Immune-related adverse events (irAEs) typically occur within 4 months of starting anti-programmed cell death protein 1 (PD-1)-based therapy anti-PD-1 ± anti-cytotoxic T-lymphocyte-associated protein ...4 (CTLA4), but delayed irAEs (onset >12 months after commencement) can also occur. This study describes the incidence, nature and management of delayed irAEs in patients receiving anti-PD-1-based immunotherapy.
Patients with delayed irAEs from 20 centres were studied. The incidence of delayed irAEs was estimated as a proportion of melanoma patients treated with anti-PD-1-based therapy and surviving >1 year. Onset, clinical features, management and outcomes of irAEs were examined.
One hundred and eighteen patients developed a total of 140 delayed irAEs (20 after initial combination with anti-CTLA4), with an estimated incidence of 5.3% (95% confidence interval 4.0-6.9, 53/999 patients at sites with available data). The median onset of delayed irAE was 16 months (range 12-53 months). Eighty-seven patients (74%) were on anti-PD-1 at irAE onset, 15 patients (12%) were <3 months from the last dose and 16 patients (14%) were >3 months from the last dose of anti-PD-1. The most common delayed irAEs were colitis, rash and pneumonitis; 55 of all irAEs (39%) were ≥grade 3. Steroids were required in 80 patients (68%), as well as an additional immunosuppressive agent in 27 patients (23%). There were two irAE-related deaths: encephalitis with onset during anti-PD-1 and a multiple-organ irAE with onset 11 months after ceasing anti-PD-1. Early irAEs (<12 months) had also occurred in 69 patients (58%), affecting a different organ from the delayed irAE in 59 patients (86%).
Delayed irAEs occur in a small but relevant subset of patients. Delayed irAEs are often different from previous irAEs, may be high grade and can lead to death. They mostly occur in patients still receiving anti-PD-1. The risk of delayed irAE should be considered when deciding the duration of treatment in responding patients. However, patients who stop treatment may also rarely develop delayed irAE.
•The incidence of delayed irAEs >12 months after commencing anti-PD-1 was 5.3%.•Delayed irAEs occurred in 118 patients; these were often high grade (39% G3+) including two delayed irAE-related deaths.•Delayed irAEs were often difficult to manage; 68% required steroids and 23% required an additional immunosuppressive agent.•Most occurred during anti-PD-1 therapy (74%), but delayed irAEs were also reported up to 26 months after stopping anti-PD-1.
Most studies of the role of biological entities as atmospheric ice-nucleating particles have focused on relatively rare supermicron particles such as bacterial cells, fungal spores and pollen grains. ...However, it is not clear that there are sufficient numbers of these particles in the atmosphere to strongly influence clouds. Here we show that the ice-nucleating activity of a fungus from the ubiquitous genus Fusarium is related to the presence of nanometre-scale particles which are far more numerous, and therefore potentially far more important for cloud glaciation than whole intact spores or hyphae. In addition, we quantify the ice-nucleating activity of nano-ice nucleating particles (nano-INPs) washed off pollen and also show that nano-INPs are present in a soil sample. Based on these results, we suggest that there is a reservoir of biological nano-INPs present in the environment which may, for example, become aerosolised in association with fertile soil dust particles.
Abiotic stresses affect plant physiology, development, growth, and alter pre-mRNA splicing. Western poplar is a model woody tree and a potential bioenergy feedstock. To investigate the extent of ...stress-regulated alternative splicing (AS), we conducted an in-depth survey of leaf, root, and stem xylem transcriptomes under drought, salt, or temperature stress. Analysis of approximately one billion of genome-aligned RNA-Seq reads from tissue- or stress-specific libraries revealed over fifteen millions of novel splice junctions. Transcript models supported by both RNA-Seq and single molecule isoform sequencing (Iso-Seq) data revealed a broad array of novel stress- and/or tissue-specific isoforms. Analysis of Iso-Seq data also resulted in the discovery of 15,087 novel transcribed regions of which 164 show AS. Our findings demonstrate that abiotic stresses profoundly perturb transcript isoform profiles and trigger widespread intron retention (IR) events. Stress treatments often increased or decreased retention of specific introns - a phenomenon described here as differential intron retention (DIR). Many differentially retained introns were regulated in a stress- and/or tissue-specific manner. A subset of transcripts harboring super stress-responsive DIR events showed persisting fluctuations in the degree of IR across all treatments and tissue types. To investigate coordinated dynamics of intron-containing transcripts in the study we quantified absolute copy number of isoforms of two conserved transcription factors (TFs) using Droplet Digital PCR. This case study suggests that stress treatments can be associated with coordinated switches in relative ratios between fully spliced and intron-retaining isoforms and may play a role in adjusting transcriptome to abiotic stresses.
The purpose of this study was to assess impact of different volumes of exercise as well as cumulative moderate to vigorous physical activity (MVPA) on energy intake (EI) and diet quality, as assessed ...by the Healthy Eating Index-2010(HEI-2010), across a 12-month weight maintenance intervention. Participants were asked to attend group behavioural sessions, eat a diet designed for weight maintenance and exercise either 150, 225 or 300 min/week. Dietary intake was assessed by 3-d food records, and MVPA was assessed by accelerometry. Two hundred and twenty-four participants (42·5 years of age, 82 % female) provided valid dietary data for at least one time point. There was no evidence of group differences in EI, total HEI-2010 score or any of the HEI-2010 component scores (all
> 0·05). After adjusting for age, sex, time, group and group-by-time interactions, there was an effect of cumulative MVPA on EI (1·08,
= 0·04), total HEI-2010 scores (-0·02,
= 0·003), Na (-0·006,
= 0·002) and empty energy scores (-0·007,
= 0·004. There was evidence of a small relationship between cumulative daily EI and weight (
: 0·00187, 95 % CI 0·001,
= 0·003). However, there was no evidence for a relationship between HEI total score (
: -0·006, 95 % CI 0·07, 0·06) or component scores (all
> 0·05) and change in weight across time. The results of this study suggest that increased cumulative MVPA is associated with clinically insignificant increases in EI and decreases in HEI.
The Axion Dark Matter eXperiment (ADMX) has previously excluded Dine-Fischler-Srednicki- Zhitnisky (DFSZ) axions between 680-790 MHz under the assumption that the dark matter is described by the ...isothermal halo model. However, the precise nature of the velocity distribution of dark matter is still unknown, and alternative models have been proposed. Here, we report the results of a non-virialized axion search over the mass range 2.81–3.31 µeV, corresponding to the frequency range 680–800 MHz. This analysis marks the most sensitive search for non-virialized axions sensitive to Doppler effects in the Milky Way Halo to date. Accounting for frequency shifts due to the detector’s motion through the Galaxy, we exclude cold flow relic axions with a velocity dispersion of $\mathscr{O}$(10-7)c with 95% confidence.
Since 2003, over 2000 cases of lymphogranuloma venereum (LGV) have been diagnosed in the U.K. in men who have sex with men (MSM). Most cases present with proctitis, but there are limited data on how ...to differentiate clinically between LGV and other pathology. We analysed the clinical presentations of rectal LGV in MSM to identify clinical characteristics predictive of LGV proctitis and produced a clinical prediction model.
A prospective multicentre case-control study was conducted at six U.K. hospitals from 2008 to 2010. Cases of rectal LGV were compared with controls with rectal symptoms but without LGV.
Data from 98 LGV cases and 81 controls were collected from patients and clinicians using computer-assisted self-interviews and clinical report forms. Univariate and multivariate logistic regression was used to compare symptoms and signs. Clinical prediction models for LGV were compared using receiver operating curves.
Tenesmus, constipation, anal discharge and weight loss were significantly more common in cases than controls. In multivariate analysis, tenesmus and constipation alone were suggestive of LGV (OR 2.98, 95% CI 0.99 to 8.98 and 2.87, 95% CI 1.01 to 8.15, respectively) and that tenesmus alone or in combination with constipation was a significant predictor of LGV (OR 6.97, 95% CI 2.71 to 17.92). The best clinical prediction was having one or more of tenesmus, constipation and exudate on proctoscopy, with a sensitivity of 77% and specificity of 65%.
This study indicates that tenesmus alone or in combination with constipation makes a diagnosis of LGV in MSM presenting with rectal symptoms more likely.
Recipients of autologous haemopoietic stem-cell transplants (auto-HSCT) have an increased risk of herpes zoster and herpes zoster-related complications. The aim of this study was to establish the ...efficacy and safety of an inactivated varicella zoster vaccine for the prevention of herpes zoster after auto-HSCT.
In this randomised, double-blind, placebo-controlled phase 3 trial, participants were recruited from 135 medical centres (ie, stem-cell transplant centres and hospitals) in North America, South America, Europe, and Asia. Patients were eligible if they were aged 18 years or older, scheduled to receive an auto-HSCT within 60 days of enrolment, and had a history of varicella infection or were seropositive for antibodies to varicella zoster virus, or both. Exclusion criteria included a history of herpes zoster within the previous year of enrolment, and intended antiviral prophylaxis for longer than 6 months after transplantation. Participants were randomly assigned according to a central randomisation schedule generated by the trial statistician, to receive either the inactivated-virus vaccine from one of three consistency lots, a high-antigen lot, or placebo, stratified by age (<50 vs ≥50 years) and intended duration of antiviral prophylaxis after transplantation (≤3 months vs >3 to ≤6 months). Participants, investigators, trial staff, and the funder's clinical and laboratory personnel were masked to group assignment. Participants were given four doses of inactivated vaccine or placebo, with the first dose 5–60 days before auto-HSCT, and the second, third, and fourth doses at about 30, 60, and 90 days after transplantation. The primary efficacy endpoint was the incidence of herpes zoster, confirmed by PCR or adjudication by a masked clinical committee, or both, assessed in all participants randomly assigned to the vaccine consistency lot group or placebo group who received at least one dose of vaccine and had auto-HSCT. Safety was assessed in all randomised participants who received at least one dose of vaccine and had follow-up data. A prespecified vaccine efficacy success criterion required the lower bound of the 95% CI be higher than 25% for the relative reduction of the hazard ratio of herpes zoster infection in participants given the vaccine from one of the consistency lots compared with those given placebo. This trial is registered on ClinicalTrials.gov (NCT01229267) and EudraCT (2010–020150–34).
Between Dec 7, 2010, and April 25, 2013, 560 participants were randomly assigned to the vaccine consistency lot group, 106 to the high-antigen lot group, and 564 to the placebo group. 249 (44%) of patients in the vaccine consistency lot group, 35 (33%) in the high-antigen lot group, and 220 (39%) in the placebo group discontinued before study end, mostly because of death or withdrawal. 51 participants were excluded from the primary efficacy endpoint analyses because they did not undergo auto-HSCT or were not vaccinated, or both (22 4% in the vaccine consistency lot group, and 29 5% in the placebo group). Mean follow-up for efficacy was 2·4 years (SD 1·3) in the vaccine consistency lot group and 2·3 years (SD 1·3) in the placebo group. 42 (8%) of 538 participants in the vaccine consistency lot group (32·9 per 1000 person-years) and 113 (21%) of 535 in the placebo group (91·9 per 1000 person-years) had a confirmed case of herpes zoster. The estimated vaccine efficacy was 63·8% (95% CI 48·4–74·6), meeting the pre-specified success criterion. For the combined vaccine groups versus the placebo group, the proportion of patients with serious adverse events (216 33% of 657 vs 181 33% of 554; risk difference 0·2%, 95% CI −5·1 to 5·5) and serious vaccine-related adverse events (five 1% vs five 1%; risk difference 0·1%, −1·4 to 1·1) were similar. Vaccine-related injection-site adverse events occurred more frequently in participants given vaccine than those given placebo (191 29% vs 36 7%; risk difference 22·6%, 95% CI 18·5–26·6; p<0·0001).
This study shows for the first time in a large phase 3 trial that early vaccination of auto-HSCT recipients during the peri-transplant period can be effective for the prevention of an opportunistic infection like herpes zoster and that the vaccine is well tolerated.
Merck & Co., Inc.
BACKGROUNDMucosal melanoma (MM) is a rare melanoma subtype with distinct biology and poor prognosis. Data on the efficacy of immune checkpoint inhibitors (ICIs) are limited. We determined the ...efficacy of ICIs in MM, analyzed by primary site and ethnicity/race. PATIENTS AND METHODSA retrospective cohort study from 25 cancer centers in Australia, Europe, USA and Asia was carried out. Patients with histologically confirmed MM were treated with anti-programmed cell death protein 1 (PD-1) ± ipilimumab. Primary endpoints were response rate (RR), progression-free survival (PFS), overall survival (OS) by primary site (naso-oral, urogenital, anorectal, other), ethnicity/race (Caucasian, Asian, Other) and treatment. Univariate and multivariate Cox proportional hazards model analyses were conducted. RESULTSIn total, 545 patients were included: 331 (63%) Caucasian, 176 (33%) Asian and 20 (4%) Other. Primary sites included 113 (21%) anorectal, 178 (32%) urogenital, 206 (38%) naso-oral and 45 (8%) other. Three hundred and forty-eight (64%) patients received anti-PD-1 and 197 (36%) anti-PD-1/ipilimumab. RR, PFS and OS did not differ by primary site, ethnicity/race or treatment. RR for naso-oral was numerically higher for anti-PD-1/ipilimumab 40%, 95% confidence interval (CI) 29% to 54% compared with anti-PD-1 (29%, 95% CI 21% to 37%). Thirty-five percent of patients who initially responded progressed. The median duration of response (mDoR) was 26 months (95% CI 18 months-not reached). Factors associated with short PFS were Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≥3 (P < 0.01), lactate dehydrogenase (LDH) more than the upper limit of normal (ULN) (P = 0.01), lung metastases (P < 0.01) and ≥1 previous treatments (P < 0.01). Factors associated with short OS were ECOG PS ≥1 (P < 0.01), LDH >ULN (P = 0.03), lung metastases (P < 0.01) and ≥1 previous treatments (P < 0.01). CONCLUSIONSMM has poor prognosis. Treatment efficacy of anti-PD-1 ± ipilimumab was similar and did not differ by ethnicity/race. Naso-oral primaries had numerically higher response to anti-PD-1/ipilimumab, without difference in survival. The addition of ipilimumab did not show greater benefit over anti-PD-1 for other primary sites. In responders, mDoR was short and acquired resistance was common. Other factors, including site and number of metastases, were associated with survival.
A review is given of recent NMR experiments at ultra-low temperatures that explore properties of quantum fluids and solids in regimes where unusual dynamics characterizes the low temperature ...behavior. It is shown how careful analysis of the NMR spin-spin and spin-lattice relaxation rates and spectral properties can determine fundamental thermodynamic features that are otherwise difficult to observe using standard thermodynamic methods. The review focuses on the observation of the diffusion of vacancies and isotopic impurities in solid hydrogen and solid helium by quantum tunneling at low temperatures.
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