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In classical Hodgkin lymphoma (cHL), the highly abundant CD4+ T cells in the vicinity of tumor cells are considered essential for tumor cell survival, but are ill-defined. Although they are activated, they consistently lack expression of activation marker CD26. In this study, we compared sorted CD4+CD26- and CD4+CD26+ T cells from cHL lymph node cell suspensions by RNA sequencing and T cell receptor variable gene segment usage analysis. This revealed that although CD4+CD26- T cells are antigen experienced, they have not clonally expanded. This may well be explained by the expression of exhaustion associated transcription factors TOX and TOX2, immune checkpoints PDCD1 and CD200, and chemokine CXCL13, which were amongst the 100 significantly enriched genes in comparison with the CD4+CD26+ T cells. Findings were validated in single-cell RNA sequencing data from an independent cohort. Interestingly, immunohistochemistry revealed predominant and high frequency of staining for TOX and TOX2 in the T cells attached to the tumor cells. In conclusion, the dominant CD4+CD26- T cell population in cHL is antigen experienced, polyclonal, and exhausted. This population is likely a main contributor to the very high response rates to immune checkpoint inhibitors in cHL.

The first satellite-based global retrievals of terrestrial sun-induced chlorophyll fluorescence (SIF) were achieved in 2011. Since then, a number of global SIF datasets with different spectral, spatial, and temporal sampling characteristics have become available to the scientific community. These datasets have been useful to monitor the dynamics and productivity of a range of vegetated areas worldwide, but the coarse spatiotemporal sampling and low signal-to-noise ratio of the data hamper their application over small or fragmented ecosystems. The recent advent of the Copernicus Sentinel-5P TROPOMI mission and the high quality of its data products promise to alleviate this situation, as TROPOMI provides daily global measurements at a much denser spatial and temporal sampling than earlier satellite instruments. In this work, we present a global SIF dataset produced from TROPOMI measurements within the TROPOSIF project funded by the European Space Agency. The current version of the TROPOSIF dataset covers the time period between May 2018 and April 2021. Baseline SIF retrievals are derived from the 743–758 nm window. A secondary SIF dataset derived from an extended fitting window (735–758 nm window) is included. This provides an enhanced signal-to-noise ratio at the expense of a higher sensitivity to atmospheric effects. Spectral reflectance spectra at seven 3 nm windows devoid of atmospheric absorption within the 665–785 nm range are also included in the TROPOSIF dataset as an important ancillary variable to be used in combination with SIF. The methodology to derive SIF and ancillary data as well as results from an initial data quality assessment are presented in this work. The TROPOSIF dataset is available through the following digital object identifier (DOI): https://doi.org/10.5270/esa-s5p_innovation-sif-20180501_20210320-v2.1-202104 (Guanter et al., 2021).

Since its launch in 2017, Tropospheric Monitoring Instrument (TROPOMI) on S-5P has provided very high quality data using daily global coverage for a number of key atmospheric trace gases. Over its first 1000 d in operation, the short-wave infrared (SWIR) module has been very stable, and the continuously monitored calibration has remained of high quality. This calibration relies on a combination of extensive pre-launch and post-launch measurements, complemented by regular monitoring of internal light sources and background measurements. In this paper we present a method and results for independent validation of the SWIR module calibration and instrument stability by examining the signal stability of a sample of 23 pseudo-invariant calibration desert sites. The data covers over 2 years of operational data. With a Lambertian surface assumption, the results show that the SWIR module has little to no instrument degradation down to an accuracy of about 0.3 % yr−1, validating results obtained from the internal calibration suite. The method presented here will be used as ongoing validation of the SWIR calibration.

IntroductionDuring the COVID-19 pandemic, certain disease modifying therapies (DMTs) used in multiple sclerosis (MS), such as anti-CD20 therapies, have been associated with decreased humoral responses after SARS-CoV-2 vaccination. Hybrid immunity, referring to immunity after both vaccination and SARS-CoV-2 infection might increase humoral responses.MethodsThis was a substudy of two prospective cohort studies on SARS-CoV-2 antibodies after SARS-CoV-2 infection and vaccination. RBD-specific IgG titers of patients with MS and healthy controls who had experienced SARS-CoV-2 infection prior to the first vaccination were compared with those patients and healthy controls without prior infection. Humoral responses were measured at various time points after SARS-CoV-2 infection in convalescent patients and all patients prior to the first vaccination, 28 days after the first vaccination, and 28 days after the second vaccination.ResultsOne hundred and two individuals [of which 34 patients with MS and DMTs (natalizumab or ocrelizumab), 30 patients without DMTs, and 38 healthy controls] were included. Fifty one of these individuals were convalescent. Median SARS-CoV-2 antibody titers were higher after the first vaccination in convalescent individuals compared with individuals without infection prior to vaccination. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody titers were comparable after the second vaccination in patients with MS with and without prior infection. However, in the convalescent ocrelizumab-treated patients, SARS-CoV-2 antibody titers did not increase after vaccinations.ConclusionIn patients with MS without anti-CD20 therapies, SARS-CoV-2 infection before vaccination increases humoral responses after the first vaccination, similar to the healthy controls. In patients with MS treated with ocrelizumab (convalescent and non-convalescent), humoral responses remained low.

Background and purpose: To determine whether the Hip disability and Osteoarthritis Outcome Score-Physical function Short-form (HOOS-PS) is able to appropriately evaluate physical function in revision hip arthroplasty patients, this study assesses psychometric properties of the Dutch HOOS-PS in this patient population. Patients and methods: We assessed psychometric properties of the HOOS-PS following the Consensus-based Standards for the selection of health Measurement Instruments (COSMIN) criteria. Content validity, including comprehensibility, comprehensiveness, and relevance of the items, was assessed using cognitive debriefing interviews in hip revision patients (n = 8) and orthopedic surgeons specialized in revision surgery (n = 7). Construct validity, responsiveness, and interpretability (floor/ceiling effects) were assessed in revision hip arthroplasty patients (baseline n = 136, follow-up n = 67). We formulated hypotheses a priori to assess construct validity and responsiveness using the EuroQol 5-Dimensions Health Questionnaire, Numeric Rating scale for pain, and Oxford Hip Score as comparators. All questionnaires were measured at baseline and 1 year postoperatively. Results: We found insufficient content validity of the HOOS-PS, as relevance and comprehensibility of the items scored < 85% on the COSMIN criteria for revision hip arthroplasty patients. Construct validity was sufficient as all hypotheses were confirmed (≥ 75% COSMIN criteria). Interpretability was sufficient (< 15% COSMIN criteria) and responsiveness was insufficient (< 75% COSMIN criteria). Interpretation: The Dutch HOOS-PS is not able to sufficiently evaluate physical function in revision hip arthroplasty patients. Minor changes in the items are needed for the HOOS-PS to become sufficiently content valid, because the HOOS-PS lacks relevant items and comprehensiveness.

Parents are often appointed a passive role in the care for their hospitalised child. In the family-integrated care (FICare) model, parental involvement in neonatal care is emulated. Parental participation in medical rounds, or family-centred rounds (FCR), forms a key element. A paucity remains of randomised trials assessing the outcomes of FCR (embedded in FICare) in families and neonates, and outcomes on an organisational level are relatively unexplored. Likewise, biological mechanisms through which a potential effect may be exerted are lacking robust evidence. Ten level two Dutch neonatal wards are involved in this stepped-wedge cluster-randomised trial FCR (embedded in FICare) by one common implementation strategy. Parents of infants hospitalised for at least 7 days are eligible for inclusion. The primary outcome is parental stress (PSS:NICU) at discharge. Secondary outcomes include parental, neonatal, healthcare professional and organisational outcomes. Biomarkers of stress will be analysed in parent–infant dyads. With a practical approach and broad outcome set, this study aims to obtain evidence on the possible (mechanistic) effect of FCR (as part of FICare) on parents, infants, healthcare professionals and organisations. The practical approach provides (experiences of) FICare material adjusted to the Dutch setting, available for other hospitals after the study.

Analysis of circulating tumor DNA (ctDNA) is a potential minimally invasive molecular tool to guide treatment decision-making and disease monitoring. A suitable diagnostic-grade platform is required for the detection of tumor-specific mutations with high sensitivity in the circulating cell-free DNA (ccfDNA) of cancer patients. In this multicenter study, the ccfDNA of 72 patients treated for advanced-stage non-small cell lung cancer (NSCLC) was evaluated using the UltraSEEK® Lung Panel on the MassARRAY® System, covering 73 hotspot mutations in EGFR, KRAS, BRAF, ERBB2, and PIK3CA against mutation-specific droplet digital PCR (ddPCR) and routine tumor tissue NGS. Variant detection accuracy at primary diagnosis and during disease progression, and ctDNA dynamics as a marker of treatment efficacy, were analyzed. A multicenter evaluation using reference material demonstrated an overall detection rate of over 90% for variant allele frequencies (VAFs) > 0.5%, irrespective of ccfDNA input. A comparison of UltraSEEK® and ddPCR analyses revealed a 90% concordance. An 80% concordance between therapeutically targetable mutations detected in tumor tissue NGS and ccfDNA UltraSEEK® analysis at baseline was observed. Nine of 84 (11%) tumor tissue mutations were not covered by UltraSEEK®. A decrease in ctDNA levels at 4–6 weeks after treatment initiation detected with UltraSEEK® correlated with prolonged median PFS (46 vs. 6 weeks; p < 0.05) and OS (145 vs. 30 weeks; p < 0.01). Using plasma-derived ccfDNA, the UltraSEEK® Lung Panel with a mid-density set of the most common predictive markers for NSCLC is an alternative tool to detect mutations both at diagnosis and during disease progression and to monitor treatment response.

Abstract Background Procalcitonin (PCT) and C-reactive protein (CRP) were previously shown to have value for the detection of secondary infections in critically ill COVID-19 patients. However, since the introduction of immunomodulatory therapy, the value of these biomarkers is unclear. We investigated PCT and CRP kinetics in critically ill COVID-19 patients treated with dexamethasone with or without tocilizumab, and assessed the value of these biomarkers to detect secondary bacterial infections. Methods In this prospective study, 190 critically ill COVID-19 patients were divided into three treatment groups: no dexamethasone, no tocilizumab (D−T−), dexamethasone, no tocilizumab (D+T−), and dexamethasone and tocilizumab (D+T+). Serial data of PCT and CRP were aligned on the last day of dexamethasone treatment, and kinetics of these biomarkers were analyzed between 6 days prior to cessation of dexamethasone and 10 days afterwards. Furthermore, the D+T− and D+T+ groups were subdivided into secondary infection and no-secondary infection groups to analyze differences in PCT and CRP kinetics and calculate detection accuracy of these biomarkers for the occurrence of a secondary infection. Results Following cessation of dexamethasone, there was a rebound in PCT and CRP levels, most pronounced in the D+T− group. Upon occurrence of a secondary infection, no significant increase in PCT and CRP levels was observed in the D+T− group (p = 0.052 and p = 0.08, respectively). Although PCT levels increased significantly in patients of the D+T+ group who developed a secondary infection (p = 0.0003), this rise was only apparent from day 2 post-infection onwards. CRP levels remained suppressed in the D+T+ group. Receiver operating curve analysis of PCT and CRP levels yielded area under the curves of 0.52 and 0.55, respectively, which are both markedly lower than those found in the group of COVID-19 patients not treated with immunomodulatory drugs (0.80 and 0.76, respectively, with p values for differences between groups of 0.001 and 0.02, respectively). Conclusions Cessation of dexamethasone in critically ill COVID-19 patients results in a rebound increase in PCT and CRP levels unrelated to the occurrence of secondary bacterial infections. Furthermore, immunomodulatory treatment with dexamethasone and tocilizumab considerably reduces the value of PCT and CRP for detection of secondary infections in COVID-19 patients.

Preservation of cancer biopsies by FFPE introduces DNA fragmentation, hindering analysis of rearrangements. Here the authors introduce FFPE Targeted Locus Capture for identification of translocations in preserved samples.