Altered human gut virome in patients undergoing antibiotics therapy for Helicobacter pylori.

Transient gut microbiota alterations have been reported after antibiotic therapy for Helicobacter pylori. However, alteration in the gut virome after H. pylori eradication remains uncertain. Here, we apply metagenomic sequencing to fecal samples of 44 H. pylori-infected patients at baseline, 6-week (N = 44), and 6-month (N = 33) after treatment. Following H. pylori eradication, we discover contraction of the gut virome diversity, separation of virome community with increased community difference, and shifting towards a higher proportion of core virus. While the gut microbiota is altered at 6-week and restored at 6-month, the virome community shows contraction till 6-month after the treatment with enhanced phage-bacteria interactions at 6-week. Multiple courses of antibiotic treatments further lead to lower virus community diversity when compared with treatment naive patients. Our results demonstrate that H. pylori eradication therapies not only result in transient alteration in gut microbiota but also significantly alter the previously less known gut virome community.

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.

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.

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.

Outcomes of community-based and home-based pulmonary rehabilitation for pneumoconiosis patients: a retrospective study.

BACKGROUND: Pneumoconiosis patients receive community-based or home-based pulmonary rehabilitation (PR) for symptom management and enhancement of physical and mental well-being. This study aimed to review the clinical benefits of community-based rehabilitation programmes (CBRP) and home-based rehabilitation programmes (HBRP) for PR of pneumoconiosis patients. METHODS: Archival data of pneumoconiosis patients who participated in CBRP and HBRP between 2008 and 2011 was analysed. There were 155 and 26 patients in the CBRP and HBRP respectively. The outcome measures used in the pre- and post-tests were Knowledge, Health Survey Short Form-12 (SF-12), Hospital Anxiety and Depression Scale (HADS), 6-Min Walk Test (6MWT), and Chronic Respiratory Questionnaire (CRQ). Paired t-tests and the Analysis of Covariance (ANCOVA) using the patients' baseline lung functions as the covariates were performed to examine the changes in the outcomes after completing the programmes. Hierarchical multiple regression analyses were used to examine the relationships between patient's programme participation factors and different scores of the outcome measures. RESULTS: After controlling for patients' baseline lung capacities, significant improvements were revealed among patients participated in CBRP in the scores of the 6MWT, Knowledge, HADS, SF-12 PCS, and CRQ emotion and mastery. The different scores in the Knowledge and HADS were correlated with the patients' levels of programme participation. In contrast, significant improvements were only found in the scores of the Knowledge and 6MWT among patients who participated in HBRP. The gain scores of the 6MWT were correlated with the patients' levels of programme participation. CONCLUSIONS: Both CBRP and HBRP benefited patients' levels of exercise tolerance and knowledge about the disease. CBRP provided greater benefits to patients' mental and psychosocial needs. In contrast, HBRP was found to improve patients' physical function, but did not have significant impacts on patients' mental health and health-related quality of life. The attendance of patients and the participation of their relatives in treatment sessions were important factors in enhancing the positive effects of CBRP and HBRP. These positive outcomes confirm the value of pulmonary rehabilitation programmes for community-dwelling pneumoconiosis patients.

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.

Cyclooxygenase-1 serves a vital hepato-protective function in chemically induced acute liver injury.

Cyclooxygenase-1 (COX-1) is the constitutive form of the COX enzyme family, which produces bioactive lipids called prostanoids. Although the role of COX-2 in liver diseases has been studied, little is known about the function of COX-1 in liver injury. We aimed to investigate the role and mechanism of COX-1 in acute liver injury. Carbon tetrachloride (CCl(4)) was administered to induce acute liver injury in wild-type or COX-1-deficient mice. Both genetic (partially or completely) deletion of COX-1 expression and pharmacological inhibition of COX-1 activity in mice exacerbated acute liver injury induced by CCl(4), revealing the (1) histopathological changes and increased serum levels of aminotransferases; (2) oxidative stress in the liver partly through the action of cytochrome P450 2E1-dependent pathway; (3) enhanced inflammatory and chemoattractive responses with increased number of activated macrophages; and (4) increased apoptosis through both intrinsic and extrinsic apoptotic pathways. These pathological changes were partly through the modulation of transcription factor-dependent pathways (eg, NF-κB and C/EBP-α). Pre-treatment with prostaglandin E2 (PGE(2)) or 5-lipoxygenase (5-LO) inhibitor in homozygous COX-1 knockout mice significantly ameliorated CCl(4)-induced hepatic injury. In addition, level of hepato-protective molecules (eg, OSM and OSMR) and associated liver regeneration pathway were significantly inhibited by the deficiency of COX-1 but restored by the addition of PGE(2) or the inhibition of 5-LO. Furthermore, the alternative arachidonic acid metabolism pathway of 5-LO, which induced additional inflammation in the liver, was activated in response to the deficiency of COX-1. In conclusion, basal expression of COX-1 is essential for the protection of liver against chemical-induced hepatotoxicity and required for hepatic homeostatic maintenance.

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.

Genetic variant in vitamin D binding protein is associated with serum 25-hydroxyvitamin D and vitamin D insufficiency in southern Chinese.

Previous large-scale genome-wide meta-analysis identified four loci affecting 25-hydroxyvitamin D (25(OH)D) concentrations. However, whether these loci are associated with 25(OH)D concentration in southern Chinese remain unknown. Our primary aim was to examine whether the four top hits (rs2282679, rs10741657, rs12785878 and rs6013897) could be replicated in 712 southern Chinese women. The associations between these single-nucleotide polymorphisms (SNPs), serum 25(OH)D concentration (continuous variable) and vitamin D insufficiency (dichotomized variable) were examined using multivariable linear regression and logistic regression, respectively. Age, body mass index and season were adjusted in the model. Among these four SNPs, rs2282679 was associated with serum 25(OH)D levels (ß=-0.066; P=9 × 10(-5)) and vitamin D insufficiency (odds ratio (OR)=1.51, 95% confidence interval (CI) 1.19-1.93; P=8.6 × 10(-4)), whereas rs12785878 was nominally associated with vitamin D insufficiency only (OR=0.79, 95% CI 0.63-0.99; P=0.042). Genotype risk score (GRS), by summing risk variants of these two SNPs, had more significant association with vitamin D insufficiency (OR=1.38; 95% CI 1.17-1.64; P(trend)=1.76 × 10(-4)) than the model that included only either SNP. The areas under receiver operating characteristic curves of rs2282679 and GRS were 0.561 (P=0.005) and 0.576 (P=5 × 10(-4)), respectively. Our study provides an independent evidence of the associations of rs2282679 and probably rs12785878 with 25(OH)D and vitamin D insufficiency in southern Chinese.

Genetic variants in GREM2 are associated with bone mineral density in a southern Chinese population.

CONTEXT: Gremlin 2 (GREM2) is a regulator of osteoblast differentiation and osteogenesis. A recent genome-wide association study identified GREM2 as a novel susceptibility gene for trabecular volumetric bone mineral density (BMD). OBJECTIVE: We investigated whether GREM2 gene variants were associated with areal BMD in southern Chinese people. RESEARCH DESIGN AND METHODS: We genotyped 108 single-nucleotide polymorphisms (SNPs) in 417 cases (defined as BMD Z-score ≤-1.28) and 359 controls (defined as BMD Z-score ≥+1). Multivariable logistic regression using an additive model was used to evaluate the association. The most associated SNPs of BMD at the spine, femoral neck, and total hip was then replicated in an additional 454 cases and 401 controls. RESULTS: Twelve, 13, and 14 SNPs showed nominal association with BMD at the spine, femoral neck, and total hip, respectively. The minor alleles of rs9728351 (odds ratio [OR] = 2.56; 95% confidence interval [CI] = 1.33-4.92), rs11588607 (OR = 1.65; 95% CI = 1.14-2.4), and rs4454537 (OR = 1.87; 95% CI = 1.22-2.86) were associated with the low BMD at the spine, femoral neck, and total hip, respectively. Among these SNPs most associated with BMD, rs4454537 was successfully replicated in an independent cohort (OR = 1.59; 95% CI = 1.05-2.4). Meta-analysis showed that the minor allele of rs4454537 was associated with low total hip BMD with an OR of 1.72 (95% CI = 1.28-2.31) (P = 3.2 × 10(-4); P(corrected) = .043). CONCLUSIONS: The minor allele of rs4454537 is significantly associated with low BMD at the total hip of southern Chinese people. Our study further suggests GREM2 as a novel susceptibility gene for osteoporosis.

Genome-wide association study identifies a susceptibility locus for thyrotoxic periodic paralysis at 17q24.3.

Thyrotoxic periodic paralysis (TPP) is a potentially life-threatening complication of thyrotoxicosis. We conducted a genome-wide association study (GWAS) and a replication study with a total of 123 southern Chinese with TPP (cases) and 1,170 healthy controls and identified a susceptibility locus on chromosome 17q24.3 near KCNJ2 (rs312691: odds ratio (OR) = 3.3; P(meta-analysis) = 1.8 × 10(-14)). All subjects with TPP also had Graves' disease, and subsequent TPP versus Graves' disease comparison confirmed that the association at 17q24.3 was specific to TPP. The area under the curve (AUC) of rs312691 genotype for risk prediction of TPP in subjects with Graves' disease was 0.73. Expression quantitative trait locus (eQTL) analysis identified SNPs in the region flanking rs312691 (±10 kb) that could potentially affect KCNJ2 expression (P = 0.0001). Our study has identified a susceptibility locus associated with TPP and provides insight into the causes of TPP.

Post-genome wide association studies and functional analyses identify association of MPP7 gene variants with site-specific bone mineral density.

Our previous genome-wide association study (GWAS) in a Hong Kong Southern Chinese population with extreme bone mineral density (BMD) scores revealed suggestive association with MPP7, which ranked second after JAG1 as a candidate gene for BMD. To follow-up this suggestive signal, we replicated the top single-nucleotide polymorphism rs4317882 of MPP7 in three additional independent Asian-descent samples (n= 2684). The association of rs4317882 reached the genome-wide significance in the meta-analysis of all available subjects (P(meta)= 4.58 × 10(-8), n= 4204). Site heterogeneity was observed, with a larger effect on spine than hip BMD. Further functional studies in a zebrafish model revealed that vertebral bone mass was lower in an mpp7 knock-down model compared with the wide-type (P= 9.64 × 10(-4), n= 21). In addition, MPP7 was found to have constitutive expression in human bone-derived cells during osteogenesis. Immunostaining of murine MC3T3-E1 cells revealed that the Mpp7 protein is localized in the plasma membrane and intracytoplasmic compartment of osteoblasts. In an assessment of the function of identified variants, an electrophoretic mobility shift assay demonstrated the binding of transcriptional factor GATA2 to the risk allele 'A' but not the 'G' allele of rs4317882. An mRNA expression study in human peripheral blood mononuclear cells confirmed that the low BMD-related allele 'A' of rs4317882 was associated with lower MPP7 expression (P= 9.07 × 10(-3), n= 135). Our data suggest a genetic and functional association of MPP7 with BMD variation.

Identification of QTL genes for BMD variation using both linkage and gene-based association approaches.

Low bone mineral density (BMD) is a risk factor for osteoporotic fracture with a high heritability. Previous large scale linkage study in Northern Chinese has identified four significant quantitative trait loci (QTL) for BMD variation on chromosome 2q24, 5q21, 7p21 and 13q21. We performed a replication study of these four QTL in 1,459 Southern Chinese from 306 pedigrees. Successful replication was observed on chromosome 5q21 for femoral neck BMD with a LOD score of 1.38 (nominal p value = 0.006). We have previously identified this locus in a genome scan meta-analysis of BMD variation in a white population. Subsequent QTL-wide gene-based association analysis in 800 subjects with extreme BMD identified CAST and ERAP1 as novel BMD candidate genes (empirical p value of 0.032 and 0.014, respectively). The associations were independently replicated in a Northern European population (empirical p value of 0.01 and 0.004 for CAST and ERAP1, respectively). These findings provide further evidence that 5q21 is a BMD QTL, and CAST and ERAP1 may be associated with femoral neck BMD variation.

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.

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.