Localization-associated immune phenotypes of clonally expanded tumor-infiltrating T cells and distribution of their target antigens in rectal cancer

The degree and type of T cell infiltration influence rectal cancer prognosis regardless of classical tumor staging. We asked whether clonal expansion and tumor infiltration are restricted to selected-phenotype T cells; which clones are accessible in peripheral blood; and what the spatial distribution of their target antigens is. From five rectal cancer patients, we isolated paired tumor-infiltrating T cells (TILs) and T cells from unaffected rectum mucosa (T(UM)) using 13-parameter FACS single cell index sorting. TCRαβ sequences, cytokine, and transcription factor expression were determined with single cell sequencing. TILs and T(UM) occupied distinct phenotype compartments and clonal expansion predominantly occurred within CD8(+) T cells. Expanded TIL clones identified by paired TCRαβ sequencing and exclusively detectable in the tumor showed characteristic PD-1 and TIM-3 expression. TCRβ repertoire sequencing identified 49 out of 149 expanded TIL clones circulating in peripheral blood and 41 (84%) of these were PD-1(-) TIM-3(-). To determine whether clonal expansion of predominantly tumor-infiltrating T cell clones was driven by antigens uniquely presented in tumor tissue, selected TCRs were reconstructed and incubated with cells isolated from corresponding tumor or unaffected mucosa. The majority of clones exclusively detected in the tumor recognized antigen at both sites. In summary, rectal cancer is infiltrated with expanded distinct-phenotype T cell clones that either i) predominantly infiltrate the tumor, ii) predominantly infiltrate the unaffected mucosa, or iii) overlap between tumor, unaffected mucosa, and peripheral blood. However, the target antigens of predominantly tumor-infiltrating TIL clones do not appear to be restricted to tumor tissue

Fluctuations and Instabilities of Ferromagnetic Domain Wall pairs in an External Magnetic Field

Soliton excitations and their stability in anisotropic quasi-1D ferromagnets are analyzed analytically. In the presence of an external magnetic field, the lowest lying topological excitations are shown to be either soliton-soliton or soliton-antisoliton pairs. In ferromagnetic samples of macro- or mesoscopic size, these configurations correspond to twisted or untwisted pairs of Bloch walls. It is shown that the fluctuations around these configurations are governed by the same set of operators. The soliton-antisoliton pair has exactly one unstable mode and thus represents a critical nucleus for thermally activated magnetization reversal in effectively one-dimensional systems. The soliton-soliton pair is stable for small external fields but becomes unstable for large magnetic fields. From the detailed expression of this instability threshold and an analysis of nonlocal demagnetizing effects it is shown that the relative chirality of domain walls can be detected experimentally in thin ferromagnetic films. The static properties of the present model are equivalent to those of a nonlinear sigma-model with anisotropies. In the limit of large hard-axis anisotropy the model reduces to a double sine-Gordon model.Comment: 15 pages RevTex 3.0 (twocolumn), 9 figures available on request, to appear in Phys Rev B, Dec (1994

Age-related differences in patterns of criminal activity among a large sample of polydrug injectors in Australia

Background: The relationship between age and criminal activity among drug-using populations is poorly understood. Methods: Data from 10 years of repeat cross-sectional surveys of sentinel samples of regular people who inject drugs (PWID) across Australia (n=5844) were used to explore the relationship between age and past-month drug dealing, property crime and violent crime, and past-year arrest. Descriptive statistics were used to explore the prevalence and frequency of each outcome. The relationship between age and each outcome was measured using multivariable Poisson regression with robust error variance. Results: After adjusting for confounding factors, each 5-year increase in age was associated with significant reductions in drug dealing (adjusted incidence rate ratio [AIRR]: 0.90, 95% confidence interval [CI]: 0.87–0.94), property crime (AIRR: 0.85, 95% CI: 0.82–0.89) and violent crime (AIRR: 0.77, 95% CI: 0.70–0.85). Older participants were also significantly less likely to report being arrested in the past 12 months (AIRR: 0.91, 95% CI: 0.88–0.93). Conclusions: Younger PWID are more heavily involved in criminal activity compared with their older counterparts. This study highlights the need for early intervention programmes to prevent offending behaviour becoming entrenched, as well as continued efforts to redirect young PWID away from the criminal justice system and into treatment and education programmes

Income inequality and alcohol attributable harm in Australia

<p>Abstract</p> <p>Background</p> <p>There is little research on the relationship between key socioeconomic variables and alcohol related harms in Australia. The aim of this research was to examine the relationship between income inequality and the rates of alcohol-attributable hospitalisation and death at a local-area level in Australia.</p> <p>Method</p> <p>We conducted a cross sectional ecological analysis at a Local Government Area (LGA) level of associations between data on alcohol caused harms and income inequality data after adjusting for socioeconomic disadvantage and remoteness of LGAs.</p> <p>The main outcome measures used were matched rate ratios for four measures of alcohol caused harm; acute (primarily related to the short term consequences of drinking) and chronic (primarily related to the long term consequences of drinking) alcohol-attributable hospitalisation and acute and chronic alcohol-attributable death. Matching was undertaken using control conditions (non-alcohol-attributable) at an LGA level.</p> <p>Results</p> <p>A total of 885 alcohol-attributable deaths and 19467 alcohol-attributable hospitalisations across all LGAs were available for analysis. After weighting by the total number of cases in each LGA, the matched rate ratios of acute and chronic alcohol-attributable hospitalisation and chronic alcohol-attributable death were associated with the squared centred Gini coefficients of LGAs. This relationship was evident after adjusting for socioeconomic disadvantage and remoteness of LGAs. For both measures of hospitalisation the relationship was curvilinear; increases in income inequality were initially associated with declining rates of hospitalisation followed by large increases as the Gini coefficient increased beyond 0.15. The pattern for chronic alcohol-attributable death was similar, but without the initial decrease. There was no association between income inequality and acute alcohol-attributable death, probably due to the relatively small number of these types of death.</p> <p>Conclusion</p> <p>We found a curvilinear relationship between income inequality and the rates of some types of alcohol-attributable hospitalisation and death at a local area level in Australia. While alcohol-attributable harms generally increased with increasing income inequality, alcohol-attributable hospitalisations actually showed the reverse relationship at low levels of income inequality. The curvilinear patterns we observed are inconsistent with monotonic trends found in previous research making our findings incompatible with previous explanations of the relationship between income inequality and health related harms.</p

Incarceration history and risk of HIV and hepatitis C virus acquisition among people who inject drugs: a systematic review and meta-analysis

Background People who inject drugs (PWID) experience a high prevalence of incarceration and might be at high risk of HIV and hepatitis C virus (HCV) infection during or after incarceration. We aimed to assess whether incarceration history elevates HIV or HCV acquisition risk among PWID. Methods In this systematic review and meta-analysis, we searched MEDLINE, Embase, and PsycINFO databases for studies in any language published from Jan 1, 2000 until June 13, 2017 assessing HIV or HCV incidence among PWID. We included studies that measured HIV or HCV incidence among community-recruited PWID. We included only studies reporting original results and excluded studies that evaluated incident infections by self-report. We contacted authors of cohort studies that met the inclusion or exclusion criteria, but that did not report on the outcomes of interest, to request data. We extracted and pooled data from the included studies using random-effects meta-analyses to quantify the associations between recent (past 3, 6, or 12 months or since last follow-up) or past incarceration and HIV or HCV acquisition (primary infection or reinfection) risk among PWID. We assessed the risk of bias of included studies using the Newcastle-Ottawa Scale. Between-study heterogeneity was evaluated using the I2 statistic and the P-value for heterogeneity. Findings We included published results from 20 studies and unpublished results from 21 studies. These studies originated from Australasia, western and eastern Europe, North and Latin America, and east and southeast Asia. Recent incarceration was associated with an 81% (relative risk [RR] 1·81, 95% CI 1·40–2·34) increase in HIV acquisition risk, with moderate heterogeneity between studies (I2=63·5%; p=0·001), and a 62% (RR 1·62, 95% CI 1·28–2·05) increase in HCV acquisition risk, also with moderate heterogeneity between studies (I2=57·3%; p=0·002). Past incarceration was associated with a 25% increase in HIV (RR 1·25, 95% CI 0·94–1·65) and a 21% increase in HCV (1·21, 1·02–1·43) acquisition risk. Interpretation Incarceration is associated with substantial short-term increases in HIV and HCV acquisition risk among PWID and could be a significant driver of HCV and HIV transmission among PWID. These findings support the need for developing novel interventions to minimise the risk of HCV and HIV acquisition, including addressing structural risks associated with drug laws and excessive incarceration of PWID

Feasibility of imaging 90Y microspheres at diagnostic activity levels for hepatic radioembolization treatment planning

PURPOSE: Prior to 90 Y hepatic radioembolization, a dosage of 99m Tc-macroaggregated albumin ( 99m Tc-MAA) is administered to simulate the distribution of the 90 Y-loaded microspheres. This pretreatment procedure enables lung shunt estimation, detection of potential extrahepatic depositions, and estimation of the intrahepatic dose distribution. However, the predictive accuracy of the MAA particle distribution is often limited. Ideally, 90 Y microspheres would also be used for the pretreatment procedure. Based on previous research, the pretreatment activity should be limited to the estimated safety threshold of 100 MBq, making imaging challenging. The purpose of this study was to evaluate the quality of intra- and extrahepatic imaging of 90 Y-based pretreatment positron emission tomography/computed tomography (PET/CT) and quantitative single photon emission computed tomography (SPECT)/CT scans, by means of phantom experiments and a patient study. METHODS: An anthropomorphic phantom with three extrahepatic depositions was filled with 90 Y chloride to simulate a lung shunt fraction (LSF) of 5.3% and a tumor to nontumor ratio (T/N) of 7.9. PET /CT (Siemens Biograph mCT) and Bremsstrahlung SPECT/CT (Siemens Symbia T16) images were acquired at activities ranging from 1999 MBq down to 24 MBq, representing post- and pretreatment activities. PET/CT images were reconstructed with the clinical protocol and SPECT/CT images were reconstructed with a quantitative Monte Carlo-based reconstruction protocol. Estimated LSF, T/N, contrast to noise ratio of all extrahepatic depositions, and liver parenchymal and tumor dose were compared with the phantom ground truth. A clinically reconstructed SPECT/CT of 150 MBq 99m Tc represented the current clinical standard. In addition, a 90 Y pretreatment scan was simulated for a patient by acquiring posttreatment PET/CT and SPECT/CT data with shortened acquisition times. RESULTS: At an activity of 100 MBq 90 Y, PET/CT overestimated LSF [+10 percentage point (pp)], underestimated liver parenchymal dose (-3 Gy/GBq), and could not detect the extrahepatic depositions. SPECT/CT more accurately estimated LSF (-0.7 pp), parenchymal dose (-0.3 Gy/GBq) and could detect all three extrahepatic depositions. 99m Tc SPECT/CT showed similar accuracy as 90 Y SPECT/CT (LSF: +0.2 pp, parenchymal dose: +0.4 Gy/GBq, all extrahepatic depositions visible), although the noise level in the liver compartment was considerably lower for 99m Tc SPECT/CT compared to 90 Y SPECT/CT. The patient's SPECT/CT simulating a pretreatment 90 Y procedure accurately represented the posttreatment 90 Y microsphere distribution. CONCLUSIONS: Quantitative SPECT/CT of 100 MBq 90 Y could accurately estimate LSF, T/N, parenchymal and tumor dose, and visualize extrahepatic depositions

Training macrosystems scientists requires both interpersonal and technical skills

Macrosystems science strives to integrate patterns and processes that span regional to continental scales. The scope of such research often necessitates the involvement of large interdisciplinary and/or multi-institutional teams composed of scientists across a range of career stages, a diversity that requires researchers to hone both technical and interpersonal skills. We surveyed participants in macrosystems projects funded by the US National Science Foundation to assess the perceived importance of different skills needed in their research, as well as the types of training they received. Survey results revealed a mismatch between the skills participants perceive as important and the training they received, particularly for interpersonal and management skills. We highlight lessons learned from macrosystems training case studies, explore avenues for further improvement of undergraduate and graduate education, and discuss other training opportunities for macrosystems scientists. Given the trend toward interdisciplinary research beyond the macrosystems community, these insights are broadly applicable for scientists involved in diverse, collaborative projects.https://esajournals.onlinelibrary.wiley.com/doi/full/10.1002/fee.228