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ObjectiveThe objective of this systematic review was to examine how the record linkage process is reported in multimorbidity research.MethodsA systematic search was conducted in Medline, Web of Science and Embase using predefined search terms, and inclusion and exclusion criteria. Published studies from 2010 to 2020 using linked routinely collected data for multimorbidity research were included. Information was extracted on how the linkage process was reported, which conditions were studied together, which data sources were used, as well as challenges encountered during the linkage process or with the linked dataset.ResultsTwenty studies were included. Fourteen studies received the linked dataset from a trusted third party. Eight studies reported variables used for the data linkage, while only two studies reported conducting prelinkage checks. The quality of the linkage was only reported by three studies, where two reported linkage rate and one raw linkage figures. Only one study checked for bias by comparing patient characteristics of linked and non-linked records.ConclusionsThe linkage process was poorly reported in multimorbidity research, even though this might introduce bias and potentially lead to inaccurate inferences drawn from the results. There is therefore a need for increased awareness of linkage bias and transparency of the linkage processes, which could be achieved through better adherence to reporting guidelines.PROSPERO registration numberCRD42021243188.

Background Antenatal detection and management of small for gestational age (SGA) is a strategy to reduce stillbirth. Large observational studies provide conflicting results on the effect of the Growth Assessment Protocol (GAP) in relation to detection of SGA and reduction of stillbirth; to the best of our knowledge, there are no reported randomised control trials. Our aim was to determine if GAP improves antenatal detection of SGA compared to standard care. Methods and findings This was a pragmatic, superiority, 2-arm, parallel group, open, cluster randomised control trial. Maternity units in England were eligible to participate in the study, except if they had already implemented GAP. All women who gave birth in participating clusters (maternity units) during the year prior to randomisation and during the trial (November 2016 to February 2019) were included. Multiple pregnancies, fetal abnormalities or births before 24+1 weeks were excluded. Clusters were randomised to immediate implementation of GAP, an antenatal care package aimed at improving detection of SGA as a means to reduce the rate of stillbirth, or to standard care. Randomisation by random permutation was stratified by time of study inclusion and cluster size. Data were obtained from hospital electronic records for 12 months prerandomisation, the washout period (interval between randomisation and data collection of outcomes), and the outcome period (last 6 months of the study). The primary outcome was ultrasound detection of SGA (estimated fetal weight <10th centile using customised centiles (intervention) or Hadlock centiles (standard care)) confirmed at birth (birthweight <10th centile by both customised and population centiles). Secondary outcomes were maternal and neonatal outcomes, including induction of labour, gestational age at delivery, mode of birth, neonatal morbidity, and stillbirth/perinatal mortality. A 2-stage cluster–summary statistical approach calculated the absolute difference (intervention minus standard care arm) adjusted using the prerandomisation estimate, maternal age, ethnicity, parity, and randomisation strata. Intervention arm clusters that made no attempt to implement GAP were excluded in modified intention to treat (mITT) analysis; full ITT was also reported. Process evaluation assessed implementation fidelity, reach, dose, acceptability, and feasibility. Seven clusters were randomised to GAP and 6 to standard care. Following exclusions, there were 11,096 births exposed to the intervention (5 clusters) and 13,810 exposed to standard care (6 clusters) during the outcome period (mITT analysis). Age, height, and weight were broadly similar between arms, but there were fewer women: of white ethnicity (56.2% versus 62.7%), and in the least deprived quintile of the Index of Multiple Deprivation (7.5% versus 16.5%) in the intervention arm during the outcome period. Antenatal detection of SGA was 25.9% in the intervention and 27.7% in the standard care arm (adjusted difference 2.2%, 95% confidence interval (CI) −6.4% to 10.7%; p = 0.62). Findings were consistent in full ITT analysis. Fidelity and dose of GAP implementation were variable, while a high proportion (88.7%) of women were reached. Use of routinely collected data is both a strength (cost-efficient) and a limitation (occurrence of missing data); the modest number of clusters limits our ability to study small effect sizes. Conclusions In this study, we observed no effect of GAP on antenatal detection of SGA compared to standard care. Given variable implementation observed, future studies should incorporate standardised implementation outcomes such as those reported here to determine generalisability of our findings. Trial registration This trial is registered with the ISRCTN registry, ISRCTN67698474.

BackgroundLocally advanced/recurrent head and neck squamous cell carcinoma (HNSCC) is associated with significant morbidity and mortality. To target upregulated ErbB dimer expression in this cancer, we developed an autologous CD28-based chimeric antigen receptor T-cell (CAR-T) approach named T4 immunotherapy. Patient-derived T-cells are engineered by retroviral transduction to coexpress a panErbB-specific CAR called T1E28ζ and an IL-4-responsive chimeric cytokine receptor, 4αβ, which allows IL-4-mediated enrichment of transduced cells during manufacture. These cells elicit preclinical antitumor activity against HNSCC and other carcinomas. In this trial, we used intratumoral delivery to mitigate significant clinical risk of on-target off-tumor toxicity owing to low-level ErbB expression in healthy tissues.MethodsWe undertook a phase 1 dose-escalation 3+3 trial of intratumoral T4 immunotherapy in HNSCC (NCT01818323). CAR T-cell batches were manufactured from 40 to 130 mL of whole blood using a 2-week semiclosed process. A single CAR T-cell treatment, formulated as a fresh product in 1–4 mL of medium, was injected into one or more target lesions. Dose of CAR T-cells was escalated in 5 cohorts from 1×107−1×109 T4+ T-cells, administered without prior lymphodepletion.ResultsDespite baseline lymphopenia in most enrolled subjects, the target cell dose was successfully manufactured in all cases, yielding up to 7.5 billion T-cells (67.5±11.8% transduced), without any batch failures. Treatment-related adverse events were all grade 2 or less, with no dose-limiting toxicities (Common Terminology Criteria for Adverse Events V.4.0). Frequent treatment-related adverse events were tumor swelling, pain, pyrexias, chills, and fatigue. There was no evidence of leakage of T4+ T-cells into the circulation following intratumoral delivery, and injection of radiolabeled cells demonstrated intratumoral persistence. Despite rapid progression at trial entry, stabilization of disease (Response Evaluation Criteria in Solid Tumors V.1.1) was observed in 9 of 15 subjects (60%) at 6 weeks post-CAR T-cell administration. Subsequent treatment with pembrolizumab and T-VEC oncolytic virus achieved a rapid complete clinical response in one subject, which was durable for over 3 years. Median overall survival was greater than for historical controls. Disease stabilization was associated with the administration of an immunophenotypically fitter, less exhausted, T4 CAR T-cell product.ConclusionsThese data demonstrate the safe intratumoral administration of T4 immunotherapy in advanced HNSCC.

Background The use of electronic patient records for assessing outcomes in clinical trials is a methodological strategy intended to drive faster and more cost-efficient acquisition of results. The aim of this manuscript was to outline the data collection and management considerations of a maternity and perinatal clinical trial using data from electronic patient records, exemplifying the DESiGN Trial as a case study. Methods The DESiGN Trial is a cluster randomised control trial assessing the effect of a complex intervention versus standard care for identifying small for gestational age foetuses. Data on maternal/perinatal characteristics and outcomes including infants admitted to neonatal care, parameters from foetal ultrasound and details of hospital activity for health-economic evaluation were collected at two time points from four types of electronic patient records held in 22 different electronic record systems at the 13 research clusters. Data were pseudonymised on site using a bespoke Microsoft Excel macro and securely transferred to the central data store. Data quality checks were undertaken. Rules for data harmonisation of the raw data were developed and a data dictionary produced, along with rules and assumptions for data linkage of the datasets. The dictionary included descriptions of the rationale and assumptions for data harmonisation and quality checks. Results Data were collected on 182,052 babies from 178,350 pregnancies in 165,397 unique women. Data availability and completeness varied across research sites; each of eight variables which were key to calculation of the primary outcome were completely missing in median 3 (range 1–4) clusters at the time of the first data download. This improved by the second data download following clarification of instructions to the research sites (each of the eight key variables were completely missing in median 1 (range 0–1) cluster at the second time point). Common data management challenges were harmonising a single variable from multiple sources and categorising free-text data, solutions were developed for this trial. Conclusions Conduct of clinical trials which use electronic patient records for the assessment of outcomes can be time and cost-effective but still requires appropriate time and resources to maximise data quality. A difficulty for pregnancy and perinatal research in the UK is the wide variety of different systems used to collect patient data across maternity units. In this manuscript, we describe how we managed this and provide a detailed data dictionary covering the harmonisation of variable names and values that will be helpful for other researchers working with these data. Trial registration Primary registry and trial identifying number: ISRCTN 67698474. Registered on 02/11/16.

BackgroundAntenatal detection and management of small for gestational age (SGA) is a strategy to reduce stillbirth. Large observational studies provide conflicting results on the effect of the Growth Assessment Protocol (GAP) in relation to detection of SGA and reduction of stillbirth; to the best of our knowledge, there are no reported randomised control trials. Our aim was to determine if GAP improves antenatal detection of SGA compared to standard care.Methods and findingsThis was a pragmatic, superiority, 2-arm, parallel group, open, cluster randomised control trial. Maternity units in England were eligible to participate in the study, except if they had already implemented GAP. All women who gave birth in participating clusters (maternity units) during the year prior to randomisation and during the trial (November 2016 to February 2019) were included. Multiple pregnancies, fetal abnormalities or births before 24+1 weeks were excluded. Clusters were randomised to immediate implementation of GAP, an antenatal care package aimed at improving detection of SGA as a means to reduce the rate of stillbirth, or to standard care. Randomisation by random permutation was stratified by time of study inclusion and cluster size. Data were obtained from hospital electronic records for 12 months prerandomisation, the washout period (interval between randomisation and data collection of outcomes), and the outcome period (last 6 months of the study). The primary outcome was ultrasound detection of SGA (estimated fetal weight <10th centile using customised centiles (intervention) or Hadlock centiles (standard care)) confirmed at birth (birthweight <10th centile by both customised and population centiles). Secondary outcomes were maternal and neonatal outcomes, including induction of labour, gestational age at delivery, mode of birth, neonatal morbidity, and stillbirth/perinatal mortality. A 2-stage cluster-summary statistical approach calculated the absolute difference (intervention minus standard care arm) adjusted using the prerandomisation estimate, maternal age, ethnicity, parity, and randomisation strata. Intervention arm clusters that made no attempt to implement GAP were excluded in modified intention to treat (mITT) analysis; full ITT was also reported. Process evaluation assessed implementation fidelity, reach, dose, acceptability, and feasibility. Seven clusters were randomised to GAP and 6 to standard care. Following exclusions, there were 11,096 births exposed to the intervention (5 clusters) and 13,810 exposed to standard care (6 clusters) during the outcome period (mITT analysis). Age, height, and weight were broadly similar between arms, but there were fewer women: of white ethnicity (56.2% versus 62.7%), and in the least deprived quintile of the Index of Multiple Deprivation (7.5% versus 16.5%) in the intervention arm during the outcome period. Antenatal detection of SGA was 25.9% in the intervention and 27.7% in the standard care arm (adjusted difference 2.2%, 95% confidence interval (CI) -6.4% to 10.7%; p = 0.62). Findings were consistent in full ITT analysis. Fidelity and dose of GAP implementation were variable, while a high proportion (88.7%) of women were reached. Use of routinely collected data is both a strength (cost-efficient) and a limitation (occurrence of missing data); the modest number of clusters limits our ability to study small effect sizes.ConclusionsIn this study, we observed no effect of GAP on antenatal detection of SGA compared to standard care. Given variable implementation observed, future studies should incorporate standardised implementation outcomes such as those reported here to determine generalisability of our findings.Trial registrationThis trial is registered with the ISRCTN registry, ISRCTN67698474.

Many important social determinants of health are also the focus for social policies. Welfare states contribute to the resources available for their citizens through cash transfer programmes and subsidised services. Although all rich nations have welfare programmes, there are clear cross-national differences with respect to their design and generosity. These differences are evident in national variations in poverty rates, especially among children and elderly people. We investigated to what extent variations in family and pension policies are linked to infant mortality and old-age excess mortality. Infant mortality rates and old-age excess mortality rates were analysed in relation to social policy characteristics and generosity. We did pooled cross-sectional time-series analyses of 18 OECD (Organisation for Economic Co-operation and Development) countries during the period 1970–2000 for family policies and 1950–2000 for pension policies. Increased generosity in family policies that support dual-earner families is linked with lower infant mortality rates, whereas the generosity in family policies that support more traditional families with gainfully employed men and homemaking women is not. An increase by one percentage point in dual-earner support lowers infant mortality by 0·04 deaths per 1000 births. Generosity in basic security type of pensions is linked to lower old-age excess mortality, whereas the generosity of earnings-related income security pensions is not. An increase by one percentage point in basic security pensions is associated with a decrease in the old age excess mortality by 0·02 for men as well as for women. The ways in which social policies are designed, as well as their generosity, are important for health because of the increase in resources that social policies entail. Hence, social policies are of major importance for how we can tackle the social determinants of health. Swedish Ministry of Health and Social Affairs.

Purpose Increased variability in cerebral blood flow (CBF) predisposes to adverse cerebrovascular events. Oscillations in arterial blood pressure and PaCO 2 induce CBF variability. Less is known about how heart rate (HR) variability affects CBF. We experimentally reduced respiration-induced HR variability in healthy subjects, hypothesizing that CBF variability would increase. Methods Internal carotid artery (ICA) blood velocity was recorded by Doppler ultrasound in ten healthy subjects during baseline, control-mode, non-invasive mechanical ventilation (NIV), i.e., with fixed respiratory rate, hypovolemia induced by lower body negative pressure, and combinations of these. ICA beat volume (ICABV) and ICA blood flow (ICABF) were calculated. HR, mean arterial blood pressure (MAP), respiratory frequency (RF), and end-tidal CO 2 were recorded. Integrals of power spectra at each subject’s RF ± 0.03 Hz were used to measure variability. Phase angle/coherence measured coupling between cardiovascular variables. Results Control-mode NIV reduced HR variability (−56%, p  = 0.002) and ICABV variability (−64%, p  = 0.006) and increased ICABF variability (+140%, p  = 0.002) around RF. NIV + hypovolemia reduced variability in HR and ICABV by 70–80% ( p  = 0.002) and doubled ICABF variability ( p  = 0.03). MAP variability was unchanged in either condition. Respiration-induced HR and ICABV oscillations were in inverse phase and highly coherent (coherence >0.9) during baseline, but this coherence decreased during NIV, in normovolemia and hypovolemia ( p  = 0.01). Conclusion Controlling respiration in awake healthy humans reduced HR variability and increased CBF variability in hypovolemia and normovolemia. We suggest respiration-induced HR variability to be a mechanism in CBF regulation. Maintaining spontaneous respiration in patients receiving ventilatory support may be beneficial also for cerebral circulatory purposes.

Intact cerebral blood flow (CBF) is essential for cerebral metabolism and function, whereas hypoperfusion in relation to hypovolemia and hypocapnia can lead to severe cerebral damage. This study was designed to assess internal carotid artery blood flow (ICA‐BF) during simulated hypovolemia and noninvasive positive pressure ventilation (PPV) in young healthy humans. Beat‐by‐beat blood velocity (ICA and aorta) were measured by Doppler ultrasound during normovolemia and simulated hypovolemia (lower body negative pressure), with or without PPV in 15 awake subjects. Heart rate, plethysmographic finger arterial pressure, respiratory frequency, and end‐tidal CO2 (ETCO2) were also recorded. Cardiac index (CI) and ICA‐BF were calculated beat‐by‐beat. Medians and 95% confidence intervals and Wilcoxon signed rank test for paired samples were used to test the difference between conditions. Effects on ICA‐BF were modeled by linear mixed‐effects regression analysis. During spontaneous breathing, ICA‐BF was reduced from normovolemia (247, 202–284 mL/min) to hypovolemia (218, 194–271 mL/min). During combined PPV and hypovolemia, ICA‐BF decreased by 15% (200, 152–231 mL/min, P = 0.001). Regression analysis attributed this fall to concurrent reductions in CI (β: 43.2, SE: 17.1, P = 0.013) and ETCO2 (β: 32.8, SE: 9.3, P = 0.001). Mean arterial pressure was maintained and did not contribute to ICA‐BF variance. In healthy awake subjects, ICA‐BF was significantly reduced during simulated hypovolemia combined with noninvasive PPV. Reductions in CI and ETCO2 had additive effects on ICA‐BF reduction. In hypovolemic patients, even low‐pressure noninvasive ventilation may cause clinically relevant reductions in CBF, despite maintained arterial blood pressure. We demonstrated a 15% decrease in cerebral blood flow (CBF) during combined hypovolemia and noninvasive ventilation. The observed drop in CBF was attributed the fall in cardiac index together with hypocapnia. In hypovolemic patients, even low‐pressure noninvasive ventilation may cause clinically relevant reductions in CBF, despite maintained arterial blood pressure.

In healthy humans, cerebral blood flow (CBF) is autoregulated against changes in arterial blood pressure. Spontaneous fluctuations in mean arterial pressure (MAP) and CBF can be used to assess cerebral autoregulation. We hypothesized that dynamic cerebral autoregulation is affected by changes in autonomic activity, MAP, and cardiac output (CO) induced by handgrip (HG), head‐down tilt (HDT), and their combination. In thirteen healthy volunteers, we recorded blood velocity by ultrasound in the internal carotid artery (ICA), HR, MAP and CO‐estimates from continuous finger blood pressure, and end‐tidal CO2. Instantaneous ICA beat volume (ICABV, mL) and ICA blood flow (ICABF, mL/min) were calculated. Wavelet synchronization index γ (0–1) was calculated for the pairs: MAP–ICABF, CO–ICABF and HR–ICABV in the low (0.05–0.15 Hz; LF) and high (0.15–0.4 Hz; HF) frequency bands. ICABF did not change between experimental states. MAP and CO were increased during HG (+16% and +15%, respectively, P < 0.001) and during HDT + HG (+12% and +23%, respectively, P < 0.001). In the LF interval, median γ for the MAP–ICABF pair (baseline: 0.23 [0.12–0.28]) and the CO–ICABF pair (baseline: 0.22 [0.15–0.28]) did not change with HG, HDT, or their combination. High γ was observed for the HR–ICABV pair at the respiratory frequency, the oscillations in these variables being in inverse phase. The unaltered ICABF and the low synchronization between MAP and ICABF in the LF interval suggest intact dynamic cerebral autoregulation during HG, HDT, and their combination. We studied the dynamic response of internal carotid artery (ICA) blood flow to spontaneous cardiovascular oscillations during rest, isometric handgrip, head‐down tilt and combined handgrip and head‐down tilt in 13 healthy humans. The wavelet synchronization index was calculated between ICA blood flow and mean arterial pressure. Unchanged ICA blood flow and low synchronization between ICA blood flow and mean arterial pressure was observed between experimental states indicating intact cerebral autoregulation during isometric exercise with or without head‐down tilt.