Use of Hyaluronic Acid Filler in Patients with Secondary Cleft Lip Deformity.

METHODS: Retrospective case note review was undertaken of all patients treated in the clinic over a two-year period. RESULTS: 20 patients underwent HA filler injections to the upper lip 26 times. Most were female (F:M = 3:1) and patients were aged 18-58 years. Most patients had a unilateral cleft lip +/- palate (n = 13, 65%). The most common indication was to address upper lip volume (n = 13, 65%). Other indications included vermillion notch (n = 5, 25%), cupid bow peak height asymmetry (n = 4, 20%), scar asymmetry (n = 1, 5%) and nasal sill flattening (n = 1, 5%). Small volumes of filler were used with an average of 0.34 ml (range 0.05-1.2 ml). There were no complications and one patient reported pruritis post procedure. CONCLUSIONS: HA filler is a safe and reliable treatment for certain aspects of asymmetry following cleft lip repair. It can be used to address volume deficiency and asymmetry, cupid bow peak height discrepancies and a vermillion notch for patients who do not want surgery. Injection of HA to the lips can be performed easily, with appropriate training, in the outpatient setting.

Heart Disease and Stroke Statistics-2021 Update: A Report From the American Heart Association.

BACKGROUND: The American Heart Association, in conjunction with the National Institutes of Health, annually reports the most up-to-date statistics related to heart disease, stroke, and cardiovascular risk factors, including core health behaviors (smoking, physical activity, diet, and weight) and health factors (cholesterol, blood pressure, and glucose control) that contribute to cardiovascular health. The Statistical Update presents the latest data on a range of major clinical heart and circulatory disease conditions (including stroke, congenital heart disease, rhythm disorders, subclinical atherosclerosis, coronary heart disease, heart failure, valvular disease, venous disease, and peripheral artery disease) and the associated outcomes (including quality of care, procedures, and economic costs). METHODS: The American Heart Association, through its Statistics Committee, continuously monitors and evaluates sources of data on heart disease and stroke in the United States to provide the most current information available in the annual Statistical Update. The 2021 Statistical Update is the product of a full year's worth of effort by dedicated volunteer clinicians and scientists, committed government professionals, and American Heart Association staff members. This year's edition includes data on the monitoring and benefits of cardiovascular health in the population, an enhanced focus on social determinants of health, adverse pregnancy outcomes, vascular contributions to brain health, the global burden of cardiovascular disease, and further evidence-based approaches to changing behaviors related to cardiovascular disease. RESULTS: Each of the 27 chapters in the Statistical Update focuses on a different topic related to heart disease and stroke statistics. CONCLUSIONS: The Statistical Update represents a critical resource for the lay public, policy makers, media professionals, clinicians, health care administrators, researchers, health advocates, and others seeking the best available data on these factors and conditions.

[Clinicopathological features of hybrid oncocytic/chromophobe renal cell tumor].

Objective: To investigate the clinicopathological features and immunohistochemical phenotypes of hybrid oncocytic/chromophobe tumor (HOCT) of the kidney and its associations with renal oncocytoma (RO) and eosinophilic chromophobe renal cell carcinoma (eChRCC). Methods: A total of 8 HOCT cases were collected from 2008 to 2019 at the Affiliated Hospital of Qingdao University (5 cases) and 971 Hospital of PLA Navy (3 cases), Qingdao, China for morphological studies, immunohistochemical staining and follow-up. The immunohistochemical results of HOCT were compared with those of 27 typical RO and 17 eChRCC. Results: Among the 8 patients, 3 were male and 5 were female. Their ages ranged from 39 to 75 years (median: 56 years). All cases were sporadic. Seven patients were asymptomatic and one suffered from lumbago. During a mean follow-up of 37 months in 7 patients, none of them developed tumor recurrence or metastasis. Seven cases were solitary and one was multiple. The tumor size ranged from 1.4 to 5.7 cm (mean, 3.6 cm). The cut surface of the tumors was dark red or yellowish. Histologically, the tumors were well-defined. Six cases were directly adjacent to the surrounding renal tissue, 2 cases had pseudocapsule, 3 cases showed entrapped renal tubules at the edge of tumor tissue, and one circumscribed with focal infiltrating borders. There were two types of histological morphology: one type (4 cases) was composed of mixed areas of otherwise typical RO and areas resembling chromophobe renal cell carcinoma; another type (4 cases) showed the morphological characteristics of both RO and eChRCC. Three second-type tumors showed nest-like, trabecular, and solid growth patterns with conspicuous edematous stroma. The cell border was conspicuous and the cytoplasm showed an eosinophilic appearance. The nuclei were small and round with clear perinuclear halo. One tumor showed a multi-nodular and solid growth pattern, and the cytoplasm was eosinophilic, hypochromatic or transparent. The nuclei were small and round, and some of them had obvious perinuclear halo. Immunohistochemically, the tumor cells in all 8 cases were positive for Ksp-cad but negative for vimentin. CD117 was diffusely positive in 6/8 cases. CK7 staining showed patchy positivity in 6/8 cases. S-100A1, cyclin D1 and claudin7 showed variable positivity in 4/8, 6/8 and 5/8 cases, respectively, but the range and intensity were narrower and weaker than those in RO and eChRCC. Conclusions: HOCT is a low-grade eosinophilic renal tumor with morphological characteristics resembling RO and eChRCC. The combined application of immunohistochemical stains of CK7, CD117, Ksp-cad, cyclin D1, claudin7 and S-100A1 may play an auxiliary role in the differentiation of the three tumors. HOCT has a good prognosis after surgical resection and can be regarded as a tumor with uncertain malignant potential.

Perceptions of nurses on inter-shift handover: A descriptive study in Hospital Kuala Lumpur, Malaysia.

INTRODUCTION: The quality of information and efficiency in the practice and care environments are important aspects of nursing care. The use of a reliable and valid scale can monitor the quality of handover and provide information for continuous improvement of practice. This study aims to describe the perception of nurses, on the domains of quality of information, efficiency, interaction and support and patient involvement. METHOD: A cross-sectional descriptive study was conducted among 450 nurses from 37 wards in Hospital Kuala Lumpur. Nurses on shift duty were recruited by convenience sampling from the Medical, Surgery, Obstetrics & Gynaecology, Orthopaedic and Paediatric wards. Using a validated questionnaire (Handover Evaluation Scale), nurses self-rated their perceptions using a 7-point scale and provided open-ended responses to the strengths and challenges that they faced. Descriptive and inferential analyses were done while open-ended questions were summarised based on key themes. RESULTS: A total of 414 nurses completed the survey (92.0% response rate). Nurses had an overall mean (SD) perception score of 5.01 (SD 0.56). They perceived good interaction and support during handover and on the quality of information that they received, with mean scores of 5.54 (SD 0.79) and 5.19 (SD 0.69), respectively. There was an association between the departments where the nurses worked and their overall perceptions on nursing handover (p<0.001). Interruptions being the most common theme emerged from the open-ended section. CONCLUSION: Despite having substantial interaction and support amongst nurses, opportunities for improvements were noted. Improvements in the quality of handover information and reducing interruptions should be the main emphases as these were perceived to be essential in the current handover practices by nurses.

Effects of a lifestyle intervention on markers of cardiometabolic risk and oxidized lipoproteins among obese adolescents with prediabetes.

OBJECTIVE: Obesity and hyperglycaemia contribute to the atherosclerotic process in part through oxidative modifications to lipoprotein particles. The present study aimed to evaluate the effects of a lifestyle intervention on markers of oxidized lipoproteins in obese Latino adolescents with prediabetes. DESIGN: Pre-post design. SETTING: Participants were enrolled into a 12-week lifestyle intervention. Measurements pre- and post-intervention included anthropometrics and body composition, lipid panel, oxidized LDL (oxLDL), oxidized HDL (oxHDL), intake of fresh fruits and vegetables, and cardiorespiratory fitness. PARTICIPANTS: Thirty-five obese Latino adolescents (seventeen females, eighteen males; mean age 15·5 (sd 1·0) years; mean BMI percentile 98·5 (sd 1·2)) with prediabetes. RESULTS: Intervention participation resulted in significant reductions in weight (-1·2 %, P = 0·042), BMI and BMI percentile (-2·0 and -0·4 %, respectively, P < 0·001), body fat (-7·0 %, P = 0·025), TAG (-11·8 %, P = 0·032), total cholesterol (-5·0 %, P = 0·002), VLDL-cholesterol (-12·5 %, P = 0·029), and non-HDL-cholesterol (-6·7 %, P = 0·007). Additionally, fitness (6·4 %, P < 0·001) and intake of fruits and vegetables (42·4 %, P = 0·025) increased significantly. OxLDL decreased significantly after the intervention (51·0 (sd 14·0) v. 48·7 (sd 12·8) U/l, P = 0·022), while oxHDL trended towards a significant increase (395·2 (sd 94·6) v. 416·1 (sd 98·4) ng/ml, P = 0·056). CONCLUSIONS: These data support the utility of lifestyle intervention to improve the atherogenic phenotype of Latino adolescents who are at high risk for developing premature CVD and type 2 diabetes.

Pan-Asian adapted ESMO consensus guidelines for the management of patients with metastatic colorectal cancer: a JSMO-ESMO initiative endorsed by CSCO, KACO, MOS, SSO and TOS.

The most recent version of the European Society for Medical Oncology (ESMO) consensus guidelines for the treatment of patients with metastatic colorectal cancer (mCRC) was published in 2016, identifying both a more strategic approach to the administration of the available systemic therapy choices, and a greater emphasis on the use of ablative techniques, including surgery. At the 2016 ESMO Asia Meeting, in December 2016, it was decided by both ESMO and the Japanese Society of Medical Oncology (JSMO) to convene a special guidelines meeting, endorsed by both ESMO and JSMO, immediately after the JSMO 2017 Annual Meeting. The aim was to adapt the ESMO consensus guidelines to take into account the ethnic differences relating to the toxicity as well as other aspects of certain systemic treatments in patients of Asian ethnicity. These guidelines represent the consensus opinions reached by experts in the treatment of patients with mCRC identified by the Presidents of the oncological societies of Japan (JSMO), China (Chinese Society of Clinical Oncology), Korea (Korean Association for Clinical Oncology), Malaysia (Malaysian Oncological Society), Singapore (Singapore Society of Oncology) and Taiwan (Taiwan Oncology Society). The voting was based on scientific evidence and was independent of both the current treatment practices and the drug availability and reimbursement situations in the individual participating Asian countries.

SPLUNC1 degradation by the cystic fibrosis mucosal environment drives airway surface liquid dehydration.

The multi-organ disease cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane regulator gene (CFTR) that lead to diminished transepithelial anion transport. CF lungs are characterised by airway surface liquid (ASL) dehydration, chronic infection/inflammation and neutrophilia. Dysfunctional CFTR may upregulate the epithelial Na+ channel (ENaC), further exacerbating dehydration. We previously demonstrated that short palate lung and nasal epithelial clone 1 (SPLUNC1) negatively regulates ENaC in normal airway epithelia.Here, we used pulmonary tissue samples, sputum and human bronchial epithelial cells (HBECs) to determine whether SPLUNC1 could regulate ENaC in a CF-like environment.We found reduced endogenous SPLUNC1 in CF secretions, and rapid degradation of recombinant SPLUNC1 (rSPLUNC1) by CF secretions. Normal sputum, containing SPLUNC1 and SPLUNC1-derived peptides, inhibited ENaC in both normal and CF HBECs. Conversely, CF sputum activated ENaC, and rSPLUNC1 could not reverse this phenomenon. Additionally, we observed upregulation of ENaC protein levels in human CF bronchi. Unlike SPLUNC1, the novel SPLUNC1-derived peptide SPX-101 resisted protease degradation, bound apically to HBECs, inhibited ENaC and prevented ASL dehydration following extended pre-incubation with CF sputum.Our data indicate that CF mucosal secretions drive ASL hyperabsorption and that protease-resistant peptides, e.g. SPX-101, can reverse this effect to rehydrate CF ASL.

Molecular basis for pH-dependent mucosal dehydration in cystic fibrosis airways.

The ability to maintain proper airway surface liquid (ASL) volume homeostasis is vital for mucus hydration and clearance, which are essential aspects of the mammalian lung's innate defense system. In cystic fibrosis (CF), one of the most common life-threatening genetic disorders, ASL dehydration leads to mucus accumulation and chronic infection. In normal airways, the secreted protein short palate lung and nasal epithelial clone 1 (SPLUNC1) effectively inhibits epithelial Na(+) channel (ENaC)-dependent Na(+) absorption and preserves ASL volume. In CF airways, it has been hypothesized that increased ENaC-dependent Na(+) absorption contributes to ASL depletion, and hence increased disease. However, this theory is controversial, and the mechanism for abnormal ENaC regulation in CF airways has remained elusive. Here, we show that SPLUNC1 is a pH-sensitive regulator of ENaC and is unable to inhibit ENaC in the acidic CF airway environment. Alkalinization of CF airway cultures prevented CF ASL hyperabsorption, and this effect was abolished when SPLUNC1 was stably knocked down. Accordingly, we resolved the crystal structure of SPLUNC1 to 2.8 Å. Notably, this structure revealed two pH-sensitive salt bridges that, when removed, rendered SPLUNC1 pH-insensitive and able to regulate ASL volume in acidic ASL. Thus, we conclude that ENaC hyperactivity is secondary to reduced CF ASL pH. Together, these data provide molecular insights into the mucosal dehydration associated with a range of pulmonary diseases, including CF, and suggest that future therapy be directed toward alkalinizing the pH of CF airways.

Colorectal endoscopic submucosal dissection at a low-volume centre: tips and tricks, and learning curve in a district hospital in Hong Kong.

INTRODUCTION: Colorectal endoscopic submucosal dissection is not a widely adopted procedure due to its technical difficulties. This study aimed to share the experience in setting up this novel procedure and to report the learning curve for such a procedure at a low-volume district hospital in Hong Kong. METHODS: This case series comprised 71 colorectal endoscopic submucosal dissections that were performed by a single endoscopist without experience in gastric or colorectal endoscopic submucosal dissection. Lesion characteristics, procedure time per unit area of tumour, en-bloc resection rate, R0 resection rate, complications, and length of stay were recorded prospectively. Results were compared for two consecutive periods to study the learning curve. RESULTS: Overall, 41 (57.7%) tumours were located in the right colon, 21 (29.6%) in the left colon, and nine (12.7%) in the rectum. The median tumour area was 4 cm(2) (range, 0.25-16 cm(2)). The median operating time was 105 (range, 47-342) minutes. The median procedure time per unit area of tumour was 24.9 min/cm(2). There was one instance of intra-operative bleeding that required conversion to laparoscopic colectomy. There was no postoperative haemorrhage. The overall perforation rate was 15.5%, in which one required conversion to laparoscopic colectomy. The overall morbidity rate was 16.9% and there was no mortality. The median hospital stay was 1 day (range, 0-11 days). The overall en-bloc resection rate and R0 resection rate was 81.2% and 58.0%, respectively. Comparison of the two study periods revealed that procedure time per unit area of tumour decreased significantly from 31.5 min/cm(2) to 21.5 min/cm(2) (P=0.032). The en-bloc resection rate improved from 78.8% to 83.3% (P=0.15). The R0 resection rate improved significantly from 39.4% to 75.0% (P<0.01). CONCLUSION: Untutored colorectal endoscopic submucosal dissection is feasible with acceptable clinical outcomes at a low-volume district hospital in Hong Kong.

Nanotopography and plasma treatment: redesigning the surface for vascular graft endothelialisation.

INTRODUCTION: Vascular graft materials in clinical use, such as polytetrafluoroethylene (PTFE) and Dacron, do not endothelialise and have low patency rates. The importance of an endothelial cell layer on the luminal surface of a vascular graft is well-known with surface topography and chemistry playing an important role. The aim of this study was to investigate the potential of plasma treatment and topographical structures on the luminal graft surface to enhance the self-endothelialisation potential of a nanocomposite vascular graft. METHODS: POSS-PCU is a polycarbonate urea urethane (PCU) with a nanoparticle, polyhedral oligomeric silsesquioxane (POSS) incorporated within it. Planar, microgrooved, and nanopit patterned polymer films were fabricated using photolithography, electron beam lithography, reactive ion etching, and replication by solvent casting. Films were then exposed to oxygen plasma treatment at different powers for a fixed time (40 W, 60 W, 80 W/60 seconds). Effects of plasma treatment were assessed using scanning electron microscopy, atomic force microscopy and water contact angle analysis. Human umbilical vein endothelial cell (HUVEC) proliferation and morphology were characterised using immunostaining, live/dead staining, and Coomassie blue staining. RESULTS: Successful embossing of the micro- and nanostructures was confirmed. Oxygen plasma treatment of the different samples showed that increasing power significantly increased the hydrophilicity of the samples (p < .0001). Improved HUVEC adhesion was seen on plasma modified compared with untreated samples (p < .0001). Coomassie blue staining showed that after 5 days, cells started to form monolayers and live/dead staining showed the cells were viable. Immunostaining showed that HUVECs expressed nitric oxide synthase on all topographies with focal adhesions appearing more pronounced on nanopit surfaces, showing retention of morphology and function. CONCLUSION: These encouraging results indicate a future important role for plasma treatment and nanotopography in the development of endothelialised vascular grafts.

Eating in the absence of hunger in college students.

Nearly one-third of college students are overweight or obese. Disinhibited eating, a phenomenon defined as the lack of self-restraint over food consumption prompted by emotional or external factors, is prevalent among college students and may be a target for intervention in this population. Eating in the absence of hunger (EAH) is a form of disinhibited eating that has been studied extensively in children and adolescents, but there is little investigation of EAH among college students. In this research, a validated measure for assessing continual and beginning EAH in children and adolescents was modified and assessed in a free-living college population (n = 457; 84% F; 24.5 ± 7.6 years; 23.4 ± 4.8 kg/m(2)). Nine subscales grouped into three latent factors (emotion, external, and physical) accounted for 68% of the variance in continual EAH, and a separate set of nine subscales grouped into the same latent factors accounted for 71% of the variance in beginning EAH (Cronbach's alpha: 0.82 for continual EAH and 0.81 for beginning EAH). Female sex and sedentary behavior were significantly related to continual EAH, relationships driven by scores for the emotion factor, and to beginning EAH, relationships driven by scores for the physical factor. BMI was weakly related to the emotion factor (p = 0.06) for continuing EAH only. The observation that a sedentary lifestyle was associated to EAH (both continuing and beginning EAH) in a college population is a novel finding and reveals a possible strategy to moderate EAH.

Quality of life (QoL) and International Normalized Ratio (INR) control of patients attending anticoagulation clinics.

OBJECTIVES: To investigate association between quality of life (QoL) and International Normalized Ratio (INR) control, with the secondary aim of assessing QoL using generic and anticoagulation-specific, the Short Form Health Survey (SF-12) and the Duke Anticoagulation Satisfaction Scale (DASS). STUDY DESIGN: This study assessed anticoagulation related QoL at three time intervals in two groups of patients on long-term warfarin therapy. METHODS: Data of 326 randomly sampled patients (163 patients each in DASS and SF-12 groups) who had been on warfarin therapy for at least one year at anticoagulation clinics were analysed. QoL was assessed at three time intervals: at the start, six months and one year of warfarin therapy. Indications and target INR ranges and subjects INR values were recorded. Time in Therapeutic Range (TTR) was estimated for four subject subgroups, based on target ranges of INR for clustered indications. RESULTS: Of the total, 43% of the subjects were aged between 50 and 64 years, and 51% were female. DASS assessed subjects older than 35 years perceived significant decrease in overall mean scores of anticoagulation related QoL, whilst all SF-12 assessed subjects perceived an increase in QoL. The mean percentage days in range for all INR target range subgroups did not exceed more than 60% but there was only a weak correlation (Rs = 0.104, P > 0.05) between INR control and overall QoL. CONCLUSION: Malaysian urban outpatients on warfarin treatment longer than one year report a significant overall decrease in QoL, as measured using a validated condition-specific instrument. These patients appeared to adapt well to lifestyle limitations imposed by long-term anticoagulation.

Hong Kong domestic health spending: financial years 1989/90 to 2011/12.

This report presents the latest estimates of Hong Kong domestic health spending for financial years 1989/90 to 2011/12, cross-stratified and categorized by financing source, provider, and function. Total expenditure on health (TEH) was HK$101 985 million in financial year 2011/12, which represents an increase of HK$8580 million or 9.2% over the preceding year. TEH grew faster relative to gross domestic product (GDP) leading to a rise in TEH as a percentage of GDP from 5.1% in 2010/11 to 5.2% in 2011/12. During the period 1989/90 to 2011/12, total health spending per capita (at constant 2012 prices) grew at an average annual rate of 4.8%, which was faster than the average annual growth rate of per capita GDP by 1.8 percentage points. In 2011/12, public and private expenditure on health increased by 8.3% and 10.0% when compared with 2010/11, reaching HK$49,262 million and HK$52,723 million respectively. Consequently, public share of total health expenditure dropped slightly from 48.7% to 48.3% over the year. Of private spending, the most important source of health financing was out-of-pocket payments by households (34.9% of TEH), followed by employer-provided group medical benefits (7.5%) and private insurance (7.4%). It is worth noting that private insurance will likely take over employers as the second largest private payer if the insurance market continues to expand at the current rate. Of the HK$101,985 million total health expenditure in 2011/12, current expenditure comprised HK$96,572 million (94.7%), whereas HK$5413 million (5.3%) was for capital expenses (ie investment in medical facilities). Analysed by health care function, services of curative care accounted for the largest share of total health spending (65.2%), which was made up of ambulatory services (33.6%), in-patient curative care (26.9%), day patient hospital services (4.1%), and home care (0.5%). Notwithstanding its small share, the total spending for day patient hospital services shows an increasing trend over the period 1989/90 to 2011/12, likely as a result of policy directives to shift the emphasis from in-patient to day patient care. Hospitals accounted for an increasing share of total spending, from 28.2% in 1989/90 to 46.8% in 2002/03 and then dropped slightly to 42% to 44% during the period 2005/06 to 2011/12, which was primarily driven by reduced expenditure of Hospital Authority. As a result of the epidemics which are of public health importance (eg avian flu, SARS, swine flu) and the expansion of private health insurance market in the last two decades, spending on provision and administration of public health programmes, and general health administration and insurance accounted for increasing, though less significant, shares of total health spending over the period. Without taking into account capital expenses (ie investment in medical facilities), public current expenditure on health amounted to HK$45,321 million (46.9% of total current expenditure) in 2011/12 with the remaining HK$51,251 million made up of private sources of funds. Public current expenditure was mostly incurred at hospitals (74.1%), whereas private current expenditure was mostly incurred at providers of ambulatory health care (51.2%). Although both public and private spending were mostly expended on personal health care services and goods (91.1% of total current spending), the distributional patterns among functional categories differed. Public expenditure was targeted at in-patient care (47.3%) and substantially less on out-patient care (27.4%). In comparison, private spending was mostly concentrated on out-patient care (42.7%), whereas in-patient care (24.7%) and medical goods outside the patient care setting (19.9%) comprised the majority of the remaining share. Compared to the Organisation for Economic Co-operation and Development countries, Hong Kong has devoted a relatively low percentage of GDP to health care in the last decade. As a share of total spending, public funding (either general government revenue or social security funds) was also lower than those in most economies with comparable economic development and public revenue collection base. Nonetheless, Hong Kong health care system achieved service quality and health outcome that fared well by global standards, indicating cost efficiency and effectiveness.

Luminal surface engineering, 'micro and nanopatterning': potential for self endothelialising vascular grafts?

OBJECTIVE: New technologies are being explored to meet the clinical need for an 'off-the-shelf' small diameter vascular graft with superior or at least equivalent properties to autologous vessel. The field of nanotechnology and fabrication promises major advances in biomaterial design and wall structure to deliver biomimetic grafts. This review brings together recent work on this topic. METHODS: A literature search was conducted of PubMed and ISI Web of Knowledge using relevant keywords. Articles published after January 2005 were given preference. Personal communications and PhD theses were also used as sources. RESULTS: An evolving focus on surface patterning of biomaterials has been found to carry great potential. Influencing cellular behaviour on prosthetic grafts using graft luminal surface modulation at the micro- and nano-levels is the basis of this recent concept in vascular graft development. CONCLUSION: This technology may deliver small diameter grafts with the potential for spontaneous in situ endothelialisation without the need for prior 'seeding', with the potential to open a new chapter in vascular graft development.

Nonantibiotic macrolides prevent human neutrophil elastase-induced mucus stasis and airway surface liquid volume depletion.

Mucus clearance is an important component of the lung's innate defense system. A failure of this system brought on by mucus dehydration is common to both cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD). Mucus clearance rates are regulated by the volume of airway surface liquid (ASL) and by ciliary beat frequency (CBF). Chronic treatment with macrolide antibiotics is known to be beneficial to both CF and COPD patients. However, chronic macrolide usage may induce bacterial resistance. We have developed a novel macrolide, 2'-desoxy-9-(S)-erythromycylamine (GS-459755), that has significantly diminished antibiotic activity against Staphylococcus aureus, Streptococcus pneumonia, Moraxella catarrhalis, and Haemophilus influenzae. Since neutrophilia frequently occurs in chronic lung disease and human neutrophil elastase (HNE) induces mucus stasis by activating the epithelial sodium channel (ENaC), we tested the ability of GS-459755 to protect against HNE-induced mucus stasis. GS-459755 had no effect on HNE activity. However, GS-459755 pretreatment protected against HNE-induced ASL volume depletion in human bronchial epithelial cells (HBECs). The effect of GS-459755 on ASL volume was dose dependent (IC50 ~3.9 µM) and comparable to the antibacterial macrolide azithromycin (IC50 ~2.4 µM). Macrolides had no significant effect on CBF or on transepithelial water permeability. However, the amiloride-sensitive transepithelial voltage, a marker of ENaC activity, was diminished by macrolide pretreatment. We conclude that GS-459755 may limit HNE-induced activation of ENaC and may be useful for the treatment of mucus dehydration in CF and COPD without inducing bacterial resistance.

Screen-detected colorectal cancers show improved cancer-specific survival when compared with cancers diagnosed via the 2-week suspected colorectal cancer referral guidelines.

AIM: Biennial screening for colorectal cancer using faecal occult blood testing has been shown to reduce the relative risk of mortality from colorectal cancer. The Norwich screening centre commenced screening in July 2006 and so far has diagnosed over 350 patients with colorectal cancer. We compared the stage at diagnosis and cancer-specific mortality and survival in patients diagnosed through screening with a cohort of symptomatic patients with colorectal cancer within the same age range. METHOD: A comparative analysis was undertaken of all screen-detected colorectal cancer patients diagnosed between July 2006 and December 2010, with an age-matched group of patients diagnosed in the Norfolk and Norwich Hospital through the 2-week suspected colorectal cancer guidelines. RESULTS: Three hundred and fifty-six cases of colorectal cancer were diagnosed through the screening programme, in patients with an age range of 60-79 years. In the same time period, 292 patients in the same age range were diagnosed with colorectal cancer through the 2-week suspected colorectal cancer pathway. Sixteen patients in the screening group had evidence of metastatic disease at presentation compared with 62 in the symptomatic group (χ(2) , P<0.001). The proportion of T1/T2 and Dukes A cancers was significantly greater in the screening group (χ(2) , P < 0.001). There were 21 colorectal cancer-related deaths in the screening group compared with 66 in the symptomatic group. Survival analysis curves showed significantly better survival in the screening group (log-rank analysis P<0.001). CONCLUSION: Screening for colorectal cancer identifies cancers at a significantly earlier stage than in symptomatic patients, with subsequent improvement in cancer-specific survival.

Examining the relative effects of fire weather, suppression and fuel treatment on fire behaviour--a simulation study.

Large budgets are spent on both suppression and fuel treatments in order to reduce the risk of wildfires. There is little evidence regarding the relative contribution of fire weather, suppression and fuel treatments in determining the risk posed from wildfires. Here we undertake a simulation study in the Sydney Basin, Australia, to examine this question using a fire behaviour model (Phoenix Rapidfire). Results of the study indicate that fire behaviour is most strongly influenced by fire weather. Suppression has a greater influence on whether a fire reaches 5 ha in size compared to fuel treatments. In contrast, fuel treatments have a stronger effect on the fire size and maximum distance the fire travels. The study suggests that fire management agencies will receive additional benefits from fuel treatment if they are located in areas which suppression resources can respond rapidly and attempt to contain the fires. No combination of treatments contained all fires, and the proportion of uncontained fires increased under more severe fire weather when the greatest number of properties are lost. Our study highlights the importance of alternative management strategies to reduce the risk of property loss.

Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with metastatic colorectal cancer.

The European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with metastatic colorectal cancer (mCRC), published in late 2022, were adapted in December 2022, according to previously established standard methodology, to produce the Pan-Asian adapted (PAGA) ESMO consensus guidelines for the management of Asian patients with mCRC. The adapted guidelines presented in this manuscript represent the consensus opinions reached by a panel of Asian experts in the treatment of patients with mCRC representing the oncological societies of China (CSCO), Indonesia (ISHMO), India (ISMPO), Japan (JSMO), Korea (KSMO), Malaysia (MOS), the Philippines (PSMO), Singapore (SSO), Taiwan (TOS) and Thailand (TSCO), co-ordinated by ESMO and the Japanese Society of Medical Oncology (JSMO). The voting was based on scientific evidence and was independent of the current treatment practices, drug access restrictions and reimbursement decisions in the different Asian countries. The latter are discussed separately in the manuscript. The aim is to provide guidance for the optimisation and harmonisation of the management of patients with mCRC across the different countries of Asia, drawing on the evidence provided by both Western and Asian trials, whilst respecting the differences in screening practices, molecular profiling and age and stage at presentation, coupled with a disparity in the drug approvals and reimbursement strategies, between the different countries.

Cleavage of endogenous γENaC and elevated abundance of αENaC are associated with increased Na⁺ transport in response to apical fluid volume expansion in human H441 airway epithelial cells.

Using human H441 airway epithelial cells cultured at air-liquid interface (ALI), we have uniquely correlated the functional response to apical fluid volume expansion with the abundance and cleavage of endogenous α- and γENaC proteins in the apical membrane. Monolayers cultured at ALI rapidly elevated I (sc) when inserted into fluid-filled Ussing chambers. The increase in I (sc) was not significantly augmented by the apical addition of trypsin, and elevation was abolished by the protease inhibitor aprotinin and an inhibitor of the proprotein convertase, furin. These treatments also increased the IC50 amiloride indicating that the effect was via inhibition of highly Na⁺-selective ENaC channels. Apical fluid, 5-500 µl for 1 h in culture, increased the spontaneous starting I (sc) in a dose-dependent manner, whilst maximal fluid-induced I (sc) in the Ussing chamber was unchanged. Apical fluid expansion increased the abundance of 63-65-kDa αENaC proteins in the apical membrane. However, this could not be attributed to increased cleavage as protease inhibitors had no effect on the ratio of cleaved to non-cleaved (90 kDa) αENaC proteins. Instead, fluid expansion increased αENaC abundance in the membrane. In contrast, function correlated well with γENaC cleavage at known sites by furin and extracellular proteases. Interestingly, cleavage of γENaC was associated with increased retrieval from the membrane via the proteosomal pathway. Thus, the response to apical fluid volume expansion in H441 airway epithelial cells involves cleavage of γENaC, and changes in α- and γENaC protein abundance at the apical membrane.