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Mei Sian Chong,1 Keng Teng Tan,2 Laura Tay,1 Yoke Moi Wong,1 Sonia Ancoli-Israel3,41Department of Geriatric Medicine, Tan Tock Seng Hospital, Singapore; 2Department of Pharmacy, Tan Tock Seng Hospital, Singapore; 3Departments of Psychiatry and Medicine, University of California, San Diego, CA, USA; 4VA Center of Excellence for Stress and Mental Health (CESAMH), San Diego, CA, USAObjective: Delirium is associated with poor outcomes following acute hospitalization. A specialized delirium management unit, the Geriatric Monitoring Unit (GMU), was established. Evening bright light therapy (2000–3000 lux; 6–10 pm daily) was added as adjunctive treatment, to consolidate circadian activity rhythms and improve sleep. This study examined whether the GMU program improved sleep, cognitive, and functional outcomes in delirious patients.Method: A total of 228 patients (mean age = 84.2 years) were studied. The clinical characteristics, delirium duration, delirium subtype, Delirium Rating Score (DRS), cognitive status (Chinese Mini–Mental State Examination), functional status (modified Barthel Index [MBI]), and chemical restraint use during the initial and predischarge phase of the patient’s GMU admission were obtained. Nurses completed hourly 24-hour patient sleep logs, and from these, the mean total sleep time, number of awakenings, and sleep bouts (SB) were computed.Results: The mean delirium duration was 6.7 ± 4.6 days. Analysis of the delirium subtypes showed that 18.4% had hypoactive delirium, 30.2% mixed delirium, and 51.3% had hyperactive delirium. There were significant improvements in MBI scores, especially for the hyperactive and mixed delirium subtypes (P < 0.05). Significant improvements were noted on the DRS sleep–wake disturbance subscore, for all delirium-subtypes. The mean total sleep time (7.7 from 6.4 hours) (P < 0.05) and length of first SB (6.0 compared with 5.3 hours) (P < 0.05) improved, with decreased mean number of SBs and awakenings. The sleep improvements were mainly seen in the hyperactive delirium subtype.Conclusion: This study shows initial evidence for the clinical benefits (longer total sleep time, increased first SB length, and functional gains) of incorporating bright light therapy as part of a multicomponent delirium management program. The benefits appear to have occurred mainly in patients with hyperactive delirium, which merits further in-depth, randomized controlled studies.Keywords: sleep, delirium, function, elderly

Herba Epimedii, Fructus Ligustri Lucidi and Fructus Psoraleae are three frequently used Chinese herbs traditionally used for tonifying the 'kidney system'. They were selected for the present study to formulate an herbal preparation with a weight ratio of 5:4:1 based on their phytochemical, nature, documented treatment efficacy and toxicity. The dosing effects (1 g/day, 0.5 g/day and 0.175 g/day) of the antiosteoporosis function of the water extract of this formula were tested in ovariectomy- and calcium deficiency-induced osteoporotic rats. Eleven weeks of herbal treatment demonstrated a beneficial effect on the preservation of bone mineral density (BMD) at the femur neck in a dose-dependent manner with the preference for higher dosage. No significant increase in uterus weight was observed in the herbal formula treated rats. In addition, microarray data of kidney tissue revealed that this herbal formula was able to down-regulate the expression of phase II drug metabolizing enzymes, similar to the effects of estrogens. [ABSTRACT FROM AUTHOR]

Introduction: Early diagnosis of Severe Combined Immunodeficiency (SCID) increases survival outcomes and quality of life while significantly minimizing healthcare burden and costs. Despite growing evidence supporting the benefits and cost-effectiveness of SCID detection through newborn screening (NBS), it has yet to be implemented in Malaysia. This study aims to explore experts' opinions on the current status, challenges, and crucial strategies needed for the successful implementation of SCID NBS., Methodology: A guided, structured interview was employed to explore opinions on the current status, barriers, and strategies for implementing SCID NBS in Malaysia. All 13 invited experts participated in this study, indicating complete participation from the entire Malaysian immunology fraternity (consisting of eight clinical immunologists and five immunopathologists)., Key Findings: Several initiatives are ongoing to establish SCID NBS in Malaysia. Hindrances such as low immunologist-to-patient ratio, unequal placements of immunologists throughout Malaysia, society's low disease awareness, national health prioritization, lack of stakeholder engagement, and inadequacy of local study/data were highlighted. Pilot research on SCID NBS, advocacy workshops, and promotion materials are among the ongoing activities outlined in the blueprint, paving the way for this nationwide NBS program to be achievable in the near future., Conclusion: This article provides recommendations to policymakers in mandating SCID NBS. Strategies by key stakeholders are underway, particularly in advocacy programs and efforts to increase awareness among clinicians and the public., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Chang, Mohd Noh, Abdul Latiff, Woo, Ismail, Abd Hamid, Siniah, Zainal Abidin, Sham, Mat Ripen, Baharin, Abdul Wahab, Zainudeen, Hashim, Wong, Ahmad Shawaludin and Ali.)

Background: Participation in everyday activities is beneficial for mental health. However, little is known about the extent to which changes in children's participation are associated with later mental health., Objectives: To investigate the association between changes in the frequency and involvement in home, school, and community activities and subsequent mental health problems in children. Methodology: We recruited 242 school-aged children. Their parents completed the Participation and Environment Measure for Children and Youth twice, and after 2 years, they completed the Strengths and Difficulties Questionnaire., Results: After controlling for demographic factors, hierarchical regression analysis revealed that reductions in children's involvement in home and community activities were significantly associated with elevated levels of externalizing and internalizing problems. Furthermore, an increase in children's involvement in school activities showed significant relationships with better mental health outcomes., Conclusion: These findings inform participation-based interventions for occupational therapists aimed at mitigating children's future mental health problems., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background and Purpose: Despite the superior dose conformity of proton therapy, the dose distribution is sensitive to daily anatomical changes, which can affect treatment accuracy. This study evaluated the dose recalculation accuracy of two synthetic computed tomography (sCT) generation algorithms in a commercial treatment planning system., Materials and Methods: The evaluation was conducted for head-and-neck, thorax-and-abdomen, and pelvis sites treated with proton therapy. Thirty patients with two cone-beam computed tomography (CBCT) scans each were selected. The sCT images were generated from CBCT scans using two algorithms, Corrected CBCT (corrCBCT) and Virtual CT (vCT). Dose recalculations were performed based on these images for comparison with "ground truth" deformed CTs., Results: The choice of algorithm influenced dose recalculation accuracy, particularly in high dose regions. For head-and-neck cases, the corrCBCT method showed closer agreement with the "ground truth", while for thorax-and-abdomen and pelvis cases, the vCT algorithm yielded better results (mean percentage dose discrepancy of 0.6 %, 1.3 % and 0.5 % for the three sites, respectively, in the high dose region). Head-and-neck and pelvis cases exhibited excellent agreement in high dose regions (2 %/2 mm gamma passing rate >98 %), while thorax-and-abdomen cases exhibited the largest differences, suggesting caution in sCT algorithm usage for this site. Significant systematic differences were observed in the clinical target volume and organ-at-risk doses in head-and-neck and pelvis cases, highlighting the importance of using the correct algorithm., Conclusions: This study provided treatment site-specific recommendations for sCT algorithm selection in proton therapy. The findings offered insights for proton beam centers implementing adaptive radiotherapy workflows., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Author(s).)

The impact of gestational diabetes mellitus (GDM) on maternal or infant microbiome trajectory remains poorly understood. Utilizing large-scale longitudinal fecal samples from 264 mother-baby dyads, we present the gut microbiome trajectory of the mothers throughout pregnancy and infants during the first year of life. GDM mothers had a distinct microbiome diversity and composition during the gestation period. GDM leaves fingerprints on the infant's gut microbiome, which are confounded by delivery mode. Further, Clostridium species positively correlate with a larger head circumference at month 12 in male offspring but not females. The gut microbiome of GDM mothers with male fetuses displays depleted gut-brain modules, including acetate synthesis I and degradation and glutamate synthesis II. The gut microbiome of female infants of GDM mothers has higher histamine degradation and dopamine degradation. Together, our integrative analysis indicates that GDM affects maternal and infant gut composition, which is associated with sexually dimorphic infant head growth., Competing Interests: Declaration of interests F.K.L.C. is a board member of CUHK Medical Centre. He is a co-founder, non-executive board chairman, and shareholder of GenieBiome Ltd. He receives patent royalties through his affiliated institutions. He has received fees as an advisor and honoraria as a speaker for EISAI Co. Ltd, AstraZeneca, Pfizer Inc., Takeda Pharmaceutical Co., and Takeda (China) Holdings Co. Ltd. S.C.N. has served as an advisory board member for Pfizer, Ferring, Janssen, and AbbVie and received honoraria as a speaker for Ferring, Tillotts, Menarini, Janssen, AbbVie, and Takeda. S.C.N. has received research grants through her affiliated institutions from Olympus, Ferring, and AbbVie. S.C.N. is a scientific co-founder and shareholder of GenieBiome Ltd. S.C.N. receives patent royalties through her affiliated institutions. F.K.L.C., S.C.N., L.Z., and H.M.T. are named inventors of patent applications held by the CUHK and MagIC that cover the therapeutic and diagnostic use of the microbiome., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Daily quality assurance is an integral part of a radiotherapy workflow to ensure the dose is delivered safely and accurately to the patient. It is performed before the first treatment of the day and needs to be time and cost efficient for a multiple gantries proton center. In this study, we introduced an efficient method to perform QA for output constancy, range verification, spot positioning accuracy and imaging and proton beam isocenter coincidence with DailyQA3., Methods: A stepped acrylic block of specific dimensions is fabricated and placed on top of the DailyQA3 device. Treatment plans comprising of two different spread-out Bragg peaks and five individual spots of 1.0 MU each are designed to be delivered to the device. A mathematical framework to measure the 2D distance between the detectors and individual spot is introduced and play an important role in realizing the spot positioning and centering QA. Lastly, a 5 months trends of the QA for two gantries are presented., Results: The outputs are monitored by two ion chambers in the DailyQA3 and a tolerance of ± 3 % $ \pm 3\% $ are used. The range of the SOBPs are monitored by the ratio of ion chamber signals and a tolerance of ± 1 mm $ \pm 1\ {\mathrm{mm}}$ is used. Four diodes at ± 10 cm $ \pm 10\ {\mathrm{cm}}$ from the central ion chambers are used for spot positioning QA, while the central ion chamber is used for imaging and proton beam isocenter coincidence QA. Using the framework, we determined the absolute signal threshold corresponding to the offset tolerance between the individual proton spot and the detector. A 1.5 mm $1.5\ {\mathrm{mm}}$ tolerances are used for both the positioning and centering QA. No violation of the tolerances is observed in the 5 months trends for both gantries., Conclusion: With the proposed approach, we can perform four QA items in the TG224 within 10 min., (© 2024 The Authors. Journal of Applied Clinical Medical Physics is published by Wiley Periodicals, Inc. on behalf of The American Association of Physicists in Medicine.)

Objective. The validation of deformable image registration (DIR) for contour propagation is often done using contour-based metrics. Meanwhile, dose accumulation requires evaluation of voxel mapping accuracy, which might not be accurately represented by contour-based metrics. By fabricating a deformable anthropomorphic pelvis phantom, we aim to (1) quantify the voxel mapping accuracy for various deformation scenarios, in high- and low-contrast regions, and (2) identify any correlation between dice similarity coefficient (DSC), a commonly used contour-based metric, and the voxel mapping accuracy for each organ. Approach . Four organs, i.e. pelvic bone, prostate, bladder and rectum (PBR), were 3D printed using PLA and a Polyjet digital material, and assembled. The latter three were implanted with glass bead and CT markers within or on their surfaces. Four deformation scenarios were simulated by varying the bladder and rectum volumes. For each scenario, nine DIRs with different parameters were performed on RayStation v10B. The voxel mapping accuracy was quantified by finding the discrepancy between true and mapped marker positions, termed the target registration error (TRE). Pearson correlation test was done between the DSC and mean TRE for each organ. Main results . For the first time, we fabricated a deformable phantom purely from 3D printing, which successfully reproduced realistic anatomical deformations. Overall, the voxel mapping accuracy dropped with increasing deformation magnitude, but improved when more organs were used to guide the DIR or limit the registration region. DSC was found to be a good indicator of voxel mapping accuracy for prostate and rectum, but a comparatively poorer one for bladder. DSC > 0.85/0.90 was established as the threshold of mean TRE ⩽ 0.3 cm for rectum/prostate. For bladder, extra metrics in addition to DSC should be considered. Significance . This work presented a 3D printed phantom, which enabled quantification of voxel mapping accuracy and evaluation of correlation between DSC and voxel mapping accuracy., (© 2024 Institute of Physics and Engineering in Medicine.)

Introduction: Clinical guidelines can contribute to medication errors but there is no overall understanding of how and where these occur., Objectives: We aimed to identify guideline-related medication errors reported via a national incident reporting system, and describe types of error, stages of medication use, guidelines, drugs, specialties and clinical locations most commonly associated with such errors., Methods: Retrospective analysis of reports to the National Reporting and Learning System for England and Wales. A hierarchical task analysis (HTA) was developed, describing expected practice when using guidelines. A free-text search was conducted of medication incident reports (2016-2021) using search terms related to common guidelines. All identified reports linked to moderate-severe harm or death, and a random sample of 5100 no/low-harm reports were coded to describe deviations from the HTA. A random sample of 500 cases were independently double-coded., Results: In total, 28,217 reports were identified, with 608 relating to moderate-severe harm or death. Fleiss' kappa for interrater reliability was 0.46. Of the 5708 reports coded, 642 described an HTA step discrepancy (including four linked to a death), suggesting over 3200 discrepancies in the entire dataset of 28,217 reports. Discrepancies related to finding guidelines (n = 300 reports), finding information within guidelines (n = 166) and using information (n = 176). Discrepancies were most frequently identified for guidelines produced by a local organisation (n = 405), and most occurred during prescribing (n = 277) or medication administration (n = 241)., Conclusion: Difficulties finding and using information from clinical guidelines contribute to thousands of prescribing and medication administration incidents, some of which are associated with substantial patient harm., (© 2024. The Author(s).)

Background and Purpose: High-density dental fillings pose a non-negligible impact on head and neck cancer treatment. For proton therapy, stopping power ratio (SPR) prediction will be significantly impaired by the associated image artifacts. Dose perturbation is also inevitable, compromising the treatment plan quality. While plenty of work has been done on metal or amalgam fillings, none has touched on composite resin (CR) and glass ionomer cement (GIC) which have seen an increasing usage. Hence, this work aims to provide a detailed characterisation of SPR and dose perturbation in proton therapy caused by CR and GIC., Materials and Methods: Four types of fillings were used: CR, Fuji Bulk (FB), Fuji II (FII) and Fuji IX (FIX). The latter three belong to GIC category. Measured SPR were compared with SPR predicted using single-energy computed tomography (SECT) and dual-energy computed tomography (DECT). Dose perturbation of proton beams with lower- and higher-energy levels was also quantified using Gafchromic films., Results: The measured SPR for CR, FB, FII and FIX were 1.68, 1.77, 1.77 and 1.76, respectively. Overall, DECT could predict SPR better than SECT. The lowest percentage error achieved by DECT was 19.7 %, demonstrating the challenge in estimating SPR, even for fillings with relatively lower densities. For both proton beam energies and all four fillings of about 4.5 mm thickness, the maximum dose perturbation was 3 %., Conclusion: This study showed that dose perturbation by CR and GIC was comparatively small. We have measured and recommended the SPR values for overriding the fillings in TPS., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Author(s).)

Background: Tolerance limit is defined on pre-treatment patient specific quality assurance results to identify "out of the norm" dose discrepancy in plan. An out-of-tolerance plan during measurement can often cause treatment delays especially if replanning is required. In this study, we aim to develop an outlier detection model to identify out-of-tolerance plan early during treatment planning phase to mitigate the above-mentioned risks., Methods: Patient-specific quality assurance results with portal dosimetry for stereotactic body radiotherapy measured between January 2020 and December 2021 were used in this study. Data were divided into thorax and pelvis sites and gamma passing rates were recorded using 2%/2 mm, 2%/1 mm, and 1%/1 mm gamma criteria. Statistical process control method was used to determine six different site and criterion-specific tolerance and action limits. Using only the inliers identified with our determined tolerance limits, we trained three different outlier detection models using the plan complexity metrics extracted from each treatment field-robust covariance, isolation forest, and one class support vector machine. The hyperparameters were optimized using the F1-score calculated from both the inliers and validation outliers' data., Results: 308 pelvis and 200 thorax fields were used in this study. The tolerance (action) limits for 2%/2 mm, 2%/1 mm, and 1%/1 mm gamma criteria in the pelvis site are 99.1% (98.1%), 95.8% (91.1%), and 91.7% (86.1%), respectively. The tolerance (action) limits in the thorax site are 99.0% (98.7%), 97.0% (96.2%), and 91.5% (87.2%). One class support vector machine performs the best among all the algorithms. The best performing model in the thorax (pelvis) site achieves a precision of 0.56 (0.54), recall of 1.0 (1.0), and F1-score of 0.72 (0.70) when using the 2%/2 mm (2%/1 mm) criterion., Conclusion: The model will help the planner to identify an out-of-tolerance plan early so that they can refine the plan further during the planning stage without risking late discovery during measurement., (© 2023 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, LLC on behalf of The American Association of Physicists in Medicine.)

Introduction: Computed tomography angiography of the aorta (CTAA) is the modality of choice for investigating aortic disease. Our aim was to evaluate the image quality, contrast enhancement and radiation dose of electrocardiograph (ECG)-triggered and non-ECG-triggered CTAA on a 256-slice single-source CT scanner. This allows the requesting clinician and the radiologist to balance radiation risk and image quality., Methods: We retrospectively assessed the data of 126 patients who had undergone CTAA on a single-source CT scanner using ECG-triggered (group 1, n = 77) or non-ECG-triggered (group 2, n = 49) protocols. Radiation doses were compared. Qualitative (4-point scale) and quantitative image quality assessments were performed., Results: The mean volume CT dose index, dose length product and effective dose in group 1 were 12.4 ± 1.9 mGy, 765.8 ± 112.4 mGy cm and 13.0 ± 1.9 mSv, respectively. These were significantly higher compared to group 2 values (9.1 ± 2.6 mGy, 624.1 ± 174.8 mGy cm and 10.6 ± 3.0 mSv, respectively) ( P < 0.001). Qualitative assessment showed the image quality at the aortic root-proximal ascending aorta was significantly higher in group 1 (median 3) than in group 2 (median 2, P < 0.001). Quantitative assessment showed significantly better mean arterial attenuation, signal-to-noise ratio and contrast-to-noise ratio in ECG-triggered CTAA compared to non-ECG-triggered CTAA., Conclusion: ECG-triggered CTAA in a single-source scanner has superior image quality and vessel attenuation of aortic root/ascending aorta, but a higher radiation dose of approximately 23%. Its use should be considered specifically when assessing aortic root/ascending aorta pathology., (Copyright © 2024 Copyright: © 2024 Singapore Medical Journal.)

Chronic pain management poses a formidable challenge to healthcare, exacerbated by current analgesic options' limitations and adverse effects. Transient receptor potential vanilloid 1 (TRPV1), a non-selective cation channel, has emerged as a promising target for novel analgesics. However, safety and tolerability concerns have constrained the development of TRPV1 modulators. In this study, we explored marine-derived natural products as a source of potential TRPV1 modulators using high-throughput dye-uptake assays. We identified chrexanthomycins, a family of hexacyclic xanthones, exhibited potent TRPV1 inhibitory effects, with compounds cC and cF demonstrating the most significant activity. High-resolution patch-clamp assays confirmed the direct action of these compounds on the TRPV1 channel. Furthermore, in vivo assays revealed that cC and cF effectively suppressed capsaicin-induced pain sensation in mice, comparable to the known TRPV1 inhibitor, capsazepine. Structural-activity relationship analysis highlighted the importance of specific functional groups in modulating TRPV1 activity. Our findings underscore the therapeutic potential of chrexanthomycins and pave the way for further investigations into marine-derived TRPV1 modulators for pain management., Competing Interests: Declaration of competing interest The authors declare the following competing interests. This work has been submitted for U.S. Patent Application (No. 63/498,526). The authors declare no other conflicts of interest., (Copyright © 2023. Published by Elsevier B.V.)

Purpose: To evaluate the functional and structural changes of the meibomian glands and ocular surface in immunoglobulin G4-related ophthalmic disease (IgG4-ROD) patients., Design: Cross-sectional, matched case-control comparison study., Methods: This study included 64 patients with biopsy-proven IgG4-ROD (aged 63.4 ± 12.2 years, 39 male) and 64 sex- and age-matched healthy controls. Patients were managed by hospitals covering the publicly funded ophthalmology service in Hong Kong. Outcome measures included anterior segment examination and keratographic and meibographic imagings., Results: A total of 64 worst-affected eyes of the 64 IgG4-ROD patients were analyzed. Corneal fluorescein staining (P = .0187), lid margin telangiectasia (P = .0360), lid-parallel conjunctival folds (P = .0112), papillae (P = .0393), meibomian gland plugging (P = .0001), meibomian gland expressibility (P = .0001), and meibum quality (P = .0001) were more significant in IgG4-ROD patients compared with healthy controls. Both upper and lower meibomian gland dropouts (P = .001 and .0003), and tear meniscus height (P = .0001) were higher in IgG4-ROD patients. Non-invasive tear break-up time (NITBUT) (P = .0166) and Schirmer test results (P = .0243) were lower in IgG4-ROD patients. Upper (r = 0.336, P = .0140) meibomian gland dropouts and NITBUT (r = -0.293, P = .0497) were positively and negatively correlated with the IgG4-ROD onset age, respectively. The number of extraocular organ involvement was negatively correlated with the Schirmer test(r = -0.341, P = .0167). Lower NITBUT was found in IgG4-ROD eyes with lacrimal gland enlargement than in IgG4-ROD eyes without lacrimal gland enlargement radiologically (P < .0001)., Conclusions: IgG4-ROD patients showed features of both aqueous tear deficiency and evaporative dry eye disease. We recommend ocular surface evaluation to all patients newly diagnosed with IgG4-ROD. Further studies are warranted to clarify the mechanism of IgG4-related dry eye disease., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective . Automatic deformable image registration (DIR) is a critical step in adaptive radiotherapy. Manually delineated organs-at-risk (OARs) contours on planning CT (pCT) scans are deformably registered onto daily cone-beam CT (CBCT) scans for delivered dose accumulation. However, evaluation of registered contours requires human assessment, which is time-consuming and subjects to high inter-observer variability. This work proposes a deep learning model that allows accurate prediction of Dice similarity coefficients (DSC) of registered contours in prostate radiotherapy. Approach . Our dataset comprises 20 prostate cancer patients with 37-39 daily CBCT scans each. The pCT scans and planning contours were deformably registered to each corresponding CBCT scan to generate virtual CT (vCT) scans and registered contours. The DSC score, which is a common contour-based validation metric for registration quality, between the registered and manual contours were computed. A Siamese neural network was trained on the vCT-CBCT image pairs to predict DSC. To assess the performance of the model, the root mean squared error (RMSE) between the actual and predicted DSC were computed. Main results . The model showed promising results for predicting DSC, giving RMSE of 0.070, 0.079 and 0.118 for rectum, prostate, and bladder respectively on the holdout test set. Clinically, a low RMSE implies that the predicted DSC can be reliably used to determine if further DIR assessment from physicians is required. Considering the event where a registered contour is classified as poor if its DSC is below 0.6 and good otherwise, the model achieves an accuracy of 92% for the rectum. A sensitivity of 0.97 suggests that the model can correctly identify 97% of poorly registered contours, allowing manual assessment of DIR to be triggered. Significance . We propose a neural network capable of accurately predicting DSC of deformably registered OAR contours, which can be used to evaluate eligibility for plan adaptation., (Creative Commons Attribution license.)

Central serous chorioretinopathy (CSCR), first described by Albrecht von Graefe in 1866, is characterized by focal serous detachment of the neural retina and/or retinal pigment epithelium (RPE) in the posterior pole. CSCR is the first ever described pachychoroid disease. Most recently, hypothetical venous overload choroidopathy is also proposed due to its distinguished morphological and pathological characteristics, including choroidal thickening, choriocapillaris hyperpermeability, remodelling, and intervortex venous anastomoses. Identification of genetic variants is necessary to comprehend the pathophysiology of CSCR. The novel multimodality imaging platforms, including the ultra-widefield imaging system, flavoprotein fluorescence, fluorescence lifetime imaging ophthalmoscopy, and multispectral imaging system, have been used for diagnosing and managing CSCR. Half-dose photodynamic therapy (PDT) remains the mainstay of clinical practice, with about 95% of patients with chronic CSCR improving to visual acuity (VA) of 20/30 or better. The use of oral eplerenone for routine clinical care remains controversial, and long-term randomized clinical trials are warranted to investigate its efficacy in acute and chronic CSCR. While CSCR has generally been recognized as a self-limiting disease with good prognosis, the underlying pathogenesis is still not fully understood, and treatments are often not fully effective. With new evidence emerging about pachydrusen being a disease precursor in both CSCR and polypoidal choroidal vasculopathy (PCV), it would be interesting to investigate whether CSCR can be a precursor to PCV. In this review, we highlighted the currently available evidence on the pathogenesis, diagnosis, multimodality imaging features, and management strategies, including recent findings related to CSCR., (© 2023. The Author(s).)

Competing Interests: The authors declare no conflict of interest.

Background: Modern patient electronic health records form a core part of primary care; they contain both clinical codes and free text entered by the clinician. Natural language processing (NLP) could be employed to generate these records through 'listening' to a consultation conversation., Objectives: This study develops and assesses several text classifiers for identifying clinical codes for primary care consultations based on the doctor-patient conversation. We evaluate the possibility of training classifiers using medical code descriptions, and the benefits of processing transcribed speech from patients as well as doctors. The study also highlights steps for improving future classifiers., Methods: Using verbatim transcripts of 239 primary care consultation conversations (the 'One in a Million' dataset) and novel additional datasets for distant supervision, we trained NLP classifiers (naïve Bayes, support vector machine, nearest centroid, a conventional BERT classifier and few-shot BERT approaches) to identify the International Classification of Primary Care-2 clinical codes associated with each consultation., Results: Of all models tested, a fine-tuned BERT classifier was the best performer. Distant supervision improved the model's performance (F1 score over 16 classes) from 0.45 with conventional supervision with 191 labelled transcripts to 0.51. Incorporating patients' speech in addition to clinician's speech increased the BERT classifier's performance from 0.45 to 0.55 F1 (p=0.01, paired bootstrap test)., Conclusions: Our findings demonstrate that NLP classifiers can be trained to identify clinical area(s) being discussed in a primary care consultation from audio transcriptions; this could represent an important step towards a smart digital assistant in the consultation room., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

This paper aims to review on fetal dose in radiotherapy and extends and updates on a previous work 1 to include proton therapy. Out-of-field doses, which are the doses received by regions outside of the treatment field, are unavoidable regardless of the treatment modalities used during radiotherapy. In the case of pregnant patients, fetal dose is a major concern as it has long been recognized that fetuses exposed to radiation have a higher probability of suffering from adverse effects such as anatomical malformations and even fetal death, especially when the 0.1Gy threshold is exceeded. In spite of the low occurrence of cancer during pregnancy, the radiotherapy team should be equipped with the necessary knowledge to deal with fetal dose. This is crucial so as to ensure that the fetus is adequately protected while not compromising the patient treatment outcomes. In this review paper, various aspects of fetal dose will be discussed ranging from biological, clinical to the physics aspects. Other than fetal dose resulting from conventional photon therapy, this paper will also extend the discussion to modern treatment modalities and techniques, namely proton therapy and image-guided radiotherapy, all of which have seen a significant increase in use in current radiotherapy. This review is expected to provide readers with a comprehensive understanding of fetal dose in radiotherapy, and to be fully aware of the steps to be taken in providing radiotherapy for pregnant patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Associazione Italiana di Fisica Medica e Sanitaria. Published by Elsevier Ltd. All rights reserved.)

Objective: To evaluate the impact of pre-operative contrast-enhanced mammography (CEM) in breast cancer patients with dense breasts., Methods: We conducted a retrospective review of 232 histologically proven breast cancers in 200 women (mean age: 53.4 years ± 10.2) who underwent pre-surgical CEM imaging across two Asian institutions (Singapore and Taiwan). Majority (95.5%) of patients had dense breast tissue (BI-RADS category C or D). Surgical decision was recorded in a simulated blinded multi-disciplinary team setting on two separate scenarios: (i) pre-CEM setting with standard imaging, and clinical and histopathological results; and (ii) post-CEM setting with new imaging and corresponding histological findings from CEM. Alterations in surgical plan (if any) because of CEM imaging were recorded. Predictors CEM of patients who benefitted from surgical plan alterations were evaluated using logistic regression., Results: CEM resulted in altered surgical plans in 36 (18%) of 200 patients in this study. CEM discovered clinically significant larger tumor size or extent in 24 (12%) patients and additional tumors in 12 (6%) patients. CEM also detected additional benign/false-positive lesions in 13 (6.5%) of the 200 patients. Significant predictors of patients who benefitted from surgical alterations found on multivariate analysis were pre-CEM surgical decision for upfront breast conservation (OR, 7.7; 95% CI, 1.9-32.1; p = 0.005), architectural distortion on mammograms (OR, 7.6; 95% CI, 1.3-42.9; p = .022), and tumor size of ≥ 1.5 cm (OR, 1.5; 95% CI, 1.0-2.2; p = .034)., Conclusion: CEM is an effective imaging technique for pre-surgical planning for Asian breast cancer patients with dense breasts., Key Points: • CEM significantly altered surgical plans in 18% (nearly 1 in 5) of this Asian study cohort with dense breasts. • Significant patient and imaging predictors for surgical plan alteration include (i) patients considered for upfront breast-conserving surgery; (ii) architectural distortion lesions; and (iii) tumor size of ≥ 1.5 cm. • Additional false-positive/benign lesions detected through CEM were uncommon, affecting only 6.5% of the study cohort., (© 2022. The Author(s).)

There are concerns about the cultural validity of applying developmental screeners developed and normed in Western countries to other sociocultural contexts. Given the scarcity of culturally validated developmental checklists for use among Chinese children, the Hong Kong Society for the Protection of Children (HKSPC) has developed the HKSPC Developmental Checklist (HKSPC-DC) for preschool teachers to identify children at risk of developmental delays through daily observation of children's functioning at school. This study explored the psychometric properties of the HKSPC-DC among 1183 preschool children aged 2-6 recruited from 14 nursery schools in Hong Kong. The HKSPC-DC showed excellent internal consistency, good interrater and test-retest reliabilities, and acceptable concurrent validity when correlated with the Taipei City Developmental Checklist for Preschoolers (Taipei II), which is the only screening instrument developed in a Chinese society and validated across 4- to 72-month-olds. The HKSPC-DC also showed good discriminatory power in identifying preschoolers potentially at risk of developmental delays. This screening tool may help facilitate early identification of children with developmental vulnerabilities in Chinese preschool populations.

Background Lumbar spine MRI studies are widely used for back pain assessment. Interpretation involves grading lumbar spinal stenosis, which is repetitive and time consuming. Deep learning (DL) could provide faster and more consistent interpretation. Purpose To assess the speed and interobserver agreement of radiologists for reporting lumbar spinal stenosis with and without DL assistance. Materials and Methods In this retrospective study, a DL model designed to assist radiologists in the interpretation of spinal canal, lateral recess, and neural foraminal stenoses on lumbar spine MRI scans was used. Randomly selected lumbar spine MRI studies obtained in patients with back pain who were 18 years and older over a 3-year period, from September 2015 to September 2018, were included in an internal test data set. Studies with instrumentation and scoliosis were excluded. Eight radiologists, each with 2-13 years of experience in spine MRI interpretation, reviewed studies with and without DL model assistance with a 1-month washout period. Time to diagnosis (in seconds) and interobserver agreement (using Gwet κ) were assessed for stenosis grading for each radiologist with and without the DL model and compared with test data set labels provided by an external musculoskeletal radiologist (with 32 years of experience) as the reference standard. Results Overall, 444 images in 25 patients (mean age, 51 years ± 20 [SD]; 14 women) were evaluated in a test data set. DL-assisted radiologists had a reduced interpretation time per spine MRI study, from a mean of 124-274 seconds (SD, 25-88 seconds) to 47-71 seconds (SD, 24-29 seconds) ( P < .001). DL-assisted radiologists had either superior or equivalent interobserver agreement for all stenosis gradings compared with unassisted radiologists. DL-assisted general and in-training radiologists improved their interobserver agreement for four-class neural foraminal stenosis, with κ values of 0.71 and 0.70 (with DL) versus 0.39 and 0.39 (without DL), respectively (both P < .001). Conclusion Radiologists who were assisted by deep learning for interpretation of lumbar spinal stenosis on MRI scans showed a marked reduction in reporting time and superior or equivalent interobserver agreement for all stenosis gradings compared with radiologists who were unassisted by deep learning. © RSNA, 2022 Online supplemental material is available for this article . See also the editorial by Hayashi in this issue.

As hospital systems plan for health care utilization surges and stress, understanding the necessary resources of a trauma system is essential for planning capacity. We aimed to describe trends in high-intensity resource utilization (operating room [OR] usage and intensive care unit [ICU] admissions) for trauma care during the initial months of the COVID-19 pandemic. Trauma registry data (2019 pre-COVID-19 and 2020 COVID-19) were collected retrospectively from 4 level I trauma centers. Direct emergency department (ED) disposition to the OR or ICU was used as a proxy for high-intensity resource utilization. No change in the incidence of direct ED to ICU or ED to OR utilization was observed (2019: 24%, 2020 23%; P = .62 and 2019: 11%, 2020 10%; P = .71, respectively). These results suggest the need for continued access to ICU space and OR theaters for traumatic injury during national health emergencies, even when levels of trauma appear to be decreasing.

Background: Results from single-region studies suggest that stay at home orders (SAHOs) had unforeseen consequences on the volume and patterns of traumatic injury during the initial months of the Coronavirus disease 2019 (COVID-19). The aim of this study was to describe, using a multi-regional approach, the effects of COVID-19 SAHOs on trauma volume and patterns of traumatic injury in the US., Methods: A retrospective cohort study was performed at four verified Level I trauma centers spanning three geographical regions across the United States (US). The study period spanned from April 1, 2020 - July 31, 2020 including a month-matched 2019 cohort. Patients were categorized into pre-COVID-19 (PCOV19) and first COVID-19 surge (FCOV19S) cohorts. Patient demographic, injury, and outcome data were collected via Trauma Registry queries. Univariate and multivariate analyses were performed., Results: A total 5,616 patients presented to participating study centers during the PCOV19 (2,916) and FCOV19S (2,700) study periods.  Blunt injury volume decreased (p = 0.006) due to a significant reduction in the number of motor vehicle collisions (MVCs) (p = 0.003). Penetrating trauma experienced a significant increase, 8% (246/2916) in 2019 to 11% (285/2,700) in 2020 (p = 0.007), which was associated with study site (p = 0.002), not SAHOs. Finally, study site was significantly associated with changes in nearly all injury mechanisms, whereas SAHOs accounted for observed decreases in calculated weekly averages of blunt injuries (p < 0.02) and MVCs (p = 0.003)., Conclusion: Results of this study suggest that COVID-19 and initial SAHOs had variable consequences on patterns of traumatic injury, and that region-specific shifts in traumatic injury ensued during initial SAHOs. These results suggest that other factors, potentially socioeconomic or cultural, confound trauma volumes and types arising from SAHOs. Future analyses must consider how regional changes may be obscured with pooled cohorts, and focus on characterizing community-level changes to aid municipal preparation for future similar events., Competing Interests: Conflicts of Interest None., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Invasive lobular carcinoma (ILC) has a greater tendency to metastasize to the peritoneum, retroperitoneum, and gastrointestinal (GI) tract as compared to invasive carcinoma of no special type (NST). Like primary ILC in the breast, ILC metastases are frequently infiltrative and hypometabolic, rather than mass forming and hypermetabolic in nature. This renders them difficult to detect on conventional and metabolic imaging studies. As a result, intra-abdominal ILC metastases are often detected late, with patients presenting with clinical complications such as liver failure, hydronephrosis, or bowel obstruction. In patients with known history of ILC, certain imaging features are very suggestive of infiltrative metastatic ILC. These include retroperitoneal or peritoneal nodularity and linitis plastica appearance of the bowel. Recognition of linitis plastica on imaging should prompt deep or repeat biopsies. In this pictorial review, the authors aim to familiarize readers with imaging features and pitfalls for evaluation of intra-abdominal metastatic ILC. Awareness of these will allow the radiologist to assess these patients with a high index of suspicion and aid detection of metastatic disease. Also, this can direct histopathology and immunohistochemical staining to obtain the correct diagnosis in suspected metastatic disease., (© 2021. The Author(s).)

Competing Interests: No financial conflicts of interest exist.

Background: Despite the widespread institution of modern massive transfusion protocols with balanced blood product ratios, survival for patients with traumatic hemorrhage receiving ultramassive transfusion (UMT) (defined as ≥20 U of packed red blood cells [RBCs]) in 24 hours) remains low and resource consumption remains high. Therefore, we aimed to identify factors associated with mortality in trauma patients receiving UMT in the modern resuscitation era., Methods: An Eastern Association for the Surgery of Trauma multicenter retrospective study of 461 trauma patients from 17 trauma centers who received ≥20 U of RBCs in 24 hours was performed (2014-2019). Multivariable logistic regression and Classification and Regression Tree analysis were used to identify clinical characteristics associated with mortality., Results: The 461 patients were young (median age, 35 years), male (82%), severely injured (median Injury Severity Score, 33), in shock (median shock index, 1.2; base excess, -9), and transfused a median of 29 U of RBCs, 22 U of fresh frozen plasma (FFP), and 24 U of platelets (PLT). Mortality was 46% at 24 hours and 65% at discharge. Transfusion of RBC/FFP ≥1.5:1 or RBC/PLT ≥1.5:1 was significantly associated with mortality, most pronounced for the 18% of patients who received both RBC/PLT and RBC/FFP ≥1.5:1 (odds ratios, 3.11 and 2.81 for mortality at 24 hours and discharge; both p < 0.01). Classification and Regression Tree identified that age older than 50 years, low initial Glasgow Coma Scale, thrombocytopenia, and resuscitative thoracotomy were associated with low likelihood of survival (14-26%), while absence of these factors was associated with the highest survival (71%)., Conclusion: Despite modern massive transfusion protocols, one half of trauma patients receiving UMT are transfused with either RBC/FFP or RBC/PLT in unbalanced ratios ≥1.5:1, with increased associated mortality. Maintaining focus on balanced ratios during UMT is critical, and consideration of advanced age, poor initial mental status, thrombocytopenia, and resuscitative thoracotomy can aid in prognostication., Level of Evidence: Prognostic, level III., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Anoctamin-1 (ANO1) (TMEM16A) is a calcium-activated chloride channel that plays critical roles in diverse physiological processes, such as sensory transduction and epithelial secretion. ANO1 levels have been shown to be altered under physiological and pathological conditions, although the molecular mechanisms that control ANO1 protein levels remain unclear. The ubiquitin-proteasome system is known to regulate the levels of numerous ion channels, but little information is available regarding whether and how ubiquitination regulates levels of ANO1. Here, we showed that two E3 ligases, TRIM23 and TRIM21, physically interact with the C terminus of ANO1. In vitro and in vivo assays demonstrated that whereas TRIM23 ubiquitinated ANO1 leading to its stabilization, TRIM21 ubiquitinated ANO1 and induced its degradation. Notably, ANO1 regulation by TRIM23 and TRIM21 is involved in chemical-induced pain sensation, salivary secretion, and heart-rate control in mice, and TRIM23 also mediates ANO1 upregulation induced by epidermal growth factor treatment. Our results suggest that these two antagonistic E3 ligases act together to control ANO1 expression and function. Our findings reveal a previously unrecognized mechanism for regulating ANO1 protein levels and identify a potential molecular link between ANO1 regulation, epidermal growth factor, and other signaling pathways., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Major depressive disorder (MDD) represents a leading cause of disability. This study examines the course of disability in patients with chronic, recurrent and remitting MDD compared to healthy controls and identifies predictors of disability in remitting MDD., Methods: We included 914 participants from the Netherlands Study of Depression and Anxiety (NESDA). DSM-IV MDD and WHO DAS II disability were assessed at baseline and at 2, 4 and 6 years. Six-year total and domain-specific disability were analysed and compared in participants with chronic (n = 57), recurrent (n = 120), remitting (n = 127) MDD and in healthy controls (n = 430). Predictors of residual disability were identified using linear regression analysis., Results: At baseline, most disability was found in chronic MDD, followed by recurrent MDD, remitting MDD and healthy controls. Across diagnostic groups, most disability was found in household activities, interpersonal functioning, participation in society and cognition. A chronic course was associated with chronic disability. Symptom remission was associated with a decrease in disability, but some disability remained. In remitting MDD, higher residual disability was predicted by older age, more severe avoidance symptoms, higher disability at baseline and late symptom remission. Severity of residual disability correlated with the severity of residual depressive symptoms., Conclusions: Symptomatic remission is a prerequisite for improvements in disability. However, disability persists despite symptom remission. Therefore, treatment of MDD should include an explicit focus on disability, especially on the more complex domains. To this end, treatments should promote behavioural activation and address subthreshold depressive symptoms in patients with remitted MDD.

Bio-hydrogen production from wastewater using sludge as inoculum is a sustainable approach for energy production. This study investigated the influence of initial pH and temperature on bio-hydrogen production from dairy wastewater using pretreated landfill leachate sludge (LLS) as an inoculum. The maximum yield of 113.2 ± 2.9 mmol H 2 /g chemical oxygen demand (COD) (12.8 ± 0.3 mmol H 2 /g carbohydrates) was obtained at initial pH 6 and 37 °C. The main products of volatile fatty acids were acetate and butyrate with the ratio of acetate:butyrate was 0.4. At optimum condition, Gibb's free energy was estimated at -40 kJ/mol, whereas the activation enthalpy and entropy were 65 kJ/mol and 0.128 kJ/mol/l, respectively. These thermodynamic quantities suggest that bio-hydrogen production from dairy wastewater using pretreated LLS as inoculum was effective and efficient. In addition, genomic and bioinformatics analyses were performed in this study., (Copyright © 2018 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.)

Study Design: A prospective radiographic comparative study., Objective: The aim of this study was to compare full-body EOS with conventional chest X-ray (CXR) for use in the preoperative evaluation of the chest in patients undergoing spine operations., Summary of Background Data: The full-body EOS reproduces an image of the chest similar to a routine CXR. The potential for the former replacing the latter is plausible. This is especially applicable in spine patients who would routinely have a preoperative full-body EOS performed., Methods: A radiographic comparative study of 266 patients was conducted at a single tertiary center from January 2013 to July 2016. Each patient had EOS and CXR done in random order <2 weeks apart. Two radiologists reported the image findings using a checklist. A third radiologist was consulted in cases of discrepancy. Interobserver agreement was calculated using Gwet AC1 and a comparison between EOS and CXR findings was analyzed using paired Chi-squared test. Multivariate analysis was performed to identify predictors for abnormal radiological findings. The institutional ethics committee approved this prospective study and waiver of informed consent was obtained., Results: There were 84 males (31.6%) and 182 females (68.4%). The mean age was 38.9 years (SD = 25.0 years). High interobserver agreement was found for EOS and CXR (Gwet AC1 0.993 and 0.988, respectively). There were no significant differences between both imaging modalities. Rare diagnoses precluded comparison of certain conditions. Age >18 years [odds ratio (OR) 7.69; P = 0.009] and American Society of Anesthesiologists physical status 3 (OR 6.64; P = 0.018) were independent predictors of abnormal radiological findings., Conclusion: EOS is not inferior to, and may be used to replace CXR in preoperative radiological screening of thoracic conditions especially in low-risk patients ≤18 years old and patients with ASA <3. Preoperative assessment should never rely on a single modality. High-risk patients should be sent for a thorough work-up before spine surgery., Level of Evidence: 4.

Three newly discovered H 2 producing bacteria namely Clostridium perfringens strain JJC, Clostridium bifermentans strain WYM and Clostridium sp. strain Ade.TY originated from landfill leachate sludge have demonstrated highly efficient H 2 production. The maximum H 2 production attained from these isolates are in the descending order of strain C. perfringens strain JJC > C. bifermentans strain WYM > Clostridium sp. strain Ade.TY with yield of 4.68 ± 0.12, 3.29 ± 0.11, and 2.87 ± 0.10 mol H 2 /mol glucose, respectively. The result has broken the conventional theoretical yield of 4 mol H 2 /mol glucose. These isolates were thermodynamically favourable with Gibbs free energy between -33 and -35 kJ/mol (under process conditions: pH 6, 37 °C and 5 g/L glucose). All three isolates favour butyrate pathway for H 2 production with the ratio of acetate and butyrate of 0.77, 0.65 and 0.80 for strain JJC, WYM and Ade.TY, respectively. This study reported provides a new insight on the potential of unique bacteria in H 2 production., (Copyright © 2017 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.)

Metastatic lung cancer is a leading cause of mortality and has a mortality rate of ≥90%. Isolinderalactone (ILL) is a sesquiterpene lactone compound that has been used in traditional Chinese medicine. Research has demonstrated that ILL has anti-inflammatory and anti-proliferative properties; however, to the best of our knowledge, studies investigating whether ILL can inhibit lung cancer cell metastasis have not been conducted. In the present study, 1-10 µM ILL was applied in the culturing of the A549 lung cancer cell line to investigate the effects of ILL on the invasion and migration of lung cancer cells, including whether the possible mechanisms of ILL are associated with the expression of matrix metalloproteinase (MMP)-2 and NME/NM23 nucleoside diphosphate kinase 1 (NM23-H1) genes. The results of the present study indicated that ILL inhibited the invasion and migration of the A549 cancer cells and exhibited a dose-response association. ILL also significantly inhibited the protein expression and activity of MMP-2 (P<0.05), exhibiting a trend similar to that of its invasion- and migration-associated properties. Further research revealed that ILL significantly increased the expression of NM23-H1 protein and inhibited the expression of β-catenin protein (P<0.05). The results of the present study is, to the best of our knowledge, the first to confirm that ILL can inhibit the invasion and migration of A549 cancer cells, with the possible mechanisms potentially involving the inhibition of MMP-2 and β-catenin protein expression resulting from the up regulation of NM23-H1 expression.

Intramural esophageal dissection is an uncommon condition, involving the separation of the esophageal mucosa from the muscular layers. To our knowledge, the temporal evolution of intramural esophageal dissection on computed tomography has not been previously demonstrated. We present a case of a 51-year-old male who first presented to the emergency department with fever, odynophagia, and dysphagia. He was treated for acute tonsillitis and discharged, but presented again after 10 days with worsening symptoms. A series of radiographs and computed tomography studies, with 3D reconstruction and cinematic virtual fly-through, in these 2 admissions depicts the temporal evolution of intramural hematoma to subsequent intramural esophageal dissection. Recognizing its appearance on imaging is invaluable in distinguishing it from other important differential diagnoses. A complete description of the case, relevant radiologic imaging, and review of the relevant literature are provided.