This trial involving critically ill adults receiving mechanical ventilation compared the effects of energy-dense and routine enteral nutrition. The use of an energy-dense formulation did not increase ...the rate of survival at 90 days.
The long-term effects of delivering approximately 100% of recommended calorie intake via the enteral route during critical illness compared with a lesser amount of calories are unknown.
Our ...hypotheses were that achieving approximately 100% of recommended calorie intake during critical illness would increase quality-of-life scores, return to work, and key life activities and reduce death and disability 6 months later.
We conducted a multicenter, blinded, parallel group, randomized clinical trial, with 3,957 mechanically ventilated critically ill adults allocated to energy-dense (1.5 kcal/ml) or routine (1.0 kcal/ml) enteral nutrition.
Participants assigned energy-dense nutrition received more calories (percent recommended energy intake, mean SD; energy-dense: 103% 28 vs. usual: 69% 18). Mortality at Day 180 was similar (560/1,895 29.6% vs. 539/1,920 28.1%; relative risk 1.05 95% confidence interval, 0.95-1.16). At a median (interquartile range) of 185 (182-193) days after randomization, 2,492 survivors were surveyed and reported similar quality of life (EuroQol five dimensions five-level quality-of-life questionnaire visual analog scale, median interquartile range: 75 60-85; group difference: 0 95% confidence interval, 0-0). Similar numbers of participants returned to work with no difference in hours worked or effectiveness at work (
= 818). There was no observed difference in disability (
= 1,208) or participation in key life activities (
= 705).
The delivery of approximately 100% compared with 70% of recommended calorie intake during critical illness does not improve quality of life or functional outcomes or increase the number of survivors 6 months later.
Colonoscopy surveillance is recommended for some patients post polypectomy. The 2002 UK surveillance guidelines classify post-polypectomy patients into low, intermediate and high risk, and recommend ...different strategies for each classification. Limited evidence supports these guidelines.
To examine, for each risk group, long-term colorectal cancer incidence by baseline characteristics and the number of surveillance visits; the effects of interval length on detection rates of advanced adenomas and colorectal cancer at first surveillance; and the cost-effectiveness of surveillance compared with no surveillance.
A retrospective cohort study and economic evaluation.
Seventeen NHS hospitals.
Patients with a colonoscopy and at least one adenoma at baseline.
Long-term colorectal cancer incidence after baseline and detection rates of advanced adenomas and colorectal cancer at first surveillance.
Hospital databases, NHS Digital, the Office for National Statistics, National Services Scotland and Public Health England.
Cox regression was used to compare colorectal cancer incidence in the presence and absence of surveillance and to identify colorectal cancer risk factors. Risk factors were used to stratify risk groups into higher- and lower-risk subgroups. We examined detection rates of advanced adenomas and colorectal cancer at first surveillance by interval length. Cost-effectiveness of surveillance compared with no surveillance was evaluated in terms of incremental costs per colorectal cancer prevented and per quality-adjusted life-year gained.
Our study included 28,972 patients, of whom 14,401 (50%), 11,852 (41%) and 2719 (9%) were classed as low, intermediate and high risk, respectively. The median follow-up time was 9.3 years. Colorectal cancer incidence was 140, 221 and 366 per 100,000 person-years among low-, intermediate- and high-risk patients, respectively. Attendance at one surveillance visit was associated with reduced colorectal cancer incidence among low-, intermediate- and high-risk patients hazard ratios were 0.56 (95% confidence interval 0.39 to 0.80), 0.59 (95% confidence interval 0.43 to 0.81) and 0.49 (95% confidence interval 0.29 to 0.82), respectively. Compared with the general population, colorectal cancer incidence without surveillance was similar among low-risk patients and higher among high-risk patients standardised incidence ratios were 0.86 (95% confidence interval 0.73 to 1.02) and 1.91 (95% confidence interval 1.39 to 2.56), respectively. For intermediate-risk patients, standardised incidence ratios differed for the lower- (0.70, 95% confidence interval 0.48 to 0.99) and higher-risk (1.46, 95% confidence interval 1.19 to 1.78) subgroups. In each risk group, incremental costs per colorectal cancer prevented and per quality-adjusted life-year gained with surveillance were lower for the higher-risk subgroup than for the lower-risk subgroup. Incremental costs per quality-adjusted life-year gained were lowest for the higher-risk subgroup of high-risk patients at £7821.
The observational design means that we cannot assume that surveillance caused the reductions in cancer incidence. The fact that some cancer staging data were missing places uncertainty on our cost-effectiveness estimates.
Surveillance was associated with reduced colorectal cancer incidence in all risk groups. However, in low-risk patients and the lower-risk subgroup of intermediate-risk patients, colorectal cancer incidence was no higher than in the general population without surveillance, indicating that surveillance might not be necessary. Surveillance was most cost-effective for the higher-risk subgroup of high-risk patients.
Studies should examine the clinical effectiveness and cost-effectiveness of post-polypectomy surveillance without prior classification of patients into risk groups.
This trial is registered as ISRCTN15213649.
This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in
; Vol. 26, No. 26. See the NIHR Journals Library website for further project information.
To determine whether impaired awareness of hypoglycemia (IAH) can be improved and severe hypoglycemia (SH) prevented in type 1 diabetes, we compared an insulin pump (continuous subcutaneous insulin ...infusion CSII) with multiple daily injections (MDIs) and adjuvant real-time continuous glucose monitoring (RT) with conventional self-monitoring of blood glucose (SMBG).
A 24-week 2 × 2 factorial randomized controlled trial in adults with type 1 diabetes and IAH was conducted. All received comparable education, support, and congruent therapeutic targets aimed at rigorous avoidance of biochemical hypoglycemia without relaxing overall control. Primary end point was between-intervention difference in 24-week hypoglycemia awareness (Gold score).
A total of 96 participants (mean diabetes duration 29 years) were randomized. Overall, biochemical hypoglycemia (≤3.0 mmol/L) decreased (53 ± 63 to 24 ± 56 min/24 h; P = 0.004 t test) without deterioration in HbA1c. Hypoglycemia awareness improved (5.1 ± 1.1 to 4.1 ± 1.6; P = 0.0001 t test) with decreased SH (8.9 ± 13.4 to 0.8 ± 1.8 episodes/patient-year; P = 0.0001 t test). At 24 weeks, there was no significant difference in awareness comparing CSII with MDI (4.1 ± 1.6 vs. 4.2 ± 1.7; difference 0.1; 95% CI -0.6 to 0.8) and RT with SMBG (4.3 ± 1.6 vs. 4.0 ± 1.7; difference -0.3; 95% CI -1.0 to 0.4). Between-group analyses demonstrated comparable reductions in SH, fear of hypoglycemia, and insulin doses with equivalent HbA1c. Treatment satisfaction was higher with CSII than MDI (32 ± 3 vs. 29 ± 6; P = 0.0003 t test), but comparable with SMBG and RT (30 ± 5 vs. 30 ± 5; P = 0.79 t test).
Hypoglycemia awareness can be improved and recurrent SH prevented in long-standing type 1 diabetes without relaxing HbA1c. Similar biomedical outcomes can be attained with conventional MDI and SMBG regimens compared with CSII/RT, although satisfaction was higher with CSII.
Patients with cancer are at increased risk of hospitalisation and mortality following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. However, the SARS-CoV-2 phenotype ...evolution in patients with cancer since 2020 has not previously been described. We therefore evaluated SARS-CoV-2 on a UK populationscale from 01/11/2020-31/08/2022, assessing case-outcome rates of hospital assessment(s), intensive care admission and mortality. We observed that the SARS-CoV-2 disease phenotype has become less severe in patients with cancer and the non-cancer population. Case-hospitalisation rates for patients with cancer dropped from 30.58% in early 2021 to 7.45% in 2022 while case-mortality rates decreased from 20.53% to 3.25%. However, the risk of hospitalisation and mortality remains 2.10x and 2.54x higher in patients with cancer, respectively. Overall, the SARS-CoV-2 disease phenotype is less severe in 2022 compared to 2020 but patients with cancer remain at higher risk than the non-cancer population. Patients with cancer must therefore be empowered to live more normal lives, to see loved ones and families, while also being safeguarded with expanded measures to reduce the risk of transmission.
Protein aggregation and oxidative stress are both key pathogenic processes in Parkinson's disease, although the mechanism by which misfolded proteins induce oxidative stress and neuronal death ...remains unknown. In this study, we describe how aggregation of alpha-synuclein (α-S) from its monomeric form to its soluble oligomeric state results in aberrant free radical production and neuronal toxicity.
We first demonstrate excessive free radical production in a human induced pluripotent stem-derived α-S triplication model at basal levels and on application of picomolar doses of β-sheet-rich α-S oligomers. We probed the effects of different structural species of α-S in wild-type rat neuronal cultures and show that both oligomeric and fibrillar forms of α-S are capable of generating free radical production, but that only the oligomeric form results in reduction of endogenous glutathione and subsequent neuronal toxicity. We dissected the mechanism of oligomer-induced free radical production and found that it was interestingly independent of several known cellular enzymatic sources.
The oligomer-induced reactive oxygen species (ROS) production was entirely dependent on the presence of free metal ions as addition of metal chelators was able to block oligomer-induced ROS production and prevent oligomer-induced neuronal death.
Our findings further support the causative role of soluble amyloid oligomers in triggering neurodegeneration and shed light into the mechanisms by which these species cause neuronal damage, which, we show here, can be amenable to modulation through the use of metal chelation.
Severe hypoglycemia is a feared complication of type 1 diabetes; yet, few trials have targeted prevention using optimized self-management (educational, therapeutic, and technological support). We ...aimed to investigate whether improved awareness and reduced severe hypoglycemia, achieved during an intensive randomized clinical trial (RCT), were sustained after return to routine care.
Ninety-six adults with type 1 diabetes (29 ± 12 years' duration) and impaired awareness of hypoglycemia at five U.K. tertiary referral diabetes centers were recruited into a 24-week 2 × 2 factorial RCT (HypoCOMPaSS). Participants were randomized to pump (continuous subcutaneous insulin infusion CSII) or multiple daily injections (MDIs) and real-time continuous glucose monitoring (RT-CGM) or self-monitoring of blood glucose (SMBG), with equal education/attention to all groups. At 24 weeks, participants returned to routine care with follow-up until 24 months, including free choice of MDI/CSII; RT-CGM vs. SMBG comparison continued to 24 months. Primary outcome was mean difference (baseline to 24 months between groups) in hypoglycemia awareness.
Improvement in hypoglycemia awareness was sustained (Gold score at baseline 5.1 ± 1.1 vs. 24 months 3.7 ± 1.9;
< 0.0001). Severe hypoglycemia rate was reduced from 8.9 ± 12.8 episodes/person-year over the 12 months prestudy to 0.4 ± 0.8 over 24 months (
< 0.0001). HbA
improved (baseline 8.2 ± 3.2% 66 ± 12 mmol/mol vs. 24 months 7.7 ± 3.1% 61 ± 10 mmol/mol;
= 0.003). Improvement in treatment satisfaction and reduced fear of hypoglycemia were sustained. There were no significant differences between interventions at 24 months.
Optimized insulin replacement and glucose monitoring underpinned by hypoglycemia-focused structured education should be provided to all with type 1 diabetes complicated by impaired awareness of hypoglycemia.
Pregnancy is a high-risk time for excessive weight gain. The rising prevalence of obesity in women, combined with excess weight gain during pregnancy, means that there are more women with obesity in ...the postnatal period. This can have adverse health consequences for women in later life and increases the health risks during subsequent pregnancies.
The primary aim was to produce evidence of whether or not a Phase III trial of a brief weight management intervention, in which postnatal women are encouraged by practice nurses as part of the national child immunisation programme to self-monitor their weight and use an online weight management programme, is feasible and acceptable.
The research involved a cluster randomised controlled feasibility trial and two semistructured interview studies with intervention participants and practice nurses who delivered the intervention. Trial data were collected at baseline and 3 months later. The interview studies took place after trial follow-up.
The trial took place in Birmingham, UK.
Twenty-eight postnatal women who were overweight/obese were recruited via Birmingham Women's Hospital or general practices. Nine intervention participants and seven nurses were interviewed.
The intervention was delivered in the context of the national child immunisation programme. The intervention group were offered brief support that encouraged self-management of weight when they attended their practice to have their child immunised at 2, 3 and 4 months of age. The intervention involved the provision of motivation and support by nurses to encourage participants to make healthier lifestyle choices through self-monitoring of weight and signposting to an online weight management programme. The role of the nurse was to provide regular external accountability for weight loss. Women were asked to weigh themselves weekly and record this on a record card in their child's health record ('red book') or using the online programme. The behavioural goal was for women to lose 0.5-1 kg per week. The usual-care group received a healthy lifestyle leaflet.
The primary outcome was the feasibility of a Phase III trial to test the effectiveness of the intervention, as assessed against three traffic-light stop-go criteria (recruitment, adherence to regular self-weighing and registration with an online weight management programme).
The traffic-light criteria results were red for recruitment (28/80, 35% of target), amber for registration with the online weight loss programme (9/16, 56%) and green for adherence to weekly self-weighing (10/16, 63%). Nurses delivered the intervention with high fidelity. In the qualitative studies, participants indicated that the intervention was acceptable to them and they welcomed receiving support to lose weight at their child immunisation appointments. Although nurses raised some caveats to implementation, they felt that the intervention was easy to deliver and that it would motivate postnatal women to lose weight.
Fewer participants were recruited than planned.
Although women and practice nurses responded well to the intervention and adherence to self-weighing was high, recruitment was challenging and there is scope to improve engagement with the intervention.
Future research should focus on investigating other methods of recruitment and, thereafter, testing the effectiveness of the intervention.
Current Controlled Trials ISRCTN12209332.
This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in
; Vol. 25, No. 49. See the NIHR Journals Library website for further project information.
•The Mai'iu fault is an active, low-angle (∼20°) normal fault at the surface.•Footwall acquired normal-polarity magnetisation during its uplift in Brunhes chron.•Mean direction indicates 24° ± 3° of ...back-tilting of footwall as fault slipped.•Original fault dip was ∼40-50° similar to that at >12 km depth today.•Rolling-hinge deformation affects continental detachment faults.
Metamorphic core complexes (MCCs) have been attributed to slip on long-lived detachment faults in extensional environments. At the surface, such faults are typically shallow dipping (<30°). This is inconsistent with Andersonian faulting theory, which requires that normal faults should nucleate and slip at steeper dips. One possible solution to this mechanical problem is a “rolling hinge” evolution for the fault during its slip history. In this model, faults initiate at steep dips (e.g. 60°) and back-tilt to shallower dips due to flexure and isostatic uplift in response to unloading of the footwall during slip. The Mai'iu fault is an active, rapidly slipping (∼1 cm/yr) low-angle (dip 20-22° at the surface) normal fault. Sampling of the footwall Goropu Metabasalt revealed a consistent normal-polarity component of magnetisation with moderate inclination that we interpret to have been acquired during uplift and cooling of the footwall rocks during the Brunhes chron. Comparison of the direction of the normal component with the expected average (geocentric axial dipole) direction at the site latitude indicates 23.9° ± 2.6° (1σ) of back-tilting of the footwall about the strike of the Mai'iu fault, consistent with a rolling hinge style of rotation. This indicates an original fault dip of 41.3-48.5°, as is consistent with independent estimates of original fault dip from fault-bedding cut-off angles and microseismicity at depth. This study is the first of its kind to demonstrate, using paleomagnetism, large-scale horizontal-axis rotations consistent with a rolling hinge evolution for a continental MCC.
Prostate cancer is the most frequently diagnosed cancer in males in developed countries. To identify common prostate cancer susceptibility alleles, we genotyped 211,155 SNPs on a custom Illumina ...array (iCOGS) in blood DNA from 25,074 prostate cancer cases and 24,272 controls from the international PRACTICAL Consortium. Twenty-three new prostate cancer susceptibility loci were identified at genome-wide significance (P < 5 × 10(-8)). More than 70 prostate cancer susceptibility loci, explaining ∼30% of the familial risk for this disease, have now been identified. On the basis of combined risks conferred by the new and previously known risk loci, the top 1% of the risk distribution has a 4.7-fold higher risk than the average of the population being profiled. These results will facilitate population risk stratification for clinical studies.
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