Role of Adjuvant Multimodality Therapy After Curative-Intent Resection of Ampullary Carcinoma

Importance: Ampullary adenocarcinoma is a rare malignant neoplasm that arises within the duodenal ampullary complex. The role of adjuvant therapy (AT) in the treatment of ampullary adenocarcinoma has not been clearly defined. Objective: To determine if long-term survival after curative-intent resection of ampullary adenocarcinoma may be improved by selection of patients for AT directed by histologic subtype. Design, setting, and participants: This multinational, retrospective cohort study was conducted at 12 institutions from April 1, 2000, to July 31, 2017, among 357 patients with resected, nonmetastatic ampullary adenocarcinoma receiving surgery alone or AT. Cox proportional hazards regression was used to identify covariates associated with overall survival. The surgery alone and AT cohorts were matched 1:1 by propensity scores based on the likelihood of receiving AT or by survival hazard from Cox modeling. Overall survival was compared with Kaplan-Meier estimates. Exposures: Adjuvant chemotherapy (fluorouracil- or gemcitabine-based) with or without radiotherapy. Main outcomes and measures: Overall survival. Results: A total of 357 patients (156 women and 201 men; median age, 65.8 years [interquartile range, 58-74 years]) underwent curative-intent resection of ampullary adenocarcinoma. Patients with intestinal subtype had a longer median overall survival compared with those with pancreatobiliary subtype (77 vs 54 months; P = .05). Histologic subtype was not associated with AT administration (intestinal, 52.9% [101 of 191]; and pancreatobiliary, 59.5% [78 of 131]; P = .24). Patients with pancreatobiliary histologic subtype most commonly received gemcitabine-based regimens (71.0% [22 of 31]) or combinations of gemcitabine and fluorouracil (12.9% [4 of 31]), whereas treatment of those with intestinal histologic subtype was more varied (fluorouracil, 50.0% [17 of 34]; gemcitabine, 44.1% [15 of 34]; P = .01). In the propensity score-matched cohort, AT was not associated with a survival benefit for either histologic subtype (intestinal: hazard ratio, 1.21; 95% CI, 0.67-2.16; P = .53; pancreatobiliary: hazard ratio, 1.35; 95% CI, 0.66-2.76; P = .41). Conclusions and relevance: Adjuvant therapy was more frequently used in patients with poor prognostic factors but was not associated with demonstrable improvements in survival, regardless of tumor histologic subtype. The value of a multimodality regimen remains poorly defined

Metabolic phenotype of methylmalonic acidemia in mice and humans: the role of skeletal muscle

<p>Abstract</p> <p>Background</p> <p>Mutations in methylmalonyl-CoA mutase cause methylmalonic acidemia, a common organic aciduria. Current treatment regimens rely on dietary management and, in severely affected patients, liver or combined liver-kidney transplantation. For undetermined reasons, transplantation does not correct the biochemical phenotype.</p> <p>Methods</p> <p>To study the metabolic disturbances seen in this disorder, we have created a murine model with a null allele at the methylmalonyl-CoA mutase locus and correlated the results observed in the knock-out mice to patient data. To gain insight into the origin and magnitude of methylmalonic acid (MMA) production in humans with methylmalonyl-CoA mutase deficiency, we evaluated two methylmalonic acidemia patients who had received different variants of combined liver-kidney transplants, one with a complete liver replacement-kidney transplant and the other with an auxiliary liver graft-kidney transplant, and compared their metabolite production to four untransplanted patients with intact renal function.</p> <p>Results</p> <p>Enzymatic, Western and Northern analyses demonstrated that the targeted allele was null and correctable by lentiviral complementation. Metabolite studies defined the magnitude and tempo of plasma MMA concentrations in the mice. Before a fatal metabolic crisis developed in the first 24–48 hours, the methylmalonic acid content per gram wet-weight was massively elevated in the skeletal muscle as well as the kidneys, liver and brain. Near the end of life, extreme elevations in tissue MMA were present primarily in the liver. The transplant patients studied when well and on dietary therapy, displayed massive elevations of MMA in the plasma and urine, comparable to the levels seen in the untransplanted patients with similar enzymatic phenotypes and dietary regimens.</p> <p>Conclusion</p> <p>The combined observations from the murine metabolite studies and patient investigations indicate that during homeostasis, a large portion of circulating MMA has an extra-heptorenal origin and likely derives from the skeletal muscle. Our studies suggest that modulating skeletal muscle metabolism may represent a strategy to increase metabolic capacity in methylmalonic acidemia as well as other organic acidurias. This mouse model will be useful for further investigations exploring disease mechanisms and therapeutic interventions in methylmalonic acidemia, a devastating disorder of intermediary metabolism.</p

Several Cancer Susceptibility Variants Also Affect Melanoma Risk

<div><p>Background</p><p>Several regions of the genome show pleiotropic associations with multiple cancers. We sought to evaluate whether 181 single-nucleotide polymorphisms previously associated with various cancers in genome-wide association studies were also associated with melanoma risk.</p><p>Methods</p><p>We evaluated 2,131 melanoma cases and 20,353 controls from three studies in the Population Architecture using Genomics and Epidemiology (PAGE) study (EAGLE-BioVU, MEC, WHI) and two collaborating studies (HPFS, NHS). Overall and sex-stratified analyses were performed across studies.</p><p>Results</p><p>We observed statistically significant associations with melanoma for two lung cancer SNPs in the <i>TERT-CLPTM1L</i> locus (Bonferroni-corrected p<2.8x10^-4), replicating known pleiotropic effects at this locus. In sex-stratified analyses, we also observed a potential male-specific association between prostate cancer risk variant rs12418451 and melanoma risk (OR=1.22, p=8.0x10^-4). No other variants in our study were associated with melanoma after multiple comparisons adjustment (p>2.8e^-4).</p><p>Conclusions</p><p>We provide confirmatory evidence of pleiotropic associations with melanoma for two SNPs previously associated with lung cancer, and provide suggestive evidence for a male-specific association with melanoma for prostate cancer variant rs12418451. This SNP is located near <i>TPCN2</i>, an ion transport gene containing SNPs which have been previously associated with hair pigmentation but not melanoma risk. Previous evidence provides biological plausibility for this association, and suggests a complex interplay between ion transport, pigmentation, and melanoma risk that may vary by sex. If confirmed, these pleiotropic relationships may help elucidate shared molecular pathways between cancers and related phenotypes.</p></div

Civil society leadership in the struggle for AIDS treatment in South Africa and Uganda

Includes abstract.Includes bibliographical references.This thesis is an attempt to theorise and operationalise empirically the notion of ‘civil society leadership’ in Sub-Saharan Africa. ‘AIDS leadership,’ which is associated with the intergovernmental institutions charged with coordinating the global response to HIV/AIDS, is both under-theorised and highly context-specific. In this study I therefore opt for an inclusive framework that draws on a range of approaches, including the literature on ‘leadership’, institutions, social movements and the ‘network’ perspective on civil society mobilisation. This framework is employed in rich and detailed empirical descriptions (‘thick description’) of civil society mobilisation around AIDS, including contentious AIDS activism, in the key case studies of South Africa and Uganda. South Africa and Uganda are widely considered key examples of poor and good leadership (from national political leaders) respectively, while the Treatment Action Campaign (TAC) and The AIDS Support Organisation (TASO) are both seen as highly effective civil society movements. These descriptions emphasise ‘transnational networks of influence’ in which civil society leaders participated (and at times actively constructed) in order to mobilise both symbolic and material resources aimed at exerting influence at the transnational, national and local levels

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

Para-infectious brain injury in COVID-19 persists at follow-up despite attenuated cytokine and autoantibody responses

To understand neurological complications of COVID-19 better both acutely and for recovery, we measured markers of brain injury, inflammatory mediators, and autoantibodies in 203 hospitalised participants; 111 with acute sera (1–11 days post-admission) and 92 convalescent sera (56 with COVID-19-associated neurological diagnoses). Here we show that compared to 60 uninfected controls, tTau, GFAP, NfL, and UCH-L1 are increased with COVID-19 infection at acute timepoints and NfL and GFAP are significantly higher in participants with neurological complications. Inflammatory mediators (IL-6, IL-12p40, HGF, M-CSF, CCL2, and IL-1RA) are associated with both altered consciousness and markers of brain injury. Autoantibodies are more common in COVID-19 than controls and some (including against MYL7, UCH-L1, and GRIN3B) are more frequent with altered consciousness. Additionally, convalescent participants with neurological complications show elevated GFAP and NfL, unrelated to attenuated systemic inflammatory mediators and to autoantibody responses. Overall, neurological complications of COVID-19 are associated with evidence of neuroglial injury in both acute and late disease and these correlate with dysregulated innate and adaptive immune responses acutely

Weather, Ocean, and Social Aspects Associated with Rip Current Deaths in the United States

The purpose of this research is to provide a better understanding of the physical and social aspects of rip currents in ocean areas that will lead to better forecasts, better governmental policies in beach areas, and ultimately to save lives. The primary factors associated with rip current formation on beaches are variations in the local beach bathymetry, wind-generated waves of significant wave height typically 1 m or higher, and lower tidal stages. The methodology followed for this study included a review of demographics from over 500 rip current drowning reports along the Atlantic Ocean, Pacific Ocean and Gulf of Mexico coasts of the United States. This research indicated that tourists are often the victims and rescuers often become the victims. For each state or sub-state area where rip current drownings are prevalent, an analysis of social aspects and associated ocean and weather patterns was conducted using buoy and tide data and composite weather patterns. It is important to understand the evolution of these fatal events with respect to the trends of wave height, period, and pressure patterns and resulting surface wind fields that produce the waves

Interrelationships among Wind Direction, Atmospheric Moisture Content and Stability with the Spatial Distribution of Rainfall and the Occurrence of Severe Weather in Pinellas County, FL

To improve the operational prediction of local mesoscale phenomena the interrelationships among wind direction, atmospheric moisture content and stability with the spatial distribution of rainfall and the occurrence of severe weather in Pinellas County in west central Florida was examined. This peninsular county has some unique topographic features and sea breeze patterns that cause forecast challenges. The 1200 UTC soundings taken at Ruskin, Florida during June-August, 1995-2009 we used to first identify the predominate wind directions over the county. The sounding data were then used to further classify days by moisture content (i.e., total precipitable water) and thermodynamic stability (i.e., Convective Available Potential Energy). Composite precipitation maps were then produced. The primary influence of rainfall distribution was wind direction, with less rain falling over the peninsula on days with westerly flow than those with easterly flow. Moisture and stability had secondary effects on the location and amount of precipitation in the county. An operational guide was developed to help forecasters develop more accurate quantitative precipitation forecasts. The likelihood of severe weather was also related to wind direction, with more events occurring during easterly flow than westerly. The most significant severe weather cases were examined to determine the influence of sea breeze and outflow boundary interactions, and also the development and vertical extent of the convection, leading to rainfall and severe weather over the county. The identification of such high impact events (tornadoes, downbursts, hail, and waterspouts) are of particular interest and an operational guide and Graphical Forecast Editor Smart Tool were developed to provide information to forecasters of the possibility of severe weather