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SUMMARY Primary pigmented nodular adrenocortical disease (PPNAD) is a rare adrenocorticotropin hormone (ACTH)-independent Cushing's syndrome (CS). Pediatric patients with PPNAD typically have unusual skin lesions and slow growth with unknown causes. We present a case of a female Chinese patient with PPNAD caused by the germline PRKACA gene copy number gain of chromosome 19. The patient initially presented with kidney stones, short stature, and obesity. After further testing, it was discovered that the patient had diabetes, mild hypertension, low bone mass, a low ACTH level, and hypercortisolemia, and neither the low-dose or high-dose dexamethasone suppression test was able to inhibit hematuric cortisol, which paradoxically increased. PPNAD was pathologically diagnosed after unilateral adrenalectomy. Chromosome microarrays and whole exon sequencing analyses of the peripheral blood, as well as testing of sectioned adrenal tissue, showed a rise in the copy number of the duplication-containing PRKACA gene on chromosome 19p13.13p13.12, a de novo but not heritable gene defect that causes disease. The clinical signs and symptoms supported the diagnosis of Carney complex (CNC). One significant mechanism of CNC pathogenesis may be the rise in germline PRKACA copy number of chromosome 19. When assessing PPNAD patients for CNC, the possibility of PRKACA gene amplification should be considered. The effect of PRKACA gene amplification on the clinical manifestations of CNC needs to be confirmed by more cases.

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Primary pigmented nodular adrenocortical disease (PPNAD) is a rare adrenocorticotropin hormone (ACTH)-independent Cushing's syndrome (CS). Pediatric patients with PPNAD typically have unusual skin lesions and slow growth with unknown causes. We present a case of a female Chinese patient with PPNAD caused by the germline PRKACA gene copy number gain of chromosome 19. The patient initially presented with kidney stones, short stature, and obesity. After further testing, it was discovered that the patient had diabetes, mild hypertension, low bone mass, a low ACTH level, and hypercortisolemia, and neither the low-dose or high-dose dexamethasone suppression test was able to inhibit hematuric cortisol, which paradoxically increased. PPNAD was pathologically diagnosed after unilateral adrenalectomy. Chromosome microarrays and whole exon sequencing analyses of the peripheral blood, as well as testing of sectioned adrenal tissue, showed a rise in the copy number of the duplication-containing PRKACA gene on chromosome 19p13.13p13.12, a de novo but not heritable gene defect that causes disease. The clinical signs and symptoms supported the diagnosis of Carney complex (CNC). One significant mechanism of CNC pathogenesis may be the rise in germline PRKACA copy number of chromosome 19. When assessing PPNAD patients for CNC, the possibility of PRKACA gene amplification should be considered. The effect of PRKACA gene amplification on the clinical manifestations of CNC needs to be confirmed by more cases.

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PURPOSE: Colorectal cancer (CRC) is a common human cancer along with higher incidence and mortality, and this study aimed to identify the effect of cincumol on CRC and its potential mechanisms. METHODS: CRC cell line HCT116 was used as the material. Cell proliferation was evaluated by CCK-8 assay, and cell migration was detected by scratch test and Transwell assay. TUNEL staining assay was used to evaluate cell apoptosis. The expression of target genes was detected by qualitative real-time polymerase chain reaction and western blot assays. RESULTS: Cincumol significantly reduced the proliferative and migratory rate and enhanced apoptotic rate of HCT116 cells. Meanwhile, the elevated levels of RBUsuh, Nicd and Tace was also observed in cincumol-treated HCT116 cells. Moreover, our findings revealed that additional cincumol inhibited the expression of p-PI3K and p-AKT, suggesting the inhibition of PI3K/AKT signaling might be involved in the protective role of cincumol on the malignant phenotypes of CRC cells in vitro. CONCLUSIONS: Cincumol inhibited the malignant phenotypes of CRC cells in vitro through inactivating PI3K/AKT signaling, suggesting that cincumol might be a potential anti-CRC agent.

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Purpose: Colorectal cancer (CRC) is a common human cancer along with higher incidence and mortality, and this study aimed to identify the effect of cincumol on CRC and its potential mechanisms. Methods: CRC cell line HCT116 was used as the material. Cell proliferation was evaluated by CCK-8 assay, and cell migration was detected by scratch test and Transwell assay. TUNEL staining assay was used to evaluate cell apoptosis. The expression of target genes was detected by qualitative real-time polymerase chain reaction and western blot assays. Results: Cincumol significantly reduced the proliferative and migratory rate and enhanced apoptotic rate of HCT116 cells. Meanwhile, the elevated levels of RBUsuh, Nicd and Tace was also observed in cincumol-treated HCT116 cells. Moreover, our findings revealed that additional cincumol inhibited the expression of p-PI3K and p-AKT, suggesting the inhibition of PI3K/AKT signaling might be involved in the protective role of cincumol on the malignant phenotypes of CRC cells in vitro. Conclusions: Cincumol inhibited the malignant phenotypes of CRC cells in vitro through inactivating PI3K/AKT signaling, suggesting that cincumol might be a potential anti-CRC agent.

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BACKGROUND: The ISCHEMIA trial (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches) postulated that patients with stable coronary artery disease (CAD) and moderate or severe ischemia would benefit from revascularization. We investigated the relationship between severity of CAD and ischemia and trial outcomes, overall and by management strategy. METHODS: In total, 5179 patients with moderate or severe ischemia were randomized to an initial invasive or conservative management strategy. Blinded, core laboratory­interpreted coronary computed tomographic angiography was used to assess anatomic eligibility for randomization. Extent and severity of CAD were classified with the modified Duke Prognostic Index (n=2475, 48%). Ischemia severity was interpreted by independent core laboratories (nuclear, echocardiography, magnetic resonance imaging, exercise tolerance testing, n=5105, 99%). We compared 4-year event rates across subgroups defined by severity of ischemia and CAD. The primary end point for this analysis was all-cause mortality. Secondary end points were myocardial infarction (MI), cardiovascular death or MI, and the trial primary end point (cardiovascular death, MI, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest). RESULTS: Relative to mild/no ischemia, neither moderate ischemia nor severe ischemia was associated with increased mortality (moderate ischemia hazard ratio [HR], 0.89 [95% CI, 0.61­1.30]; severe ischemia HR, 0.83 [95% CI, 0.57­1.21]; P=0.33). Nonfatal MI rates increased with worsening ischemia severity (HR for moderate ischemia, 1.20 [95% CI, 0.86­1.69] versus mild/no ischemia; HR for severe ischemia, 1.37 [95% CI, 0.98­1.91]; P=0.04 for trend, P=NS after adjustment for CAD). Increasing CAD severity was associated with death (HR, 2.72 [95% CI, 1.06­6.98]) and MI (HR, 3.78 [95% CI, 1.63­8.78]) for the most versus least severe CAD subgroup. Ischemia severity did not identify a subgroup with treatment benefit on mortality, MI, the trial primary end point, or cardiovascular death or MI. In the most severe CAD subgroup (n=659), the 4-year rate of cardiovascular death or MI was lower in the invasive strategy group (difference, 6.3% [95% CI, 0.2%­12.4%]), but 4-year all-cause mortality was similar. CONCLUSIONS: Ischemia severity was not associated with increased risk after adjustment for CAD severity. More severe CAD was associated with increased risk. Invasive management did not lower all-cause mortality at 4 years in any ischemia or CAD subgroup.

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The prognosis of COVID-19 (coronavirus disease 2019) is usually poor when it occurs in aged adults or in patients with chronic diseases, which brought a great challenge to clinical practice. Furthermore, widespread depression, anxiety, and panic related to SARS-CoV-2 (severe acute respiratory syndrome-coronavirus 2) infection affected treatment compliance and recovery. Here we report the successful treatment of a 57-year-old male with severe COVID-19, schizophrenia, hypertension, and type 2 diabetes. The patient's negative emotions (such as tension, panic, and anxiety), particularly his aggression and paranoia, seriously hindered treatment, leading to a deteriorating condition. Psychological counseling and supportive psychotherapy were given but the effect was weak. To improve adherence, risperidone and quetiapine fumarate were replaced by olanzapine for anti-schizophrenic treatment to reduce insomnia and anxiety side effects, associated with sedative-hypnotic drugs as well as psychological counseling. The treatment compliance of the patient improved significantly. The patient's serum alanine aminotransferase increased abnormally in the late stage of hospitalization, suggesting potential liver damage after complex medication strategies. We also monitored the changes of lymphocyte subsets and retrospectively analyzed the virus-specific antibody response. The results suggested that dynamic monitoring of lymphocyte subsets and virus-specific antibody response could facilitate disease progression evaluation and timely treatment plan adjustments. An effective psychotropic drug intervention associated with psychological counselling and psychotherapy are essential for the successful adherence, treatment, and rehabilitation of psychiatric disorders in COVID-19 patients.

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Recent infrastructure development in China and other developing countries has attracted global attention. As a control project of traffic engineering, tunnels also have rapidly increased. However, fire accidents induced by traffic accident or gas explosion frequently occur in tunnels, causing irreversible damage to the tunnel rocks. Moreover, the corrosive effects of acid rain or polluted groundwater have a long-term effect on the tunnel and surrounding rocks. In this paper, physical and thermophysical properties tests as well as Brazilian splitting test were conducted on red sandstone specimens after heating at a variety of different temperature and acidic solution erosion. The responses of surface features, mass, P wave velocity, porosity and thermal conductivity, and the tensile strength of the red sandstone were compared and analyzed. In addition, the effects of high temperature (25-1000 °C) and acidic solution on microscopic structures, defect morphology, and mineral reaction of the red sandstone were observed and analyzed. The experimental results show that high temperature and acidic chemical solution significantly affects the physical and mechanical properties of the rock mass. The typical parameters, such as surface features, mass and P wave velocity, porosity, thermal conductivity, and tensile strength, are closely affected by acidity. In addition, we observed that the physical properties of red sandstones change with temperature and can be divided into three stages, and at 300-800 °C stage, they significantly declined. The results provide a basis for rock damage and failure induced by fire and acidic groundwater seepage in tunnels.

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The prognosis of COVID-19 (coronavirus disease 2019) is usually poor when it occurs in aged adults or in patients with chronic diseases, which brought a great challenge to clinical practice. Furthermore, widespread depression, anxiety, and panic related to SARS-CoV-2 (severe acute respiratory syndrome-coronavirus 2) infection affected treatment compliance and recovery. Here we report the successful treatment of a 57-year-old male with severe COVID-19, schizophrenia, hypertension, and type 2 diabetes. The patient's negative emotions (such as tension, panic, and anxiety), particularly his aggression and paranoia, seriously hindered treatment, leading to a deteriorating condition. Psychological counseling and supportive psychotherapy were given but the effect was weak. To improve adherence, risperidone and quetiapine fumarate were replaced by olanzapine for anti-schizophrenic treatment to reduce insomnia and anxiety side effects, associated with sedative-hypnotic drugs as well as psychological counseling. The treatment compliance of the patient improved significantly. The patient's serum alanine aminotransferase increased abnormally in the late stage of hospitalization, suggesting potential liver damage after complex medication strategies. We also monitored the changes of lymphocyte subsets and retrospectively analyzed the virus-specific antibody response. The results suggested that dynamic monitoring of lymphocyte subsets and virus-specific antibody response could facilitate disease progression evaluation and timely treatment plan adjustments. An effective psychotropic drug intervention associated with psychological counselling and psychotherapy are essential for the successful adherence, treatment, and rehabilitation of psychiatric disorders in COVID-19 patients.

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BACKGROUND: Antithrombotic therapy plays an important role in the treatment of non-ST-segment elevation acute coronary syndromes (NSTE ACS) but is associated with bleeding risk. Advanced age may modify the relationship between efficacy and safety. METHODS: Efficacy and safety of vorapaxar (a protease-activated receptor 1 antagonist) was analyzed across ages as a continuous and a categorical variable in the 12,944 patients with NSTE ACS enrolled in the TRACER trial. To evaluate the effect of age, Cox regression models were developed to estimate hazard ratios (HRs) with the adjustment of other baseline characteristics and randomized treatment for the primary efficacy composite of cardiovascular death, myocardial infarction (MI), stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization, and the primary safety composite of moderate or severe Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) bleeding. RESULTS: The median age of the population was 64years (25th, 75th percentiles = 58, 71). Also, 1,791 patients (13.8%) were ≤54years of age, 4,968 (38.4%) were between 55 and 64 years, 3,979 (30.7%) were between 65 and 74 years, and 2,206 (17.1%) were 75years or older. Older patients had higher rates of hypertension, renal insufficiency, and previous stroke and worse Killip class. The oldest age group (≥75years) had substantially higher 2-year rates of the composite ischemic end point and moderate or severe GUSTO bleeding compared with the youngest age group (≤54years). The relationships between treatment assignment (vorapaxar vs placebo) and efficacy outcomes did not vary by age. For the primary efficacy end point, the HRs (95% CIs) comparing vorapaxar and placebo in the 4 age groups were as follows: 1.12 (0.88-1.43), 0.88 (0.76-1.02), 0.89 (0.76-1.04), and 0.88 (0.74-1.06), respectively (P value for interaction = .435). Similar to what was observed for efficacy outcomes, we did not observe any interaction between vorapaxar and age on bleeding outcomes. For the composite of moderate or severe bleeding according to the GUSTO classification, the HRs (95% CIs) comparing vorapaxar and placebo in the 4 age groups were 1.73 (0.89-3.34), 1.39 (1.04-1.86), 1.10 (0.85-1.42), and 1.73 (1.29-2.33), respectively (P value for interaction = .574). CONCLUSION: Older patients had a greater risk for ischemic and bleeding events; however, the efficacy and safety of vorapaxar in NSTE ACS were not significantly influenced by age.

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BACKGROUND: REG1 is a novel anticoagulation system consisting of pegnivacogin, an RNA aptamer inhibitor of coagulation factor IXa, and anivamersen, a complementary sequence reversal oligonucleotide. We tested the hypothesis that near complete inhibition of factor IXa with pegnivacogin during percutaneous coronary intervention, followed by partial reversal with anivamersen, would reduce ischaemic events compared with bivalirudin, without increasing bleeding. METHODS: We did a randomised, open-label, active-controlled, multicentre, superiority trial to compare REG1 with bivalirudin at 225 hospitals in North America and Europe. We planned to randomly allocate 13,200 patients undergoing percutaneous coronary intervention in a 1:1 ratio to either REG1 (pegnivacogin 1 mg/kg bolus [>99% factor IXa inhibition] followed by 80% reversal with anivamersen after percutaneous coronary intervention) or bivalirudin. Exclusion criteria included ST segment elevation myocardial infarction within 48 h. The primary efficacy endpoint was the composite of all-cause death, myocardial infarction, stroke, and unplanned target lesion revascularisation by day 3 after randomisation. The principal safety endpoint was major bleeding. Analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, identifier NCT01848106. The trial was terminated early after enrolment of 3232 patients due to severe allergic reactions...

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Methods: Efficacy and safety of vorapaxar (a protease-activated receptor 1 antagonist) was analyzed across ages as a continuous and a categorical variable in the 12,944 patients with NSTE ACS enrolled in the TRACER trial. To evaluate the effect of age, Cox regression models were developed to estimate hazard ratios (HRs) with the adjustment of other baseline characteristics and randomized treatment for the primary efficacy composite of cardiovascular death, myocardial infarction (MI), stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization, and the primary safety composite of moderate or severe Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) bleeding. ResultsThe median age of the population was 64 years (25th, 75th percentiles = 58, 71). Also, 1,791 patients (13.8%) were ≤54 years of age, 4,968 (38.4%) were between 55 and 64 years, 3,979 (30.7%) were between 65 and 74 years, and 2,206 (17.1%) were 75 years or older. Older patients had higher rates of hypertension, renal insufficiency, and previous stroke and worse Killip class. The oldest age group (≥75 years) had substantially higher 2-year rates of the composite ischemic end point and moderate or severe GUSTO bleeding compared with the youngest age group (≤54 years). The relationships between treatment assignment (vorapaxar vs placebo) and efficacy outcomes did not vary by age. For the primary efficacy end point, the HRs (95% CIs) comparing vorapaxar and placebo in the 4 age groups were as follows: 1.12 (0.88-1.43), 0.88 (0.76-1.02), 0.89 (0.76-1.04), and 0.88 (0.74-1.06), respectively (P value for interaction = .435)...

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