Impact of a novel pre-hospital stroke notification programme on acute stroke care key performance indicators in Hong Kong: a multicentre prospective cohort study with historical controls.

INTRODUCTION: Early identification and initiation of reperfusion therapy is essential for suspected acute ischaemic stroke. A pre-hospital stroke notification (PSN) protocol using FASE (facial drooping, arm weakness, speech difficulties, and eye palsy) was implemented to improve key performance indicators (KPIs) in acute stroke care delivery. We assessed KPIs and clinical outcomes before and after PSN implementation in Hong Kong. METHODS: This prospective cohort study with historical controls was conducted in the Accident and Emergency Departments of four public hospitals in Hong Kong. Patients were screened using the PSN protocol between August 2021 and February 2022. Suspected stroke patients between August 2020 and February 2021 were included as historical controls. Door-to-needle (DTN) and door-to-computed tomography (DTC) times before and after PSN implementation were compared. Clinical outcomes including National Institutes of Health Stroke Scale score at 24 hours and modified Rankin Scale score at 3 months after intravenous recombinant tissue-type plasminogen activator (IV-rtPA) were also assessed. RESULTS: Among the 715 patients (266 PSN and 449 non-PSN) included, 50.8% of PSN patients and 37.7% of non-PSN patients had a DTC time within 25 minutes (P<0.001). For the 58 PSN and 134 non-PSN patients given IV-rtPA, median DTN times were 67 and 75.5 minutes, respectively (P=0.007). The percentage of patients with a DTN time within 60 minutes was higher in the PSN group than in the non-PSN group (37.9% vs 21.6%; P=0.019). No statistically significant differences in clinical outcomes were observed. CONCLUSION: Although the PSN protocol shortened DTC and DTN times, clinical outcomes did not significantly differ.

Clinical Recommendations for the use of Neurotropic B vitamins (B1, B6, and B12) for the Management of Peripheral Neuropathy: Consensus from a Multidisciplinary Expert Panel.

INTRODUCTION: Peripheral neuropathy (PN) is an insidious disease that is often asymptomatic during the early stages but which can have a significant impact on quality of life at later stages when nerve damage occurs. There is currently no guidance on the use of neurotropic B vitamins (B1, B6, and B12) for the management of asymptomatic and symptomatic PN. OBJECTIVE: To provide guidance to primary care physicians on an integrated approach to managing PN with neurotropic B vitamins (B1, B6, and B12). MATERIALS AND METHODS: A multidisciplinary panel of eight experts participated in an iterative quasi-anonymous Delphi survey consisting of two rounds of questions and a virtual meeting. A literature review formed the basis of the survey questions. The first round included multiple select, qualitative, and Likert Scale questions; the subsequent round consisted of 2-point scale (agree or disagree) questions that sought to develop consensus-based statements refined from the first round and recommendations derived from discussions during the virtual expert panel meeting. RESULTS: Clinical recommendations for the use of neurotropic B vitamins (B1, B6, and B12) have been developed for the prevention of PN progression or to delay onset in patients at high risk of developing PN. Recommendations have also been provided for the assessment of PN etiology and considerations for the use of loading dose (high dose) and maintenance dose (lower dose) of these neurotropic B vitamins (B1, B6, and B12). CONCLUSION: These clinical recommendations provide an initial step towards formulating comprehensive guidelines for the early and long-term management of PN with neurotropic B vitamins (B1, B6, and B12) and move beyond addressing only neuropathic pain associated with the late stages of PN.

Incidence and trends of nosocomial infection in a tertiary general hospital in China from 2018 to 2021: a retrospective observational study.

OBJECTIVE: This study aimed to investigate the current status and changing trend of nosocomial infection in a tertiary general hospital in China, to provide a reference for the prevention and control of healthcare-associated/acquired infection (HAI). PATIENTS AND METHODS: A retrospective investigation of the clinical data of HAI patients in Dongying People's Hospital in China from January 1, 2018, to December 31, 2021, was carried out. The incidence of HAI in different units and sites, distribution of pathogenic microorganisms, and antimicrobial use were investigated. RESULTS: The incidence of HAI was 0.93%. It was on the rise from 2018 to 2020 but declined in 2021. The departments with the highest rate of HAI were the Intensive Care Unit (ICU), neurosurgery department, cardiothoracic surgery department, and hematology department. HAI often occurs in the lower respiratory tract, urinary tract, and in blood. The most common pathogenic microorganisms in cases of HAI were Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannii, and Staphylococcus aureus. The rate of bacterial culture delivery for therapeutic drugs has increased from year to year. CONCLUSIONS: This study shows that the incidence of HAI in the hospital is generally low. Gram-negative bacteria are still the main source of HAI. The rate of bacterial culture delivery for therapeutic use improved over the years and has gradually been standardized. It is necessary to focus on the management of HAI in the ICU, neurosurgery, cardiothoracic surgery, and hematology departments.

Study on the effects of arm abduction angle and cushion support during sonographic examination on the stiffness of supraspinatus muscle of sonographers using shear wave elastography.

OBJECTIVES: The incidence of work-related musculoskeletal disorder remains high in sonography. The aims of this study are to determine the changes in muscle stiffness with different arm abduction angles, and to investigate the effect of cushion support on reducing muscle load in the supraspinatus when sonographers scan with the arm abducted to different angles. METHODS: This is a prospective crossover study. Twenty-three healthy female subjects aged between 20 and 23 years were included. Subjects were instructed to simulate performing standardized abdominal ultrasound scans. The changes in muscle stiffness of supraspinatus, measured as shear modulus, at rest and at 30°, 45°, and 60° arm abduction angles with and without cushion support were evaluated using shear-wave elastography. Styrofoam support was used for the cushion support. RESULTS: Mean shear moduli of supraspinatus were 27.77 ± 5.84 kPa at rest and 41.63 ± 7.09 kPa, 63.88 ± 14.43 kPa, and 89.76 ± 16.55 kPa for 30°, 45°, and 60° arm abduction respectively, which corresponds to 53%, 116% increase in muscle stiffness when scanning arm abducted from 30° to 45° and 60° (p < .001). After applying cushion support, shear moduli dropped to 24.04 ± 5.60 kPa, 31.98 ± 6.06 kPa, 37.47 ± 5.61 kPa for arm abducted to 30°, 45°, and 60° respectively (p < .001). The muscle stiffnesses between 30° abduction without support and 60° abduction with support had no significant difference (p > .05). CONCLUSIONS: Muscle stiffness of supraspinatus increased with increasing arm abduction angle during ultrasound scanning. Utilizing cushion support underneath the arm was effective in reducing muscle stiffness in supraspinatus. Our results provide scientific justification on postural modifications for sonographers.

Alanine metabolism in Bacillus subtilis.

Both isomeric forms of alanine play a crucial role in bacterial growth and viability; the L-isomer of this amino acid is one of the building blocks for protein synthesis, and the D-isomer is incorporated into the bacterial cell wall. Despite a long history of genetic manipulation of Bacillus subtilis using auxotrophic markers, the genes involved in alanine metabolism have not been characterized fully. In this work, we genetically characterized the major enzymes involved in B. subtilis alanine biosynthesis and identified an alanine permease, AlaP (YtnA), which we show has a major role in the assimilation of D-alanine from the environment. Our results provide explanations for the puzzling fact that growth of B. subtilis does not result in the significant accumulation of extracellular D-alanine. Interestingly, we find that in B. subtilis, unlike E. coli where multiple enzymes have a biochemical activity that can generate alanine, the primary synthetic enzyme for alanine is encoded by alaT, although a second gene, dat, can support slow growth of an L-alanine auxotroph. However, our results also show that Dat mediates the synthesis of D-alanine and its activity is influenced by the abundance of L-alanine. This work provides valuable insights into alanine metabolism that suggests that the relative abundance of D- and L-alanine might be linked with cytosolic pool of D and L-glutamate, thereby coupling protein and cell envelope synthesis with the metabolic status of the cell. The results also suggest that, although some of the purified enzymes involved in alanine biosynthesis have been shown to catalyze reversible reactions in vitro, most of them function unidirectionally in vivo.

Epidemiology of surgically treated patient in road traffic accident with lower extremity vascular injury from a single centre in Kelantan.

INTRODUCTION: Lower extremity vascular injury can result in either temporary or permanent disability. METHODS: This is a clinical audit involving all patients admitted to our institution from January 2008 to June 2018 of those who had undergone revascularization surgery for lower limb trauma. RESULTS: Fifty-nine patients were in this study with a mean age of 28.1 years. Most of the patients were motorcyclist involved in road traffic accidents with cars (n=30, 50.8%). The popliteal artery was most commonly seen injury (n=41, 69.5%). The mean duration of ischaemia was 14.1 hours. The limb salvage rate was 89.8%. CONCLUSION: Lower extremity vascular injury caused by RTA treated in our institution predominantly involved young patients aged between 18-30 years associated with long bone fractures causing contusion and thrombosis of the popliteal artery.

Development of a nomogram for the estimation of long-term adherence to clozapine therapy using neutrophil fluorescence.

AIMS: Previously, we have reported an association between clozapine use and elevated FL3 neutrophil fluorescence, a flow-cytometric parameter for cell viability. Here, we developed and evaluated a pharmacokinetic-pharmacodynamic model relating FL3-fluorescence to clozapine exposure and derived a nomogram for estimation of long-term adherence. METHODS: Data from 27 patients initiating clozapine were analysed using nonlinear mixed effects modelling. A previously described pharmacokinetic model for clozapine was coupled to a FL3 fluorescence model. For this, an effect compartment with clozapine concentrations as input and a first order decay rate as output was linked with an Emax model to FL3-fluorescence. FL3-fluorescence was simulated for clozapine doses of 50, 150 and 400 mg daily (n = 10 000) to establish the nomogram. Finally, true simulated adherence (% of daily doses taken over 100 days) was compared to nomogram-estimated adherence to evaluate the performance of the nomogram. RESULTS: The half-life of FL3-fluorescence was estimated at 228 h (coefficient of variation 35%). Median absolute prediction errors of the nomogram in case of fully random adherence for 50, 150 and 400 mg ranged from -0.193% to -0.525%. The nomogram performed slightly worse in case of nonrandom adherence (median prediction error up to 5.19%), but was still clinically acceptable. Compliance patterns containing longer drug holidays revealed that the nomogram adequately estimates compliance over approximately the last 3 weeks prior to FL3-measurement. CONCLUSION: Our nomogram could provide information regarding long-term adherence based on prescribed clozapine dose and FL3-fluorescence. Future studies should further explore the clinical value of this biomarker and nomogram.

Impact of infant pneumococcal conjugate vaccination on community acquired pneumonia hospitalization in all ages in the Netherlands.

BACKGROUND: The long-term impact of pneumococcal conjugate vaccines on pneumonia hospitalizations in all age-groups varies between countries. In the Netherlands, the 7-valent pneumococcal conjugate vaccine (PCV7) was implemented for newborns in 2006 and replaced by PCV10 in 2011. We assessed the impact of PCVs on community-acquired pneumonia (CAP) hospitalization rates in all age-groups. METHODS: A time series analysis using Poisson regression was performed on 155,994 CAP hospitalizations. Hospitalization rates were calculated using the total number of hospitalizations as denominator. The time trend in the pre-PCV period (1999-2006) was extrapolated to predict the hospitalization rate in the post-PCV period (2006-2014) if PCV had not been implemented. Rate ratios over time were calculated by comparing observed and predicted time trends. RESULTS: In children <5 years of age, the observed hospitalization rates during the post-PCV period were significantly lower than predicted if PCV had not been implemented (0-6 months: 0.62, 95% CI: 0.41-0.96; 6 months - 1 year: 0.67, 95% CI: 0.50-0.90; 2-4 years: 0.78, 95% CI: 0.61-0.97). In all other age-groups, rate ratios declined over time but did not reach statistical significance. CONCLUSIONS: After introduction of PCV, CAP hospitalizations declined in young children but no clear impact of PCV on CAP hospitalizations was seen in other age-groups.

Venous, Arterialized-Venous, or Capillary Glucose Reference Measurements for the Accuracy Assessment of a Continuous Glucose Monitoring System.

BACKGROUND: Different reference methods are used for the accuracy assessment of continuous glucose monitoring (CGM) systems. The effect of using venous, arterialized-venous, or capillary reference measurements on CGM accuracy is unclear. METHODS: We evaluated 21 individuals with type 1 diabetes using a capillary calibrated CGM system. Venous or arterialized-venous reference glucose samples were taken every 15 min at two separate visits and assessed per YSI 2300 STAT Plus. Arterialization was achieved by heated-hand technique. Capillary samples were collected hourly during the venous reference visit. The investigation sequence (venous or arterialized-venous) was randomized. Effectiveness of arterialization was measured by comparing free venous oxygen pressure (PO2) of both visit days. Primary endpoint was the median absolute relative difference (ARD). RESULTS: Median ARD using arterialized-venous reference samples was not different from venous samples (point estimated difference 0.52%, P = 0.181). When comparing the three reference methods, median ARD was also not different over the full glycemic range (venous 9.0% [n = 681], arterialized-venous 8.3% [n = 684], and capillary 8.1% [n = 205], P = 0.216), nor over the separate glucose ranges. Arterialization was successful (PO2 venous 5.4 kPa vs. arterialized-venous 8.9 kPa, P < 0.001). Arterialized-venous glucose was significantly higher than venous glucose and numerically higher than capillary glucose (arterialized-venous 142 mg/dL vs. venous 129 mg/dL [P < 0.001] and vs. capillary 134 mg/dL [P = 0.231]). Inconvenience related to arterialization included transient mild edema and redness of the hand in 4 out of 21 (19%) patients. CONCLUSIONS: The use of venous, arterialized-venous, or capillary reference measurements did not significantly impact CGM accuracy. Venous reference seems preferable due to its ease of operation.

Insight into the Endocrine System and the Immune System: A Review of the Inflammatory Role of Prolactin in Rheumatoid Arthritis and Psoriatic Arthritis.

Rheumatoid arthritis (RA) is a chronic autoimmune disease that affects females three times more frequently than males. A potential role for hormones, such as prolactin (PRL), may in part explain this phenomenon. The risk of developing RA is increased in women who are lactating after the first pregnancy, which might be related to breastfeeding and the release of PRL. Other studies found a protective effect of PRL on RA development. Some studies have reported that hyperprolactinemia is more common in RA and serum PRL levels are correlated with several disease parameters, although others could not confirm these findings. Overall the plasma PRL levels are on average not elevated in RA. Previously, a small number of open-label clinical trials using bromocriptine, which indirectly decreases PRL levels, were performed in RA patients and showed clinical benefit, although others found the opposite effect. Locally produced PRL at the site of inflammation may have a crucial role in RA as well, as it has been shown that PRL can be produced by synovial macrophages. Locally produced PRL has both pro-inflammatory and anti-inflammatory effects in arthritis. Psoriatic arthritis (PsA) is also an autoinflammatory disease, in which the prolactin receptor is also expressed in macrophages. The aim of this review is to provide an overview of the potential role of PRL signaling in inflammatory joint diseases (RA and PsA) and its potential as a therapeutic target.

[Investigation on epidemic status of clonorchiasis sinensis based on inpatients in Zhongshan City, China].

Objective To understand the prevalence and epidemiological features of clonorchiasis sinensis based on inpatients in Zhongshan City. Methods All of the 23 town hospitals in Zhongshan City were selected as the surveillance hospitals in 2016. Among the inpatients from those hospitals, those lived in the city longer than 6 months were selected as the surveillance subjects. The stool specimens of the subjects were collected and examined by the modified Kato-Katz thick smear method for the eggs of Clonorchis sinensis. The crude infection rates of C. sinensis of the subjects were standardized according to the age and sex compositions of the population in Zhongshan City, 2016. Meanwhile, the infection rates of the subjects from different towns and those combined with related clinical diseases were analyzed. Results A total of 2 667 people were included in the surveillance, among which 219 were tested as positives, with a crude infection rate of 8.21%. For the positives, the male accounted for 81.74% (179/219), and their age ranged from 4 to 89 years with the mean value of (62.20±13.80) years. After standardization by age and sex composition, the infection rate was 3.62% for the whole population, the rates of the male and the female were 5.46% and 1.53%, respectively, and the former was 3.57 times as high as the latter. Both the infection rates of the male and the female rose as the age increasing (χ2male = 99.91, χ2female = 16.51, both P < 0.01). The standardized infection rates among the subjects in different towns ranged from 0 to 10.40%, and the rates in the north towns were higher than those in the south towns. The standardized rate was 9.22% for the subjects combined with gallstone, 3.40% for those not combined with gallstone, and the former was 2.71 times as high as that of the latter. Conclusion The people aged 30 years and above, with gallstone or living in towns with high C. sinensis infection rates are the key population for prevention and control of clonorchiasis in Zhongshan City.

Patient compliance with cervical smear surveillance in a shared-care setting.

OBJECTIVE: To examine patient compliance with cervical smear surveillance at a primary care center. METHODS: A retrospective study included data from patients referred from a tertiary center, to a University of Hong Kong primary care center following colposcopy for continuing cervical smear surveillance between January 1, 2005 and December 31, 2006. Patient records were reviewed and details of the initial screening or treatment that led to referral and the three subsequent follow-up screenings were examined. A multivariate analysis was performed to identify factors that were associated with increased odds of patients not attending follow-up screening. RESULTS: In total, records from 833 patients were included. Of these patients, 348 (41.8%) failed to attend at least one screening, with 172 (49.4%) of this group attending after being reminded. The compliance rate prior to patients being reminded of screening follow-up decreased across the three follow-up screenings, with 706 (84.8%) patients attending their first follow-up visit and 561 (67.3%) patients attending the third. In the multivariate analysis, being younger than 50years old, having a history of smoking, and not having undergone medical treatment related to cervical cancer screening previously were associated with increased odds of not attending follow-up screening (all P<0.05). CONCLUSION: Patients at increased risk of non-compliance with screening follow-up should receive particular attention and counselling regarding screening.

Klotho and smoking--An interplay influencing the skeletal muscle function deficits that occur in COPD.

BACKGROUND: Klotho is an 'anti-ageing' hormone and transmembrane protein; Klotho deficient mice develop a similar ageing phenotype to smokers including emphysema and muscle wasting. The objective of this study was to evaluate skeletal muscle and circulating Klotho protein in smokers and COPD patients and to relate Klotho levels to relevant skeletal muscle parameters. We sought to validate our findings by undertaking complimentary murine studies. METHODS: Fat free mass, quadriceps strength and spirometry were measured in 87 participants (61 COPD, 13 'healthy smokers' and 13 never smoking controls) in whom serum and quadriceps Klotho protein levels were also measured. Immunohistochemistry was performed to demonstrate the location of Klotho protein in human skeletal muscle and in mouse skeletal muscle in which regeneration was occurring following injury induced by electroporation. In a separate study, gastrocnemius Klotho protein was measured in mice exposed to 77 weeks of smoke or sham air. RESULTS: Quadriceps Klotho levels were lower in those currently smoking (p = 0.01), irrespective of spirometry, but were not lower in patients with COPD. A regression analysis identified current smoking status as the only independent variable associated with human quadriceps Klotho levels, an observation supported by the finding that smoke exposed mice had lower gastrocnemius Klotho levels than sham exposed mice (p = 0.005). Quadriceps Klotho levels related to local oxidative stress but were paradoxically higher in patients with established muscle wasting or weakness; the unexpected relationship with low fat free mass was the only independent association. Within locomotor muscle, Klotho localized to the plasma membrane and to centralized nuclei in humans and in mice with induced muscle damage. Serum Klotho had an independent association with quadriceps strength but did not relate to quadriceps Klotho levels or to spirometric parameters. CONCLUSIONS: Klotho is expressed in skeletal muscle and levels are reduced by smoking. Despite this, quadriceps Klotho protein expression in those with established disease appears complex as levels were paradoxically elevated in COPD patients with established muscle wasting. Whilst serum Klotho levels were not reduced in smokers or COPD patients and were not associated with quadriceps Klotho protein, they did relate to quadriceps strength.

The health of parents with and without intellectual impairment in the UK.

BACKGROUND: Little is known about the health and well-being of the 'hidden majority' of parents with mild intellectual disability (ID), who are less likely to be in contact with disability services. METHOD: We sought to add to knowledge in this area by examining the health and living conditions of parents with and without intellectual impairment in a large contemporary nationally representative sample of UK parents aged between 16 and 49 years old (n = 14 371). RESULTS: Our results indicated that, as expected, parents with intellectual impairment were at significantly greater risk than other parents of having poorer self-reported general, mental and physical health. They were also at significantly greater risk of experiencing higher rates of household socio-economic disadvantage and environmental adversities and lower rates of neighbourhood social capital and intergenerational support. Adjusting risk estimates to take account of between group differences in household socio-economic disadvantage eliminated statistically significant differences in health status between parents with and without intellectual impairment on all but one indicator (obesity). Further adjusting risk estimates to take account of between group differences in neighbourhood adversity, neighbourhood social capital and intergenerational support had minimal impact on the results. CONCLUSIONS: That controlling for between-group differences in exposure to socio-economic disadvantage largely eliminated evidence of poorer health among parents with intellectual impairment is consistent with the view that a significant proportion of the poorer health of people with IDs may be attributable to their poorer living conditions rather than biological factors associated with ID per se.

Joint Estimation of Hydraulic and Poroelastic Parameters from a Pumping Test.

The coupling of hydraulic and poroelastic processes is critical in predicting processes involving the deformation of the geologic medium in response to fluid extraction or injection. Numerical models that consider the coupling of hydraulic and poroelastic processes require the knowledge of relevant parameters for both aquifer and aquitard units. In this study, we jointly estimated hydraulic and poroelastic parameters from pumping test data exhibiting "reverse water level fluctuations," known as the Noordbergum effect, in aquitards adjacent to a pumped aquifer. The joint estimation was performed by coupling BIOT2, a finite element, two-dimensional, axisymmetric, groundwater model that considers poroelastic effects with the parameter estimation code PEST. We first tested our approach using a synthetic data set with known parameters. Results of the synthetic case showed that for a simple layered system, it was possible to reproduce accurately both the hydraulic and poroelastic properties for each layer. We next applied the approach to pumping test data collected at the North Campus Research Site (NCRS) on the University of Waterloo (UW) campus. Based on the detailed knowledge of stratigraphy, a five-layer system was modeled. Parameter estimation was performed by: (1) matching drawdown data individually from each observation port and (2) matching drawdown data from all ports at a single well simultaneously. The estimated hydraulic parameters were compared to those obtained by other means at the site yielding good agreement. However, the estimated shear modulus was higher than the static shear modulus, but was within the range of dynamic shear modulus reported in the literature, potentially suggesting a loading rate effect.

Effects of the consumption of rice from non-KBD areas and selenium supplementation on the prevention and treatment of paediatric Kaschin-Beck disease: an epidemiological intervention trial in the Qinghai Province.

OBJECTIVE: Based on the aetiological hypothesis of Kaschin-Beck disease (KBD), different interventions were adopted, and the preventive and therapeutic effects of interventions was observed and evaluated in this trial. DESIGN: A total of 358 children from seven villages of Qinghai Province in China were examined, and 280 children aged 6-11 years old were eligible for the trial. The children were divided into three groups that received either no intervention (n = 64), 150 kg/person of rice from non-KBD areas (n = 103) or 7 kg/family of selenium-iodine salt (n = 113) for 12 months. Data were collected and used to calculate the proportion of patients with X-ray lesions, the proportion of new patients and the metaphyseal repair rate. All indicators were analysed with Pearson chi-square or Fisher's exact tests. The registration number of this trial is ChiCTR-PNRC-12002309 (http://www.chictr.org). RESULTS: After interventions, the proportion of patients with X-ray lesions increased dramatically in the control group and decreased significantly in two intervention groups; significant differences were seen between the control group and two intervention groups (P < 0.05). Moreover, significant differences were observed in the proportions of new patients and the metaphyseal repair rates between the control group and two intervention groups (P < 0.05). Additionally, the proportion of new patients was lowest and the metaphyseal repair rate was highest in group B. CONCLUSIONS: The effects of eating rice from non-KBD areas and selenium supplementation on the prevention and treatment of paediatric KBD were notable, the consumption of rice might be the most effective and safest intervention and should be encouraged.

Heterogeneous expression pattern of interleukin 17A (IL-17A), IL-17F and their receptors in synovium of rheumatoid arthritis, psoriatic arthritis and osteoarthritis: possible explanation for nonresponse to anti-IL-17 therapy?

INTRODUCTION: Accumulating evidence suggests an important role for interleukin 17 (IL-17) in the pathogenesis of several inflammatory diseases, including rheumatoid arthritis (RA) and psoriatic arthritis (PsA). Accordingly, clinical trials aimed at blocking IL-17 have been initiated, but clinical results between patients and across different diseases have been highly variable. The objective was to determine the variability in expression of IL-17A, IL-17F and their receptors IL-17RA and IL-17RC in the synovia of patients with arthritis. METHODS: Synovial biopsies were obtained from patients with RA (n = 11), PsA (n = 15) and inflammatory osteoarthritis (OA, n = 14). For comparison, synovia from noninflamed knee joints (n = 7) obtained from controls were included. Frozen sections were stained for IL-17A, IL-17F, IL-17RA and IL-17RC and evaluated by digital image analysis. We used confocal microscopy to determine which cells in the synovium express IL-17A and IL-17F, double-staining with CD4, CD8, CD15, CD68, CD163, CD31, von Willebrand factor, peripheral lymph node address in, lymphatic vessel endothelial hyaluronan receptor 1, mast cell tryptase and retinoic acid receptor-related orphan receptor γt (RORγt). RESULTS: IL-17A, IL-17F, IL-17RA and IL-17RC were abundantly expressed in synovial tissues of all patient groups. Whereas IL-17RA was present mostly in the synovial sublining, IL-17RC was abundantly expressed in the intimal lining layer. Digital image analysis showed a significant (P < 0.05) increase of only IL-17A in arthritis patients compared to noninflamed control tissues. The expression of IL-17A, IL-17F and their receptors was similar in the different patient groups, but highly variable between individual patients. CD4+ and CD8+ cells coexpressed IL-17A, and few cells coexpressed IL-17F. IL-17A and IL-17F were not expressed by CD15+ neutrophils. Mast cells were only occasionally positive for IL-17A or IL-17F. Interestingly, IL-17A and IL-17F staining was also observed in macrophages, as well as in blood vessels and lymphatics. This staining probably reflects receptor-bound cytokine staining. Many infiltrated cells were positive for the transcription factor RORγt. Colocalisation between RORγt and IL-17A and IL-17F indicates local IL-17 production. CONCLUSIONS: Increased expression of IL-17A is not restricted to synovial tissues of RA and PsA patients; it is also observed in inflammatory OA. The heterogeneous expression levels may explain nonresponse to anti-IL-17 therapy in subsets of patients.

p53 deficiency enhances mitotic arrest and slippage induced by pharmacological inhibition of Aurora kinases.

A number of small-molecule inhibitors of Aurora kinases have been developed and are undergoing clinical trials for anti-cancer therapies. Different Aurora kinases, however, behave as very different targets: while inhibition of Aurora A (AURKA) induces a delay in mitotic exit, inhibition of Aurora B (AURKB) triggers mitotic slippage. Furthermore, while it is evident that p53 is regulated by Aurora kinase-dependent phosphorylation, how p53 may in turn regulate Aurora kinases remains mysterious. To address these issues, isogenic p53-containing and -negative cells were exposed to classic inhibitors that target both AURKA and AURKB (Alisertib and ZM447439), as well as to new generation of inhibitors that target AURKA (MK-5108), AURKB (Barasertib) individually. The fate of individual cells was then tracked with time-lapse microscopy. Remarkably, loss of p53, either by gene disruption or small interfering RNA-mediated depletion, sensitized cells to inhibition of both AURKA and AURKB, promoting mitotic arrest and slippage respectively. As the p53-dependent post-mitotic checkpoint is also important for preventing genome reduplication after mitotic slippage, these studies indicate that the loss of p53 in cancer cells represents a major opportunity for anti-cancer drugs targeting the Aurora kinases.

Cholera risk factors, Papua New Guinea, 2010.

BACKGROUND: Cholera is newly emergent in Papua New Guinea but may soon become endemic. Identifying the risk factors for cholera provides evidence for targeted prevention and control measures. METHODS: We conducted a hospital-based case-control study to identify cholera risk factors. Using stool culture as the standard, we evaluated a cholera point of care test in the field. RESULTS: 176 participants were recruited: 54 cases and 122 controls. Independent risk factors for cholera were: being over 20 years of age (aOR 2.5; 95%CI 1.1, 5.4), defecating in the open air (or river) (aOR 4.5; 95% CI 1.4, 14.4) and knowing someone who travelled to a cholera affected area (aOR 4.1; 95%CI 1.6, 10.7); while the availability of soap for handwashing at home was protective (aOR 0.41; 95%CI 0.19, 0.87). Those reporting access to a piped water distribution system in the home were twice as likely to report the availability of soap for handwashing. The sensitivity and specificity of the rapid test were 72% (95% CI 47-90) and 71% (95%CI 44-90%). CONCLUSIONS: Improving population access to the piped water distribution system and sanitation will likely reduce transmission by enabling enhanced hygiene and limiting the contamination of water sources. The One step V. cholerae O1/O139 Antigen Test is of limited utility for clinical decision making in a hospital setting with access to traditional laboratory methods. Settlement dwellers and mobile populations of all age groups should be targeted for interventions in Papua New Guinea.