90% of the patient population. While the reason for this male predominance remains unknown, one hypothesis is that the androgen receptor (AR) plays a critical role in DSRCT and elevated testosterone levels in males help drive tumor growth. Here, we demonstrate that AR is highly expressed in DSRCT relative to other fusion-driven sarcomas and that the AR antagonists enzalutamide and flutamide reduce DSRCT growth. However, despite these findings, which suggest an important role for AR in DSRCT, we show that DSRCT cell lines form xenografts in female mice at the same rate as male mice and AR depletion does not significantly alter DSRCT growth in vitro. Further, we find that AR antagonists reduce DSRCT growth in cells depleted of AR, establishing an AR-independent mechanism of action. These findings suggest that AR dependence is not the reason for male predominance in DSRCT and that AR-targeted therapies may provide therapeutic benefit primarily through an AR-independent mechanism that requires further elucidation.

Comprehensive Transcriptomic Analysis of EWSR1::WT1 Targets Identifies CDK4/6 Inhibitors as an Effective Therapy for Desmoplastic Small Round Cell Tumors.

Desmoplastic small round cell tumors (DSRCT) are a type of aggressive, pediatric sarcoma characterized by the EWSR1::WT1 fusion oncogene. Targeted therapies for DSRCT have not been developed, and standard multimodal therapy is insufficient, leading to a 5-year survival rate of only 15% to 25%. Here, we depleted EWSR1::WT1 in DSRCT and established its essentiality in vivo. Transcriptomic analysis revealed that EWSR1::WT1 induces unique transcriptional alterations compared with WT1 and other fusion oncoproteins and that EWSR1::WT1 binding directly mediates gene upregulation. The E-KTS isoform of EWSR1::WT1 played a dominant role in transcription, and it bound to the CCND1 promoter and stimulated DSRCT growth through the cyclin D-CDK4/6-RB axis. Treatment with the CDK4/6 inhibitor palbociclib successfully reduced growth in two DSRCT xenograft models. As palbociclib has been approved by the FDA for the treatment of breast cancer, these findings demonstrate the sensitivity of DSRCT to palbociclib and support immediate clinical investigation of palbociclib for treating this aggressive pediatric cancer. SIGNIFICANCE: EWSR1::WT1 is essential for desmoplastic small round cell tumors and upregulates the cyclin D-CDK4/6-RB axis that can be targeted with palbociclib, providing a targeted therapeutic strategy for treating this deadly tumor type.