Smoking induces shifts in cellular composition and transcriptome within the bronchial mucus barrier.

BACKGROUND AND OBJECTIVE: Smoking disturbs the bronchial-mucus-barrier. This study assesses the cellular composition and gene expression shifts of the bronchial-mucus-barrier with smoking to understand the mechanism of mucosal damage by cigarette smoke exposure. We explore whether single-cell-RNA-sequencing (scRNA-seq) based cellular deconvolution (CD) can predict cell-type composition in RNA-seq data. METHODS: RNA-seq data of bronchial biopsies from three cohorts were analysed using CD. The cohorts included 56 participants with chronic obstructive pulmonary disease [COPD] (38 smokers; 18 ex-smokers), 77 participants without COPD (40 never-smokers; 37 smokers) and 16 participants who stopped smoking for 1 year (11 COPD and 5 non-COPD-smokers). Differential gene expression was used to investigate gene expression shifts. The CD-derived goblet cell ratios were validated by correlating with staining-derived goblet cell ratios from the COPD cohort. Statistics were done in the R software (false discovery rate p-value < 0.05). RESULTS: Both CD methods indicate a shift in bronchial-mucus-barrier cell composition towards goblet cells in COPD and non-COPD-smokers compared to ex- and never-smokers. It shows that the effect was reversible within a year of smoking cessation. A reduction of ciliated and basal cells was observed with current smoking, which resolved following smoking cessation. The expression of mucin and sodium channel (ENaC) genes, but not chloride channel genes, were altered in COPD and current smokers compared to never smokers or ex-smokers. The goblet cell-derived staining scores correlate with CD-derived goblet cell ratios. CONCLUSION: Smoking alters bronchial-mucus-barrier cell composition, transcriptome and increases mucus production. This effect is partly reversible within a year of smoking cessation. CD methodology can predict goblet-cell percentages from RNA-seq.

Determinants of SARS-CoV-2 receptor gene expression in upper and lower airways

BackgroundThe recent outbreak of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), has led to a worldwide pandemic. A subset of COVID-19 patients progresses to severe disease, with high mortality and limited treatment options. Detailed knowledge of the expression regulation of genes required for viral entry into respiratory epithelial cells is urgently needed. MethodsHere we assess the expression patterns of genes required for SARS-CoV-2 entry into cells, and their regulation by genetic, epigenetic and environmental factors, throughout the respiratory tract using samples collected from the upper (nasal) and lower airways (bronchi). FindingsGenes encoding viral receptors and activating protease are increased in the nose compared to the bronchi in matched samples and associated with the proportion of secretory epithelial cells in cellular deconvolution analyses. Current or ex-smoking was found to increase expression of these genes only in lower airways, which was associated with a significant increase in the predicted proportion of goblet cells. Both acute and second hand smoke exposure were found to increase ACE2 expression while inhaled corticosteroids decrease ACE2 expression in the lower airways. A strong association of DNA- methylation with ACE2 and TMPRSS2- mRNA expression was identified. InterpretationGenes associated with SARS-CoV-2 viral entry into cells are high in upper airways, but strongly increased in lower airways by smoke exposure. In contrast, ICS decreases ACE2 expression, indicating that inhaled corticosteroids are unlikely to increase the risk for more severe COVID-19 disease. FundingThis work was supported by a Seed Network grant from the Chan Zuckerberg Initiative to M.C.N. and by the European Unions H2020 Research and Innovation Program under grant agreement no. 874656 (discovAIR) to M.C.N. U BIOPRED was supported by an Innovative Medicines Initiative Joint Undertaking (No. 115010), resources from the European Unions Seventh Framework Programme (FP7/2007-2013) and EFPIA companies in kind contribution (www.imi.europa.eu). Longfonds Junior Fellowship. We acknowledge the contribution of the whole U-BIOPRED team as listed in the Appendix S1. SDB, FM and RFS would like to thank the Helmholtz Association, Germany, for support." NIH K08HL146943; Parker B. Francis Fellowship; ATS Foundation/Boehringer Ingelheim Pharmaceuticals Inc. Research Fellowship in IPF. RCR is part funded by Cancer Research UK Cambridge Centre and the Cambridge NIHR Biomedical Research Centre. BAP was funded by programme support from Cancer Research UK. The CRUKPAP Study was supported by the CRUK Cambridge Cancer Centre, by the NIHR Cambridge Biomedical Research Centre and by the Cambridge Bioresource. PIAMA was supported by The Netherlands Organization for Health Research and Development; The Netherlands Organization for Scientific Research; The Netherlands Lung Foundation (with methylation studies supported by AF 4.1.14.001); The Netherlands Ministry of Spatial Planning, Housing, and the Environment; and The Netherlands Ministry of Health, Welfare, and Sport. Dr. Qi is supported by a grant from the China Scholarship Council.

Low-dose naltrexone: a novel treatment for Hailey-Hailey disease.

Hailey-Hailey disease (chronic benign familial pemphigus) is a rare inherited dermatosis typically characterized by erosions at intertriginous sites preceded by minor trauma or stress. We report a case of treatment-resistant Hailey-Hailey disease having failed topical and oral steroids, prophylactic aciclovir and doxycycline, and systemic therapies including dapsone, acitretin and ciclosporin. Low-dose naltrexone 4·5 mg once daily was commenced following an incidental benefit in this patient's similarly affected sister. The clinical and psychological response to date has been considerable.

[Effects of government supervision on quality of integrated diabetes care: a cluster randomized controlled trial]. / Effecten van overheidstoezicht op kwaliteit van diabetesketenzorg: een clustergerandomiseerde gecontroleerde trial.

OBJECTIVES: The quality of integrated diabetes care is important for reducing the burden of diabetes. Therefore, we have evaluated the effect of a supervision program on the quality of integrated diabetes care in the Netherlands in the 2011-2012 period. METHODS: In this cluster RCT, the supervision program was assigned to randomly selected care groups providing care to diabetes patients. The supervision program included announcements of inspections, site visits, and sending individualized reports. Indicators of effectiveness were derived from the structures, processes, and outcomes of care. These indicators were collected from patients' files, before and after the supervision program. Hierarchical linear and logistic regression models were used to analyze data from 356 patients of 10 intervention and 8 control care groups. RESULTS: Structures and processes of care did not improve more in the intervention groups than in the control care groups. Moreover, health outcomes did not improve more in the intervention groups than in the control care groups. Although structures of care improved over time in the total population of intervention and control care groups, there were no changes in process of care or health outcomes. CONCLUSIONS: In this cluster RCT, we could not demonstrate improvements in quality of integrated diabetes care resulting from the supervision program. Although structures of care did improve over time, other quality-improvement initiatives are necessary to substantially strengthen integrated care for diabetes patients.

Effects of Government Supervision on Quality of Integrated Diabetes Care: A Cluster Randomized Controlled Trial.

OBJECTIVES: The quality of integrated diabetes care is important for reducing the burden of diabetes. Therefore, we have evaluated the effect of a supervision program on the quality of integrated diabetes care in the Netherlands in the 2011-2012 period. METHODS: In this cluster RCT, the supervision program was assigned to randomly selected care groups providing care to diabetes patients. The supervision program included announcements of inspections, site visits, and sending individualized reports. Indicators of effectiveness were derived from the structures, processes, and outcomes of care. These indicators were collected from patients' files, before and after the supervision program. Hierarchical linear and logistic regression models were used to analyze data from 356 patients of 10 intervention and 8 control care groups. RESULTS: Structures and processes of care did not improve more in the intervention groups than in the control care groups. Moreover, health outcomes did not improve more in the intervention groups than in the control care groups. Although structures of care improved over time in the total population of intervention and control care groups, there were no changes in process of care or health outcomes. CONCLUSIONS: In this cluster RCT, we could not demonstrate improvements in quality of integrated diabetes care resulting from the supervision program. Although structures of care did improve over time, other quality-improvement initiatives are necessary to substantially strengthen integrated care for diabetes patients.

Comparison of the Bradley Method and HypnoBirthing Childbirth Education Classes.

The purpose of this article is to compare and contrast two forms of childbirth education: HypnoBirthing (the Mongan Method) and the Bradley Method (husband-coached natural childbirth). Evidence was obtained using a formal literature review, reading published books and workbooks on the two methods, and attending classes to document content delivered. Similarities and differences in content are reported along with birth outcomes from evaluations of the two methods. Tables with this content were formatted so that they can be used by educators and providers.

Unannounced, compared with announced inspections: a systematic review and exploratory study in nursing homes.

Politicians and regulators have high expectations of unannounced inspections. Unannounced inspections, unlike announced ones, would, they believe, lead to a clearer insight into the risks and a reduction of the regulatory burden. In order to verify these assumptions, a systematic review of the scientific literature and an exploratory study were conducted. In the systematic review only three relevant articles were found concerned with research into the difference between unannounced and announced inspections. In the exploratory study, Dutch nursing homes were inspected, unannounced, and later announced, in order to compare the risks detected during the inspections. It is concluded that unannounced inspections did not reveal more or different risks, but provided a better insight into the quality of care delivered. Announced inspections are the best option for the assessment both of the organization and of its preconditions for good care. Evidence was found that an unannounced inspection leads to a reduction of the regulatory burden.

Molecular signature of smoking in human lung tissues.

Cigarette smoking is the leading risk factor for lung cancer. To identify genes deregulated by smoking and to distinguish gene expression changes that are reversible and persistent following smoking cessation, we carried out genome-wide gene expression profiling on nontumor lung tissue from 853 patients with lung cancer. Gene expression levels were compared between never and current smokers, and time-dependent changes in gene expression were studied in former smokers. A total of 3,223 transcripts were differentially expressed between smoking groups in the discovery set (n = 344, P < 1.29 × 10(-6)). A substantial number of smoking-induced genes also were validated in two replication sets (n = 285 and 224), and a gene expression signature of 599 transcripts consistently segregated never from current smokers across all three sets. The expression of the majority of these genes reverted to never-smoker levels following smoking cessation, although the time course of normalization differed widely among transcripts. Moreover, some genes showed very slow or no reversibility in expression, including SERPIND1, which was found to be the most consistent gene permanently altered by smoking in the three sets. Our findings therefore indicate that smoking deregulates many genes, many of which reverse to normal following smoking cessation. However, a subset of genes remains altered even decades following smoking cessation and may account, at least in part, for the residual risk of lung cancer among former smokers. Cancer Res; 72(15); 3753-63. ©2012 AACR.

Integrated care requires integrated supervision.

INTRODUCTION: Given recent developments in integrated care, it is becoming increasingly important for the Dutch Health Care Inspectorate to direct its supervision in a way that may help speed up the implementation of integrated care. DESCRIPTION OF CARE PRACTICE: Since the implementation of integrated care for chronic patients is facing obstacles, alternative methods are required to ensure that the implementation process does not run into any delays. By applying a risk-based approach to integrated care providers, the Inspectorate can analyse the care providers' performance by means of quality indicators and rank them. In order to be effective, appropriated supervision arrangements will be applied to the care providers of integrated care. DISCUSSION: With a ranking model transparency will be improved and this may encourage integrated care providers to strive for greater quality due to the competition inherent in the system. Supervision based on advice and encouragement might be helpful in the implementation of integrated care. CONCLUSION: Integrated care also requires integrated supervision, which means the Inspectorate may have to reconsider its working methods and the composition of its inspection teams.

Effect of fluoride exposure on cariostatic potential of orthodontic bonding agents: an in vitro evaluation.

AIMS: The aims of this in vitro study were to compare the cariostatic potential of a resin modified glass ionomer cement (Fuji Ortho LC) to that of a resin control (Transbond) for bracket bonding and to compare the effect of extrinsic fluoride application on the cariostatic potential of each material. SETTING: Ex vivo study. MATERIALS AND METHODS: Orthodontic brackets were bonded to 40 extracted premolars, 20 with Fuji Ortho LC and 20 with Transbond. The teeth were subjected to pH cycling, pH 4.55, and pH 6.8, over a 30-day period. Ten teeth bonded with each material were immersed in a 1000 ppm fluoride solution for 2 minutes each day. Fluoride release was measured throughout the study from all teeth. After 30 days, the teeth were assessed visually for signs of enamel decalcification. RESULTS: Significant differences in decalcification existed macroscopically between all four groups of teeth, with the exception of those bonded with Fuji Ortho LC alone compared with Transbond alone (P = 0.22), and Fuji Ortho LC alone compared with Transbond with added fluoride (P = 0.3). Fluoride release from Fuji Ortho LC alone fell to minimal values, but with the addition of extrinsic fluoride the levels fell initially and then followed an upward trend. There was minimal fluoride release, from Transbond alone, but with daily addition of extrinsic fluoride, subsequent fluoride release was increased. Significant differences existed in the amount of fluoride released between all groups, except comparing Fuji Ortho LC alone and Transbond with added fluoride. CONCLUSIONS: The results of this study have indicated that with an in vitro tooth-bracket model, the creation of white spot inhibition could best be achieved by the use of a resin-modified glass ionomer cement, supplemented with fluoride exposure. The least protection was afforded by the composite control. The resin-modified glass ionomer cement alone and the composite with added fluoride demonstrated equivalent protection.

Coadministration of mefloquine and chloroqine: use of a pharmacokinetic-based approach to reduce toxicity.

A child with malaria from a chloroquine-resistant area received an accidental overdose of chloroquine administered by a parent. Application of pharmacokinetics permitted definitive treatment with mefloquine in a safe and effective manner.

Utilization of library outreach services by dental school alumni, 1988-1998.

BACKGROUND: The University of Missouri-Kansas City School of Dentistry Library outreach service includes the Dental Reference Service, or DRS; Loansome Doc service, Career Opportunity Center, or COC; and the Instructional Resources Library, or IRL. The author reviewed usage of services for 1988-1998 to analyze use by alumni and nonalumni and to determine possible trends. METHODS: The author reviewed the UMKC School of Dentistry Library outreach service database from 1988-1998 to determine the total number of contacts for all services, numbers of contacts for each service, overall number of items sent and the number of dental health professionals contacting the services. RESULTS: The author found that the COC received 55 percent of contacts for the years 1988-1998, while the DRS received 26 percent of the total contacts and the IRL service received 19 percent. The DRS had the highest usage by alumni (80 percent); Loansome Doc service accounted for 11 percent of the DRS contacts. Total number of items sent in response to all requests was 34,325, of which 22,647 (66 percent) were to alumni. Alumni usage of all outreach services was consistent, ranging from 54 to 63 percent of the total. CONCLUSIONS: It appears that UMKC School of Dentistry alumni are active information-seekers. Several questions, however, remain, indicating that additional research should be done in the area of dental informatics. PRACTICE IMPLICATIONS: Information-seeking behaviors are an important part of the active clinical practice and may become more important as evidenced-based dentistry becomes more prevalent.

Hours of work, and perceptions of fatigue among truck drivers.

Drivers and companies operating in the heavy road transport industry were surveyed about drivers' hours of work and perceptions of the causes and magnitude of fatigue as an industry problem. These drivers were operating in a state which, at the time of the survey, did not restrict driving hours for heavy haulage drivers. On the day of the interview, estimates based on retrospective and prospective reports, suggest that in a 24 hour period about 38% of drivers exceed 14 hours of driving, and 51% exceed 14 hours of driving plus other non-driving work. About 12% of drivers reported less than 4 hours of sleep on one or more working days in the week preceding the interview. These drivers are likely to be operating their vehicles while having a significant sleep debt. About 20% of drivers reported less than 6 hours sleep before starting their current journey, but nearly 40% of dangerous events that occurred on the journey were reported by these drivers (p < 0.05). Many drivers and company representatives reported fatigue to be a problem for other drivers, but considered themselves or their companies' drivers to be relatively unaffected by fatigue. There were differences between drivers' and companies' perceptions about causes of fatigue, and strategies that should be used to manage it. The results obtained from these drivers in an unregulated state were compared with earlier findings from drivers in states where driving hours restrictions are in place.

The computer bandwagon--has everyone else jumped on?

A survey of 1,179 dentists in Kansas and Missouri was mailed in an effort to determine their current use of computers. There was a completed return of 458 surveys (39 percent). Of those responding, 64.4 percent indicated they had a computer in their home or office. Of those with computers, 73 percent were IBM or IBM compatible, 11.5 percent were Macintosh and 15.5 percent were other. Comparison of this survey with a similar survey completed in Indiana indicates that computer usage by dentists appears to be increasing but not at the same rate as the advances in computer technology.

A survey of the publication history of randomly selected IADR/AADR abstracts presented in 1983 and 1984.

IADR/AADR abstracts of research projects to be presented at the Annual Meeting are published each year in the Journal of Dental Research. An assumption often made is that the material in these abstracts is subsequently published as journal articles. The validity of this assumption was assessed in this study. Following a review of the literature to establish study criteria, the specific objectives of this study were to determine: (1) the percentage of IADR/AADR abstracts subsequently published as articles, (2) the length of time from abstract to publication, and (3) the amount of discrepancy between abstract and article. Ten percent of the IADR/AADR abstracts from the years 1983 (n = 125) and 1984 (n = 150) were randomly selected and surveyed for their publication history. Major reference sources were checked for determination of whether articles had resulted from the abstracts. Of the 1983-1984 abstracts surveyed, the results indicated that more abstracts were not published (78.5% in 1983/76.0% in 1984) than were published (21.6% in 1983/24.0% in 1984). Of those articles previously published as abstracts, the greatest number (44.4% in 1983 47.2% in 1984) were published within ten to 21 months following presentation. The greatest amount of discrepancy between the abstract and the article involved names and numbers of authors, titles, purpose statements, and results/conclusions. In other health disciplines, the percentage of abstracts subsequently published as articles ranged from 31.1% to 53.9%. Since a smaller percentage of the IADR/AADR abstracts surveyed in this study were ultimately published (21.6% to 24%). IADR/AADR should consider various strategies to improve the quality of abstracts and their accessibility.