A nomogram based on ultrasound radiomics for predicting the invasiveness of cN0 single papillary thyroid microcarcinoma.

Background: Up to 15.3% of papillary thyroid microcarcinoma (PTMC) patients with negative clinical lymph node metastasis (cN0) were confirmed to have pathological lymph node metastasis in level VI. Conventional ultrasound (US) focuses on the characteristics of tumor capsule and the periphery to determine whether the tumor has invasive growth. However, due to its small size, the typical features of invasiveness shown by conventional 2-dimensional (2D) US are not well visualized. US-based radiomics makes use of artificial intelligence and big data to build a model that can help improving diagnostic accuracy and providing prognostic implication of the disease. We hope to establish and assess the value of a nomogram based on US radiomics combined with independent risk factors in predicting the invasiveness of a single PTMC without clinical lymph node metastasis (cN0). Methods: A total of 317 patients with cN0 single PTMC who underwent US examination and operation were included in this retrospective cohort study. Patients were randomly divided into training and testing set in the ratio of 8:2. The US images of all patients were segmented, and the radiomics features were extracted. In the training dataset, the US with features of minimum redundancy maximum relevance (mRMR) and the least absolute shrinkage and selection operator (LASSO) were selected and radiomics signatures were then established according to their respective weighting coefficients. Univariate and multivariate logistic regression analyses were employed to generate the risk factors of possible invasive PTMC. The nomogram is then made by combining high risk factors and the radiomics signature. The efficiency of the nomogram was evaluated by the receiver operating characteristic (ROC) curve and calibration curve, and its clinical application value was assessed by decision curve analysis (DCA). The testing dataset was used to validate the model. Results: In the model, seven radiomics features were selected to establish the radiomics signature. A nomogram was made by incorporating clinically independent risk factors and the radiomics signature. Both the ROC curve and calibration curve showed good prediction efficiency. The area under the curve (AUC), accuracy, sensitivity, and specificity of the nomogram in the training data were 0.76 [95% confidence interval (CI): 0.71-0.82], 0.811, 0.914, and 0.727, respectively whereas the results of the testing dataset were 0.71 (95% CI: 0.58-0.84), 0.841, 0.533, and 0.868. As such, the efficacy of the nomogram in predicting the invasiveness of PTMC was subsequently validated by the DCA. Conclusions: Nomogram based on thyroid US radiomics has an excellent predictive value of the potential invasiveness of a single PTMC without clinical lymph node metastasis. With these promising results, it can potentially be the imaging marker used in daily clinical practice.

T cells: Friends and foes in NASH pathogenesis and hepatocarcinogenesis.

In association with the pandemic spreading of obesity and metabolic syndrome, the prevalence of NAFLD-related HCC is increasing almost exponentially. In recent years, many of the underlining multifactorial causes of NAFLD have been identified, and the cellular mechanisms sustaining disease development have been dissected up to the single-cell level. However, there is still an urgent need to provide clinicians with more therapeutic targets, with particular attention on NAFLD-induced HCC, where immune checkpoint inhibitors do not work as efficiently. Whereas much effort has been invested in elucidating the role of innate immune response in the hepatic NAFLD microenvironment, only in the past decade have novel critical roles been unraveled for T cells in driving chronic inflammation toward HCC. The metabolic and immune microenvironment interact to recreate a tumor-promoting and immune-suppressive terrain, responsible for resistance to anticancer therapy. In this article, we will review the specific functions of several T-cell populations involved in NAFLD and NAFLD-driven HCC. We will illustrate the cellular crosstalk with other immune cells, regulatory networks or stimulatory effects of these interactions, and role of the metabolic microenvironment in influencing immune cell functionality. Finally, we will present the pros and cons of the current therapeutic strategies against NAFLD-related HCC and delineate possible novel approaches for the future.

Application of droplet digital polymerase chain reaction of plasma methylated septin 9 on detection and early monitoring of colorectal cancer.

Methylated septin 9 (SEPT9) has been approved for non-invasive screening of colorectal cancer (CRC), but data on monitoring of CRC is sparse. Droplet digital polymerase chain reaction (ddPCR), with higher detection precision and simpler quantification than conventional PCR, has not been applied in SEPT9 detection. We explored the role of SEPT9 ddPCR for CRC detection and to measure serial SEPT9 levels in blood samples of CRC patients before and 3-month after surgery. SEPT9 methylated ratio, methylated abundance, and CEA levels were all higher in CRC patients than normal controls (all P < 0.05). The area under the curve (AUC) for methylated ratio and abundance to detect CRC was 0.707 and 0.710, respectively. There was an increasing trend for SEPT9 methylated abundance from proximal to distal cancers (P = 0.017). At 3-month after surgery, both methylated abundance and ratio decreased (P = 0.005 and 0.053, respectively), especially methylated abundance in stage III and distal cancer (both P < 0.01). We have developed a ddPCR platform for the quantitative detection of plasma SEPT9 in CRC patients. SEPT9 methylated abundance had an early post-operative decline, which may be useful in monitoring of treatment response.

Metabolism-Associated Epigenetic and Immunoepigenetic Reprogramming in Liver Cancer.

Metabolic reprogramming and epigenetic changes have been characterized as hallmarks of liver cancer. Independently of etiology, oncogenic pathways as well as the availability of different energetic substrates critically influence cellular metabolism, and the resulting perturbations often cause aberrant epigenetic alterations, not only in cancer cells but also in the hepatic tumor microenvironment. Metabolic intermediates serve as crucial substrates for various epigenetic modulations, from post-translational modification of histones to DNA methylation. In turn, epigenetic changes can alter the expression of metabolic genes supporting on the one hand, the increased energetic demand of cancer cells and, on the other hand, influence the activity of tumor-associated immune cell populations. In this review, we will illustrate the most recent findings about metabolic reprogramming in liver cancer. We will focus on the metabolic changes characterizing the tumor microenvironment and on how these alterations impact on epigenetic mechanisms involved in the malignant progression. Furthermore, we will report our current knowledge about the influence of cancer-specific metabolites on epigenetic reprogramming of immune cells and we will highlight how this favors a tumor-permissive immune environment. Finally, we will review the current strategies to target metabolic and epigenetic pathways and their therapeutic potential in liver cancer, alone or in combinatorial approaches.

XCR1+ type 1 conventional dendritic cells drive liver pathology in non-alcoholic steatohepatitis.

Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are prevalent liver conditions that underlie the development of life-threatening cirrhosis, liver failure and liver cancer. Chronic necro-inflammation is a critical factor in development of NASH, yet the cellular and molecular mechanisms of immune dysregulation in this disease are poorly understood. Here, using single-cell transcriptomic analysis, we comprehensively profiled the immune composition of the mouse liver during NASH. We identified a significant pathology-associated increase in hepatic conventional dendritic cells (cDCs) and further defined their source as NASH-induced boost in cycling of cDC progenitors in the bone marrow. Analysis of blood and liver from patients on the NAFLD/NASH spectrum showed that type 1 cDCs (cDC1) were more abundant and activated in disease. Sequencing of physically interacting cDC-T cell pairs from liver-draining lymph nodes revealed that cDCs in NASH promote inflammatory T cell reprogramming, previously associated with NASH worsening. Finally, depletion of cDC1 in XCR1DTA mice or using anti-XCL1-blocking antibody attenuated liver pathology in NASH mouse models. Overall, our study provides a comprehensive characterization of cDC biology in NASH and identifies XCR1+ cDC1 as an important driver of liver pathology.

Trust as a mediator in the relationship between childhood sexual abuse and IL-6 level in adulthood.

Childhood sexual abuse (CSA) has been shown to predict the coupling of depression and inflammation in adulthood. Trust within intimate relationships, a core element in marital relations, has been shown to predict positive physical and mental health outcomes, but the mediating role of trust in partners in the association between CSA and inflammation in adulthood requires further study. The present study aimed to examine the impact of CSA on inflammatory biomarkers (IL-6 and IL-1ß) in adults with depression and the mediating role of trust. A cross-sectional survey data set of adults presenting with mood and sleep disturbance was used in the analysis. CSA demonstrated a significant negative correlation with IL-6 level (r = -0.28, p<0. 01) in adults with clinically significant depression, while trust showed a significant positive correlation with IL-6 level (r = 0.36, p < .01). Sobel test and bootstrapping revealed a significant mediating role for trust between CSA and IL-6 level. CSA and trust in partners were revealed to have significant associations with IL-6 level in adulthood. Counterintuitively, the directions of association were not those expected. Trust played a mediating role between CSA and adulthood levels of IL-6. Plausible explanations for these counterintuitive findings are discussed.

Combined Use of Common Fecal and Blood Markers for Detection of Endoscopically Active Inflammatory Bowel Disease.

INTRODUCTION: Monitoring of disease activity is essential in patients with inflammatory bowel disease. Although endoscopic remission is the ideal therapeutic goal, noninvasive biomarkers (blood and fecal) are more acceptable to patients and are less costly. We evaluated the performance of combinations of fecal and blood markers on the detection of endoscopically active disease. METHODS: Patients with ulcerative colitis (UC) or Crohn's disease (CD) on stable medications were recruited. Blood markers included C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), albumin, platelet count (PLT), and hemoglobin. Fecal biomarkers included fecal calprotectin (FCT) and fecal immunochemical test (FIT). These markers were compared with the endoscopic Mayo score for UC and the Simple Endoscopic Score for CD. RESULTS: One hundred thirteen patients (mean age 44.7 years, 63.7% men, 54.9% patients with UC and 45.1% patients with CD) were recruited. FCT correlated well with FIT (r = 0.58), CRP (r = 0.56), ESR (r = 0.40), albumin (r = -0.54), PLT (r = 0.61), and hemoglobin (r = -0.35; all Ps < 0.001). Among 66 patients with endoscopic evaluation, 39.4% with endoscopically active disease had higher FCT, FIT, CRP, ESR, PLT, lower albumin, and hemoglobin compared with those in endoscopic remission (all Ps < 0.01). All 7 markers demonstrated good area under receiver operating characteristics (>0.7), with FCT being the best (0.91) for endoscopically active disease. Combining FCT and FIT improved the specificity to 95%, but the sensitivity decreased to 65.4%. In the subgroup analysis of UC, adding PLT to FIT improved the sensitivity and specificity to 100% and 90.9%, respectively. DISCUSSION: The combined use of fecal biomarkers and blood indexes is superior to the use of fecal biomarkers alone in identifying endoscopically active disease.

Impact of Locally Adopted Simulation-Based Crew Resource Management Training on Patient Safety Culture: Comparison Between Operating Room Personnel and General Health Care Populations Pre and Post Course.

Crew resource management (CRM) was introduced to enhance patient safety and reduce medical errors through multidisciplinary learning experience. This study investigates the impact of locally adopted simulation-based CRM training on participants' perceptions and knowledge. A 32-item web-based questionnaire was administered pre course, 1 month, and 1 year post course to assess changes in perceptions and knowledge. Another 12-item paper-based questionnaire was administered immediately post course to assess reactions. Among 712 participants analyzed, 165 were operating room staff. The majority agreed that the training is useful and relevant in daily practice. All participants showed significant improvements in perception and knowledge 1 month post course; however, these improvements declined 1 year post course. The CRM course is associated with satisfactory reaction (Kirkpatrick level 1) and improvement in attitude and knowledge (level 2) toward patient safety. However, the effect may be short-lived and regular refresher courses should be mandatory to sustain momentum of ongoing change.

Methylated Septin 9 and Carcinoembryonic Antigen for Serological Diagnosis and Monitoring of Patients with Colorectal Cancer After Surgery.

With the increasing incidence and mortality of colorectal cancer (CRC), early and accurate diagnosis is of paramount priority to combat this cancer. Epigenetic alterations such as DNA methylation are innovative biomarkers for CRC, due to their stability, frequency, and accessibility in bodily fluids. In this study, blood samples were prospectively collected from patients before and after operation for CRC for determination of methylated septin 9 (mSEPT9) and compared to carcinoembryonic antigen (CEA). The sensitivity of using mSEPT9 methylation status for diagnosing CRC was significantly higher than using elevated CEA levels (73.2% vs 48.2%; p value < 0.001). The sensitivities of both tests increased with higher tumor staging (P = 0.004 and 0.04 respectively). Combined mSEPT9 and CEA had higher accuracy than single CEA or mSEPT9 (P = 0.009 and 0.532 separately). An increase in the methylation level of mSEPT9 detected in the post-operative samples was associated with a higher mortality rate (15.2% vs 1.8%; P = 0.024) and the presence of metastasis (27.3% vs 7.0%; P = 0.013). mSEPT9 was more sensitive than CEA for diagnosing CRC, and combined mSEPT9 and CEA was more accurate. After curative resection, detection of increased mSEPT9 methylation level may indicate adverse outcomes.

Managing serious clinical deterioration in a tertiary hospital in Hong Kong: from indicators development to multiple measures in reducing the rates.

RATIONALE, AIMS AND OBJECTIVES: Timely detection and management of acutely deteriorating patients can save lives. Tuen Mun Hospital (TMH), a 1800-bed acute tertiary hospital serving more than 1.06 million populations in Hong Kong, is exploring to quantitatively monitor serious clinical deterioration (SCD) and uses it to guide patient care improvement initiatives. METHODS: Literature review on definition and measurement of SCD was conducted. Monthly SCD rates of TMH were first calculated according to the published methodology and benchmarked against those of international centres. A refined composite clinical indicator good for local use was compiled. In the second phase, p-control charts of SCD have been plotted based on cumulative data. RESULTS: TMH's performance was comparable with that of international centres. SCD on p-control charts has been plotting since January 2013. There were peaks in all 4 SCD rates during the winter surge period in 2013-2014. In the third phase, multiple measures have been taking to reduce the SCD rates including targeting the 3 main factors of winter surge situation. We are delighted to observe that the pattern did not repeat in the rate of cardiac arrest without do not attempt cardiopulmonary resuscitation (DNACPR) and rate of death without DNACPR in the same period in 2014-2015. CONCLUSIONS: SCD becomes a clinical governance tool to monitor the performance of clinical teams in treating acutely deteriorating patients in TMH. Any abnormal patterns or indications of special cause variations in the control charts would alert leaders to look for root causes of special cause variations and manage accordingly. We hope that this project will extend to corporate level and become a sustainable clinical indicator to guide audits, quality improvement initiatives and strategic planning.

Impact of Death Work on Self: Existential and Emotional Challenges and Coping of Palliative Care Professionals.

Palliative care professionals, such as social workers, often work with death and bereavement. They need to cope with the challenges on "self" in working with death, such as coping with their own emotions and existential queries. In this study, the authors explore the impact of death work on the self of palliative care professionals and how they perceive and cope with the challenges of self in death work by conducting a qualitative study. Participants were recruited from the palliative care units of hospitals in Hong Kong. In-depth interviews were conducted with 22 palliative care professionals: five physicians, 11 nurses, and six social workers. Interviews were transcribed to text for analysis. Emotional challenges (for example, aroused emotional distress from work) and existential challenges (for example, shattered basic assumptions on life and death) were identified as key themes. Similarly, emotional coping (for example, accepting and managing personal emotions) and existential coping (for example, rebuilding and actualizing life-and-death assumptions) strategies were identified. This study enhances the understanding of how palliative care professionals perceive and cope with the challenges of death work on the self. Findings may provide insights into how training can be conducted to enhance professionals' self-competence in facing these challenges.

Meta-analysis of genome-wide association studies identifies two loci associated with circulating osteoprotegerin levels.

Osteoprotegerin (OPG) is involved in bone homeostasis and tumor cell survival. Circulating OPG levels are also important biomarkers of various clinical traits, such as cancers and atherosclerosis. OPG levels were measured in serum or in plasma. In a meta-analysis of genome-wide association studies in up to 10 336 individuals from European and Asian origin, we discovered that variants >100 kb upstream of the TNFRSF11B gene encoding OPG and another new locus on chromosome 17q11.2 were significantly associated with OPG variation. We also identified a suggestive locus on chromosome 14q21.2 associated with the trait. Moreover, we estimated that over half of the heritability of OPG levels could be explained by all variants examined in our study. Our findings provide further insight into the genetic regulation of circulating OPG levels.

Comparing noncancer and cancer deaths in Hong Kong: a retrospective review.

This retrospective study aimed to compare noncancer deaths with cancer deaths in the following: 1) utilization of the public health care system in the last six months of life; 2) end-of-life care received; and 3) documentation of the advance care planning (ACP) process. The following sample was recruited from the deaths in 2006 in four public hospitals for analysis: 656 noncancer deaths consisting of 239 deaths from chronic renal failure (CRF), 242 deaths from chronic obstructive pulmonary disease (COPD) and 175 deaths from congestive heart failure (CHF), and 183 cancer deaths. Only 1.4% of noncancer patients received palliative care, compared with 79.2% of cancer patients. As compared with cancer, the noncancer patients were older (79.1±9.5 vs. 71.1±12.4 years, P<0.001) and had more comorbid conditions (2.3±1.4 vs. 1.6±1.4, P<0.001). Utilization of public health care was more intensive in noncancer patients, with more intensive care unit admissions, more ward admissions, more bed days occupied, and more clinic attendances. Within the last two weeks of life, the noncancer patients had more invasive interventions initiated, fewer symptoms documented, less analgesics and sedatives prescribed, less do-not-resuscitate orders in place, and more cardiopulomonary resuscitation performed. Dyspnea, edema, pain, and fatigue were among the most documented symptoms in both cancer and noncancer patients. A higher proportion of ACP discussions were first documented within three days before death in COPD and CHF patients as compared with CRF and cancer patients. There is a need to develop palliative care for noncancer patients in Hong Kong.

Factors associated with lower quality of life among patients receiving palliative care.

AIM: This paper is a report of a study conducted to (1) assess the quality of life (QoL) and physical functioning status of patients diagnosed with advanced cancer and receiving palliative care; (2) determine if there was a statistically significant relationship between their physical functioning and QoL and (3) identify the demographic and disease-related variables related to their QoL. BACKGROUND: Achieving the best possible QoL is a major goal in palliative care. However, research findings about the relationship between QoL and demographic variables have been inconsistent. METHOD: Three hundred patients with advanced cancer were recruited from four district hospitals in Hong Kong between February 2005 and July 2006. Their QoL and physical functioning status were assessed by face-to-face interview, using the McGill Quality of Life Questionnaire (Hong Kong version) and the Palliative Performance Scale respectively. RESULTS: Participants reported reduced ambulation, inability to perform hobbies or housework, and the need for occasional assistance in self-care (mean: 64.6 out of 100, sd: 19.3, range: 20-100). QoL was fair (mean: 6.2 out of 10, sd: 1.5, range: 0.9-10). There was a weak positive association between physical functioning and QoL scores. Multiple regression analysis showed that patients who were older, female, had ever been married, or had higher physical functioning tended to have better QoL. CONCLUSION: More could be done in symptom and psychosocial management to improve patients' QoL, in particular for those who are younger, male or single, or who have lower physical functioning.

Increased fetal abortion rate in autoimmune thyroid disease is related to circulating TPO autoantibodies in an autoimmune thyroiditis animal model.

OBJECTIVE: To determine the fertility and abortion rates in a mouse model of autoimmune thyroiditis and its relationship with circulating anti-thyroid peroxidase (TPO) antibody. DESIGN: Experimental animal study. SETTING: University research laboratory. ANIMAL(S): C57bl/6 mice. INTERVENTION(S): Female C57bl/6 mice immunized with recombinant mouse TPO (rmTPO) in complete Freund adjuvant (CFA) or glutathione-S-transferase (GST-CFA) were allowed to mate. The pregnant mice were killed on day 14 of pregnancy for assessment of fetal development. The effects of TPO antibody on preimplantation embryo development and implantation rate were also studied. MAIN OUTCOME MEASURE(S): Litter size, resorption rate, preimplantation embryo development, and implantation rate. RESULT(S): All of the mice immunized with rmTPO-CFA possessed anti-TPO antibody. They had reduced litter size and increased incidence of resorbed fetus compared with the control. Higher serum TSH levels, but not T(4) levels, were demonstrated after rmTPO-CFA immunization. Anti-TPO antibody bound to preimplantation embryos. Treatment of the embryos with the antibody marginally decreased the formation of 3/4-cell embryos but had no effect on the subsequent development and implantation compared with the nonimmune control sera. CONCLUSION(S): Autoimmune thyroiditis is associated with reduced fertility and higher incidence of fetal loss. The anti-TPO antibody may affect post-implantation embryo development, leading to fetal loss.

Variability of the prevalence of undiagnosed airflow obstruction in smokers using different diagnostic criteria.

PURPOSES: To estimate the prevalence of undiagnosed airflow obstruction (AFO) in Hong Kong smokers with no previous diagnosis of respiratory disease, and to assess its variability when applying different prediction equations and diagnostic criteria. METHODS: A multicenter, population-based, cross-sectional prevalence study was performed in smokers aged 20 to 80 years. Three different criteria (fixed 70% [Global Initiative for Chronic Obstructive Lung Disease and British Thoracic Society], fixed 75%, and European Respiratory Society [ERS]) were applied to define a lower limit of normal (LLN) of the FEV(1)/FVC ratio to compare with the Hong Kong Chinese reference equation (criterion 1), which had used a distribution-free method to obtain the lower fifth percentile of FEV(1)/FVC ratio as the LLN. RESULTS: In 525 male patients, using criterion 1 (local internal prediction equation) and defining AFO as FEV(1)/FVC less than LLN, the overall prevalence of AFO was 13.7%: 8.3% in age > or = 20 to 40 years, 14.0% in age > or = 40 to 60 years, and 17.8% in age > or = 60 to 80 years. When the local internal prediction equation was used as the comparison reference, the fixed-ratio methods tended to miss AFO in younger age groups and overdiagnose AFO in old age, while the ERS criteria, which uses an almost lower fifth percentile-equivalent method, showed less of such a trend but still only showed moderate agreement with criterion 1. CONCLUSIONS: Undiagnosed AFO was prevalent in Hong Kong smokers. Estimated prevalence rates were highly affected by the criteria used to define AFO. The predicted lower fifth percentile values calculated from a local reference equation as the LLN of FEV(1)/FVC ratio should be used for the diagnosis of AFO.

Assessing quality of life of patients with advanced chronic obstructive pulmonary disease in the end of life.

Given the limitations of existing health-related quality-of-life (QOL) measures in capturing the end-of-life experience of patients with advanced chronic diseases, an empirically grounded instrument, the quality-of-life concerns in the end of life questionnaire (QOLC-E), was developed. Though it was built on the McGill quality of life questionnaire (MQOL), its sphere is more holistic and culturally specific for the Chinese patients in Hong Kong. One hundred and forty-nine patients with advanced chronic obstructive pulmonary disease (COPD) or metastatic cancer completed the questionnaire. Seven factors (28 items) which emerged from the factor analysis were grouped into four positive (support, value of life, food-related concerns, and healthcare concerns) and four negative (physical discomfort, negative emotions, sense of alienation, and existential distress) subscales. Good internal consistency and concurrent validity were shown. The results also revealed that these two groups of patients had similar QOL concerns. The validity of applying QOLC-E as an outcome measure to evaluate the effectiveness of palliative and psychoexistential interventions has yet to be tested.

Cutaneous and pulmonary sarcoidosis in a Hong Kong Chinese woman with silicone breast prostheses.

Sarcoidosis is rarely reported in Hong Kong. We report cutaneous and pulmonary sarcoidosis in a 54-year-old Chinese woman, who presented with papular lesions over the face and neck. She had silicone breast augmentation surgery 4 years earlier. Skin biopsy revealed granulomatous inflammation and anti-tuberculosis treatment was started empirically but stopped 2 months later owing to a poor response. A right supraclavicular lymph node was aspirated and revealed granulomatous inflammation. The CXR was normal initially but subsequently showed diffuse reticulonodular opacities and a small right-sided pleural effusion. High-resolution CT of the thorax showed mediastinal lymphadenopathy and diffuse perilymphatic nodular opacities consistent with sarcoidosis. Sputum mycobacterial culture was negative. Fibreoptic bronchoscopy showed no endobronchial lesion but the transbronchial biopsy showed granulomatous inflammation with no evidence of infection, malignancy or foreign body. Pulmonary function tests were normal except for impairment of transfer factor. One year later, most of the cutaneous lesions had healed spontaneously. The CXR showed partial improvement of the right pleural opacification but little change in the lung field. The features of sarcoidosis and its association with silicone are reviewed.