Cost-effectiveness analysis of a placebo-controlled randomized trial evaluating the effectiveness of arthroscopic subacromial decompression in patients with subacromial shoulder pain

Aims The aims of this study were to compare the use of resources, costs, and quality of life outcomes associated with subacromial decompression, arthroscopy only (placebo surgery), and no treatment for subacromial pain in the United Kingdom National Health Service (NHS), and to estimate their cost-effectiveness. Patients and Methods The use of resources, costs, and quality-adjusted life-years (QALYs) were assessed in the trial at six months and one year. Results were extrapolated to two years after randomization. Differences between treatment arms, based on the intention-to-treat principle, were adjusted for covariates and missing data were handled using multiple imputation. Incremental cost-effectiveness ratios were calculated, with uncertainty around the values estimated using bootstrapping. Results Cumulative mean QALYs/mean costs of health care service use and surgery per patient from baseline to 12 months were estimated as 0.640 (standard error (se) 0.024)/£3147 (se 166) in the decompression arm, 0.656 (se 0.020)/£2830 (se 183) in the arthroscopy only arm and 0.522 (se 0.029)/£1451 (se 151) in the no treatment arm. Statistically significant differences in cumulative QALYs and costs were found at six and 12 months for the decompression versus no treatment comparison only. The probabilities of decompression being cost-effective compared with no treatment at a willingness-to-pay threshold of £20 000 per QALY were close to 0% at six months and approximately 50% at one year, with this probability potentially increasing for the extrapolation to two years. Discussion The evidence for cost-effectiveness at 12 months was inconclusive. Decompression could be cost-effective in the longer-term, but results of this analysis are sensitive to the assumptions made about how costs and QALYs are extrapolated beyond the follow-up of the trial

Politics in Spain: A Case of Monitory Democracy

Analysing the current political context in Spain is a major challenge to political theory. Spain is experiencing the accumulation of trends that in recent years have focused the attention of most theorists and political scientists: discrediting of the major parties, falling numbers of party members, disaffection, etc. In parallel, this trend has been accompanied by citizen mobilisations that, since 15 May 2011, are manifest in numerous channels and strategies. The aim of this paper was to analyse the complex Spanish context from the monitory democracy proposal. The results show how in recent years processes of public scrutiny have been consolidated through a range of citizen initiatives. The study offers an in-depth analysis of the main characteristics of the most notable cases and monitoring initiatives, and also reflects on their democratising potential.El análisis del contexto político actual en España es un reto importante para la teoría política. España está experimentando la acumulación de tendencias que en años recientes han centrado la atención de la mayor parte de teóricos y científicos políticos: desacreditación de los principales partidos, caída del número de miembros de los partidos, desafección, etc. Paralelamente, esta tendencia se ha visto acompañada por movilizaciones ciudadanas que, desde el 15 de mayo de 2011, son manifiestas en numerosos canales y estrategias. El objetivo de este documento es analizar el complejo contexto español desde la propuesta de democracia monitorizada. Los resultados muestran que en años recientes se han consolidado los procesos de escrutinio público mediante una serie de iniciativas ciudadanas. El estudio ofrece un análisis en profundidad de las principales características de los casos e iniciativas de monitorización más notables, y reflexiona también sobre su potencial democratizador

The Level of Protein in Milk Formula Modifies Ileal Sensitivity to LPS Later in Life in a Piglet Model

Background: Milk formulas have higher protein contents than human milk. This high protein level could modify the development of intestinal microbiota, epithelial barrier and immune functions and have long-term consequences. Methodology/Principal findings: We investigated the effect of a high protein formula on ileal microbiota and physiology during the neonatal period and later in life. Piglets were fed from 2 to 28 days of age either a normoprotein (NP, equivalent to sow milk) or a high protein formula (HP, +40% protein). Then, they received the same solid diet until 160 days. During the formula feeding period ileal microbiota implantation was accelerated in HP piglets with greater concentrations of ileal bacteria at d7 in HP than NP piglets. Epithelial barrier function was altered with a higher permeability to small and large probes in Ussing chambers in HP compared to NP piglets without difference in bacterial translocation. Infiltration of T cells was increased in HP piglets at d28. IL-1b and NF-kappa B sub-units mRNA levels were reduced in HP piglets at d7 and d28 respectively; plasma haptoglobin also tended to be reduced at d7. Later in life, pro-inflammatory cytokines secretion in response to high doses of LPS in explants culture was reduced in HP compared to NP piglets. Levels of mRNA coding the NF-kappa B pathway sub-units were increased by the challenge with LPS in NP piglets, but not HP ones. Conclusions/Significance: A high protein level in formula affects the postnatal development of ileal microbiota, epithelial barrier and immune function in piglets and alters ileal response to inflammatory mediators later in life

Restricting Microbial Exposure in Early Life Negates the Immune Benefits Associated with Gut Colonization in Environments of High Microbial Diversity

Background: Acquisition of the intestinal microbiota in early life corresponds with the development of the mucosal immune system. Recent work on caesarean-delivered infants revealed that early microbial composition is influenced by birthing method and environment. Furthermore, we have confirmed that early-life environment strongly influences both the adult gut microbiota and development of the gut immune system. Here, we address the impact of limiting microbial exposure after initial colonization on the development of adult gut immunity. Methodology/Principal Findings: Piglets were born in indoor or outdoor rearing units, allowing natural colonization in the immediate period after birth, prior to transfer to high-health status isolators. Strikingly, gut closure and morphological development were strongly affected by isolator-rearing, independent of indoor or outdoor origins of piglets. Isolator-reared animals showed extensive vacuolation and disorganization of the gut epithelium, inferring that normal gut closure requires maturation factors present in maternal milk. Although morphological maturation and gut closure were delayed in isolatorreared animals, these hard-wired events occurred later in development. Type I IFN, IL-22, IL-23 and Th17 pathways were increased in indoor-isolator compared to outdoor-isolator animals during early life, indicating greater immune activation in pigs originating from indoor environments reflecting differences in the early microbiota. This difference was less apparent later in development due to enhanced immune activation and convergence of the microbiota in all isolator-reared animals. This correlated with elevation of Type I IFN pathways in both groups, although T cell pathways were still more affected in indoor-reared animals. Conclusions/Significance: Environmental factors, in particular microbial exposure, influence expression of a large number of immune-related genes. However, the homeostatic effects of microbial colonization in outdoor environments require sustained microbial exposure throughout development. Gut development in high-hygiene environments negatively impacts on normal succession of the gut microbiota and promotes innate immune activation which may impair immune homeostasis

Pharmacokinetic-Pharmacodynamic Modeling in Pediatric Drug Development, and the Importance of Standardized Scaling of Clearance.

Pharmacokinetic/pharmacodynamic (PKPD) modeling is important in the design and conduct of clinical pharmacology research in children. During drug development, PKPD modeling and simulation should underpin rational trial design and facilitate extrapolation to investigate efficacy and safety. The application of PKPD modeling to optimize dosing recommendations and therapeutic drug monitoring is also increasing, and PKPD model-based dose individualization will become a core feature of personalized medicine. Following extensive progress on pediatric PK modeling, a greater emphasis now needs to be placed on PD modeling to understand age-related changes in drug effects. This paper discusses the principles of PKPD modeling in the context of pediatric drug development, summarizing how important PK parameters, such as clearance (CL), are scaled with size and age, and highlights a standardized method for CL scaling in children. One standard scaling method would facilitate comparison of PK parameters across multiple studies, thus increasing the utility of existing PK models and facilitating optimal design of new studies

Prescrição e preparo de medicamentos sem formulação adequada para crianças: um estudo de base hospitalar

Este trabalho teve como objetivo identificar medicamentos cuja forma ou formulação farmacêutica representa um problema em pediatria (Medicamento Problema - MP), bem como analisar as estratégias empregadas pelos médicos, para sua utilização nas crianças e os riscos envolvidos. Trata-se de um estudo descritivo, que tem como base um inquérito com pediatras de um hospital de referência do SUS em Fortaleza-Ceará, conduzido para identificação dos MPs em julho-agosto de 2004; uma análise das prescrições contendo adaptação de formas sólidas e uma observação direta do preparo dos medicamentos, que foram conduzidas em dezembro de 2004 e janeiro de 2005, respectivamente. Os medicamentos foram agrupados pela classificação ATC e pelo cálculo de frequências das variáveis. Os pediatras (N=48, 98%) identificaram: 16 produtos sem forma injetável, 32 injetáveis necessários em concentrações menores e 30 MP sem formulação líquida para uso oral. Foram analisadas 89 prescrições contendo adaptação de formas sólidas, envolvendo 119 itens de medicamentos; todas continham inadequações, sendo a principal a partição de comprimidos. As doses prescritas corresponderam ao preconizado em 33,6% dos casos. Adaptações foram realizadas em local inadequado, por profissional não qualificado e sem as boas práticas. Concluindo, a carência de formulações apropriadas ao uso pediátrico repercute na prática médica e é agravada pela inexistência de condições adequadas para a manipulação de medicamentos por farmacêuticos, nos hospitais brasileiros.This work aimed to identify medicines whose form or pharmaceutical formula presents a problem to pediatrics (Problem Medication - PM), the strategies employed by doctors to use them in children, and the potential risks involved. Descriptive study: based on a survey with pediatricians from a SUS (Public Health System) reference hospital in Fortaleza-CE (Northeastern Brazil), in order to identify PMs, from July to August 2004; an analysis of prescriptions containing modification of medicines in the solid forms; and a follow-up of medicinal preparations, developed in December 2004 and January 2005, respectively. The medications were grouped by an anatomic, therapeutic and chemical classification and by means of a calculation of variables frequency. The pediatricians (N=48, 98% of the total) identified as PMs: 16 products without an injectable form; 32 in an injectable form that should be presented in lesser concentrations; and 30 without a liquid formula for oral use. Eighty two (82) prescriptions containing modifications of solid forms, involving 111 medicinal items were analyzed, all of which contained inadequacies; the main one being the partition of pills. In 33.6% of the cases, the prescribed doses were in accordance with that generally recommended. The modifications were carried out in inadequate places, by nonqualified professionals and without the use of best practices. The lack of appropriate formulae for pediatric use has an impact on medical practices. It is aggravated by the lack of appropriate conditions for medicines manipulation by pharmacists, in Brazilian hospitals, and this impact involves risks to patients

Arthroscopic subacromial decompression for subacromial shoulder pain (CSAW): a multicentre, pragmatic, parallel group, placebo-controlled, three-group, randomised surgical trial

Background Arthroscopic sub-acromial decompression (decompressing the sub-acromial space by removing bone spurs and soft tissue arthroscopically) is a common surgery for subacromial shoulder pain, but its effectiveness is uncertain. We did a study to assess its effectiveness and to investigate the mechanism for surgical decompression. Methods We did a multicentre, randomised, pragmatic, parallel group, placebo-controlled, three-group trial at 32 hospitals in the UK with 51 surgeons. Participants were patients who had subacromial pain for at least 3 months with intact rotator cuff tendons, were eligible for arthroscopic surgery, and had previously completed a non-operative management programme that included exercise therapy and at least one steroid injection. Exclusion criteria included a full-thickness torn rotator cuff. We randomly assigned participants (1:1:1) to arthroscopic subacromial decompression, investigational arthroscopy only, or no treatment (attendance of one reassessment appointment with a specialist shoulder clinician 3 months after study entry, but no intervention). Arthroscopy only was a placebo as the essential surgical element (bone and soft tissue removal) was omitted. We did the randomisation with a computer-generated minimisation system. In the surgical intervention groups, patients were not told which type of surgery they were receiving (to ensure masking). Patients were followed up at 6 months and 1 year after randomisation; surgeons coordinated their waiting lists to schedule surgeries as close as possible to randomisation. The primary outcome was the Oxford Shoulder Score (0 [worst] to 48 [best]) at 6 months, analysed by intention to treat. The sample size calculation was based upon a target difference of 4·5 points (SD 9·0). This trial has been registered at ClinicalTrials.gov, number NCT01623011. Findings Between Sept 14, 2012, and June 16, 2015, we randomly assigned 313 patients to treatment groups (106 to decompression surgery, 103 to arthroscopy only, and 104 to no treatment). 24 [23%], 43 [42%], and 12 [12%] of the decompression, arthroscopy only, and no treatment groups, respectively, did not receive their assigned treatment by 6 months. At 6 months, data for the Oxford Shoulder Score were available for 90 patients assigned to decompression, 94 to arthroscopy, and 90 to no treatment. Mean Oxford Shoulder Score did not differ between the two surgical groups at 6 months (decompression mean 32·7 points [SD 11·6] vs arthroscopy mean 34·2 points [9·2]; mean difference −1·3 points (95% CI −3·9 to 1·3, p=0·3141). Both surgical groups showed a small benefit over no treatment (mean 29·4 points [SD 11·9], mean difference vs decompression 2·8 points [95% CI 0·5–5·2], p=0·0186; mean difference vs arthroscopy 4·2 [1·8–6·6], p=0·0014) but these differences were not clinically important. There were six study-related complications that were all frozen shoulders (in two patients in each group). Interpretation Surgical groups had better outcomes for shoulder pain and function compared with no treatment but this difference was not clinically important. Additionally, surgical decompression appeared to offer no extra benefit over arthroscopy only. The difference between the surgical groups and no treatment might be the result of, for instance, a placebo effect or postoperative physiotherapy. The findings question the value of this operation for these indications, and this should be communicated to patients during the shared treatment decision-making process. Funding Arthritis Research UK, the National Institute for Health Research Biomedical Research Centre, and the Royal College of Surgeons (England)

Rehabilitation versus surgical reconstruction for non-acute anterior cruciate ligament injury (ACL SNNAP): a pragmatic randomised controlled trial

Background: Anterior cruciate ligament (ACL) rupture is a common debilitating injury that can cause instability of the knee. We aimed to investigate the best management strategy between reconstructive surgery and non-surgical treatment for patients with a non-acute ACL injury and persistent symptoms of instability. Methods: We did a pragmatic, multicentre, superiority, randomised controlled trial in 29 secondary care National Health Service orthopaedic units in the UK. Patients with symptomatic knee problems (instability) consistent with an ACL injury were eligible. We excluded patients with meniscal pathology with characteristics that indicate immediate surgery. Patients were randomly assigned (1:1) by computer to either surgery (reconstruction) or rehabilitation (physiotherapy but with subsequent reconstruction permitted if instability persisted after treatment), stratified by site and baseline Knee Injury and Osteoarthritis Outcome Score—4 domain version (KOOS4). This management design represented normal practice. The primary outcome was KOOS4 at 18 months after randomisation. The principal analyses were intention-to-treat based, with KOOS4 results analysed using linear regression. This trial is registered with ISRCTN, ISRCTN10110685, and ClinicalTrials.gov, NCT02980367. Findings: Between Feb 1, 2017, and April 12, 2020, we recruited 316 patients. 156 (49%) participants were randomly assigned to the surgical reconstruction group and 160 (51%) to the rehabilitation group. Mean KOOS4 at 18 months was 73·0 (SD 18·3) in the surgical group and 64·6 (21·6) in the rehabilitation group. The adjusted mean difference was 7·9 (95% CI 2·5–13·2; p=0·0053) in favour of surgical management. 65 (41%) of 160 patients allocated to rehabilitation underwent subsequent surgery according to protocol within 18 months. 43 (28%) of 156 patients allocated to surgery did not receive their allocated treatment. We found no differences between groups in the proportion of intervention-related complications. Interpretation: Surgical reconstruction as a management strategy for patients with non-acute ACL injury with persistent symptoms of instability was clinically superior and more cost-effective in comparison with rehabilitation management. Funding: The UK National Institute for Health Research Health Technology Assessment Programme