Effective Dose and Adverse Effects of Maintenance Bacillus Calmette-Gue´Rin in Intermediate and High Risk Non-muscle Invasive Bladder Cancer: a Meta-analysis of Randomized Clinical Trial

Aim: to evaluate the effective dose and adverse effects of BCG doses. Methods: we searched published RCTs in Medline and Cochrane database before October 2013. Article using maintenance BCG after TUR in intermediate-high risk non-muscle invasive bladder cancer (NMIBC) and followed for effectiveness, local and systemic side effect are included. Low risk patients, other dose and MIBC were excluded. Results: meta-analysis of 6 clinical trials involving 2719 intermediate-high risk NMIBC patients showed recurrence rate in full dose (81 mg), low dose (27 mg) and very low dose (13.5 mg) were 33.3%, 34.7% and 30%, respectively. Meta-analysis of 2175 patients, 81 mg BCG was found to be superior to 27 mg in reducing tumour recurrences (RR 0.86; 95% CI 0.77-0.96, I2 = 0% and p=0.008). Meta-analysis of 544 patients, the effectiveness reducing tumour recurrences in 27 mg BCG was found to be superior to 13,5 BCG (RR 0.66; 95% CI 0.49-0.89, I2 = 8.8% and p=0.006). Systemic side effects were happened in 25%, 28.5%, and 15.5% in the doses 81.27 and 13.5 mg BCG, respectively. Low dose was superior to full dose in affecting systemic side effect (p=0,000) but no difference in affecting local side effect (p=0.137) in the meta-analysis of 1816 patients in 2 clinical trials. Conclusion: full dose BCG had superior outcome to reduce recurrences compared to low dose and very low dose. There were no significant differences between each dose in local side effect. However full dose regimen has higher systemic side effect compared to low and very low dose. Key words: Bacillus Calmette-Gue´Rin, dose and adverse effect, non-muscle invasive bladder cancer (NMIBC)

PACAP and Cocaine Reinstatement: A Neuropeptide Expressed by Corticostriatal Neurons that Regulates Nucleus Accumbens Astrocytes

Drug addiction involves heightened relapse vulnerability arising from persistent drug-induced neuro-adaptations, including a) hypofrontality which is thought to reflect reduced firing of cortical afferents to the nucleus accumbens (NAcc) and b) altered glutamate homeostasis in NAcc that likely involves reduced glutamate release and uptake by astrocytes. An important question is whether these forms of pathological plasticity are functionally linked such that reduced corticostriatal firing may result in aberrant regulation of astrocytes in the NAcc. To begin to evaluate this possibility, we first determined whether neurons regulate system xc- (Sxc) activity, a mechanism of non-vesicular glutamate release by astrocytes. We found that the rate of Sxc activity in astrocyte cultures was significantly increased in cells exposed to neuronal conditioned media achieved using neuronal inserts. These experiments demonstrate that releasable neuronal factors significantly upregulate Sxc activity. We hypothesize that the pituitary adenylyl cyclase activating peptide (PACAP) may be the neuronal factor regulating glutamate release by astrocytes involving Sxc. First we determined that PACAP mimics a neuronal insert in that it significantly upregulates Sxc activity in astrocytes. Next, we verified the expression of PACAP in neurons from the prefrontal cortex (PFC) projecting to NAcc. Together, these data support the hypothesis that reduced corticostriatal firing may result in decreased PACAP release in NAcc which could potentially blunt Sxc activity in NAcc astrocytes. To determine whether this would impact relapse vulnerability, we microinjected PACAP into the NAcc and found that this significantly reduced cocaine-primed reinstatement, suggesting that increased PACAP signaling, consistent with other approaches capable of increasing Sxc activity, may blunt relapse vulnerability. In order to determine whether reduced PACAP signaling is sufficient to increase relapse vulnerability, we microinjected the PAC1R inhibitor PACAP6-38 into the NAcc. Preliminary data indicate that this is sufficient to produce an increase in cocaine reinstatement. Collectively, these studies demonstrate that neuropeptide PACAP is a powerful regulator of cocaine-related behaviors, likely through the modulation of glutamate homeostasis as maintained by astrocytes. As a result, an unrecognized consequence of hypofrontality may be impairing neuron-astrocyte interactions in a manner that determines the magnitude of relapse vulnerability

A Comprehensive Resource for Induced Pluripotent Stem Cells from Patients with Primary Tauopathies.

Primary tauopathies are characterized neuropathologically by inclusions containing abnormal forms of the microtubule-associated protein tau (MAPT) and clinically by diverse neuropsychiatric, cognitive, and motor impairments. Autosomal dominant mutations in the MAPT gene cause heterogeneous forms of frontotemporal lobar degeneration with tauopathy (FTLD-Tau). Common and rare variants in the MAPT gene increase the risk for sporadic FTLD-Tau, including progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). We generated a collection of fibroblasts from 140 MAPT mutation/risk variant carriers, PSP, CBD, and cognitively normal controls; 31 induced pluripotent stem cell (iPSC) lines from MAPT mutation carriers, non-carrier family members, and autopsy-confirmed PSP patients; 33 genome engineered iPSCs that were corrected or mutagenized; and forebrain neural progenitor cells (NPCs). Here, we present a resource of fibroblasts, iPSCs, and NPCs with comprehensive clinical histories that can be accessed by the scientific community for disease modeling and development of novel therapeutics for tauopathies

Relationship between West African ancestry with lung cancer risk and survival in African Americans

Purpose: African Americans, especially men, have a higher incidence of lung cancer compared with all other racial and ethnic groups in the US. Self-reported race is frequently used in genomic research studies to capture an individual's race or ethnicity. However, it is clear from studies of genetic admixture that human genetic variation does not segregate into the same biologically discrete categories as socially defined categories of race. Previous studies have suggested that the degree of West African ancestry among African Americans can contribute to cancer risk in this population, though few studies have addressed this question in lung cancer. Methods: Using a genetic ancestry panel of 100 SNPs, we estimated West African, European, and Native American ancestry in 1,407 self-described African Americans and 2,413 European Americans. Results: We found that increasing West African ancestry was associated with increased risk of lung cancer among African American men (ORQ5 vs Q1 = 2.55 (1.45-4.48), p = 0.001), while no association was observed in African American women (ORQ5 vs Q1 = 0.90 (0.51-1.59), p = 0.56). This relationship diminished following adjustment for income and education. Conclusions: Genetic ancestry is not a major contributor to lung cancer risk or survival disparities

Landscapes in transition: an analysis of sustainable policy initiatives and emerging corporate commitments in the palm oil industry

The recent Southeast Asian haze crisis has generated intense public scrutiny over the rate, methods and types of landscape change in the tropics. Debate has centred on the environmental impacts of large-scale agricultural expansion, particularly the associated loss of high carbon stock forest and forests of high conservation value. Focusing on palm oil—a versatile food crop and source of bioenergy—this paper analyses national, international and corporate policy initiatives in order to clarify the current and future direction of oil palm expansion in Malaysia and Indonesia. The policies of ‘zero burn’, ‘no deforestation’ and ‘no planting on peatlands’ are given particular emphasis in the paper. The landscape implications of corporate commitments are analysed to determine the amount of land, land types and geographies that could be affected in the future. The paper concludes by identifying key questions related to the further study of sustainable land use policy and practice

Spatial distribution and long-term persistence of Wolbachia-infected Aedes aegypti in the Mentari Court, Malaysia

Dengue is endemic in Malaysia, and vector control strategies are vital to reduce dengue transmission. The Wolbachia strain wAlbB carried by both sexes of Ae. aegypti was released in Mentari Court, a high-rise residential site, in October 2017 and stopped after 20 weeks. Wolbachia frequencies are still being monitored at multiple traps across this site, providing an opportunity to examine the spatiotemporal distribution of Wolbachia and mosquito density with respect to year, residential block, and floor, using spatial interpolation in ArcGIS, GLMs, and contingency analyses. In just 12 weeks, Wolbachia-infected mosquitoes were established right across the Mentari Court site with an overall infection frequency of >90%. To date, the Wolbachia frequency of Ae. aegypti has remained high in all areas across the site despite releases finishing four years ago. Nevertheless, the Wolbachia invaded more rapidly in some residential blocks than others, and also showed a relatively higher frequency on the eighth floor. The Ae. aegypti index tended to differ somewhat between residential blocks, whilst the Ae. albopictus index was relatively higher at the top and bottom floors of buildings. In Mentari Court, only a short release period was required to infiltrate Wolbachia completely and stably into the natural population. The results inform future releases in comparable sites in a dengue control programme

Adapting Agriculture to Climate Change: A Synopsis of Coordinated National Crop Wild Relative Seed Collecting Programs across Five Continents

The Adapting Agriculture to Climate Change Project set out to improve the diversity, quantity, and accessibility of germplasm collections of crop wild relatives (CWR). Between 2013 and 2018, partners in 25 countries, heirs to the globetrotting legacy of Nikolai Vavilov, undertook seed collecting expeditions targeting CWR of 28 crops of global significance for agriculture. Here, we describe the implementation of the 25 national collecting programs and present the key results. A total of 4587 unique seed samples from at least 355 CWR taxa were collected, conserved ex situ, safety duplicated in national and international genebanks, and made available through the Multilateral System (MLS) of the International Treaty on Plant Genetic Resources for Food and Agriculture (Plant Treaty). Collections of CWR were made for all 28 targeted crops. Potato and eggplant were the most collected genepools, although the greatest number of primary genepool collections were made for rice. Overall, alfalfa, Bambara groundnut, grass pea and wheat were the genepools for which targets were best achieved. Several of the newly collected samples have already been used in pre-breeding programs to adapt crops to future challenges.info:eu-repo/semantics/publishedVersio

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P < 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely