MR-guided adaptive versus ITV-based stereotactic body radiotherapy for hepatic metastases (MAESTRO): a randomized controlled phase II trial.

BACKGROUND: Stereotactic body radiotherapy (SBRT) is an established local treatment method for patients with hepatic oligometastasis or oligoprogression. Liver metastases often occur in close proximity to radiosensitive organs at risk (OARs). This limits the possibility to apply sufficiently high doses needed for optimal local control. Online MR-guided radiotherapy (oMRgRT) is expected to hold potential to improve hepatic SBRT by offering superior soft-tissue contrast for enhanced target identification as well as the benefit of gating and daily real-time adaptive treatment. The MAESTRO trial therefore aims to assess the potential advantages of adaptive, gated MR-guided SBRT compared to conventional SBRT at a standard linac using an ITV (internal target volume) approach. METHODS: This trial is conducted as a prospective, randomized, three-armed phase II study in 82 patients with hepatic metastases (solid malignant tumor, 1-3 hepatic metastases confirmed by magnetic resonance imaging (MRI), maximum diameter of each metastasis ≤ 5 cm (in case of 3 metastases: sum of diameters ≤ 12 cm), age ≥ 18 years, Karnofsky Performance Score ≥ 60%). If a biologically effective dose (BED) ≥ 100 Gy (α/ß = 10 Gy) is feasible based on ITV-based planning, patients will be randomized to either MRgRT or ITV-based SBRT. If a lesion cannot be treated with a BED ≥ 100 Gy, the patient will be treated with MRgRT at the highest possible dose. Primary endpoint is the non-inferiority of MRgRT at the MRIdian Linac® system compared to ITV-based SBRT regarding hepatobiliary and gastrointestinal toxicity CTCAE III or higher. Secondary outcomes investigated are local, locoregional (intrahepatic) and distant tumor control, progression-free survival, overall survival, possible increase of BED using MRgRT if the BED is limited with ITV-based SBRT, treatment-related toxicity, quality of life, dosimetric parameters of radiotherapy plans as well as morphological and functional changes in MRI. Potential prognostic biomarkers will also be evaluated. DISCUSSION: MRgRT is known to be both highly cost- and labor-intensive. The MAESTRO trial aims to provide randomized, higher-level evidence for the dosimetric and possible consecutive clinical benefit of MR-guided, on-table adaptive and gated SBRT for dose escalation in critically located hepatic metastases adjacent to radiosensitive OARs. TRIAL REGISTRATION: The study has been prospectively registered on August 30th, 2021: Clinicaltrials.gov, "Magnetic Resonance-guided Adaptive Stereotactic Body Radiotherapy for Hepatic Metastases (MAESTRO)", NCT05027711.

Striatal dopamine synthesis capacity and its association with negative symptoms upon resolution of positive symptoms in first-episode schizophrenia and delusional disorder.

RATIONALE: How striatal dopamine synthesis capacity (DSC) contributes to the pathogenesis of negative symptoms in first-episode schizophrenia (SZ) and delusional disorder (DD) has seldom been explored. As negative symptoms during active psychotic episodes can be complicated by secondary influences, such as positive symptoms, longitudinal investigations may help to clarify the relationship between striatal DSC and negative symptoms and differentiate between primary and secondary negative symptoms. OBJECTIVE: A longitudinal study was conducted to examine whether baseline striatal DSC would be related to negative symptoms at 3 months in first-episode SZ and DD patients. METHODS: Twenty-three first-episode age- and gender-matched patients (11 DD and 12 SZ) were consecutively recruited through an early intervention service for psychosis in Hong Kong. Among them, 19 (82.6%) patients (9 DD and 10 SZ) were followed up at 3 months. All patients received an 18F-DOPA PET/MR scan at baseline. RESULTS: Baseline striatal DSC (Kocc;30-60) was inversely associated with negative symptoms at 3 months in first-episode SZ patients (rs = - 0.80, p = 0.010). This association remained in SZ patients even when controlling for baseline negative, positive, and depressive symptoms, as well as cumulative antipsychotic dosage (ß = - 0.69, p = 0.012). Such associations were not observed in first-episode DD patients. Meanwhile, the severity of negative symptoms at 3 months was associated with more positive symptoms in DD patients (rs = 0.74, p = 0.010) and not in SZ patients. CONCLUSIONS: These findings highlight the role of striatal DSC in negative symptoms upon resolution of active psychotic episodes among first-episode SZ patients. Baseline striatal dopamine activity may inform future symptom expression with important treatment implications.

Poor health literacy associated with stronger perceived barriers to breast cancer screening and overestimated breast cancer risk.

Background: Low health literacy (HL) is negatively associated with mammography screening uptake. However, evidence of the links between poor HL and low mammography screening participation is scarce. Methods: We conducted a cross-sectional questionnaire survey among participants of a cancer screening program. We measured HL using a validated Chinese instrument. We assessed breast cancer screening-related beliefs using the Health Belief Model and the accuracy of risk perception. We used multivariable regression models to estimate the relationship between HL and the outcomes. Results: A total of 821 females were included. 264 (32.2%) had excellent or sufficient, 353 (43.0%) had problematic, and 204 (24.8%) had inadequate health literacy (IHL). Women with IHL were more likely to agree that high price (ß = -0.211, 95% CI -0.354 to -0.069), lack of time (ß = -0.219, 95% CI -0.351 to -0.088), inconvenient service time (ß = -0.291, 95% CI -0.421 to -0.160), long waiting time (ß = -0.305, 95% CI -0.447 to -0.164), fear of positive results (ß = -0.200, 95% CI -0.342 to -0.058), embarrassment (ß = -0.225, 95% CI -0.364 to -0.086), fear of pain (ß = -0.154, 95% CI -0.298 to -0.010), fear of radiation (ß = -0.177, 95% CI -0.298 to -0.056), lack of knowledge on service location (ß = -0.475, 95% CI -0.615 to -0.335), and lack of knowledge on mammography (ß = -0.360, 95% CI -0.492 to -0.228) were barriers. They were also less likely to have an accurate breast cancer risk perception (aOR 0.572, 95% CI 0.341 to 0.956). Conclusion: Women with lower HL could have stronger perceived barriers to BC screening and an over-estimation of their breast cancer risk. Tackling emotional and knowledge barriers, financial and logistical assistance, and guidance on risk perception are needed to increase their breast cancer screening uptake.

Joint effect between bisphenol A and alcohol consumption on benign prostatic hyperplasia: A case-control study in Hong Kong Chinese males.

BACKGROUND: Whether bisphenol A (BPA) exposure is a contributing factor to benign prostatic hyperplasia (BPH) remains unclear. This study evaluated the association between chronic BPA exposure and BPH risk, and explored whether this association was modified by alcohol drinking. METHODS: This study included a total of 650 BPH cases and 650 controls recruited from the same hospital in Hong Kong during 2011-2016. Chronic BPA exposure level was estimated by a validated cumulative BPA exposure index (CBPAI). We performed unconditional logistic regression model to examine the association of BPH risk with potential sources of BPA exposure via oral intake and CBPAI. We further tested the interactions between CBPAI and alcohol consumption habits on BPH risk. RESULTS: A positive exposure-response relationship was observed between CBPAI and BPH risk. Frequent BPA exposure via oral intake of foods heated in a plastic box/bag (odds ratio [OR] = 3.52, 95% confidence interval [CI]: 1.51-8.22), cooling water in a plastic bottle (OR = 2.65, 95% CI: 1.33-5.27), or using a plastic cup to contain hot water (OR = 4.14, 95% CI: 1.02-16.89), was significantly associated with increased BPH risk. Compared with nonalcohol drinkers, alcohol drinkers was insignificantly associated with BPH risk (OR = 1.10, 95% CI: 0.77-1.57), but it demonstrated a more remarkable positive gradient between CBPAI exposure and BPH risk among alcohol drinkers, indicating an additive interaction between CBPAI and alcohol on BPH risk (synergy index = 4.24, 95% CI: 1.21-14.94). CONCLUSIONS: Chronic oral BPA exposure increased BPH risk with a positive exposure-response relationship among Hong Kong Chinese, and alcohol drinking amplified the effect of BPA on BPH. Hence, minimizations of containing food or water/beverage in plastic containers and drinking alcohol are recommended in the community to mitigate BPH risk. Future larger and designated studies are warranted.

Virulence factors and determination of antifungal susceptibilities of Candida species isolated from palm wine and sorghum beer.

Since it has been considered that Candida species in food or drinks may, following ingestion, enter the bloodstream and cause fungaemia, the presence of these yeast species in traditional alcoholic beverages may be of some clinical significance. Thus we attempted to assess virulence factors and antifungal susceptibility profile of Candida strains and other potential pathogenic yeasts isolated from palm wine and sorghum beer (tchapalo). Of the 23 yeast isolates from palm wine, phospholipase, esterase and haemolysin production was revealed amongst 69.6%, 65.2% and 100% isolates respectively with high activity belonging to Candida tropicalis strains. All the isolates were biofilm producers at variable degree but none showed proteinase activity. When the isolates were tested for their susceptibility to five antifungal agents, we found that ketoconazole (91.3%) followed by fluconazole (78.3%) and amphotericin B (73.9%) were the most potent agents. Of the 14 isolates from tchapalo, 57.1%, 87.5% and 57.1% exhibited phospholipase, haemolysin and esterase activity respectively. They did not also show proteinase activity while 87.5% produced biofilm. The majority of the isolates were susceptible to azoles (92.7%) and amphotericin B (85.3%) but they were 5-flucytosine resistant like palm wine strains.

Candida species in tchapalo and bangui, two traditional alcoholic beverages from Côte d'Ivoire.

The increase of infections due to non-Candida albicans species made it very necessary to conduct adequate characterization to be able to identify the species of Candida isolated from traditional fermented foods. In this study, based on their hue on Candida Chromogenic Agar medium, a total of 136 yeast strains were isolated from tchapalo and bangui. Molecular identification based on PCR-RFLP of internal transcribed spacers of rDNA (ITS) and sequencing of the ITS and the D1/D2 regions allowed us to assign these isolates to seven species: Candida tropicalis, Candida inconspicua, Candida rugosa, Saccharomyces cerevisiae, Kluyveromyces marxianus, Hanseniaspora guilliermondii, Trichosporon asahii. With the respect to each beverage, six species were found among with four species are regarded as opportunistic pathogens. From these, C. tropicalis, C. inconspicua and K. marxianus were the most commonly encountered. The enzyme activities of the potential pathogens assessed using API ZYM system showed that almost strains had esterase, esterase lipase, valine and cystine arylamidase, alpha chymotrypsin, alkaline phosphatase and naphthol phosphohydrolase activities. The activity of α-glucosidase was found only in C. tropicalis and C. inconspicua strains isolated from tchapalo while ß-glucosidase activity was found in all strains from tchapalo and only in C. inconspicua isolated from bangui.

Endovascular stenting for treatment of a left internal mammary artery pseudoaneurysm following redo-sternotomy: a case report.

An 85-year-old gentlemen with a history of previous triple vessel coronary bypass grafting presented with severe aortic stenosis and occlusion of the previous saphenous vein grafts but with patent left internal mammary artery (LIMA)-left anterior descending. The patient underwent uncomplicated repeat sternotomy and aortic valve replacement with repeated coronary bypass. On post-operative day 21 the patient was successfully resuscitated from a pulseless electrical activity (PEA) arrest, and was found to have a 1-cm pseudoaneurysm of the left internal mammary artery at the level of sternomanubrial junction with associated hemothorax. The LIMA remained patent and a pinhole source of extravasation was discovered by angiography at the aneurysmal site. The defect was successfully repaired by endovascular implant of a 3.5 mm × 12 mm Graft Master covered stent (Abbott Vascular). The patient recovered well from the procedure without further complications and was discharged after a total of 48 days of hospital stay. Our experience confirms the feasibility of repairing post-operative pseudoaneurysm in the internal mammary artery by endovascular stent grafting, thereby avoiding the risks and complications of a repeat open chest procedure.

An fMRI study showing the effect of acupuncture in chronic stage stroke patients with aphasia.

Acupuncture is used as a treatment in stroke patients with aphasia, yet the underlying neural mechanisms are unknown. This study aims to examine the relationship between changes in language function and brain activation using functional magnetic resonance imaging in chronic stroke patients with aphasia who underwent an 8-week acupuncture protocol. Seven chronic stroke patients were identified from a stroke database of a regional acute hospital in Hong Kong between January and July 2007. Patients were treated three times a week over a period of 8 weeks. Four acupoints were stimulated on the weak side of the patient's body. No other rehabilitation was given during the study period. Changes in language function were measured by aphasia quotient (AQ) of Cantonese Aphasia Battery (CAB). Functional magnetic resonance imaging blood oxygen level dependent signals were used to demonstrate the correlation between changes in AQ and brain activation after treatment. The patients were divided into well-recovered and poorly- recovered groups based on their CAB scores at entry. The well-recovered group showed significant improvement in CAB scores after receiving acupuncture treatment. A significant correlation between changes in AQ and blood oxygen level dependent activation in the lesioned Wernicke's speech area was found. These preliminary results suggest that acupuncture may be beneficial to language recovery in chronic stroke patients.

Chlamydophila pneumoniae infection leads to smooth muscle cell proliferation and thickening in the coronary artery without contributions from a host immune response.

Chlamydophila pneumonia (C. pneumonia) infection has been associated with the progression of atherosclerosis. It remains unclear, however, whether C. pneumoniae in the absence of an immune response can alone initiate atherogenic events within a complex vessel environment. Left anterior descending coronary arteries isolated from porcine hearts were dissected and placed in culture medium for 72 hours before infection with C. pneumoniae. C. pneumoniae replicated within the arterial wall for the duration of the experiment (up to 10 days). A significant increase in chlamydial-HSP60 protein expression from day 2 to 10 post-infection (pi) indicated the presence of metabolically active C. pneumonia within infected vessels. Significant arterial thickening in infected coronary segments was observed by a considerable decrease in the ratio of lumen to total vessel area (48 +/- 3% at day 4 pi versus 23 +/- 3% at day 10 pi) and a significant increase in the ratio of media to luminal area (113 +/- 16% at day 4 pi versus 365 +/- 65% at day 10 pi). Structural changes were accompanied by an up-regulation of host HSP60 and proliferating cell nuclear antigen expression levels. Immunohistochemical staining confirmed proliferating cell nuclear antigen expression to be primarily localized within smooth muscle cells of the medial area. These results demonstrate that C. pneumoniae infection can stimulate arterial thickening in a complex vessel environment without the presence of a host immune response and further supports the involvement of HSP60 in this action.

Dietary flaxseed inhibits atherosclerosis in the LDL receptor-deficient mouse in part through antiproliferative and anti-inflammatory actions.

Dietary flaxseed has been shown to have potent antiatherogenic effects in rabbits. The purpose of the present study was to investigate the antiatherogenic capacity of flaxseed in an animal model that more closely represents the human atherosclerotic condition, the LDL receptor-deficient mouse (LDLrKO), and to identify the cellular mechanisms for these effects. LDLrKO mice were administered a regular diet (RG), a 10% flaxseed-supplemented diet (FX), or an atherogenic diet containing 2% cholesterol alone (CH) or supplemented with 10% flaxseed (CF), 5% flaxseed (CF5), 1% flaxseed (CF1), or 5% coconut oil (CS) for 24 wk. LDLrKO mice fed a cholesterol-supplemented diet exhibited a rise in plasma cholesterol without a change in triglycerides and an increase in atherosclerotic plaque formation. The CS mice exhibited elevated levels of plasma cholesterol, triglycerides, and saturated fatty acids and an increase in plaque development. Supplementation of the cholesterol-enriched diet with 10% (wt/wt) ground flaxseed lowered plasma cholesterol and saturated fatty acids, increased plasma ALA, and inhibited plaque formation in the aorta and aortic sinus compared with mice fed a diet supplemented with only dietary cholesterol. The expression of proliferating cell nuclear antigen (PCNA) and the inflammatory markers IL-6, mac-3, and VCAM-1 was increased in aortic tissue from CH and CS mice. This expression was significantly reduced or normalized when flaxseed was included in the diet. Our results demonstrate that dietary flaxseed can inhibit atherosclerosis in the LDLrKO mouse through a reduction of circulating cholesterol levels and, at a cellular level, via antiproliferative and anti-inflammatory actions.

Inhibition of coxsackievirus B3 replication by small interfering RNAs requires perfect sequence match in the central region of the viral positive strand.

Coxsackievirus B3 (CVB3) is the most common causal agent of viral myocarditis, but existing drug therapies are of limited value. Application of small interfering RNA (siRNA) in knockdown of gene expression is an emerging technology in antiviral gene therapy. To investigate whether RNA interference (RNAi) can protect against CVB3 infection, we evaluated the effects of RNAi on viral replication in HeLa cells and murine cardiomyocytes by using five CVB3-specific siRNAs targeting distinct regions of the viral genome. The most effective one is siRNA-4, targeting the viral protease 2A, achieving a 92% inhibition of CVB3 replication. The specific RNAi effects could last at least 48 h, and cell viability assay revealed that 90% of siRNA-4-pretreated cells were still alive and lacked detectable viral protein expression 48 h postinfection. Moreover, administration of siRNAs after viral infection could also effectively inhibit viral replication, indicating its therapeutic potential. Further evaluation by combination found that no enhanced inhibitory effects were observed when siRNA-4 was cotransfected with each of the other four candidates. In mutational analysis of the mechanisms of siRNA action, we found that siRNA functions by targeting the positive strand of virus and requires a perfect sequence match in the central region of the target, but mismatches were more tolerated near the 3' end than the 5' end of the antisense strand. These findings reveal an effective target for CVB3 silencing and provide a new possibility for antiviral intervention.

A phosphorothioate antisense oligodeoxynucleotide specifically inhibits coxsackievirus B3 replication in cardiomyocytes and mouse hearts.

Antisense oligodeoxynucleotides (AS-ODNs) are promising therapeutic agents for the treatment of virus-induced diseases. We previously reported that coxsackievirus B3 (CVB3) infectivity could be inhibited effectively in HeLa cells by phosphorothioate AS-ODNs complementary to different regions of the 5' and 3' untranslated regions of CVB3 RNA. The most effective target is the proximal terminus of the 3' untranslated region. To further investigate the potential antiviral role of the AS-ODN targeting this site in cardiomyocytes (HL-1 cell line), corresponding AS-ODN (AS-7) was transfected into the HL-1 cells and followed by CVB3 infection. Analyses by RT-PCR, Western blotting and plaque assay demonstrated that AS-7 strongly inhibits viral RNA and viral protein synthesis as compared to scrambled AS-ODNs. The percent inhibitions of viral RNA transcription and capsid protein VP1 synthesis were 87.6 and 40.1, respectively. Moreover, AS-7 could inhibit ongoing CVB3 infection when it was given after virus infection. The antiviral activity was further evaluated in a CVB3 myocarditis mouse model. Adolescent A/J mice were intravenously administrated with AS-7 or scrambled AS-ODNs prior to and after CVB3 infection. Following a 4-day therapy, the myocardium CVB3 RNA replication decreased by 68% and the viral titers decreased by 0.5 log(10) in the AS-7-treated group as compared to the group treated with the scrambled AS-ODNs as determined by RT-PCR, in situ hybridization and viral plaque assay. Taken together, our results demonstrated a great potential for AS-7 to be further developed into an effective treatment towards viral myocarditis as well as other diseases caused by CVB3 infection.

Hypodensity of >1/3 middle cerebral artery territory versus Alberta Stroke Programme Early CT Score (ASPECTS): comparison of two methods of quantitative evaluation of early CT changes in hyperacute ischemic stroke in the community setting.

BACKGROUND: The one third middle cerebral artery territory ((1/3) MCA) method and the Alberta Stroke Program Early CT Score (ASPECTS) were used to detect significant early ischemic changes (EIC) on CT brain of acute stroke patients. We sought to compare the reliability of the 2 methods in routine clinical practice. METHODS: Eighty consecutive patients admitted to a community hospital in Hong Kong with suspected acute ischemic stroke and a CT brain scan performed within 6 hours of symptom onset were included. Five blinded observers (1 neurologist, 2 general radiologists, and 2 neuroradiologists) independently evaluated the scans, using the ATLANTIS/CT Summit criteria for >(1/3) MCA involvement, and ASPECTS (1/3) MCA involvement, all observers agreed in 57 cases (71%), with moderate interobserver agreement (kappa=0.49). For ASPECTS