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Objective To quantify the comparative risk of thrombosis with thrombocytopenia syndrome or thromboembolic events associated with use of adenovirus based covid-19 vaccines versus mRNA based covid-19 vaccines. Design International network cohort study. Setting Routinely collected health data from contributing datasets in France, Germany, the Netherlands, Spain, the UK, and the US. Participants Adults (age ≥18 years) registered at any contributing database and who received at least one dose of a covid-19 vaccine (ChAdOx1-S (Oxford-AstraZeneca), BNT162b2 (Pfizer-BioNTech), mRNA-1273 (Moderna), or Ad26.COV2.S (Janssen/Johnson & Johnson)), from December 2020 to mid-2021. Main outcome measures Thrombosis with thrombocytopenia syndrome or venous or arterial thromboembolic events within the 28 days after covid-19 vaccination. Incidence rate ratios were estimated after propensity scores matching and were calibrated using negative control outcomes. Estimates specific to the database were pooled by use of random effects meta-analyses. Results Overall, 1 332 719 of 3 829 822 first dose ChAdOx1-S recipients were matched to 2 124 339 of 2 149 679 BNT162b2 recipients from Germany and the UK. Additionally, 762 517 of 772 678 people receiving Ad26.COV2.S were matched to 2 851 976 of 7 606 693 receiving BNT162b2 in Germany, Spain, and the US. All 628 164 Ad26.COV2.S recipients from the US were matched to 2 230 157 of 3 923 371 mRNA-1273 recipients. A total of 862 thrombocytopenia events were observed in the matched first dose ChAdOx1-S recipients from Germany and the UK, and 520 events after a first dose of BNT162b2. Comparing ChAdOx1-S with a first dose of BNT162b2 revealed an increased risk of thrombocytopenia (pooled calibrated incidence rate ratio 1.33 (95% confidence interval 1.18 to 1.50) and calibrated incidence rate difference of 1.18 (0.57 to 1.8) per 1000 person years). Additionally, a pooled calibrated incidence rate ratio of 2.26 (0.93 to 5.52) for venous thrombosis with thrombocytopenia syndrome was seen with Ad26.COV2.S compared with BNT162b2. Conclusions In this multinational study, a pooled 30% increased risk of thrombocytopenia after a first dose of the ChAdOx1-S vaccine was observed, as was a trend towards an increased risk of venous thrombosis with thrombocytopenia syndrome after Ad26.COV2.S compared with BNT162b2. Although rare, the observed risks after adenovirus based vaccines should be considered when planning further immunisation campaigns and future vaccine development.

Polymeric carbon nitride materials have been successfully used in numerous light-to-energy conversion applications ranging from photocatalysis to optoelectronics. For a new application and modelling, we first refined the crystal structure of potassium poly(heptazine imide) (K-PHI) – a benchmark carbon nitride material in photocatalysis – by means of X-ray powder diffraction and transmission electron microscopy. Using the crystal structure of K-PHI, periodic DFT calculations were performed to calculate the density-of-states and localize intra band states (IBS). IBS were found to be responsible for the enhanced K-PHI absorption in the near IR region, to serve as electron traps, and to be useful in energy transfer reactions. Once excited with visible light, carbon nitrides, beside the direct recombination, can also undergo singlet-triplet intersystem crossing. We utilized the K-PHI centered triplet excited states to trigger a cascade of energy transfer reactions and, in turn, to sensitize, for example, singlet oxygen (1O2) as a starting point to synthesis up to 25 different N-rich heterocycles.

Background\udPre-clinically, phosphoinositide 3-kinase (PI3K) inhibition radiosensitises tumours by increasing intrinsic radiosensitivity and by reducing tumour hypoxia. We assessed whether buparlisib, a class 1 PI3K inhibitor, can be safely combined with radiotherapy in patients with non-small cell lung carcinoma (NSCLC) and investigated its effect on tumour hypoxia.\udMethods\udThis was a 3 + 3 dose escalation and dose expansion phase I trial in patients with advanced NSCLC. Buparlisib dose levels were 50 mg, 80 mg and 100 mg once daily orally for 2 weeks, with palliative thoracic radiotherapy (20 Gy in 5 fractions) delivered during week 2. Tumour hypoxic volume (HV) was measured using 18F-fluoromisonidazole positron-emission tomography–computed tomography at baseline and following 1 week of buparlisib.\udResults\udTwenty-one patients were recruited with 9 patients evaluable for maximum tolerated dose (MTD) analysis. No dose-limiting toxicity was reported; therefore, 100 mg was declared the MTD, and 10 patients received this dose in the expansion phase. Ninety-four percent of treatment-related adverse events were ≤grade 2 with fatigue (67%), nausea (24%) and decreased appetite (19%) most common per patient. One serious adverse event (grade 3 hypoalbuminaemia) was possibly related to buparlisib. No unexpected radiotherapy toxicity was reported. Ten (67%) of 15 patients evaluable for imaging analysis were responders with 20% median reduction in HV at the MTD.\udConclusion\udThis is the first clinical trial to combine a PI3K inhibitor with radiotherapy in NSCLC and investigate the effects of PI3K inhibition on tumour hypoxia. This combination was well tolerated and PI3K inhibition reduced hypoxia, warranting investigation into whether this novel class of radiosensitisers can improve radiotherapy outcomes.

Background Induction chemotherapy followed by chemoradiation is a treatment option for patients with locally advanced pancreatic cancer (LAPC). However, overall survival is comparable to chemotherapy alone and local progression occurs in nearly half of all patients, suggesting chemoradiation strategies should be optimised. SCALOP-2 is a randomised phase II trial testing the role of radiotherapy dose escalation and/or the addition of the radiosensitiser nelfinavir, following induction chemotherapy of gemcitabine and nab-paclitaxel (GEMABX). A safety run-in phase (stage 1) established the nelfinavir dose to administer with chemoradiation in the randomised phase (stage 2). Methods Patients with locally advanced, inoperable, non-metastatic pancreatic adenocarcinoma receive three cycles of induction GEMABX chemotherapy prior to radiological assessment. Those with stable/responding disease are eligible for further trial treatment. In Stage 1, participants received one further cycle of GEMABX followed by capecitabine-chemoradiation with escalating doses of nelfinavir in a rolling-six design. Stage 2 aims to register 262 and randomise 170 patients with responding/stable disease to one of five arms: capecitabine with high- (arms C + D) or standard-dose (arms A + B) radiotherapy with (arms A + C) or without (arms B + D) nelfinavir, or three more cycles of GEMABX (arm E). Participants allocated to the chemoradiation arms receive another cycle of GEMABX before chemoradiation begins. Co-primary outcomes are 12-month overall survival (radiotherapy dose-escalation question) and progression-free survival (nelfinavir question). Secondary outcomes include toxicity, quality of life, disease response rate, resection rate, treatment compliance, and CA19–9 response. SCALOP-2 incorporates a detailed radiotherapy quality assurance programme. Discussion SCALOP-2 aims to optimise chemoradiation in LAPC and incorporates a modern induction regimen. Trial registration Eudract No: 2013–004968-56; ClinicalTrials.gov: NCT02024009.

Aim We aim to investigate the potential role for a biological boost in anal cancer by assessing whether subvolumes of high FDG avidity, identified at outset, are spatially consistent during a course of chemoradiotherapy (CRT). Methods FDG-PET scans from 21 patients enrolled into the ART study (NCT02145416) were retrospectively analysed. A total of twenty-nine volumes including both primary tumours and involved nodes >2 cm were identified. FDG-PET scans were performed prior to treatment and day 8 or 9 of CRT. FDG subvolumes were created using a percentage of maximum FDG avidity at thresholds of 34%, 40%, 50%, on the pre-treatment scans, and 70% and 80% on the subsequent scans. Both FDG-PET scans were deformably registered to the planning CT scan. The overlap fraction (OF) and vector distance (VD) were calculated to assess spatial consistency. FDG subvolumes for further investigation had OF >0.7, as this has been defined in previous publications as a “good” correlation. Results The median OF between the diagnostic FDG-PET subvolumes 34%, 40% and 50% of max SUV and subsequent FDG-PET subvolumes of 70% of max SUV were 0.97, 0.92 and 0.81. The median OF between the diagnostic FDG-PET subvolumes 34%, 40% and 50% and subsequent FDG-PET subvolumes of 80% were 1.00, 1.00 and 0.92. The median (range) VD values between diagnostic FDG-PET subvolumes 34%, 40% and 50% and subsequent FDG-PET subvolumes of 80% were 0.74mm (0.19-2.94) 0.74mm (0.19-3.39) and 0.71 (0.2-3.29) respectively. Twenty out of 29 volumes (69.0%) achieved a threshold of >0.7 between the FDG 50% subvolume on the diagnostic scan and the FDG 80% subvolume on the subsequent scan. Conclusion FDG avid subvolumes identified at baseline were spatially consistent during a course of CRT treatment. The subvolume of 50% of SUVmax on the pre-treatment scan could be considered as a potential target for dose escalation.

The anti-retroviral agent, nelfinavir, demonstrates radiosensitising effects in pre-clinical models of pancreatic cancer. The primary objective of Stage 1 was to establish the maximum tolerated dose (MTD) of nelfinavir combined with capecitabine-chemoradiation (CRT) after gemcitabine+nab-paclitaxel (GEMABX) induction chemotherapy. Other outcomes included overall survival and progression-free survival.

Supplemental Digital Content is Available in the Text. Low back pain trajectories identified previously appear generalizable. Effective management tailored to individual trajectories needs to be identified., Low back pain (LBP) is a major health challenge globally. Research has identified common trajectories of pain over time. We aimed to investigate whether trajectories described in 1 primary care cohort can be confirmed in another, and to determine the prognostic value of factors collected 5 years prior to the identification of the trajectory. The study was conducted on 281 patients who had consulted primary care for LBP, at that point completed a baseline questionnaire, and then returned a questionnaire at 5-year follow-up plus at least 3 (of 6) subsequent monthly questionnaires. Baseline factors were measured using validated tools. Pain intensity scores from the 5-year follow-up and monthly questionnaires were used to assign participants into 4 previously derived pain trajectories (no or occasional mild, persistent mild, fluctuating, and persistent severe), using latent class analysis. Posterior probabilities of belonging to each cluster were estimated for each participant. The posterior probabilities for the assigned clusters were very high (>0.90) for each cluster except for the smallest “fluctuating” cluster (0.74). Lower social class and higher pain intensity were significantly associated with a more severe trajectory 5 years later, as were patients' perceptions of the greater consequences and longer duration of pain, and greater passive behavioural coping. Low back pain trajectories identified previously appear generalizable. These allow better understanding of the long-term course of LBP, and effective management tailored to individual trajectories needs to be identified.

hemotherapy followed by consolidation chemoradiotherapy (CRT) is a treatment option for locally advanced non-metastatic pancreatic cancer (LAPC), but outcome remains poor. The SCALOP trial identified a feasible, safe, and effective CRT regimen for LAPC: capecitabine (830mg/m2 oral bd) as radiosensitisation + 50.4Gy in 28 fractions. The two-stage SCALOP-2 trial aims to improve this regimen by increasing radiotherapy dose intensity and adding nelfinavir as an additional radiosensitising AKT inhibitor.

Chemotherapy followed by consolidation chemoradiotherapy (CRT) is a treatment option for locally advanced non-metastatic pancreatic cancer (LAPC), but outcome remains poor. The SCALOP trial identified a feasible, safe, and effective CRT regimen for LAPC: capecitabine (830mg/m2 oral bd) as radiosensitisation + 50.4Gy in 28 fractions. The two-stage SCALOP-2 trial aims to improve this regimen by increasing radiotherapy dose intensity and adding nelfinavir as an additional radiosensitising AKT inhibitor.