Impact of surrogate outcomes in randomized controlled trials for shoulder rotator cuff tears.

PURPOSE: Surrogate outcomes are clinical endpoints that are used as substitutes for direct measures of how a patient feels, functions, or survives. The present study aims to analyze the impact of surrogate outcomes on the results of randomized controlled trials on shoulder rotator cuff tears disorders. METHODS: Randomized controlled trials (RCTs) related to rotator cuff tear conditions published up until 2021 were retrieved from the PubMed and ACCESSSS databases. The primary outcome of the article was considered a surrogate outcome when the authors used radiological, physiologic, or functional variables. The result of the article was considered positive when results supported the intervention based on the trial's primary outcome. We recorded the sample size, the mean follow-up, and the type of funding. Statistical significance was set at p < 0.05. RESULTS: A total of 112 papers were included in the analysis. The mean sample size was 87.6 patients; mean follow-up period was 25.97 months. Thirty-six out of 112 RCTs used a surrogate outcome as a primary endpoint. More than half of papers using surrogate outcomes reported a positive finding (20 out of 36), while 10 out of 71 RCTs using patient-centered outcomes favored the intervention (14.08%, p < 0.001) [RR = 3.94 (95% CI 2.07-7.51)]. The mean sample size was smaller in trials using surrogate endpoints (75.11 vs 92.35 patients, respectively, p = 0.049), while the follow-up was shorter (14.12 m vs. 31.9 m, p < 0.001). Approximately 25% of the papers that reported surrogate endpoints (22.58%) were industry-funded projects. CONCLUSIONS: The substitution of surrogate endpoints for patient-important outcomes in shoulder rotator cuff trials quadruplicates the chances of obtaining a favorable result that favors the analyzed intervention.

Surgical treatment of proximal humeral fractures with the transosseous suture fixation.

BACKGROUND: The surgical treatment of displaced proximal humeral fractures is commonly affected by implant-related complications. We evaluated the functional and radiographic results of transosseous suture fixation in a series of displaced proximal humeral fractures (PHF). METHODS: Sixty-four patients were retrospectively classified by age, sex, and the Neer fracture classification. Two-part greater tuberosity (2pGT) displaced fractures and 3-part (varus and valgus) and 4-part valgus impacted fractures were managed with fragment reduction and transosseous suture fixation. Patients with minimum follow-up of 24 months and assessed with the Constant-Murley score (CMS) were included. Radiological and medical complications, as well as reinterventions were also recorded. RESULTS: Forty-six patients with a mean follow-up of 58 (24-132) and a mean age of 58 years old were analyzed. Patients with 2pGT (n = 10) fractures had a CMS of 76 points (59-89); patients with 3-part fractures (n = 22) had a score of 67 points (13-91); and those with 4-part fractures (n = 14) had a score of 64 (24-76) points. The overall complication rate was 6 out of 46, and 4 patients required reintervention for different reasons. Patients presenting with 3-part varus fractures had significantly lower functional outcomes scores (p = 0.007). Humeral head osteonecrosis was present in 9 patients and significantly affected the functional outcomes (p < 0.05). However, only three out of nine patients with osteonecrosis required subsequent surgery at the indicated follow-up. CONCLUSIONS: The fracture reduction and transosseous fixation technique represents a safe technique with low complication and reintervention rates. The presence of humeral head necrosis did not lead to subsequent surgical intervention because no hardware had protruded. LEVEL OF EVIDENCE: Level IV, retrospective study.

NLRP3 is involved in long bone edification and the maturation of osteogenic cells.

Overexpression of the nucleotide-binding leucine-rich repeat protein 3 (NLRP3) inflammasome in chronic auto-immune diseases leads to skeletal anomalies, with severe osteopenia due to the activation of osteoclasts. Reproducing this phenotype in Nlrp3 knock-in mice has provided insights into the role of NLRP3 in bone metabolism. We studied the role of NLRP3 in physiological bone development using a complete Nlrp3 knock-out mouse model. We found impaired skeletal development in Nlrp3-/- mice, resulting in a shorter stature than that of Nlrp3+/+  mice. These growth defects were associated with altered femur bone growth, characterized by a deficient growth plate and an osteopenic profile of the trabeculae. No differences in osteoclast recruitment or activity were observed. Instead, Nlrp3-/- femurs showed a less mineralized matrix in the trabeculae than those of Nlrp3+/+  mice, as well as less bone sialoprotein (BSP) expressing hypertrophic chondrocytes. In vitro, primary osteoblasts lacking NLRP3 expression showed defective mineralization, together with the downregulation of BSP expression. Finally, follow-up by micro-CT highlighted the role of NLPR3 in bone growth, occurring early in living mice, as the osteopenic phenotype diminishes over time. Overall, our data suggest that NLRP3 is involved in bone edification via the regulation of hypertrophic chondrocyte maturation and osteoblast activity. Furthermore, the defect appeared to be transitory, as the skeleton recovered with aging.

Socioeconomic inequalities and the equity impact of population-level interventions for adolescent health: an overview of systematic reviews.

OBJECTIVES: Despite robust evidence on health inequalities in adulthood, less attention has been paid to inequalities in adolescence. The aim of this overview was to examine systematic review (SR) evidence on the equity impact of population-level interventions intended to improve health, happiness and wellbeing for adolescents. STUDY DESIGN: An overview (review of systematic reviews). METHODS: Eleven electronic databases were systematically searched to identify SRs of population-level interventions for adolescent health. A secondary data analysis of socioeconomic inequality was conducted to identify whether SRs reported on primary studies in terms of disadvantage, by measures of socioeconomic status (SES) and by differential effects. RESULTS: 35,310 review titles were screened; 566 full texts were retrieved and 140 SRs met the predefined selection criteria. Differential intervention effects were considered in 42/140 (30%) SRs, 18/140 (13%) reported primary studies using an SES measure and 16/140 (11%) explicitly reported differential effects. 15/140 SRs (11%) explicitly focused on socioeconomic inequalities; of these 4/15 reported differential intervention effects in more detail, 7/15 concluded there was insufficient primary evidence to identify the impact of interventions on socioeconomic inequalities and 4/15 planned to examine differential effects by SES, but this was not reported further. CONCLUSIONS: Our overview identifies that there is limited SR evidence on the equity impact of population-level interventions for adolescent health. Strengthening the evidence on whether interventions narrow or widen inequalities for adolescents must be a priority for public health research.

Human placental villi contain stromal macrovesicles associated with networks of stellate cells.

Placental function is essential for fetal development and establishing the foundations for lifelong health. The placental villous stroma is a connective tissue layer that supports the fetal capillaries and villous trophoblast. All the nutrients that cross the placenta must also cross the stroma, and yet little is known about this region. This study uses high-resolution three-dimensional imaging to explore the structural complexity of this region within the placental villi. Serial block-face scanning electron microscopy and confocal microscopy were used to image the placental villous stroma in three-dimensions. Transmission electron microscopy (TEM) was used to generate high resolution two-dimensional images. Stereological approaches were used to quantify volumes of stromal constituents. Three-dimensional imaging identified stromal extracellular vesicles, which constituted 3.9% of the villous stromal volume. These stromal extracellular vesicles were ovoid in shape, had a median length of 2750 nm (range 350-7730 nm) and TEM imaging confirmed that they were bounded by a lipid bilayer. Fifty-nine per cent of extracellular vesicles were in contact with a fibroblast-like stellate cell and these vesicles were significantly larger than those where no contact was observed. These stellate cells formed local networks with adherent junctions observed at contact points. This study demonstrates that the villous stroma contains extracellular macrovesicles which are considerably larger than any previously described in tissue or plasma. The size and abundance of these macrovesicles in the villous stroma highlight the diversity of extracellular vesicle biology and their roles within connective tissues.

Defective NOTCH signaling drives increased vascular smooth muscle cell apoptosis and contractile differentiation in bicuspid aortic valve aortopathy: A review of the evidence and future directions.

Bicuspid aortic valve (BAV) disease remains the most common congenital cardiac disease and is associated with an increased risk of potentially fatal aortopathy including aortic aneurysm and dissection. Mutations in the NOTCH1 gene are one of only a few genetic anomalies identified in BAV disease; however evidence for defective NOTCH signaling, and its involvement in the characteristic histological changes of VSMC apoptosis and differentiation in ascending aortae of BAV patients is lacking. This review scrutinizes the evidence for the interactions of NOTCH signaling, cellular differentiation and apoptosis in the context of aortic VSMCs and provides focus for future research efforts in the diagnosis of BAV aortopathy and prevention of catastrophic complications through NOTCH signaling manipulation.

Reverse shoulder arthroplasty for acute proximal humeral fractures: Postoperative complications at 7 days, 90 days and 1 year.

BACKGROUND: In the last decade, the biomechanics of reverse shoulder arthroplasty (RSA) for proximal humeral fractures in the elderly have led to more functional outcomes and greater pain relief. However, its use has also introduced a significant rate of complications. The purpose of this study is to assess the complication rate of RSA in these cases as well as the relationship to ASA score and basic disease history. METHODS: We evaluate patients who underwent RSA due to acute proximal humeral fractures at three hospitals from 2010 to 2016. We analyze previous disease and anticoagulant treatment, American Society of Anesthesiologists (ASA) Physical Status Classification, and the transfusion rate to correlate these factors with major and minor postoperative complications at 7, 90, and 365 days. RESULTS: We include 103 patients (104 shoulders) over 65 years of age. Mean age is 77.31 years (62-91), 20 of which are male. The overall rate of complications is 25%, with 17.4% minor and 7.6% major complications. We observe a statistically significant relationship between a higher ASA score (3,4) and major complication at 90 days (p = 0.024) and a trend (p = 0.072) towards a higher ASA score with minor complication during the first week. Rheumatoid disease significantly increases major complications at 90 days (p = 0.037). The transfusion rate is 11.5%. CONCLUSIONS: The overall major complication rate of RSA for acute fractures is low in the elderly population. Although, the patient's history (e.g. previous rheumatoid pathology, neurological diseases, or anticoagulant treatment) as well as their ASA score should be considered before RSA surgery. The higher the ASA score and the presence of rheumatoid disease, leads to a higher rate of major complications during the first 90 days after surgery. LEVEL OF EVIDENCE: Level IV; Case series; Treatment study.

Retaining or excising the supraspinatus tendon in complex proximal humeral fractures treated with reverse prosthesis: a biomechanical analysis in two different designs.

PURPOSE: We aimed to biomechanically evaluate the effect of the supraspinatus tendon on tuberosity stability using two different reverse shoulder arthroplasty (RSA) models for complex proximal humeral fractures (PHFs). METHODS: Four-part proximal humeral fractures were simulated in 20 cadaveric shoulders. Two different RSA designs were implemented: a glenosphere-medialized model and a glenosphere-lateralized model. Tuberosities were reconstructed, and displacement of bony fragments was measured (mm) by placing three sensors: in the humeral diaphysis (D), in the greater tuberosity (GT), and in the lesser tuberosity (LT). Axial forces were induced and measured in Newton (N). The test was performed twice in each specimen, with and without the supraspinatus tendon. The regression line (RL) was measured in mm/N. RESULTS: In the medialized model, the GT-D displacement was greater in the supraspinatus preserving model than that in the tendon excision model (p < 0.001), as well as for the LT-D displacement (p < 0.001). In the lateralized model, GT-D displacement and GT-LT distance were greater in the preserving model than that in the excision model (p < 0.001, p = 0.04). CONCLUSION: The supraspinatus tendon resection leads to a more biomechanically stable tuberosity construct when performing RSA for PHFs, while the rest of the rotator cuff tendons (infraspinatus and teres minor) are retained in the greater tuberosity. LEVEL OF EVIDENCE: Basic science study. Cadaveric study.

Teaching Patients How to Reduce a Shoulder Dislocation: A Randomized Clinical Trial Comparing the Boss-Holzach-Matter Self-Assisted Technique and the Spaso Method.

BACKGROUND: There are many different techniques for reducing acute anterior dislocations of the shoulder, and their use depends on surgeon preference. The objective of this study was to compare the pain experienced by a patient performing a self-reduction technique with the pain felt during a reduction performed by a trained physician. METHODS: The study was carried out at the emergency department of a tertiary referral center. Patients between 18 and 60 years of age with an acute anterior shoulder dislocation were randomly allocated into 2 groups. In 1 group the emergency doctor actively guided the reduction process with the Spaso technique (Sp group), and in the other group the patient used the Boss-Holzach-Matter (also known as Davos or Aronen) self-reduction technique (BHM group). The pain experienced by the patient during the reduction was recorded by means of a visual analogue scale (VAS) ranging from 0 to 10. Other recorded data included demographic characteristics, reduction time, and success rate. RESULTS: Of 378 patients assessed for eligibility from May 2015 until February 2017, 197 did not meet the inclusion criteria, 58 met exclusion criteria, 22 declined to participate, and 41 withdrew before randomization. Sixty acute anterior shoulder dislocations were randomized into the Sp group (n = 30) or the BHM group (n = 30). The BHM group experienced significantly less pain during reduction than the Sp group (p = 0.047), with mean pain scores of 3.57 (standard deviation [SD] = 2.1]) and 5.26 (SD = 2.9), respectively. No significant difference between groups was found with respect to reduction time (105 seconds [range, 10 to 660 seconds] in the Sp group and 90 seconds [range, 5 to 600 seconds] in the BHM group; p = 0.6) or success rate (67% and 77%, respectively; p = 0.39). CONCLUSIONS: The self-reduction technique results in less pain than, and is as efficient in achieving reduction of anterior shoulder dislocations as, the Spaso technique. These findings favor the use of the self-assisted method as an effective first-line treatment for shoulder dislocations seen in the emergency department as well as its use by patients with recurrent dislocation. LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.

Do we publish what we preach? Analysis of Spanish Shoulder and Elbow Surgery Society publication rates. / ¿Publicamos lo que predicamos? Tasa de publicación de los congresos de la Sociedad Española de Cirugía de Hombro y Codo.

INTRODUCTION: The purpose of this study is to analyse the publication rate of studies presented as podium presentations in the Spanish Society of Shoulder and Elbow Surgery (SECHC) congresses. METHODS: One hundred and twenty-two abstracts presented at the SECHC congresses held in 2007, 2009 and 2011 were included for the purpose of the study. The oral communications were categorized by study type, sample included and follow-up. In June 2017, possible publications of these studies were searched in PubMed. Type of study, delay in publication, journal and impact factor obtained were recorded. The concordance between the information presented at the congress and their subsequent full-text publications was analysed. RESULTS: The publication rate was 17.21% (21 of the 122 abstracts studied) after 6 years, with a mean time spent for publications of 36.71 months, and a mean impact factor of 1.51. There were no differences between results initially presented at the congresses and those subsequently published (P>0.05). DISCUSSION: The majority of papers presented at SECHC congresses do not end up with a publication. The papers that are published do not usually contain significant differences compared to the content delivered at the congress.

Do we publish what we preach? Analysis of the European Society for Surgery of the Shoulder and Elbow Congress publication rates.

BACKGROUND: Scientific congresses have become the most expedient method to communicate novel findings on any research topic. However, an important question is whether this information will be published in peer-reviewed journals. Our aim was to determine the publication rate of the abstracts presented at the European Society for Surgery of the Shoulder and Elbow Congress and analyze factors that may influence this rate. METHODS: A total of 398 abstracts reported in the Abstract Book from the 2008 European Society for Surgery of the Shoulder and Elbow Congress were examined and categorized by oral and poster presentations, topic, and the number of authors listed. A search in PubMed and Google Scholar for subsequent peer-reviewed publications was performed in September 2015. The time to publication after the meeting had been held; the type of journal and its impact factor at the time to publication were recorded for those abstracts that reached peer-reviewed journal publication. RESULTS: The overall publication rate for the 2008 European Society for Surgery of the Shoulder and Elbow oral and poster presentations was 45.20% after 7 years. The mean time to publication was 18.53 months, and the mean impact factor value was 2.32. Oral presentations were significantly better represented in journals than posters (64.40 vs. 35.40%, p < 0.001). Abstracts with a greater number of authors listed had better publication rates (p < 0.001). CONCLUSION: Less than half of the oral presentations and posters at the 21st European Society for Surgery of the Shoulder and Elbow Congress were published in peer-reviewed journals. Oral presentations with a higher number of authors had an increased likelihood of being published.

Phase contrast synchrotron radiation computed tomography of muscle spindles in the mouse soleus muscle.

Muscle spindles are skeletal muscle sensory organs involved in the sensation of position and movement of the body. We have explored the capability of phase contrast computed tomography to visualise muscle spindles in murine skeletal muscle. In particular, we have validated the visualisation of nerve fibres through phase contrast computed tomography using light microscopy on stained histological sections. We further present the first three-dimensional visualisation of muscle spindles in mouse soleus skeletal muscle in conjunction with the neurovascular bundle associated with it.

[Morbidity and mortality of surgically treated proximal humerus fractures]. / Morbimortalidad en fracturas de húmero proximal tratadas quirúrgicamente.

BACKGROUND: The aim of the present study is to analyse the factors associated with mortality and the capacity to perform daily life activities (DLA) in patients with surgically treated proximal humeral fractures. METHODS: A retrospective study was conducted on 94 patients with a surgically treated proximal humeral fracture, with a mean follow-up of 8 years (2 - 12 years). A correlation analysis was performed to determine the relationship between the type of fracture, surgical technique, comorbidities and mortality and DLA. The Student t test was used for statistical analysis. RESULTS: A total of 72 patients were identified, 18.6% of them died during follow-up, all diagnosed with some comorbidity. There was no correlation between mortality, type of fracture or the technique used. Most of the patients (85.4%) had comorbidities, and 79.5% were completely independent for DLA. Although there was no relationship with the type of fracture, there was a significant reduction in the performing of DLA in patients treated with hemiarthroplasty, and in patients with neurological disorders. CONCLUSIONS: There was a mortality of 18.6% among patients with surgically treated proximal humerus fractures. The majority of surgically treated patients were fully independent for DLA at long-term follow-up.

The microvasculature: a target for nutritional programming and later risk of cardio-metabolic disease.

There is compelling evidence that microvascular deficits affecting multiple tissues and organs play an important role in the aetiopathogenesis of cardio-metabolic disease. Furthermore, both in humans and animal models, deficits in small vessel structure and function can be detected early, often before the onset of macrovascular disease and the development of end-organ damage that is common to hypertension and obesity-associated clinical disorders. This article considers the growing evidence for the negative impact of an adverse maternal diet on the long-term health of her child, and how this can result in a disadvantageous vascular phenotype that extends to the microvascular bed. We describe how structural and functional modifications in the offspring microcirculation during development may represent an important and additional risk determinant to increase susceptibility to the development of cardio-metabolic disease in adult life and consider the cell-signalling pathways associated with endothelial dysfunction that may be 'primed' by the maternal environment. Published studies were identified that reported outcomes related to the microcirculation, endothelium, maternal diet and vascular programming using NCBI PubMed.gov, MEDLINE and ISI Web of Science databases from 1980 until April 2013 using pre-specified search terms. Information extracted from over 230 original reports and review articles was critically evaluated by the authors for inclusion in this review.

Developmental exposure to bisphenol A leads to cardiometabolic dysfunction in adult mouse offspring.

Bisphenol A (BPA) is a chemical compound that has adverse health outcomes in adults when exposed during the perinatal period. However, its effect on cardiovascular function remains to be elucidated. In this study, we examined the effects of daily administration of BPA to pregnant mice from gestational days 11 to 19 on cardiometabolic outcomes in the adult offspring. Prenatal BPA exposure resulted in altered growth trajectory and organ size, increase adiposity and impaired glucose homeostasis in male and female offspring. In addition, these BPA offspring exhibited raised systolic blood pressure, and in the males this was accompanied by impaired vascular tone. The aortas in females, but not in males, from the BPA group also showed reduced estrogen receptor gene expression. These results indicate that prenatal exposure to BPA increased susceptibility of the offspring to developing cardiovascular and metabolic dysfunction later in life.

Feeding a protein-restricted diet during pregnancy induces altered epigenetic regulation of peroxisomal proliferator-activated receptor-α in the heart of the offspring.

Impaired flexibility in the use of substrates for energy production in the heart is implicated in cardiomyopathy. We investigated the effect of maternal protein restriction during pregnancy in rats on the transcription of key genes in cardiac lipid and carbohydrate metabolism in the offspring. Rats were fed protein-sufficient or protein-restricted (PR) diets during pregnancy. Triacylglycerol concentration in adult (day 105) heart was altered by maternal protein intake contingent on post-weaning fat intake and sex. mRNA expression of peroxisomal proliferator-activated receptor (PPAR)-α and carnitine palmitoyltransferase-1 was increased by the maternal PR diet in adult, but not neonatal, offspring. PPARα promoter methylation was lower in adult and neonatal heart from PR offspring. These findings suggest that prenatal nutrition alters the future transcriptional regulation of cardiac energy metabolism in the offspring through changes in epigenetic regulation of specific genes. However, changes in gene functional changes may not be apparent in early life.

Glycine rectifies vascular dysfunction induced by dietary protein imbalance during pregnancy.

Protein restriction in rat pregnancy programmes the development of elevated systolic blood pressure and vascular dysfunction in the offspring. A recent study has shown that hypertension is reversed by maternal glycine supplementation. Whether this protective effect is exerted directly on the embryo and fetus, or indirectly via effects on the mother, is unknown although we have previously shown abnormalities in the maternal vasculature. We tested the hypothesis that dietary glycine repletion would reverse endothelial dysfunction in protein-restricted pregnant rat dams using wire myography. Impaired acetylcholine- (P < 0.01) and isoprenaline-induced (P < 0.05) vasodilatation in isolated mesenteric arteries (MA) from protein-restricted pregnant dams was accompanied by reduced vascular nitric oxide (NO) release (P < 0.05). Dietary glycine supplementation reversed vascular dysfunction in MA (P < 0.05) and improved NO release thus potentially protecting the maternal circulation. The impaired NO release in the MA of low protein diet dams was not accompanied by reduced eNOS mRNA expression, suggesting that eNOS activity was altered. Protein restriction did not alter the vascular function of a conduit artery, the thoracic aorta. These results provide evidence that adequate provision of glycine, a conditionally essential amino acid in pregnancy, may play a role in the vascular adaptations to pregnancy, protecting the fetus from abnormal programming of the cardiovascular system.

Cubonavicular coalition: a case report and literature review.

Tarsal coalitions are uncommon entities. Talocalcaneal and calcaneonavicular synostosis are present in most of the reported cases. Cubonavicular coalition represents only 1% of all the cases in the literature reviewed. The current authors report on a new case of bilateral cubonavicular coalition and present a literature review. The authors also report on the etiology, clinical and radiologic findings, and the treatment to be used. Tarsal coalitions are uncommon entities that must be suspected in an adolescent with painful feet who also has decreased mobility and deformity of the feet.