A synthetic small-molecule Isoxazole-9 protects against methamphetamine relapse.

Adult neurogenesis in the dentate gyrus (DG) is strongly influenced by drug-taking behavior and may have a role in the etiology of drug-seeking behavior. However, mechanistic studies on the relationship of neurogenesis on drug seeking are limited. Outbred Wistar rats experienced extended access methamphetamine self-administration and individual differences in drug taking defined animals with higher preferred and lower preferred levels of drug intake. Forced abstinence from higher preferred levels of drug taking enhanced neurogenesis and neuronal activation of granule cell neurons (GCNs) in the DG and produced compulsive-like drug reinstatement. Systemic treatment with the drug Isoxazole-9 (a synthetic small molecule known to modulate neurogenesis in the adult rodent brain) during abstinence blocked compulsive-like context-driven methamphetamine reinstatement. Isoxazole-9 modulated neurogenesis, neuronal activation and structural plasticity of GCNs, and expression of synaptic proteins associated with learning and memory in the DG. These findings identify a subset of newly born GCNs within the DG that could directly contribute to drug-seeking behavior. Taken together, these results support a direct role for the importance of adult neurogenesis during abstinence in compulsive-like drug reinstatement.

The effect of increasing body mass index on laparoscopic surgery for colon and rectal cancer.

AIM: Obesity is common in Western countries and its prevalence is increasing. Colorectal cancer is common, and surgery for colorectal cancer is technically more challenging in obese patients. Laparoscopic surgery for colon cancer has been shown to be oncologically equivalent, with improved short- term outcomes. Laparoscopic surgery for rectal cancer has proven technically challenging, and recent results have raised concerns about oncological equivalence. Our aim was to evaluate the effect of body mass index (BMI) on the clinical and oncological outcomes of surgery for colorectal cancer, including the rate at which laparoscopic surgery is attempted and the rate at which laparoscopic surgery is converted to open surgery. METHOD: A retrospective analysis of prospectively collected data from two tertiary institutions was performed. Data were obtained from the Cabrini Monash University colorectal neoplasia database for patients having surgical resection for colon and rectal cancers between 1 January 2010 and 30 June 2015. Surgical and medical complications, tumour recurrence and overall survival and laparoscopic surgery and conversion rates were investigated. RESULTS: This large case series of 1464 patients undergoing elective surgery for colorectal cancer has demonstrated that an elevated BMI is associated with a lower likelihood of attempting laparoscopic surgery and a higher conversion rate to open surgery when laparoscopy is attempted. Conversion was 1.9 times more likely in obese patients with colon cancer and 4.1 times more likely in obese patients with rectal cancer. The critical BMI for colon cancer patients was > 35 kg/m2 , and for rectal cancer patients > 30 kg/m2 . Obesity is also associated with increased rates of surgical complications, including anastomotic leakage and wound complications. Pathological parameters, tumour recurrence and survival were not affected by elevated BMI. CONCLUSION: In the surgical management of colorectal cancer, obesity is associated with a lower likelihood of laparoscopic surgery being attempted, a higher likelihood of conversion to open surgery when laparoscopic surgery is attempted, and a higher rate of surgical complications.

Characterisation of invasive clinical Haemophilus influenzae isolates in Queensland, Australia using whole-genome sequencing.

Haemophilus influenzae is an important aetiological organism of both adult and child respiratory disease. The number of non-typeable (NTHi) invasive H. influenzae isolates referred to the Queensland (QLD) Public Health Microbiology laboratory has increased notably year-by-year. In this study we used whole-genome sequencing to molecularly characterise 100 referred invasive H. influenzae, including 74 NTHi isolates over a 15-year period, observing the carriage of capsular and putative virulence genes, including the major adhesins, antimicrobial resistance genes and population diversity. Encapsulated isolates were largely clonal, however NTHi isolates displayed high genetic variability by MLST and single nucleotide polymorphism typing with no dominant clone observed. The only mechanism for ß-lactam resistance identified in the QLD isolates was ß-lactamase production. No single set of virulence determinants was conclusively associated with invasive QLD NTHi isolates.

The impact of intensive care in a private hospital on patients aged 80 and over: health-related quality of life, functional status and burden versus benefit.

BACKGROUND: Greater numbers of persons aged over 80 years are admitted to intensive care units (ICU) compared with 15 years ago. Outcomes other than death such as physical dependence and cognitive impairment and treatment burden are important to older people. AIMS: The aims of this study were to determine the long-term outcomes of functional impairment, health-related quality of life (HRQoL) and the self-reported burden of treatment in a sample of patients aged 80 years and above admitted to ICU. Half of the cohort were admitted for elective cardiac surgery, the rest for non-cardiac surgery and medical conditions. METHODS: In this longitudinal cohort study, in a tertiary level ICU, we measured HRQoL using the SF-36 and functional status using the modified Barthel Index at several time points over a 2-year follow-up period. We also assessed treatment burden by asking participants whether they thought the episode of care was worthwhile. RESULTS: A total of 348 patients was recruited into the study. One-fifth of the cohort had died by the 2-year follow-up data collection point. There was an improvement in physical functioning in the cardiac surgery group at 6 months which was not sustained. There was no change in HRQoL at 2 years in either group. The majority valued the episode of care. CONCLUSION: We demonstrated that HRQoL and previous lifestyle is preserved in the majority following ICU admission, associated with a high level of patient valuation of the episode of care.

Molecular characterization of an Australian serotype 1 Streptococcus pneumoniae outbreak.

Serotype 1 Streptococcus pneumoniae is a cause of invasive pneumococcal disease (IPD) worldwide and has been associated with IPD outbreaks, while carriage is rarely detected in healthy adults or children. This study details an Australian multi-state and territory outbreak of serotype 1 S. pneumoniae IPD between 2010 and 2012. Molecular characterization demonstrated the outbreak was largely due to the clonal expansion of sequence type 306, MLVA type 261 S. pneumoniae serotype 1.

Risk factors for herpes zoster in rheumatoid arthritis patients: the role of tumour necrosis factor-α inhibitors.

AIM: To determine whether exposure to tumour necrosis factor (TNF)-α inhibitors increases the risk of herpes zoster (HZ) among people with rheumatoid arthritis (RA). METHODS: We performed a cohort study of people with RA participating in the Australian Rheumatology Association Database. We identified self-reported cases of HZ and verified using medical records. For the primary analysis, we only included doctor-verified cases. For TNF-α inhibitor exposed groups, we excluded HZ episodes that occurred before TNF-α inhibitor initiation, and for the control group we excluded HZ episodes that occurred prior to 2000 or RA diagnosis. The risk of HZ among participants exposed versus not exposed to TNF-α inhibitors was compared using Cox proportional hazards models including significant covariates affecting the risk. Adjusted hazard ratios (HR) were calculated for TNF inhibitors as a class and for individual agents. RESULTS: Among 2157 active RA participants, there were 442 self-reported cases of HZ. From 346 responses from doctors, 249 cases were verified and four were false positives (false positive rate 1.6%). Crude incidence of verified HZ in the entire RA cohort was 15.9/1000 person-years (95% confidence interval (CI): 13.5-18.8). An increased risk of HZ was found for all TNF-α inhibitors combined (fully adjusted HR 1.71; 95% CI: 1.00-2.92) and adalimumab (fully adjusted HR 2.33; 95% CI: 1.22-4.45), but in the fully adjusted model was not increased with etanercept (fully adjusted HR 1.65; 95% CI: 0.90-3.03). No increased risk was found with infliximab (HR 1.29; 95% CI: 0.37-4.47). CONCLUSIONS: TNF-α inhibitors are associated with an increased risk of HZ in people with RA compared with those who have not been exposed.

Can frailty predict complicated care needs and length of stay?

The Reported Edmonton Frail Scale was used to describe the prevalence of frailty in an acute general medical unit. The relationship between frailty, discharge destination, mortality and length of hospital stay was explored. We found that age was associated with frailty, and frailty correlated to an increasing length of hospital stay. Significantly, frailty was associated with complexity in discharge, and this process created a longer length of hospital stay.

Association of Asian ethnicity with disease activity in SLE: an observational study from the Monash Lupus Clinic.

OBJECTIVE: Systemic lupus erythematosus (SLE), an autoimmune condition with diverse clinical manifestations, is reported to have different expression in populations of different ancestry. Most previous studies compared patients of different ethnic groups from geographically distinct cohorts. In our study, we aimed to characterize disease manifestations in patients of different ethnic groups from a single centre, and studied patterns of disease activity over time. METHODS: Demographics, baseline disease characteristics and autoantibody profiles, and disease activity (SLEDAI) measured at each visit, were captured from all consenting patients prospectively followed between 2007 and 2011 in an urban teaching hospital lupus clinic. Ethnicity was self-reported. RESULTS: Asian ethnicity was significantly associated with more clinically severe SLE. Time-adjusted mean SLEDAI (p = 0.01) and maximum SLEDAI (p = 0.0018) were significantly higher in Asian patients. Asians were more likely to have renal disease (OR 2.9, 95% CI 1.4-5.98; p = 0.004) and persistently active disease (PAD) (OR 2.14, 95% CI 1.05-4.38, p = 0.04). Asian lupus patients also had a significantly higher proportion of autoantibody positivity to anti-dsDNA, anti-RNP, anti-Sm, anti-Ro and anti-La, as well as increased likelihood of hypocomplementaemia and immunosuppressant use. CONCLUSION: In this single-cohort study, Asian ethnicity was found to be associated with increased SLE disease activity. This suggests significant inter-ethnic genetic contributions to the regulation of autoimmune responses and disease severity in SLE.

How receptive are patients to medical students in Australian hospitals? A cross-sectional survey of a public and a private hospital.

BACKGROUND: Medical student numbers in Australian universities have more than doubled since 2000. There are concerns about the ability for existing clinical training sites to accommodate this increase in student numbers, and there have been calls to increase training in private hospitals. The receptiveness of patients in private hospitals will influence the success of such placements. AIMS: We aimed to evaluate whether patients in a private hospital are as receptive to medical students as patients in a public hospital. METHODS: Cross-sectional survey of patients conducted at a private and a public teaching hospital in Melbourne, Australia. Main outcome measures were willingness to allow a medical student to participate in an interview, physical examination and procedures (electrocardiogram, venepuncture and digital rectal examination), and patient attitudes towards medical students as assessed by a series of 20 attitude statements and a summative attitude score. RESULTS: Patients at the private hospital were more willing than patients at the public hospital to allow a medical student to take their history unsupervised (112/146, 76.7% vs 90/141, 63.8%; P = 0.02). The distribution of patient willingness did not otherwise differ between hospitals for physical examination or procedures. There was no difference in the mean attitude score between hospitals (15.3 ± 0.8 private vs 15.4 ± 1.2 public, P = 0.38), and responses differed between hospitals for only four of the 20 attitude statements. CONCLUSIONS: Our findings suggest that patients in a private hospital are at least as receptive to medical students as patients in a public hospital.

The Role of Sleep-Disordered Breathing Symptoms in Neurocognitive Function Among Youth With Sickle Cell Disease.

OBJECTIVE: To examine associations between sleep-disordered breathing (SDB) and executive/attentional function in pediatric sickle cell disease (SCD). METHODS: Sixty youth with SCD ages 8-18 years and caregivers completed the Pediatric Sleep Questionnaire (PSQ), Delis Kaplan Executive Function System Trail Making Test (DKEFS TMT), Psychomotor Vigilance Test (PVT), and the Behavior Rating Inventory Of Executive Function, Second Edition (BRIEF-2) Parent Report. RESULTS: The PSQ significantly predicted the BRIEF-2 Parent Report, F(1, 58) = 44.64, p < .001, R2 = 0.44, f2 = 0.77. CONCLUSIONS: Sleep-disordered breathing symptoms may predict informant-rated executive dysfunction in pediatric SCD, but not performance-based executive function.

Lymph node yield following injection of patent blue V dye into colorectal cancer specimens.

AIM: The study aimed to assess whether the ex vivo injection of patent blue V dye would increase lymph node yield in operative specimens of colorectal cancer. METHOD: A randomized controlled trial was carried out in which patients undergoing resection for colonic cancer were allocated to patent V blue or no patent blue V dye submucosal injection of the operative specimen. The number of lymph nodes found in each group was compared. RESULTS: Between 1 January and 31 December 2008, 68 patients were randomized. Thirty-three patients received patent blue V dye and 34 did not. In the former group the median number of blue nodes identified was 11, compared with a median of 9 in the no dye group. After the application of Carnoy's solution lymph node count was 16 in each group. There was no significant difference between all these results. CONCLUSION: Ex vivo injection of patent blue V dye submucosally in a peritumour location did not increase the lymph node count or the percentage of specimens having more than 12 lymph nodes identified.

The rate of abdominoperineal resections for rectal cancer in the state of Victoria, Australia: a population-based study.

PURPOSE: The aim of this study was to document a population-based rate of abdominoperineal resections for adenocarcinoma of the rectum in the state of Victoria, Australia. It also determined whether surgeon caseload or specialist colorectal training affects this rate. METHODS: All resections for adenocarcinoma of the rectum (International Classification of Diseases for Oncology, 3rd edition C20) that were performed in Victoria in the year 2005 were included. Procedures for rectosigmoid or colon cancer were excluded. The sample was taken from the Victorian Cancer Registry. The rate of abdominoperineal resections was calculated by dividing the total number of abdominoperineal resections by the total number of procedures for rectal cancer. Mixed-effects logistic regression was used to estimate the odds ratio for surgeon caseload and specialist colorectal training. RESULTS: There were 582 resections available for analysis. Patients were mostly males (66%) and over 60 years of age (67.7%). The overall rate of abdominoperineal resection was 23.4%. The rate of abdominoperineal resections for low rectal cancers was lower (42.8%) among surgeons who had specialist colorectal training compared with those who did not (60.6%) (OR = 2.06; 95% CI, 1.24-3.42). CONCLUSION: The rate of abdominoperineal resection in Victoria for 2005 was 23.4%. Patients with low rectal cancer operated on by surgeons who had had specialist colorectal training were significantly less likely to undergo an abdominoperineal resection compared with patients undergoing an operation by surgeons who did not have specialist colorectal training.

Impact of dermoscopy and short-term sequential digital dermoscopy imaging for the management of pigmented lesions in primary care: a sequential intervention trial.

BACKGROUND: Studies have shown the benign to malignant ratio of excised pigmented skin lesions is suboptimal in primary care. OBJECTIVES: To assess the impact of dermoscopy and short-term sequential digital dermoscopy imaging (SDDI) on the management of suspicious pigmented skin lesions by primary care physicians. METHODS: A total of 63 primary care physicians were trained in the use of dermoscopy and SDDI (interventions) and then recruited pigmented lesions requiring biopsy or referral in routine care by naked eye examination. They were then given a dermatoscope and the option of a SDDI instrument, and change of diagnosis and management was assessed. RESULTS: Following the use of the interventions on 374 lesions a total of 163 lesions (43.6%) were excised or referred, representing a reduction of 56.4%. Of the 323 lesions confirmed to be benign, 118 (36.5%) were excised or referred, leading to a reduction of 63.5% (P < 0.0005) in those requiring excision or referral. The baseline naked eye examination benign to melanoma ratio was 9.5 : 1 which decreased to 3.5 : 1 after the diagnostic interventions (P < 0.0005). Of the 42 malignant lesions included in the study (34 melanoma, six pigmented basal cell carcinoma and two Bowen disease) only one in situ melanoma was incorrectly managed (patient to return if changes occur) resulting in the correct management of 97.6% and 97.1% of malignant pigmented lesions and melanoma, respectively. CONCLUSIONS: In a primary care setting the combination of dermoscopy and short-term SDDI reduces the excision or referral of benign pigmented lesions by more than half while nearly doubling the sensitivity for the diagnosis of melanoma.

Role of lymph node yield and lymph node ratio in predicting outcomes in non-metastatic colorectal cancer.

Background: Lymph node yield (LNY) of 12 or more in resection of colorectal cancer is recommended in current international guidelines. Although a low LNY (less than 12) is associated with poorer outcome in some studies, its prognostic value is unclear in patients with early-stage colorectal or rectal cancer with a complete pathological response following neoadjuvant therapy. Lymph node ratio (LNR), which reflects the proportion of positive to total nodes obtained, may be more accurate in predicting outcome in stage III colorectal cancer. This study aimed to identify factors correlating with LNY and evaluate the prognostic role of LNY and LNR in colorectal cancer. Methods: An observational study was performed on patients with colorectal cancer treated at three hospitals in Melbourne, Australia, from January 2010 to March 2016. Association of LNY and LNR with clinical variables was analysed using linear regression. Disease-free (DFS) and overall (OS) survival were investigated with Cox regression and Kaplan-Meier survival analyses. Results: Some 1585 resections were analysed. Median follow-up was 27·1 (range 0·1-71) months. Median LNY was 16 (range 0-86), and was lower for rectal cancers, decreased with increasing age, and increased with increasing stage. High LNY (12 or more) was associated with better DFS in colorectal cancer. Subgroup analysis indicated that low LNY was associated with poorer DFS and OS in stage III colonic cancer, but had no effect on DFS and OS in rectal cancer (stages I-III). Higher LNR was predictive of poorer DFS and OS. Conclusion: Low LNY (less than 12) was predictive of poor DFS in stage III colonic cancer, but was not a factor for stage I or II colonic disease or any rectal cancer. LNR was a predictive factor in DFS and OS in stage III colonic cancer, but influenced DFS only in rectal cancer.

Should ongoing airway education be a mandatory component of continuing professional development for College of Intensive Care Medicine Fellows?

This study aimed to determine whether airway education should be introduced to the continuing professional development (CPD) program for College of Intensive Care Medicine (CICM) Fellows. A random representative sample of 11 tertiary intensive care units (ICUs) was chosen from the list of 56 units accredited for 12 or 24 months of CICM training. All specialist intensive care Fellows (n=140) currently practising at the eleven ICUs were sent the questionnaire via email. Questionnaire data collection and post-collection data analysis was used to determine basic respondent demographics, frequency of certain airway procedures in the past 12 months, confidence with advanced airway practices in ICU, participation in airway education in the past three years, knowledge of can't intubate, can't oxygenate (CICO) algorithms, preference for certain airway equipment/techniques, and support for required airway education as a component of the CICM CPD program. All responses were tabled for comparison. Data was analysed to establish any significant effect of another specialty qualification and current co-practice in anaesthesia on volume of practice, confidence with multiple airway procedures, use of airway equipment, and support for airway education. In total, 112 responses (response rate 80%) to the questionnaire were received within four weeks; 107 were completed in full (compliance 96%). All results were tabled. There is currently widespread support amongst CICM Fellows for airway skills education as a CPD requirement for CICM Fellows. Volumes of practice and confidence levels with different airway procedures vary amongst Fellows and further support the need for education.

Surgical outcome after standard abdominoperineal resection: A 15-year cohort study from a single cancer centre.

BACKGROUND: Abdominoperineal resection (APR) is associated with a poorer oncological outcome than anterior resection. This may be due to higher rates of intra-operative perforation and circumferential resection margin involvement. The aim of this study was to audit our short and long-term results of abdominoperineal resection performed using conventional techniques and to compare this with other published series. MATERIALS AND METHODS: A retrospective review of all patients who had standard APR between January 2000 and December 2016 in a single institution, Cabrini Hospital, Melbourne, Australia. A total of 163 cases performed by nine different colorectal surgeons for primary rectal adenocarcinoma were identified, with their clinicopathological data analysed. RESULTS: Using standard APR, only six patients (3.7%) were found to have a positive circumferential resection margin (CRM). There were two cases of intra-operative perforation (1.2%). Local recurrence rate was 5.6% of patients, with distant recurrence found in 24.9%. Disease-free survival at five years was 73.1%. Five-year overall survival was 66.7%, 67.9% of all deaths were cancer-related. CONCLUSION: Short and long-term outcomes after standard APR in this study were comparable to previous published studies. The CRM rate of 3.7% compares favourably to published positive CRM rates for standard APR which ranged from 6 to 18%. Standard APR remains a viable technique for the treatment of rectal cancer. Patient selection and adequate training remain important factors.

Discovery of Streptococcus pneumoniae serogroup 35 variants in Australian patients.

OBJECTIVES: Streptococcus pneumoniae isolates from Australian invasive pneumococcal disease cases displaying an atypical 35B phenotype. Whole genome sequencing was used to analyse these strains and identify changes to the capsule gene regions. METHODS: Four atypical serogroup 35 isolates from Australian reference laboratories were unable to be assigned to one of the four known group 35 serotypes by the Quellung serotyping method. Genetic characterization of the capsule locus was performed by bioinformatic analysis of whole genome sequencing data for all isolates. RESULTS: Genetic analysis identified four independent disruptions to the wciG gene, which encodes an O-acetyltransferase responsible for the O-acetylation of the 6Galß1 residue in the capsular polysaccharide repeat unit of serotype 35B. CONCLUSIONS: This is the first published report on the incidence and capsular gene characteristics of a S. pneumoniae 35B variant.

Purification of the bifunctional enzyme, imidazoleglycerolphosphate dehydratase-histidinol phosphatase, of Salmonella typhimurium.

Mn2+ precipitation, antibody affinity chromatography, and selective proteolysis have been used to purify a bifunctional core of the hisB enzyme from Salmonella typhimurium. The core is homogeneous in subunit molecular weight; however, it is heterogeneous in its charge properties, probably as a result of multiple cleavage points produced by limited proteolytic digestion. The resistance of the enzyme to irreversible denaturation by urea allowed the use of urea to elute the hisB enzyme from a column of anti-hisB IgG immobilized on Sepharose. Heterogeneous oligomeric forms of the enzyme were demonstrated by electrophoretic analysis and exist as multiples of the 46,000 molecular weight monomer.

Developmental effects of wheel running on hippocampal glutamate receptor expression in young and mature adult rats.

Recent evidence suggests that the behavioral benefits associated with voluntary wheel running in rodents may be due to modulation of glutamatergic transmission in the hippocampus, a brain region implicated in learning and memory. However, the expression of the glutamatergic ionotropic N-methyl-d-aspartate receptor (GluN) in the hippocampus in response to chronic sustained voluntary wheel running has not yet been investigated. Further, the developmental effects during young and mature adulthood on wheel running output and GluN expression in hippocampal subregions has not been determined, and therefore is the main focus of this investigation. Eight-week-old and 16-week-old male Wistar rats were housed in home cages with free access to running wheels and running output was monitored for 4weeks. Wheel access was terminated and tissues from the dorsal and ventral hippocampi were processed for Western blot analysis of GluN subunit expression. Young adult runners demonstrated an escalation in running output but this behavior was not evident in mature adult runners. In parallel, young adult runners demonstrated a significant increase in total GluN (1 and 2A) subunit expression in the dorsal hippocampus (DH), and an opposing effect in the ventral hippocampus (VH) compared to age-matched sedentary controls; these changes in total protein expression were not associated with significant alterations in the phosphorylation of the GluN subunits. In contrast, mature adult runners demonstrated a reduction in total GluN2A expression in the DH, without producing alterations in the VH compared to age-matched sedentary controls. In conclusion, differential running activity-mediated modulation of GluN subunit expression in the hippocampal subregions was revealed to be associated with developmental effects on running activity, which may contribute to altered hippocampal synaptic activity and behavioral outcomes in young and mature adult subjects.