Cell-free fetal DNA for genetic evaluation in Copenhagen Pregnancy Loss Study (COPL): a prospective cohort study.

BACKGROUND: One in four pregnancies end in a pregnancy loss. Although the effect on couples is well documented, evidence-based treatments and prediction models are absent. Fetal aneuploidy is associated with a higher chance of a next successful pregnancy compared with euploid pregnancy loss in which underlying maternal conditions might be causal. Ploidy diagnostics are therefore advantageous but challenging as they require collection of the pregnancy tissue. Cell-free fetal DNA (cffDNA) from maternal blood has the potential for evaluation of fetal ploidy status, but no large-scale validation of the method has been done. METHODS: In this prospective cohort study, women with a pregnancy loss were recruited as a part of the Copenhagen Pregnancy Loss (COPL) study from three gynaecological clinics at public hospitals in Denmark. Women were eligible for inclusion if older than 18 years with a pregnancy loss before gestational age 22 weeks (ie, 154 days) and with an intrauterine pregnancy confirmed by ultrasound (including anembryonic sac), and women with pregnancies of unknown location or molar pregnancies were excluded. Maternal blood was collected while pregnancy tissue was still in situ or within 24 h after pregnancy tissue had passed and was analysed by genome-wide sequencing of cffDNA. Direct sequencing of the pregnancy tissue was done as reference. FINDINGS: We included 1000 consecutive women, at the time of a pregnancy loss diagnosis, between Nov 12, 2020, and May 1, 2022. Results from the first 333 women with a pregnancy loss (recruited between Nov 12, 2020, and Aug 14, 2021) were used to evaluate the validity of cffDNA-based testing. Results from the other 667 women were included to evaluate cffDNA performance and result distribution in a larger cohort of 1000 women in total. Gestational age of fetus ranged from 35-149 days (mean of 70·5 days [SD 16·5], or 10 weeks plus 1 day). The cffDNA-based test had a sensitivity for aneuploidy detection of 85% (95% CI 79-90) and a specificity of 93% (95% CI 88-96) compared with direct sequencing of the pregnancy tissue. Among 1000 cffDNA-based test results, 446 (45%) were euploid, 405 (41%) aneuploid, 37 (4%) had multiple aneuploidies, and 112 (11%) were inconclusive. 105 (32%) of 333 women either did not manage to collect the pregnancy tissue or collected a sample classified as unknown tissue giving a high risk of being maternal. INTERPRETATION: This validation of cffDNA-based testing in pregnancy loss shows the potential and feasibility of the method to distinguish euploid and aneuploid pregnancy loss for improved clinical management and benefit of future reproductive medicine and women's health research. FUNDING: Ole Kirks Foundation, BioInnovation Institute Foundation, and the Novo Nordisk Foundation.

Efficacy and tolerability of initial triple combination therapy with metformin, dapagliflozin and saxagliptin compared with stepwise add-on therapy in drug-naïve patients with type 2 diabetes (TRIPLE-AXEL study): A multicentre, randomized, 104-week, open-label, active-controlled trial.

AIM: To evaluate the efficacy and tolerability of an initial triple combination therapy (TCT) compared with conventional stepwise add-on therapy (SAT) in patients with newly diagnosed type 2 diabetes (T2D). MATERIALS AND METHODS: This multicentre, randomized, 104-week, open-label trial randomized 105 patients with drug-naïve T2D (with HbA1c level ≥ 8.0%, < 11.0%) to the TCT (1000 mg of metformin, 10 mg of dapagliflozin and 5 mg of saxagliptin once daily) or SAT (initiated with metformin, followed by glimepiride and sitagliptin) groups. The primary outcome was the proportion of patients who achieved an HbA1c level of less than 6.5% without hypoglycaemia, weight gain of 5% or higher, or discontinuation of drugs because of adverse events at week 104. RESULTS: HbA1c reduction from baseline at week 104 was similar between the groups (the least squares mean change was -2.56% in the TCT group vs. -2.75% in the SAT group). The primary outcome was achieved in 39.0% and 17.1% of the TCT and SAT groups, respectively, with a risk difference of 22.0 (95% confidence interval 3.0, 40.8; P = .027). HbA1c level less than 6.5% at week 104 was 46.3% in both the TCT and SAT groups, whereas the incidence of hypoglycaemia, weight gain, or discontinuation of drugs was 16.7% and 62.0% in the TCT and SAT groups, respectively (P < .001). TCT was well-tolerated and had fewer adverse events than SAT. CONCLUSIONS: Among newly diagnosed patients with T2D, initial TCT effectively lowered HbA1c levels with higher tolerability and safety than SAT for 104 weeks, suggesting a novel strategy for initial combination therapy in T2D patients.

Dual add-on therapy of gemigliptin and dapagliflozin in patients with type 2 diabetes inadequately controlled with metformin alone: The SOLUTION 2 study.

AIM: To evaluate the efficacy and safety of gemigliptin and dapagliflozin dual add-on therapy (GEMI + DAPA) to metformin in type 2 diabetes (T2D) patients who had inadequate glycaemic control on metformin alone, compared with a single add-on of either gemigliptin (GEMI) or dapagliflozin (DAPA) to metformin. MATERIALS AND METHODS: In this randomized, double-blind, double-dummy, active-controlled, parallel-group, phase 3 study, 469 T2D patients treated with a stable dose of metformin for 8 weeks or longer were randomized to receive GEMI + DAPA (n = 157) and either GEMI (n = 156) or DAPA (n = 156). The primary endpoint was change in HbA1c levels from baseline at week 24. RESULTS: Baseline characteristics including body mass index and T2D duration were similar among groups. At week 24, the least square mean changes in HbA1c from baseline were -1.34% with GEMI + DAPA, -0.90% with GEMI (difference between GEMI + DAPA vs. GEMI -0.44% [95% confidence interval {CI}: -0.58% to -0.31%], P < .01) and -0.78% with DAPA (difference between GEMI + DAPA vs. DAPA -0.56% [95% CI: -0.69% to -0.42%], P < .01). Both upper CIs were less than 0, demonstrating the superiority of GEMI + DAPA for lowering HbA1c. The rates of responders achieving HbA1c less than 7% and less than 6.5% were greater with GEMI + DAPA (84.9%, 56.6%) than with GEMI (55.3%, 32.2%) and DAPA (49.3%, 15.3%). The incidence rate of adverse events was similar across groups, with low incidence rates of hypoglycaemia, urinary tract infection and genital infection. CONCLUSIONS: These results suggest that the addition of GEMI + DAPA to metformin as triple combination therapy was effective, safe and well-tolerated, especially for T2D patients who experienced poor glycaemic control on metformin alone.

Effects of dapagliflozin compared with glimepiride on body composition in Asian patients with type 2 diabetes inadequately controlled with metformin: The BEYOND study.

AIMS: To evaluate the effect of dapagliflozin on body composition such as total body fat (BF) mass, abdominal visceral adipose tissue (VAT), and subcutaneous adipose tissue (SAT) areas compared with glimepiride in Korean patients with type 2 diabetes. MATERIALS AND METHODS: This was a 52-week, multicentre, randomized, parallel-group, open-label, Phase IV (NCT02564926) study. Patients with inadequate glycaemic control (glycated haemoglobin ≥7.0% and <10.0%) on metformin monotherapy (≥1000 mg/day) were randomized 1:1 to receive dapagliflozin 10 mg/day or glimepiride 1-2 mg/day for 12 months as an add-on to metformin. Baseline and end of study body composition evaluations included dual-energy X-ray absorptiometry and abdominal computed tomography scans. RESULTS: Of 124 enrolled patients from 14 centres, 121 received study treatment (dapagliflozin: 60; glimepiride: 61) and 106 (85.5%) completed the study. Over 52 weeks, the dapagliflozin group showed the following differences versus the glimepiride group: -2.59 kg BF mass, -1.94% BF%, -17.55 cm2 VAT area, -18.39 cm2 SAT area, -0.46% glycated haemoglobin, -18.25 mg/dl fasting blood glucose, -3.7 kg weight, -2.21 cm waist circumference, -1.37 kg/m2 body mass index, -6.81 mmHg systolic blood pressure and +657.71 ng/ml in adiponectin; all were statistically significant. Both groups had similar incidences of adverse events; however, hypoglycaemic events were mainly (12 of 15) reported in the glimepiride group. CONCLUSION: Dapagliflozin reduced total BF mass, abdominal VAT and SAT areas, and showed better glycaemic control than glimepiride. Being safe and well-tolerated, dapagliflozin appears to be a more favourable alternative to sulphonylureas as add-on therapy after metformin monotherapy failure in Korean patients with type 2 diabetes.

Compliance Challenges in a Longitudinal COVID-19 Cohort Using Wearables for Continuous Monitoring: Observational Study.

BACKGROUND: The WEAICOR (Wearables to Investigate the Long Term Cardiovascular and Behavioral Impacts of COVID-19) study was a prospective observational study that used continuous monitoring to detect and analyze biometrics. Compliance to wearables was a major challenge when conducting the study and was crucial for the results. OBJECTIVE: The aim of this study was to evaluate patients' compliance to wearable wristbands and determinants of compliance in a prospective COVID-19 cohort. METHODS: The Biostrap (Biostrap USA LLC) wearable device was used to monitor participants' biometric data. Compliance was calculated by dividing the total number of days in which transmissions were sent by the total number of days spent in the WEAICOR study. Univariate correlation analyses were performed, with compliance and days spent in the study as dependent variables and age, BMI, sex, symptom severity, and the number of complications or comorbidities as independent variables. Multivariate linear regression was then performed, with days spent in the study as a dependent variable, to assess the power of different parameters in determining the number of days patients spent in the study. RESULTS: A total of 122 patients were included in this study. Patients were on average aged 41.32 years, and 46 (38%) were female. Age was found to correlate with compliance (r=0.23; P=.01). In addition, age (r=0.30; P=.001), BMI (r=0.19; P=.03), and the severity of symptoms (r=0.19; P=.03) were found to correlate with days spent in the WEAICOR study. Per our multivariate analysis, in which days spent in the study was a dependent variable, only increased age was a significant determinant of compliance with wearables (adjusted R2=0.1; ß=1.6; P=.01). CONCLUSIONS: Compliance is a major obstacle in remote monitoring studies, and the reasons for a lack of compliance are multifactorial. Patient factors such as age, in addition to environmental factors, can affect compliance to wearables.

On-site Ultrasound Screens out Asymptomatic Knee Lesions in Elite Adolescent Male Basketball Players.

Basketball is a popular sport worldwide with a high injury risk. In this study, we conducted survey composed of clinical symptom reporting scale, physical examination and meticulous portable musculoskeletal ultrasound to 19 elite male high school basketball players and 15 regular male high school students. Our study showed the incidence of ultrasonographic findings of any lesion, suprapatellar effusion and proximal patellar tendinopathy is significantly higher in player group, and the incidence of asymptomatic ultrasonographic lesion is also higher in player group. Screening for asymptomatic lesions bares clinical relevance and plays a role in prevention of symptom development. With the concise and easy-to-perform ultrasonography protocol we performed and being interpreted by sports team physician, the protocol can offer precise diagnosis of common injury and screening for asymptomatic lesion potentially progressive.

Estimation of breeding value and accuracy using pedigree and genotype of Hanwoo cows (Korean cattle).

The genetic improvement of Hanwoo is dependent on the estimated breeding value (EBV) of pedigree-based Korean proven bull's number, and the genetic evaluation for cows is difficult due to insufficient pedigree and test records. Genomic selection involves utilizing the individual's genotype to estimate the breeding value (BV) and is determined to be an appropriate evaluation method for cows who lack test information. This study used pedigree and genotype to estimate and analyse BV and accuracy of Hanwoo cows in the Gyeongnam area using pedigree best linear unbiased prediction (PBLUP) and genomic best linear unbiased prediction (GBLUP). The test group acquired pedigree and genotype of 919 Hanwoo cows in the Gyeongnam area. The traits used for analysis were carcass weight (CWT), eye muscle areas (EMA), backfat thickness (BFT) and marbling score (MS). PBLUP used Reference group 1 containing the pedigree and phenotype of 919 Hanwoo cows and 545,483 heads to construct the numeric relationship matrix and estimated the EBV and accuracy. GBLUP used Reference group 2 containing the genotype and phenotype of 919 Hanwoo cows and 17,226 heads to construct the genomic relationship matrix and estimated the genomic EBV (GEBV) and accuracy. In the order of CWT, EMA, BFT and MS, the accuracy of PBLUP was 0.488, 0.480, 0.482 and 0.486 while the accuracy of GBLUP was higher with 0.779, 0.758, 0.766 and 0.791. And for 104 cows without relationship coefficient on pedigree to the reference group, the accuracy as PBLUP was estimated to be 0, but for GBLUP, it was possible to estimate the accuracy for all individuals. If GBLUP is applied to cows raised in general farms, the genetic evaluation can be performed even on animals without pedigree and high-accuracy estimation, enabling selection of excellent cows. Accordingly, by securing the genetic diversity of cows, it is expected to increase the profitability of farms by decreasing the inbreeding rate and increasing efficiency of elite calf production.

Facing the loss of siblings in childhood: Interactions and dynamics between bereaved siblings and their parents.

INTRODUCTION: The loss of a child in a family is a painful experience. Despite this, most studies focus on the grieving experience of parents. Our understanding of sibling bereavement therefore remains underexplored. This study aims to address this gap by exploring the bereavement experience of younger bereaved siblings from the perspective of the bereaved child and the parents. METHOD: This study is a qualitative study conducted in Hong Kong. We recruited eleven bereaved families from 2019 to 2020. Semi-structured interviews were conducted separately with bereaved children and parents. Thematic analyses were performed. FINDINGS: Eleven bereaved siblings, aged 5 to 11, and their parents were interviewed. Four themes were generated: Parents' unawareness of bereaved siblings' grief, protecting parents from grief, comparison with the deceased siblings, and learning how to grieve. CONCLUSION: Our findings suggest that the family dynamics and interactions in the grieving experience are complex. The impact of grief on the bereaved child could emanate from the loss of the sibling or from the grief of the parents or from family interactions. PRACTICE IMPLICATIONS: This study highlights the importance of viewing the sibling bereavement experience in a family context and of enhancing sibling bereavement services. Helping professionals should not only provide more bereavement support to the bereaved siblings individually, but they should also enhance parents' capacity to support their bereaved children.

Emotional Distress of the COVID-19 Cluster Infection on Health Care Workers Working at a National Hospital in Korea.

BACKGROUND: Frontline healthcare workers responding to coronavirus disease 2019 (COVID-19) inevitably face tremendous psychological burden. Thus, the present study aimed to identify the psychological impact and the factors contributing to the likely increase in emotional distress of healthcare workers. METHODS: The participants include a total of 99 healthcare workers at Bugok National Hospital. Psychometric scales were used to assess emotional distress (12-item General Health Questionnaire; GHQ-12), depression symptoms (Patient Health Questionnaire-9; PHQ-9), and post-traumatic stress disorder-related symptoms (Impact of Events Scale-Revised; IES-R). A supplementary questionnaire was administered to investigate the experience of healthcare workers exposed to COVID-19-infected patients. Based on the results of GHQ-12 survey, participants were categorized into two groups: distress and non-distress. All the assessed scores were compared between the two groups. A logistic regression model was constructed to identify factors associated with emotional distress. RESULTS: Emotional distress was reported by 45.3% (n = 45) of all participants. The emotionally distressed group was more likely to be female, manage close contacts, have higher scores on PHQ-9 and IES-R, feel increased professional risk, and report that proper infection control training was not provided. Female gender, managing close contacts, higher scores on PHQ-9, and a feeling that proper infection control training was not provided were associated with emotional distress in logistic regression. CONCLUSION: Frontline healthcare workers face tremendous psychological burden during the COVID-19 pandemic. Therefore, appropriate psychological interventions should be provided to the HCWs engaged in the management of COVID-19-infected patients.

Physiotherapist as primary assessor for patients with suspected knee osteoarthritis in primary care-a randomised controlled pragmatic study.

BACKGROUND: In Swedish primary care, the healthcare process for patients with knee osteoarthritis (KOA) can be initiated by a physician or physiotherapist assessment. However, it is unclear how the different assessments affect the healthcare processes and patient reported outcomes over time. The purpose of this study was to examine the differences in health-related quality of life (HrQoL), adjusted for pain and physical function, for patients with KOA when the healthcare process is initiated by a physiotherapist assessment compared to a physician assessment in primary care. METHODS: An assessor-blinded randomised controlled pragmatic trial. Using a computer-generated list of random numbers, patients seeking primary care during 2013-2017 with suspected KOA were randomised to either a physiotherapist or physician for primary assessment and treatment. Data was collected before randomisation and at 3, 6, and 12-month follow-ups. Primary outcome was HrQoL using EuroQol 5 dimensions 3 levels questionnaire, index (EQ-5D-3L index) and a visual analogue scale (VAS) (EQ-5D-3L VAS); pain intensity was measured with VAS (0-100) and physical function measured with the 30-s chair stand test. Mixed effect model analyses compared repeated measures of HrQoL between groups. The significance level was p < 0.05 and data was applied with intention-to-treat. RESULTS: Patients were randomised to either a physiotherapist (n = 35) or physician (n = 34) for primary assessment. All 69 patients were included in the analyses. There were no significant differences in HrQoL for patients assessed by a physiotherapist or a physician as primary assessor (EQ-5D-3L index, p = 0.18; EQ-5D-3L VAS, p = 0.49). We found that HrQoL changed significantly 12 months after baseline assessment for all patients regardless of assessor (EQ-5D-3L index, p < 0.001; EQ-5D-3 L VAS, p = 0.0049). No adverse events or side effects were reported. CONCLUSIONS: There were no differences in HrQoL, when adjusted for pain and physical function, for patients with KOA when the healthcare process was initiated with physiotherapist assessment compared to physician assessment in primary care. Both assessments resulted in significantly higher HrQoL at the 12-month follow-up. The results imply that physiotherapists and physicians in primary care are equally qualified as primary assessors. TRIAL REGISTRATION: Retrospectively registered at http://clinicaltrial.gov , ID: NCT03715764.

Predictors of High-Risk Adenoma Occurrence at Surveillance Colonoscopy in Patients Who Undergo Colorectal Adenoma Removal.

OBJECTIVES: Surveillance colonoscopy is recommended after polypectomy because adenoma recurrence is common. The aim of this study was to evaluate the predictors of high-risk adenoma occurrence at surveillance colonoscopy in patients who undergo colorectal adenoma removal and to clarify the association between age and recurrent colorectal adenoma. METHODS: This retrospective study included 563 patients who had colorectal adenomas at baseline colonoscopy and who underwent surveillance colonoscopy. The risk factors for recurrent adenoma were evaluated and the 5-year cumulative incidence rates of overall and high-risk adenoma were compared according to age group. RESULTS: During a mean follow-up period of 3.1 years, 305 (54.2%) patients had overall adenoma recurrence, and 80 (14.2%) patients had high-risk adenoma at surveillance colonoscopy. In a multivariate analysis, old age (≥60 years) and presence of multiple adenomas (3 or more) were significantly associated with high-risk adenoma (p = 0.002 and p = 0.006 respectively). The 5-year cumulative incidence rates of high-risk adenoma were 7.4, 16.7, and 24.1% in the < 50, 50-59, and ≥60 years group respectively (p < 0.001). CONCLUSIONS: Old age (≥60 years) and presence of multiple adenomas (3 or more) were strongly associated with the occurrence of high-risk adenoma at surveillance colonoscopy. The 5-year cumulative incidence of high-grade adenoma was significantly high in the old age group.

Development of a mouse model of eosinophilic chronic rhinosinusitis with nasal polyp by nasal instillation of an Aspergillus protease and ovalbumin.

One subtype of chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by the development of a T-helper type 2 (Th2) response and eosinophilic infiltration. Here, we aimed to establish an eosinophilic CRSwNP murine model, which would be essential to understand the underlying pathogenesis and establish a treatment strategy. C57BL/6 mice were challenged intranasally with a mixture of an Aspergillus oryzae-derived protease (AP) and ovalbumin (OVA) for 6, 8, or 12 consecutive weeks (12 mice/group); control mice received the same volume of phosphate-buffered saline for 12 weeks (n = 12). Sinonasal samples were evaluated histologically, and interleukin (IL)-4, IL-5, IL-13, eotaxin, keratinocyte chemoattractant, and macrophage inflammatory protein-2 mRNA levels in sinonasal mucosa were measured by real-time PCR. Protein levels of Th2 cytokines, INF-γ, IL-17A, and chemokines in nasal lavage fluid, and total serum IgE were measured by ELISA. Greater eosinophil infiltration in the subepithelial layer was observed in the challenged groups, compared with the control group. Polypoid mucosal lesions were predominantly observed in the 12-week group, which also exhibited mucosal thickening on micro-CT scans. The IL-4, IL-5, and IL-13 mRNA and protein levels were elevated in the sinonasal mucosa and nasal lavage fluid. INF-γ and IL-17A were undetectable or not elevated relative to the control group levels. In contrast, eotaxin levels were particularly elevated in the sinonasal mucosa and nasal lavage fluid in the 12-week group. In conclusion, intranasal AP and OVA exposure successfully induced Th2-specific CRSwNP in a murine model.

Evidence for glucagon-like peptide-1 receptor signaling to activate ATP-sensitive potassium channels in pancreatic beta cells.

Glucagon-like peptide-1 (GLP-1) is a gut peptide that promotes insulin release from pancreatic beta cells. GLP-1 has been shown to confer glucose-insensitive beta cells with glucose sensitivity by modulation of the activity of the ATP-sensitive potassium (KATP) channel. The channel closing effect of GLP-1, interacting with corresponding G-protein-coupled receptors, has been well established; however, to our knowledge, no study has shown whether GLP-1 directly induces activation of beta-cell KATP channels. Here, we aimed to evaluate whether the activation of beta-cell KATP channels by GLP-1 exists and affects intracellular Ca(2+) levels ([Ca(2+)]i). KATP channel activity was measured in isolated rat pancreatic beta cells by whole-cell perforated patch-clamp recordings with a diazoxide-containing pipette solution. Changes in [Ca(2+)]i and the subcellular localization of KATP channels were observed using the calcium-sensitive dye fura-4/AM and anti-Kir6.2 antibodies in INS-1 beta cells, respectively. To eliminate the well-known inhibitory effects of GLP-1 on KATP channel activity, channels were fully inhibited by pretreatment with methyl pyruvate and epigallocatechin-3-gallate. In the pretreated beta cells, GLP-1 and exendin-4 promptly activated the channels, reducing [Ca(2+)]i. The phosphoinositide 3-kinase (PI3K) inhibitor LY294002 blocked the effects of GLP-1 on channel activity. Moreover, phosphatidylinositol-3,4,5-trisphosphate mimicked the effects of GLP-1. These results suggested that beta-cell GLP-1 receptor signaling involved activation of KATP channels via a PI3K-dependent pathway. This alternative mechanism of GLP-1 function may act as a negative feedback pathway, modulating the glucose-dependent GLP-1 inhibition on KATP channel activity.

Internal carotid artery agenesis associated with a rare collateral pathway: supraclinoid-supraclinoid anastomosis. A case report.

Internal carotid artery (ICA) agenesis is an infrequent vascular anomaly, less than 0.01% of the population. Here we report a case of internal carotid agenesis with a rare collateral pathway, via supraclinoid ICA anastomosis to the contralateral supraclinoid ICA.

Infliximab partially alleviates the bite force reduction in a mouse model of temporomandibular joint pain.

Temporomandibular joint (TMJ) disorder is clinically important because of its prevalence, chronicity, and therapy-refractoriness of the pain. In this study, we investigated the effect of infliximab in a mouse model of TMJ pain using a specially-engineered transducer for evaluating the changes in bite force (BF). The mice were randomly divided into three groups (7 mice per group): the control group, the complete Freund's adjuvant (CFA) group, and the infliximab group. BF was measured at day 0 (baseline BF). After measuring the baseline BF, CFA or incomplete Freund's adjuvant was injected into both TMJs and then the changes in BF were measured at days 1, 3, 5, 7, 9, and 13 after the TMJ injection. For measuring the BF, we used a custom-built BF transducer. Control, CFA, and infliximab groups showed similar baseline BF at day 0. From day 1, a significant reduction in BF was observed in the CFA group, and this reduction in BF was statistically significant compared to that in the control group (P < 0.05). This reduction in BF was maintained until day 7, and BF started to recover gradually from day 9. In the infliximab group also, the reduction in BF was observed on day 1, and this reduction was maintained until day 7. However, the degree of reduction in BF was less remarkable compared to that in the CFA group. The reduction in BF caused by injection of CFA into the TMJ could be partially alleviated by the injection of anti-tumor necrosis factor alpha, infliximab.

Melatonin prevents pancreatic ß-cell loss due to glucotoxicity: the relationship between oxidative stress and endoplasmic reticulum stress.

Prolonged hyperglycemia results in pancreatic ß-cell dysfunction and apoptosis, referred to as glucotoxicity. Although both oxidative and endoplasmic reticulum (ER) stresses have been implicated as major causative mechanisms of ß-cell glucotoxicity, the reciprocal importance between the two remains to be elucidated. The aim of this study was to evaluate the differential effect of oxidative stress and ER stress on ß-cell glucotoxicity, by employing melatonin which has free radical-scavenging and antioxidant properties. As expected, in ß-cells exposed to prolonged high glucose levels, cell viability and glucose-stimulated insulin secretion (GSIS) were significantly impaired. Melatonin treatment markedly attenuated cellular apoptosis by scavenging reactive oxygen species via its plasmalemmal receptor-independent increase in antioxidant enzyme activity. However, treatments with antioxidants alone were insufficient to recover the impaired GSIS. Interestingly, 4-phenylbutyric acid (4-PBA), a chemical chaperone that attenuate ER stress by stabilizing protein structure, alleviated the impaired GSIS, but not apoptosis, suggesting that glucotoxicity induces oxidative and ER stress independently. We found that cotreatment of glucotoxic ß-cells with melatonin and 4-PBA dramatically improved both their survival and insulin secretion. Taken together, these results suggest that ER stress may be the more critical mechanism for prolonged high-glucose-induced GSIS impairment, whereas oxidative stress appears to be more critical for the impaired ß-cell viability. Therefore, combinatorial therapy of melatonin with an ER stress modifier may help recover pancreatic ß-cells under glucotoxic conditions in type 2 diabetes.

Diagnostic Accuracy of Deep Learning for the Prediction of Osteoporosis Using Plain X-rays: A Systematic Review and Meta-Analysis.

(1) Background: This meta-analysis assessed the diagnostic accuracy of deep learning model-based osteoporosis prediction using plain X-ray images. (2) Methods: We searched PubMed, Web of Science, SCOPUS, and Google Scholar from no set beginning date to 28 February 2023, for eligible studies that applied deep learning methods for diagnosing osteoporosis using X-ray images. The quality of studies was assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 criteria. The area under the receiver operating characteristic curve (AUROC) was used to quantify the predictive performance. Subgroup, meta-regression, and sensitivity analyses were performed to identify the potential sources of study heterogeneity. (3) Results: Six studies were included; the pooled AUROC, sensitivity, and specificity were 0.88 (95% confidence interval [CI] 0.85-0.91), 0.81 (95% CI 0.78-0.84), and 0.87 (95% CI 0.81-0.92), respectively, indicating good performance. Moderate heterogeneity was observed. Mega-regression and subgroup analyses were not performed due to the limited number of studies included. (4) Conclusion: Deep learning methods effectively extract bone density information from plain radiographs, highlighting their potential for opportunistic screening. Nevertheless, additional prospective multicenter studies involving diverse patient populations are required to confirm the applicability of this novel technique.