Ticagrelor was associated with lower fracture risk than clopidogrel in the dual anti-platelet regimen among patients with acute coronary syndrome treated with percutaneous coronary intervention.

PURPOSE: Patients with coronary artery disease have increased fracture risks. P2Y12 inhibitors may impact fracture risks. We compared the fracture risks associated with ticagrelor and clopidogrel in dual anti-platelet therapy (DAPT). METHODS: We identified all adults who underwent first-ever percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS) between 2010 and 2017 from a territory-wide PCI registry in Hong Kong. Following 1:1 propensity-score matching for baseline characteristics, patients were followed up till event occurrence, death, or 30 June 2022. Outcomes of interest were major osteoporotic fractures (MOF) identified by validated ICD-9-CM codes. Cox proportional hazards regression was used to compute the hazard ratio (HR) for MOF associated with ticagrelor versus clopidogrel use. RESULTS: 3018 ticagrelor users and 3018 clopidogrel users were identified after propensity-score matching (mean age: 61.4 years; 84.1% men). Upon median follow-up of 6.5 years, 59 ticagrelor users and 119 clopidogrel users sustained MOF (annualized fracture risks: 0.34% and 0.56%, respectively). Ticagrelor use was associated with lower risks of MOF (HR 0.60, 95%CI 0.44-0.83; p = 0.002). Consistent HRs were observed for fractures over vertebrae, hip and upper limbs. Subgroup analyses showed no interaction according to age, sex, presence of diabetes, presence of chronic kidney disease and prior fracture history. CONCLUSION: Among adults who underwent first-ever PCI for ACS, ticagrelor use in the DAPT was associated with a lower risk of MOF compared with clopidogrel. Our results support the use of ticagrelor in the DAPT from the perspective of bone health.

Preclinical evaluation of the VEGF/Ang2 bispecific nanobody BI 836880 in nasopharyngeal carcinoma models.

Epstein-Barr virus (EBV)-associated nasopharyngeal carcinoma (NPC) is endemic to parts of Asia and overexpression of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1α are common in NPC. Anti-vascular agents have known clinical activity in patients with recurrent/ metastatic NPC and in this study, we investigated the anti-tumor effect of BI 836880, a humanized bispecific nanobody against VEGF and angiopoietin-2 (Ang2), in preclinical models of EBV-positive and EBV-negative NPC. The efficacy of BI 836880 was also compared with bevacizumab, a recombinant humanized monoclonal antibody against VEGF. We found that BI 836880 could exert growth-inhibitory effect on endothelial cells (HUVEC-C) and the EBV-negative NPC cell line (HK1), but to a lesser extent in the EBV-positive NPC cell lines, C17C and C666-1. In patients-derived xenograft (PDX) models of NPC - Xeno-2117 and Xeno-666, BI 836880 could suppress tumor growth and Ki67, as well as induce tumor necrosis and reduce microvessel density. Moreover, treatment with BI 836880 increased the level of macrophage infiltration in both PDX tumor models of NPC, suggesting that BI 836880 may exert immunomodulatory effect on the NPC immune microenvironment. When compared with bevacizumab, BI 836880 appeared to show at least comparable activity as bevacizumab in terms of its anti-proliferative and anti-angiogenic effects. This study showed that BI 836880 has anti-proliferative, anti-angiogenic and possibly immunomodulatory effect in clinical models of NPC, therefore the dual targeting of VEGF and Ang2 signaling in NPC should be further investigated.

Expedient synthesis of imino-C-nucleoside fleximers featuring a one-pot procedure to prepare aryl triazoles.

Nucleoside analogues such as the antiviral agents galidesivir and ribavirin are of synthetic interest. This work reports a "one-pot" preparation of similar fleximers using a bifunctional copper catalyst that generates the aryl azide in situ, which is captured by a terminal alkyne to effect triazole formation.

Thermal Disorder in Finite-Length Carbon Nanowire.

Enhancement in chemisorption is one of the active research areas in carbon materials. To remedy the thermally degraded chemisorption occurring at high temperatures, we report a comprehensive study of kink structures in free-standing monoatomic carbon nanowires upon heating. Our Monte Carlo simulation considers multi-monoatomic carbon chains laterally interacting by van der Waals forces. Our study reveals that carbon nanowires maintain their linearity regardless of chain length at low temperatures, but this is not the case at high temperatures. Disordered kink structure is observed in short carbon chains, especially above the Peierls transition temperature. A severe kink structure may increase the possibility of attaching negatively charged atoms, thereby contributing to the development of next-generation materials for chemisorption at high temperatures. We have also provided an important indication that any physical property of the finite-length carbon chain predicted by ab initio calculation should reconsider the atomic rearrangement due to thermal instability at high temperatures.

Integrating postradiotherapy plasma Epstein-Barr virus DNA and TNM stage for risk stratification of nasopharyngeal carcinoma to adjuvant therapy.

BACKGROUND: After curative radiotherapy (RT) or chemoradiation (CRT), there is no validated tool to accurately identify patients for adjuvant therapy in nasopharyngeal carcinoma (NPC). Post-RT circulating plasma Epstein-Barr virus (EBV) DNA can detect minimal residual disease and is associated with recurrence and survival independent of TNM (tumor-lymph node-metastasis) stage. We aimed to develop and validate a risk model for stratification of NPC patients after completion of RT/CRT to observation or adjuvant therapy. PATIENTS AND METHODS: The prospective multicenter 0502 EBV DNA screening cohort (Hong Kong NPC Study Group 0502 trial) enrolled from 2006 to 2015 (n = 745) was used for model development. For internal validation, we pooled independent patient cohorts from prospective clinical studies enrolled from 1997 to 2006 (n = 340). For external validation, we used retrospective cohort of NPC patients treated at Sun Yat-sen University Cancer Center from 2009 to 2012 (n = 837). Eligible patients had histologically confirmed NPC of Union for International Cancer Control (UICC) 7th Edition stage II-IVB who completed curative RT/CRT with or without neoadjuvant chemotherapy, had post-RT EBV DNA tested within 120 days after RT and received no adjuvant therapy. The primary end point was overall survival (OS). We used recursive-partitioning analysis (RPA) to classify patients into groups of low, intermediate, and high risk of death. RESULTS: Combining post-RT EBV DNA level (0, 1-49, 50-499, and ≥500 copies/ml) and TNM stage (II, III, IVAB), RPA model classified patients into low-, intermediate-, and high-risk groups with 5-year OS of 89.4%, 78.5% and 37.2%, respectively. The RPA low-risk group had comparable OS to TNM stage II (5-year OS 88.5%) but identified more patients (64.8% versus stage II 28.1%) that could potentially be spared adjuvant therapy toxicity. The RPA model (c-index 0.712) showed better risk discrimination than either the TNM stage (0.604) or post-RT EBV DNA alone (0.675) with improved calibration and consistence. These results were validated in both internal and external cohorts. CONCLUSION: Combining post-RT EBV DNA and TNM stage improved risk stratification in NPC.

Enormous enhancement of p-orbital magnetism and band gap in the lightly doped carbyne.

This paper presents a path to tailor adapted magnetic and electronic properties in carbyne. Although p-orbital magnetism is generally much weaker than d-orbital magnetism, we demonstrate that the charge fluctuation of the free radical electrons triggered by a time-varying electric dipole moment leads to enormous p-orbital magnetism. By introducing 25% arsenic and 12.5% fluorine into the monoatomic carbon chain, the magnetic moment of the arsenic atom reaches 2.9 µB, which is ∼1.3 times stronger than magnetic moment of bulk Fe. This magnetically optimized carbyne composite carries an exchange-correlation energy of 22 meV (∼270 K). On the other hand, we convert the carbyne (in beta-form) from metallic to a semiconducting state by using anionic dopants. After doping 12.5% nitrogen and 12.5% oxygen into the beta-carbyne, the semiconducting gap of this composite is optimized at 1.6 eV, which is 1.4 times larger than the band gap of bulk silicon.

Creation of Si quantum dots in a silica matrix due to conversion of radiation defects under pulsed ion-beam exposure.

In this work we present an innovative method of creating Si quantum dots under pulsed ion-beam exposure. The evolution of defect structure ODC(II) → E'→ ODC(I) → Si QDs in glassy SiO2 under ion-beam implantation was established by optical absorption and photoluminescence spectroscopies. Depending on the mode of ion exposure, it is possible to easily control the type and concentration of defects in the host and modify its optical properties for novel applications. Ab initio calculations confirm that bond softening in SiO2 is attainable via the use of Gd ion implantation. According to our experimental and theoretical results, the three-stage interaction of primary oxygen-deficient centers leads to the formation of stable silicon quantum dots with a size of 3.6 nm and luminescence at 1.8 eV excited by incoherent light.

Impact of whole egg intake on blood pressure, lipids and lipoproteins in middle-aged and older population: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND AND AIM: Effects of whole egg consumption on cardiovascular diseases (CVD) risk in the middle-aged and older population remain unclear due to inconsistent findings from observational and randomized controlled trials (RCTs). This meta-analysis aimed to assess the impacts of whole egg and egg category (whole eggs versus egg substitutes) intake quantity on CVD risk factors from systematically searched RCTs. Egg substitutes were hypothesized to have minimal effects of the blood lipid and lipoprotein profile as they are void of dietary cholesterol. METHODS AND RESULTS: As many as 434 studies identified from PubMed, Cochrane Library, CINAHL and Medline (Ovid) databases were screened and data were extracted from 8 selected RCTs. Quality of the selected studies were assessed and the overall effect sizes of weighted mean differences (WMD) were calculated using a random effects model. Non-differential effects in blood pressures, lipids and lipoproteins were observed when >4 whole eggs/week compared to ≤4 whole eggs/week were consumed. Intake of >4 whole eggs/week compared to equivalent amounts of egg substitutes caused greater elevations in blood total cholesterol (WMD: 0.198 mmol/L; 95% CIs: 0.056, 0.339), HDL cholesterol (WMD: 0.068 mmol/L; 95% CIs: 0.006, 0.130) and LDL cholesterol (WMD: 0.171 mmol/L; 95% CIs: 0.028, 0.315) but did not differentially affect triglycerides concentration. CONCLUSION: Overall, the results support the notion that quantity of whole egg intake does not affect CVD risk factors and consuming egg substitutes may also be beneficial compared to whole eggs on lowering CVD risk in the middle-aged and older population.

Mutations during the Adaptation of H9N2 Avian Influenza Virus to the Respiratory Epithelium of Pigs Enhance Sialic Acid Binding Activity and Virulence in Mice.

The natural reservoir for influenza viruses is waterfowl, and from there they succeeded in crossing the barrier to different mammalian species. We analyzed the adaptation of avian influenza viruses to a mammalian host by passaging an H9N2 strain three times in differentiated swine airway epithelial cells. Using precision-cut slices from the porcine lung to passage the parental virus, isolates from each of the three passages (P1 to P3) were characterized by assessing growth curves and ciliostatic effects. The only difference noted was an increased growth kinetics of the P3 virus. Sequence analysis revealed four mutations: one each in the PB2 and NS1 proteins and two in the HA protein. The HA mutations, A190V and T212I, were characterized by generating recombinant viruses containing either one or both amino acid exchanges. Whereas the parental virus recognized α2,3-linked sialic acids preferentially, the HA190 mutant bound to a broad spectrum of glycans with α2,6/8/9-linked sialic acids. The HA212 mutant alone differed only slightly from the parental virus; however, the combination of both mutations (HA190+HA212) increased the binding affinity to those glycans recognized by the HA190 mutant. Remarkably, only the HA double mutant showed a significantly increased pathogenicity in mice. In contrast, none of those mutations affected the ciliary activity of the epithelial cells which is characteristic for virulent swine influenza viruses. Taken together, our results indicate that shifts in the HA receptor affinity are just an early adaptation step of avian H9N2 strains; further mutational changes may be required to become virulent for pigs.IMPORTANCE Swine play an important role in the interspecies transmission of influenza viruses. Avian influenza A viruses (IAV) of the H9N2 subtype have successfully infected hosts from different species but have not established a stable lineage. We have analyzed the adaptation of IAV-H9N2 virus to target cells of a new host by passaging the virus three times in differentiated porcine respiratory epithelial cells. Among the four mutations detected, the two HA mutations were analyzed by generating recombinant viruses. Depending on the infection system used, the mutations differed in their phenotypic expression, e.g., sialic acid binding activity, replication kinetics, plaque size, and pathogenicity in inbred mice. However, none of the mutations affected the ciliary activity which serves as a virulence marker. Thus, early adaptive mutation enhances the replication kinetics, but more mutations are required for IAV of the H9N2 subtype to become virulent.

Views of faculty members in a medical school with regards to error disclosure and reporting to parents and/or higher authorities.

BACKGROUND: Little is known about the views of faculty members who train medical students concerning open disclosure. OBJECTIVES: The objectives of this study were to determine the views of faculty in a medical school on: 1 what constitutes a medical error and the severity of such an error in relation to medication use or diagnosis; 2 information giving following such an adverse event, based on severity; and 3 acknowledgement of responsibility, remedial action, compensation, disciplinary action, legal action, and reporting to a higher body in relation to such adverse event. METHODS: We adapted and contextualized a questionnaire developed from a previous study. The questionnaire had 4 case vignettes that described 1 clear medication error with lifelong disability; 2 possible diagnostic error with lifelong disability; 3 possible diagnostic error without harm; and 4 clear medication error without harm. We invited all faculty members attached to the medical school at the International Medical University to participate in the study. RESULTS: Seventy faculty members took part. Faculty members viewed a medical error as having taken place depending on how clearly an error had occurred (94% and 73% versus 53% and 27%). They viewed cases as more severe based on the severity of complications (85% and 46% versus 5% and 10%). With increasing severity, they tended to attribute responsibility for the event and the duty to disclose towards more senior clinicians. They were also more agreeable with remedial action, compensation, disciplinary action, and reporting to a higher agency. There was no strong evidence of association between these areas and the demographics of faculty members. CONCLUSIONS: Faculty members are more likely to perceive an error had occurred depending on the clarity of the circumstances. They viewed severity based on the presence of complications. Severity determined how they attributed responsibility, duty to disclose, and other areas related to open disclosure.

Parental preferences with regards to disclosure following adverse events occurring in relation to medication use or diagnosis in the care of their children - perspectives from Malaysia.

INTRODUCTION: Open disclosure is poorly understood in Malaysia but is an ethical and professional responsibility. The objectives of this study were to determine: (1) the perception of parents regarding the severity of medical error in relation to medication use or diagnosis; (2) the preference of parents for information following the medical error and its relation to severity; and (3) the preference of parents with regards to disciplinary action, reporting, and legal action. METHODS: We translated and contextualised a questionnaire developed from a previous study. The questionnaire consisted of four case vignettes that described the following: medication error with a lifelong complication; diagnostic error with a lifelong complication; diagnostic error without lifelong effect; and medication error without lifelong effect. Each case vignette was followed by a series of questions examining the subject's perception on the above areas. We also determined the content validity of the questionnaire. We invited parents of Malaysian children admitted to the paediatric wards of Tuanku Jaafar Hospital to participate in the study. RESULTS: One hundred and twenty-three parents participated in the study. The majority of parents wanted to be told regarding the event. As the severity of the case vignettes increased, the desire for information, remedial action, acknowledgement of responsibility, compensation, punishment, legal action, and reporting to a higher agency also increased. The findings did not have strong evidence of a relationship with subject's demographics. CONCLUSION: This study gives insights into previously unexplored perspectives and preferences of parents in Malaysia regarding open disclosure. It also highlights the opportunity for more research in this area with potentially broad applications.

Epilepsy in patients with primary brain tumors: The impact on mood, cognition, and HRQOL.

BACKGROUND: A primary brain tumor (PBT) is often a fatal disease of the nervous system and has a serious impact on health-related quality of life (HRQOL). Presence of epilepsy and adverse reactions from tumor and epilepsy treatments may cause additional decline in HRQOL. OBJECTIVES: We aimed to study the impact of epileptic seizures on cognition, mood, and HRQOL in patients with brain tumor-related epilepsy. MATERIALS AND METHOD: Patients were grouped on an ordinal scale according to epilepsy burden from none to severe based on the presence of epileptic seizures and seizure frequency: L1, no epilepsy; L2, with epilepsy, seizure-free in the last 6 months with antiepileptic drugs; and L3, with epilepsy, at least one seizure in the last 6 months with AEDs. Health-related quality of life was measured by Functional Assessment of Cancer Therapy-Brain (FACT-Br) and Quality of Life in Epilepsy-31 (QOLIE-31) tools, cognition by the Montreal Cognitive Assessment (MoCA) tool and Frontal Assessment Battery (FAB), mood by the Hospital Anxiety and Depression Scale (HADS), activities of daily living (ADLs) by the Barthel Index (BI), and performance status by the Karnofsky Performance Status (KPS) scale in patients with primary brain tumors at least one month following neurosurgery with or without radiotherapy and chemotherapy. RESULTS: Eighty-one patients with a diagnosis of primary brain tumors were recruited. Sixty-eight percent of patients were diagnosed with primary brain tumor-related epilepsy, 50.61% patients had cognitive impairment, 33% had abnormal scores in the anxiety scale, and 34% had abnormal scores in the depression scale. There were no statistically significant differences in these scores among L1, L2, and L3 groups. There were statistically significant differences in duration of disease and KPS and BI scores between L1 and L3 groups. The L3 group has significantly longer duration of disease and scored low in both the BI and KPS scale when compared to the L1 group. All patients with primary brain tumors scored significantly low in FACT-Br 'physical well-being' (PWB) and 'emotional well-being' (EWB) and high in 'social well-being' (SWB) when compared to healthy controls. When scores of each group were individually compared to healthy controls, the L3 group showed the lowest scores in PWB, EWB, and 'functional well-being'. In SWB, L1 and L2 groups showed statistically significantly high scores when compared to normative data. The QOLIE-31 applied to groups with epilepsy showed statistically significantly lower scores in the L3 group when compared to the L2 group in 'cognitive' and 'social functioning' domains. On multivariate analysis, both poor performance status and frequency of seizures were found to be independent risk factors for poor HRQOL when FACT-Br mean scores were compared. Level of seizures was found to be an independent risk factor for poor HRQOL when QOLIE-31 scores were compared between L2 and L3 groups. DISCUSSION: Presence of brain tumors could be attributed to cognitive impairment irrespective of the presence of epilepsy in our cohort. High seizure burden is an independent risk factor for poor HRQOL in patients with primary brain tumors. The QOLIE-31 is a more sensitive tool than the FACT-Br because of the presence of a seizure-related questionnaire.

Early diagnosis of necrotizing fasciitis.

BACKGROUND: Necrotizing fasciitis is a rapidly progressing skin infection characterized by necrosis of the fascia and subcutaneous tissue, accompanied by severe systemic toxicity. The objective of this systematic review was to identify clinical features and investigations that will aid early diagnosis. METHODS: A systematic literature search of PubMed was undertaken using the keywords 'necrotising fasciitis', 'necrotising skin infection', 'diagnosis' and 'outcome'. Case series of 50 or more subjects with information on symptoms and signs at initial presentation, investigations and clinical outcome were included. RESULTS: Nine case series were selected, with a total of 1463 patients. Diabetes mellitus was a co-morbidity in 44.5 per cent of patients. Contact with marine life or ingestion of seafood in patients with liver disease were risk factors in some parts of Asia. The top three early presenting clinical features were: swelling (80.8 per cent), pain (79.0 per cent) and erythema (70.7 per cent). These being non-specific features, initial misdiagnosis was common and occurred in almost three-quarters of patients. Clinical features that helped early diagnosis were: pain out of proportion to the physical findings; failure to improve despite broad-spectrum antibiotics; presence of bullae in the skin; and gas in the soft tissue on plain X-ray (although this occurred in only 24.8 per cent of patients). CONCLUSION: A high index of suspicion of necrotizing fasciitis is needed in a patient presenting with cutaneous infection causing swelling, pain and erythema, with co-morbidity of diabetes or liver disease. The presence of bullae, or gas on plain X-ray can be diagnostic. Early surgical exploration is the best approach in the uncertain case.

Synergistic activities of Panobinostat and doxorubicin in soft tissue sarcomas.

BACKGROUND: Soft tissue sarcomas (STS) are rare diseases typically arising from connective tissues in children and adults. However, chemotherapies involved in the treatment of STS may cause toxic side effects and multi-drug chemoresistance, making the treatment even more challenging. Histone deacetylase inhibitors (HDACi) are epigenetic agents which have shown anti-tumor effects as single agent as well as combination use with other drugs. Our project intends to prove the same effects in STS. METHODS: Panobinostat (LBH589) plus doxorubicin was selected for investigations based on our previous research. Tumor xenografts were tried in an epithelioid sarcoma model to validate good synergy effects in vivo and a leiomyosarcoma model was used as a negative comparison group. Gene profile changes were studied afterwards. The possible pathway changes caused by HDACi were explored and validated by several assays. RESULTS: Synergy effect of LBH589 plus doxorubicin was successfully validated in STS cell lines and an epithelioid sarcoma mice model. We tried to reduce the dose of doxorubicin to a lower level and found the drug combination can still inhibit tumor size in mice. Furthermore, gene profile changes caused by LBH589 was studied by RNA-Sequencing analysis. Results showed LBH589 can exert effects on a group of target genes which can regulate potential biological functions especially in the cell cycle pathway.

Tailored treatment of female indirect inguinal hernias by using single-port laparoscopic percutaneous internal ring suture: a comparison between children and adults.

PURPOSE: To compare the outcome of indirect inguinal hernias repaired by using single-port laparoscopic percutaneous internal ring suture (SPIRS) between the pediatric and adult females. METHODS: The medical records of females who were clinically assessed to have inguinal hernia from Oct. 2016 to May 2022 were reviewed. Patients who received laparoscopy for the diagnosis of the hernia type and customized treatment according to their hernia type were included, while those who chose other operation methods initially were excluded. The patients were divided into the adult and pediatric groups based on their age. The demographic characteristics, hernia types, operation durations, and outcomes were analyzed between these two groups. RESULTS: A total of 65 adults and 60 children were included in this study. The median age was 38 years. (range: 23-88) for group A and 3 years (range: 0.1-16) for group P. Indirect hernias were present in 85% of adults and 100% of children. All the indirect hernias were repaired by SPIRS uneventfully. Incidence of contralateral patent processus vaginalis was 24% in adults and 50% in children (p = 0.016). The average operation time was 22/46 min (one/two sides) for the adults and 9/15 min (one/two sides) for the pediatrics (p < 0.010 for both). The overall complication rates were 5.4% and 3.3% for the adult and pediatric group respectively (p = 0.106). No recurrence was observed in the pediatric group, but two adults experienced recurrence and another had chronic postoperative inguinal pain, necessitating reoperation. The mean follow-up period was 38.6 ± 15.4 months for adults and 42.8 ± 18.9 months for children (p = 0.198). CONCLUSION: Our results support that the pathogenesis of indirect inguinal hernia for the female adults is due to the non-obliteration of a congenital processus vaginalis. Tailored treatment of the female IIH by using single-port laparoscopic percutaneous internal ring suture may be an alternative for the management of female IHs.