The cellular Notch1 protein promotes KSHV reactivation in an Rta-dependent manner.

The cellular Notch signal transduction pathway is intimately associated with infections by Kaposi's sarcoma-associated herpesvirus (KSHV) and other gamma-herpesviruses. RBP-Jk, the cellular DNA binding component of the canonical Notch pathway, is the key Notch downstream effector protein in virus-infected and uninfected animal cells. Reactivation of KSHV from latency requires the viral lytic switch protein, Rta, to form complexes with RBP-Jk on numerous sites within the viral DNA. Constitutive Notch activity is essential for KSHV pathophysiology in models of Kaposi's sarcoma (KS) and Primary Effusion Lymphoma (PEL), and we demonstrate that Notch1 is also constitutively active in infected Vero cells. Although the KSHV genome contains >100 RBP-Jk DNA motifs, we show that none of the four isoforms of activated Notch can productively reactivate the virus from latency in a highly quantitative trans-complementing reporter virus system. Nevertheless, Notch contributed positively to reactivation because broad inhibition of Notch1-4 with gamma-secretase inhibitor (GSI) or expression of dominant negative mastermind-like1 (dnMAML1) coactivators severely reduced production of infectious KSHV from Vero cells. Reduction of KSHV production is associated with gene-specific reduction of viral transcription in both Vero and PEL cells. Specific inhibition of Notch1 by siRNA partially reduces the production of infectious KSHV, and NICD1 forms promoter-specific complexes with viral DNA during reactivation. We conclude that constitutive Notch activity is required for the robust production of infectious KSHV, and our results implicate activated Notch1 as a pro-viral member of a MAML1/RBP-Jk/DNA complex during viral reactivation. IMPORTANCE: Kaposi's sarcoma-associated herpesvirus (KSHV) manipulates the host cell oncogenic Notch signaling pathway for viral reactivation from latency and cell pathogenesis. KSHV reactivation requires that the viral protein Rta functionally interacts with RBP-Jk, the DNA-binding component of the Notch pathway, and with promoter DNA to drive transcription of productive cycle genes. We show that the Notch pathway is constitutively active during KSHV reactivation and is essential for robust production of infectious virus progeny. Inhibiting Notch during reactivation reduces the expression of specific viral genes yet does not affect the growth of the host cells. Although Notch cannot reactivate KSHV alone, the requisite expression of Rta reveals a previously unappreciated role for Notch in reactivation. We propose that activated Notch cooperates with Rta in a promoter-specific manner that is partially programmed by Rta's ability to redistribute RBP-Jk DNA binding to the virus during reactivation.

A magnetar-powered X-ray transient as the aftermath of a binary neutron-star merger.

Mergers of neutron stars are known to be associated with short γ-ray bursts1-4. If the neutron-star equation of state is sufficiently stiff (that is, the pressure increases sharply as the density increases), at least some such mergers will leave behind a supramassive or even a stable neutron star that spins rapidly with a strong magnetic field5-8 (that is, a magnetar). Such a magnetar signature may have been observed in the form of the X-ray plateau that follows up to half of observed short γ-ray bursts9,10. However, it has been expected that some X-ray transients powered by binary neutron-star mergers may not be associated with a short γ-ray burst11,12. A fast X-ray transient (CDF-S XT1) was recently found to be associated with a faint host galaxy, the redshift of which is unknown13. Its X-ray and host-galaxy properties allow several possible explanations including a short γ-ray burst seen off-axis, a low-luminosity γ-ray burst at high redshift, or a tidal disruption event involving an intermediate-mass black hole and a white dwarf13. Here we report a second X-ray transient, CDF-S XT2, that is associated with a galaxy at redshift z = 0.738 (ref. 14). The measured light curve is fully consistent with the X-ray transient being powered by a millisecond magnetar. More intriguingly, CDF-S XT2 lies in the outskirts of its star-forming host galaxy with a moderate offset from the galaxy centre, as short γ-ray bursts often do15,16. The estimated event-rate density of similar X-ray transients, when corrected to the local value, is consistent with the event-rate density of binary neutron-star mergers that is robustly inferred from the detection of the gravitational-wave event GW170817.

Broadband nonlinear conversion and random quasi-phase-matching in transparent glass composite.

With the development of laser technology, nonlinear optics plays a crucial role in frequency conversion. However, the generation of second harmonics in nonlinear optical crystals is generally subject to rigorous phase-matching conditions that hinder the performance of broadband tunability. It is believed that introducing disorders in nonlinear optical materials is helpful to overcome this obstacle. In this work, we have prepared a nonlinear microcrystal-doped glass (NMG) composite material, allowing for tunable and polarization-independent nonlinear conversion from visible to near-infrared. The linear dependence of SHG intensity versus sample thickness indicated the facilitation of random quasi-phase matching by using the NMG. Our results provide a more stable and promising platform for disordered nonlinear photonic materials and suggest the possibility of more efficient nonlinear conversions using the NMG composite glass fibers in future.

Trimester-specific association between fetal growth and physical activity in pregnant women: total physical activity vs moderate-to-vigorous exercise.

OBJECTIVE: To investigate the trimester-specific associations between maternal total physical activity level vs moderate-to-vigorous exercise and fetal growth disorders. METHODS: We analyzed 2062 mother-neonate pairs participating in the longitudinal China Medical University Birth Cohort Study. The Pregnancy Physical Activity Questionnaire was used to assess the physical activity level of women during the three trimesters. A higher level of total physical activity was defined as meeting or exceeding the cohort-specific 75th percentile, and a higher level of exercise was defined according to the Physical Activity Guidelines for Americans. Fetal growth disorder was defined as small-for-gestational age (SGA) or large-for-gestational age (LGA) at birth. RESULTS: Of the neonates included in this study, 7.1% were SGA and 15.5% were LGA. A higher level of total physical activity during the first trimester (adjusted relative risk (aRR), 0.62 (95% CI, 0.42-0.91)) and second trimester (aRR, 0.62 (95% CI, 0.41-0.95)) was associated with a lower risk of SGA, and a higher level of total physical activity during the third trimester was associated with a lower risk of LGA (aRR, 0.73 (95% CI, 0.54-0.97)). When analyzing physical activity by subtype, a higher level of occupational physical activity during the first and second trimesters was associated negatively with SGA risk, and higher levels of occupational and low-intensity physical activity during the first trimester were associated negatively with LGA risk. No significant association was found between maternal adherence to the Physical Activity Guidelines for Americans and risk of fetal growth disorders. CONCLUSIONS: A higher total physical activity level during the first and second trimesters was associated with a decreased risk of SGA, whereas a higher total physical activity level in the third trimester was associated with a decreased risk of LGA. Pregnant women should be advised to increase their total physical activity levels instead of focusing on engaging in only moderate-to-vigorous exercise. © 2024 International Society of Ultrasound in Obstetrics and Gynecology.

Corrigendum: Commensal bacteria make GPCR ligands that mimic human signalling molecules.

This corrects the article DOI: 10.1038/nature23874.

Prevalence and clinical correlates of abnormal lipid metabolism in older Chinese patients with first-episode drug-naïve major depressive disorder.

BACKGROUND: Older major depressive disorder (MDD) patients have more complex clinical symptoms and higher abnormal lipid metabolism (ALM) rates. This study aimed to compare clinical differences between those with and without ALM in a sample of older first-episode drug naïve (FEDN) patients. METHODS: We recruited 266 older MDD patients. Socio-demographic variables, clinical data, and lipid parameters were obtained. The Hamilton Depression Rating Scale (HAMD), Hamilton Anxiety Rating Scale (HAMA), and the positive subscale of the Positive and Negative Syndrome Scale (PANSS-P) were conducted to evaluate patients' depression, anxiety and psychotic symptoms, respectively. RESULTS: In this study, we found that the prevalence of comorbid ALM was 86.1% in older MDD patients. Compared with the non-abnormal lipid metabolism (NALM) group, the ALM group had a higher duration of illness, higher clinical global impression of severity scale (CGI-S) and HAMD scores, higher thyroid stimulating hormone (TSH) and glucose levels. Logistic regression analysis indicated that duration of illness (OR = 1.11, P = 0.023, 95%CI = 1.015-1.216) and CGI-S score (OR = 2.28, P = 0.014, 95%CI = 1.18-4.39) were associated with ALM in older MDD patients. CONCLUSION: The importance of regular lipid assessment in older MDD patients needs to be taken into account.

The complexity of glucose time series is associated with short- and long-term mortality in critically ill adults: a multi-center, prospective, observational study.

BACKGROUND: The wealth of data taken from continuous glucose monitoring (CGM) remains to be fully used. We aimed to evaluate the relationship between a promising new CGM metric, complexity of glucose time series index (CGI), and mortality in critically ill patients. METHODS: A total of 293 patients admitted to mixed medical/surgical intensive care units from 5 medical centers in Shanghai were prospectively included between May 2020 and November 2021. CGI was assessed using intermittently scanned CGM, with a median monitoring period of 12.0 days. Outcome measures included short- and long-term mortality. RESULTS: During a median follow-up period of 1.7 years, a total of 139 (47.4%) deaths were identified, of which 73 (24.9%) occurred within the first 30 days after ICU admission, and 103 (35.2%) within 90 days. The multivariable-adjusted HRs for 30-day mortality across ascending tertiles of CGI were 1.00 (reference), 0.68 (95% CI 0.38-1.22) and 0.36 (95% CI 0.19-0.70), respectively. For per 1-SD increase in CGI, the risk of 30-day mortality was decreased by 51% (HR 0.49, 95% CI 0.35-0.69). Further adjustment for HbA1c, mean glucose during hospitalization and glucose variability partially attenuated these associations, although the link between CGI and 30-day mortality remained significant (per 1-SD increase: HR 0.57, 95% CI 0.40-0.83). Similar results were observed when 90-day mortality was considered as the outcome. Furthermore, CGI was also significantly and independently associated with long-term mortality (per 1-SD increase: HR 0.77, 95% CI 0.61-0.97). CONCLUSIONS: In critically ill patients, CGI is significantly associated with short- and long-term mortality.

Interaction between nutrition-related parameters and sexual orientation on depression.

OBJECTIVES: Sexual minorities may be more vulnerable to mental disorders. Previous studies have found associations between diet and depression, but no studies have focused on the interaction between nutrition-related parameters and sexual orientation regarding depression. This study aims to explore the interaction between nutrition-related parameters and sexual orientation regarding depression. STUDY DESIGN: Cross-sectional analysis using NHANES 2007-2016 data. METHODS: This study utilized data from NHANES 2007-2016, with 11,065 participants involved. Nutrition-related parameters were evaluated using the healthy eating index-2015 (HEI-2015) and the dietary inflammation index (DII), while depression was obtained through Patient Health Questionnaire (PHQ-9). Logistic regression and stratified analysis of subgroups were used in this study. RESULTS: Compared to those who consumed healthy and anti-inflammatory diets, the ORs for depression in groups consuming unhealthy and pro-inflammatory diets were 1.366 (95%CI:1.073,1.738) and 1.652 (95%CI:1.345,2.028), respectively. Sexual minorities have a higher risk of depression than heterosexuals. There is an interaction effect (P = 0.037) between HEI-2015 and sexual orientation on depression, while it was not found in DII. Subgroup analysis indicated that the interaction between sexual orientation and HEI-2015 persisted in males (P = 0.024), but not in females. CONCLUSION: Both diet and sexual orientation had impacts on depression. There was an interaction between HEI-2015 and sexual orientation on depression, and this association was different by gender. Sexual minorities who are Gay/lesbian, Bisexual, and Something else are at higher risk for depression, and adopting healthy eating patterns and anti-inflammatory diets that are consistent with the recommendations of the USDA may appropriately reduce the risk of depression.

Incidental findings during donor liver assessment: Single center experience.

Intraoperative consultation of donor liver is an important part of transplant evaluation and determination of liver eligibility. In this study, we describe incidental pathologic findings discovered during the pretransplant evaluation of liver donors in our Institution from 1/2010 to 12/2022. During this 13-year period 369 intraoperative consultations from 262 liver donors were performed. Of those cases, incidental findings were identified in 22 cases (5.9 %) from 19 donors (7.3 %); two donors had more than one lesion. The median age of this subset of patients was 53 years (range: 18-70) and females predominated (63 %). Sixteen of the donors had abnormal findings in the liver: 6 bile duct hamartoma (BDH), 5 hyalinized nodule with Histoplasma capsulatum, 5 focal nodular hyperplasia (FNH), 2 bile duct adenomas (BDA), 1 biliary cyst and 1 hemangioma. One donor had both FNH and a BDH. One BDH and 1 BDA case was misdiagnosed as malignancy during the frozen section evaluation. Three donors had extrahepatic pathologies: a pancreatic tail schwannoma, a low-grade appendiceal mucinous neoplasm, and a lymph node with metastatic endometrial endometrioid adenocarcinoma. Of the 19 livers, the final organ disposition was available for 9: 6 were transplanted (67 %) and 3 were discarded (33 %). Two of the 3 discarded organs were misdiagnosed BDH and BDA cases, and one was incorrectly reported as having 90 % microvesicular steatosis during the frozen assessment. We present the clinicopathologic characteristics of liver donors with incidental findings during the pre-transplant evaluation which could lead to unwarranted graft dismissal if misdiagnosed. Additionally, incidental fungal infections can have implications for immunosuppressive therapy and the decision to use or reject the graft.

[Practical application of the Paris system for reporting urinary cytology].

Objective: To validate the diagnostic performance of the Paris system for reporting urinary cytology (TPS). Methods: A total of 7 046 urine cytology samples from 3 402 patients collected in the Department of Pathology, Beijing Hospital, China from January 2020 to January 2022 were analyzed. 488 patients had a biopsy or resection specimen during the follow-up period of 6 months. The sensitivity, specificity, risk of malignancy (ROM) and risk of high-grade malignancy (ROHM) of the TPS were evaluated using histological diagnosis as the golden standard. Results: Among the 7 046 samples, high-grade urothelial carcinoma (HGUC) accounted for 5.7% (399/7 046), suspicious for high-grade urothelial carcinoma (SHGUC) for 3.2% (227/7 046), atypical urothelial cells (AUC) for 8.4% (593/7 046), and negative for high-grade urothelial carcinoma (NHGUC) for 72.9% (5 139/7 046) including low-grade urothelial neoplasm (LGUN) for 0.8% (59/7 046) and insufficient samples for 9.8% (688/7 046). 488 patients had a bladder biopsy or resection in the follow-up of six months, including 314 males and 174 females, aged 27 to 92 years (average, 66 years). The ROHM of TPS was 94.7% in HGUC, 83.3% in SHGUC, 41.3% in AUC and 18.8% in NHGUC. The sensitivity and specificity of urine cytology were 70.1% (169/241) and 97.0% (162/167), respectively. The negative predictive value of NHGUC was 69.2% (162/234). Conclusions: The study has shown that TPS classification has high sensitivity and specificity, high ROHM for HGUC and SHGUC, and high negative predictive value for NHGUC. The application of TPS reporting system can better interpret the clinical significance of cytology samples, improve the accuracy of urine cytopathology and ensure continuous diagnostic consistency.

[Application of cell blocks to assist in precise cytological diagnosis of serous effusion].

Objective: To investigate the importance of cell block and immunohistochemistry in the accurate diagnosis of serous effusion. Methods: A retrospective study was conducted on 3 124 cases of serous effusion from the Department of Pathology, Beijing Hospital from 2018 to 2022, include 2 213 cases of pleural effusion, 768 cases of peritoneal effusion, 143 cases of pericardial effusion. There were 1 699 males (54.4%) and 1 425 females (45.6%), average age 69 years old. Of which 1 292 cases were prepared with cell blocks and examined with immunohistochemical stain. Results: The percentage of malignant diagnosis increased from 64.9% (839/1 292) to 84.0% (1 086/1 292) after cell block preparation, and 1 086 cases were accurately diagnosed with histological type and/or origin of primary tumor. The undetermined diagnosis of suspected malignancy decreased from 13.3% (172/1 292) to 0.1% (1/1 292) and that of atypical hyperplasia from 18.8% (243/1 292) to 0.4% (5/1 292). The negative result for malignancy rate increased from 3.0% (38/1 292) to 15.5% (200/1 292). The differences highlighted above were statistically significant (Pearson's chi-squared test=12.739, P<0.01). Conclusion: Application of immunohistochemistry based on cell block can significantly improve malignant diagnosis in serous effusion, identify tumor origin and histological type as well as decrease the uncertain diagnosis.

[Quantitative HER2 mRNA assay in breast cancer with HER2 immunohistochemistry 0].

Objective: To investigate HER2 mRNA expression in breast cancer with HER2 immunohistochemistry (IHC) 0 and to analyze the feasibility of distinguishing between the tumor with HER2 µltra-low expression and the one without expression of HER2 (no staining by IHC) by HER2 mRNA level preliminarily. Methods: HER2 mRNA was analyzed by reverse transcription digital PCR in 41 cases of formalin-fixed paraffin-embedded surgical tissue samples of invasive breast cancer obtained between January 2020 and March 2023 at Peking Union Medical College Hospital. The cohort included 21 HER2 IHC 1+ and 20 IHC 0 (12 ultra-low and 8 non-expression of HER2). HER2 mRNA expression level was quantitatively evaluated by the FAM (HER2)/VIC (reference gene) ratio. Results: The expression of HER2 mRNA for the cases with 1+, ultra-low, and non-expression of HER2 by IHC was 0.30 to 1.78 (average 0.90, median 0.82), 0.55 to 1.51 (average 0.93, median 0.90) and 0.22 to 0.78 (average 0.41, median 0.36), respectively. For the mean and median HER2 mRNA levels, there was no significant difference between HER2 IHC 1+ and HER2 ultra-low expression diseases (P=0.757). A remarkable difference in HER2 gene expression was found between the tumors with 1+ and non-expression of HER2 by IHC (P=0.002). And, HER2 ultra-low cases contained statistically higher levels of HER2 mRNA compared with non-expression of HER2 subgroup by IHC (P=0.001). Conclusions: Based on HER2 mRNA, HER2 non-expression and HER2 weak expression (including HER2 IHC 1+ and ultra-low) belong to two different types of the tumor and the disease with HER2 IHC 1+ and HER2 ultra-low expression may be the same. It is necessary to further test the performance of HER2 mRNA detection for stratifying the HER2 weak expression subgroup and to determine the threshold.

[Clinicopathological features of breast cancer with HER2 low expression: a real-world retrospective study].

Objective: To investigate the clinical and pathological characteristics of breast cancer with HER2 low expression. Methods: The data from 3 422 patients with invasive breast cancer which archived in Peking Union Medical College Hospital between April 2019 and July 2022 were retrospectively reviewed. Among them, 136 patients were treated with neoadjuvant chemotherapy. The tumor size, histological type, tumor differentiation, lymph node metastasis, Ki-67 index, the status of estrogen receptor, progesterone receptor and HER2 as well as pathological complete response (pCR) rate were collected. Results: The HER2 status of 3 286 patients without neoadjuvant therapy, 616 (616/3 286, 18.7%) score 0, 1 047 (1 047/3 286, 31.9%) score 1+, 1 099 (1 099/3 286,33.4%) score 2+ and 524 (524/3 286,15.9%) score 3+ by immunohistochemistry (IHC). Among the 1 070 IHC 2+ cases, 161 were classified as HER2 positive by reflex fluorescence in situ hybridization (FISH) assay. In our cohort, 1 956 cases of HER2-low (IHC 1+ and IHC 2+/FISH-) breast cancer were identified. Compared to the HER2 IHC 0 group, HER2-low tumors more frequently occurred in patients with hormone receptor (HR) positive (P<0.001), Ki-67 index below 35% (P<0.001), well or moderate differentiation (P<0.001) and over the age of 50 (P=0.008). However, there were no significant differences in histological type, tumor size, and lymph node metastasis between HER2-low and HER2 IHC 0 group. For patients who had neoadjuvant therapy, the pCR rate in the patients with HER2-low was lower than those with HER2 IHC 0 (13.3%, 23.9%), but there was no significant difference. Although HER2-low breast cancers showed a slightly lower pCR rate than HER2 IHC 0 tumors, no remarkable difference was observed between tumors with HER2-low and HER2 IHC 0 regardless of hormone receptor status. Conclusions: The clinicopathological features of HER2-low breast cancers are different from those with HER2 IHC 0. It is necessary to accurately distinguish HER2-low breast cancer from HER2 IHC 0 and to reveal whether HER2-low tumor is a distinct biological entity.

[SRF-rearranged cellular perivascular myoid tumor: a clinicopathological analysis of two cases].

Objective: To investigate the clinicopathological features, immunophenotype, diagnosis and differential diagnosis of SRF-rearranged cellular perivascular myoid tumor. Methods: Two cases of SRF-rearranged cellular perivascular myoid tumor diagnosed in the Department of Pathology, Fudan University Shanghai Cancer Center from October 2021 to March 2022 were collected. Immunohistochemical staining, fluorescence in-situ hybridization (FISH) and next-generation sequencing (NGS) were performed, and the literature was reviewed. Results: Case 1, a 3-month-old boy presented with a painless tumor of the scalp, measuring about 2 cm in diameter. Case 2, a 3-year-old girl complained with a painless tumor of the knee, measuring approximately 1.5 cm in diameter. Microscopically, the tumor had a clear boundary and showed multinodular growth. The tumor was mainly composed of spindle cells arranged in long intersecting fascicles associated with thin, slit-like or branching ectatic vessels, focally forming hemangiopericytoma-like appearance. The tumor cells were abundant, but there was no obvious atypia. Mitotic figures (3-4/10 HPF) were noted. H-caldesmon and SMA were positive in both cases. Case 1 showed diffuse and strong positivity for Desmin, and focally for CKpan. Ki-67 proliferation index was 20% and 30%, respectively. FISH displayed NCOA2 gene translocation in case 1 and the RELA gene translocation in case 2. NGS detected the SRF-NCOA2 gene fusion in case 1 and the SRF-RELA gene fusion in case 2. Both patients underwent local excisions. During the follow-up of 5-14 months, case 1 had no local recurrence, while case 2 developed local recurrence 1 year post operatively. Conclusions: SRF-rearranged cellular perivascular myoid tumor is a novel variant of perivascular cell tumor, which tends to occur in children and adolescents. The tumor forms a broad morphologic spectrum ranging from a pericytic pattern to a myoid pattern, and include hybrid tumors with a mixture of pericytic and myoid patterns. Due to its diffuse hypercellularity and increased mitotic figures and smooth muscle-like immunophenotype, the tumor is easy to be misdiagnosed as myogenic sarcomas. The tumor usually pursues a benign clinical course and rare cases may locally recur.

[Study on the application value of portable pulse oximeter in adult patients with obstructive sleep apnea].

Objective: To evaluate the application value of portable pulse oximeter in adult obstructive sleep apnea (OSA). Methods: This study prospectively enrolled adult patients who underwent polysomnography (PSG) due to snoring at the Respiratory and Sleep Medicine Department of Peking University People's Hospital from July 2022 to July 2023. During PSG monitoring, CS-WOxi was continuously used to monitor blood oxygen levels. The consistency between 3% oxygen desaturation index (ODI3) measured by portable pulse oximeter and ODI3 of polysomnography was evaluated using difference test, Pearson's correlation coefficient, and Bland-altman method. Receiver operating characteristic curve was used to determine the optimal threshold for diagnosing OSA. Results: A total of 184 subjects were included, including 121 males (65.8%) and 63 females (34.2%). The mean age was 46.0 (34.3, 59.0) years, body mass index was 26.0 (23.3, 29.6) kg/m², and the apnea-hypopnea index was 18.2 (5.8, 40.8) events/h. There was a significant difference between CS-ODI3 and PSG-ODI3 [17.1(6.2, 42.7) vs. 14.0(2.9, 32.6), P<0.001], and the Pearson correlation coefficient was 0.93 (P<0.001). There was a good correlation between CS-ODI3 and PSG-AHI (r=0.92, P<0.001). Bland-Altman consistency test showed that the average difference between the two was 0.7 events/h, and the 95% consistency limit was (-17.9, 19.3 events/h). When the CS-ODI3≥5 events/h was used to identify OSA, the sensitivity was 94.4%, the specificity was 80.0%, and the accuracy was 91.3%. When PSG-AHI≥5 events/h was used as the diagnostic criteria, the area under the receiver operating characteristic curve was 0.933. Conclusion: Portable pulse oximeter can monitor pulse oxygen saturation accurately and has good sensitivity and specificity for OSA high-risk patients, and is a reliable tool for OSA screening.

[A case of acute inhalation dinitrogen tetroxide poisoning].

Dinitrogen tetroxide is often used as an oxidant in rocket propellant and has strong irritant and corrosive properties. This paper analyzes the clinical data of a patient with dinitrogen tetroxide poisoning admitted in the 63710 Army Hospital of Chinese People's Liberation Army, so as to further explore the poisoning mechanism, clinical characteristics and key points of acute inhaled dinitrogen tetroxide poisoning.

A real-world pharmacovigilance study of abaloparatide based on the FDA Adverse Event Reporting System (FAERS).

Abaloparatide (ABL) is a US Food and Drug Administration-approved parathyroid hormone-related peptide analog for treatment of osteoporosis in postmenopausal women at high risk of fracture. However, real-world data regarding its long-term safety and tolerability in large sample population are incomplete. We evaluated abaloparatide-associated safety signals by data mining of the FDA pharmacovigilance database. INTRODUCTION: We investigated 33,480(0.14%) ABL-related adverse events (AEs) through data mining of Food and Drug Administration Adverse Event Reporting System (FAERS) retrospectively. METHODS: Reporting odds ratio (ROR), the proportional reporting ratio (PRR), the Bayesian confidence propagation neural network (BCPNN), and the multi-item gamma Poisson shrinker (MGPS) were employed to quantify the signals of ABL-related AEs from 2017Quarter2 to 2022.Serious and non-serious cases were compared by Mann-Whitney U test or Chi-squared (χ2) test. RESULTS: We collected 8,470,497 reports from the FAERS database, including 11,487 reports defined ABL as the primary suspected (PS) drug. Additionally, 36.16% of the reports were submitted by healthcare professionals (n=4154), compared to 62.26% reported by consumers (n=7140). A total 99 signals simultaneously conforming to four algorithms were detected, among which, 35 signals were identified as unexpected signals. Such as growing pains (n=13), waist circumference increased (n=21), sensory disturbance (n=103), tinnitus (n=65), visual acuity reduced (n=54), blood alkaline phosphatase increased (n=61), and hair growth abnormal (n=13). Patient age (p < 0.001) might be associated with an increased risk of AEs severity. The most common timeframe for AE occurrence was 0-7 days. CONCLUSION: Our study provided a deeper and broader understanding of abaloparatide's safety profiles, which would help healthcare professionals to mitigate the risk of AEs in clinical practice, a low number of unexpected AEs supporting ongoing additional pharmacovigilance.

Mass Measurement of Upper fp-Shell N=Z-2 and N=Z-1 Nuclei and the Importance of Three-Nucleon Force along the N=Z Line.

Using a novel method of isochronous mass spectrometry, the masses of ^{62}Ge, ^{64}As, ^{66}Se, and ^{70}Kr are measured for the first time, and the masses of ^{58}Zn, ^{61}Ga, ^{63}Ge, ^{65}As, ^{67}Se, ^{71}Kr, and ^{75}Sr are redetermined with improved accuracy. The new masses allow us to derive residual proton-neutron interactions (δV_{pn}) in the N=Z nuclei, which are found to decrease (increase) with increasing mass A for even-even (odd-odd) nuclei beyond Z=28. This bifurcation of δV_{pn} cannot be reproduced by the available mass models, nor is it consistent with expectations of a pseudo-SU(4) symmetry restoration in the fp shell. We performed ab initio calculations with a chiral three-nucleon force (3NF) included, which indicate the enhancement of the T=1 pn pairing over the T=0 pn pairing in this mass region, leading to the opposite evolving trends of δV_{pn} in even-even and odd-odd nuclei.

Commensal bacteria make GPCR ligands that mimic human signalling molecules.

Commensal bacteria are believed to have important roles in human health. The mechanisms by which they affect mammalian physiology remain poorly understood, but bacterial metabolites are likely to be key components of host interactions. Here we use bioinformatics and synthetic biology to mine the human microbiota for N-acyl amides that interact with G-protein-coupled receptors (GPCRs). We found that N-acyl amide synthase genes are enriched in gastrointestinal bacteria and the lipids that they encode interact with GPCRs that regulate gastrointestinal tract physiology. Mouse and cell-based models demonstrate that commensal GPR119 agonists regulate metabolic hormones and glucose homeostasis as efficiently as human ligands, although future studies are needed to define their potential physiological role in humans. Our results suggest that chemical mimicry of eukaryotic signalling molecules may be common among commensal bacteria and that manipulation of microbiota genes encoding metabolites that elicit host cellular responses represents a possible small-molecule therapeutic modality (microbiome-biosynthetic gene therapy).

Effects of adverse childhood experiences on the Charlson comorbidity index in US adults.

OBJECTIVES: The aim of this article was to explore the association between adverse childhood experiences (ACEs) and the Charlson comorbidity index (CCI) and to provide valuable information for public health professionals and policymakers to improve quality of life and reduce mortality. STUDY DESIGN: A cross-sectional analysis was conducted using data pooled from the 2020 Behavioral Risk Factor Surveillance System (BRFSS). METHODS: This study involved 102,393 US adult participants from the 2020 BRFSS. The zero-inflated negative binomial (ZINB) and mixed graphical model (MGM) models were used to explore the effect of ACEs on CCI and the interaction between ACEs. RESULTS: In the count part of the model (CCI ≥0), sexual abuse had the strongest association with CCI (relative risk [RR] = 1.111, P < 0.001). In the logit part of the model (CCI = 0), the likelihood of having CCI equal to 0 decreased by 23.0% for household substance abuse, which was the highest percentage decrease for all ACEs. Compared to those with ACE scores equal to 0, individuals with ACE scores ≥4 have an expected CCI RR of 1.222, and the likelihood of having CCI equal to 0 decreased by 50.2%. Household substance abuse and incarceration history in the home had the strongest association among interactions of ACEs (0.85). CONCLUSIONS: Associations between ACEs and CCI were observed in this study, and these associations differed between genders. The findings of this study provide data to design strategies for disease prevention and improvement of quality of life.