Optimizing the MIC breakpoints of amoxicillin and tetracycline for antibiotic selection in the rescue therapy of H. pylori with bismuth quadruple regimen.

PURPOSE: H. pylori with triple-drug resistance (TR) to clarithromycin, metronidazole, and levofloxacin limits the success of rescue therapy. We aimed to identify the optimal breakpoints of antibiotic minimal inhibitory concentration (MIC) to predict the success of rescue therapy for TR H. pylori infection. METHODS: We consecutively enrolled 430 patients with at least one course of failed H. pylori eradications to receive an H. pylori culture for antibiotic MIC test. Seventy-three (17%) had TR H. pylori infection (MIC of clarithromycin > 0.5, levofloxacin > 1, and metronidazole > 8 mg/L, respectively). Sixty-nine cases with TR H. pylori infection received rescue therapy with either ATBP (amoxicillin, tetracycline, bismuth, and PPI) or MTBP (metronidazole, tetracycline, bismuth and PPI) for 7-14 days. Fourteen patients with positive 13C-urea breath test after the first rescue therapy were retreated with a crossover second rescue therapy. RESULTS: The MTBP regimen had higher eradication success than the ATBP regimen as the first rescue therapy for TR H. pylori (intent-to-treat (ITT) analysis, 70.3 vs. 46.9%, p = 0.048; per protocol (PP) analysis, 78.8% vs. 51.7%, p = 0.025). For MTBP regimen, tetracycline MIC ≤ 0.094 mg/L (p < 0.001) with a 14-day treatment duration (p = 0.037) could predict eradication success with 100% accuracy. For the ATBP regimen, amoxicillin MIC selected as ≤ 0.032 mg/L could optimally determine eradication success (72.2 vs. 33.3%, p = 0.025). CONCLUSION: Optimizing the MIC breakpoints of amoxicillin and tetracycline resistance better predicts the outcome of bismuth quadruple therapy. Further prospective studies using the revised MIC breakpoints to select antibiotics are warranted.

Hepatic Stellate Cells Enhance Liver Cancer Progression by Inducing Myeloid-Derived Suppressor Cells through Interleukin-6 Signaling.

The tumor microenvironment, which consists of fibroblasts, smooth muscle cells, endothelial cells, immune cells, epithelial cells, and extracellular matrices, plays a crucial role in tumor progression. Hepatic stellate cells (HSCs), a class of unique liver stromal cells, participate in immunomodulatory activities by inducing the apoptosis of effector T-cells, generation of regulatory T-cells, and development of myeloid-derived suppressor cells (MDSCs) to achieve long-term survival of islet allografts. This study provides in vitro and in vivo evidences that HSCs induce the generation of MDSCs to promote hepatocellular carcinoma (HCC) progression through interleukin (IL)-6 secretion. HSC-induced MDSCs highly expressed inducible nitric oxide synthase (iNOS) and arginase 1 mRNA and presented potent inhibitory T-cell immune responses in the tumor environment. Wild-type HSC-induced MDSCs expressed lower levels of CD40, CD86, and MHC II, and a higher level of B7-H1 surface molecules, as well as increased the production of iNOS and arginase I compared with MDSCs induced by IL-6-deficient HSCs in vitro. A murine-transplanted model of the liver tumor showed that HCCs cotransplanted with HSCs could significantly enhance the tumor area and detect more MDSCs compared with HCCs alone or HCCs cotransplanted with HSCs lacking IL-6. In conclusion, the results indicated that MDSCs are induced mainly by HSCs through IL-6 signaling and produce inhibitory enzymes to reduce T-cell immunity and then promote HCC progression within the tumor microenvironment. Therapies targeting the pathway involved in MDSC production or its immune-modulating pathways can serve as an alternative immunotherapy for HCC.

Characterization of Human Norovirus Nonstructural Protein NS1.2 Involved in the Induction of the Filamentous Endoplasmic Reticulum, Enlarged Lipid Droplets, LC3 Recruitment, and Interaction with NTPase and NS4.

Human noroviruses (HuNVs) are the leading cause of gastroenteritis worldwide. NS1.2 is critical for HuNV pathogenesis, but the function is still unclear. The GII NS1.2 of HuNVs, unlike GI NS1.2, was localized to the endoplasmic reticulum (ER) and lipid droplets (LDs) and is accompanied by a distorted-filamentous ER morphology and aggregated-enlarged LDs. LC3 was recruited to the NS1.2-localized membrane through an autophagy-independent pathway. NS1.2, expressed from a cDNA clone of GII.4 norovirus, formed complexes with NTPase and NS4, which exhibited aggregated vesicle-like structures that were also colocalized with LC3 and LDs. NS1.2 is structurally divided into three domains from the N terminus: an inherently disordered region (IDR), a region that contains a putative hydrolase with the H-box/NC catalytic center (H-box/NC), and a C-terminal 251-330 a.a. region containing membrane-targeting domain. All three functional domains of NS1.2 were required for the induction of the filamentous ER. The IDR was essential for LC3 recruitment by NS1.2. Both the H-Box/NC and membrane-targeting domains are required for the induction of aggregated-enlarged LDs, NS1.2 self-assembly, and interaction with NTPase. The membrane-targeting domain was sufficient to interact with NS4. The study characterized the NS1.2 domain required for membrane targeting and protein-protein interactions, which are crucial for forming a viral replication complex.

Effects of Random Nanosized TiN Grain on Characteristic of Gate-All-Around FinFETs with Ferroelectric HZO Layer.

In this paper, we computationally study electrical characteristics for gate-all-around fin field effect transistors (GAA FinFETs) and negative capacitance GAA FinFETs (NC-GAA FinFETs) for sub-3-nm technological nodes. For the devices with the fin height of 55 nm, the on-state current increases (about 33% improvement) and the off-state current decreases (about 73% suppression) due to the NC effect. NC-GAA FinFETs have larger standard deviation of threshold voltage induced by the workfunction fluctuation (WKF) for both N-/P-type devices than those of GAA FinFETs. It is attributed to the variation of polarization in the different position of the ferroelectric layer. Notably, the inverter of NC-GAA FinFETs has larger noise margin and shorter delay time, compared with the inverter of GAA FinFETs; however, the characteristics of inverter of NC-GAA FinFETs suffer larger variability induced by the WKF.

The Association between Skull Bone Fractures and the Mortality Outcomes of Patients with Traumatic Brain Injury.

Introduction: Skull fractures are often found in patients with traumatic brain injury (TBI). Although skull fractures may indicate greater force impact and are associated with local or diffuse brain injuries, the prognostic value of skull fractures remains unclear. This retrospective study aimed to assess the association between skull fractures and mortality in patients with TBI. Methods: This study included 5,430 TBI patients registered in the trauma registry system from January 2009 to December 2018. Clinical and demographic data including age, sex, trauma mechanisms, comorbidities, Glasgow Coma Scale (GCS) score, abbreviated injury score (AIS)-head, injury severity score (ISS), and in-hospital mortality were acquired. Multiple logistic regression and propensity score matching were used to elucidate the effect of skull fractures on mortality outcomes of TBI patients. Results: Compared to TBI patients without skull fracture, patients with skull fractures were predominantly male, younger, had lower GCS upon arrival at the emergency room, and had higher AIS-head, ISS, and in-hospital mortality. The patients with skull fracture had 1.7-fold adjusted odds of mortality (95% confidence interval (CI): 1.27-2.25; p < 0.001) than those without skull fracture, controlling for age, sex, comorbidities, and AIS-head. Additionally, the propensity score-matched analysis of 1,023 selected paired patients revealed that skull fracture was significantly associated with increased 1.4-fold odds of risk for mortality (95% CI: 1.02-1.88; p=0.036). Conclusions: Using a propensity score-matched cohort to attenuate the confounding effect of age, comorbidities, and injury severity, skull fracture was identified as a significant independent risk factor for mortality in patients with TBI.

Inspiratory muscle training in bronchiectasis patients: a prospective randomized controlled study.

OBJECTIVE: To investigate the efficacy and feasibility of home-based inspiratory muscle training in patients with bronchiectasis. DESIGN: A prospective, single-blind, randomized, controlled study. SETTING: Outpatient clinic of a tertiary care medical centre. METHODS: Twenty-six patients with bronchiectasis were randomly divided into inspiratory muscle training and control groups. In the inspiratory muscle training group (n = 13), the training programme started with an intensity of 30% maximal inspiratory pressure (MIP), which was increased by 2 cmH(2)O each week, for 30 minutes daily, 5 days a week for eight weeks. The control group (n = 13) did not receive inspiratory muscle training. Main outcome measures included spirometry, resting oxyhaemoglobin saturation by pulse oximetry (SpO(2)), lowest SpO(2) and Borg Scale during 6-minute walking tests, 6-minute walking distance (6MWD), 6-minute walking work (6M(work)), MIP, maximal expiratory pressure (MEP) and St George's Respiratory Questionnaire. RESULTS: There were significant differences in change from baseline in 6MWD (411.9 (133.5) vs. 473.2 (117.2) m, P = 0.021), 6M(work) (21 051.0 (8286.7) vs. 23 915.5 (8343.0) kg-m, P = 0.022), MIP (60.8 (21.8) vs. 84.6 (29.0) cmH(2)O, P = 0.004), and MEP (72.3 (31.1) vs. 104.2 (35.7) cmH(2)O, P = 0.004) in the inspiratory muscle training group. Significant improvements in both MIP (23.8 (25.3) vs. 2.3 (16.4) cmH(2)O, adjusted P-value = 0.005) and MEP (31.9 (30.8) vs. 11.5 (20.8) cmH(2)O, adjusted P-value = 0.038) levels after adjusting for age by linear regression analysis were observed between groups. CONCLUSIONS: An eight-week home-based inspiratory muscle training is feasible and effective in improving both inspiratory and expiratory muscle strength, but has no effect on respiratory function and quality of life in patients with bronchiectasis.

Reply to Comment on Tsai, Y.-C., et al. Association of Stress-Induced Hyperglycemia and Diabetic Hyperglycemia with Mortality in Patients with Traumatic Brain Injury: Analysis of a Propensity Score-Matched Population. Int. J. Environ. Res. Public Health 2020, 17, 4266.

Thank you for Eduardo Mekitarian Filho's appreciation of our work on the study of stress-induced hyperglycemia (SIH) and diabetic hyperglycemia (DH) in patients with traumatic brain injuries [...].

Association of Stress-Induced Hyperglycemia and Diabetic Hyperglycemia with Mortality in Patients with Traumatic Brain Injury: Analysis of a Propensity Score-Matched Population.

Background: Hyperglycemia at the time of hospital admission is associated with higher morbidity and mortality rates in patients with traumatic brain injury (TBI). Using data from the Chang Gung Research Database (CGRD), this study aimed to compare mortality outcomes between patients with stress-induced hyperglycemia (SIH), diabetic hyperglycemia (DH), and nondiabetic normoglycemia (NDN). The study occurred at Keelung, Linkou, Chiayi, and Kaohsiung Chang Gung Memorial Hospitals (CGMHs). Methods: A total of 1166, 6318, 3622, and 5599 health records from Keelung, Linkou, Chiayi, and Kaohsiung CGMHs, respectively, were retrieved from the CGRD for hospitalized patients with TBI between January 2001 and December 2015. After propensity score matching for sex, age, and Glasgow Coma Scale (GCS) score, the matched cohorts were compared to evaluate differences in the primary outcome between patients with SIH, DH, and NDN. In-hospital mortality was the primary outcome. Results: The analysis of matched patient populations revealed that at the Kaohsiung CGMH, patients with SIH had 1.63-fold (95% CI: 1.09-2.44; p = 0.017) and 1.91-fold (95% CI: 1.12-3.23; p = 0.017) higher odds of mortality than patients with NDN and DH, respectively. Similar patterns were found at the Linkou CGMH; patients with SIH had higher odds of mortality than patients with NDN and DH. In contrast, at the Keelung CGMH, patients with SIH had significantly higher odds of mortality than those with NDN (OR: 3.25; 95% CI: 1.06-9.97; p = 0.039). At the Chiayi CGMH, there were no significant differences in mortality rates among all groups. Conclusions: This study's results suggest that SIH and DH differ in their effect on the outcomes of patients with TBI. The results were similar between medical centers but not nonmedical centers; in the medical centers, patients with SIH had significantly higher odds of mortality than patients with either NDN or DH.

Risk factors and complications contributing to mortality in elderly patients with fall-induced femoral fracture: A cross-sectional analysis based on trauma registry data of 2,407 patients.

BACKGROUND: This study aimed to identify the risk factors and complications associated with mortality in elderly patients with femoral fracture after a fall from the ground level. METHODS: This retrospective study reviewed data pertaining to elderly patients aged ≥65 years who were admitted into a Level I trauma center, between January 1, 2009 and December 31, 2017. Multivariate logistic regression analysis was performed to identify independent effects of univariate predictive variables on the occurrence of mortality. RESULTS: Of 2407 enrolled elderly patients, there were 42 mortal and 2365 survival patients. A greater percentage of fatal patients than survival patients had a head injury with abbreviated injury scale (AIS) score ≥ 2 in the head/neck region (4.8% vs. 0.7%, respectively; p = 0.042). Multivariate logistic regression analysis revealed that the age (odds ration [OR] 1.1, 95% confident interval [CI] 1.0-1.1, p < 0.001), pre-existence of end-stage renal disease (ESRD) (OR 3.2, 95% CI 1.2-8.7, p = 0.023), and subarachnoid hemorrhage (SAH) (OR 12.1, 95% CI 1.3-113.9, p = 0.029) were significant independent risk factors for mortality in elderly patients with a femoral fracture resulting from a ground level fall. The patients in mortality group had a significantly higher rates of pneumonia (OR 28.6, 95% CI 14.6-55.9, p < 0.001), respiratory failure (OR 68.7, 95% CI 32.2-146.4, p < 0.001), sepsis (OR 26.3, 95% CI 10.9-63.4, p < 0.001), and pulmonary embolism (OR 14.4, 95% CI 1.6-131.6, p = 0.002) than those in the survival groups. CONCLUSIONS: This study identified age, pre-existence of ESRD, and SAH as significant independent risk factors for mortality in elderly patients with femoral fracture in a fall. However, ESRD and SAH only contribute to the mortality in a small group of patients. In contrast, respiratory complications contributed greatly to mortality. Thus aggressive chest-protective measures are encouraged to decrease the respiratory complications associated with femoral fracture in elderly patients.

The effect of lowering the legal blood alcohol concentration limit on driving under the influence (DUI) in southern Taiwan: a cross-sectional retrospective analysis.

OBJECTIVES: We aimed to profile the epidemiological changes of driving under the influence (DUI) in southern Taiwan after the legal blood alcohol concentration (BAC) limit was lowered from 50 to 30 mg/dL in 2013. SETTING: Level 1 trauma medical centre in southern Taiwan. PARTICIPANTS: Data from 7447 patients (4375 males and 3072 females) were retrieved from the trauma registry system of a single trauma centre to examine patient characteristics (gender, age and BAC), clinical outcome variables (Abbreviated Injury Score, Injury Severity Score and mortality) and vehicular crash-related factors (vehicle type, airbag use in car crashes, helmet use in motorcycle crashes and time of crash) before and after the BAC limit change. RESULTS: Our results indicated that the percentage of DUI patients significantly declined from 10.99% (n=373) to 6.64% (n=269) after the BAC limit was lowered. Airbag use in car crashes (OR: 0.30, 95% CI 0.10 to 0.88, p=0.007) and helmet use in motorcycle crashes (OR: 0.20, 95% CI 0.15 to 0.26, p<0.001) was lower in DUI patients compared with non-DUI patients after the BAC limit change, with significant negative correlation. DUI behaviour increased crash mortality risk before the BAC limit change (OR: 4.33, 95% CI 2.20 to 8.54), and even more so after (OR: 5.60, 95% CI 3.16 to 9.93). The difference in ORs for mortality before and after the change in the BAC legal limit was not significant (p=0.568). CONCLUSION: This study revealed that lowering the BAC limit to 30 mg/dL significantly reduced the number of DUI events, but failed to result in a significant reduction in mortality in these trauma patients.

Systolic blood pressure lower than the heart rate indicates a poor outcome in patients with severe isolated traumatic brain injury: A cross-sectional study.

BACKGROUND: A systolic blood pressure (SBP) lower than the heart rate (HR) could indicate a poor condition in trauma patients. In such scenarios, the reversed shock index (RSI) is < 1, as calculated by the SBP divided by the HR. This study aimed to clarify whether RSI could be used to identify high-risk adult patients with isolated traumatic brain injury (TBI). METHODS: This retrospective study reviewed 1216 hospitalized adult patients with isolated TBI at a Level I trauma center between January 1, 2009 and December 31, 2015. The patients were grouped and analyzed according to RSI (<1 or ≥ 1). Subgroups of patients with severe TBI (Glasgow Coma Scale [GCS] ≤ 8) or non-severe TBI (GCS > 8) were also compared. The primary outcome was in-hospital mortality. The odds ratios (ORs) of categorical variables were calculated by chi-square tests with 95% confidence intervals (CIs). Mann-Whitney U-tests were used to analyze non-normally distributed continuous data. RESULTS: Among patients with isolated TBI, those with an RSI <1 had higher mortality (44.7% vs. 7.1%, OR: 10.5, 95% CI: 5.36-20.75; P < 0.001) than those with an RSI ≥1. An RSI <1 indicated a higher risk of mortality (OR: 5.1, 95% CI: 2.08-12.49; P < 0.001) in patients with severe isolated TBI but not in patients with non-severe isolated TBI (OR: 3.6, 95% CI: 0.45-28.71; P = 0.267). CONCLUSION: Patients with isolated TBI may be at risk for shock. In trauma patients with severe isolated TBI, an SBP lower than the HR indicates a poor outcome.

Administration of cytokine-induced myeloid-derived suppressor cells ameliorates renal fibrosis in diabetic mice.

BACKGROUND: Diabetes is a proinflammatory state. Fibrosis of the renal glomerulus is the most common cause of end-stage renal disease. Glomerulosclerosis is caused by the accumulation of extracellular matrix (ECM) proteins in the mesangial interstitial space. Mesangial cells are unique stromal cells in the renal glomerulus that form the vascular pole of the renal corpuscle along with the mesangial matrix. Myeloid-derived suppressor cells (MDSCs) are heterogeneous immature myeloid cells that rapidly expand to regulate host immunity during inflammation, infection, and cancer. High concentrations of granulocyte-macrophage colony-stimulating factor (GM-CSF) alone or in combination with other molecules represent the most common ex-vivo protocol for differentiating MDSCs from bone marrow or from peripheral blood mononuclear cells. In this study, we analyzed and characterized the functions of MDSCs under the influence of mouse mesangial cells (MMCs) in a hyperglycemic environment and investigated whether cytokine-induced MDSCs ameliorated renal glomerulosclerosis in diabetic mice. METHODS: Cytokine-induced MDSCs were propagated from bone marrow cells cultured with mouse recombinant GM-CSF, IL-6, and IL-1ß. Diabetic mice were induced with streptozotocin (STZ) and maintained at a blood glucose concentration exceeding 350 mg/dl. The ECM of the renal cortex and fibronectin expression of MMCs were analyzed through immunohistochemistry and western blotting. Arginase 1 and inducible NO synthase expressions of MDSCs were evaluated using quantitative reverse-transcriptase PCR. Cytokines released from MMCs were examined using a cytokine array assay. RESULTS: MDSCs in the diabetic mice were redistributed from the bone marrow into peripheral organs. An increase in fibronectin production was also observed in the renal glomerulus. MMCs in vitro produced more fibronectin and proinflammatory cytokines, such as macrophage inflammatory protein-2, RANTES, and stromal-cell-derived factor-1, under hyperglycemic conditions. The adoptive transfer of cytokine-induced MDSCs into STZ-induced mice normalized the glomerular filtration rate to reduce the kidney to body weight ratio and decrease fibronectin production in the renal glomerulus, ameliorating renal fibrosis. These results demonstrate the anti-inflammatory properties of cytokine-induced MDSCs and offer an alternative immunotherapy protocol for the management of diabetic nephropathy. CONCLUSIONS: The application of cytokine-induced MDSCs provides a promising treatment for renal fibrosis and the prevention of diabetic nephropathy.

Preliminary investigation of cardiopulmonary function in stroke patients with stable heart failure and exertional dyspnea.

The aim of this study was to investigate the relationships between pulmonary function, respiratory muscle strength, perceived dyspnea, degree of fatigue, and activity of daily living with motor function and neurological status in stroke patients with stable congestive heart failure (CHF).This was a cohort study in a tertiary care medical center. Stroke patients with CHF and exertional dyspnea (New York Heart Association class I-III) were recruited. The baseline characteristics included duration of disease, Brunnstrom stage, spirometry, resting heart rate, resting oxyhemoglobin saturation (SpO2), maximal inspiratory pressure (MIP), maximal expiratory pressure (MEP), Borg scale, fatigue scale, and Barthel index.A total of 47 stroke patients (24 males, 23 females, mean age 65.9 ±â€Š11.5 years) were included. The average Brunnstrom stages of affected limbs were 3.6 ±â€Š1.3 over the proximal parts and 3.5 ±â€Š1.4 over the distal parts of upper limbs, and 3.9 ±â€Š0.9 over lower limbs. The average forced vital capacity (FVC) was 2.0 ±â€Š0.8 L, with a predicted FVC% of 67.9 ±â€Š18.8%, forced expiratory volume in the first second (FEV1) of 1.6 ±â€Š0.7 L, predicted FEV1% of 70.6 ±â€Š20.1%, FEV1/FVC of 84.2 ±â€Š10.5%, and maximum mid-expiratory flow of 65.4 ±â€Š29.5%. The average MIP and MEP were -52.9 ±â€Š33.3 cmH2O and 60.8 ±â€Š29.0 cmH2O, respectively. The Borg scale was 1.5 ±â€Š0.8. MIP was negatively associated with the average Brunnstrom stage of the proximal (r = -0.318, P < 0.05) and distal (r = -0.391, P < 0.01) parts of the upper extremities and lower extremities (r = -0.288, P < 0.05), FVC (r = -0.471, P < 0.01), predicted FVC% (r = -0.299, P < 0.05), and FEV1 (r = -0.397, P < 0.01). MEP was positively associated with average Brunnstrom stage of the distal area of the upper extremities (r = 0.351, P < 0.05), FVC (r = 0.526, P < 0.01), FEV1 (r = 0.429, P < 0.01), and FEV1/FVC (r = -0.482, P < 0.01). FEV1/FVC was negatively associated with the average Brunnstrom stage over the proximal (r = -0.414, P < 0.01) and distal (r = -0.422, P < 0.01) parts of the upper extremities and lower extremities (r = -0.311, P < 0.05) and Barthel index (r = -0.313, P < 0.05).Stroke patients with stable CHF and exertional dyspnea had restrictive lung disorder and respiratory muscle weakness, which were associated with the neurological status of the affected limbs. FVC was more strongly associated with MIP and MEP than predicted FVC%. FEV1/FVC may be used as a reference for the pulmonary dysfunction.

Inspiratory muscle training in stroke patients with congestive heart failure: A CONSORT-compliant prospective randomized single-blind controlled trial.

BACKGROUND: Cardiopulmonary function can be adversely affected after a cerebrovascular accident in patients with congestive heart failure (CHF). The aim of this study was to investigate the efficacy and feasibility of inspiratory muscle training (IMT) for stroke patients with CHF. METHODS: A prospective randomized single-blind controlled trial was conducted in a single tertiary medical center in southern Taiwan between May 2011 and July 2015. Forty-one patients were enrolled, of whom 21 completed the study (IMT group n = 11 and control group n = 10). Both groups participated in a conventional stroke rehabilitation program. Patients in the IMT group received an additional IMT program beginning with an intensity of 30% maximal inspiratory pressure (MIP), then increased by 2cmH2O each week for 30 minutes daily for at least 5 days a week for 10 weeks. MIP, maximal expiratory pressure, spirometry, resting oxyhemoglobin saturation, modified Borg Scale, Fatigue Assessment Scale, and Barthel Index were assessed in each patient. RESULTS: There were significant differences from baseline in MIP (P = 0.008), percent predicted forced vital capacity (P = 0.033), forced expiratory volume in 1 second (FEV1) (P = 0.008), percent predicted FEV1 (P = 0.008), and Barthel Index (P = 0.012) in the IMT group, and Barthel Index (P = 0.027) in the control group. There were significant differences between groups in MIP (20.91 ±â€Š19.73 vs -9.00 ±â€Š26.01, adjusted P value = 0.023) and Barthel Index (24.55 ±â€Š22.30 vs 7.50 ±â€Š8.25, adjusted P value = 0.044). CONCLUSION: The 10-week IMT was feasible and effective in improving inspiratory force and activities of daily living for the stroke patients with CHF.

A stochastic inference of de novo CNV detection and association test in multiplex schizophrenia families.

The copy number variation (CNV) is a type of genetic variation in the genome. It is measured based on signal intensity measures and can be assessed repeatedly to reduce the uncertainty in PCR-based typing. Studies have shown that CNVs may lead to phenotypic variation and modification of disease expression. Various challenges exist, however, in the exploration of CNV-disease association. Here we construct latent variables to infer the discrete CNV values and to estimate the probability of mutations. In addition, we propose to pool rare variants to increase the statistical power and we conduct family studies to mitigate the computational burden in determining the composition of CNVs on each chromosome. To explore in a stochastic sense the association between the collapsing CNV variants and disease status, we utilize a Bayesian hierarchical model incorporating the mutation parameters. This model assigns integers in a probabilistic sense to the quantitatively measured copy numbers, and is able to test simultaneously the association for all variants of interest in a regression framework. This integrative model can account for the uncertainty in copy number assignment and differentiate if the variation was de novo or inherited on the basis of posterior probabilities. For family studies, this model can accommodate the dependence within family members and among repeated CNV data. Moreover, the Mendelian rule can be assumed under this model and yet the genetic variation, including de novo and inherited variation, can still be included and quantified directly for each individual. Finally, simulation studies show that this model has high true positive and low false positive rates in the detection of de novo mutation.

Human papilloma virus and female lung adenocarcinoma.

Lung cancer is the leading cause of cancer among women worldwide, and adenocarcinoma is the most common histological subtype among non-smoking women. Previous studies showed that human papillomavirus (HPV) infection may relate to the tumorigenesis of pulmonary adenocarcinoma. Women with anogenital malignancy have a higher risk of lung cancer, which raises the possibility of HPV transmission from the cervix to the lung. Two postulated pathways are discussed in this work. First, HPV may infect the female cervix and then move to the lung by blood circulation. The second transmission route is the HPV infection of oral cavity resulting from dangerous sexual contacts, and subsequently transmitted to the lung. This chapter also reviews the techniques for detecting the existence, subtypes, and viral load of HPV. Future studies are needed to demonstrate the causal inference between HPV infection and the risk of female lung adenocarcinoma.