Implementation of evidence on management of pleural diseases: insights from a territory-wide survey of clinicians in Hong Kong.

BACKGROUND: Major advances in management of common pleural diseases have taken place in the past decade. However, pleural diseases are often managed by physicians of diverse training background and research on implementation of new knowledge is scanty. We aim to evaluate the practice pattern in pleural medicine among physicians in Hong Kong, for identification of possible gaps for clinical service improvement. METHODS: The Hong Kong Thoracic Society undertook a cross-sectional questionnaire survey in 2019, targeting clinicians of various subspecialties in internal medicine and levels of experience (basic and higher trainees, specialists) from twelve regional hospitals of diverse service scopes throughout Hong Kong. Respondents were selected by non-probability quota sampling. The questionnaire tool consisted of 46 questions covering diagnostic and therapeutic aspects of common pleural diseases. The responses were anonymous, and analysed independently using SPSS statistics software. RESULTS: The survey collected 129 responses, 47(36%) were from clinicians specialized in respiratory medicine. Majority of the respondents (98%) managed pleural diseases, including performing pleural procedures in their practice. Fifty-five percent of all the respondents had not received any formal training in transthoracic ultrasonography. A significant proportion of clinicians were unaware of pleuroscopy for investigation of exudative pleural effusion, indwelling pleural catheter for recurrent malignant pleural effusion, and combined intra-pleural Alteplase plus DNase for treatment of pleural infection (30%, 15% and 70% of non-respiratory clinicians respectively). Significant heterogeneity was found in the management of pleural infection, malignant pleural effusion and pneumothorax among respiratory versus non-respiratory clinicians. Contributing factors to the observed heterogeneity included lack of awareness or training, limited accessibility of drugs, devices, or dedicated service support. CONCLUSION: Significant heterogeneity in management of pleural diseases was observed among medical clinicians in Hong Kong. Continuous medical education and training provision for both specialists and non-specialists has to be strengthened to enhance the implementation of advances, improve quality and equity of healthcare provision in pleural medicine.

Employment Status and Health Literacy in Denmark: A Population-Based Study.

Objectives: Examining whether specific population groups who are not working and those who have an employment have the same health literacy level. Methods: Data were retrieved from a nationally representative cross-sectional study of the Danish population conducted with the health literacy questionnaire (HLS-EU-Q16) in 2016 and 2017. Socio-demographic characteristics were drawn from national registers. Odds ratio for the association between employment status and health literacy was estimated from logistic regression models, adjusted for socio-demographic characteristics. Probability weights were used to adjust for differences in responses. Results: Logistic regression analyses showed that receiving unemployment benefits, social assistance, employment and support allowance, retirement pension and sickness benefit were significantly associated with having inadequate health literacy compared to being employed in any industry. The highest odds ratio for inadequate health literacy was present for receiving unemployment benefit OR = 1.78 (95% CI: 1.23-2.56). Conclusion: Population groups not working and receiving economic public support have higher odds of inadequate health literacy competencies compared to those active in the labor force, considering age and socioeconomic factors. The result contributes to understanding health disparities in connection to occupational situation.

The hospital telemedicine TELEMED database: Providing information on evidence-based telemedicine services to hospital managers and healthcare professionals.

BACKGROUND: Increased use of telemedicine in the healthcare system is a political goal in Denmark. Although the number of hospital patients using interventions such as the video consultation has increased in recent years only a small proportion of the outpatient and inpatient visits involve telemedicine. The TELEMED database (https://telemedicine.cimt.dk/) has been launched at the Center for Innovative Medical Technology in Denmark to ensure that hospital managers and healthcare professionals have access to information about telemedicine services and their effectiveness. This article describes the development and the content of the TELEMED database. METHODS: A structured literature search was made in the PubMed Database for randomised controlled trials or observational studies with a control group that investigated the effect of telemedicine interventions for hospital patients. Data were extracted from each article on the clinical effectiveness, patient perceptions, economic effects and implementation challenges. As the database should only provide inspiration to healthcare professionals regarding possibilities for use of telemedicine, the risk of bias in the studies was not assessed. RESULTS: The literature search resulted in 2825 hits. Based on full text assessment, 331 articles were included for data extraction and assessment. These articles present telemedicine services used in 22 different medical specialities. Forty-eight percent of the studies found a positive, statistically significant clinical effect, while 47% showed no statistically significant difference. In 48% of the studies, patients' experiences were examined and of these 68% found positive patient experiences. Fifty-four percent of the articles included information on the economic effects and, of these, 51% found reduction in healthcare utilization. In the majority of studies between two and four types of implementation challenges were found.Conclusions and recommendations: The TELEMED database provides an easily accessible overview of existing evidence-based telemedicine services for use by hospital managers and health professionals, who whish to to implement telemedicine. The database is freely available and expected to be continuously improved and broadened over time.

Cefoxitin treatment of MRSA leads to a shift in the IL-12/IL-23 production pattern in dendritic cells by a mechanism involving changes in the MAPK signaling.

Methicillin resistant Staphylococcus aureus (MRSA) constitute a serious health care problem worldwide. This study addresses the effect of ß-lactam treatment on the ability of clinically relevant MRSA strains to induce IL-12 and IL-23. MRSA strains induced a dose-dependent IL-12 response in murine bone-marrow-derived dendritic cells that was dependent on endocytosis and acidic degradation. Facilitated induction of IL-12 (but not of IL-23) called for activation of the MAP kinase JNK, and was suppressed by p38. Compromised peptidoglycan structure in cefoxitin-treated bacteria - as denoted by increased sensitivity to mutanolysin -caused a shift from IL-12 towards IL-23. Moreover, cefoxitin treatment of MRSA led to a p38 MAPK-dependent early up-regulation of Dual Specificity Phosphatase (DUSP)-1. Compared to common MRSA, characteristics associated with a persister phenotype increased intracellular survival and upon cefoxitin treatment, the peptidoglycan was not equally compromised and the cytokine induction still required phagosomal acidification. Together, these data demonstrate that ß-lactam treatment changes the MRSA-induced IL-12/IL-23 pattern determined by the activation of JNK and p38. We suggest that accelerated endosomal degradation of the peptidoglycan in cefoxitin-treated MRSA leads to an early expression of DUSP-1 and accordingly, a reduction in the IL-12/IL-23 ratio in dendritic cells. This may influence the clearance of S. aureus.

Reduced granulation tissue and wound strength in the absence of α11ß1 integrin.

Previous wound healing studies have failed to define a role for either α1ß1 or α2ß1 integrin in fibroblast-mediated wound contraction, suggesting the involvement of another collagen receptor in this process. Our previous work demonstrated that the integrin subunit α11 is highly induced during wound healing both at the mRNA and protein level, prompting us to investigate and dissect the role of the integrin α11ß1 during this process. Therefore, we used mice with a global ablation of either α2 or α11 or both integrin subunits and investigated the repair of excisional wounds. Analyses of wounds demonstrated that α11ß1 deficiency results in reduced granulation tissue formation and impaired wound contraction, independently of the presence of α2ß1. Our combined in vivo and in vitro data further demonstrate that dermal fibroblasts lacking α11ß1 are unable to efficiently convert to myofibroblasts, resulting in scar tissue with compromised tensile strength. Moreover, we suggest that the reduced stability of the scar is a consequence of poor collagen remodeling in α11(-/-) wounds associated with defective transforming growth factor-ß-dependent JNK signaling.

In vivo hyperglycemia and its effect on Glut-1 expression in the embryonic heart.

BACKGROUND: Maternal diabetes exposes embryos to periods of hyperglycemia. Glucose is important for normal cardiogenesis, and Glut-1 is the predominant glucose transporter in the embryo. METHODS: Pregnant mice were exposed to 6 or 12 hr hyperglycemia during organogenesis using intraperitoneal (IP) injections of D-glucose on gestational day (GD) 9.5 (plug = GD 0.5). Embryos were examined for morphology and total cardiac protein, and embryonic hearts were evaluated for Glut-1 protein and mRNA expression immediately after treatment (GD 9.75, GD 10.0), as well as on GD 10.5 and GD 12.5. RESULTS: IP glucose injections were effective in producing sustained maternal hyperglycemia. Maternal hyperglycemia for 6 or 12 hr on GD 9.5, followed by normoglycemia, produced a decrease in overall size and total cardiac protein in embryos evaluated on GD 10.5 but no difference on GD 12.5. Cardiac Glut-1 expression was immediately upregulated in embryos exposed to 6 or 12 hr maternal hyperglycemia. On GD 10.5, cardiac Glut-1 expression was not different in embryos exposed to maternal hyperglycemia for 6 hr but was downregulated in embryos exposed for 12 hr. On GD 12.5, cardiac Glut-1 expression in embryos exposed to maternal hyperglycemia on GD 9.5 for 6 or 12 hr, followed by normoglycemia, was not different from controls. The temporal pattern was the same for Glut-1 protein and mRNA expression. CONCLUSIONS: Hyperglycemia-induced alterations in Glut-1 expression likely interfere with balance of glucose available to the embryonic heart that may affect cardiac morphogenesis.

Hypoglycemia induced changes in cell death and cell proliferation in the organogenesis stage embryonic mouse heart.

BACKGROUND: Hypoglycemia is a side effect of diabetes therapy and causes abnormal heart development. Embryonic heart cells are largely resistant to teratogen-induced apoptosis. METHODS: Hypoglycemia was tested for effects on cell death and cell proliferation in embryonic heart cells by exposing mouse embryos on embryonic day (E) 9.5 (plug = E0.5) to hypoglycemia (30-50 mg/dl glucose) in vivo or in vitro for 24 hr. Long-term effects of in vivo exposure on conceptus viability were evaluated at E18.5. Cell death was evaluated on E10.5 by: 1) two TUNEL assays in sectioned embryos to demonstrate DNA fragmentation; 2) confocal microscopy in whole embryos stained with Lysotracker; 3) flow cytometry in dispersed heart cells stained for TUNEL and myosin heavy chain (MHC) to quantify and characterize cell type susceptibility; and 4) immunohistochemistry (IHC) and Western analysis in sectioned embryos to evaluate potential involvement of caspase-3 active subunit and p53. Effects on cell proliferation were evaluated by IHC and Western analysis of proliferating cell nuclear antigen (PCNA). RESULTS: In vivo hypoglycemic exposure on E9.5 reduced viability in conceptuses examined on E18.5. Hearts examined on E10.5 demonstrated increased TUNEL and Lysotracker staining. In hearts of embryos exposed to hypoglycemia, flow cytometry demonstrated increased TUNEL-positive cells and cells dual-labeled for TUNEL and MHC. Protein expression of caspase-3 active subunit and p53 was increased and PCNA was markedly reduced in hearts of embryos exposed to hypoglycemia. CONCLUSIONS: Hypoglycemia reduces embryonic viability, induces significant cell death, and reduces cell proliferation in the E9.5 mouse heart, and these processes may involve active caspase-3 and p53.

Noninvasive ventilation in patients with acute hypercapnic exacerbation of chronic obstructive pulmonary disease who refused endotracheal intubation.

OBJECTIVE: To determine the long-term outcome of noninvasive ventilation in chronic obstructive pulmonary disease patients who refused intubation for acute hypercapnic respiratory failure. DESIGN: Prospective, observational study. SETTING: Noninvasive ventilation unit in an acute regional hospital in Hong Kong. METHODS: The study recruited 37 chronic obstructive pulmonary disease patients who had the do-not-intubate code and developed acute hypercapnic respiratory failure. They were offered noninvasive ventilation, and their long-term outcomes were followed. Survival and event-free survival (an event is death or recurrent acute hypercapnic respiratory failure) were analyzed by survival analysis. Their disease profile and outcome were compared with another 43 chronic obstructive pulmonary disease patients without the do-not-intubate codes, who had acute hypercapnic respiratory failure and received noninvasive ventilation during the study period (usual care group). RESULTS: Patients in the do-not-intubate group were significantly older (p =.029), had worse dyspnea score (p <.001), worse Katz Activities of Daily Living score (p <.001), worse comorbidity score (p =.024), worse Acute Physiology and Chronic Health Evaluation II score (p =.032), lower hemoglobin (p =.001), and longer stay in the hospital during the past year (p =.001) than patients who received usual care. In the do-not-intubate group, the median survival was 179 days, and 1-yr actuarial survival was 29.7%; in the usual care group, the median survival was not reached during follow-up, and 1-yr actuarial survival was 65.1% (p <.0001). In the do-not-intubate group, the median event-free survival was 102 days, and 1-yr event-free survival was 16.2%; in the usual care group, median event-free survival was 292 days, and 1-yr event-free survival was 46.5% (p =.0004). CONCLUSIONS: A 1-yr survival of about 30% was recorded in chronic obstructive pulmonary disease patients with the do-not-intubate code who developed acute hypercapnic respiratory failure requiring noninvasive ventilation. The majority of survivors developed another life-threatening event in the following year. Information generated from this study is important to physicians and chronic obstructive pulmonary disease patients when they are considering using noninvasive ventilation as a last resort.

Influence of pregnancy on the pathogenesis of listeriosis in mice inoculated intragastrically.

Pregnancy increases the risk of listeriosis, a systemic disease caused by Listeria monocytogenes. However, there is incomplete agreement on the reasons for this increased risk. We examined two features of listeriosis in gravid and nongravid female mice following intragastric (gavage) inoculation, namely, (i) disease severity (measured by lethality) and (ii) listerial infectivity (measured by liver and spleen colonization levels up to 120 h postinoculation). Two listerial strains of differing serotype (1/2a and 4nonb) were initially employed. Neither strain produced a lethal infection in nonpregnant female mice (dose range, 10(6) to 10(9) CFU/mouse), and only the 4nonb strain produced lethalities in pregnant mice (dose range, 10(6) to 10(8) CFU/mouse). The 4nonb strain also produced a higher level of liver and spleen colonization than the 1/2a strain following gavage administration. (The two strains showed similar levels of colonization if parenterally administered.) Both strains were equally capable of binding to and forming plaques upon cultured mouse enterocytes. The ability of the 4nonb strain to produce a lethal infection in pregnant animals did not correlate with an increased incidence or level of liver and spleen colonization over that in nonpregnant females. However, the lethality rate did correlate well with the rate at which embryos and their surrounding decidual covering became infected, suggesting that intrauterine infection could be responsible for the increased disease severity in the gravid females.

13C-NMR study of hypoglycemia-induced glycolytic changes in embryonic mouse heart.

BACKGROUND: Glucose metabolites can be detected in embryonic mouse tissues using 13C-NMR spectroscopy. The advantage of this method is in its chemical specificity and the ability to follow metabolic changes. METHODS: In this study, CD-1 mice were mated and embryos excised on gestational day (GD) 10.5 (plug = GD 0.5). Hearts were isolated and cultured in 150 mg/dl glucose (normoglycemic medium) or 40 mg/dl glucose (hypoglycemic medium) for 6 hr. 13C-labeled glucose comprised 62%-64% of total glucose in the culture medium. Pre- and postculture media were treated with deuterated water (D2O), and 13C spectra were obtained using a Bruker Avance 500 MHz spectrometer operating at 11.744 tesla (125.7 MHz for 13C). NMR spectra demonstrated resonances for 13C-glucose in preculture normoglycemic and hypoglycemic media. Postculture spectra for normoglycemic and hypoglycemic media demonstrated 13C-glucose signals as well as a signal for 13C-lactate. Area under the curve (AUC) was measured for the [1-(13)C-glucose] resonance from preculture media and the [3-(13)C-lactate] resonance from postculture media. The ratios of AUC for postculture [3-(13)C-lactate] to preculture [1-(13)C-glucose] were calculated and found to be higher in hypoglycemic than in normoglycemic media. RESULTS: Our results confirm earlier findings using radiolabeled substrates and suggest that 13C-NMR spectroscopy can be used to study glucose metabolism in isolated embryonic hearts exposed to hypoglycemia. CONCLUSIONS: NMR effectively measures glucose and its metabolite, lactate, in the same spectrum and thus determines metabolic flux in the isolated embryonic heart after exposure to hypoglycemia and normoglycemia. This method could evaluate glucose metabolism in embryonic tissues following other teratogenic exposures.

Embryotoxicity of the pesticide mirex in vitro.

Mirex is a pesticide that is environmentally stable, accumulates in body tissues, and is embryo- and feto-toxic at high concentrations in vivo. This study is the first to evaluate the effects of mirex on organogenesis-stage embryos in vitro. Mouse embryos were exposed on gestation day 8.5 for 24 h in whole-embryo culture to mirex at 100, 200, or 400 microg/ml dissolved in xylene and compared with xylene-treated controls (1, 2, or 4 microl/ml, respectively) and untreated controls. Embryos were evaluated for malformations, somite number, total protein content, and visceral yolk sac circulation. Potential embryotoxic mechanisms were evaluated by using PCNA stain for cell proliferation and the TUNEL assay for apoptotic cell death. Mirex-exposed embryos demonstrated increased malformation rates and decreased total embryonic protein contents at > or =200 microg/ml mirex, and decreased somite numbers and VYS circulation at > or =100 microg/ml mirex, compared with xylene-treated controls. There was no difference in PCNA levels or TUNEL staining in mirex-treated embryos compared with xylene-treated controls or untreated controls. Thus, mirex is embryotoxic in vitro to early organogenesis stage mouse embryos at concentrations > or =100 microg/ml, but the effects do not appear to be mediated by changes in cell proliferation or apoptotic cell death.

Tolbutamide alters glucose transport and metabolism in the embryonic mouse heart.

BACKGROUND: Tolbutamide is a sulfonylurea oral hypoglycemic agent widely used for the treatment of non insulin-dependent diabetes mellitus. Tolbutamide produces dysmorphogenesis in rodent embryos and becomes concentrated in the embryonic heart after maternal oral dosing. Tolbutamide increases glucose metabolism in extra-pancreatic adult tissues, but this has not previously been examined in embryonic heart. METHODS: CD-1 mouse embryos were exposed on GD 9.5 to tolbutamide (0, 100, 250, or 500 microg/ml) for 6, 12, or 24 hr in whole-embryo culture. Isolated hearts were evaluated for (3)H-2DG uptake and conversion of (14)C-glucose to (14)C-lactate. Glut-1, HKI, and GRP78 protein levels were determined by Western analysis, and Glut-1 mRNA was measured by RT-PCR. RESULTS: Cardiac (3)H-2DG uptake increased after exposure to 500 microg/ml tolbutamide for 6 hr, and 100, 250, or 500 microg/ml tolbutamide for 24 hr, compared to controls. Glycolysis increased after exposure to 500 microg/ml tolbutamide for 6 or 24 hr compared to controls. Glut-1 protein levels increased in hearts exposed to 500 microg/ml tolbutamide for 12 or 24 hr, and Glut-1 mRNA increased in hearts exposed to 500 microg/ml tolbutamide for 24 hr compared to controls. HKI protein levels increased in hearts exposed to 500 microg/ml tolbutamide for 6 hr, but not 12 or 24 hr. There was no effect on GRP78 protein levels in hearts exposed to tolbutamide for 6, 12, or 24 hr. CONCLUSIONS: Tolbutamide stimulates glucose uptake and metabolism in the embryonic heart, as occurs in adult extra-pancreatic tissues. Glut-1 and HKI, but not GRP78, are likely involved in tolbutamide-induced cardiac dysmorphogenesis.

Hypoglycemia and embryonic heart development.

Abnormal embryonic development is a complication of the diabetic pregnancy, and heart defects are among the most common and detrimental congenital malformations of the diabetic embryopathy. Hypoglycemia is a common side effect of diabetes therapy and is a potential teratogen. An association between hypoglycemia and congenital defects has been difficult to demonstrate in humans, but in vivo and in vitro animal studies have illustrated the importance of glucose as a substrate for normal development. Hypoglycemia alters embryonic heart morphology, producing abnormal looping and chamber expansion, decreased myocardial thickness, disorganized layers, and decreased overall size. Hypoglycemia decreases embryonic heart rate and vascularity, and it alters embryonic heart metabolism by increasing glucose uptake and glycolysis. Hypoglycemia also affects protein expression in the embryonic heart, increasing the expression of glucose regulated proteins, hexokinase, and glucose transport protein. Thus, hypoglycemia interferes with normal cardiogenesis and alters morphology, function, metabolism, and expression of certain proteins in the developing heart. It is likely that these factors contribute to heart defects observed in the diabetic embryopathy, but the definitive link has yet to be made. Future studies are expected to further elucidate mechanisms mediating hypoglycemia-induced cardiac dysmorphogenesis.

THE EFFECTS OF 5-AZA-2'-DEOXYCYTIDINE (D-AZA) ON SONIC HEDGEHOG EXPRESSION IN MOUSE EMBRYONIC LIMB BUDS.

5-Aza-2'-deoxycytidine (d-AZA) causes temporally-related defects in the mouse. At 1.0 mg/kg on gestational day (GD) 10, d-AZA causes hindlimb phocomelia. Sonic hedgehog (Shh) plays a significant role in the normal development of limbs in rodent species. Sonic hedgehog peptides, found in the posterior mesenchyme of limb buds, are involved in patterning functions and in the regulation of both anterior-posterior polarity and proximal-distal outgrowth of the limb. The objective of the present study was to analyze alterations in Shh expression subsequent to d-AZA exposure. Pregnant mice were treated with d-AZA via intraperitonlal injection on GD 10. Controls were untreated. The reverse transcription-polymerase chain reaction (RT-PCR), whole mount in situ hybridization (ISH), and whole mount immunohistochemistry (WMI) were used to analyze expression patterns of Shh . For RT-PCR, embryonic hindlimb buds (buds) were taken 0, 4, 8, 12, or 24 hr after exposure. Cyclophilin was used as the baseline monitor. RNA was transcribed to cDNA and used as template with Shh specific primers for amplification. Whole embryos were collected 12 and 24 hr posttreatment for ISH. An antisense primer specific for Shh was used in an oligo-based ISH protocol. Whole embryos were collected 36 and 48 hr posttreatment for WMI. The antibody corresponding to the amino terminal subunit of the Shh peptide was used. There was a treatment related up-regulation of Shh transcripts by 12 and 24 hr posttreatment. The protein response of up-regulation was detectable by 36 and 48 hr posttreatment. Our data suggest that 5-aza-2'-deoxycytidine-induced hindlimb defects may be associated with alterations in the level of Shh expression. This may be part of a cascade of signaling events involved in d-AZA-induced hindlimb defects. Work is ongoing to determine the relationship of other gene species that may cooperate with Shh in the induction of the hindlimb defects.

Molecular characteristics of the CA 125 antigen produced by human endometrial epithelial cells: comparison between eutopic and heterotopic epithelial cells.

OBJECTIVE: To characterize the CA 125 antigen purified from the conditioned media using an in vitro system that we have established for the culture of epithelial cells from human uterine endometrium. STUDY DESIGN: CA 125 was purified separately from the conditioned media of eutopic and heterotopic epithelial cells by gel chromatography and OC 125 immunoaffinity column chromatography. RESULTS: Western blot analysis of conditioned media from eutopic epithelial cells revealed a single polydisperse band of 200 kd, whereas two major CA 125 isoforms of 200 and 110 kd, as well as two minor forms of 100 and 70 kd, were observed in heterotopic epithelial cells. The 110 kd CA 125 was more prominent than the 200 kd antigen in heterotopic epithelial cells. CONCLUSION: These results strongly suggest that CA 125 antigens purified by immunoaffinity chromatography have different molecular mass in eutopic and heterotopic epithelial cells even though the OC 125 binding site may remain intact.

Quantitative and qualitative assessment of CA-125 production by human endometrial epithelial cells: comparison of eutopic and heterotopic epithelial cells.

We have established an in vitro system for the culture of epithelial cells (ECs) from human uterine endometrium to examine the production of CA 125 and to characterize the CA-125 antigen purified from the conditioned media. CA-125 secretion was higher in heterotopic ECs than in eutopic ECs and it was more significant after heterotopic ECs reached confluence than during the logarithmic growth phase. CA-125 expression was observed mainly in the G0/G1-phase. CA-125 expression on cell membranes did not correlate with the volume of CA 125 released per cell, and there was no amplification of CA-125 expression in heterotopic EC membranes. Treatment of the purified CA-125 antigen with 6 M urea yielded a much lower molecular-mass peak (200 kDa). The results of Western blot indicated the presence of a single polydisperse band of 200 kDa in the conditioned media from eutopic ECs, whereas 2 major CA-125 isoforms of 200 kDa and 110 kDa, as well as 2 minor forms of 100 kDa and 70 kDa, were observed in the conditioned media of the heterotopic ECs. We conclude that, in heterotopic ECs, the 110-kDa CA-125 is more prominent than the 200-kDa antigen, and that the elevation of CA-125 levels in the conditioned media could be attributed to significantly increased release of 110-kDa CA-125 from heterotopic ECs.