Mucosal-associated invariant T (MAIT) cells are activated in the gastrointestinal tissue of patients with combination ipilimumab and nivolumab therapy-related colitis in a pathology distinct from ulcerative colitis.

The aim of this study was to investigate the pathogenesis of combination ipilimumab and nivolumab-associated colitis (IN-COL) by measuring gut-derived and peripheral blood mononuclear cell (GMNC; PBMC) profiles. We studied GMNC and PBMC from patients with IN-COL, IN-treated with no adverse-events (IN-NAE), ulcerative colitis (UC) and healthy volunteers using flow cytometry. In the gastrointestinal-derived cells we found high levels of activated CD8+ T cells and mucosal-associated invariant T (MAIT) cells in IN-COL, changes that were not evident in IN-NAE or UC. UC, but not IN-C, was associated with a high proportion of regulatory T cells (Treg ). We sought to determine if local tissue responses could be measured in peripheral blood. Peripherally, checkpoint inhibition instigated a rise in activated memory CD4+ and CD8+ T cells, regardless of colitis. Low circulating MAIT cells at baseline was associated with IN-COL patients compared with IN-NAE in one of two cohorts. UC, but not IN-COL, was associated with high levels of circulating plasmablasts. In summary, the alterations in T cell subsets measured in IN-COL-affected tissue, characterized by high levels of activated CD8+ T cells and MAIT cells and a low proportion of Treg , reflected a pathology distinct from UC. These tissue changes differed from the periphery, where T cell activation was a widespread on-treatment effect, and circulating MAIT cell count was low but not reliably predictive of colitis.

Early changes in bone turnover and inflammatory biomarkers and clinically significant bone mineral density loss over 48 weeks among HIV-infected patients with virological failure of a standard first-line antiretroviral therapy regimen in the SECOND-LINE study.

OBJECTIVES: We assessed whether changes at week 12 in markers of bone turnover, inflammation, and immune activation were associated with clinically important (≥ 5%) bone mineral density (BMD) loss from baseline to week 48 at the proximal femur (hip) and lumbar spine in the SECOND-LINE study. METHODS: We measured concentrations of procollagen type 1 pro-peptide (P1NP), carboxyl-terminal collagen crosslinks (CTX), high-sensitivity C-reactive protein (hs-CRP), D-dimer, interleukin (IL)-6, tumor necrosis factor (TNF), neopterin, and soluble CD14 and 163 at weeks 0, 12, and 48 in 123 SECOND-LINE dual-energy X-ray absorptiometry (DXA) substudy participants. Linear regression was used to compare changes in biomarkers. Predictors of ≥ 5% BMD loss were examined using multivariable regression. RESULTS: The mean age was 38 years, the mean CD4 T-cell count was 252 cells/µL and the mean viral load was 4.2 log HIV-1 RNA copies/mL; 56% of participants were female and 47% were randomized to receive a nucleos(t)ide reverse transcriptase inhibitor [N(t)RTI]-based regimen [91% (53/58) were randomized to receive a tenofovir disoproxil fumarate (TDF)-containing regimen]. Over 48 weeks, 71% in the N(t)RTI arm experienced ≥ 5% hip BMD loss vs. 29% in the raltegravir arm (P = 0.001). Week 12 changes in P1NP and CTX were significantly greater among patients experiencing ≥ 5% hip BMD loss, patients randomized to N(t)RTI, and male patients. Predictors of ≥ 5% hip BMD loss at week 48 were P1NP increase [odds ratio (OR) 5.0; 95% confidence interval (CI) 1.1-27; P < 0.043]; N(t)RTI randomization (OR 6.7; 95% CI 2.0-27.1; P < 0.003), being African, higher baseline CD4 T cell count , and smoking. CONCLUSIONS: In a diverse cohort of viraemic HIV-infected patients, switching to second-line antiretroviral therapy (ART) was associated with clinically significant BMD loss, which was correlated with an early increase in P1NP. Measurement of P1NP may facilitate timely interventions to reduce rapid BMD loss among at-risk patients.

Week 96 results of the randomized, multicentre Maraviroc Switch (MARCH) study.

OBJECTIVES: The Maraviroc Switch (MARCH) study week 48 data demonstrated that maraviroc, a chemokine receptor-5 (CCR5) inhibitor, was a safe and effective switch for the ritonavir-boosted protease inhibitor (PI/r) component of a two nucleos(t)ide reverse transcriptase inhibitor [N(t)RTI] plus PI/r-based antiretroviral regimen in patients with R5-tropic virus. Here we report the durability of this finding. METHODS: MARCH, an international, multicentre, randomized, 96-week open-label switch study, enrolled HIV-1-infected adults with R5-tropic virus who were stable (> 24 weeks) and virologically suppressed [plasma viral load (pVL) < 50 HIV-1 RNA copies/mL]. Participants were randomized to continue their current PI/r-based regimen (PI/r) or to switch to MVC plus two N(t)RTIs (MVC) (1:2 randomization). The primary endpoint was the difference in the proportion with pVL < 200 copies/mL at 96 weeks. The switch arm was defined as noninferior if the lower limit of the 95% confidence interval (CI) for the difference was < -12% in the intention-to-treat (ITT) population. Safety endpoints (the difference in the mean change from baseline or a comparison of proportions) were analysed as key secondary endpoints. RESULTS: Eighty-two (PI/r) and 156 (MVC) participants were randomized and included in the ITT analysis; 71 (87%) and 130 (83%) were in follow-up and on therapy at week 96. At week 96, 89.0% and 90.4% in the PI/r and MVC arms, respectively, had pVL < 50 copies/mL (95% CI -6.6, 10.2). Moreover, in those switching away from PI/r, there were significant reductions in mean total cholesterol (differences 0.31 mmol/L; P = 0.02) and triglycerides (difference 0.44 mmol/L; P < 0.001). Changes in CD4 T-cell count, renal function, and serious and nonserious adverse events were similar in the two arms. CONCLUSIONS: MVC as a switch for a PI/r is safe and effective at maintaining virological suppression while having significant lipid benefits over 96 weeks.

Rosenbluth Separation of the π

We report the first longitudinal-transverse separation of the deeply virtual exclusive π^{0} electroproduction cross section off the neutron and coherent deuteron. The corresponding four structure functions dσ_{L}/dt, dσ_{T}/dt, dσ_{LT}/dt, and dσ_{TT}/dt are extracted as a function of the momentum transfer to the recoil system at Q^{2}=1.75 GeV^{2} and x_{B}=0.36. The ed→edπ^{0} cross sections are found compatible with the small values expected from theoretical models. The en→enπ^{0} cross sections show a dominance from the response to transversely polarized photons, and are in good agreement with calculations based on the transversity generalized parton distributions of the nucleon. By combining these results with previous measurements of π^{0} electroproduction off the proton, we present a flavor decomposition of the u and d quark contributions to the cross section.

JLab Measurements of the

The charge and magnetic form factors, F_{C} and F_{M}, respectively, of ^{3}He are extracted in the kinematic range 25 fm^{-2}≤Q^{2}≤61 fm^{-2} from elastic electron scattering by detecting ^{3}He recoil nuclei and scattered electrons in coincidence with the two High Resolution Spectrometers of the Hall A Facility at Jefferson Lab. The measurements find evidence for the existence of a second diffraction minimum for the magnetic form factor at Q^{2}=49.3 fm^{-2} and for the charge form factor at Q^{2}=62.0 fm^{-2}. Both minima are predicted to exist in the Q^{2} range accessible by this Jefferson Lab experiment. The data are in qualitative agreement with theoretical calculations based on realistic interactions and accurate methods to solve the three-body nuclear problem.

Publisher's Note: JLab Measurements of the

This corrects the article DOI: 10.1103/PhysRevLett.119.162501.

Hepatitis C-specific effector and regulatory CD4 T-cell responses are associated with the outcomes of primary infection.

Clearance of primary hepatitis C virus (HCV) infection has been associated with strong and broadly targeted cellular immune responses. This study aimed to characterize HCV-specific CD4+ effector and regulatory T-cell numbers and cytokine production during primary infection. Antigen-specific CD4+ T-cell responses were investigated in a longitudinal cohort of subjects from pre-infection to postoutcome, including subjects who cleared [n=12] or became chronically infected [n=17]. A cross-sectional cohort with previously cleared, or chronic infection [n=15 for each], was also studied. Peripheral blood mononuclear cells were incubated with HCV antigens and surface stained for T-effector (CD4+CD25high CD134+CD39-) and T-regulatory (CD4+CD25high CD134+CD39+) markers, and culture supernatants assayed for cytokine production. Contrary to expectations, the breadth and magnitude of the HCV-specific CD4+ T-cell responses were higher in subjects who became chronically infected. Subjects who cleared the virus had HCV-specific CD4+ T-cell responses dominated by effector T cells and produced higher levels of IFN-γ, in contrast to HCV-specific CD4+ T-cell responses dominated by regulatory T cells and more IL-10 production in those who became chronically infected. Better understanding of the role of antigen-specific CD4+ T-cell responses in primary HCV will further define pathogenesis and help guide development of a preventative vaccine.

Rosenbluth Separation of the π

We present deeply virtual π^{0} electroproduction cross-section measurements at x_{B}=0.36 and three different Q^{2} values ranging from 1.5 to 2 GeV^{2}, obtained from Jefferson Lab Hall A experiment E07-007. The Rosenbluth technique is used to separate the longitudinal and transverse responses. Results demonstrate that the cross section is dominated by its transverse component and, thus, is far from the asymptotic limit predicted by perturbative quantum chromodynamics. Nonetheless, an indication of a nonzero longitudinal contribution is provided by the measured interference term σ_{LT}. Results are compared with several models based on the leading-twist approach of generalized parton distributions (GPDs). In particular, a fair agreement is obtained with models in which the scattering amplitude includes convolution terms of chiral-odd (transversity) GPDs of the nucleon with the twist-3 pion distribution amplitude. This experiment, together with previous extensive unseparated measurements, provides strong support to the exciting idea that transversity GPDs can be accessed via neutral pion electroproduction in the high-Q^{2} regime.

Polarization Transfer in Wide-Angle Compton Scattering and Single-Pion Photoproduction from the Proton.

Wide-angle exclusive Compton scattering and single-pion photoproduction from the proton have been investigated via measurement of the polarization transfer from a circularly polarized photon beam to the recoil proton. The wide-angle Compton scattering polarization transfer was analyzed at an incident photon energy of 3.7 GeV at a proton scattering angle of θ_{cm}^{p}=70°. The longitudinal transfer K_{LL}, measured to be 0.645±0.059±0.048, where the first error is statistical and the second is systematic, has the same sign as predicted for the reaction mechanism in which the photon interacts with a single quark carrying the spin of the proton. However, the observed value is ~3 times larger than predicted by the generalized-parton-distribution-based calculations, which indicates a significant unknown contribution to the scattering amplitude.

Anal intraepithelial neoplasia and squamous cell carcinoma in HIV-infected adults.

Anal cancer is one of the most common non-AIDS-defining malignancies in the era of combination antiretroviral therapy. Its precursor lesion, anal intraepithelial neoplasia (AIN), is highly prevalent in HIV-infected populations. More than 90% of anal squamous cell cancers are attributable to human papillomavirus (HPV). While the biology of HPV-related intraepithelial neoplasia is consistent across lower anogenital sites, the natural history of AIN is not well established and cannot be assumed to be identical to that of cervical intraepithelial neoplasia. Screening strategies to prevent anal cancer should be developed based on robust natural history data in HIV-infected and uninfected populations. Likewise, treatments need to be tested in randomized clinical trials, and reserved for those at significant risk of progression to cancer. This review covers the epidemiology, pathogenesis and immunology of HPV infection, AIN and anal cancer, and summarizes the current diagnosis, screening and treatment strategies in HIV-infected adults.

Precision measurement of the neutron twist-3 matrix element d(2)(n): probing color forces.

Double-spin asymmetries and absolute cross sections were measured at large Bjorken x (0.25≤x≤0.90), in both the deep-inelastic and resonance regions, by scattering longitudinally polarized electrons at beam energies of 4.7 and 5.9 GeV from a transversely and longitudinally polarized (3)He target. In this dedicated experiment, the spin structure function g(2)((3)He) was determined with precision at large x, and the neutron twist-3 matrix element d(2)(n) was measured at ⟨Q(2)⟩ of 3.21 and 4.32 GeV(2)/c(2), with an absolute precision of about 10(-5). Our results are found to be in agreement with lattice QCD calculations and resolve the disagreement found with previous data at ⟨Q(2)⟩=5 GeV(2)/c(2). Combining d(2)(n) and a newly extracted twist-4 matrix element f(2)(n), the average neutron color electric and magnetic forces were extracted and found to be of opposite sign and about 30 MeV/fm in magnitude.

Probing the repulsive core of the nucleon-nucleon interaction via the (4)He(e,e'pN) triple-coincidence reaction.

We studied simultaneously the (4)He(e,e'p), (4)He(e,e'pp), and (4)He(e,e'pn) reactions at Q(2)=2(GeV/c)(2) and x(B)>1, for an (e,e'p) missing-momentum range of 400 to 830 MeV/c. The knocked-out proton was detected in coincidence with a proton or neutron recoiling almost back to back to the missing momentum, leaving the residual A=2 system at low excitation energy. These data were used to identify two-nucleon short-range correlated pairs and to deduce their isospin structure as a function of missing momentum, in a region where the nucleon-nucleon (NN) force is expected to change from predominantly tensor to repulsive. The abundance of neutron-proton pairs is reduced as the nucleon momentum increases beyond ∼500 MeV/c. The extracted fraction of proton-proton pairs is small and almost independent of the missing momentum. Our data are compared with calculations of two-nucleon momentum distributions in (4)He and discussed in the context of probing the elusive repulsive component of the NN force.

JLab measurement of the 4He charge form factor at large momentum transfers.

The charge form factor of 4He has been extracted in the range 29 fm(-2) ≤ Q2 ≤ 77 fm(-2) from elastic electron scattering, detecting 4He recoil nuclei and electrons in coincidence with the high resolution spectrometers of the Hall A Facility of Jefferson Lab. The measurements have uncovered a second diffraction minimum for the form factor, which was predicted in the Q2 range of this experiment. The data are in qualitative agreement with theoretical calculations based on realistic interactions and accurate methods to solve the few-body problem.

Transmission of megawatt relativistic electron beams through millimeter apertures.

High-power, relativistic electron beams from energy-recovering linacs have great potential to realize new experimental paradigms for pioneering innovation in fundamental and applied research. A major design consideration for this new generation of experimental capabilities is the understanding of the halo associated with these bright, intense beams. In this Letter, we report on measurements performed using the 100 MeV, 430 kW cw electron beam from the energy-recovering linac at the Jefferson Laboratory's Free Electron Laser facility as it traversed a set of small apertures in a 127 mm long aluminum block. Thermal measurements of the block together with neutron measurements near the beam-target interaction point yielded a consistent understanding of the beam losses. These were determined to be 3 ppm through a 2 mm diameter aperture and were maintained during a 7 h continuous run.

Search for a new gauge boson in electron-nucleus fixed-target scattering by the APEX experiment.

We present a search at the Jefferson Laboratory for new forces mediated by sub-GeV vector bosons with weak coupling α' to electrons. Such a particle A' can be produced in electron-nucleus fixed-target scattering and then decay to an e + e- pair, producing a narrow resonance in the QED trident spectrum. Using APEX test run data, we searched in the mass range 175-250 MeV, found no evidence for an A'→ e+ e- reaction, and set an upper limit of α'/α ~/= 10(-6). Our findings demonstrate that fixed-target searches can explore a new, wide, and important range of masses and couplings for sub-GeV forces.

A quality assurance programme for cell salvage in cardiac surgery.

At the same time as cell salvage was introduced into our institution for all patients undergoing cardiac surgery with cardiopulmonary bypass, we established a supporting programme of quality assurance to reassure clinicians regarding safety and efficacy. Data collected in patients operated on between 2001 and 2007 included pre- and post-wash heparin concentration, haemoglobin concentration and free haemoglobin concentration. Cell salvage was used in 6826 out of a total of 7243 patients (94%). Post-wash heparin concentration was consistently low (always < 0.4 IU.ml(-1)). There was a significant decrease in post-wash haemoglobin concentration in 2003 compared to 2001, from a median (IQR [range]) of 19.6 (16.7-22.2 [12.9-25.5]) g.dl(-1) to 17.5 (13.6-20.8 [12.6-23.7]) g.dl(-1) (p < 0.015). In addition, there was a significant increase in free plasma haemoglobin in 2006 compared to 2001, from 0.5 (0.3-0.8 [0.1-2.6]) g.l(-1) to 0.8 (0.3-1.4 [0.3-5.2]) g.l(-1) (p < 0.001). This programme led to the detection of a change in operator behaviour in 2003 and progressive machine deterioration resulting in appropriate fleet replacement in 2006. You can respond to this article at http://www.anaesthesiacorrespondence.com.

Oligoclonal expansions of CD8(+) T cells in chronic HIV infection are antigen specific.

Acute HIV infection is associated with a vigorous immune response characterized by the proliferation of selected T cell receptor V beta (BV)-expressing CD8(+) T cells. These 'expansions', which are commonly detected in the peripheral blood, can persist during chronic HIV infection and may result in the dominance of particular clones. Such clonal populations are most consistent with antigen-driven expansions of CD8(+) T cells. However, due to the difficulties in studying antigen-specific T cells in vivo, it has been hard to prove that oligoclonal BV expansions are actually HIV specific. The use of tetrameric major histocompatibility complex-peptide complexes has recently enabled direct visualization of antigen-specific T cells ex vivo but has not provided information on their clonal composition. We have now made use of these tetrameric complexes in conjunction with anti-BV chain-specific monoclonal antibodies and analysis of cytotoxic T lymphocyte lines/clones to show that chronically clonally expanded CD8(+) T cells are HIV specific in vivo.

Clustered mutations in HIV-1 gag are consistently required for escape from HLA-B27-restricted cytotoxic T lymphocyte responses.

The immune response to HIV-1 in patients who carry human histocompatibility leukocyte antigen (HLA)-B27 is characterized by an immunodominant response to an epitope in p24 gag (amino acids 263-272, KRWIILGLNK). Substitution of lysine (K) or glycine (G) for arginine (R) at HIV-1 gag residue 264 (R264K and R264G) results in epitopes that bind to HLA-B27 poorly. We have detected a R264K mutation in four patients carrying HLA-B27. In three of these patients the mutation occurred late, coinciding with disease progression. In another it occurred within 1 yr of infection and was associated with a virus of syncytium-inducing phenotype. In each case, R264K was tightly associated with a leucine to methionine change at residue 268. After the loss of the cytotoxic T lymphocyte (CTL) response to this epitope and in the presence of high viral load, reversion to wild-type sequence was observed. In a fifth patient, a R264G mutation was detected when HIV-1 disease progressed. Its occurrence was associated with a glutamic acid to aspartic acid mutation at residue 260. Phylogenetic analyses indicated that these substitutions emerged under natural selection rather than by genetic drift or linkage. Outgrowth of CTL escape viruses required high viral loads and additional, possibly compensatory, mutations in the gag protein.

Measurements of the electric form factor of the neutron up to Q2=3.4 GeV2 using the reaction 3He(e,e'n)pp.

The electric form factor of the neutron was determined from studies of the reaction 3He(e,e'n)pp in quasielastic kinematics in Hall A at Jefferson Lab. Longitudinally polarized electrons were scattered off a polarized target in which the nuclear polarization was oriented perpendicular to the momentum transfer. The scattered electrons were detected in a magnetic spectrometer in coincidence with neutrons that were registered in a large-solid-angle detector. More than doubling the Q2 range over which it is known, we find G(E)(n)=0.0236±0.0017(stat)±0.0026(syst), 0.0208±0.0024±0.0019, and 0.0147±0.0020±0.0014 for Q(2)=1.72, 2.48, and 3.41 GeV2, respectively.

Transmission of triple-class, drug-resistant HIV-1 in Australia.

We report the first two cases of transmitted triple-class, drug-resistant HIV-1 in Australia. Baseline testing of a newly diagnosed man showed four reverse transcriptase resistance mutations (affecting two drug classes) and six protease resistance mutations. A source patient was identified, and a likely second case newly infected 1 year later, suggesting sequential transmission. This raises therapeutic implications for the individual patients, as well as public health concerns.