The Efficacy of Sodium Channel Blockers to Prevent Phencyclidine-Induced Cognitive Dysfunction in the Rat: Potential for Novel Treatments for Schizophrenia □ S

ABSTRACT Sodium channel inhibition is a well precedented mechanism used to treat epilepsy and other hyperexcitability disorders. The established sodium channel blocker and broad-spectrum anticonvulsant lamotrigine is also effective in the treatment of bipolar disorder and has been evaluated in patients with schizophrenia. Double-blind placebo-controlled clinical trials found that the drug has potential to reduce cognitive symptoms of the disorder. However, because of compound-related side-effects and the need for dose titration, a conclusive evaluation of the drug's efficacy in patients with schizophrenia has not been possible. In this series of studies in the rat, we compared the efficacy of the two new molecules to prevent a cognitive deficit induced by the N-methyl-D-aspartic acid receptor antagonist phencyclidine (PCP) in the reversal-learning paradigm in the rat. We also explored the effects of the drugs to prevent brain activation and neurochemical effects of PCP. We found that, like lamotrigine, both GSK2 and GSK3 were able to prevent the deficit in reversal learning produced by PCP, thus confirming their potential in the treatment of cognitive symptoms of schizophrenia. However, higher doses than those required for anticonvulsant efficacy of the drugs were needed for activity in the reversal-learning model, suggesting a lower therapeutic window relative to mechanism-dependent central side effects for this indication

Improving psychosocial outcomes for caregivers of people with poor prognosis gastrointestinal cancers: a randomized controlled trial (Family Connect)

Abstract Purpose This study investigated the effectiveness of a structured telephone intervention for caregivers of people diagnosed with poor prognosis gastrointestinal cancer to improve psychosocial outcomes for both caregivers and patients. Methods Caregivers of patients starting treatment for upper gastrointestinal or Dukes D colorectal cancer were randomly assigned (1:1) to the Family Connect telephone intervention or usual care. Caregivers in the intervention group received four standardized telephone calls in the 10 weeks following patient hospital discharge. Caregivers' quality of life (QOL), caregiver burden, unmet supportive care needs and distress were assessed at 3 and 6 months. Patients' QOL, unmet supportive care needs, distress and health service utilization were also assessed at these time points. Results Caregivers (128) were randomized to intervention or usual care groups. At 3 months, caregiver QOL scores and other caregiver-reported outcomes were similar in both groups. Intervention group participants experienced a greater sense of social support (p=.049) and reduced worry about finances (p=.014). Patients whose caregiver was randomized to the intervention also had fewer emergency department presentations and unplanned hospital readmissions at 3 months post-discharge (total 17 vs. 5, p=.01). Conclusions This standardized intervention did not demonstrate any significant improvements in caregiver well-being but did result in a decrease in patient emergency department presentations and unplanned hospital readmissions in the immediate post-discharge period. The trend towards improvements in a number of caregiver outcomes and the improvement in health service utilization support further development of telephone-based caregiver-focused supportive care interventions

Global patient outcomes after elective surgery: prospective cohort study in 27 low-, middle- and high-income countries.

BACKGROUND: As global initiatives increase patient access to surgical treatments, there remains a need to understand the adverse effects of surgery and define appropriate levels of perioperative care. METHODS: We designed a prospective international 7-day cohort study of outcomes following elective adult inpatient surgery in 27 countries. The primary outcome was in-hospital complications. Secondary outcomes were death following a complication (failure to rescue) and death in hospital. Process measures were admission to critical care immediately after surgery or to treat a complication and duration of hospital stay. A single definition of critical care was used for all countries. RESULTS: A total of 474 hospitals in 19 high-, 7 middle- and 1 low-income country were included in the primary analysis. Data included 44 814 patients with a median hospital stay of 4 (range 2-7) days. A total of 7508 patients (16.8%) developed one or more postoperative complication and 207 died (0.5%). The overall mortality among patients who developed complications was 2.8%. Mortality following complications ranged from 2.4% for pulmonary embolism to 43.9% for cardiac arrest. A total of 4360 (9.7%) patients were admitted to a critical care unit as routine immediately after surgery, of whom 2198 (50.4%) developed a complication, with 105 (2.4%) deaths. A total of 1233 patients (16.4%) were admitted to a critical care unit to treat complications, with 119 (9.7%) deaths. Despite lower baseline risk, outcomes were similar in low- and middle-income compared with high-income countries. CONCLUSIONS: Poor patient outcomes are common after inpatient surgery. Global initiatives to increase access to surgical treatments should also address the need for safe perioperative care. STUDY REGISTRATION: ISRCTN5181700

Role of hypoxia inducible factor-1 in keratinocyte inflammatory response and neutrophil recruitment

Background: Hypoxia inducible factor-1 (HIF-1) is a major regulator of the cellular adaption to low oxygen stress and the innate immune function of myeloid cells. Treatment with the novel HIF-1 stabilizing drug AKB-4924 has been shown to enhance the bactericidal activity of keratinocytes as well as phagocytic cells. In this study, we sought to investigate the effect of pharmacological boosting of HIF-1 with AKB-4924 in keratinocytes and their contribution to the innate immune response. Findings. Treatment with the novel HIF-1 stabilizing drug AKB-4924 can increase keratinocyte production of pro-inflammatory cytokines in vitro and enhance neutrophil recruitment in vivo. Conclusions: HIF plays an important role in cytokine production by keratinocytes and in neutrophil recruitment to the skin. The HIF-boosting drug AKB-4924 has the potential to enhance the immune response even in the complex environment of bacterial skin infections

Impact of calorie labelling in worksite cafeterias: a stepped wedge randomised controlled pilot trial.

BACKGROUND: For working adults, about one-third of energy is consumed in the workplace making this an important context in which to reduce energy intake to tackle obesity. The aims of the current study were first, to identify barriers to the feasibility and acceptability of implementing calorie labelling in preparation for a larger trial, and second, to estimate the potential impact of calorie labelling on energy purchased in worksite cafeterias. METHODS: Six worksite cafeterias were randomised to the intervention starting at one of six fortnightly periods, using a stepped wedge design. The trial was conducted between August and December 2016, across 17 study weeks. The intervention comprised labelling all cafeteria products for which such information was available with their calorie content (e.g. "250 Calories") displayed in the same font style and size as for price. A post-intervention survey with cafeteria patrons and interviews with managers and caterers were used to assess the feasibility and acceptability of the intervention. Intervention impact was assessed using generalised linear mixed modelling. The primary outcome was the total energy (kcal) purchased from intervention items in each cafeteria each day. RESULTS: Recruitment and retention of worksite cafeterias proved feasible, with post-intervention feedback suggesting high levels of intervention acceptability. Several barriers to intervention implementation were identified, including chefs' discretion at implementing recipes and the manual recording of sales data. There was no overall effect of the intervention: -0.4% (95%CI -3.8 to 2.9, p = .803). One site showed a statistically significant effect of the intervention, with an estimated 6.6% reduction (95%CI -12.9 to - 0.3, p = .044) in energy purchased in the day following the introduction of calorie labelling, an effect that diminished over time. The remaining five sites did not show robust changes in energy purchased when calorie labelling was introduced. CONCLUSIONS: A calorie labelling intervention was acceptable to both cafeteria operators and customers. The predicted effect of labelling to reduce energy purchased was only evident at one out of six sites studied. Before progressing to a full trial, the calorie labelling intervention needs to be optimised, and a number of operational issues resolved. TRIAL REGISTRATION: ISRCTN52923504 ; Registered: 22/09/2016; retrospectively registered

Current Perspectives on the Importance of Pathological Features in Prognostication and Guidance of Adjuvant Chemotherapy in Colon Cancer

There is not a clear consensus on which pathological features and biomarkers are important in guiding prognosis and adjuvant therapy in colon cancer. The Pathology in Colon Cancer, Prognosis and Uptake of Adjuvant Therapy (PiCC UP) Australia and New Zealand questionnaire was distributed to colorectal surgeons, medical oncologists and pathologists after institutional board approval. The aim of this study was to understand current specialist attitudes towards pathological features in the prognostication of colon cancer and adjuvant therapy in stage II disease. A 5-scale Likert score was used to assess attitudes towards 23 pathological features for prognosis and 18 features for adjuvant therapy. Data were analysed using a rating scale and graded response model in item response theory (IRT) on STATA (Stata MP, version 15; StataCorp LP). One hundred and sixty-four specialists (45 oncologists, 86 surgeons and 33 pathologists) participated. Based on IRT modelling, the most important pathological features for prognosis in colon cancer were distant metastases, lymph node metastases and liver metastases. Other features seen as important were tumour rupture, involved margin, radial margin, CRM, lymphovascular invasion and grade of differentiation. Size of tumour, location, lymph node ratio and EGFR status were considered less important. The most important features in decision making for adjuvant therapy in stage II colon cancer were tumour rupture, lymphovascular invasion and microsatellite instability. BRAF status, size of tumour, location, tumour budding and tumour infiltrating lymphocytes were factored as lesser importance. Biomarkers such as CDX2, EGFR, KRAS and BRAF status present areas for further research to improve precision oncology. This study provides the most current status on the importance of pathological features in prognostication and recommendations for adjuvant therapy in Australia and New Zealand. Results of this nationwide study may be useful to help in guiding prognosis and adjuvant treatment in colon cancer

Laparoscopic partial cholecystectomy: A way of getting out of trouble Article ID: 100057IJHPDPY2016 *********

ABSTRACT were collected. Results: A total of 404 patients underwent LC during the two year study period of which 23 were LPC's. Patients who underwent LPC tended to be older and more likely of the male gender. These patients were also more likely to be an emergency operation and have a higher ASA grade compared to the LC group. Length of stay and operative time tended to be longer. There were five (22%) bile leaks postoperatively and all were successfully managed with postoperative ERCP and stenting. The major complication rate was 35% (8/23) with no bile duct injury or perioperative mortality. Conclusion: This current case series adds further evidence to suggest that LPC is a viable alternative to conversion in cases of difficult LC