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Kai-Ming Jhang,1,* Wen-Fu Wang,1,2,* Hsin-Fang Chang,3,* Ming-Che Chang,4 Hsin-Hung Wu3,5,6 1Department of Neurology, Changhua Christian Hospital, Changhua, Taiwan; 2Department of Holistic Wellness, Ming Dao University, Changhua, Taiwan; 3Department of Business Administration, National Changhua University of Education, Changhua, Taiwan; 4Department of Nuclear Medicine, Changhua Christian Hospital, Changhua, Taiwan; 5Department of M-Commerce and Multimedia Applications, Asia University, Taichung City, Taiwan; 6Faculty of Education, State University of Malang, Malang, East Java, Indonesia*These authors contributed equally to this workCorrespondence: Hsin-Hung Wu Email hhwu@cc.ncue.edu.twPurpose: The aim of this study was to elucidate the factors and caring scenarios associated with a moderate to severe care burden in the caregivers of patients with vascular cognitive impairment (VCI).Patients and Methods: This cross-sectional study included 158 patients with VCI and their caregivers who were managed by the dementia collaborative care team at Changhua Christian Hospital, Taiwan. Gender, age, clinical dementia rating, walking ability, behavioral symptoms, and psychological symptoms were the variables from the patients with VCI. Age, marital status, relation to the VCI patient, education, employment status, help of key activities, type of primary care, frequency of care, ZBI (Zarit burden interview) caregiving burden, and caregiver’s mood were the evaluated variables for the caregivers. The Apriori algorithm was used to identify the attributes that resulted in different caregiving burdens from a comprehensive viewpoint of both VCI patients and their caregivers.Results: A total of 1193 rules were identified with 1134 rules belonging to caregivers with a mild to moderate burden and 59 rules belonging to caregivers with a moderate to severe burden. Seven general rules were created based on a summary of these 59 rules. The results showed that an employed female caregiver who was taking care of her husband alone for ≥ 6 days per week, and who was helping with all key activities was likely to experience a moderate to severe burden when the patient had VCI. Moreover, if the caregiver had a relatively low education level and expressed an abnormal mood during the assessment, this increased the likelihood of the caregiver having a moderate to severe burden.Conclusion: The caregiver’s gender, relation to the care recipient, education level, mood status, employment status, and care loading were associated with a higher burden of care for caregivers of patients with VCI. Therefore, a dementia care team should provide personalized training for caregivers about the disease, care skills for specific behaviors and psychological symptoms of dementia (BPSD), and strategies to cope with their own feelings. Caregivers should also be referred to appropriate social resources, such as support groups or respite care.Keywords: vascular cognitive impairment, dementia, caregivers, caregiving burden, Zarit burden interview, caring scenario, Apriori algorithm

Kai-Ming Jhang,1,* Wen-Fu Wang,1,2,* Hao-Fang Chang,3,* Yu-Huei Liu,4– 6,* Ming-Che Chang,7 Hsin-Hung Wu3,8,9 1Department of Neurology, Changhua Christian Hospital, Changhua, Taiwan; 2Department of Holistic Wellness, Ming Dao University, Changhua, Taiwan; 3Department of Business Administration, National Changhua University of Education, Changhua, Taiwan; 4Graduate Institute of Integrated Medicine, China Medical University, Taichung City, Taiwan; 5Drug Development Center, China Medical University, Taichung City, Taiwan; 6Department of Medical Genetics and Medical Research, China Medical University Hospital, Taichung City, Taiwan; 7Department of Nuclear Medicine, Changhua Christian Hospital, Changhua, Taiwan; 8Department of M-Commerce and Multimedia Applications, Asia University, Taichung City, Taiwan; 9Faculty of Education, State University of Malang, Malang, East Java, Indonesia*These authors contributed equally to this workCorrespondence: Hsin-Hung Wu No. 2 Shida Road, Changhua City 500, TaiwanTel +886 4 7232105 ext. 7412Fax +886 4-7211292Email hhwu@cc.ncue.edu.twPurpose: The aim of this study was to identify the care needs of male patients with vascular cognitive impairment (VCI) and their caregivers.Patients and Methods: This cross-sectional study enrolled 389 male patients with VCI and their caregivers who were cared for by the dementia collaborative care team at Changhua Christian Hospital, Taiwan. Fifteen care needs consisting of most of quality measures for people living with dementia and their caregivers were developed by the care team. Through face-to-face evaluations, individualized care needs were collected. The Apriori algorithm was used to identify care bundles for the patients and their caregivers.Results: Six basic care needs for patients and their caregivers were identified, including appropriate schedule of activities, regular outpatient follow-up treatment, introduction and referral of social resources, referral to family support groups and care skills training, care for the mood of the caregiver, and health education for dementia and behavioral and psychological symptoms of dementia. Compared to subjects with all dementia subtypes from the previous studies, care for the mood of the caregiver was an important and frequent care need for the male patients with VCI and their caregivers. A comparison among the study and similar studies was made to highlight the strength of this study concentrating on the precise selection of care needs.Conclusion: Collaborative dementia care teams should monitor for caregivers’ depression and include this care need into the care bundle when assessing male subjects with VCI.Keywords: male patients with vascular cognitive impairment, people living with dementia, behavioral and psychological symptoms of dementia, dementia collaborative care model, care need, Apriori algorithm

Trust is often posited to substitute for management control in interfirm transactions. However, this raises questions of how trust arises in new relationships, and whether trust that is not based on prior experience transacting together is sufficient to persuade managers to forgo investments in management controls. We use an experiment to test whether two features of the early stage of an interfirm relationship influence a buyer's initial trust in a supplier and have consequences for subsequent investments in management controls and in the collaboration. These two features are the autonomy of the buyer's manager to choose a supplier (i.e., delegation of decision-making authority) and the supplier's willingness to share information with the buyer. We find that the buyer manager's initial trust in the supplier is associated positively with both the autonomy to choose the supplier and the supplier's willingness to share information. Information content and supplier characteristics are held constant, so these results are novel and distinct from prior studies of the antecedents of trust. We find that higher initial trust is associated with reduced expenditures for management controls and increased investments in the collaboration. Thus, we conclude that delegation of decision-making authority and supplier information-sharing behavior in the early stages of a relationship influence the formation of initial trust, which has real consequences for investments in management control and in the collaboration.

Objective: To study the patterns and morphologic characteristics of blunt head injury and analyse its formative mechanism in attempt to provide references for medicolegal expertise.Methods: The statistical analysis was done in terms of gender, age, as well as the nature, pattern, location, and feature of the injuries.Results: Among the 202 cases of head injury-induced death, 124 were male and 78 female with the age ranging from 1-81 years. Death caused by homicide was dominant (106, 52.5%), followed by suicide (49, 24.3%) and accident (44, 21.8%). The majority of suicide-induced death were by falling from height, and traffic crash was responsible for majority of unexpected death cases. The morphology and pathogenesis of the injuries varied according to differences on the mode, magnitude, and orientation of the outside force giving rise to blunt injury as well as the character of vulnerants.Conclusion: Studies on the morphology and its formative rationale of blunt head injury will offer easy access to medicolegal expertise on the mode and character of the injury. [ABSTRACT FROM AUTHOR]

Objective: By studying the mode and morphologic character of high fall injuries on the scene, and exploring the injury situation of different heights, different fall ways and postures, to provide a reference for the forensic identification of high fall injury.Methods: All the high fall cases were statistically analysed according to their gender, age, ground-touching posture, fall height, site and type of the injury.Results: Among 134 high fall cases, 98 were male and 36 were female with the age ranging from 2-71 years (37.6+/-16.9 on average), in which, 10-60 years old group consisted of 110 cases (82%). Most cases fell from windows or roofs (73%) and the touching objects were cement ground or shaft bottom of elevators. Among these cases, head injury was generally serious, followed by chest and abdominal injuries. The morphologic changes depend upon the height, nature, as well as the posture at the point while the body touches the ground.Conclusion: Morphologic study of high fall injury assists medicolegal physicians to make correct identifications of the cause and nature of high fall injuries. [ABSTRACT FROM AUTHOR]

Morphinan antagonists, which block opioid effects at mu-opioid receptors, have been studied for their analgesic potential. Previous studies have suggested that these antagonists elicit analgesia with fewer adverse effects in the presence of the mutant mu-opioid receptor (MOR; S196A). However, introducing a mutant receptor for medical applications represents significant challenges. We hypothesize that binding a chemical compound to the MOR may elicit a comparable effect to the S196A mutation. Through high-throughput screening and structure-activity relationship studies, we identified a modulator, 4-(2-(4-fluorophenyl)-4-oxothiazolidin-3-yl)-3-methylbenzoic acid (BPRMU191), which confers agonistic properties to small-molecule morphinan antagonists, which induce G protein-dependent MOR activation. Co-application of BPRMU191 and morphinan antagonists resulted in MOR-dependent analgesia with diminished side effects, including gastrointestinal dysfunction, antinociceptive tolerance, and physical and psychological dependence. Combining BPRMU191 and morphinan antagonists could serve as a potential therapeutic strategy for severe pain with reduced adverse effects and provide an avenue for studying G protein-coupled receptor modulation., Competing Interests: Declaration of interests S.-H.U., S.-H.Y., S.-Y.L., H.H.L., and C.S. have a granted patent (no. US10544113 B2) covering BPRMU191., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

SYNTAXIN-11 (STX11) is a SNARE protein that mediates the fusion of cytotoxic granules with the plasma membrane at the immunological synapses of CD8 T or NK cells. Autosomal recessive inheritance of deleterious STX11 variants impairs cytotoxic granule exocytosis, causing familial hemophagocytic lymphohistiocytosis type 4 (FHL-4). In several FHL-4 patients, we also observed hypogammaglobulinemia, elevated frequencies of naive B cells, and increased double-negative DN2:DN1 B cell ratios, indicating a hitherto unrecognized role of STX11 in humoral immunity. Detailed analysis of Stx11-deficient mice revealed impaired CD4 T cell help for B cells, associated with disrupted germinal center formation, reduced isotype class switching, and low antibody avidity. Mechanistically, Stx11-/- CD4 T cells exhibit impaired membrane fusion leading to reduced CD107a and CD40L surface mobilization and diminished IL-2 and IL-10 secretion. Our findings highlight a critical role of STX11 in SNARE-mediated membrane trafficking and vesicle exocytosis in CD4 T cells, important for successful CD4 T cell-B cell interactions. Deficiency in STX11 impairs CD4 T cell-dependent B cell differentiation and humoral responses., (© 2024 Kögl et al.)

We previously reported that a combined myo -inositol, probiotics, and enriched micronutrient supplement (intervention) taken preconception and in pregnancy reduced postpartum blood loss (PBL) and major postpartum hemorrhage compared with a standard micronutrient supplement (control), as secondary outcomes of the NiPPeR trial. This study aimed to identify the intervention components that may contribute to this effect. Associations of plasma concentrations of myo -inositol and vitamins B2, B6, B12, and D at preconception (before and after supplementation), early (~7-weeks), and late pregnancy (~28-weeks) with PBL were assessed by multiple linear regression, adjusting for site, ethnicity, preconception BMI, parity, and previous cesarean section. Amongst 583 women, a higher concentration of myo -inositol in early pregnancy was associated with a PBL reduction [β adj -1.26 (95%CI -2.23, -0.29) mL per µmol/L myo -inositol increase, p = 0.011]. Applying this co-efficient to the increase in mean 7-week- myo -inositol concentration of 23.4 µmol/L with the intervention equated to a PBL reduction of 29.5 mL (~8.4% of mean PBL of 350 mL among controls), accounting for 84.3% of the previously reported intervention effect of 35 mL. None of the examined vitamins were associated with PBL. Therefore, myo -inositol may be a key intervention component mediating the PBL reduction. Further work is required to determine the mechanisms involved., Competing Interests: S.-Y.C., W.S.C., and K.M.G. are part of an academic consortium that report grants from Société Des Produits Nestlé S.A. during the conduct of the study and are co-inventors on patent filings by Nestlé S.A. relating to the NiPPeR intervention or its components. S.-Y.C. has received reimbursement and honoraria into her research funds from Nestlé Nutrition Institute and EGOI (Experts Group on Inositols) for speaking at conferences. K.M.G. has received reimbursement for speaking at conferences sponsored by companies selling nutritional products. L.L., J.M.R.-N., J.-P.G., and I.S.-Z. are employees of Société Des Produits Nestlé S.A. All other authors declare no competing interests.

Aim: Myo-inositol supplementation from ~13 weeks' gestation reportedly improves glycaemia regulation in metabolically at-risk women, with speculation that earlier supplementation might bring further improvement. However, the NiPPeR trial of a myo-inositol-containing supplement starting preconception did not lower gestational glycaemia in generally healthy women. We postulated that the earlier timing of supplementation influences the maternal metabolic adaptation for gestational glycaemia regulation., Methods: In total, 585 women were recruited from Singapore, UK and New Zealand for the NiPPeR study. We examined associations of plasma myo-inositol concentrations at 7 and 28 weeks' gestation with 28 weeks plasma glucose (PG; fasting, and 1 h and 2 h in 75 g oral glucose tolerance test) and insulin indices using linear regression adjusting for covariates., Results: Higher 7-week myo-inositol, but not 28-week myo-inositol, associated with higher 1 h PG [β adj (95% confidence intervals) 0.05 (0.01, 0.09) log e mmol/L per log e μmol/L, p = .022] and 2 h PG [0.08 (0.03, 0.12), p = .001]; equivalent to 0.39 mmol/L increase in 2 h PG for an average 7-week myo-inositol increase of 23.4 μmol/L with myo-inositol supplementation. Higher 7-week myo-inositol associated with a lower 28-week Stumvoll index (first phase), an approximation of insulin secretion [-0.08 (-0.15, -0.01), p = .020] but not with 28-week Matsuda insulin sensitivity index. However, the clinical significance of a 7-week myo-inositol-related increase in glycaemia was limited as there was no association with gestational diabetes risk, birthweight and cord C-peptide levels. In-silico modelling found higher 28-week myo-inositol was associated with lower gestational glycaemia in White, but not Asian, women after controlling for 7-week myo-inositol effects., Conclusion: To our knowledge, our study provides the first evidence that increasing first trimester plasma myo-inositol may slightly exacerbate later pregnancy post-challenge glycaemia, indicating that the optimal timing for starting prenatal myo-inositol supplementation needs further investigation., (© 2024 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Thallium (Tl) is a non-essential metal mobilized through industrial processes which can lead to it entering the environment and exerting toxic effects. Plants are fundamental components of all ecosystems. Therefore, understanding the impact of Tl on plant growth and development is of great importance for assessing the potential environmental risks of Tl. Here, the responses of Arabidopsis thaliana to Tl were elucidated using physiological, genetic, and transcriptome analyses. Thallium can be absorbed by plant roots and translocated to the aerial parts, accumulating at comparable concentrations throughout plant parts. Genetic evidence supported the regulation of Tl uptake and movement by different molecular compartments within plants. Thallium primarily caused growth inhibition, oxidative stress, leaf chlorosis, and the impairment of K homeostasis. The disturbance of redox balance toward oxidative stress was supported by significant differences in the expression of genes involved in oxidative stress and antioxidant defense under Tl exposure. Reduced GSH levels in cad2-1 mutant rendered plants highly sensitive to Tl, suggesting that GSH has a prominent role in alleviating Tl-triggered oxidative responses. Thallium down-regulation of the expression of LCHII-related genes is believed to be responsible for leaf chlorosis. These findings illuminate some of the mechanisms underlying Tl toxicity at the physiological and molecular levels in plants with an eye toward the future environment management of this heavy metal., 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 The Authors. Published by Elsevier Inc. All rights reserved.)

Observational studies have reported associations between nutrition during pregnancy and mental wellbeing. As secondary outcomes, the NiPPeR double-blind randomized trial in women planning conception investigated whether a myo-inositol, probiotics and enriched micronutrients formulation (intervention) taken preconception and throughout pregnancy could improve mental wellbeing during pregnancy and post-delivery, compared with a standard micronutrient supplement (control). Mood and anxiety symptoms were ascertained (Edinburgh Postnatal Depression Scale (EPDS), State-Trait Anxiety Inventory (STAI-state)) at preconception (baseline), 7, 28 and 34 weeks gestation, 3-weeks and 6-months post-delivery. EPDS>=13 was categorised as low mood; STAI-state>=45 as high anxiety. Change in mental health functioning was assessed as difference between preconception baseline and 6-month post-delivery 12-item Short-Form Health Survey (SF-12v2) mental component scores. Adjusting for site, ethnicity and baseline scores, there were no robust differences in EPDS and STAI-state scores between intervention and control groups across pregnancy (n = 630) and post-delivery (n = 532). Compared to controls, intervention group women averaged a 1.21 (95 %CI 0.04,2.39) higher change in SF-12v2 mental component score from preconception to 6-months post-delivery. Taking a myo-inositol, micronutrient and probiotic supplement during preconception/pregnancy had no effect on mood and anxiety, but there was evidence of a modest improvement in mental health functioning from preconception to 6-months post-delivery., Competing Interests: Declaration of competing interest KG, YSC, WC and SC report grants from Société Des Produits Nestlé S.A. during the conduct of the study, and are co-inventors on patent filings by Nestlé S.A. relating to the NiPPeR intervention or its components. KG, SB, YSC, WC and SC are part of an academic consortium that has received grants from Nestlé S.A. and BenevolentAI Bio Ltd outside the submitted work. All other authors declare no competing interests, (Copyright © 2024. Published by Elsevier B.V.)

Electric fields (EF) play an essential role in cancer cell migration. Numerous cancer cell types exhibit electrotaxis under direct current electric fields (dcEF) of physiological electric field strength (EFs). This study investigated the effects of doxycycline on the electrotactic responses of U87 cells. After EF stimulation, U87 cells migrated toward the cathode, whereas doxycycline-treated U87 cells exhibited enhanced cell mobility but hindered cathodal migration. We further investigated the expression of the metastasis-correlated proteins matrix metallopeptidase-2 (MMP-2) and MMP-9 in U87 cells. The levels of MMP-2 in the cells were not altered under EF or doxycycline stimulation. In contrast, the EF stimulation greatly enhanced the levels of MMP-9 and then repressed in doxycycline-cotreated cells, accompanied by reduced cathodal migration. Our results demonstrated that an antibiotic at a non-toxic concentration could suppress the enhanced cell migration accelerated by EF of physiological strength. This finding may be applied as an anti-metastatic treatment for cancers., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Authors.)

Objective: Parents of children who died of a medical condition experience a range of psychosocial outcomes. The current scoping review aims to summarize the outcomes assessed, methodology, and sample characteristics of recent psychosocial research conducted with this population., Methods: Included studies were limited to peer-reviewed, psychosocial outcomes research published between August 2011 and August 2022, written in English, and including caregiver study participants of children who died of a medical condition. Data sources were scholarly journal articles from 9 electronic databases, including Scopus, Web of Science, Academic Search Primer, ProQuest Research Library, PubMed, Embase, PsycINFO, Psychology & Behavioral Sciences Collection, and Health Source: Nursing/Academic Edition. The Mixed Methods Appraisal Tool-2018 evaluated methodological quality., Results: The study sample included 106 studies, most of which were either qualitative (60%) or quantitative (29%). Mixed-methods studies (8%) and randomized clinical trials (2%) were also identified. Study quality was variable, but most studies met all quality criteria (73%). Studies primarily represented cancer populations (58%), White participants (71%), and mothers (66%). Risk-based psychosocial outcomes (e.g., grief) were more commonly assessed than resilience-based outcomes., Conclusions: The current scoping review revealed that recent research assessing the psychosocial outcomes of bereaved parents is limited in the representation of diverse populations, primarily qualitative, of broadly strong methodological quality, and oriented to psychosocial risk. To enhance the state of the science and inform evidence-based psychosocial services, future research should consider varied methodologies to comprehensively assess processes of risk and resilience with demographically and medically diverse populations., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society of Pediatric Psychology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Glutathione (GSH) is a major antioxidant in organisms. An alteration in GSH concentration has been implicated in a number of pathological conditions. Therefore, GSH sensing has become a critical issue. In this study, a disposable strip used for tyrosinase-modified electrochemical testing was fabricated for the detection of GSH levels in vivo . The system is based on tyrosinase as a biorecognition element and a screen-printed carbon electrode (SPCE) as an amperometric transducer. On the tyrosinase-SPCE strips, the oxidation reaction from catechol to o -quinone was catalyzed by tyrosinase. The tyrosinase-SPCE strips were modified with gold nanoparticles (AuNPs). In the presence of AuNPs of 25 nm diameter, the cathodic peak current of cyclic voltammetry (CV) was significantly enhanced by 5.2 fold. Under optimized conditions (250 μM catechol, 50 mM phosphate buffer, and pH 6.5), the linear response of the tyrosinase-SPCE strips ranged from 31.25 to 500 μM GSH, with a detection limit of approximately 35 μM (S/N > 3). The tyrosinase-SPCE strips have been used to detect real samples of plasma and tissue homogenates in a mouse experiment. The mice were orally administrated with N -acetylcysteine (NAC) 100 mg kg -1 once a day for 7 days; the plasma GSH significantly enhanced 2.8 fold as compared with saline-treated mice (1123 vs. 480 μM μg -1 protein). NAC administration also could alleviate the adverse effect of GSH reduction in the mice treated with doxorubicin., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Introduction: There are increased calls to address psychosocial needs among individuals with classical congenital adrenal hyperplasia (CAH). However, cross-cultural disparities exist in treatment practices and psychosocial outcomes that impact the generalizability of evidence-based recommendations. To date, this disparity has not been quantified. The present scoping review uses a dual approach to contrast rates of CAH diagnosis with CAH psychosocial research rates across countries., Methods: Six electronic database searches were conducted for: (1) CAH incidence/birth/prevalence rates; and (2) psychosocial research with affected individuals and their families. Two authors reviewed each abstract for inclusion criteria., Results: Sixty-eight and 93 full-text articles, respectively, were evaluated for incidence and country. The countries/regions with the highest reported CAH rates are Thailand, Ghana, and India. Those with the greatest portion of psychosocial publications are the USA, Germany, and the UK., Conclusion: A discrepancy exists between those countries with the highest CAH rates and those publishing psychosocial research. Specifically, increased rates of CAH are seen in non-Western countries/regions, whereas most psychosocial research arises out of Western Europe and the USA. Due to cultural differences between these regions, increased global collaboration is needed to both inform psychosocial research and translate findings in ways that are representative worldwide., (© 2023 S. Karger AG, Basel.)

Infantile hemangiomas (IHs) of the lips are associated with an increased risk of incomplete involution and ulceration, causing disfigurement. Treatment with oral propranolol (OPT) has credible efficacy but takes months to complete. Thus, this study aimed to investigate the efficacy of intralesional betamethasone injection (IBI) as an alternative treatment for protruding localized IHs of the lips. To investigate the efficacies of OPT and IBI, we designed a prospective, noninferiority, parallel-group study. The primary outcome assessed was treatment response rate. Secondary outcome assessments included lesion size changes and surgical rate. Additionally, complication rates and treatment durations of OPT and IBI were compared. The treatment response rate of IBI was not inferior to that of OPT (95.7% vs. 76.0%, respectively; a difference of 19.7%, 95% confidence interval [CI], -4.4% to 41.6%). The average surgical rate in the IBI group was significantly lower than that in the OPT group (8.7% vs. 40%, respectively; p = 0.012), and the average duration of treatment for IBI was shorter than that of OPT (2.1 months vs. 6.3 months, respectively; p < 0.001). There were no severe adverse drug events in either group. If not managed properly, small, localized lip IHs may cause disfigurement in a child. Our study demonstrated that IBI is as effective as OPT in treating protruding localized lip IHs. Moreover, IBI treatment has a shorter duration and lower surgical rate than OPT. With proper care, IBI is an effective treatment modality for small and localized lip IHs., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest related to the content of the manuscript., (Copyright © 2023 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.)

The compelling demand of a consummate analgesic medication without addiction is rising due to the clinical mistreatment. Additionally, the series of severe untoward effects usually deterred the utilization while coping with serious pain. As a possible turning point, we revealed that compound 14 is a dual agonist of mu opioid receptor (MOR) and nociceptin-orphanin FQ opioid peptide (NOP) receptor in this study. More importantly, compound 14 achieves pain relieving at very small doses, meanwhile, reduces several unwanted side effects such as constipation, reward, tolerance and withdrawal effects. Here, we evaluated the antinociception and side effects of this novel compound from wild type and humanized mice to further develop a safer prescription analgesic drug., 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 Elsevier Masson SAS. All rights reserved.)

Indium is a potentially toxic element that could enter human food chains, including soil-rice systems. The submerged environment in rice paddy soil results in temporal and spatial variations in the chemical properties of the rice rhizosphere and bulk soils, expected to cause changes in indium's chemical speciation and consequently affect its bioavailability. Therefore, this study aimed to investigate indium speciation and fractionation in soils at different periods of rice growth under continuous submergence using X-ray absorption spectroscopy and a sequential extraction method. The predominant indium species were identified as indium-associated Fe hydroxide, and indium hydroxide and phosphate precipitates. The reductive dissolution of indium-associated Fe hydroxides led to the release of indium into the soil solution under continuous submergence of soils, and the released indium concentration decreased with time due to re-sorption and re-precipitation. Meanwhile, indium hydroxide was found to be the predominant species in rice rhizosphere using μ-X-ray absorption spectroscopy. The relative depletion of indium-associated Fe hydroxides in the rice rhizosphere was attributed to the low mobility of indium from bulk soil to rice rhizosphere and the root uptake of indium associated with Fe hydroxide around rice roots. Consequently, indium uptake by rice roots was lower during the reproductive and grain-ripening stage of rice growth. Understanding the behavior of indium will help develop a strategy to minimize uptake into crops in indium-contaminated paddy soils., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Shan-Li Wang reports financial support was provided by National Council of Science and Technology. Shan-Li Wang reports financial support was provided by National Taiwan University., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Aldosterone excess is present in obesity and is associated with involvement in the pathogenesis of obesity. We evaluate the impact of body obesity as measured by body composition monitor (BCM) on clinical outcomes in patients with unilateral primary aldosteronism (uPA) after adrenalectomy. The BCM device was used to assess body composition before and after adrenalectomy. We used fat mass (FM) and body mass index (BMI) to classify obesity and divided obesity into three groups: clinical overweight (BMI (kg/m 2 ) ≥25); normal weight obesity (NWO, FM (%) ≥ 35 for women, >25 for men & BMI < 25); and no obesity (FM < 35 for women, <25 for men & BMI < 25). A total of 130 unilateral PA (uPA) patients received adrenalectomy, and 27 EH patients were identified; uPA patients with hypertension remission were found to have lower FM (p = 0.046), BMI (p < 0.001), and lower prevalence of overweight (p = 0.001). In the logistic regression model, patients with clinical overweight (OR = 2.9, p = 0.007), NWO (OR = 3.04, p = 0.041) and longer HTN duration (years, OR = 1.065, p = 0.013) were at the risk of persistent hypertension after adrenalectomy. Obesity status was strongly associated with persistent hypertension in uPA patients after adrenalectomy. However, patients in the NWO group also carried higher risk of persistent hypertension. Therefore, assessment of pre-obesity and overweight in uPA patients are extremely important, especially in those who have normal BMI., (© 2023. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

Objective: To determine whether a combined myo-inositol, probiotics and micronutrient nutritional supplement impacts time-to-natural-conception and clinical pregnancy rates., Design: Secondary outcomes of a double-blind randomized controlled trial., Setting: Community recruitment., Patients: Women aged 18 to 38 years planning to conceive in the United Kingdom, Singapore, and New Zealand, excluding those with diabetes mellitus or receiving fertility treatment., Intervention: A standard (control) supplement (folic acid, iron, calcium, iodine, β-carotene), compared with an intervention additionally containing myo-inositol, probiotics, and other micronutrients (vitamins B2, B6, B12, D, zinc)., Main Outcome Measures: Number of days between randomization and estimated date of natural conception of a clinical pregnancy, as well as cumulative pregnancy rates at 3, 6, and 12 months., Results: Of 1729 women randomized, 1437 (83%; intervention, n=736; control, n=701) provided data. Kaplan-Meier curves of conception were similar between intervention and control groups; the time at which 20% achieved natural conception was 90.5 days (95% confidence interval: 80.7, 103.5) in the intervention group compared with 92.0 days (76.0, 105.1) in the control group. Cox's proportional hazard ratios (HRs) comparing intervention against control for cumulative achievement of pregnancy (adjusted for site, ethnicity, age, body mass index, and gravidity) were similar at 3, 6, and 12 months. Among both study groups combined, overall time-to-conception lengthened with higher preconception body mass index, and was longer in non-White than in White women. Among women who were overweight the intervention shortened time-to-conception compared with control regardless of ethnicity (12-month HR=1.47 [1.07, 2.02], P=.016; 20% conceived by 84.5 vs. 117.0 days) and improved it to that comparable to nonoverweight/nonobese women (20% conceived by 82.1 days). In contrast, among women with obesity, time-to-conception was lengthened with intervention compared with control (12-month HR=0.69 [0.47, 1.00]; P=.053; 20% conceived by 132.7 vs. 108.5 days); an effect predominantly observed in non-White women with obesity., Conclusions: Time-to-natural-conception and clinical pregnancy rates within a year were overall similar in women receiving the intervention supplement compared with control. Overweight women had a longer time-to-conception but there was suggestion that the supplement may shorten their time-to-conception to that comparable to the nonoverweight/nonobese women. Further studies are required to confirm this., Clinical Trial Registration Number: clinicaltrials.gov (NCT02509988)., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Numerous alterations in CD8 + T cells contribute to impaired immune responses in elderly individuals. However, the discrimination between cell-intrinsic dysfunctions and microenvironmental changes is challenging. TCR transgenic OT-I mice are utilized to investigate CD8 + T-cell immunity, but their immunodeficient phenotype hampers their use especially in aging. Here, we demonstrate that using a heterozygous OT-I model minimizes the current limitations and provides a valuable tool to assess antigen-specific T-cell responses even at old age. We analyzed phenotypic and functional characteristics of CD8 + T cells from OT-I +/+ and OT-I +/- mice to prove the applicability of the heterozygous system. Our data reveal that OVA-activated CD8 + T cells from adult OT-I +/- mice proliferate, differentiate, and exert cytolytic activity equally to their homozygous counterparts. Moreover, common age-related alterations in CD8 + T cells, including naive T-cell deterioration and decreased proliferative capacity, also occur in elderly OT-I +/- mice, indicating the wide range of applications for in vivo and in vitro aging studies. We used the OT-I +/- model to investigate cell-intrinsic alterations affecting the cytotoxic behavior of aged CD8 + T cells after antigen-specific in vitro activation. Time-resolved analysis of antigen-directed target cell lysis confirmed previous observations that the cytotoxic capacity of CD8 + T cells increases with age. Surprisingly, detailed single cell analysis revealed that transcriptional upregulation of perforin in aged CD8 + T cells shifts the mode of target cell death from granzyme-mediated apoptosis to rapid induction of necrosis. This unexpected capability might be beneficial or detrimental for the aging host and requires detailed evaluation., (© 2023 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Regulated exocytosis is a central mechanism of cellular communication. It is not only the basis for neurotransmission and hormone release, but also plays an important role in the immune system for the release of cytokines and cytotoxic molecules. In cytotoxic T lymphocytes (CTLs), the formation of the immunological synapse is required for the delivery of the cytotoxic substances such as granzymes and perforin, which are stored in lytic granules and released via exocytosis. The molecular mechanisms of their fusion with the plasma membrane are only partially understood. In this review, we discuss the molecular players involved in the regulated exocytosis of CTL, highlighting the parallels and differences to neuronal synaptic transmission. Additionally, we examine the strengths and weaknesses of both systems to study exocytosis., 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 Chang, Schirra, Pattu, Krause and Becherer.)

Cytotoxic CD8+ T cells contribute to neuronal damage in inflammatory and degenerative CNS disorders, such as multiple sclerosis (MS). The mechanism of cortical damage associated with CD8+ T cells is not well understood. We developed in vitro cell culture and ex vivo brain slice co-culture models of brain inflammation to study CD8+ T cell-neuron interactions. To induce inflammation, we applied T cell conditioned media, which contains a variety of cytokines, during CD8+ T cell polyclonal activation. Release of IFNγ and TNFα from co-cultures was verified by ELISA, confirming an inflammatory response. We also visualized the physical interactions between CD8+ T cells and cortical neurons using live-cell confocal imaging. The imaging revealed that T cells reduced their migration velocity and changed their migratory patterns under inflammatory conditions. CD8+ T cells increased their dwell time at neuronal soma and dendrites in response to added cytokines. These changes were seen in both the in vitro and ex vivo models. The results confirm that these in vitro and ex vivo models provide promising platforms for the study of the molecular details of neuron-immune cell interactions under inflammatory conditions, which allow high-resolution live microscopy and are readily amenable to experimental manipulation.

Mutations in parkin, a neuroprotective protein, are the predominant cause of autosomal recessive juvenile Parkinson's disease. Neuroinflammation-derived nitrosative stress has been implicated in the etiology of the chronic neurodegeneration. However, the interactions between genetic predisposition and nitrosative stress contributing to the degeneration of dopaminergic (DA) neurons remain incompletely understood. Here, we used the SH-SY5Y neuroblastoma cells to investigate the function of parkin and its pathogenic mutants in relation to cell survival under nitric oxide (NO) exposure. The results showed that overexpression of wild-type parkin protected SH-SY5Y cells from NO-induced apoptosis in a reactive oxygen species-dependent manner. Under nitrosative stress conditions, parkin selectively upregulated the inositol-requiring enzyme 1α/X-box binding protein 1 (IRE1α/XBP1) signaling axis, an unfolded protein response signal through the sensor IRE1α, which controls the splicing of XBP1 mRNA. Inhibition of XBP1 mRNA splicing either by pharmacologically inhibiting IRE1α endoribonuclease activity or by genetically knocking down XBP1 interfered with the protective activity of parkin. Furthermore, pathogenic parkin mutants with a defective protective capacity showed a lower ability to activate the IRE1α/XBP1 signaling. Finally, we demonstrated that IRE1α activity augmented by parkin was possibly mediated through interacting with IRE1α to regulate its phosphorylation/oligomerization processes, whereas mutant parkin diminished its binding to and activation of IRE1α. Thus, these results support a direct link between the protective activity of parkin and the IRE1α/XBP1 pathway in response to nitrosative stress, and mutant parkin disrupts this function.

Background/aim: Signal transducer and activator of transcription 3 (STAT3), Janus Kinase 1 (JAK1), extracellular signal-regulated kinase (ERK), and protein kinase B (AKT) are essential for malignant transformation and progression in colorectal cancer (CRC) and can be considered as targets for therapeutic interventions. Hyperforin, an active constituent from Hypericum perforatum, has been reported to inhibit inflammation. However, whether hyperforin may suppress CRC progression via inactivation of JAK/STAT3, ERK or AKT signaling remains unclear., Materials and Methods: Human CRC cells were used to identify the treatment efficacy of hyperforin and its underlying mechanisms of action by MTT, flow cytometry, wound healing, and western blotting assays., Results: Hyperforin not only induced cytotoxicity, extrinsic/intrinsic apoptosis signaling, but also suppressed the invasion/migration ability of CRC. The phosphorylation of STAT3, JAK1, ERK and AKT was found to be decreased by hyperforin., Conclusion: Hyperforin inactivates multiple oncogenic kinases and induces apoptosis signaling in CRC cells., (Copyright © 2023, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Subcellular fractionation is an important tool used to separate intracellular organelles, structures or proteins. Here, we describe a stepwise protocol to isolate two types of lytic granules, multicore (MCG), and single core (SCG), from primary murine CTLs. We used cell disruption by nitrogen cavitation followed by separation of organelles via discontinuous sucrose density gradient centrifugation. Immunoisolation with a Synaptobrevin 2 antibody attached to magnetic beads was then used to harvest Synaptobrevin 2 positive granules for immunoblotting, mass spectrometry, electron, and light microscopy., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Currently, there is a significant unmet need for novel analgesics with fewer side effects. In this study, we carried out structural modification of a hit compound previously identified in an artificial-intelligence (AI) virtual screening and discovered the potent analgesic, benzo[b]thiophene-2-carboxamide analog (compound 25) with new structural scaffold. We investigated the signaling pathways of opioid receptors mediated by compound 25, and found this racemic compound activated mu-opioid receptor through the cyclic adenosine monophosphate (cAMP) and β-arrestin-2-mediated pathways with strong potency and efficacy, and accompanying nociceptin-orphanin FQ opioid peptide and delta-opioid receptors through the cAMP pathway with weak potencies. Compound 25 elicited potent antinociception in thermal-stimulated pain (ED 50 value of 127.1 ± 34.65 μg/kg) and inflammatory-induced allodynia models with less gastrointestinal transit inhibition and antinociceptive tolerance than morphine. Overall, this study revealed a novel analgesic with reduced risks of side effects., 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 Elsevier Masson SAS. All rights reserved.)

Extensive studies showed increased subjective pain sensitivity in Parkinson's disease (PD), which appeared to be partially reversed by dopaminergic (DA) treatment. Although cell replacement represents an attractive therapeutic strategy, its potential for PD-related hyperalgesia remains unclear. We investigated re-establishment of DA function via allografting exogenic DA cells on pain hypersensitivity in a rat model of PD. We evaluated the anti-nociceptive effects of fetal ventral mesencephalic (rVM) tissue allografts in PD rats after unilateral 6-OHDA-induced toxicity in the medial forebrain bundle. The drug -induced rotation test was used to validate the severity of the nigrostriatal lesion; von Frey and thermal pain tests were employed to evaluate nociceptive function. Nociception-induced cerebral blood volume (CBV) response was measured using a 4.7-T MR system. Finally, the immunohistochemical (IHC) studies were performed and the results were compared with the imaging findings from functional magnetic resonance imaging (fMRI). The grafts significantly improved drug-induced rotation behavior and increased mechanical and thermal nociceptive thresholds in PD rats. The elevation of CBV signals significantly recovered on the grafted striatum, whereas this effect was inhibited by the D2R antagonist eticlopride in each striatum. Quantitative IHC analysis revealed the transplantation markedly increased the numbers of tyrosine hydroxylase immunoreactive cells. Therefore, we concluded transplantation of rVM tissue results in anti-nociceptive effects and improves motor function. Moreover, in vivo CBV response confirmed the key role of D2R-mediated pain modulation. Therefore, we demonstrate fMRI as a reliable imaging index in evaluating the anti-nociceptive therapeutic effects of fetal rVM transplantation in the rat model of PD., 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 © 2022 Chiu, Weng, Yeh, Jhao, Chang, Huang, Cheng, Yeh and Ma.)

Background: Evidence that nutritional supplementation before and during pregnancy improves peripartum outcomes is sparse. In the Nutritional Intervention Preconception and During Pregnancy to Maintain Healthy Glucose Metabolism and Offspring Health (NiPPeR) trial, we previously reported that a combined myo-inositol, probiotics, and micronutrient supplement started at preconception showed no difference in the primary outcome of gestational glycemia, but did reduce the risk of preterm delivery, preterm prelabor rupture of membranes, and major postpartum hemorrhage., Objective: This study aimed to examine the hypothesis that a reduction in major postpartum hemorrhage following a combined nutritional (myo-inositol, probiotics, and micronutrients) intervention is linked with promotion of labor progress and reduced operative delivery., Study Design: This double-blind randomized controlled trial recruited 1729 women from the United Kingdom, Singapore, and New Zealand, aged 18 to 38 years, and planning conception between 2015 and 2017. The effects of the nutritional intervention compared with those of a standard micronutrient supplement (control), taken at preconception and throughout pregnancy, were examined for the secondary outcomes of peripartum events using multinomial, Poisson, and linear regression adjusting for site, ethnicity, and important covariates., Results: Of the women who conceived and progressed beyond 24 weeks' gestation with a singleton pregnancy (n=589), 583 (99%) provided peripartum data. Between women in the intervention (n=293) and control (n=290) groups, there were no differences in rates of labor induction, oxytocin augmentation during labor, instrumental delivery, perineal trauma, and intrapartum cesarean delivery. Although duration of the first stage of labor was similar, the second-stage duration was 20% shorter in the intervention than in the control group (adjusted mean difference, -12.0 [95% confidence interval, -22.2 to -1.2] minutes; P=.029), accompanied by a reduction in operative delivery for delayed second-stage progress (adjusted risk ratio, 0.61 [0.48-0.95]; P=.022). Estimated blood loss was 10% lower in the intervention than in the control group (adjusted mean difference, -35.0 [-70.0 to -3.5] mL; P=.047), consistent with previous findings of reduced postpartum hemorrhage., Conclusion: Supplementation with a specific combination of myo-inositol, probiotics, and micronutrients started at preconception and continued in pregnancy reduced the duration of the second stage of labor, the risk of operative delivery for delay in the second stage, and blood loss at delivery., (Copyright © 2022 Elsevier Inc. All rights reserved.)

We identified, via high-throughput screening using a FLIPR® calcium assay, compound 1, which incorporated a dihydroquinolinyl-2-oxoethylsulfanyl-(1H,5H)-pyrimidinedione core and activated the μ-opioid receptor (MOR) in the presence of naloxone or naltrexone. A structure-activity relationship study of the analogs of 1 led to the design of compound 21, which activated MOR in the presence of naloxone with an EC 50 of 3.3 ± 0.2 μM. MOR activation by the compound 21-antagonist pair was antagonist-dependent. Compound 21 did not affect the potency of the orthosteric agonist, morphine, toward MOR, indicating that it affected the function of MOR antagonists rather than that of the agonists. Computer modeling of the compound 21-MOR-naloxone complex revealed major interactions between compound 21 and MOR, including hydrogen bonding with Ser196, π-π stacking with Tyr149, and sulfur-aromatic interaction with Trp192. This study may pave the way for developing agents capable of safe and effective MOR modulation., 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 Elsevier Inc. All rights reserved.)

Traffic simulation is widely used for modeling, planning, and analyzing different strategies for traffic control and road development in a cost-efficient manner. In order to perform an intersection simulation, random vehicle trip data are typically applied to an intersection network, making them unrealistic. In this paper, we address this issue by presenting two different methods of incorporating actual turning movement count (TMC) data and comparing their similarity for intersection simulation and analysis. The TMC of three intersections in Las Vegas are estimated separately for one hour using a developed vision-based tracking system and they are incorporated into Simulation of Urban MObility (SUMO) for estimating traffic measurements and traffic signal design. t -tests with a 95% confidence interval on the simulation variables demonstrate the importance of using a route-based creation method which injects vehicles into a simulation environment based on the frame-level departure time. The intersection analyses and comparisons are performed based on estimated traffic measurements such as travel time, density, lane density, occupancy, and normalized waiting time. Since the critical edge of each intersection network is identified based on a higher normalized waiting time, new traffic signal designs are suggested based on the actual critical turning movements and improvements in vehicle travel time are achieved to better accommodate the actual traffic demand.

Background: Oral propranolol can effectively activate and accelerate infantile hemangioma (IH) involution; however, could the final outcome of oral propranolol treatment for IHs commensurate that of spontaneous involution?, Objective: This study aimed to investigate the long-term therapeutic effect of oral propranolol for IHs., Methods: We present an individual matching comparative study with (1) oral propranolol therapy for mixed and deep IHs on the lips, nose, and parotid and (2) lesion type- and lesion location-matched untreated IHs as controls. Patients' follow-up photographs were assessed by 3 surgeons blinded of their treatment. Outcome measures were the quantification of the degree of sequelae ranging from 1 to 4 and the age at which IH achieved involution arrest., Results: Ten groups of oral propranolol and untreated patients with matched lesions were assessed. Average age at which lesions stabilized and reached no change in appearance was 1.7 years old and 6.3 years old for propranolol group and untreated group ( t = 5.663, P < 0.001). There was no significant difference in the quantified degree of sequelae for oral propranolol group and untreated group upon follow-up (1.60 vs 1.40, respectively; t = 1.259, P = 0.240)., Conclusions: Oral propranolol therapy accelerates IH involution but does not have a superior effect than spontaneous involution on the overall outcome of problematic IHs., Competing Interests: Conflicts of interest and sources of funding: This research is supported by the National Natural Science Foundation of China (grant numbers 81971847 and 81772100)., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Importance: In an era of increasing health care expenditure, reduction of redundant head and neck surgical instrumentation may minimize waste., Objective: To (1) optimize head and neck surgical instrument trays at a single large academic tertiary care center and (2) identify associated direct cost savings., Design, Setting, and Participants: This prospective quality improvement initiative was conducted at an academic tertiary care medical center from July 2017 through July 2021. Participants were a multidisciplinary surgical quality team consisting of head and neck surgeons, operating room nurses, surgical technicians, and supply chain analysts., Main Outcomes and Measures: The 4 primary surgical instrument trays (major otolaryngology [Oto], Oto plastics, direct laryngoscopy, and microdirect laryngoscopy) used in all head and neck procedures were reviewed by 10 head and neck surgical faculty with detailed case observation of instrument utilization performed by trained operating room nurses and surgical technologists. Instruments used in less than 40% of cases were excluded from surgical trays, and novel instrument trays were established based on faculty feedback and utilization. Data on instrument processing, utilization, and associated institutional direct costs were prospectively collected over a 3-year period. The primary outcome measure was change in operating room direct costs. Surgeon satisfaction with the quality improvement intervention was the secondary outcome. Direct cost savings were identified as a function of surgical volume, labor and supply costs, and instrument depreciation., Results: More than 1500 eligible surgical cases were reviewed during the preintervention period. Of the 149 instruments in the major Oto tray, only 118 (79%) instruments were used in more than 40% of cases. There were 58 (49%) and 32 (21%) instruments in this tray that were used in more than 40% of neck dissections and sentinel lymph node biopsies, respectively. Resulting intervention included development of a streamlined major Oto tray with 118 instruments and novel neck dissection and sentinel lymph node biopsy trays. Similar processes were applied to the remaining head and neck trays, with a total of 257 instruments removed. Over a 3-year postintervention period, streamlined surgical trays were used 9284 times with direct cost savings of $228 338 (95% CI, $227 817-$228 854). Overall surgeon satisfaction with the optimized head and neck surgical trays was 100%., Conclusions and Relevance: In this quality improvement study, surgeon-led elimination of redundant or rarely used instruments from surgical instrument trays was associated with reduced operating room direct costs while maintaining stakeholder satisfaction.

Cortical neural circuits are complex but very precise networks of balanced excitation and inhibition. Yet, the molecular and cellular mechanisms that form the balance are just beginning to emerge. Here, using conditional γ-aminobutyric acid receptor B1- deficient mice we identify a γ-aminobutyric acid/tumor necrosis factor superfamily member 12-mediated bidirectional communication pathway between parvalbumin-positive fast spiking interneurons and oligodendrocyte precursor cells that determines the density and function of interneurons in the developing medial prefrontal cortex. Interruption of the GABAergic signaling to oligodendrocyte precursor cells results in reduced myelination and hypoactivity of interneurons, strong changes of cortical network activities and impaired social cognitive behavior. In conclusion, glial transmitter receptors are pivotal elements in finetuning distinct brain functions., (© 2022. The Author(s).)

Objective: The Baby-Friendly Hospital Initiative (BFHI) enables maternity units to be centers of breastfeeding support to increase breastfeeding rates. This study evaluates the impact of the 20-hour BFHI training course on nurses' breastfeeding knowledge, attitude, and confidence in breastfeeding practice in a tertiary hospital in Singapore., Study Design: Seventeen sessions of the 20-hour BFHI training course were conducted by lactation consultants from 2010 to 2013 at the National University Hospital, Singapore. An anonymous self-administered survey on knowledge, attitude, and confidence in breastfeeding practices were distributed to nurses before (2009) and after (2014) the training courses to assess effectiveness of training., Results: One-hundred forty nurses and one hundred forty-eight nurses participated in the surveys in 2009 and 2014, respectively. Majority were registered nurses who worked in the postnatal wards and the neonatal intensive care unit. After training, there were significant improvements for five of eight items in infant feeding knowledge, including greater awareness of the International Code of Marketing of Breastmilk Substitutes and medical contraindication for breastfeeding. Participants reported more confidence in assisting mothers on breastfeeding, 77.1 to 88.5% ( p  = 0.019); advising hand expressing breast milk, 75.7 to 86.5% ( p  = 0.012); and advising attachment to the breast, 75.7 to 89.2% ( p  = 0.004) in 2014 compared with 2009. However, despite having high levels of confidence, only about half the nurses reported being able to assist mothers in breastfeeding, mainly due to time constraints., Conclusion: Implementation of the 20-hour BFHI training program positively influenced nurses' breastfeeding knowledge, attitude, and confidence in breastfeeding practices. Hospital procedures and manpower requirements should be re-examined to overcome nursing constraints in providing breastfeeding help to postpartum mothers., Key Points: · Nurses have low breastfeeding knowledge pretraining.. · The 20-hour BFHI training course is effective.. · Nurses have inadequate time to support breastfeeding.., Competing Interests: None declared., (Thieme. All rights reserved.)

Cytotoxic T lymphocytes (CTL) kill malignant and infected cells through the directed release of cytotoxic proteins into the immunological synapse (IS). The cytotoxic protein granzyme B (GzmB) is released in its soluble form or in supramolecular attack particles (SMAP). We utilize synaptobrevin2-mRFP knock-in mice to isolate fusogenic cytotoxic granules in an unbiased manner and visualize them alone or in degranulating CTLs. We identified two classes of fusion-competent granules, single core granules (SCG) and multi core granules (MCG), with different diameter, morphology and protein composition. Functional analyses demonstrate that both classes of granules fuse with the plasma membrane at the IS. SCG fusion releases soluble GzmB. MCGs can be labelled with the SMAP marker thrombospondin-1 and their fusion releases intact SMAPs. We propose that CTLs use SCG fusion to fill the synaptic cleft with active cytotoxic proteins instantly and parallel MCG fusion to deliver latent SMAPs for delayed killing of refractory targets., (© 2022. The Author(s).)

Gallium (Ga) is widely used in high-tech industries and is an emerging contaminant in the environment. This study aimed to determine Ga speciation in soils and Ga accumulation in rice plants (Oryza sativa L.) grown in three Ga-contaminated soils. The results showed that, among the soils, the acidic soil with a coarse texture had the highest soil Ga availability, which enhanced Ga uptake by rice roots. The Ga K-edge X-ray absorption near edge structure and sequential extraction results of the soils showed that the predominant species of Ga associated with iron hydroxides transformed to Ga(OH) 3 precipitates, and the residue fraction increased with rice-growing time, resulting in lower Ga uptake by rice roots in the second half period of rice cultivation. A large fraction of Ga was accumulated in the rice roots, with only a small portion of Ga was transferred to the shoots and then to the rice grains. This study revealed that Ga speciation in soil-rice plant systems varied during rice cultivation and determined soil Ga availability to rice plants. Gallium accumulated in rice grains is distributed homogenously in the endosperm of the grains, suggesting a potential risk to public health via the intake of rice grains harvested from Ga-contaminated paddy fields., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Ovarian cancer is the most lethal gynecological cancer, and it is frequently diagnosed at advanced stages, with recurrences after treatments. Treatment failure and resistance are due to hypoxia-inducible factors (HIFs) activated by cancer cells adapt to hypoxia. IGFBP3, which was previously identified as a growth/invasion/metastasis suppressor of ovarian cancer, plays a key role in inhibiting tumor angiogenesis. Although IGFBP3 can effectively downregulate tumor proliferation and vasculogenesis, its effects are only transient. Tumors enter a hypoxic state when they grow large and without blood vessels; then, the tumor cells activate HIFs to regulate cell metabolism, proliferation, and induce vasculogenesis to adapt to hypoxic stress. After IGFBP3 was transiently expressed in highly invasive ovarian cancer cell line and heterotransplant on mice, the xenograft tumors demonstrated a transient growth arrest with de-vascularization, causing tumor cell hypoxia. Tumor re-proliferation was associated with early HIF-1α and later HIF-2α activations. Both HIF-1α and HIF-2α were related to IGFBP3 expressions. In the down-expression of IGFBP3 in xenograft tumors and transfectants, HIF-2α was the major activated protein. This study suggests that HIF-2α presentation is crucial in the switching of epithelial ovarian cancer from dormancy to proliferation states. In highly invasive cells, the cancer hallmarks associated with aggressiveness could be activated to escape from the growth restriction state., (© 2021. The Author(s).)

Real-time monitoring on displacement and acceleration of a structure provides vital information for people in different applications such as active control and damage warning systems. Recent developments of the Internet of Things (IoT) and client-side web technologies enable a wireless microcontroller board with sensors to process structural-related data in real-time and to interact with servers so that end-users can view the final processed results of the servers through a browser in a computer or a mobile phone. Unlike traditional structural health monitoring (SHM) systems that deliver warnings based on peak acceleration of earthquake, we built a real-time SHM system that converts raw sensor results into movements and rotations on the monitored structure's three-dimensional (3D) model. This unique approach displays the overall structural dynamic movements directly from measured displacement data, rather than using force analysis, such as finite element analysis, to predict the displacement statically. As an application to our research outcomes, patterns of movements related to its structure type can be collected for further cross-validating the results derived from the traditional stress-strain analysis. In this work, we overcome several challenges that exist in displaying the 3D effects in real-time. From our proposed algorithm that converts the global displacements into element's local movements, our system can calculate each element's (e.g., column's, beam's, and floor's) rotation and displacement at its local coordinate while the sensor's monitoring result only provides displacements at the global coordinate. While we consider minimizing the overall sensor usage costs and displaying the essential 3D movements at the same time, a sensor deployment method is suggested. To achieve the need of processing the enormous amount of sensor data in real-time, we designed a novel structure for saving sensor data, where relationships among multiple sensor devices and sensor's spatial and unique identifier can be presented. Moreover, we built a sensor device that can send the monitoring data via wireless network to the local server or cloud so that the SHM web can integrate what we develop altogether to show the real-time 3D movements. In this paper, a 3D model is created according to a two-story structure to demonstrate the SHM system functionality and validate our proposed algorithm.

The COVID-19 pandemic is an ongoing global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 2020-2021. COVID-19 is becoming one of the most fatal pandemics in history and brings a huge challenge to the global healthcare system. Opportune detection, confinement, and early treatment of infected cases present the first step in combating COVID-19. Diagnosis via viral nucleic acid amplification tests (NAATs) is frequently employed and considered the standard procedure. However, with an increasing urge for point-of-care tests, rapid and cheaper immunoassays are widely utilized, such as lateral flow immunoassay (LFIA), which can be used for rapid, early, and large-scale detection of SARS-CoV-2 infection. In this narrative review, the principle and technique of LFIA applied in COVID-19 antigen and antibody detection are introduced. The diagnostic sensitivity and specificity of the commercial LFIA tests are outlined and compared. Generally, LFIA antigen tests for SARS-CoV-2 are less sensitive than viral NAATs, the "gold standard" for clinical COVID-19 diagnosis. However, antigen tests can be used for rapid and mass testing in high-risk congregate housing to quickly identify people with COVID-19, implementing infection prevention and control measures, thus preventing transmission. LFIA anti-SARS-CoV-2 antibody tests, IgM and/or IgG, known as serology tests, are used for identification if a person has previously been exposed to the virus or vaccine immunization. Notably, advanced techniques, such as LFT-based CRISPR-Cas9 and surface-enhanced Raman spectroscopy (SERS), have added new dimensions to the COVID-19 diagnosis and are also discussed in this review.

Physiological electric fields (EF) play vital roles in cell migration, differentiation, division, and death. This paper describes a microfluidic cell culture system that was used for a long-term cell differentiation study using microscopy. The microfluidic system consists of the following major components: an optically transparent electrotactic chip, a transparent indium-tin-oxide (ITO) heater, a culture media-filling pump, an electrical power supply, a high-frequency power amplifier, an EF multiplexer, a programmable X-Y-Z motorized stage, and an inverted phase-contrast microscope equipped with a digital camera. The microfluidic system is beneficial in simplifying the overall experimental setup and, in turn, the reagent and sample consumption. This work involves the differentiation of neural stem and progenitor cells (NPCs) induced by direct current (DC) pulse stimulation. In the stem cell maintenance medium, the mouse NPCs (mNPCs) differentiated into neurons, astrocytes, and oligodendrocytes after the DC pulse stimulation. The results suggest that simple DC pulse treatment could control the fate of mNPCs and could be used to develop therapeutic strategies for nervous system disorders. The system can be used for cell culture in multiple channels, for long-term EF stimulation, for cell morphological observation, and for automatic time-lapse image acquisition. This microfluidic system not only shortens the required experimental time, but also increases the accuracy of control on the microenvironment.

Background/objectives: Maternal glycaemia promotes fetal adiposity. Inositol, an insulin sensitizer, has been trialled for gestational diabetes prevention. The placenta has been implicated in how maternal hyperglycaemia generates fetal pathophysiology, but no studies have examined whether placental inositol biology is altered with maternal hyperglycaemia, nor whether such alterations impact fetal physiology. We aimed to investigate whether the effects of maternal glycaemia on offspring birthweight and adiposity at birth differed across placental inositol levels., Methods: Using longitudinal data from the Growing Up in Singapore Towards healthy Outcomes cohort, maternal fasting glucose (FPG) and 2-hour plasma glucose (2hPG) were obtained in pregnant women by a 75-g oral glucose tolerance test around 26 weeks' gestation. Relative placental inositol was quantified by liquid chromatography-mass spectrometry. Primary outcomes were birthweight (n = 884) and abdominal adipose tissue (AAT) volumes measured by neonatal MRI scanning in a subset (n = 262) of term singleton pregnancies. Multiple linear regression analyses were performed., Results: Placental inositol was lower in those with higher 2hPG, no exposure to tobacco smoke antenatally, with vaginal delivery and shorter gestation. Positive associations of FPG with birthweight (adjusted β [95% CI] 164.8 g [109.1, 220.5]) and AAT (17.3 ml [11.9, 22.6] per mmol glucose) were observed, with significant interactions between inositol tertiles and FPG in relation to these outcomes (p < 0.05). Stratification by inositol tertiles showed that each mmol/L increase in FPG was associated with increased birthweight and AAT volume among cases within the lowest (birthweight = 174.2 g [81.2, 267.2], AAT = 21.0 ml [13.1, 28.8]) and middle inositol tertiles (birthweight = 202.0 g [103.8, 300.1], AAT = 19.7 ml [9.7, 29.7]). However, no significant association was found among cases within the highest tertile (birthweight = 81.0 g [-21.2, 183.2], AAT = 0.8 ml [-8.4, 10.0])., Conclusions: High placental inositol may protect the fetus from the pro-adipogenic effects of maternal glycaemia. Studies are warranted to investigate whether prenatal inositol supplementation can increase placental inositol and reduce fetal adiposity.

The increasing use of indium in high-tech industries has inevitably caused its release into the environment. However, knowledge of its environmental fate has been very limited so far. This study investigates the indium uptake and accumulation by two staple crops, rice ( Oryza sativa L.) and wheat ( Triticum aestivum L.), and evaluates potential risks associated with their consumption. Rice and wheat were grown on three kinds of soil, including acidic soils spiked with a high indium concentration (1.0 mmol kg -1 ), which is considered the worst-case scenario, because high soil acidity promotes indium bioavailability. The results revealed that a large portion of soil indium was associated with iron hydroxides, even in acidic soils. Indium precipitates in soils resulted in relatively low availability at the plant root site. Most absorbed indium accumulated at the roots, with only a tiny portion reaching the grains. The corresponding Hazard Quotient indicated no adverse effects on human health. Due to the low translocation of indium from soil to grain, the consumption of rice and wheat grains harvested from indium-contaminated soils may pose an insignificant risk to human health. Further field studies are necessary to better elucidate the risks associated with consuming crops grown in indium-contaminated soils.

Machine learning is a well-known approach for virtual screening. Recently, deep learning, a machine learning algorithm in artificial neural networks, has been applied to the advancement of precision medicine and drug discovery. In this study, we performed comparative studies between deep neural networks (DNN) and other ligand-based virtual screening (LBVS) methods to demonstrate that DNN and random forest (RF) were superior in hit prediction efficiency. By using DNN, several triple-negative breast cancer (TNBC) inhibitors were identified as potent hits from a screening of an in-house database of 165,000 compounds. In broadening the application of this method, we harnessed the predictive properties of trained model in the discovery of G protein-coupled receptor (GPCR) agonist, by which computational structure-based design of molecules could be greatly hindered by lack of structural information. Notably, a potent (~ 500 nM) mu-opioid receptor (MOR) agonist was identified as a hit from a small-size training set of 63 compounds. Our results show that DNN could be an efficient module in hit prediction and provide experimental evidence that machine learning could identify potent hits in silico from a limited training set.

Understanding T cell function in vivo is of key importance for basic and translational immunology alike. To study T cells in vivo, we developed a new knock-in mouse line, which expresses a fusion protein of granzyme B, a key component of cytotoxic granules involved in T cell-mediated target cell-killing, and monomeric teal fluorescent protein from the endogenous Gzmb locus. Homozygous knock-ins, which are viable and fertile, have cytotoxic T lymphocytes with endogeneously fluorescent cytotoxic granules but wild-type-like killing capacity. Expression of the fluorescent fusion protein allows quantitative analyses of cytotoxic granule maturation, transport and fusion in vitro with super-resolution imaging techniques, and two-photon microscopy in living knock-ins enables the visualization of tissue rejection through individual target cell-killing events in vivo. Thus, the new mouse line is an ideal tool to study cytotoxic T lymphocyte biology and to optimize personalized immunotherapy in cancer treatment., Competing Interests: PC, HC, PM, CH, KR, EK, CS, TL, FB, JR No competing interests declared, MA works as a consultant for Biocrine, an unlisted biotech company that is using the ACE technique as a research tool. PB is cofounder and CEO of Biocrine, an unlisted biotech company that is using the ACE technique as a research tool. NB Reviewing editor, eLife, (© 2020, Chitirala et al.)

Cytotoxic T lymphocytes (CTL) are an essential part of our immune system by killing infected and malignant cells. To fully understand this process, it is necessary to study CTL function in the physiological setting of a living organism to account for their interplay with other immune cells like CD4 + T helper cells and macrophages. The anterior chamber of the eye (ACE), originally developed for diabetes research, is ideally suited for non-invasive and longitudinal in vivo imaging. We take advantage of the ACE window to observe immune responses, particularly allorejection of islets of Langerhans cells by CTLs. We follow the onset of the rejection after vascularization on islets until the end of the rejection process for about a month by repetitive two-photon microscopy. We find that CTLs show reduced migration on allogeneic islets in vivo compared to in vitro data, indicating CTL activation. Interestingly, the temporal infiltration pattern of T cells during rejection is precisely regulated, showing enrichment of CD4 + T helper cells on the islets before arrival of CD8 + CTLs. The adaptation of the ACE to immune responses enables the examination of the mechanism and regulation of CTL-mediated killing in vivo and to further investigate the killing in gene-deficient mice that resemble severe human immune diseases., Competing Interests: The authors declare no conflict of interest.

A one-step sputtering process using a quaternary target has been demonstrated to be a simple route to form Cu(In,Ga)Se 2 (CIGSe) absorber without post-selenization; however, the lack of a Ga-grading structure in the CIGSe absorber confines its efficiency. Here, we demonstrate a one-step cosputtering process to control the Ga profile in the CIGSe absorber on flexible stainless steel substrates. Special attention was paid to the formation of second phases and their effects on the cell performance. Although the normal Ga-grading and efficiency enhancement could be achieved by cosputtering of CIGSe and Ga 2 Se 3 targets, high-energy ion bombardment during the sputtering process might cause the decomposition of the Ga 2 Se 3 target, leading to the formation of Ga 2 O 3 in the CIGSe absorber, which gradually degraded the device performance. We replaced the Ga 2 Se 3 target with a stoichiometric CuGaSe 2 target for cosputtering, which can further enhance the cell efficiency due to the elimination of Ga 2 O 3 . However, when the Ga content at the back side of CIGSe is further increased by raising the deposition power of the CuGaSe 2 target, the phase separation of CuGaSe 2 may take place, resulting in the formation of Cu 2- X Se and CuGaSe 2 at the back side of the CIGSe absorber; therefore, the recombination at the back side is increased. By cosputtering a CIGSe target with a Cu-deficient CuGaSe 2 target, we can suppress the formation of second phases and achieve designable normal grading, leading to the highest efficiency of 15.63% without post-selenization on flexible substrates.