Clinical and cost-effectiveness of autologous chondrocyte implantation for cartilage defects in knee joints : systematic review and economic evaluation

Objective: To support a review of the guidance issued by the National Institute for Health and Clinical Excellence (NICE) in December 2000 by examining the current clinical and cost-effectiveness evidence on autologous cartilage transplantation. Data sources: Electronic databases. Review methods: Evidence on clinical effectiveness was obtained from randomised trials, supplemented by data from selected observational studies for longer term results, and for the natural history of chondral lesions. Because of a lack of long-term results on outcomes such as later osteoarthritis and knee replacement, only illustrative modelling was done, using a range of assumptions that seemed reasonable, but were not evidence based. Results: Four randomised controlled trials were included, as well as observational data from case series. The trials studied a total of 266 patients and the observational studies up to 101 patients. Two studies compared autologous chondrocyte implantation (ACI) with mosaicplasty, the third compared ACI with microfracture, and the fourth compared matrix-guided ACI (MACI®) with microfracture. Follow-up was 1 year in one study, and up to 3 years in the remaining three studies. The first trial of ACI versus mosaicplasty found that ACI gave better results than mosaicplasty at 1 year. Overall, 88% had excellent or good results with ACI versus 69% with mosaicplasty. About half of the biopsies after ACI showed hyaline cartilage. The second trial of ACI versus mosaicplasty found little difference in clinical outcomes at 2 years. Disappointingly, biopsies from the ACI group showed fibrocartilage rather than hyaline cartilage. The trial of ACI versus microfracture also found only small differences in outcomes at 2 years. Finally, the trial of MACI versus microfracture contained insufficient long-term results at present, but the study does show the feasibility of doing ACI by the MACI technique. It also suggested that after ACI, it takes 2 years for full-thickness cartilage to be produced. Reliable costs per quality-adjusted life-year (QALY) could not be calculated owing to the absence of necessary data. Simple short-term modelling suggests that the quality of life gain from ACI versus microfracture would have to be between 70 and 100% greater over 2 years for it to be more cost-effective within the £20,000–30,000 per QALY costeffectiveness thresholds. However, if the quality of life gains could be maintained for a decade, increments relative to microfracture would only have to be 10–20% greater to justify additional treatment costs within the cost-effectiveness band indicated above. Follow-up from the trials so far has only been up to 2 years, with longer term outcomes being uncertain. Conclusions: There is insufficient evidence at present to say that ACI is cost-effective compared with microfracture or mosaicplasty. Longer term outcomes are required. Economic modelling using some assumptions about long-term outcomes that seem reasonable suggests that ACI would be cost-effective because it is more likely to produce hyaline cartilage, which is more likely to be durable and to prevent osteoarthritis in the longer term (e.g. 20 years). Further research is needed into earlier methods of predicting long-term results. Basic science research is also needed into factors that influence stem cells to become chondrocytes and to produce high-quality cartilage, as it may be possible to have more patients developing hyaline cartilage after microfracture. Study is also needed into cost-effective methods of rehabilitation and the effect of early mobilisation on cartilage growth

The clinical effectiveness and cost-effectiveness of computed tomography screening for lung cancer : systematic reviews

Screening for lung cancer has been the subject of debate for the past three decades. This has largely stemmed from the results of chest X-ray screening studies where improvements in survival were obtained but without reductions in disease-specific, or total, mortality. The debate raises two issues: the design of studies to evaluate screening for lung cancer, in particular the choice of comparator; and the potential role of overdiagnosis of well-differentiated, slow-growing tumours that would not have led to symptoms or death in the lifetime of the affected patient. Lung cancer is the leading cause of death from cancer in the UK, killing approximately 34,000 people per year. By the time symptoms develop, the tumour is often at an advanced stage and the prognosis is bleak. Treatment at a less advanced stage of disease with surgical resection has been shown to substantially reduce mortality. Screening would be attractive if it could detect presymptomatic lung cancer at a stage when surgical intervention is feasible

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Multiorgan MRI findings after hospitalisation with COVID-19 in the UK (C-MORE): a prospective, multicentre, observational cohort study

Introduction: The multiorgan impact of moderate to severe coronavirus infections in the post-acute phase is still poorly understood. We aimed to evaluate the excess burden of multiorgan abnormalities after hospitalisation with COVID-19, evaluate their determinants, and explore associations with patient-related outcome measures. Methods: In a prospective, UK-wide, multicentre MRI follow-up study (C-MORE), adults (aged ≥18 years) discharged from hospital following COVID-19 who were included in Tier 2 of the Post-hospitalisation COVID-19 study (PHOSP-COVID) and contemporary controls with no evidence of previous COVID-19 (SARS-CoV-2 nucleocapsid antibody negative) underwent multiorgan MRI (lungs, heart, brain, liver, and kidneys) with quantitative and qualitative assessment of images and clinical adjudication when relevant. Individuals with end-stage renal failure or contraindications to MRI were excluded. Participants also underwent detailed recording of symptoms, and physiological and biochemical tests. The primary outcome was the excess burden of multiorgan abnormalities (two or more organs) relative to controls, with further adjustments for potential confounders. The C-MORE study is ongoing and is registered with ClinicalTrials.gov, NCT04510025. Findings: Of 2710 participants in Tier 2 of PHOSP-COVID, 531 were recruited across 13 UK-wide C-MORE sites. After exclusions, 259 C-MORE patients (mean age 57 years [SD 12]; 158 [61%] male and 101 [39%] female) who were discharged from hospital with PCR-confirmed or clinically diagnosed COVID-19 between March 1, 2020, and Nov 1, 2021, and 52 non-COVID-19 controls from the community (mean age 49 years [SD 14]; 30 [58%] male and 22 [42%] female) were included in the analysis. Patients were assessed at a median of 5·0 months (IQR 4·2–6·3) after hospital discharge. Compared with non-COVID-19 controls, patients were older, living with more obesity, and had more comorbidities. Multiorgan abnormalities on MRI were more frequent in patients than in controls (157 [61%] of 259 vs 14 [27%] of 52; p&lt;0·0001) and independently associated with COVID-19 status (odds ratio [OR] 2·9 [95% CI 1·5–5·8]; padjusted=0·0023) after adjusting for relevant confounders. Compared with controls, patients were more likely to have MRI evidence of lung abnormalities (p=0·0001; parenchymal abnormalities), brain abnormalities (p&lt;0·0001; more white matter hyperintensities and regional brain volume reduction), and kidney abnormalities (p=0·014; lower medullary T1 and loss of corticomedullary differentiation), whereas cardiac and liver MRI abnormalities were similar between patients and controls. Patients with multiorgan abnormalities were older (difference in mean age 7 years [95% CI 4–10]; mean age of 59·8 years [SD 11·7] with multiorgan abnormalities vs mean age of 52·8 years [11·9] without multiorgan abnormalities; p&lt;0·0001), more likely to have three or more comorbidities (OR 2·47 [1·32–4·82]; padjusted=0·0059), and more likely to have a more severe acute infection (acute CRP &gt;5mg/L, OR 3·55 [1·23–11·88]; padjusted=0·025) than those without multiorgan abnormalities. Presence of lung MRI abnormalities was associated with a two-fold higher risk of chest tightness, and multiorgan MRI abnormalities were associated with severe and very severe persistent physical and mental health impairment (PHOSP-COVID symptom clusters) after hospitalisation. Interpretation: After hospitalisation for COVID-19, people are at risk of multiorgan abnormalities in the medium term. Our findings emphasise the need for proactive multidisciplinary care pathways, with the potential for imaging to guide surveillance frequency and therapeutic stratification

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Sources of evidence for systematic reviews of interventions in diabetes

Aims To analyse the effect on systematic reviews in diabetes interventions of including only trials that are indexed in medline, and to assess the impact of adding trials from other databases and the grey literature. Methods All systematic reviews of diabetes interventions which included a meta-analysis of randomized controlled trials, and were published since 1996, were selected. The impact on the meta-analysis of including only those trials indexed in medline, and the effect of then adding trials from other sources, was assessed. Where possible this was measured quantitatively, by redoing the meta-analysis, otherwise a qualitative estimate was made. Results Forty-four systematic reviews met our inclusion criteria. There were 120 articles reporting trial data which were not indexed in medline. These came from 52% of the reviews. In 34% of the reviews, basing a meta-analysis on a search of only medline would miss trials that could affect the result. Sources of non-medline data which had the biggest effect on the meta-analyses were journal articles from central and embase (mainly in Diabetes, Nutrition and Metabolism) and unpublished data (mainly from industry). The exceptions were journal articles on herbal medicine, mostly indexed in Chinese language databases. Conclusions A search of only the medline database is insufficient for systematic reviews of diabetes, because in about 34% of reviews the missed trials could affect the results of the meta-analysis. It is recommended that central (on the Cochrane Library) also be searched. Scanning meeting abstracts, and seeking unpublished data are also recommended if the intervention has only recently been introduced

Use of a brief version of the self-compassion inventory with an international sample of people with HIV/AIDS.

The objective of this study was to extend the psychometric evaluation of a brief version of the Self-Compassion Scale (SCS). A secondary analysis of data from an international sample of 1967 English-speaking persons living with HIV disease was used to examine the factor structure, and reliability of the 12-item Brief Version Self-Compassion Inventory (BVSCI). A Maximum Likelihood factor analysis and Oblimin with Kaiser Normalization confirmed a two-factor solution, accounting for 42.58% of the variance. The BVSCI supported acceptable internal consistencies, with 0.714 for the total scale and 0.822 for Factor I and 0.774 for Factor II. Factor I (lower self-compassion) demonstrated strongly positive correlations with measures of anxiety and depression, while Factor II (high self-compassion) was inversely correlated with the measures. No significant differences were found in the BVSCI scores for gender, age, or having children. Levels of self-compassion were significantly higher in persons with HIV disease and other physical and psychological health conditions. The scale shows promise for the assessment of self-compassion in persons with HIV without taxing participants, and may prove essential in investigating future research aimed at examining correlates of self-compassion, as well as providing data for tailoring self-compassion interventions for persons with HIV

Unhealthy substance-use behaviors as symptom-related self-care in persons with HIV/AIDS.

Unhealthy substance-use behaviors, including a heavy alcohol intake, illicit drug use, and cigarette smoking, are engaged in by many HIV-positive individuals, often as a way to manage their disease-related symptoms. This study, based on data from a larger randomized controlled trial of an HIV/AIDS symptom management manual, examines the prevalence and characteristics of unhealthy behaviors in relation to HIV/AIDS symptoms. The mean age of the sample (n = 775) was 42.8 years and 38.5% of the sample was female. The mean number of years living with HIV was 9.1 years. The specific self-reported unhealthy substance-use behaviors were the use of marijuana, cigarettes, a large amount of alcohol, and illicit drugs. A subset of individuals who identified high levels of specific symptoms also reported significantly higher substance-use behaviors, including amphetamine and injection drug use, heavy alcohol use, cigarette smoking, and marijuana use. The implications for clinical practice include the assessment of self-care behaviors, screening for substance abuse, and education of persons regarding the self-management of HIV