Polycystic ovary syndrome: associations with cardiovascular disease.

Polycystic ovary syndrome (PCOS), characterized by abnormal menstrual periods, elevated androgen levels and polycystic ovary morphology on ultrasound, is the most common endocrine disorder among females. PCOS is associated with cardiovascular disease (CVD) risk factors including diabetes, obesity, metabolic syndrome, adverse pregnancy outcomes such as pre-eclampsia and psychosocial distress including depression. Previous evidence on the association between PCOS and CVD is inconclusive but the latest 2023 International Evidence-Based PCOS Guideline identifies PCOS as a risk factor for CVD. This review will discuss the relationship between PCOS and CVD along with current direction for CVD screening and prevention among individuals with PCOS.

The effect of non-oncology drugs on clinical and genomic risk in early luminal breast cancer.

BACKGROUND: An effect of non-oncology medications on cancer outcome has been proposed. In this study, we aimed to systematically examine the impact of commonly prescribed non-oncology drugs on clinical risk and on the genomic risk [based on the Oncotype DX recurrence score (RS)] in early breast cancer (BC). EXPERIMENTAL DESIGN: We collected data on clinical risk (stage and grade), genomic risk (Oncotype DX RS), and on non-oncology medications administered to 1423 patients with estrogen receptor-positive human epidermal growth factor receptor 2-negative BC during the month of their surgery. The influence of various medications on clinical and genomic risks was evaluated by statistical analysis. RESULTS: Out of the multiple drugs we examined, levothyroxine was significantly associated with a high Oncotype DX RS (mean 24.78; P < 0.0001) and metformin with a low Oncotype DX RS (mean 14.87; P < 0.01) compared with patients not receiving other non-oncology drugs (mean 18.7). By contrast, there were no differences in the clinical risk between patients receiving metformin, levothyroxine, or no other non-oncology drugs. Notably, there was no association between the consumption of levothyroxine and metformin and proliferation marker (Ki67) levels, but both drugs were significantly associated with progesterone-related features, suggesting that they influence genomic risk through estrogen-dependent signaling. CONCLUSIONS: The results of this study indicate a significant impact of metformin and levothyroxine on clinical decisions in luminal BC, with potential impact on the clinical course of these patients.

Responses of Blood System to Doxorubicin/Docetaxel Chemotherapy in Patients with Breast Cancer.

We studied the effects of combined chemotherapy with doxorubicin/docetaxel on erythroid and granulocytic hematopoietic lineages with particular attention focused on their recovery in patients with stages III-IV breast cancer. Intensification of differentiation of erythroid and granulocytic CFU (even under conditions of their suppressed proliferation) provided the increase in the content of mature and morphologically differentiated elements in the bone marrow and peripheral blood. High proliferative activity of erythroid and granulomonocytic precursors resulted from enhanced production of hematopoiesis-stimulating activities by microenvironment elements.

Mechanisms of Granulocytopoiesis Recovery Stimulation with Filgrastim in Breast Cancer Patients Receiving Chemotherapy.

We studied myelotoxicity of modern schemes of chemotherapy for breast cancer (docetaxel/doxorubicin and cyclophosphamide/doxorubicin/5-fluorouracil) towards granulocytopoiesis, the mechanisms determining the differences of hematological effects of these schemes, and the efficiency of correction of the observed changes with granulocyte CSF (filgrastim). Granulocytopoiesis stimulation with filgrastim during the treatment with docetaxel/doxorubicin combination was more pronounced than during cyclophosphamide/doxorubicin/5-fluorouracil therapy. The observed differences were found at all levels of granulocyte lineage organization (central and peripheral), which is related to different effects of the cytostatic substances used in the proposed protocols on the structures controlling hemopoiesis.

Evaluation of the 1st metatarso-sesamoid joint using standing CT - The Stanmore classification.

BACKGROUND: Little is understood about the role that relative sesamoid displacement and chondral wear have on outcome after hallux valgus (HV) surgery. All existing methods to evaluate relative sesamoid displacement have limitations and furthermore, there have been no radiographic studies evaluating metatarso-sesamoid joint wear. Standing CT scan circumvents many of the existing problems in evaluation of relative sesamoid displacement, and also enables the first radiographic study assessing metatarso-sesamoid joint wear. METHODS: Fifty feet (in 43 patients) with symptomatic HV (Group A) were compared with a control group of 50 feet (50 patients) (Group B). All images were standardised to enable reproducible measurements. The hallux valgus angle, Intermetatarsal angle, sesamoid rotation angle, sesamoid position and metatarso-sesamoid joint space were measured in all patients. RESULTS: The intra and inter-observer reliability correlation showed that the standing CT assessment of sesamoid position (1.000), rotation (0.991) and metatarso-sesamoid joint space (0.960) were highly reproducible. There was a highly significant difference (p<0.0001) in sesamoid position, sesamoid rotation and metatarso-sesamoid joint space between Group A and Group B. CONCLUSIONS: Standing CT has been shown to be a reproducible and accurate method of assessing the relative sesamoid displacement and metatarso-sesamoid joint space narrowing. The results have been used to propose a novel standing CT based classification of hallucal sesamoids, considering the degree of displacement and wear. This classification may ultimately facilitate research to provide new insight into the effect relative sesamoid displacement and chondral wear have on outcomes from hallux valgus surgery.

Assessment of Erythroid and Granulocytic Hematopoietic Lineages in Patients with Non-Small-Cell Lung Carcinoma.

The toxic effects of combined cisplatin/docetaxel therapy cycles on erythroid and granulocytic hematopoietic lineages as well as their intercycle recovery were examined in patients with stage III-IV non-small-cell lung carcinoma. Responsiveness of the blood system to this therapy remained at a high level. Combined therapy pronouncedly activated the key elements of the erythroid and granulocytic hematopoietic lineages leading to accumulation of immature and mature myelokaryocytes in the bone marrow, enlargement of the medullary pool of mature neutrophils, and increase in the count of medullary erythroid and granulocytic precursor cells under conditions of their accelerated maturation.

Manejo del síndrome de abstinencia alcohólica en los pacientes críticos / Management of the syndrome of alcohol withdrawal in critical patients

El manejo del síndrome de abstinencia alcohólica es un desafío en los pacientes críticos. Con frecuencia, se desconocen los antecedentes de consumo de alcohol o este dato es incompleto, lo que limita la identificación de quienes pueden desarrollar este síndrome. El cese abrupto del consumo de alcohol coloca a estos pacientes en alto riesgo de sufrir síndrome de abstinencia alcohólica grave. Típicamente, las benzodiacepinas son consideradas las drogas de primera línea para el manejo de estos casos. Sin embargo, si el paciente progresa a un estado más grave con convulsiones o delirium tremens, puede ser necesario administrar medicación adyuvante a las benzodiacepinas, como el propofol o la dexmedetomidina, o emplear estas últimas drogas como terapias alternativas en aquellos que no responden a las benzodiacepinas. La aparición de convulsiones representa un fuerte factor de riesgo para la progresión a un síndrome de abstinencia alcohólica grave, con el desarrollo posterior de delirium tremens hasta en el 30% de los casos. El delirium tremens es el cuadro más grave y ocurre en el 5-20% de los pacientes con este síndrome, con una mortalidad hasta del 25% sin tratamiento y que se reduce al 0-1% con tratamiento. Es importante conocer el antecedente del consumo de alcohol para evitar el síndrome de abstinencia alcohólica o tratar rápidamente sus síntomas más graves, y mejorar la supervivencia de estos pacientes.(AU)

Alcohol withdrawal syndrome (AWS) is a well-known and a challenging condition occurring in critically ill patients. Frequently, history of alcohol abuse is unknown when the patient is admitted to the intensive care unit, limiting the identification of those who could develop AWS. The abrupt cessation of a heavy or constant drinking put these patients in high risk of suffering from this syndrome in its severe form. Typically, benzodiazepines are considered the first line of treatment. However, if clinical conditions progress to epileptic seizures or delirium tremens or are refractory to benzodiazepines, adjuvant drugs like propofol or dexmedetomidine might be an option to control the severe symptoms. Delirium tremens can occur in up to 30% of patients; it is the most severe picture with a mortality of 25% without treatment and that can be reduced to almost 0-1% with treatment. It is important to appropriately identify alcohol abuse in order to avoid the early clinical manifestations of AWS or rapidly treat its most severe symptoms and improve survival.(AU)

Can a urine dipstick test be used to assess smoking status in patients undergoing planned orthopaedic surgery? a prospective cohort study.

AIMS: Smoking is associated with post-operative complications but smokers often under-report the amount they smoke. Our objective was to determine whether a urine dipstick test could be used as a substitute for quantitative cotinine assays to determine smoking status in patients. PATIENTS AND METHODS: Between September 2013 and July 2014 we conducted a prospective cohort study in which 127 consecutive patients undergoing a planned foot and ankle arthrodesis or osteotomy were included. Patients self-reported their smoking status and were classified as: 'never smoked' (61 patients), 'ex-smoker' (46 patients), or 'current smoker' (20 patients). Urine samples were analysed with cotinine assays and cotinine dipstick tests. RESULTS: There was a high degree of concordance between dipstick and assay results (Kappa coefficient = 0.842, p < 0.001). Compared with the quantitative assay, the dipstick had a sensitivity of 88.9% and a specificity of 97.3%. Patients claiming to have stopped smoking just before surgery had the highest rate of disagreement between reported smoking status and urine testing. CONCLUSION: Urine cotinine dipstick testing is cheap, fast, reliable, and easy to use. It may be used in place of a quantitative assay as a screening tool for detecting patients who may be smoking. A positive test may be used as a trigger for further assessment and counselling. Cite this article: Bone Joint J 2016;98-B:1418-24.

Team-based model for non-operating room airway management: validation using a simulation-based study.

BACKGROUND: Non-operating room (non-OR) airway management has previously been identified as an area of concern because it carries a significant risk for complications. One reason for this could be attributed to the independent practice of residents in these situations. The aim of the present study was to ascertain whether differences in performance exist between residents working alone vs with a resident partner when encountering simulated non-OR airway management scenarios. METHODS: Thirty-six anaesthesia residents were randomized into two groups. Each group experienced three separate scenarios (two scenarios initially and then a third 6 weeks later). The scenarios consisted of one control scenario and two critical event scenarios [i.e. asystole during laryngoscopy and pulseless electrical activity (PEA) upon post-intubation institution of positive pressure ventilation]. One group experienced the simulated non-OR scenarios alone (Solo group). The other group consisted of resident pairs, participating in the same three scenarios (Team group). RESULTS: Although the time to intubation did not differ between the Solo and Team groups, there were several differences in performance. The Team group received better overall performance ratings for the asystole (8.5 vs 5.5 out of 10; P<0.001) and PEA (8.5 vs 5.8 out of 10; P<0.001) scenarios. The Team group was also able to recognize asystole and PEA conditions faster than the Solo group [10.1 vs 23.5 s (P<0.001) and 13.3 vs 36.0 s (P<0.001), respectively]. CONCLUSIONS: Residents who performed a simulated intubation with a second trained provider had better overall performance than those who practised independently. The residents who practised in a group were also faster to diagnose serious complications, including peri-intubation asystole and PEA. Given these data, it is reasonable that training programmes consider performing all non-OR airway management with a team-based method.

Knee surgery and its evidence base.

INTRODUCTION: Evidence driven orthopaedics is gaining prominence. It enables better management decisions and therefore better patient care. The aim of our study was to review a selection of the leading publications pertaining to knee surgery to assess changes in levels of evidence over a decade. METHODS: Articles from the years 2000 and 2010 in The Knee, the Journal of Arthroplasty, Knee Surgery, Sports Traumatology, Arthroscopy, the Journal of Bone and Joint Surgery (American Volume) and the Bone and Joint Journal were analysed and ranked according to guidelines from the Centre for Evidence-Based Medicine. The intervening years (2003, 2005 and 2007) were also analysed to further define the trend. RESULTS: The percentage of high level evidence (level I and II) studies increased albeit without reaching statistical significance. Following a significant downward trend, the latter part of the decade saw a major rise in levels of published evidence. The most frequent type of study was therapeutic. CONCLUSIONS: Although the rise in levels of evidence across the decade was not statistically significant, there was a significant drop and then rise in these levels in the interim. It is therefore important that a further study is performed to assess longer-term trends. Recent developments have made clear that high quality evidence will be having an ever increasing influence on future orthopaedic practice. We suggest that journals implement compulsory declaration of a published study's level of evidence and that authors consider their study designs carefully to enhance the quality of available evidence.

A Site-Specific Integrated Col2.3GFP Reporter Identifies Osteoblasts Within Mineralized Tissue Formed In Vivo by Human Embryonic Stem Cells.

The use of human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) for study and treatment of bone diseases or traumatic bone injuries requires efficient protocols to differentiate hESCs/iPSCs into cells with osteogenic potential and the ability to isolate differentiated osteoblasts for analysis. We have used zinc finger nuclease technology to deliver a construct containing the Col2.3 promoter driving GFPemerald to the AAVS1 site (referred to as a "safe harbor" site), in human embryonic stem cells (H9Zn2.3GFP), with the goal of marking the cells that have become differentiated osteoblasts. In teratomas formed using these cells, we identified green fluorescent protein (GFP)-positive cells specifically associated with in vivo bone formation. We also differentiated the cells into a mesenchymal stem cell population with osteogenic potential and implanted them into a mouse calvarial defect model. We observed GFP-positive cells associated with alizarin complexone-labeled newly formed bone surfaces. The cells were alkaline phosphatase-positive, and immunohistochemistry with human specific bone sialoprotein (BSP) antibody indicates that the GFP-positive cells are also associated with the human BSP-containing matrix, demonstrating that the Col2.3GFP construct marks cells in the osteoblast lineage. Single-cell cloning generated a 100% Col2.3GFP-positive cell population, as demonstrated by fluorescence in situ hybridization using a GFP probe. The karyotype was normal, and pluripotency was demonstrated by Tra1-60 immunostaining, pluripotent low density reverse transcription-polymerase chain reaction array and embryoid body formation. These cells will be useful to develop optimal osteogenic differentiation protocols and to isolate osteoblasts from normal and diseased iPSCs for analysis.

Pathogenesis and outcomes of traumatic injuries of the esophagus.

Traumatic injury of the esophagus is extremely uncommon. The aims of this study were to use the Pennsylvania Trauma Outcome Study (PTOS) database to identify clinical factors predictive of esophageal trauma, and to report the morbidity and mortality of this injury. A cross-sectional review of patients presenting to 20 Level I trauma centers in Pennsylvania from 2004 to 2010 was performed. We compared clinical and demographic variables between patients with and without esophageal trauma both prior to and after arrival in the emergency room (ER). Primary mechanism of injury and clinical outcomes were analyzed. There were 231 694 patients and 327 (0.14%) had esophageal trauma. Patients with esophageal trauma were considerably younger than those without this injury. The risk of esophageal trauma was markedly increased in males (odds ratio [OR] = 2.62 [CI 1.98-3.47]). The risk was also increased in African Americans (OR = 4.61 [CI 3.65-5.82]). Most cases were from penetrating gunshot and stab wounds. Only 34 (10.4%) of esophageal trauma patients underwent an upper endoscopy; diagnosis was usually made by CT, surgery, or autopsy. Esophageal trauma patients were more likely to require surgery (35.8% vs. 12.5%; P < 0.001). Patients with esophageal trauma had a substantially higher mortality than those without the injury (20.5% vs. 1.4%; P < 0.005). In logistic regression modeling, traumatic injury of the esophagus (OR = 3.43 [2.50-4.71]) and male gender (OR = 1.52 [1.46-1.59]) were independently associated with mortality. For those patients with esophageal trauma, there was an association between trauma severity and mortality (OR = 1.10 [1.07-1.12]) but not for undergoing surgery within the first 24 hours of hospitalization (OR = 0.84; 0.39-1.83). Our study on traumatic injury of the esophagus is in concordance with previous studies demonstrating that this injury is rare but carries considerable morbidity (∼46%) and mortality (∼20%). The injury has a higher morbidity and mortality when the thoracic esophagus is involved compared to the cervical esophagus alone. The injury most commonly occurs in younger, Black males suffering gunshot wounds. Efforts to control gun violence in Pennsylvania are of paramount importance.

Developmental-like bone regeneration by human embryonic stem cell-derived mesenchymal cells.

The in vivo osteogenesis potential of mesenchymal-like cells derived from human embryonic stem cells (hESC-MCs) was evaluated in vivo by implantation on collagen/hydroxyapatite scaffolds into calvarial defects in immunodeficient mice. This study is novel because no osteogenic or chondrogenic differentiation protocols were applied to the cells prior to implantation. After 6 weeks, X-ray, microCT, and histological analysis showed that the hESC-MCs had consistently formed a highly vascularized new bone that bridged the bone defect and seamlessly integrated with host bone. The implanted hESC-MCs differentiated in situ to functional hypertrophic chondrocytes, osteoblasts, and osteocytes forming new bone tissue via an endochondral ossification pathway. Evidence for the direct participation of the human cells in bone morphogenesis was verified by two separate assays: with Alu and by human mitochondrial antigen positive staining in conjunction with co-localized expression of human bone sialoprotein in histologically verified regions of new bone. The large volume of new bone in a calvarial defect and the direct participation of the hESC-MCs far exceeds that of previous studies and that of the control adult hMSCs. This study represents a key step forward for bone tissue engineering because of the large volume, vascularity, and reproducibility of new bone formation and the discovery that it is advantageous to not over-commit these progenitor cells to a particular lineage prior to implantation. The hESC-MCs were able to recapitulate the mesenchymal developmental pathway and were able to repair the bone defect semi-autonomously without preimplantation differentiation to osteo- or chondroprogenitors.

Ring-substituted analogs of 3,3'-diindolylmethane (DIM) induce apoptosis and necrosis in androgen-dependent and -independent prostate cancer cells.

We recently reported that novel ring-substituted analogs of 3,3'-diindolylmethane (ring-DIMs) have anti-androgenic and growth inhibitory effects in androgen-dependent prostate cancer cells. The objectives of this study were to confirm the ability of 4,4'- and 7,7'-dibromo- and dichloro-substituted ring-DIMs to inhibit androgen-stimulated proliferation of androgen-dependent LNCaP human prostate cancer cells using a non-invasive, real-time monitoring technique. In addition, their ability to induce apoptotic and necrotic cell death in androgen-dependent as well as -independent (PC-3) prostate cancer cells was studied. Prostate cancer cells were treated with increasing concentrations of DIM and ring-DIMs (0.3-30 µM) and effects on cell proliferation were measured in real-time using an xCELLigence cellular analysis system. Chromatin condensation and loss of membrane integrity were determined by Hoechst and propidium iodide staining, respectively. Apoptotic protein markers were measured by immunoblotting and activation of caspases determined using selective fluorogenic substrates. Intra- and extracellular concentrations of DIM and ring-DIMs were assessed by electrospray ionization tandem mass spectrometry. Ring-DIMs inhibited androgen-stimulated LNCaP cell proliferation and induced apoptosis and necrosis in LNCaP and PC-3 cells with 2-4 fold greater potencies than DIM. DIM and the ring-DIMs increased caspases -3, -8 and -9 activity, elevated expression of Fas, FasL, DR4 and DR5 protein, and induced PARP cleavage in both cell lines. The cytotoxicity of the most potent ring-DIM, 4,4'-dibromoDIM, but not the other compounds was decreased by an inhibitor of caspase -3. The 4,4'-dibromoDIM was primarily found in the extracellular medium, whereas all other compounds were present to a much larger extent in the cell. In conclusion, ring-DIMs inhibited prostate cancer cell growth and induced cell death in LNCaP and PC-3 cells with greater potencies than DIM; they also structure-dependently activated different cell death pathways suggesting that these compounds have clinical potential as chemopreventive and chemotherapeutic agents in prostate cancer, regardless of hormone-dependency.

An information revolution in orthopaedics.

With the established success of the National Joint Registry and the emergence of a range of new national initiatives for the capture of electronic data in the National Health Service, orthopaedic surgery in the United Kingdom has found itself thrust to the forefront of an information revolution. In this review we consider the benefits and threats that this revolution poses, and how orthopaedic surgeons should marshal their resources to ensure that this is a force for good.

One-step derivation of mesenchymal stem cell (MSC)-like cells from human pluripotent stem cells on a fibrillar collagen coating.

Controlled differentiation of human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) into cells that resemble adult mesenchymal stem cells (MSCs) is an attractive approach to obtain a readily available source of progenitor cells for tissue engineering. The present study reports a new method to rapidly derive MSC-like cells from hESCs and hiPSCs, in one step, based on culturing the cells on thin, fibrillar, type I collagen coatings that mimic the structure of physiological collagen. Human H9 ESCs and HDFa-YK26 iPSCs were singly dissociated in the presence of ROCK inhibitor Y-27632, plated onto fibrillar collagen coated plates and cultured in alpha minimum essential medium (alpha-MEM) supplemented with 10% fetal bovine serum, 50 uM magnesium L-ascorbic acid phosphate and 100 nM dexamethasone. While fewer cells attached on the collagen surface initially than standard tissue culture plastic, after culturing for 10 days, resilient colonies of homogenous spindle-shaped cells were obtained. Flow cytometric analysis showed that a high percentage of the derived cells expressed typical MSC surface markers including CD73, CD90, CD105, CD146 and CD166 and were negative as expected for hematopoietic markers CD34 and CD45. The MSC-like cells derived from pluripotent cells were successfully differentiated in vitro into three different lineages: osteogenic, chondrogenic, and adipogenic. Both H9 hES and YK26 iPS cells displayed similar morphological changes during the derivation process and yielded MSC-like cells with similar properties. In conclusion, this study demonstrates that bioimimetic, fibrillar, type I collagen coatings applied to cell culture plates can be used to guide a rapid, efficient derivation of MSC-like cells from both human ES and iPS cells.

Body mass index and the risk of obesity in coeliac disease treated with the gluten-free diet.

BACKGROUND: Coeliac disease is increasingly diagnosed and weight changes are common after adoption of a gluten-free diet (GFD), however data on body mass index (BMI) changes are limited. AIM: To assess changes in BMI after diagnosis in a large coeliac population. METHODS: A total of 1018 patients with biopsy confirmed coeliac disease seen at our centre were studied retrospectively. Initial and follow-up BMIs were recorded, as was GFD adherence as assessed by an expert dietitian. RESULTS: A total of 679 patients with at least two recorded BMIs and GFD adherence data were included in the study. Mean follow-up was 39.5 months. Compared to regional population data, the coeliac cohort was significantly less likely to be overweight or obese (32% vs. 59%, P < 0.0001). Mean BMI increased significantly after GFD initiation (24.0 to 24.6; P < 0.001). 21.8% of patients with normal or high BMI at study entry increased their BMI by more than two points. CONCLUSIONS: Individuals with coeliac disease have lower BMI than the regional population at diagnosis. BMI increases on the GFD, especially in those that adhere closely to the GFD. On the GFD, 15.8% of patients move from a normal or low BMI class into an overweight BMI class, and 22% of patients overweight at diagnosis gain weight. These results indicate that weight maintenance counselling should be an integral part of coeliac dietary education.

Pulpal progenitors and dentin repair.

Mesenchymal stem cells are present in the dental pulp. They have been shown to contribute to dentin-like tissue formation in vitro and to participate in bone repair after a mandibular lesion. However, their capacity to contribute efficiently to reparative dentin formation after pulp lesion has never been explored. After pulp exposure, we have identified proliferative cells within 3 zones. In the crown, zone I is near the cavity, and zone II corresponds to the isthmus between the mesial and central pulp. In the root, zone III, near the apex, at a distance from the inflammatory site, contains mitotic stromal cells which may represent a source of progenitor cells. Stem-cell-based strategies are promising treatments for tissue injury in dentistry. Our experiments focused on (1) location of stem cells induced to leave their quiescent state early after pulp injury and (2) implantation of pulp progenitors, a substitute for classic endodontic treatments, paving the way for pulp stem-cell-based therapies.