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Xiaowu Wang,1,* Bo Xu,1,* Hongliang Liang,1 Shuyun Jiang,1 Hongmei Tan,1 Xinrong Wang,1 Xia Wang,2 Shiqiang Yu,1 Jincheng Liu1 1Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, Shaanxi, People’s Republic of China; 2Department of Health Statistics, Faculty of Preventive Medicine, Fourth Military Medical University, Xi’an 710032, Shaanxi, People’s Republic of China *These authors contributed equally to this work Purpose: Oral warfarin anticoagulation is a long-term treatment that is required after heart valve replacement. This treatment can prevent serious complications, such as embolism, thereby increasing patients’ postoperative survival rates and quality of life. Patients treated with artificial mechanical heart valve replacement were followed up over the phone at different times after the procedure, which is an effective method for preventing accidents related to postoperative oral warfarin anticoagulation. Our goal was to determine a method for providing theoretical guidance to patients on oral warfarin anticoagulation following heart valve replacement. Patients and methods: The participants of this study were patients who received artificial mechanical heart valve replacements and were followed up for 2 years after the procedure. Patient adherence to medical advice was calculated, and the distribution characteristics of adherence to prescribed timing, prescribed dose, and regular clinical follow-up among patients of both sexes and of different ages, regions, and educational levels attained were compared. Results: Univariate and multifactorial logistic regression analyses were used to evaluate the factors influencing adherence. Our analyses showed that adherence to oral warfarin anticoagulation in patients after heart valve replacement is influenced by sex, age, residential location, and educational attainment. The medication habits of patients can be evaluated accordingly via phone follow-up. As such, dose adjustment recommendations can be provided, significantly increasing the adherence to oral warfarin anticoagulation in patients after heart valve replacement. Conclusion: Adherence to oral warfarin anticoagulation among patients after heart valve replacement is affected by sex, age, type of residence, and educational level, as well as adherence to clinical follow-up over the phone. The follow-up sessions help establish good doctor–patient communication, which is critical for timely medication guidance, thus shortening medication administration delays and decreasing the overall length of therapy. Keywords: warfarin, artificial mechanical heart valve replacement, AMHVR, telephone follow-up, adherence, distribution characteristics

Combined ganglioneuroma-schwannoma is an exceedingly rare tumor that has only been described in isolated case reports. We document a 64-year-old man with an incidentally discovered combined ganglioneuroma-schwannoma of the retroperitoneum that was intimately associated with sympathetic ganglia. We highlight the morphological and immunohistochemical findings of this rare tumor, and show evidence of its origin from sympathetic ganglia., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Competing Interests: Conflict of Interest: None.

The present study successfully synthesized a novel biochar adsorbent (M-L-BC) using litchi seed modified with zinc chloride for PFASs removal in water. M-L-BC greatly enhanced removal of all examined PFASs (>95 %) as compared to the pristine biochar (<40 %). The maximum adsorption capacity was observed for PFOS, reaching 29.6 mg/g. Adsorption kinetics of PFASs followed the pseudo-second-order model (PSO), suggesting the predominance of chemical adsorption. Moreover, characterization and density functional theory (DFT) calculations jointly revealed involvement of surface complexation, electrostatic interactions, hydrogen bonding, and hydrophobic interactions in PFAS adsorption. Robust PFAS removal was demonstrated for M-L-BC across a wide range of pH (3-9), and coexisting ions had limited impact on adsorption of PFASs except PFBA. Furthermore, M-L-BC showed excellent performance in real water samples and retained reusability after five cycles of regeneration. Overall, M-L-BC represents a promising and high-quality adsorbent for efficient and sustainable removal of PFASs from water., 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 © 2024 Elsevier Ltd. All rights reserved.)

In this pilot study, we investigated the utility of handheld ultrasound-guided photoacoustic (US-PA) imaging probe for analyzing ex-vivo breast specimens obtained from female patients who underwent breast-conserving surgery (BCS). We aimed to assess the potential of US-PA in detecting biochemical markers such as collagen, lipids, and hemoglobin, and compare these findings with routine imaging modalities (mammography, ultrasound) and histopathology results, particularly across various breast densities. Twelve ex-vivo breast specimens were obtained from female patients with a mean age of 59.7 ± 9.5 years who underwent BCS. The tissues were illuminated using handheld US-PA probe between 700 and 1100 nm across all margins and analyzed for collagen, lipids, and hemoglobin distribution. The obtained results were compared with routine imaging and histopathological assessments. Our findings revealed that lipid intensity and distribution decreased with increasing breast density, while collagen exhibited an opposite trend. These observations were consistent with routine imaging and histopathological analyses. Moreover, collagen intensity significantly differed (P < 0.001) between cancerous and normal breast tissue, indicating its potential as an additional biomarker for risk stratification across various breast conditions. The study results suggest that a combined assessment of PA biochemical information, such as collagen and lipid content, superimposed on grey-scale ultrasound findings could aid in distinguishing between normal and malignant breast conditions, as well as assist in BCS margin assessment. This underscores the potential of US-PA imaging as a valuable tool for enhancing breast cancer diagnosis and management, offering complementary information to existing imaging modalities and histopathology., (© 2024. The Author(s).)

Objective: This study aimed to investigate the level of family caregivers' (FC) burden and the extent to which patient- and caregiver-related factors influence the caregiving burden among FCs of urologic cancer (UC) patients., Method: A cross-sectional survey was conducted on caregivers of UC patients who sought cancer care. The modified caregiver strain index (MCSI) was used to assess FC burden., Results: Just over half (54.3%) of FCs had moderate/high MCSI scores (score 9-26). By demographics, FCs who were unemployed (OR = 5.55, 95%CI 1.50-20.60) and perceived their current health condition as moderate/poor (OR = 6.05, 95%CI 1.95-18.78) reported higher odds of increased FC burden. Patient performance status played a pivotal role in exacerbating FC burden, whereby the odds of higher FC burden was 13 times higher in caregivers of UC patients having an Eastern Cooperative Oncology Group (ECOG) performance rating score of 3-4 (OR = 13.06, 95%CI 1.44-111.26) than those with a score of 0. Perceived lower levels of confidence in care provision were significantly associated with a higher level of strain (OR = 6.76, 985%CI 1.02-44.90)., Conclusion: Care recipient performance status was a strong patient-related factor associated with higher FC burden regardless of duration of caregiving and other caregiver-related factors after adjusting for caregiver demographics., 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 © 2024 Elsevier Inc. All rights reserved.)

The negative coordination of growth hormone secretagogue receptor (GHS-R) and growth hormone-releasing hormone receptor (GHRH-R) involves in the repair processes of cellular injury. The allosteric U- or H-like modified GHRH dimer Grinodin and 2Y were comparatively evaluated in normal Kunming mice and hamster infertility models induced by CPA treatment. 1-3-9 µg of Grinodin or 2Y per hamster stem-cell-exhaustion model was subcutaneously administered once a week, respectively inducing 75-69-46 or 45-13-50 % of birth rates. In comparison, the similar mole of human menopausal gonadotropin (hMG) or human growth hormone (hGH) was administered once a day but caused just 25 or 20 % of birth rates. Grinodin induced more big ovarian follicles and corpora lutea than 2Y, hMG, hGH. The hMG-treated group was observed many distorted interstitial cells and more connective tissues and the hGH-treated group had few ovarian follicles. 2Y had a plasma lifetime of 21 days and higher GH release in mice, inducing lower birth rate and stronger individual specificity in reproduction as well as only promoting the proliferation of mesenchymal-stem-cells (MSCs) in the models. In comparison, Grinodin had a plasma lifetime of 30 days and much lower GH release in mice. It significantly promoted the proliferation and activation of ovarian MSCs together with the development of follicles in the models by increasing Ki67 and GHS-R expressions, and decreasing GHRH-R expression in a dose-dependent manner. However, the high GH and excessive estrogen levels in the models showed a dose-dependent reduction in fertility. Therefore, unlike 2Y, the low dose of Grinodin specifically shows low GHS-R and high GHRH-R expressions thus evades GH and estrogen release and improves functions of organs, resulting in an increase of fertility., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction: Pharmacogenetics currently supports clinical decision-making on the basis of a limited number of variants in a few genes and may benefit paediatric prescribing where there is a need for more precise dosing. Integrating genomic information such as methylation into pharmacogenetic models holds the potential to improve their accuracy and consequently prescribing decisions. Cytochrome P450 2D6 ( CYP2D6 ) is a highly polymorphic gene conventionally associated with the metabolism of commonly used drugs and endogenous substrates. We thus sought to predict epigenetic loci from single nucleotide polymorphisms (SNPs) related to CYP2D6 in children from the GUSTO cohort., Methods: Buffy coat DNA methylation was quantified using the Illumina Infinium Methylation EPIC beadchip. CpG sites associated with CYP2D6 were used as outcome variables in Linear Regression, Elastic Net and XGBoost models. We compared feature selection of SNPs from GWAS mQTLs, GTEx eQTLs and SNPs within 2 MB of the CYP2D6 gene and the impact of adding demographic data. The samples were split into training (75%) sets and test (25%) sets for validation. In Elastic Net model and XGBoost models, optimal hyperparameter search was done using 10-fold cross validation. Root Mean Square Error and R-squared values were obtained to investigate each models' performance. When GWAS was performed to determine SNPs associated with CpG sites, a total of 15 SNPs were identified where several SNPs appeared to influence multiple CpG sites., Results: Overall, Elastic Net models of genetic features appeared to perform marginally better than heritability estimates and substantially better than Linear Regression and XGBoost models. The addition of nongenetic features appeared to improve performance for some but not all feature sets and probes. The best feature set and Machine Learning (ML) approach differed substantially between CpG sites and a number of top variables were identified for each model., Discussion: The development of SNP-based prediction models for CYP2D6 CpG methylation in Singaporean children of varying ethnicities in this study has clinical application. With further validation, they may add to the set of tools available to improve precision medicine and pharmacogenetics-based dosing., 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 © 2023 Fong, Tan, Garg, Teh, Pan, Gupta, Krishna, Chen, Purwanto, Yap, Tan, Chan, Chan, Goh, Rane, Tan, Jiang, Han, Meaney, Wang, Keppo and Tan.)

Introduction: The heterogeneity of depressive and anxiety disorders complicates clinical management as it may account for differences in trajectory and treatment response. Self-schemas, which can be determined by Self-Referential Judgements (SRJs), are heterogeneous yet stable. SRJs have been used to characterize personality in the general population and shown to be prognostic in depressive and anxiety disorders., Methods: In this study, we used SRJs from a Self-Referential Encoding Task (SRET) to identify clusters from a clinical sample of 119 patients recruited from the Institute of Mental Health presenting with depressive or anxiety symptoms and a non-clinical sample of 115 healthy adults. The generated clusters were examined in terms of most endorsed words, cross-sample correspondence, association with depressive symptoms and the Depressive Experiences Questionnaire and diagnostic category., Results: We identify a 5-cluster solution in each sample and a 7-cluster solution in the combined sample. When perturbed, metrics such as optimum cluster number, criterion value, likelihood, DBI and CHI remained stable and cluster centers appeared stable when using BIC or ICL as criteria. Top endorsed words in clusters were meaningful across theoretical frameworks from personality, psychodynamic concepts of relatedness and self-definition, and valence in self-referential processing. The clinical clusters were labeled "Neurotic" (C1), "Extraverted" (C2), "Anxious to please" (C3), "Self-critical" (C4), "Conscientious" (C5). The non-clinical clusters were labeled "Self-confident" (N1), "Low endorsement" (N2), "Non-neurotic" (N3), "Neurotic" (N4), "High endorsement" (N5). The combined clusters were labeled "Self-confident" (NC1), "Externalising" (NC2), "Neurotic" (NC3), "Secure" (NC4), "Low endorsement" (NC5), "High endorsement" (NC6), "Self-critical" (NC7). Cluster differences were observed in endorsement of positive and negative words, latency biases, recall biases, depressive symptoms, frequency of depressive disorders and self-criticism., Discussion: Overall, clusters endorsing more negative words tended to endorse fewer positive words, showed more negative biases in reaction time and negative recall bias, reported more severe depressive symptoms and a higher frequency of depressive disorders and more self-criticism in the clinical population. SRJ-based clustering represents a novel transdiagnostic framework for subgrouping patients with depressive and anxiety symptoms that may support the future translation of the science of self-referential processing, personality and psychodynamic concepts of self-definition to clinical applications., 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 Tan, Wang, Tan, Ong, Ooi, Lee, Rane, Tey, Chua, Goh, Lam, Chakraborty, Yew, Ong, Kee, Lim, Hashim, Lu, Meany, Tolomeo, Lee, Tan and Keppo.)

The SLC7A11/xCT cystine and glutamate antiporter has emerged as an attractive target for cancer therapy due to its selective overexpression in multiple cancers and its role in preventing ferroptosis. Utilizing pharmacological and genetic approaches in hepatocellular carcinoma cell lines, we demonstrate that overexpression of SLC7A11 engenders hypersensitivity towards l-selenocystine, a naturally occurring diselenide that bears close structural similarity to l-cystine. We find that the abundance of SLC7A11 positively correlates with sensitivity to l-selenocystine, but surprisingly, not to Erastin, an inhibitor of SLC7A11 activity. Our data indicate that SLC7A11 acts as a transport channel for l-selenocystine, which preferentially incites acute oxidative stress and damage eventuating to cell death in cells that highly express SLC7A11. Hence, our findings raise the prospect of l-selenocystine administration as a novel strategy for targeting cancers that up-regulate SLC7A11 expression., (© 2023 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Background: Testosterone replacement therapy is known to improve sexual function in men younger than 40 years with pathological hypogonadism. However, the extent to which testosterone alleviates sexual dysfunction in older men and men with obesity is unclear, despite the fact that testosterone is being increasingly prescribed to these patient populations. We aimed to evaluate whether subgroups of men with low testosterone derive any symptomatic benefit from testosterone treatment., Methods: We did a systematic review and meta-analysis to evaluate characteristics associated with symptomatic benefit of testosterone treatment versus placebo in men aged 18 years and older with a baseline serum total testosterone concentration of less than 12 nmol/L. We searched major electronic databases (MEDLINE, Embase, Science Citation Index, and the Cochrane Central Register of Controlled Trials) and clinical trial registries for reports published in English between Jan 1, 1992, and Aug 27, 2018. Anonymised individual participant data were requested from the investigators of all identified trials. Primary (cardiovascular) outcomes from this analysis have been published previously. In this report, we present the secondary outcomes of sexual function, quality of life, and psychological outcomes at 12 months. We did a one-stage individual participant data meta-analysis with a random-effects linear regression model, and a two-stage meta-analysis integrating individual participant data with aggregated data from studies that did not provide individual participant data. This study is registered with PROSPERO, CRD42018111005., Findings: 9871 citations were identified through database searches. After exclusion of duplicates and publications not meeting inclusion criteria, 225 full texts were assessed for inclusion, of which 109 publications reporting 35 primary studies (with a total 5601 participants) were included. Of these, 17 trials provided individual participant data (3431 participants; median age 67 years [IQR 60-72]; 3281 [97%] of 3380 aged ≥40 years) Compared with placebo, testosterone treatment increased 15-item International Index of Erectile Function (IIEF-15) total score (mean difference 5·52 [95% CI 3·95-7·10]; τ 2 =1·17; n=1412) and IIEF-15 erectile function subscore (2·14 [1·40-2·89]; τ 2 =0·64; n=1436), reaching the minimal clinically important difference for mild erectile dysfunction. These effects were not found to be dependent on participant age, obesity, presence of diabetes, or baseline serum total testosterone. However, absolute IIEF-15 scores reached during testosterone treatment were subject to thresholds in patient age and baseline serum total testosterone. Testosterone significantly improved Aging Males' Symptoms score, and some 12-item or 36-item Short Form Survey quality of life subscores compared with placebo, but it did not significantly improve psychological symptoms (measured by Beck Depression Inventory)., Interpretation: In men aged 40 years or older with baseline serum testosterone of less than 12 nmol/L, short-to-medium-term testosterone treatment could provide clinically meaningful treatment for mild erectile dysfunction, irrespective of patient age, obesity, or degree of low testosterone. However, due to more severe baseline symptoms, the absolute level of sexual function reached during testosterone treatment might be lower in older men and men with obesity., Funding: National Institute for Health and Care Research Health Technology Assessment Programme., Competing Interests: Declaration of interests CNJ reports a research grant from Logixx Pharma. ShB reports research grants from AbbVie and the US NIH; participation on the OKPO Health data safety monitoring board; consulting fees from Aditum, a leadership or fiduciary role from the Endocrine Society; and a patent relating to the diagnosis and treatment of androgen disorders (US patent number 10386375). SSE reports a research grant from AbbVie. MG reports research grants from Otsuka, Bayer, Lilly, Weight Watchers, Novartis, National Health and Medical Research Council (Australia); speaker honoraria from Besins Healthcare, Bayer, and Otsuka; consulting fees from Bayer; and royalties from Walter and Eliza Hall Institute Melbourne Australia. KLH is supported by the National Institute on Aging K23 Career Development Award; reports an unpaid role in the Executive Committee, Kavod Senior Life Board of Directors; and stock or stock options from Medaware Systems. NO reports research grants from Dexcom, Roche Diabetes, Medtronic Diabetes; speaker honoraria from Roche Diabetes; consulting fees from Roche Diabetes and Medtronic Diabetes; payment for expert testimony (Bird and Bird); and a patent issued for an automatic closed loop glucose control system with an adaptive meal bolus calculator. SR reports a research grant from North Staffordshire Medical Institute; and support for meetings or travel from Besins Healthcare. PJS reports a research grant from AbbVie; and payment for expert testimony from Teva. RQ reports speaker honoraria and support for attending meetings or travel from Bayer. SiB reports speaker honoraria from the Obstetrical & Gynaecological Society of Singapore and pharmaceutical companies (Merck and Ferring); a financial role as a non-executive member of NHS Grampian Health Board; and royalties from Cambridge University Press. GBB reports speaker honoraria and consulting fees from Acerus Pharmaceutical. HMT reports speaker honoraria from Besin Healthcare. EmJG reports provision of study materials from Bayer. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Per-and polyfluoroalkyl substances (PFASs) have received great attention due to their persistence, bioaccumulation and toxicity. Various activated carbons (ACs) exhibit wide variability in adsorptive performance towards PFASs. In order to gain a systematic understanding of adsorptive removal of legacy and emerging PFASs by ACs, the adsorption of ten PFASs on various ACs was comprehensively investigated. Results showed that granular activated carbon-1 (GAC-1) and powdered activated carbon-1 (PAC-1) removed more than 90% of all target PFASs. Particle size, surface charge, and micropores quantity of ACs were closely related to their performance for PFASs removal. Electrostatic interaction, hydrophobic interaction, surface complexation and hydrogen bonding were the adsorption mechanisms, with hydrophobic interaction being the predominant adsorptive force. Physical and chemical adsorption were both involved in PFAS adsorption. The removal rates of PFASs by GAC-1 decreased from 93%-100% to 15%-66% in the presence of 5 mg/L fulvic acid (FA). GAC was able to remove more PFASs under acidic medium, whereas PAC removed hydrophobic PFASs better under the neutral medium. The removal rates of PFASs by GAC-3 increased significantly from 0%-21% to 52%-97% after being impregnated with benzalkonium chlorides (BACs), demonstrating the superiority of this modification method. Overall, this study provided theoretical support for removing PFASs from water phase with ACs., 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 © 2023. Published by Elsevier Inc.)

Objectives: Systemic strategies for combating antimicrobial resistance (AMR) currently focus on limiting antibiotic use and have been generally insufficient in preventing the rise of AMR. Additionally, they often generate other adverse incentives, such as discouraging pharmaceutical companies from investing in research and development of new antibiotics, further exacerbating the problem. This paper proposes a novel systemic strategy for tackling AMR, which we term 'antiresistics': any intervention (whether a small molecule, genetic element, phage, or whole organism) that reduces resistance rates in pathogen populations. A prime example of an antiresistic would be a small molecule that specifically disrupts the maintenance of antibiotic resistance plasmids. Of note, an antiresistic would be expected to have a population-level effect and not necessarily be useful on a time scale relevant to individual patients., Methods: We developed a mathematical model to assess the effect of antiresistics on population resistance levels and calibrated it to longitudinal data available at the country level. We also estimated potential effects on idealised rates for the introduction of new antibiotics., Results: The model shows that greater use of antiresistics allows for greater usage of existing antibiotics. This leads to an ability to maintain a constant overall rate of antibiotic efficacy with a slower rate of developing new antibiotics; subsequently, antiresistics have a positive benefit on the effective lifetime and thus profitability of antibiotics., Conclusions: By directly reducing resistance rates, antiresistics can provide clear qualitative benefits (which may be quantitatively large) in terms of existing antibiotic efficacy, longevity, and alignment of incentives., (Copyright © 2023. Published by Elsevier Ltd.)

Through a comprehensive analysis of the gene expression and dependency in HCC patients and cell lines, LAT1 was identified as the top amino acid transporter candidate supporting HCC tumorigenesis. To assess the suitability of LAT1 as a HCC therapeutic target, we used CRISPR/Cas9 to knockout (KO) LAT1 in the epithelial HCC cell line, Huh7. Knockout of LAT1 diminished its branched chain amino acid (BCAA) transport activity and significantly reduced cell proliferation in Huh7. Consistent with in vitro studies, LAT1 ablation led to suppression of tumor growth in a xenograft model. To elucidate the mechanism underlying the observed inhibition of cell proliferation upon LAT1 KO, we performed RNA-sequencing analysis and investigated the changes in the mTORC1 signaling pathway. LAT1 ablation resulted in a notable reduction in phosphorylation of p70S6K, a downstream target of mTORC1, as well as its substrate S6RP. This reduced cell proliferation and mTORC1 activity were rescued when LAT1 was overexpressed. These findings imply an essential role of LAT1 for maintenance of tumor cell growth and additional therapeutic angles against liver cancer.

Introduction: Penile reconstructive and prosthetic surgery remains a highly specialized field where potential complications can be devastating, and unrealistic patient expectations can often be difficult to manage. Furthermore, surgical practice can vary depending on locoregional expertise and sociocultural factors., Methods: The Asia Pacific Society of Sexual Medicine (APSSM) panel of experts reviewed contemporary evidence regarding penile reconstructive and prosthetic surgery with an emphasis on key issues relevant to the Asia-Pacific (AP) region and developed a consensus statement and set of clinical practice recommendations on behalf of the APSSM. The Medline and EMBASE databases were searched using the following terms: "penile prosthesis implant," "Peyronie's disease," "penile lengthening," "penile augmentation," "penile enlargement," "buried penis," "penile disorders," "penile trauma," "transgender," and "penile reconstruction" between January 2001 and June 2022. A modified Delphi method was undertaken, and the panel evaluated, agreed, and provided consensus statements on clinically relevant penile reconstructive and prosthetic surgery, namely (1) penile prosthesis implantation, (2) Peyronie's disease, (3) penile trauma, (4) gender-affirming (phalloplasty) surgery, and (5) penile esthetic (length and/or girth enlargement) surgery., Main Outcome Measures: Outcomes were specific statements and clinical recommendations according to the Oxford Centre for Evidence-Based Medicine, and if clinical evidence is lacking, a consensus agreement is adopted. The panel provided statements on clinical aspects of surgical management in penile reconstructive and prosthetic surgery., Results: There is a variation in surgical algorithms in patients based on sociocultural characteristics and the availability of local resources. Performing preoperative counseling and obtaining adequate informed consent are paramount and should be conducted to discuss various treatment options, including the pros and cons of each surgical intervention. Patients should be provided with information regarding potential complications related to surgery, and strict adherence to safe surgical principles, preoperative optimization of medical comorbidities and stringent postoperative care are important to improve patient satisfaction rates. For complex patients, surgical intervention should ideally be referred and performed by expert high-volume surgeons to maximize clinical outcomes., Clinical Implications: Due to the uneven distribution of surgical access and expertise across the AP region, development of relevant comprehensive surgical protocols and regular training programs is desirable., Strengths and Limitations: This consensus statement covers comprehensive penile reconstructive and prosthetic surgery topics and is endorsed by the APSSM. The variations in surgical algorithms and lack of sufficient high-level evidence in these areas could be stated as a limitation., Conclusion: This APSSM consensus statement provides clinical recommendations on the surgical management of various penile reconstructive and prosthetic surgeries. The APSSM advocates for surgeons in AP to individualize surgical options based on patient condition(s) and needs, surgeon expertise, and local resources., (© The Author(s) 2023. Published by Oxford University Press on behalf of The International Society of Sexual Medicine.)

Per- and polyfluoroalkyl substances (PFASs) have received extensive attention due to their various harmful effects. In this study, the adsorptive removal of 10 legacy and emerging PFASs by four anion-exchange resins (including gel and macroreticular resins) were systematically investigated. Our results showed that the capacities of resins absorbing PFASs were ranked in the following order: gel strong base HPR4700 (297~300 μg/g) ≈ macroreticular strong base S6368 (294~300 μg/g) ≈ macroreticular weak base A111S (289~300 μg/g) > gel weak base WA10 (233~297 μg/g). Adsorption kinetic results indicated that the adsorption process might involve chemical and Henry regime adsorption or reaction control. Intraparticle diffusion was probably the major removal step. Co-existing fulvic acid (0.5, 1, 5 mg/L) and inorganic anions (5 mg/L of sulfate, carbonate, bicarbonate) would hinder the PFAS removal by resins with WA10 showing the highest inhibition rate of 17% and 71%, respectively. The adsorption capacities of PFBA decreased from 233 μg/g to 194 μg/g, and from 233 μg/g to 67 μg/g in the presence of fulvic acid and inorganic anions, respectively. PFASs were more easily removed by HPR4700, S6368, and A111S under neutral and alkaline environment. Moreover, WA10 was not able to remove PFASs under an alkaline medium. This study offered theoretical support for removing PFASs from aqueous phases with various resins.

A 50-year-old woman with no past medical history presented with a left anterior chest wall mass that was clinically soft, mobile, and non-tender. A targeted ultrasound (US) showed findings suggestive of a lipoma. However, focal "mass-like" nodules seen within the inferior portion suggested malignant transformation of a lipomatous lesion called for cross sectional imaging, such as MRI or invasive biopsy or excision for histological confirmation. A T1-weighted image demonstrated a large lipoma that has a central fat-containing region surrounded by an irregular hypointense rim in the inferior portion, confirming the benignity of the lipoma. An ultrasound-guided photoacoustic imaging (PA) of the excised specimen to derive the biochemical distribution demonstrated the "mass-like" hypoechoic regions on US as fat-containing, suggestive of benignity of lesion, rather than fat-replacing suggestive of malignancy. The case showed the potential of PA as an adjunct to US in improving the diagnostic confidence in lesion characterization.

Objective: To explore the impact of environmental temperature exposure on eczema visits. Methods: Eczema clinic data from January 1, 2016 to December 31, 2019 were collected from the Huizhou Dermatology Hospital, and data on meteorological factors (average daily temperature and relative humidity) for the same period were derived from 86 meteorological stations of the Guangdong Provincial Climate Center. A distributed lag nonlinear model (DLNM) was used to assess the lagged effect of environmental temperature exposure on eczema, and a natural smooth spline function was used to control the nonlinear confounding of humidity. Results: There were 254 053 eczema outpatient visits at the Huizhou Dermatology Hospital within four years, with an average of 173.89 visits per day. The relationship between daily average temperature and the number of visits was non-linear (U shape). The risk of eczema increased by 2.20% (1.19%-3.21%) for every 1 ℃ decrease for the low temperature, and increased by 2.35% (1.24%-3.5%) for every 1 ℃ increase for the high temperature. The effect of high temperature was greater than that of low temperature. In all cases, 1.60% (0.44%-2.68%) of eczema outpatient visits were attributed to low temperature and the attributable number was 4 065 (1 128-6 798), while 6.33% (1.40%-10.87%) of eczema outpatient visits were due to high temperature and the attributable number was 16 082 (3 557-27 616). Conclusion: Both high temperature and low temperature are associated with increased risk of eczema.

Adipocytic tumors are the most common subtype of soft tissue tumors. In current clinical practice, distinguishing benign lipomas from well-differentiated liposarcomas (WDLPS), as well as dedifferentiated liposarcomas (DDLPS) from their morphologic mimics, remains a significant diagnostic challenge. This is especially so when examining small biopsy samples and without the aid of additional ancillary tests. Recognizing the important role that microRNAs (miRNAs) play in tumorigenesis and their potential utility in tumor classification, we analyzed routine clinical tissue samples of benign and malignant lipomatous tumors, as well as other sarcoma mimics, to identify distinguishing miRNA-based signatures that can aid in the differential diagnosis of these entities. We discovered a 6-miRNA signature that separated lipomas from WDLPS with high confidence (AUC of 0.963), as well as a separate 6-miRNA signature that distinguished DDLPS from their more aggressive histologic mimics (AUC of 0.740). Functional enrichment analysis unveiled possible mechanistic involvement of these predictive miRNAs in adipocytic cancer-related biological processes and pathways such as PI3K/AKT/mTOR and MAPK signaling, further supporting the relevance of these miRNAs as biomarkers for adipocytic tumors. Our results demonstrate that miRNA expression profiling may potentially be used as an adjunctive tool for the diagnosis of benign and malignant adipocytic tumors. Further validation studies are warranted.

Environmental accumulation of non-degradable polystyrene (PS) microparticles from plastic waste poses potential adverse impact on marine life and human health. Herein, microparticles from a degradable PS analogue (dePS) are formulated and their immuno-modulatory characteristics are comprehensively evaluated. Both dePS copolymer and microparticles are chemically degradable under accelerated hydrolytic condition. In vitro studies show that dePS microparticles are non-toxic to three immortalized cell lines. While dePS microparticles do not induce macrophage polarization in vitro, dePS microparticles induce in vivo upregulation of both pro-inflammatory and anti-inflammatory biomarkers in immuno-competent mice, suggesting the coexistence of mixed phenotypes of macrophages in the host immune response to these microparticles. Interestingly, on day 7 following subcutaneous in mice, dePS microparticles induce a lower level of several immuno-modulatory biomarkers (matrix metallo-proteinases (MMPs), tumor necrosis factor (TNF-α), and arginase activity) compared to that of reference poly(lactic-co-glycolic acid) microparticles. Remarkably, compared to PS microparticles, dePS microparticles exhibit similar in vitro and in vivo bioactivity while acquiring additional chemical degradability. Overall, this study gains new insights into the host immune response to dePS microparticles and suggests that this dePS analogue might be explored as an alternative material choice for biomedical and consumer care applications., (© 2022 Wiley-VCH GmbH.)

To date, studies which utilized ultrasound (US) and optoacoustic tomography (OT) fusion (US-OT) in biochemical differentiation of malignant and benign breast conditions have relied on limited biochemical data such as oxyhaemoglobin (OH) and deoxyhaemoglobin (DH) only. There has been no data of the largest biochemical components of breast fibroglandular tissue: lipid and collagen. Here, the authors believe the ability to image collagen and lipids within the breast tissue could serve as an important milestone in breast US-OT imaging with many potential downstream clinical applications. Hence, we would like to present the first-in-human US-OT demonstration of lipid and collagen differentiation in an excised breast tissue from a 38-year-old female., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Goh Yonggeng has patent #IBB-016 issued to Licensee., (© 2022 Published by Elsevier GmbH.)

Background: Testosterone is the standard treatment for male hypogonadism, but there is uncertainty about its cardiovascular safety due to inconsistent findings. We aimed to provide the most extensive individual participant dataset (IPD) of testosterone trials available, to analyse subtypes of all cardiovascular events observed during treatment, and to investigate the effect of incorporating data from trials that did not provide IPD., Methods: We did a systematic review and meta-analysis of randomised controlled trials including IPD. We searched MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, MEDLINE Epub Ahead of Print, Embase, Science Citation Index, the Cochrane Controlled Trials Register, Cochrane Database of Systematic Reviews, and Database of Abstracts of Review of Effects for literature from 1992 onwards (date of search, Aug 27, 2018). The following inclusion criteria were applied: (1) men aged 18 years and older with a screening testosterone concentration of 12 nmol/L (350 ng/dL) or less; (2) the intervention of interest was treatment with any testosterone formulation, dose frequency, and route of administration, for a minimum duration of 3 months; (3) a comparator of placebo treatment; and (4) studies assessing the pre-specified primary or secondary outcomes of interest. Details of study design, interventions, participants, and outcome measures were extracted from published articles and anonymised IPD was requested from investigators of all identified trials. Primary outcomes were mortality, cardiovascular, and cerebrovascular events at any time during follow-up. The risk of bias was assessed using the Cochrane Risk of Bias tool. We did a one-stage meta-analysis using IPD, and a two-stage meta-analysis integrating IPD with data from studies not providing IPD. The study is registered with PROSPERO, CRD42018111005., Findings: 9871 citations were identified through database searches and after exclusion of duplicates and of irrelevant citations, 225 study reports were retrieved for full-text screening. 116 studies were subsequently excluded for not meeting the inclusion criteria in terms of study design and characteristics of intervention, and 35 primary studies (5601 participants, mean age 65 years, [SD 11]) reported in 109 peer-reviewed publications were deemed suitable for inclusion. Of these, 17 studies (49%) provided IPD (3431 participants, mean duration 9·5 months) from nine different countries while 18 did not provide IPD data. Risk of bias was judged to be low in most IPD studies (71%). Fewer deaths occurred with testosterone treatment (six [0·4%] of 1621) than placebo (12 [0·8%] of 1537) without significant differences between groups (odds ratio [OR] 0·46 [95% CI 0·17-1·24]; p=0·13). Cardiovascular risk was similar during testosterone treatment (120 [7·5%] of 1601 events) and placebo treatment (110 [7·2%] of 1519 events; OR 1·07 [95% CI 0·81-1·42]; p=0·62). Frequently occurring cardiovascular events included arrhythmia (52 of 166 vs 47 of 176), coronary heart disease (33 of 166 vs 33 of 176), heart failure (22 of 166 vs 28 of 176), and myocardial infarction (10 of 166 vs 16 of 176). Overall, patient age (interaction 0·97 [99% CI 0·92-1·03]; p=0·17), baseline testosterone (interaction 0·97 [0·82-1·15]; p=0·69), smoking status (interaction 1·68 [0·41-6·88]; p=0.35), or diabetes status (interaction 2·08 [0·89-4·82; p=0·025) were not associated with cardiovascular risk., Interpretation: We found no evidence that testosterone increased short-term to medium-term cardiovascular risks in men with hypogonadism, but there is a paucity of data evaluating its long-term safety. Long-term data are needed to fully evaluate the safety of testosterone., Funding: National Institute for Health Research Health Technology Assessment Programme., Competing Interests: CNJ reports research grants from Logixx Pharma. SBhas reports research grants from AbbVie and National Institutes of Health; consulting fees from Aditum; participation on the Data Safety Monitoring board of OKPO; a leadership or fiduciary role in the Endocrine Society; and a patent (free T calculator based on the ensemble allosteric model, reference 20200174026). SSE reports research grants from AbbVie. MG reports research grants from Otsuka, Bayer, Lilly, Weight Watchers, Novartis, National Health and the Medical Research Council Australia; speaker honoraria from Besins Healthcare, Bayer, and Otsuka; consulting fees from Bayer; and Royalties from Walter and Eliza Hall Institute Melbourne Australia. KLH reports research grants from NIA K23 Career Development Award; a leadership or fiduciary role from Kavod Senior Life Board of Directors, Executive Committee; and stock or stock options from Medaware Systems. NO reports research grants from Dexcom, Roche Diabetes, and Medtronic Diabetes; speaker honoraria from Roche Diabetes; consulting fees from Roche Diabetes and Medtronic Diabetes; payment for expert testimony from London law firm Wilmer Hale; and an issued patent for automatic closed loop glucose control with an adaptive meal bolus calculator. SR reports research grants from North Staffordshire Medical Institute and support for attending meetings or travel from Besins Healthcare. PJS reports research grants from Abbvie and payment for expert testimony from Teva. RQ reports speaker honoraria and support for attending meetings or travel from Bayer. SBhat reports speaker honoraria from Obstetrical & Gynaecological Society of Singapore, Merck SMART Masterclass, and Merck FERRING Forum; leadership or fiduciary role at National Health Service Grampian; editorial role (Editor in Chief of Human Reproduction Open, Special Senior Editor of Cochrane Gynaecology and Fertility); membership of NHS Grampian Board; other financial or non-financial interests from Oxford University Press; and Royalties from Cambridge University Press (Royalties for book Reproductive Medicine for the MRCOG, Cambridge University Press). GBB reports speaker honoraria and consulting fees from Acerus Pharmaceutical. HMT reports consulting fees from Besin Healthcare. EJGil reports provision of study materials from Bayer. All other authors declare no competing interests., (© 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license.)

Per-and polyfluoroalkyl substances (PFASs) have attracted extensive attention since this century due to their wide distribution, persistence, bioaccumulation/biomagnification potential, and (eco)toxicity. In the present study, we investigated the sorption kinetics, sorption isotherms and desorption behaviors of legacy and emerging PFASs with different chain lengths and functional end groups onto marine sediments at four different salinities (0, 10, 20, and 30 practical salinity units (psu)). Results revealed that the sorption of PFASs onto sediment can be well described by the pseudo-second-order kinetic model. PFASs sorption was influenced by both compound-specific and solution-specific parameters. The distribution coefficient (K d ) for PFASs were increased with the increase of perfluorocarbon chain length and salinity, suggesting that hydrophobic and electrostatic interactions were involved in the adsorption process. 6:2 FTSA showed the lowest adsorption among PFASs with eight carbon atoms (6:2 FTSA, PFOA and PFOS). The increase of perfluorocarbon chain length of PFASs and salinity would result in the decrease of desorption rate of PFASs from sediment. In addition, PFCAs were desorbed more easily from the sediment than the PFSAs with the same perfluorocarbon chain length at all salinity groups. The present study demonstrated that salinity can apparently influence the fate of PFASs in aquatic environment and provided valuable data for modeling the fate of PFASs in real environment., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: COVID-19 booster uptake remained poor among healthcare workers (HCW) despite evidence of improved immunity against Delta and Omicron variants. While most studies used a questionnaire to assess hesitancy, this study aimed to identify factors affecting booster hesitancy by examining actual vaccine uptake across time., Method: COVID-19 vaccination database records among HCW working at seven Singaporean public primary care clinics between January to December 2021 were extracted, with sex, profession, place of practice, vaccination type, and dates. Time to booster was calculated from the date of vaccination minus date of eligibility. Chi-square test was used to compare the relationship between first dose and booster hesitancy, Kaplan-Meier method and log-rank test were adopted to evaluate differences in cumulative booster uptake. Multivariate Cox regression was used to investigate predictors for timely booster vaccination. Vaccination rate was charted across time and corroborated with media releases pertaining to legislative changes., Results: A total of 877 of 891 (98.9%) primary care HCW were fully vaccinated, 73.8% of eligible HCW had taken the booster. HCW were less booster hesitant [median 16 (5-31.3) days] compared to the first dose [median 39 (13-119.3) days]. First dose-hesitant HCW were more likely to be booster hesitant (OR = 3.66, 95%CI 2.61-5.14). Adjusting for sex, workplace, and time to first dose, ancillary (HR = 1.53, 95%CI 1.03-2.28), medical (HR = 1.8, 95%CI 1.18-2.74), and nursing (HR = 1.8, 95%CI 1.18-2.37) received boosters earlier compared with administrative staff. No temporal relationship was observed between booster uptake, legislative changes, and COVID-19 infection numbers., Conclusion: Vaccine hesitancy among HCW had improved from first dose to booster, with timely booster vaccination among medical and nursing staff. Tailored education, risk messaging, and strategic legislation might help to reduce delayed booster vaccination.

With the rapid development of various coronavirus disease 2019 (COVID-19) vaccines in a bid to counter and contain the COVID-19 pandemic, unusual and uncommon side effects of COVID-19 vaccination have been increasingly reported in the literature. Ipsilateral lymphadenopathy is a fairly common side effect of vaccination of any kind, with its etiology most commonly related to reactive lymphadenopathy. However, Kikuchi-Fujimoto Disease (KFD) or necrotizing histiocytic lymphadenitis is rarely observed post-vaccination, with only one other case of KFD post COVID-19 vaccination reported to date. We report two more cases of KFD post COVID-19 vaccination in the Asian population, highlighting the clinical course and salient clinical, radiological and histologic findings. In addition, we provide a literature review of the existing cases of lymphadenopathy post COVID-19 vaccination with cytologic and/or histologic correlation.

We describe a case of ectopic cervical thyroid tissue which was involved by fibrosing Hashimoto's thyroiditis and which mimicked metastatic papillary thyroid carcinoma both on fine needle aspiration cytology and biopsy. The patient underwent total thyroidectomy which revealed fibrosing Hashimoto's thyroiditis, but no carcinoma. The entire thyroidectomy specimen was submitted for histopathological assessment. Even in the resected thyroidectomy specimen, there were cytological changes that were strongly reminiscent of papillary thyroid carcinoma. However, interpreted in the correct clinico-pathological context, these cytological alterations were deemed to be reactive secondary to the fibro-inflammatory process.

The Singapore Preconception Study of Long-Term Maternal and Child Outcomes (S-PRESTO) is a preconception, longitudinal cohort study that aims to study the effects of nutrition, lifestyle, and maternal mood prior to and during pregnancy on the epigenome of the offspring and clinically important outcomes including duration of gestation, fetal growth, metabolic and neural phenotypes in the offspring. Between February 2015 and October 2017, the S-PRESTO study recruited 1039 Chinese, Malay or Indian (or any combinations thereof) women aged 18-45 years and who intended to get pregnant and deliver in Singapore, resulting in 1032 unique participants and 373 children born in the cohort. The participants were followed up for 3 visits during the preconception phase and censored at 12 months of follow up if pregnancy was not achieved (N = 557 censored). Women who successfully conceived (N = 475) were characterised at gestational weeks 6-8, 11-13, 18-21, 24-26, 27-28 and 34-36. Follow up of their index offspring (N = 373 singletons) is on-going at birth, 1, 3 and 6 weeks, 3, 6, 12, 18, 24 and 36 months and beyond. Women are also being followed up post-delivery. Data is collected via interviewer-administered questionnaires, metabolic imaging (magnetic resonance imaging), standardized anthropometric measurements and collection of diverse specimens, i.e. blood, urine, buccal smear, stool, skin tapes, epithelial swabs at numerous timepoints. S-PRESTO has extensive repeated data collected which include genetic and epigenetic sampling from preconception which is unique in mother-offspring epidemiological cohorts. This enables prospective assessment of a wide array of potential determinants of future health outcomes in women from preconception to post-delivery and in their offspring across the earliest development from embryonic stages into early childhood. In addition, the S-PRESTO study draws from the three major Asian ethnic groups that represent 50% of the global population, increasing the relevance of its findings to global efforts to address non-communicable diseases.

Objective: This study examined the prevalence of self-perceived burden (SPB) and its association with health-related quality of life (HRQoL) among urologic cancer patients., Methods: This was a prospective, cross-sectional study. A total of 429 respondents diagnosed with urologic cancers (prostate, bladder and renal cancer) from Sarawak General Hospital and Subang Jaya Medical Centre in Malaysia were interviewed by using a structured questionnaire. SPB and HRQoL were measured by the Self-perceived Burden Scale and the Functional Assessment of Cancer Therapy-General 7 Item Scale respectively., Results and Conclusion: Self-perceived burden was experienced by 73.2% of the respondents. Respondents who had a lower education level, a monthly household income

Background: The Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) aims to provide a common language for risk stratification and management. We examine the incidence of MSRSGC categories and the corresponding risk of malignancy (ROM) within a tertiary referral centre in Southeast Asia., Methods: Salivary gland fine needle aspirations (FNAs) performed within a 10-year period were classified retrospectively according to the MSRSGC. Cytohistologic correlation was performed. The results were compared with the existing literature, including Asian and Western studies., Results: A total of 1384 salivary gland FNAs were evaluated, 421 with corresponding histology. The category distribution was: nondiagnostic, 28.9%; nonneoplastic, 18.0%; atypia of undetermined significance (AUS), 9.8%; benign neoplasm, 32.9%; salivary gland neoplasm of uncertain malignant potential (SUMP), 5.7%; suspicious for malignancy, 1.6%; and malignant, 3.2%. The ROMs were: nondiagnostic, 10.0%; nonneoplastic, 17.5%; AUS, 29.5%; benign neoplasm, 0.5%; SUMP, 17.1%; suspicious for malignancy, 83.3%; and malignant, 100.0%. Our relatively high nondiagnostic rate likely reflects preanalytical factors, whereas our low malignancy rate may be related to population and health care accessibility. Our nonneoplastic ROM was 17.5% compared with 5% to 10% in the literature, likely due to the relatively small number of excised cases; the ROM for SUMP was 17.1% versus 21% to 44% in the literature, possibly reflecting a significant proportion of benign basaloid neoplasms on histology. Interestingly, all false-negative cases in the nonneoplastic category were lymphoid-rich lesions., Conclusion: This is one of the largest single-institution studies in the existing literature documenting both the incidence and ROMs of MSRSGC categories. We also highlight specific challenges surrounding lymphoid-rich lesions., (© 2020 American Cancer Society.)

Purpose: This study examined the prevalence of financial toxicity (FT) and associated factors among urologic cancer patients. The association between FT and health-related quality of life (HRQoL) was also investigated., Methods: A total of 429 respondents diagnosed with urologic cancers (prostate cancer, bladder and renal cancer) from Sarawak General Hospital and Subang Jaya Medical Centre in Malaysia were interviewed using a structured questionnaire. Objective and subjective FT were measured by catastrophic health expenditure (healthcare-cost-to-income ratio greater than 40%) and the Personal Financial Well-being Scale, respectively. HRQoL was measured with the Functional Assessment of Cancer Therapy - General 7 Items scale., Results: Objective and subjective FT were experienced by 16.1 and 47.3% of the respondents, respectively. Respondents who sought treatment at a private hospital and had out-of-pocket health expenditures were more likely to experience objective FT, after adjustment for covariates. Respondents who were female and had a monthly household income less than MYR 5000 were more likely to experience average to high subjective FT. Greater objective FT (OR = 2.75, 95% CI 1.09-6.95) and subjective FT (OR = 4.68, 95% CI 2.63-8.30) were associated with poor HRQoL., Conclusions: The significant association between both objective and subjective FT and HRQoL highlights the importance of reducing FT among urologic cancer patients. Subjective FT was found to have a greater negative impact on HRQoL.

Caregiving insensitivity and fear dysregulation predict anxiety symptoms in children. It is unclear, however, whether sensitive parental care during infancy predicts fear regulation later in childhood. To address this question, we asked whether observed maternal sensitivity, measured at 6 months, predicts 42-month-old children's laboratory-induced fear responses (n=213) during a fear-eliciting episode. We predicted that higher levels of maternal sensitivity would be associated with greater fear regulation. We operationalized fear regulation as decreases in fear over repeated trials of a novel, potentially frightening, stimulus. Two aspects of fear responses were considered: expressed fear and startle. Expressed fear scores did not decrease over time but children exhibited less startle behavior in the second half of the task. Maternal sensitivity predicted this startle attenuation across trials. These findings highlight the contribution of maternal sensitivity during infancy to the development of fear regulation in early childhood, further suggesting its influence on offspring anxiety problems.

Background Shengui Sansheng Pulvis (SSP) has about 300 years history used for stroke treatment, and evidences suggest it has beneficial effects on neuro-angiogenesis and cerebral energy metabolic amelioration post-stroke. However, its protective action and mechanisms on blood-brain barrier (BBB) is still unknown. Purpose Based on multiple neuroprotective properties of vasoactive intestinal peptide (VIP) in neurological disorders, we investigate if SSP maintaining BBB integrity is associated with VIP pathway in rat permanent middle cerebral artery occlusion (MCAo) model. Methods Three doses of SSP extraction were administered orally. Evaluations of motor and balance abilities and detection of brain edema were performed, and BBB permeability were assessed by Evans blue (EB) staining. Primary brain microvascular endothelial cells (BMECs) were subjected to oxygen-glucose deprivation, and incubated with high dose SSP drug-containing serum and VIP-antagonist respectively. Transendothelial electrical resistance (TEER) assay and Tetramethylrhodamine isothiocyanate (TRITC)-dextran (4.4 kDa) and fluorescein isothiocyanate (FITC)-dextran (70 kDa) were used to evaluate the features of paracellular junction. Western blot detected the expressions of Claudin-5, ZO-1, Occludin and VE-cadherin, matrix metalloproteinase (MMP) 2/9 and VIP receptors 1/2, and immunofluorescence staining tested VIP and Claudin-5 expressions. Results Our results show that SSP significantly reduces EB infiltration in dose-dependent manner in vivo and attenuates TRITC- dextran and FITC-dextran diffusion in vitro, and strengthens endothelial junctional complexes as represented by decreasing Claudin-5, ZO-1, Occludin and VE-cadherin degradations and MMP 2/9 expression, as well as promoting TEER in BMECs after ischemia. Moreover, it suggests that SSP notably enhances VIP and its receptors 1/2 expressions. VIP-antagonist exacerbates paracellular barrier of BMECs, while the result is reversed after incubation with high dose SSP drug-containing serum. Additionally, SSP also improve brain edema and motor and balance abilities after ischemic stroke. Conclusions we firstly demonstrate that the ameliorated efficacy of SSP on BBB permeability is related to the enhancements of VIP and its receptors, suggesting SSP might be an effective therapeutic agent on maintaining BBB integrity post-stroke., Competing Interests: Declaration of Competing Interest All authors declare that they have no competing interests., (Copyright © 2019 Elsevier GmbH. All rights reserved.)

Damage to the drug diffusion coat barrier of controlled release pellets by the compaction force when preparing multiple-unit pellet system tablets is a major concern. Previous studies have shown that pellets located at the tablet axial and radial peripheral surfaces were more susceptible to damage when compacted due to the considerable shear encountered at these locations. Hence, this study was designed to assess with precision the impact of pellet spatial position in the compact on the extent of coat damage by the compaction force via a single pellet in minitablet (SPIM) system. Microcrystalline cellulose (MCC) pellet cores were consecutively coated with a drug layer followed by a sustained release layer. Chlorpheniramine maleate was the model drug used. Using a compaction simulator, the coated pellets were compacted singly into 3 mm diameter SPIMs with MCC as the filler. SPIMs with individual pellets placed in seven positions were prepared. The uncompacted and compacted coated pellets, as SPIMs, were subjected to drug release testing. The dissolution results showed that pellets placed at the top-radial position were the most susceptible to coat damage by the compaction force, while pellets positioned within the minitablet at the middle and upper quadrant positions showed the least damage. The SPIM system was found to be effective at defining the extent of coat damage to the pellet spatial position in the compact. This study confirmed that coated pellets located at the periphery were more susceptible to damage by compaction, with pellets located at the top-radial position showing the greatest extent of coat damage. However, if the pellet was completely encrusted by the cushioning filler, coat damage could be mitigated. Further investigations were directed at how the extent of coat damage impacted drug release. Interestingly, small punctures were found to be most detrimental to drug release whilst coats with large surface cuts did not completely fail. A damaged pellet coat has some self-sealing ability and failure is not total. Thus, this study provides a deeper understanding of the consequence of coat damage to drug release when sustained release coated pellets are breached., (Copyright © 2019 Elsevier B.V. All rights reserved.)

A new type of ion source is being developed for proton beam writing and other focused ion beam applications. The potential of this source as well as achieved performance of the nano aperture ion source will be evaluated. Based on the ideal source parameters, critical geometrical parameters constraining chromatic aberrations and a possible pathway to achieve this performance will be presented. Finally, an electronic control system to minimize chromatic and spherical aberrations to an acceptable level will be demonstrated.

Maternal care may predict limbic development, though relations may vary by age and type of assessment. Here, we examined maternal behavior during early infancy (i.e., six months postpartum) in relation to offspring hippocampal and amygdala volume and microstructure development between 4.5 (n = 99) and 6 (n = 111) years. In interaction with offspring sex, maternal sensitivity predicted left amygdala volume at 6.0 years (β=-0.214, p = 0.032, df = 89) and independently predicted predominately left lateralized aspects of amygdala and hippocampal microstructure at both time points (hippocampus: left FA at 4.5 years [β=-0.241, p = 0.043, df = 68], and, in interaction with sex, left [(β = 0.349, p = 0.022, df = 86) and right FA at 6 years (β = 0.357, p = 0.016, df = 86] and left MD growth [β = -0.517, p = 0.021, df = 37]; amygdala: left MD at 4.5 years [β = -0.319, p = 0.007, df = 69] and, in interaction with offspring sex, left MD growth [β = -0.546, p = 0.019, df = 37]). Results suggest exposure to non-extreme, early insensitive care impacts neuroanatomy important to learning and stress regulation, perhaps by accelerating development. This underscores the need to promote sensitive caregiving during early infancy within community samples., (Copyright © 2019 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: To examine the results of the Malaysian Advanced Prostate Cancer Consensus Conference (MyAPCCC) 2018, held for assessing the generalizability of consensus reached at the Advanced Prostate Cancer Consensus Conference (APCCC 2017) to Malaysia, a middle-income country., Methods: Six key sections were chosen: (1) high-risk localized and locally advanced prostate cancer, (2) oligometastatic prostate cancer, (3) castration-naïve prostate cancer, (4) castrate resistant prostate cancer, (5) use of osteoclast-targeted therapy and (6) global access to prostate cancer drugs. There were 101 consensus questions, consisting of 91 questions from APCCC 2017 and 10 new questions from MyAPCCC 2018, selected and modified by the steering committee; of which, 23 questions were assessed in both ideal world and real-world settings. A panel of 22 experts, comprising of 11 urologists and 11 oncologists, voted on 101 predefined questions anonymously. Final voting results were compared with the APCCC 2017 outcomes., Results: Most voting results from the MyAPCCC 2018 were consistent with the APCCC 2017 outcomes. No consensus was achieved for controversial topics with little level I evidence, such as management of oligometastatic disease. No consensus was reached on using high-cost drugs in castration-naïve or castration-resistant metastatic prostate cancer in real-world settings. All panellists recommended using generic drugs when available., Conclusions: The MyAPCCC 2018 voting results reflect the management of advanced prostate cancer in a middle-income country in a real-world setting. These results may serve as a guide for local clinical practices and highlight the financial challenges in modern healthcare., (© 2019 The Authors BJU International © 2019 BJU International Published by John Wiley & Sons Ltd.)

Attachment disorganization is a risk factor for difficulties in attention, social relationships, and mental health. Conceptually, attachment disorganization may indicate a breakdown in fear regulation resulting from repeated exposure to frightening maternal care. In addition, past research has examined the influence of stress-inducing contextual factors and/or child factors upon the development of disorganization. However, no past work has assessed whether infant neuroanatomy, important to stress regulation, moderates the association between maternal care and levels of disorganized behavior. Here, utilizing data from a subsample of 82 dyads taking part in the "Growing Up in Singapore towards Healthy Outcomes" (GUSTO) cohort, we assessed the prediction from maternal sensitive caregiving at 6 mo and levels of attachment disorganization at 1.5 y, as moderated by hippocampal and amygdala volume determined within the first 2 weeks of life. Results indicate a significant interaction between neonatal left hippocampal volume and maternal sensitivity upon levels of disorganized behavior. Although these results require substantiation in further research, if replicated, they may enable new strategies for the identification of processes important to child mental health and points for intervention. This is because neonatal neuroanatomy, as opposed to genetic variation and sociodemographic risk, may be more directly linked to stress responses within individuals., Competing Interests: The authors declare no conflict of interest.