Forecasting healthcare demand is essential in epidemic settings, both to inform situational awareness and facilitate resource planning. Ideally, forecasts should be robust across time and locations. ...During the COVID-19 pandemic in England, it is an ongoing concern that demand for hospital care for COVID-19 patients in England will exceed available resources.
We made weekly forecasts of daily COVID-19 hospital admissions for National Health Service (NHS) Trusts in England between August 2020 and April 2021 using three disease-agnostic forecasting models: a mean ensemble of autoregressive time series models, a linear regression model with 7-day-lagged local cases as a predictor, and a scaled convolution of local cases and a delay distribution. We compared their point and probabilistic accuracy to a mean-ensemble of them all and to a simple baseline model of no change from the last day of admissions. We measured predictive performance using the weighted interval score (WIS) and considered how this changed in different scenarios (the length of the predictive horizon, the date on which the forecast was made, and by location), as well as how much admissions forecasts improved when future cases were known.
All models outperformed the baseline in the majority of scenarios. Forecasting accuracy varied by forecast date and location, depending on the trajectory of the outbreak, and all individual models had instances where they were the top- or bottom-ranked model. Forecasts produced by the mean-ensemble were both the most accurate and most consistently accurate forecasts amongst all the models considered. Forecasting accuracy was improved when using future observed, rather than forecast, cases, especially at longer forecast horizons.
Assuming no change in current admissions is rarely better than including at least a trend. Using confirmed COVID-19 cases as a predictor can improve admissions forecasts in some scenarios, but this is variable and depends on the ability to make consistently good case forecasts. However, ensemble forecasts can make forecasts that make consistently more accurate forecasts across time and locations. Given minimal requirements on data and computation, our admissions forecasting ensemble could be used to anticipate healthcare needs in future epidemic or pandemic settings.
Abstract Dental age assessment is one the most accurate methods for estimating the age of an unknown person. Demirjian's dataset on a French-Canadian population has been widely tested for its ...applicability on various ethnic groups including southern Chinese. Following inaccurate results from these studies, investigators are now confronted with using alternate datasets for comparison. Testing the applicability of other reliable datasets which result in accurate findings might limit the need to develop population specific standards. Recently, a Reference Data Set (RDS) similar to the Demirjian was prepared in the United Kingdom (UK) and has been subsequently validated. The advantages of the UK Caucasian RDS includes versatility from including both the maxillary and mandibular dentitions, involvement of a wide age group of subjects for evaluation and the possibility of precise age estimation with the mathematical technique of meta-analysis. The aim of this study was to evaluate the applicability of the United Kingdom Caucasian RDS on southern Chinese subjects. Dental panoramic tomographs (DPT) of 266 subjects (133 males and 133 females) aged 2–21 years that were previously taken for clinical diagnostic purposes were selected and scored by a single calibrated examiner based on Demirjian's classification of tooth developmental stages (A–H). The ages corresponding to each stage of tooth developmental stage were obtained from the UK dataset. Intra-examiner reproducibility was tested and the Cohen kappa (0.88) showed that the level of agreement was ‘almost perfect’. The estimated dental age was then compared with the chronological age using a paired t -test, with statistical significance set at p < 0.01. The results showed that the UK dataset, underestimated the age of southern Chinese subjects by 0.24 years but the results were not statistically significant. In conclusion, the UK Caucasian RDS may not be suitable for estimating the age of southern Chinese subjects and there is a need for an ethnic specific reference dataset for southern Chinese.
Abstract
Purpose
The aim of this study is to report the safety and eff-cacy of soft-tissue surgery incorporating split transfer of tibi-alis anterior to peroneus brevis (SPLATT-PB) for children with ...hemiplegic spastic equinovarus.
Methods
This was a retrospective case series of children and adolescents with spastic hemiplegia who had a novel combination of SPLATT-TB, intramuscular tenotomy of tibialis posterior and either spasticity management or gastrocsole-us lengthening as the index surgery. The principal outcome measures were changes in pain and difficulty with shoe wear and radiological parameters obtained from weight-bearing anteroposterior and lateral radiographs of the affected foot before and after surgery.
Results
A total of 63 patients with symptomatic spastic equinovarus met the inclusion criteria. Mean age at surgery was 9.8 years (6 to 18) and the mean follow-up was seven years (range 3 to 10 years). Foot pain and problems with shoe wear improved after surgery. Seven radiological criteria showed a clinically and statistically significant improvement at follow-up, the majority being in the normal range. There were 11 surgical adverse events, all classified as Modified Cla-vien-Dindo Grade II. Three patients required further surgery for recurrent equinus, eight patients required further surgery for valgus deformities and four patients required bony surgery for residual varus deformities.
Conclusion
Soft-tissue surgery for spastic equinovarus was successful in the majority of children with spastic hemiplegia, particularly between ages eight and 12 years, resulting in a plantigrade, flexible foot with minimal pain or limitations in shoe-wear. Children younger than 8 years at index surgery were more prone to overcorrection into valgus. Children older than 12 years had persistent varus deformities requiring bony surgery.
Level of evidence
Level IV, retrospective case series
Vitamin D deficiency is prevalent in patients with chronic spinal cord injury (SCI) and has been implicated as an aetiologic factor of osteoporosis and various skeletal and extra-skeletal issues in ...SCI patients. Few data were available regarding vitamin D status in patients with acute SCI or immediately assessed at hospital admission. This retrospective cross-sectional study evaluated vitamin D status in SCI patients at admission to a UK SCI centre in January–December 2017. A total of 196 eligible patients with serum 25(OH)D concentration records at admission were recruited. The results found that 24 % were vitamin D deficient (serum 25(OH)D < 25 nmol/l), 57 % of the patients had serum 25(OH)D < 50 nmol/l. The male patients, patients admitted in the winter–spring time (December–May), and patients with serum sodium < 135 mmol/l or with non-traumatic causes had a significant higher prevalence of vitamin D deficiency than their counterparts (28 % males v. 11⋅8 % females, P = 0⋅02; 30⋅2 % in winter–spring v. 12⋅9 % in summer–autumn, P = 0⋅007; 32⋅1 % non-traumatic v. 17⋅6 % traumatic SCI, P = 0⋅03; 38⋅9 % low serum sodium v. 18⋅8 % normal serum sodium, P = 0⋅010). There was a significant inverse association of serum 25(OH)D concentration with body mass index (BMI) (r = −0⋅311, P = 0⋅002), serum total cholesterol (r = −0⋅168, P = 0⋅04) and creatinine concentrations (r = −0⋅162, P = 0⋅02) that were also significant predictors of serum 25(OH)D concentration. Strategies for systematic screening and efficacy of vitamin D supplementation in SCI patients need to be implemented and further investigated to prevent the vitamin D deficiency-related chronic complications.
•Brain endothelial cells mediate detrimental actions of IL-1 in cerebral ischemia.•Neuronal cholinergic IL-1R1 also mediate detrimental actions of IL-1 in brain injury.•Brain endothelial IL-1 actions ...reduce cortical perfusion after cerebral ischemia.•Ubiquitous IL-1R1 deletion does not affect injury, suggesting compensatory mechanisms.
The cytokine interleukin-1 (IL-1) is a key contributor to neuroinflammation and brain injury, yet mechanisms by which IL-1 triggers neuronal injury remain unknown. Here we induced conditional deletion of IL-1R1 in brain endothelial cells, neurons and blood cells to assess site-specific IL-1 actions in a model of cerebral ischaemia in mice. Tamoxifen treatment of IL-1R1 floxed (fl/fl) mice crossed with mice expressing tamoxifen-inducible Cre-recombinase under the Slco1c1 promoter resulted in brain endothelium-specific deletion of IL-1R1 and a significant decrease in infarct size (29%), blood-brain barrier (BBB) breakdown (53%) and neurological deficit (40%) compared to vehicle-treated or control (IL-1R1fl/fl) mice. Absence of brain endothelial IL-1 signalling improved cerebral blood flow, followed by reduced neutrophil infiltration and vascular activation 24 h after brain injury. Conditional IL-1R1 deletion in neurons using tamoxifen inducible nestin-Cre mice resulted in reduced neuronal injury (25%) and altered microglia-neuron interactions, without affecting cerebral perfusion or vascular activation. Deletion of IL-1R1 specifically in cholinergic neurons reduced infarct size, brain oedema and improved functional outcome. Ubiquitous deletion of IL-1R1 had no effect on brain injury, suggesting beneficial compensatory mechanisms on other cells against the detrimental effects of IL-1 on endothelial cells and neurons. We also show that IL-1R1 signalling deletion in platelets or myeloid cells does not contribute to brain injury after experimental stroke. Thus, brain endothelial and neuronal (cholinergic) IL-1R1 mediate detrimental actions of IL-1 in the brain in ischaemic stroke. Cell-specific targeting of IL-1R1 in the brain could therefore have therapeutic benefits in stroke and other cerebrovascular diseases.
•Diffusion weighted imaging of heterogeneity can aid selection for ‘watch-and-wait’.•Apparent diffusion coefficient 75th and 90th quantiles were predictive of response.•Dynamic contrast enhanced ...imaging did not add value in response prediction.•Functional mapping of tumour heterogeneity may be used for targeting.
Prediction of chemoradiotherapy response (CRT) in locally advanced rectal cancer would enable stratification of management. The purpose was to prospectively evaluate multi-parametric magnetic resonance imaging (MRI) assessment of tumour heterogeneity combining diffusion weighted imaging (DWI) and dynamic contrast enhanced (DCE) MRI for the prediction of CRT response in locally advanced rectal cancer.
Patients with Stage II or III rectal adenocarcinoma undergoing neoadjuvant CRT and surgery underwent MRI (DWI and DCE) before, during (week 3), and after CRT (1 week before surgery). Patients with histopathology tumour regression grade (TRG) 0–1 were classified as responders, and TRG 2–3 were classified as non-responders. A whole tumour voxel-wise technique was used to produce apparent diffusion coefficient (ADC) and Ktrans (Tofts model) histograms derived from DWI and DCE-MRI, respectively. Logistic regression was used to predict response status for ADC and Ktrans quantiles.
Thirty-three patients were included in this analysis; 16 responders, and 17 non-responders. On heterogeneity analysis, odds of being a responder were significantly higher after CRT (before surgery) for higher ADC 75th (p = 0.049) and ADC 90th (p = 0.034) percentile values. The Ktrans quantiles were lower in non-responders than responders before and during CRT, and higher after CRT although no significant association with response status was observed (p ≥ 0.10).
DWI-MRI after CRT (before surgery) incorporating a histogram analysis of whole tumour heterogeneity was predictive of CRT response in patients with locally advanced rectal cancer. DCE-MRI did not add value in response prediction.
Australian New Zealand Clinical Trials Registry (ANZCTR) number ACTRN12616001690448.
Moderate to severe neonatal hypoxic ischemic encephalopathy remains an important cause of infant death and childhood disability. Early and accurate diagnosis of encephalopathy is difficult but ...critical for timely intervention. Thus, we have utilized a clinically relevant large animal model of asphyxia in-utero, followed by immediate lamb delivery, resuscitation and clinical care over the next 72h for assessment of potential biomarkers of brain injury. In-utero asphyxia was induced in twelve near-term lambs and outcomes compared with seven controls. Asphyxia resulted in bradycardia (97±12beats/min), hypotension (12.1±1mm Hg) and metabolic acidosis (pH6.9±0.02; base-excess −13.8±0.8mmol/l). 72h following asphyxia, cerebrospinal concentrations of malondialdehyde and S100B were elevated 2-fold and 5-fold, respectively, in asphyxic lambs compared to control lambs. Magnetic resonance spectroscopy (MRS) at 72h showed a significant decrease in n-acetyl aspartate: choline ratio in asphyxia lambs compared to that observed at 12h (0.56±0.23 vs. 0.82±0.15, respectively); lactate:choline ratio was not changed over this time. Marked neuropathology was observed in asphyxia lambs with neuronal degeneration in the hippocampus, thalamus, striatum and cortex. Astrogliosis was observed in the hippocampus and thalamus. Early blood markers of metabolic state showed limited predictive value of histological damage at 72h. MRS outcomes at 72h showed a modest but significant correlation with histological evidence of neuronal brain injury (lactate:N-acetyl aspartate ratio in the thalamus r2=0.2, p<0.01). MRS at 72h was best able to detect established brain injury, but a combination of biomarkers over multiple phases of injury may be able to assess the evolution of neonatal brain injury.
•We developed a clinically relevant newborn lamb model of hypoxia–ischemia.•Early assessment of blood lactate, and pH correlated with neuronal degeneration.•Late assessment of magnetic resonance correlated with neuronal degeneration.•Combinations of biomarkers are needed to assess neonatal brain injury.
In rats and mice, the renal stanniocalcin-1 (STC-1) gene is expressed in most nephron segments, but is differentially induced in response to dehydration. In cortical segments STC-1 mRNA levels are ...upregulated by the hypertonicity of dehydration, while hypovolemia causes gene induction in the inner medulla (papilla). In both cases induction is mediated by arginine vasopressin (AVP) acting via the V2 receptor (V2R). The intent of STC-1 gene upregulation during dehydration has yet to be established. Therefore, to narrow down the range of possible actions, we mapped out the pathway by which V2R occupancy upregulates the gene. V2R occupancy activates two different renal pathways in response to dehydration. The first is antidiuretic in nature and is mediated by direct V2R occupancy. The second pathway is indirect and counter-regulates AVP-mediated antidiuresis. It involves COX-2 (cyclooxygenase-2) and the prostanoids, and is activated by the V2R-mediated rise in medullary interstitial osmolality. The resulting prostanoids counter-regulate AVP-mediated antidiuresis. They also upregulate renal cytoprotective mechanisms. The present studies employed models of COX inhibition and COX gene deletion to address the possible involvement of the COX pathway. The results showed that both general and specific inhibitors of COX-2 blocked STC-1 gene induction in response to dehydration. Gene induction in response to dehydration was also abolished in COX-2 null mice (cortex and papilla), but not in COX-1 null mice. STC-1 gene induction in response to V2R occupancy was also uniquely abolished in COX-2 nulls (both regions). These findings therefore collectively suggest that AVP-mediated elevations in STC-1 gene expression are wholly dependent on functional COX-2 activity. As such, a permissive role for STC-1 in AVP-mediated antidiuresis can be ruled out, and its range of possible actions has been narrowed down to AVP counter-regulation and renal cytoprotection.
Abstract
Background
Prenatal exposure to maternal smoking is detrimental to child health but its association with risk of cancer has seldom been investigated. Maternal smoking induces widespread and ...long-lasting DNA methylation changes, which we study here for association with risk of cancer in adulthood.
Methods
Eight prospective case-control studies nested within the Melbourne Collaborative Cohort Study were used to assess associations between maternal-smoking-associated methylation marks in blood and risk of several cancers: breast (N = 406 cases), colorectal (N = 814), gastric (N = 166), kidney (N = 139), lung (N = 327), prostate (N = 847) and urothelial cancer (N = 404) and B-cell lymphoma (N = 426). We used conditional logistic regression models to estimate odds ratios (OR) and 95% confidence intervals (CI) for associations between cancer and five methylation scores calculated as weighted averages for 568, 19, 15, 28, and 17 CpG sites. Models were adjusted for confounders, including personal smoking history (smoking status, pack-years, age at starting and quitting), and methylation scores for personal smoking.
Results
All methylation scores for maternal smoking were strongly positively associated with risk of urothelial cancer. Risk estimates were only slightly attenuated after adjustment for smoking history, other potential confounders and methylation scores for personal smoking. Potential inverse associations were observed with risk of lung cancer and B-cell lymphoma.
Conclusions
We found that methylation marks of prenatal exposure to maternal smoking are associated with increased risk of urothelial cancer.
Key messages
Our study demonstrates the potential for using DNA methylation to investigate the impact of early-life, unmeasured exposures on later-life cancer risk.
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