Malaria Host Candidate Genes Validated by Association With Current, Recent, and Historical Measures of Transmission Intensity

Background: Human malaria susceptibility is determined by multiple genetic factors. It is unclear, however, which genetic variants remain important over time. Methods: Genetic associations of 175 high-quality polymorphisms within several malaria candidate genes were examined in a sample of 8096 individuals from northeast Tanzania using altitude, seroconversion rates, and parasite rates as proxies of historical, recent, and current malaria transmission intensity. A principal component analysis was used to derive 2 alternative measures of overall malaria propensity of a location across different time scales. Results: Common red blood cell polymorphisms (ie, hemoglobin S, glucose-6-phosphate dehydrogenase, and α-thalassemia) were the only ones to be associated with all 3 measures of transmission intensity and the first principal component. Moderate associations were found between some immune response genes (ie, IL3 and IL13) and parasite rates, but these could not be reproduced using the alternative measures of malaria propensity. Conclusions: We have demonstrated the potential of using altitude and seroconversion rate as measures of malaria transmission capturing medium- to long-term time scales to detect genetic associations that are likely to persist over time. These measures also have the advantage of minimizing the deleterious effects of random factors affecting parasite rates on the respective association signals

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

Fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin with gemtuzumab ozogamicin improves event-free survival in younger patients with newly diagnosed aml and overall survival in patients with npm1 and flt3 mutations

Purpose To determine the optimal induction chemotherapy regimen for younger adults with newly diagnosed AML without known adverse risk cytogenetics. Patients and Methods One thousand thirty-three patients were randomly assigned to intensified (fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin [FLAG-Ida]) or standard (daunorubicin and Ara-C [DA]) induction chemotherapy, with one or two doses of gemtuzumab ozogamicin (GO). The primary end point was overall survival (OS). Results There was no difference in remission rate after two courses between FLAG-Ida + GO and DA + GO (complete remission [CR] + CR with incomplete hematologic recovery 93% v 91%) or in day 60 mortality (4.3% v 4.6%). There was no difference in OS (66% v 63%; P = .41); however, the risk of relapse was lower with FLAG-Ida + GO (24% v 41%; P < .001) and 3-year event-free survival was higher (57% v 45%; P < .001). In patients with an NPM1 mutation (30%), 3-year OS was significantly higher with FLAG-Ida + GO (82% v 64%; P = .005). NPM1 measurable residual disease (MRD) clearance was also greater, with 88% versus 77% becoming MRD-negative in peripheral blood after cycle 2 (P = .02). Three-year OS was also higher in patients with a FLT3 mutation (64% v 54%; P = .047). Fewer transplants were performed in patients receiving FLAG-Ida + GO (238 v 278; P = .02). There was no difference in outcome according to the number of GO doses, although NPM1 MRD clearance was higher with two doses in the DA arm. Patients with core binding factor AML treated with DA and one dose of GO had a 3-year OS of 96% with no survival benefit from FLAG-Ida + GO. Conclusion Overall, FLAG-Ida + GO significantly reduced relapse without improving OS. However, exploratory analyses show that patients with NPM1 and FLT3 mutations had substantial improvements in OS. By contrast, in patients with core binding factor AML, outcomes were excellent with DA + GO with no FLAG-Ida benefit

The Future of Our Farmland: An Agricultural Inventory for Scott County, Minnesota

Scott County contains some of the most productive agricultural soils in the metropolitan region and provides a valuable resource to produce local foods for the Twin Cities population. However, suburban growth has significantly increased land values in the rural parts of the county, creating a potential conflict between the use of land for agriculture and future urbanization. Scott County's 2030 Comprehensive Plan designates much of the existing farmland around the growing cities of Jordan, Belle Plaine, and New Prague as 'urban expansion' or 'urban transition' areas eligible for higher density development. U-CGO worked with the Scott County Department of Planning to conduct an inventory of existing agricultural uses in the county and document the impacts of agricultural production on the local economy.This project was supported by a grant from the Community Growth Options (U-CGO) program, a joint project of the Center for Urban and Regional Affairs (CURA) and the Humphrey Institute of Public Affairs at the University of Minnesota, with funding from the McKnight Foundation

Lent Township Rural Transit Center

Lent Township is located in Chisago County, along Interstate 35W. A large percentage of Lent's residents are employed in the Twin Cities and patronize merchants in communities along the I-35 travel corridor. The township also borders several well-established commercial centers in North Branch and Stacy that compete for local consumers. In 2008, Lent assumed planning and zoning authority from the county. One of its first acts was to establish a 320-acre Rural Transit Center (RTC) at the intersection of Interstate 35 and County Road 17, a busy local feeder route. Limited commercial uses are now permitted in the RTC by right or as conditional uses. Graduate students in urban and regional planning helped the township assess the potential for future commercial-industrial development in the RTC. This final report assesses market demand for, infrastructure and service needs of, employment opportunities from, and overall feasibility of three development scenarios for the RTC: (1) a light-industrial and manufacturing park (the township's preferred alternative); (2) a trail-oriented development along the Sunrise Prairie Trail, a multiuse recreational trail that has been identified as the alignment for the proposed Rush Line commuter-rail corridor; and (3) a mixed-use assisted-living and senior housing development with supportive service-retail establishments.This project was supported by a grant from the Community Growth Options (U-CGO) program, a joint project of the Center for Urban and Regional Affairs (CURA) and the Humphrey Institute of Public Affairs at the University of Minnesota, with funding from the McKnight Foundation

The closure of coal mines and local development responses in Coal-Rim Cluster, northern KwaZulu-Natal, South Africa

The impact of mine closure can have a devastating effect on the local economies of the towns that they once supported. Drawing on comparative, international material, this article examines the nature and effectiveness of the local economic development responses that have been initiated in the former coal-mining towns in northern KwaZulu-Natal in South Africa. Although a range of innovative locally identified strategies have been embarked upon, considerably greater effort and investment will be needed in order to catalyse significant and meaningful regeneration endeavours.

Safety and efficacy of pazopanib therapy prior to planned nephrectomy in metastatic clear cell renal cancer

ImportanceThe role of cytoreductive nephrectomy in patients with metastatic renal cancer in the era of targeted therapy is uncertain.ObjectiveTo establish the safety and efficacy of upfront pazopanib therapy prior to cytoreductive nephrectomy in previously untreated patients with metastatic clear cell renal cancer.Design, Setting, and ParticipantsSingle-arm phase 2 study of 104 previously untreated patients with metastatic clear cell renal cancer recruited between June 2008 and October 2012 at cancer treatment centers with access to nephrectomy services. The minimum follow-up was 30 months.InterventionsPatients received 12 to 14 weeks of preoperative pazopanib therapy prior to planned cytoreductive nephrectomy and continued pazopanib therapy after surgery. Treatment was stopped at disease progression.Main Outcomes and MeasuresThe primary end point was clinical benefit (using Response Evaluation Criteria in Solid Tumors, version 1.1) prior to surgery (at 12-14 weeks). Secondary end points included surgical complications, progression-free survival (PFS), overall survival (OS), and biomarker analysis.ResultsOf 104 patients recruited, 100 patients were assessable for clinical benefit prior to planned nephrectomy; 80 of 104 (76.9%) were men; median [interquartile range] age, 64 [56-71] years). Overall, 84 of 100 (84% [95% CI, 75%-91%]) gained clinical benefit before planned nephrectomy. The median reduction in the size of the primary tumor was 14.4% (interquartile range, 1.4%-21.1%). No patients were unable to undergo surgery as a result of local progression of disease. Nephrectomy was performed in 63 (61%) of patients; 14 (22%) reported surgical complications. The 2 most common reasons for not undergoing surgery were progression of disease (n=13) and patient choice (n=9). There was 1 postoperative surgical death. The median PFS and OS for the whole cohort were 7.1 (95% CI, 6.0-9.2) and 22.7 (95% CI, 14.3-not estimable) months, respectively. Patients with MSKCC poor-risk disease or progressive disease prior to surgery had a poor outcome (median OS, 5.7 [95% CI, 2.6-10.8] and 3.9 [95% CI, 0.5-9.1] months, respectively). Surgical complications were observed in 14 (22%) of the nephrectomies. Biomarker analysis from sequential tissue samples revealed a decrease in CD8 expression (20.00 vs 13.75; P=.05) and significant reduction in expression of von Hippel–Lindau tumor suppressor (100 vs 40; P&lt;.001) and C-MET (300 vs 100; P&lt;.001) and increased programmed cell death ligand 1 expression (0 vs 1.5; P&lt;.001) in the immune component. No on-treatment biomarker correlated with response.Conclusions and RelevanceNephrectomy after upfront pazopanib therapy could be performed safely and was associated with good outcomes in patients with intermediate-risk metastatic clear cell renal cancer