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Topical 17-beta-estradiol (E2) regulates the hair cycle, hair shaft differentiation, and sebum production. Vitamin A also regulates sebum production. Vitamin A metabolism proteins localized to the pilosebaceous unit (PSU; hair follicle and sebaceous gland); and were regulated by E2 in other tissues. This study tests the hypothesis that E2 also regulates vitamin A metabolism in the PSU. First, aromatase and estrogen receptors localized to similar sites as retinoid metabolism proteins during mid-anagen. Next, female and male wax stripped C57BL/6J mice were topically treated with E2, the estrogen receptor antagonist ICI 182,780 (ICI), letrozole, E2 plus letrozole, or vehicle control (acetone) during mid-anagen. E2 or one of its inhibitors regulated most of the vitamin A metabolism genes and proteins examined in a sex-dependent manner. Most components were higher in females and reduced with ICI in females. ICI reductions occurred in the premedulla, sebaceous gland, and epidermis. Reduced E2 also reduced RA receptors in the sebaceous gland and bulge in females. However, reduced E2 increased the number of retinal dehydrogenase 2 positive hair follicle associated dermal dendritic cells in males. These results suggest that estrogen regulates vitamin A metabolism in the skin. Interactions between E2 and vitamin A have implications in acne treatment, hair loss, and skin immunity.

Ileal pouch-anal anastomosis (IPAA) is a common surgical treatment for ulcerative colitis. Afferent limb stenosis is an infrequent complication following IPAA, suggesting underlying Crohn’s disease (CD). We hypothesized that CD-related single nucleotide polymorphisms (SNPs) are associated with afferent limb stenosis. Afferent limb stenosis and CD control group patients were recruited from a prospective institutional inflammatory bowel disease database and associated biobank. Patient demographics, Montreal classification, and medication use were recorded. Ten SNPs associated with stricturing Crohn’s disease were examined in genomic DNA and compared among afferent limb stenosis, stricturing CD, and non-stricturing CD controls. Twenty-seven afferent limb stenosis and 162 CD control group patients (108 stricturing, 54 non-stricturing) were identified. Patients were gender and race matched. Afferent limb stenosis and stricturing CD controls were younger at diagnosis (Montreal A1/A2 vs. A3) compared to non-stricturing CD controls (both p < 0.05). The majority of afferent limb stenosis patients were non-smokers compared to CD controls (74% vs. 36%, p < 0.01) and did not use biologic therapies (4% vs. 37%, p < 0.001). The FUT2 G allele was more frequent in afferent limb stenosis and stricturing CD controls compared to non-stricturing CD controls (both p < 0.05). The NOD2 T allele was more frequent in stricturing CD controls compared to afferent limb stenosis and non-stricturing CD controls (both p < 0.05). Afferent limb stenosis patients are phenotypically similar to stricturing CD controls, but differ with lower smoking rates and lower NOD2 allele frequency. Such differences could contribute to the presentation delay with a stricturing phenotype. Selective SNP assessment may help categorize patients likely to develop afferent limb stenosis.

BACKGROUND Opioid use has grown exponentially over the last decade. The effect of preoperative opioid prescription in patients with Crohn's disease undergoing surgery is unknown. OBJECTIVE The purpose of this study was to identify whether preoperative opioid prescription is associated with adverse postoperative outcomes in Crohn's disease. DESIGN This is a single-institution retrospective observational study. SETTINGS This study was performed at an academic tertiary care center. Details of preoperative opioid prescription were collected from the Kentucky All-Schedule Prescription Electronic Reporting database and the electronic databases of bordering states. PATIENTS Consecutive patients undergoing ileocolic resection for Crohn's disease from 2014 to 2018 were included. MAIN OUTCOME MEASURES The outcomes examined were major complications (Clavien-Dindo ≥3a), length of stay, and 30-day hospital readmission. RESULTS Fifty one of 118 patients were prescribed opioids within 6 months preoperatively (range, 0-33,760 morphine milligram equivalents). Patients with preoperative opioid prescription compared with no preoperative opioid prescription required more daily opioids during hospital admission (p = 0.024). Nineteen patients had a major postoperative complication (preoperative opioid prescription: 26% (13/51) vs no preoperative opioid prescription: 9% (6/67)). On multivariable analysis, preoperative opioid prescription (OR = 2.994 (95% CI, 1.024-8.751); p = 0.045) was a significant risk factor for a major complication. Preoperative opioid prescription was associated with increased length of stay (p < 0.001) and was a risk factor for readmission (OR = 2.978 (95% CI, 1.075-8.246); p = 0.036). Twenty-four patients were readmitted. Using a cutoff for higher opioid prescription of 300 morphine milligram equivalents within 6 months preoperation (eg, 60 tablets of hydrocodone/acetaminophen 5/325), preoperative opioid prescription remained a risk factor for major postoperative complications (OR = 3.148 (95% CI, 1.110-8.928); p = 0.031). LIMITATIONS This was a retrospective study and could not assess nonprescribed opioid use. CONCLUSIONS Preoperative opioid prescription was a significant risk factor for adverse outcomes in patients with Crohn's disease undergoing elective ileocolic resection. See Video Abstract at http://links.lww.com/DCR/B113. LA PRESCRIPCION PREOPERATORIA DE OPIOIDES SE ASOCIA CON COMPLICACIONES MAYORES EN PACIENTES CON ENFERMEDAD DE CROHN SOMETIDOS A RESECCION ILEOCOLICA ELECTIVA: El uso de opioides ha crecido exponencialmente en la ultima decada. Se desconoce el efecto de la prescripcion preoperatoria de opioides en pacientes con enfermedad de Crohn sometidos a cirugia.Identificar si la prescripcion preoperatoria de opioides esta asociada con resultados postoperatorios adversos en la enfermedad de Crohn.Este es un estudio observacional retrospectivo de una sola institucion.Este estudio se realizo en un centro academico de atencion terciaria. Los detalles de la prescripcion preoperatoria de opiaceos se recopilaron de la base de datos de "Kentucky All-Schedule Prescription Electronic Reporting" y de las bases de datos electronicas de los estados fronterizos.Pacientes consecutivos sometidos a reseccion ileocolica por enfermedad de Crohn entre 2014-2018.Los resultados examinados fueron complicaciones mayores (Clavien-Dindo ≥3a), duracion de la estancia y el reingreso hospitalario de 30 dias.A cincuenta y uno de 118 pacientes se le recetaron opioides dentro de los 6 meses preoperatorios (rango, 0 a 33,760 equivalentes de miligramos de morfina). Los pacientes con prescripcion preoperatoria de opioides en comparacion con ninguna prescripcion preoperatoria de opioides requirieron mas opioides diarios durante el ingreso hospitalario (p = 0,024). Diecinueve pacientes tuvieron una complicacion postoperatoria importante (prescripcion preoperatoria de opioides: 26% [13/51] frente a ninguna prescripcion preoperatoria de opioides: 9% [6/67]). En el analisis multivariable, la prescripcion de opioides preoperatorios (OR = 2.994, IC 95%: 1.024-8.751, p = 0.045) fueron factores de riesgo significativos para una complicacion mayor. La prescripcion preoperatoria de opioides se asocio con un aumento de la duracion de la estadia (p

X-linked hypophosphatemia (XLH) is a hereditary musculoskeletal disorder caused by loss-of-function mutations in the PHEX gene. In XLH, increased circulating fibroblast growth factor 23 (FGF23) levels cause renal phosphate wasting and low concentrations of 1,25-dihydroxyvitamin D, leading to an early clinical manifestation of rickets. Importantly, hearing loss is commonly observed in XLH patients. We present here data from two XLH patients with marked conductive hearing loss. To decipher the underlying pathophysiology of hearing loss in XLH, we utilized the Hyp mouse model of XLH and measured auditory brain stem responses (ABRs) and distortion product otoacoustic emissions (DPOAEs) to functionally assess hearing. As evidenced by the increased ABR/DPOAE threshold shifts in the mid-frequency range, these measurements indicated a predominantly conductive hearing loss in Hyp mice compared to wild-type (WT) mice. Therefore, we carried out an in-depth histomorphometric and scanning electron microscopic analysis of the auditory ossicles. Quantitative backscattered electron imaging (qBEI) indicated a severe hypomineralization of the ossicles in Hyp mice, evidenced by lower calcium content (CaMean) and higher void volume (ie, porosity) compared to WT mice. Histologically, voids correlated with unmineralized bone (ie, osteoid), and the osteoid volume per bone volume (OV/BV) was markedly higher in Hyp mice than WT mice. The density of osteocyte lacunae was lower in Hyp mice than in WT mice, whereas osteocyte lacunae were enlarged. Taken together, our findings highlight the importance of ossicular mineralization for hearing conduction and point toward the potential benefit of improving mineralization to prevent hearing loss in XLH. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Glucocorticoid (GC)‐induced osteoporosis is a widespread health problem that is accompanied with increased fracture risk. Detrimental effects of anti‐inflammatory GC therapy on bone have been ascribed to the excess in GC exposure, but it is unknown whether there is also a role for disruption of the endogenous GC rhythm that is inherent to GC therapy. To investigate this, we implanted female C57Bl/6J mice with slow‐release corticosterone (CORT) pellets to blunt the rhythm in CORT levels without inducing hypercortisolism. Flattening of CORT rhythm reduced cortical and trabecular bone volume and thickness, whilst bone structure was maintained in mice injected with supraphysiologic CORT at the time of their endogenous GC peak. Mechanistically, mice with a flattened CORT rhythm showed disrupted circadian gene expression patterns in bone, along with changes in circulating bone turnover markers indicative of a negative balance in bone remodelling. Indeed, double calcein labelling of bone in vivo revealed a reduced bone formation in mice with a flattened CORT rhythm. Collectively, these perturbations in bone turnover and structure decreased bone strength and stiffness, as determined by mechanical testing. In conclusion, we demonstrate for the first time that flattening of the GC rhythm disrupts the circadian clock in bone and results in an osteoporotic phenotype in mice. Our findings indicate that at least part of the fracture risk associated with GC therapy may be the consequence of a disturbed GC rhythm, rather than excess GC exposure alone, and that a dampened GC rhythm may contribute to the age‐related risk of osteoporosis., Negative effects of glucocorticoid (GC) therapy on bone have been ascribed to the excess in GC exposure, but it is unknown whether disruption of endogenous GC rhythm also plays a role. Here, we show that flattening of the GC rhythm without increasing GC exposure in mice disrupts the circadian clock in bone and results in an osteoporotic phenotype, whilst bone quality is maintained in mice injected with supraphysiologic GCs at the time of their endogenous GC peak. These data indicate that disruption of GC rhythm may underlie age‐related osteoporosis, and could in itself contribute to negative effects of GC therapy on bone.

Hypophosphatasia (HPP) is a hereditary musculoskeletal disorder characterized by low serum alkaline phosphatase (ALP) activity leading to poor bone mineralization. On a micro-morphological level, this may not only be reflected by an enrichment of osteoid but also a degradation of bone quality. Asfotase alfa is an enzyme replacement therapy that was recently demonstrated to improve bone mineralization as well as clinical status (e.g. growth, muscle strength and quality of life). However, the underlying changes of bone quality parameters on asfotase alfa treatment are currently not known. In the present study, we report a 24-year-old woman with genetically confirmed infantile-onset HPP and recurrent fractures. While the initiated asfotase alfa treatment was followed by rapid clinical improvements (i.e., disappearance of bone marrow edema, increase of muscle strength), the BMD assessed by DXA at the hip and spine increased moderately at two years follow-up. A detailed skeletal assessment using high-resolution peripheral quantitative computed tomography (HR-pQCT) and a high-resolution analysis of two consecutive iliac crest bone biopsies revealed only minor improvements of bone microarchitecture but a remarkable reduction of osteoid parameters. Furthermore, the high mineralization heterogeneity at baseline assessed by quantitative backscattered electron imaging (qBEI) decreased after 2 year of asfotase alfa treatment. Finally, we found an increase in mineral maturation reflected by higher mineral-to-matrix and carbonate-to-phosphate ratios using Fourier transform infrared spectroscopy (FTIR) imaging as well as increased local mechanical properties using reference point indentation (RPI). Taken together, our findings provide evidence for an improvement of bone quality indices beyond the mere reduction of osteoid indices and thereby contribute to the understanding of fracture risk reduction in HPP patients on asfotase alfa treatment.

Objective: Synthetic meshes and acellular dermal matrices are increasingly used in implant based breast reconstruction. The objective of this study was to determine the incidence and severity of complications following the implantation of the partially absorbable bi-component soft mesh SERAGYN ® BR and assess risk factors for adverse operative outcomes. Methods: A retrospective clinical study was performed: The SERAGYN ® BR soft mesh was utilized in 148 operations (skin-sparing mastectomy, nipple-sparing mastectomy, breast conserving surgery, secondary reconstruction after mastectomy) in four different institutions in Germany from June 2012 to February 2014. We analyzed whether the results were affected by tumor morphology (e.g. grading), patient characteristics and co-morbidities, previous surgery or therapies and use of alloplastic materials. Results: The SERAGYN ® BR soft mesh was successfully implanted in 131 of 148 operations. The rate of reconstructive failure was 11.5 %. The most common complication was seroma (25.7 %), followed by hematoma and skin infection (each 14.2%). Wound healing issues were detected in 13.5% cases, secondary wound infections in 10.8%. 83.8% of operations had no severe complications. Independent predictors for reconstructive failure were wound healing issues, nipple- or skin necrosis, wound- or skin infections, a high volume of excised tissue, hematomas, seromas and sentinel lymph node excisions. A higher body mass index was correlated with a higher rate of infection. Conclusion: SERAGYN ® BR mesh can be used successfully in breast reconstructive surgery. Rates of major complications or reconstructive failure are comparable to the use of other synthetic or biological meshes. Citation Format: Machleidt A, Schmidt-Feuerheerd N, Blohmer J-U, Ohlinger R, Küper J, von Waldenfels G, Dittmer S, Paepke S, Klein E. Reconstructive breast surgery with partially absorbable bi-component Seragyn® BR soft mesh: An outcome analysis [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-16-16.

Disparities are prevalent in numerous areas of healthcare. We sought to investigate whether there were racial/ethnic disparities among pregnant women with the most severe form of alloimmunization who require intrauterine transfusions (IUT). We reviewed patients who underwent IUT for alloimmunization at a single fetal treatment center between 2015 and 2020. This "IUT cohort" was compared to an "Alloimmunization cohort": patients seen at our institution with a diagnosis of alloimmunization during pregnancy, who did not receive IUT. We collected maternal demographics including self-identified race/ethnicity and primary language, transfusion, and antibody characteristics. The cohorts were compared using unpaired t-tests, Mann-Whitney tests, and Fischer's exact tests, as appropriate. The IUT cohort included 43 patients and the alloimmunization cohort included 1049 patients. Compared to the alloimmunization cohort, there were significantly more patients of Latina descent in the IUT cohort (23.3% vs. 3.4%, p

Background Early antenatal care (ANC) reduces maternal and neonatal morbidity and mortality through identification of pregnancy-related complications, yet 44% of Rwandan women present to ANC after 16 weeks gestational age (GA). The objective of this study was to identify factors associated with delayed initiation of ANC and describe differences in the obstetric risks identified at the first ANC visit (ANC-1) between women presenting early and late to care. Methods This secondary data analysis included 10,231 women presenting for ANC-1 across 18 health centers in Rwanda (May 2017-December 2018). Multivariable logistic regression models were constructed using backwards elimination to identify predictors of presentation to ANC at ≥16 and ≥24 weeks GA. Logistic regression was used to examine differences in obstetric risk factors identified at ANC-1 between women presenting before and after 16- and 24-weeks GA. Results Sixty-one percent of women presented to ANC at ≥16 weeks and 24.7% at ≥24 weeks GA, with a mean (SD) GA at presentation of 18.9 (6.9) weeks. Younger age (16 weeks: OR = 1.36, 95% CI: 1.06, 1.75; 24 weeks: OR = 1.33, 95% CI: 0.95, 1.85), higher parity (16 weeks: 1–4 births, OR = 1.55, 95% CI: 1.39, 1.72; five or more births, OR = 2.57, 95% CI: 2.17, 3.04; 24 weeks: 1–4 births, OR = 1.93, 95% CI: 1.78, 2.09; five or more births, OR = 3.20, 95% CI: 2.66, 3.85), lower educational attainment (16 weeks: primary, OR = 0.75, 95% CI: 0.65, 0.86; secondary, OR = 0.60, 95% CI: 0.47,0.76; university, OR = 0.48, 95% CI: 0.33, 0.70; 24 weeks: primary, OR = 0.64, 95% CI: 0.53, 0.77; secondary, OR = 0.43, 95% CI: 0.29, 0.63; university, OR = 0.12, 95% CI: 0.04, 0.32) and contributing to household income (16 weeks: OR = 1.78, 95% CI: 1.40, 2.25; 24 weeks: OR = 1.91, 95% CI: 1.42, 2.55) were associated with delayed ANC-1 (≥16 and ≥24 weeks GA). History of a spontaneous abortion (16 weeks: OR = 0.74, 95% CI: 0.66, 0.84; 24 weeks: OR = 0.70, 95% CI: 0.58, 0.84), pregnancy testing (16 weeks: OR = 0.48, 95% CI: 0.33, 0.71; 24 weeks: OR = 0.41, 95% CI: 0.27, 0.61; 24 weeks) and residing in the same district (16 weeks: OR = 1.55, 95% CI: 1.08, 2.22; 24 weeks: OR = 1.73, 95% CI: 1.04, 2.87) or catchment area (16 weeks: OR = 1.53, 95% CI: 1.05, 2.23; 24 weeks: OR = 1.84, 95% CI: 1.28, 2.66; 24 weeks) as the health facility were protective against delayed ANC-1. Women with a prior preterm (OR, 0.71, 95% CI, 0.53, 0.95) or low birthweight delivery (OR, 0.72, 95% CI, 0.55, 0.95) were less likely to initiate ANC after 16 weeks. Women with no obstetric history were more likely to present after 16 weeks GA (OR, 1.18, 95% CI, 1.06, 1.32). Conclusion This study identified multiple predictors of delayed ANC-1. Focusing existing Community Health Worker outreach efforts on the populations at greatest risk of delaying care and expanding access to home pregnancy testing may improve early care attendance. While women presenting late to care were less likely to present without an identified obstetric risk factor, lower than expected rates were identified in the study population overall. Health centers may benefit from provider training and standardized screening protocols to improve identification of obstetric risk factors at ANC-1.

Introduction: Bone biopsies have been obtained for many centuries and are one of the oldest known medical procedures in history. Despite the introduction of new noninvasive radiographic imaging techniques and genetic analyses, bone biopsies are still valuable in the diagnosis of bone diseases. Advanced techniques for the assessment of bone quality in bone biopsies, which have emerged during the last decades, allows in-depth tissue analyses beyond structural changes visible in bone histology. In this review, we give an overview of the application and advantages of the advanced techniques for the analysis of bone biopsies in the clinical setting of various rare metabolic bone diseases. Method: A systematic literature search on rare metabolic bone diseases and analyzing techniques of bone biopsies was performed in PubMed up to 2019 week 34. Results: Advanced techniques for the analysis of bone biopsies were described for rare metabolic bone disorders including Paget’s disease of bone, osteogenesis imperfecta, fibrous dysplasia, Fibrodysplasia ossificans progressiva, PLS3 X-linked osteoporosis, Loeys-Diets syndrome, osteopetrosis, Erdheim-Chester disease, and Cherubism. A variety of advanced available analytical techniques were identified that may help to provide additional detail on cellular, structural, and compositional characteristics in rare bone diseases complementing classical histopathology. Discussion: To date, these techniques have only been used in research and not in daily clinical practice. Clinical application of bone quality assessment techniques depends upon several aspects such as availability of the technique in hospitals, the existence of reference data, and a cooperative network of researchers and clinicians. The evaluation of rare metabolic bone disorders requires a repertoire of different methods, owing to their distinct bone tissue characteristics. The broader use of bone material obtained from biopsies could provide much more information about pathophysiology or treatment options and establish bone biopsies as a valuable tool in rare metabolic bone diseases.

Type 2 diabetes mellitus (T2DM), a metabolic disease on the rise, is associated with substantial increase in bone fracture risk. Because individuals with T2DM have normal or high bone mineral density (BMD), osteodensitometric measurements of BMD do not predict fracture risk with T2DM. Here, we aim to identify the underlying mechanism of the diabetes-induced fracture risk using a high-resolution multi-scale analysis of human cortical bone with special emphasis on osseous cellular activity. Specifically, we show increased cortical porosity in a subgroup of T2DM individuals accompanied by changed mineralization patterns and glycoxidative damage to bone protein, caused by non-enzymatic glycation of bone by reducing sugar. Furthermore, the high porosity T2DM subgroup presents with higher regional mineralization heterogeneity and lower mineral maturity, whereas in the T2DM subgroup regional higher mineral-to-matrix ratio was observed. Both T2DM groups show significantly higher carboxymethyl-lysine accumulation. Our results show a dimorphic pattern of cortical bone reorganization in individuals afflicted with T2DM and hence provide new insight into the diabetic bone disease leading to increased fracture risk.

Background & Aims Non-alcoholic steatohepatitis is a leading cause of end-stage liver disease. Hepatic steatosis and lipotoxicity cause chronic necroinflammation and direct hepatocellular injury resulting in cirrhosis, end-stage liver disease and hepatocellular carcinoma. Emricasan is a pan-caspase inhibitor that inhibits excessive apoptosis and inflammation; it has also been shown to decrease portal pressure and improve synthetic function in mice with carbon tetrachloride-induced cirrhosis. Methods This double-blind, placebo-controlled study randomized 217 individuals with decompensated NASH cirrhosis 1:1:1 to emricasan (5 mg or 25 mg) or placebo. Patients were stratified by decompensation status and baseline model for end-stage liver disease-sodium (MELD-Na) score. The primary endpoint comprised all-cause mortality, a new decompensation event (new or recurrent variceal hemorrhage, new ascites requiring diuretics, new unprecipitated hepatic encephalopathy ≥grade 2, hepatorenal syndrome, spontaneous bacterial peritonitis), or an increase in MELD-Na score ≥4 points. Results There was no difference in event rates between either of the emricasan treatment groups and placebo, with hazard ratios of 1.02 (95% CI 0.59–1.77; p = 0.94) and 1.28 (95% CI 0.75–2.21; p = 0.37) for 5 mg and 25 mg of emricasan, respectively. MELD-Na score progression was the most common outcome. There was no significant effect of emricasan treatment on MELD-Na score, international normalized ratio, total serum bilirubin, albumin level or Child-Pugh score. Emricasan was generally safe and well-tolerated. Conclusions Emricasan was safe but ineffective for the treatment of decompensated NASH cirrhosis. However, this study may guide the design and conduct of future clinical trials in decompensated NASH cirrhosis. Lay summary Patients with decompensated cirrhosis related to non-alcoholic steatohepatitis are at high risk of additional decompensation events and death. Post hoc analyses in previous pilot studies suggested that emricasan might improve portal hypertension and liver function. In this larger randomized study, emricasan did not decrease the number of decompensation events or improve liver function in patients with a history of decompensated cirrhosis related to non-alcoholic steatohepatitis. ClinicalTrials.gov Identifier NCT03205345 .

Diagnosis and management of adult individuals with low bone mass and increased bone fragility before the age of 50 can be challenging. A number of these patients are diagnosed with mild osteogenesis imperfecta (OI) through detection of COL1A1 or COL1A2 mutations; however, a clinical differentiation from early-onset osteoporosis (EOOP) may be difficult. The purpose of this study was to determine the bone microstructural differences between mild OI and EOOP patients. 29 patients showed mutations in COL1A1 or COL1A2 and were classified as OI. Skeletal assessment included dual-energy X-ray absorptiometry (DXA), high-resolution peripheral quantitative computed tomography (HR-pQCT), and bone turnover serum analyses. Bone microstructure of 21/29 OI patients was assessed and compared to 23 age- and sex-matched patients clinically classified EOOP but without mutations in the known disease genes as well as to 20 healthy controls. In the OI patients, we did not observe an age-dependent decrease in DXA Z-scores. HR-pQCT revealed a significant reduction in volumetric BMD and microstructural parameters in the distal radius and tibia in both the OI and EOOP cohorts compared to the healthy controls. When comparing the bone microstructure of OI patients with the EOOP cohort, significant differences were found in terms of bone geometry in the radius, while no significant changes were detected in all other HR-pQCT parameters at the radius and tibia. Taken together, adult mild OI patients demonstrate a predominantly high bone turnover trabecular bone loss syndrome that shows minor microstructural differences compared to EOOP without mutation detection.

Excessive skeletal deformations and brittle fractures in the vast majority of patients suffering from osteogenesis imperfecta (OI) are a result of substantially reduced bone quality. Because the mechanical competence of bone is dependent on the tissue characteristics at small length scales, it is of crucial importance to assess how OI manifests at the micro- and nanoscale of bone. In this context, the Chihuahua (Chi/+) zebrafish, carrying a heterozygous glycine substitution in the α1 chain of collagen type I, has recently been proposed as a suitable animal model of classical dominant OI, showing skeletal deformities, altered mineralization patterns, and a smaller body size. This study assessed the bone quality properties of Chi/+ at multiple length scales using micro-computed tomography (micro-CT), histomorphometry, quantitative back-scattered electron imaging, Fourier-transform infrared spectroscopy, nanoindentation, and X-ray microscopy. At the skeletal level, the Chi/+ displays smaller body size, deformities, and fracture calli in the ribs. Morphological changes at the whole bone level showed that the vertebrae in Chi/+ had a smaller size, smaller thickness, and distorted shape. At the tissue level, Chi/+ displayed a higher degree of mineralization, lower collagen maturity, lower mineral maturity, altered osteoblast morphology, and lower osteocyte lacunar density compared to wild-type zebrafish. The alterations in the cellular, compositional, and structural properties of Chi/+ bones bear an explanation for the impaired local mechanical properties, which promote an increase in overall bone fragility in Chi/+. The quantitative assessment of bone quality in Chi/+ thus further validates this mutant as an important model reflecting osseous characteristics associated with human classical dominant OI. © 2018 American Society for Bone and Mineral Research.

Primary biliary cholangitis (PBC) is known to be a major risk factor for osteoporosis reflected by a reduction of bone mineral density (BMD). However, both the extent of the macro- and microstructural alterations of bone as well as the causative factors are unknown. We have retrospectively analyzed a total of 96 patients with PBC and 53 healthy controls matched for age, sex, and body mass index. In addition to dual-energy X-ray absorptiometry (DXA) measurements at the lumbar spine and hip, high-resolution peripheral quantitative computed tomography (HR-pQCT) was used to assess the geometric, volumetric, and microstructural changes of bone at the distal radius and tibia. Furthermore, serum analyses and measures of disease duration and stage including transient elastography were performed. Total, cortical, and trabecular volumetric BMD as well as geometric parameters were significantly reduced in PBC patients. Microstructural analysis revealed a significantly lower cortical thickness (p < 0.001) and bone volume per tissue volume (p < 0.001) in the radius and tibia but unchanged trabecular number in patients with PBC (radius: p = 0.42; tibia: p = 0.12). Multivariate regression models pointed out that disease duration and stage are the primary factors that are independently associated with bone loss in PBC. A subgroup analysis of patients with additional autoimmune hepatitis (AIH) revealed no significant changes in bone structure compared with PBC only. Taken together, PBC patients demonstrate severe alterations in bone microstructure that are positively associated with disease duration and stage. By applying HR-pQCT in the distal radius and tibia, a combined bone loss syndrome expressed by a predominant decrease in BMD and cortical thickness could be detected. © 2018 American Society for Bone and Mineral Research.

Colorectal cancer (CRC) is associated with significant morbidity and mortality as many patients are diagnosed with advanced stage disease. MicroRNAs are small, noncoding RNA molecules that have a major role in gene expression regulation and are dysregulated in CRC. The miR-200 family is involved in epithelial-mesenchymal transition (EMT). This systematic review describes the roles of the miR-200 family in EMT in CRC. A search of electronic databases (PubMed and Embase) was conducted between January 2000 and July 2017. Both in vitro and human studies reporting on the miR-200 family and CRC were included. Studies describing molecular pathways and the role of the miR-200 family in the diagnostic and therapeutic management of CRC were analyzed. Thirty-four studies (22 in vitro and 18 human studies) were included. miR-200 family expression is regulated epigenetically and via transcriptional factor regulation. In vitro studies show that transfection of miR-200 family members into chemo-resistant colon cancer cell lines results in improved chemo-sensitivity and epithelial phenotype restoration. There is intra-tumoral variability in the tissue expression of miR-200 family members with decreased expression at the invasive front. Clinical studies in CRC patients have shown decreased primary tumor tissue expression of miR-429, miR-200a and miR-200c may be associated with worse survival. Conversely, increased blood levels of miR-141, miR-200a and miR-200c may be associated with worse outcomes. The miR-200 family has a central role in EMT. The miR200 family has potential for both prognostic and therapeutic management of CRC.

Background. Prospective memory refers to the ability to remember to carry out future intentions at a certain time, following a specific event, or upon the completion of another task [1]. Normal prospective memory functions are particularly important in older age (e.g., remember to take your medication) as they maintain functional independence and well-being [2], [3]. Attentional control (i.e., focusing on relevant information while ignoring other information) has been discussed to be of key relevance for proper prospective memory functions [4]. In the current study, we will apply non-invasive brain stimulation on areas, known to be associated with both attentional control and prospective memory to find out whether this would lead to performance changes in either of the two or both. Method. In a double blind, sham-controlled, and parallel group study, we will include n=105 healthy older volunteers (60-75 years of age; 50% female). They will be randomly assigned to one of six stimulation groups (or sham). We will use high-definition transcranial direct current stimulation (Soterix medical). Participants will receive either cathodal or anodal stimulation of the left inferior frontal, right inferior frontal, or right superior parietal gyrus for 20 min (1mA) during which they will complete an attentional control task as well as a prospective memory task. We will also assess performance prior to and following stimulation. Outlook. The results of our study will help to clarify the role of attentional control in older adults“ prospective memory performance. With our findings we may help to create new interventions to counteract age-related decline of prospective memory. References [1] J. Ellis, “Prospective Memory: Theory and Applications”, in Prospective memory or the realization of delayed intentions: A conceptual framework for research, M. Brandimonte, G. O. Einstein, und M. A. McDaniel, Hrsg. New York: Psychology Press, 1996, S. 1–22. [2] A. Hering, M. Kliegel, P. G. Rendell, F. I. M. Craik, und N. S. Rose, “Prospective memory is a key predictor of functional independence in older adults”, Journal of the International Neuropsychological Society, Bd. 24, Nr. 6, S. 640–645, Juli 2018, doi: 10.1017/S1355617718000152. [3] D. Sheppard, A. Matchanova, K. Sullivan, S. Kazimi, und S. Woods, “Prospective memory partially mediates the association between aging and everyday functioning.”, Clin Neuropsychol., Bd. 34, Nr. 4, S. 755–774, 2020, doi: 10.1080/13854046.2019.1637461. [4] McDaniel, M. A., Umanath, S., Einstein, G. O., & Waldum, E. R. (2015). Dual pathways to prospective remembering. Frontiers in Human Neuroscience, 9. https://doi.org/10.3389/fnhum.2015.00392

Dual-energy X-ray absorptiometry (DXA) and high-resolution peripheral quantitative computed tomography (HR-pQCT) are commonly used to assess the areal bone mineral density (aBMD) and peripheral microstructure, respectively. While DXA is the standard to diagnose osteoporosis, HR-pQCT provides information about the cortical and trabecular architecture. Many fragility fractures occur in patients who do not meet the osteoporosis criterion (i.e., T-score≤-2.5). We hypothesize that patients with T-score above -2.5 and fragility fracture may have abnormal bone microarchitecture. Therefore, in this retrospective clinical study, HR-pQCT data obtained from patients with fragility fractures and T-scores≥-2.5 (n=71) were compared to corresponding data from patients with fragility fractures and T-scores≤-3.5 (n=56). Types of secondary osteoporosis were excluded from the study. To verify the dependency of alterations in bone microarchitecture and T-score, the association between HR-pQCT values and aBMD as reflected by the T-score at both proximal femora, was assessed. At the distal tibia, cortical thickness was lower (p0.001), cortical porosity was similar (p=0.61), trabecular number was higher (p0.001), and bone volume fraction (BV/TV) was higher (p0.001) in patients with T-scores≥-2.5 than in patients with T-scores≤-3.5. Trabecular number and BV/TV correlated with T-score (r=0.68, p0.001; r=0.61, p0.001), whereas the cortical values did not. Our results thus demonstrate the importance of bone structure, as assessed by HR-pQCT, in addition to the standard DXA T-score in the diagnosis of osteoporosis.

Introduction To test for colposcopic differences between CIN2+ and non CIN2+ lesions of the “major changes” of the RIO 2011 nomenclature of the International Federation of Cervical Pathology (IFCPC). Material and methods Retrospective cohort analysis of colposcopic examinations of patients with histologically confirmed CIN2+ (n = 99) and non CIN2+ (n = 102) lesions during a four years period. Main outcome measures: leukoplakia, coarse mosaic and punctuation, dense acetowhitening, sharp boarders, ridge sign, atypical vessels. Results Only coarse punctuation (P ≤ 0.001; OR 9.64; 95% CI 2.15–43.13), coarse mosaic (P ≤ 0.001; OR 4.00; 95% CI 1.83–8.73) and dense acetowhitening (P ≤ 0.05; OR 1.86; 95% CI 1.06–3.26) occurred more frequently in CIN2+ lesions which were confirmed as predictors by a regression analysis. Conclusions Only coarse punctuation and coarse mosaic followed by dense acetowhitening as part of the “major changes” of the IFCPC Rio 2011 nomenclature achieve predictive values for CIN2+ lesions and should be therefore emphasized in colposcopy.

Aging and many disease conditions, most notably diabetes, are associated with the accumulation of non-enzymatic cross-links in the bone matrix. The non-enzymatic crosslinks, also known as advanced glycation end products (AGEs), occur at the collagen tissue level, where they are associated with reduced plasticity and increased fracture risk. In this study, Fourier-transform infrared (FTIR) imaging was used to detect spectroscopic changes associated with the formation of non-enzymatic cross-links in human bone collagen. Here, the non-enzymatic cross-link profile was investigated in one cohort with an in vitro ribose treatment as well as another cohort with an in vivo bisphosphonate treatment. With FTIR imaging, the two-dimensional (2D) spatial distribution of collagen quality associated with non-enzymatic cross-links was measured through the area ratio of the 1678/1692 cm−1 subbands within the amide I peak, termed the non-enzymatic crosslink-ratio (NE-xLR). The NE-xLR increased by 35% in the ribation treatment group in comparison to controls (p< 0.005), with interstitial bone tissue being more susceptible to the formation of non-enzymatic cross-links. Ultra high performance liquid chromatography, fluorescence microscopy, and fluorometric assay confirm a correlation between the non-enzymatic cross-link content and the NE-xLR ratio in the control and ribated groups. High resolution FTIR imaging of the 2D bone microstructure revealed enhanced accumulation of non-enzymatic cross-links in bone regions with higher tissue age (i.e., interstitial bone). This non-enzymatic cross-link ratio (NE-xLR) enables researchers to study not only the overall content of AGEs in the bone but also its spatial distribution, which varies with skeletal aging and diabetes mellitus and provides an additional measure of bone's propensity to fracture.

Pregnancy and lactation-associated osteoporosis (PLO) is a rare form of osteoporosis, which occurs in the last trimester or postpartum. So far 100 cases have been published. The leading symptoms are severe low back pain or less frequently hip pain. Many patients develop postpartum depression due to inability to care for the baby and vertebral fractures. The therapeutic decision has to be made individually but teriparatid and bisphosphonates seem to be the best option. We report the clinical course (16 years) of a 37-year-old patient with PLO, who suffered 6 vertebral fractures. There were severe physical limitations and mental problems caused by the disease. The patient was treated by multimodal therapy including physiotherapy and psychotherapy and bisphosphonates were given. The time between the onset of symptoms and diagnosis was 5 months. No further fractures occurred in the following 16 years. The physical and mental condition significantly improved.

Immunotherapy is considered a new treatment option for many tumor entities, as decades of research into cancer immunotherapy have recently yielded promising results. Indeed, impressive clinical results of checkpoint blockade inhibitors in malignant melanoma and non-small cell lung cancer indicate the therapeutic potential of tumor-specific immune restoration. Over the years, different immunotherapeutic approaches have been evaluated for the treatment of hepatocellular carcinoma (HCC) with some respectable results. In this review article, we will summarize the key studies of the past 30 years and will elucidate in which direction the dynamic field of HCC immunotherapy is currently moving.

Immobilization as a result of long-term bed rest can lead to gradual bone loss. Because of their distribution throughout the bone matrix and remarkable interconnectivity, osteocytes represent the major mechanosensors in bone and translate mechanical into biochemical signals controlling bone remodeling. To test whether immobilization affects the characteristics of the osteocyte network in human cortical bone, femoral diaphyseal bone specimens were analyzed in immobilized female individuals and compared with age-matched postmenopausal individuals with primary osteoporosis. Premenopausal and postmenopausal healthy individuals served as control groups. Cortical porosity, osteocyte number and lacunar area, the frequency of hypermineralized lacunae, as well as cortical bone calcium content (CaMean) were assessed using bone histomorphometry and quantitative backscattered electron imaging (qBEI). Bone matrix properties were further analyzed by Fourier transform infrared spectroscopy (FTIR). In the immobilization group, cortical porosity was significantly higher, and qBEI revealed a trend toward higher matrix mineralization compared with osteoporotic individuals. Osteocyte density and canalicular density showed a declining rate from premenopausal toward healthy postmenopausal and osteoporotic individuals with peculiar reductions in the immobilization group, whereas the number of hypermineralized lacunae accumulated inversely. In conclusion, reduced osteocyte density and impaired connectivity during immobilization are associated with a specific bone loss pattern, reflecting a phenotype clearly distinguishable from postmenopausal osteoporosis. Immobilization periods may lead to a loss of survival signals for osteocytes, provoking bone loss that is even higher than in osteoporosis states, whereas osteocytic osteolysis remains absent. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.

Hepatitis C virus (HCV) infections are more common among US veterans receiving care through Veterans Affairs (VA) Medical Centers than among the general population. Historically, HCV therapies had lower efficacy rates in VA patients, possibly due to common comorbidities such as psychiatric disorders and substance abuse. The direct‐acting antivirals ombitasvir/paritaprevir/ritonavir and dasabuvir (OBV/PTV/r+DSV)±ribavirin (RBV) are approved in the US for HCV genotype 1 (GT1)‐infected adults with or without cirrhosis. This study prospectively evaluated the safety and efficacy of OBV/PTV/r+DSV±RBV in VA patients with HCV GT1 infection. TOPAZ‐VA was a phase 3b, open‐label trial. Adult US veterans with HCV GT1 infection, without cirrhosis or with compensated cirrhosis, were eligible for enrollment. Patients with GT1a infection received OBV/PTV/r +DSV+RBV for 12 weeks or 24 weeks (for those with cirrhosis); GT1b‐infected patients without cirrhosis received OBV/PTV/r +DSV for 12 weeks; those with cirrhosis received OBV/PTV/r +DSV with RBV. The primary endpoint was sustained virologic response at posttreatment week 12 (SVR12); safety was also assessed. Ninety‐nine patients were enrolled at 10 sites from May through November 2015. The majority were male (96%), white (60%), and with GT1a infection (68%); 49% reported ongoing psychiatric disorders. Overall, 94% (93/99) achieved SVR12; three patients had a virologic failure. The most common AEs were fatigue (28%), headache (20%), and nausea (15%); six patients discontinued treatment due to AEs. In US veterans with HCV GT1 infection, OBV/PTV/r +DSV±RBV yielded a 94% overall SVR12 rate and was well tolerated. The presence of psychiatric disorders and/or injection drug use did not impact efficacy., Highlights Chronic hepatitis C virus (HCV) infection occurs at a higher prevalence in the VA Health System than in the general population.These patients are also at a higher risk of psychiatric disorders and substance abuse, which were historically risk factors for successful treatment of HCV.We treated 99 patients in the VA Health System with ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin for 12 to 24 weeks.Sustained virologic response was achieved in 93 of 99 patients, with safety and tolerability comparable to the general population.The presence of psychiatric or substance abuse disorders did not impact treatment success.

Unter einer Mastozytose versteht man eine klonale Vermehrung von Mastzellen. Wir berichten uber 4 Patienten mit schwerer Osteoporose bei histologisch gesicherter Mastozytose. Bei den Patienten kam es unter antiresorptiver Therapie zu weiteren Frakturen. Es bestanden starke Knochenschmerzen. Bei therapierefraktaren oder ungeklarten Osteoporoseformen ist die systemische Mastozytose eine wichtige Differenzialdiagnose. Eine Urticaria pigmentosa ist nur selten vorhanden, meist handelt es sich um einen isolierten Befall des Knochenmarks. Die Bestimmung der Tryptase im Serum kann Hinweise auf eine systemische Mastozytose geben, beweisend ist nur die Knochenstanze. Die Patienten sind stark frakturgefahrdet, die Therapie sollte in spezialisierten osteologischen Schwerpunktzentren DVO erfolgen. Die besten Daten existieren zum Bisphosphonat Zoledronat.

Background Migrant mothers in developed countries often experience more complicated pregnancy outcomes and less fewer women access preventive gynecology services. To enlighten health care providers to potential barriers, the objective of this paper is to explore barriers to reproductive health services in Geneva described by migrant women from a qualitative perspective. Methods In this qualitative study, thirteen focus groups (FG) involving 78 women aged 18 to 66 years were conducted in seven languages. All the FG discussions were audio-recorded and later transcribed. The data was classified, after which the main themes and sub-themes were manually extracted and analyzed. Results Barriers were classified either into structural or personal barriers aiming to describe factors influencing the accessibility of reproductive health services vs. those influencing client satisfaction. The five main themes that emerged were financial accessibility, language barriers, real or perceived discrimination, lack of information and embarrassment. Conclusion Structural improvements which might meet the needs of the emergent extremely diverse population are the (1) provision of informative material that is easy to understand and available in multiple languages, (2) provision of sensitive cultural training including competence skill for all health professionals, (3) provision of specifically trained nurses or social assistance to guide migrants through the health system and (4) inclusion of monitoring and evaluation programs for the prevention of personal and systemic discrimination.

Within the mineralized bone, osteocytes form a multifunctional mechanosensitive network orchestrating bone remodelling. A preserved osteocyte population is a crucial determinant of bone quality. In human auditory ossicles, the early decrease in osteocyte numbers but maintained integrity remains an unexplained phenomenon that might serve for sound transmission from air to the labyrinth. Here we analysed the frequency, size and composition of osteocyte lacunae in the auditory ossicles of 22 individuals from early postnatal period to old age. Mineralization of the bone matrix was determined using backscattered electron imaging. No signs of bone remodelling were observed above the age of 1 year. We detected characteristics of early bone tissue aging, such as decrease in osteocytes, lower total lacunar density and lacunar area, as well as high matrix mineralization accompanied by distinct accumulation of micropetrotic lacunae and decreased indentation depths. The majority of these changes took place in the first months and years of life, while afterwards only minor reorganization was present. With osteocyte apoptosis potentially being a consequence of low mechanical stimuli, the early loss of osteocytes without initiation of bone remodelling indicates an adaptive response conserving the architecture of the auditory ossicles and ensuring stable sound transmission throughout life.

Bone microarchitecture and strength are impaired by obesity and physical inactivity, but the underlying molecular regulation of bone metabolism in response to these factors is not well understood. Therefore, we analyzed bone and energy metabolism in male mice fed a high-fat or standard chow diet for 12 weeks with or without free access to running wheels. High-fat diet (HFD) mimicked the human condition of obesity and insulin resistance, including symptoms such as elevated serum glucose and insulin levels and reduced insulin-stimulated glucose uptake into muscle and adipose tissue. Interestingly, HFD also decreased (−44%) glucose uptake into bone marrow. Bone mass was reduced (−45%) by HFD due to a diminished (−45%) bone remodeling rate. Bone matrix quality aspects, such as biomechanical stability, were additionally decreased. Concurrently, the bone marrow adiposity increased (+63%) in response to a HFD. Further, we detected elevated expression of the Wnt signaling inhibitor dickkopf-1 (Dkk-1, +42%) in mice fed a HFD, but this was not reflected in serum samples obtained from obese humans. In mice, exercise attenuated the adverse effects of HFD by reversing the glucose uptake into bone marrow, improving the bone mass and bone matrix quality while decreasing the bone marrow adiposity. This data shows that exercise prevents some, but not all of the negative effects of HFD on bone health and suggests that insulin signaling in bone marrow and Dkk-1 signaling may be involved in the pathogenesis of bone loss induced by HFD.

Supplemental Digital Content is available in the text., Background— There is a lack of data on the comparative efficacy and procedural safety of open irrigated radiofrequency (RF) and cryoballoon catheter (CB) ablation for pulmonary vein isolation in patients with paroxysmal atrial fibrillation. Methods and Results— In a prospective, noninferiority study, 315 patients were randomly assigned to RF (n=159) or CB (n=156) ablation. The primary end point was freedom from atrial arrhythmia with absence of persistent complications. Patients were largely comparable between groups with more vascular disease in the RF group (8.2% versus 2.6% for CB; P=0.028). The primary end point at 12 months was achieved by 70.7% with RF and 73.6% with CB (multiple procedure success), including 31 redo procedures in each group (19.5% of RF versus 19.9% of CB; P=0.933). For the intention-to-treat population, noninferiority of CB was revealed for the predefined inferiority margin (risk difference, 0.029; 95% confidence interval, −0.074 to 0.132; P

The main hallmark of high bone mass (HBM) disorders is increased bone mineral density, potentially visible in conventional radiographs and quantifiable by other radiographic methods. While one of the most common forms of HBM is CLCN7-related autosomal dominant osteopetrosis type II (ADO II), there is no consensus on diagnostic thresholds. We therefore wanted to assess whether CLCN7-osteopetrosis patients differ from benign HBM cases in terms of (1) bone mineral density, (2) bone structure, and (3) microarchitectural abnormalities. 16 patients meeting the criteria of HBM (DXA T/Z-score ≥ 2.5 at all sites) were included in this retrospective study. Osteologic assessment using dual-energy X-ray absorptiometry (DXA), high-resolution peripheral quantitative computed tomography (HR-pQCT), and serum analyses was performed. The presence of CLCN7 and/or other HBM gene mutations affecting bone mass were tested using a custom designed bone panel. While a DXA threshold for ADO II could be implemented (DXA Z-score ≥ + 6.0), the differences in bone microarchitecture were of lesser extent compared to the benign HBM group. All adult patients with ADO II suffered from elevated fracture rates independent from Z-score. In HR-pQCT, structural alterations, such as bone islets were found only inconsistently. In cases of HBM, a DXA Z-score ≥ 6 may be indicative for an inheritable HBM disorder, such as ADO II. Microarchitectural bone alterations might represent local microfracture repair or accumulation of cartilage remnants due to impaired osteoclast function, but seem not to be correlated with fracture risk.

Effective treatment of paroxysmal atrial fibrillation (AF) is essential for reducing the risk of stroke and heart failure. Cryoballoon (CB) ablation has been developed as an alternative to the use of radiofrequency (RF) energy for electrical isolation of the pulmonary veins. Herein, we provide long-term data regarding the efficacy of CB ablation in comparison to RF. FreezeAF was a randomised non-inferiority study comparing CB ablation with RF ablation for the treatment of patients with drug-refractory paroxysmal AF. Procedural success for the long-term follow-up (30 months) was defined as freedom from AF with an absence of persistent complications. Of the 315 patients that were randomised and received catheter ablation, 292 (92.7%) completed the 30-month follow-up (147 in the RF group and 145 in the CB group). The baseline characteristics of the RF and CB groups were similar. Single-procedure success was achieved by 40% of patients in the RF group and 42% of the CB group (p

BACKGROUND:\ud \ud Metformin might reduce insulin requirement and improve glycaemia in patients with type 1 diabetes, but whether it has cardiovascular benefits is unknown. We aimed to investigate whether metformin treatment (added to titrated insulin therapy) reduced atherosclerosis, as measured by progression of common carotid artery intima-media thickness (cIMT), in adults with type 1 diabetes at increased risk for cardiovascular disease.\ud \ud METHODS:\ud \ud REMOVAL was a double-blind, placebo-controlled trial undertaken at 23 hospital diabetes clinics in five countries (Australia, Canada, Denmark, the Netherlands, and the UK). Adults aged 40 years and older with type 1 diabetes of at least 5 years' duration and at least three of ten specific cardiovascular risk factors were randomly assigned (via an interactive voice response system) to oral metformin 1000 mg twice daily or placebo. Participants and site staff were masked to treatment allocation. The primary outcome was averaged mean far-wall cIMT, quantified annually for 3 years, analysed in a modified intention-to-treat population (all randomly assigned participants with post-randomisation data available for the outcome of interest at any given timepoint, irrespective of subsequent adherence or study participation), using repeated measures regression. Secondary outcomes were HbA1c, LDL cholesterol, estimated glomerular filtration rate (eGFR), incident microalbuminuria (not reported), incident retinopathy, bodyweight, insulin dose, and endothelial function, also analysed in all participants with post-randomisation data available for the outcome of interest at any given timepoint. This trial is registered with ClinicalTrials.gov, number NCT01483560.\ud \ud FINDINGS:\ud \ud Between Dec 14, 2011, and June 24, 2014, 493 participants entered a 3 month run-in to optimise risk factor and glycaemic control (single-blind placebo in the final month). Of 428 randomly assigned patients, 219 were allocated to metformin and 209 to placebo. Progression of mean cIMT was not significantly reduced with metformin (-0·005 mm per year, 95% CI -0·012 to 0·002; p=0·1664), although maximal cIMT (a prespecified tertiary outcome) was significantly reduced (-0·013 mm per year, -0·024 to -0·003; p=0·0093). HbA1c (mean 8·1% [SD 0·9] for metformin and 8·0% [0·8] for placebo at baseline) was reduced on average over 3 years by metformin (-0·13%, 95% CI -0·22 to -0·037; p=0·0060), but this was accounted for by a reduction at the 3-month timepoint (-0·24%, -0·34 to -0·13; p

Sowohl eine hypo- als auch eine hyperdopaminerge Dysbalance konnen zu gravierenden Verhaltensstorungen bei Patienten mit Morbus Parkinson fuhren, die einen erheblichen Einfluss auf den Alltag der Patienten haben. Typische hypodopaminerge Zustande konnen im Rahmen des Dopamin-Entzugssyndroms, des Dopaminagonisten-Entzugssyndroms und der oft erheblichen Medikamentenreduktion nach der Tiefen Hirnstimulation des Nucleus subthalamicus auftreten. Die Symptome bestehen aus einer Apathie, Antriebsarmut, Aspontaneitat, gelegentlich auch aus psychischen Storungen wie Depressionen, Anhedonie und autonomen Storungen wie einer orthostatischen Dysregulation. Eine hyperdopaminerge Dysbalance kann bei einer Behandlung mit Dopaminagonisten auftreten oder beim Dopamin-Dysregulationssyndrom. Impulskontrollstorungen wie Hypersexualitat, Essattacken, Kaufzwang und das pathologische Glucksspiel sind neben dem Punding typische Symptome einer hyperdopaminergen Verhaltensstorung. Kontrollierte Therapiestudien zur Behandlung dieser Storungen sind rar und die Therapie muss auf den individuellen Fall abgestimmt sein. Beide Storungsbilder – die hypo- und die hyperdopaminerge Dysbalance – werden mit Veranderungen im mesolimbischen dopaminergen Belohnungssystem in Verbindung gebracht.

It is well known that smoking during pregnancy can affect offspring health. Prenatal tobacco exposure has been associated with negative behavioral and cognitive outcomes in childhood, adolescence, and young adulthood. These associations between prenatal tobacco exposure and psychopathology in offspring could possibly be explained by the influence of prenatal tobacco exposure on brain development. In this prospective study, we investigated the association between prenatal tobacco exposure, behavioral and emotional functioning and brain morphology in young children. On the basis of age and gender, we matched 113 children prenatally exposed to tobacco with 113 unexposed controls. These children were part of a population-based study in the Netherlands, the Generation R Study, and were followed from pregnancy onward. Behavioral and emotional functioning was assessed at age 6 with the Child Behavior Checklist. We assessed brain morphology using magnetic resonance imaging techniques in children aged 6–8 years. Children exposed to tobacco throughout pregnancy have smaller total brain volumes and smaller cortical gray matter volumes. Continued prenatal tobacco exposure was associated with cortical thinning, primarily in the superior frontal, superior parietal, and precentral cortices. These children also demonstrated increased scores of affective problems. In addition, thickness of the precentral and superior frontal cortices was associated with affective problems. Importantly, brain development in offspring of mothers who quit smoking during pregnancy resembled that of nonexposed controls (no smaller brain volumes and no thinning of the cortex). Our findings suggest an association between continued prenatal tobacco exposure and brain structure and function in school-aged children.

Compliance and persistence are often underestimated in breast cancer (BC) treatment. The aim of our study was to analyze the persistence with tamoxifen (TAM) and aromatase inhibitors (AI) in postmenopausal women with hormone-receptor-positive BC and to identify determinants of non-persistence. We used data of the Disease Analyzer database (IMS HEALTH, Germany) including 2,067 general practices and 397 gynecological practices. Out of a dataset of 15 million patients, we identified BC patients with a first-time TAM or AI prescriptions from October 2001 to December 2010. For persistence analyses, 12,412 women on tamoxifen, 2,796 on anastrozole, 647 on exemestane, and 1,657 on letrozole met the inclusion/exclusion criteria. Within 3 years of follow-up, the discontinuation rates increased to 52.2 % for tamoxifen, 47 % for anastrozole, 55.1 % for exemestane, and 44.3 % for letrozole treated women. A minor proportion of patients switched to a different endocrine treatment; 33 % tamoxifen, 20 % anastrozole, 22.9 % exemestane, and 23 % letrozole. The multivariate hazard ratios of the cox regression models showed that patients younger than 50 were most likely to discontinue initial therapy when compared with the reference group of women over 70 (p < 0.001). In contrast, patients treated in gynecologist practice had significantly longer persistence than patients who obtained their prescriptions in general practitioner practice (p < 0.001). In addition, the presence of the co morbidities like diabetes (p < 0.001) or depression (p < 0.002) was also associated with decreased risk of treatment discontinuation. Persistence with all endocrine treatments in women with hormone-receptor-positive BC is low and needs to be significantly increased to improved outcome in clinical practice. Further research is required to understand this complex issue.

BackgroundAs the era of interferon-alpha (IFN)-based therapy for hepatitis C ends, long-term treatment outcomes are now being evaluated.AimTo more fully understand the natural history of hepatitis C infection by following a multisite cohort of patients.MethodsPatients with chronic HCV were prospectively enrolled in 1999-2000 from 11 VA medical centers and followed through retrospective medical record review.ResultsA total of 2211 patients were followed for an average of 8.5years after enrollment. Thirty-one percent of patients received HCV antiviral therapy, 15% with standard IFN/ribavirin only, 16% with pegylated IFN/ribavirin, and 26.7% of treated patients achieved sustained virologic response (SVR). Cirrhosis developed in 25.8% of patients. Treatment nonresponders had a greater than twofold increase in the hazard of cirrhosis and hepatocellular carcinoma, compared to untreated patients, whereas SVR patients were only marginally protected from cirrhosis. Nearly 6% developed hepatocellular carcinoma, and 27.1% died during the follow-up period. Treated patients, regardless of response, had a significant survival benefit compared to untreated patients (HR 0.58, CI 0.46-0.72). Improved survival was also associated with college education, younger age, lower levels of alcohol consumption, and longer duration of medical service follow-up-factors typically associated with treatment eligibility.ConclusionsAs more hepatitis C patients are now being assessed for all-oral combination therapy, these results highlight that patient compliance and limiting harmful behaviors contribute a significant proportion of the survival benefit in treated patients and that the long-term clinical benefits of SVR may be less profound than previously reported.

Interest in improving care for the growing number of individuals with chronic conditions is rising. However, access to care is limited by distance, disability, and distribution of doctors. Small-scale studies in Parkinson disease, a prototypical chronic condition, have suggested that delivering care using video house calls is feasible, offers similar clinical outcomes to in-person care, and reduces travel burden.We are conducting a randomized comparative effectiveness study (Connect.Parkinson) comparing usual care in the community to usual care augmented by virtual house calls with a Parkinson disease specialist. Recruitment is completed centrally using online advertisements and emails and by contacting physicians, support groups, and allied health professionals. Efforts target areas with a high proportion of individuals not receiving care from neurologists. Approximately 200 individuals with Parkinson disease and their care partners will be enrolled at 20 centers throughout the United States and followed for one year. Participants receive educational materials, then are randomized in a 1:1 ratio to continue their usual care (control arm) or usual care and specialty care delivered virtually (intervention arm). Care partners are surveyed about their time and travel burden and their perceived caregiver burden. Participants are evaluated via electronic survey forms and videoconferencing with a blinded independent rater at baseline and at 12 months. All study activities are completed remotely.The primary outcomes are: (1) feasibility, as measured by the proportion of visits completed, and (2) quality of life, as measured by the 39-item Parkinson's Disease Questionnaire. Secondary outcomes include measures of clinical benefit, quality of care, time and travel burden, and caregiver burden.Connect.Parkinson will evaluate the feasibility and effectiveness of using technology to deliver care into the homes of individuals with Parkinson disease. The trial may serve as a model for increasing access and delivering patient-centered care at home for individuals with chronic conditions.This trial was registered on clinicaltrials.gov on January 8, 2014 [NCT02038959].

Radioactive isotopes of radioiodine are frequently used in differentiated thyroid carcinoma (DTC) both for diagnosis and therapy. Their accumulation in thyroid cancer tissue is dependent on the expression and activity of the sodium-iodide symporter (NIS). Scintigraphic imaging using either planar or single-photon emission computed tomography (SPECT) cameras allows the visualization of their distribution within the human body. Due to only a poor visualization of morphology by these techniques, their diagnostic accuracy is, however, limited. This limitation is overcome when hybrid systems integrating a SPECT camera with an X-ray CT scanner are used. Roughly one third of patients with diagnostically unclear foci of radioiodine accumulation will benefit from the use of SPECT/CT, also in terms of therapeutic management. SPECT/CT has, therefore, become the gold standard of nuclear imaging in DTC. NIS expression may be absent in DTC. In this case, the glucose transporters are usually upregulated. Therefore, PET/CT using 18F-deoxyglucose can be used to diagnose and localize tumor recurrence as a prerequisite to, in particular, surgical intervention.

Background. Leiomyosarcomas (LMS) represent a heterogeneous subset of soft tissue sarcomas. Factors influencing prognosis for patients with metastatic extrauterine LMS (euLMS) are not well described. Limited data are available regarding responses to systemic therapy.Methods. We collected clinical and pathologic information for all patients with metastatic euLMS seen at Memorial Sloan Kettering Cancer Center between 1989 and 2012. Objective responses to first-line therapy were analyzed for a subset of patients with available baseline and on-treatment imaging using RECIST 1.1.Results. 215 patients with metastatic euLMS had a median overall survival (OS) of 2.6 years from the time of metastasis. Older age, male sex, and ≥3 initial sites of metastasis were associated with worse OS on multivariate analysis. Objective response rate (ORR) inN=113was 19% overall and 25%, 26%, and 25% for gemcitabine, gemcitabine plus docetaxel, and anthracycline-alkylator combinations. Patients whose tumors objectively responded to first-line therapy had a lower risk of death versus those who did not (Hazard Ratio 0.46; 95% CI: 0.26–0.79,p=0.005).Conclusions. Anthracycline- and gemcitabine-based regimens have similar activity in this cohort of euLMS. Prognostic factors for OS include older age, male sex, and ≥3 initial sites.

Background & Aims EPIC-3 is a prospective, international study that has demonstrated the efficacy of PEG-IFN alfa-2b plus weight-based ribavirin in patients with chronic hepatitis C and significant fibrosis who previously failed any interferon–alfa/ribavirin therapy. The aim of the present study was to assess FibroTest (FT), a validated non-invasive marker of fibrosis in treatment-naive patients, as a possible alternative to biopsy as the baseline predictor of subsequent early virologic (EVR) and sustained virologic response (SVR) in previously treated patients. Methods Of 2312 patients enrolled, 1459 had an available baseline FT, biopsy, and complete data. Uni- (UV) and multi-variable (MV) analyses were performed using FT and biopsy. Results Baseline characteristics were similar as in the overall population; METAVIR stage: 28% F2, 29% F3, and 43% F4, previous relapsers 29%, previous PEG-IFN regimen 41%, high baseline viral load (BVL) 64%. 506 patients (35%) had undetectable HCV-RNA at TW12 (TW12neg), with 58% achieving SVR. The accuracy of FT was similar to that in naive patients: AUROC curve for the diagnosis of F4 vs F2=0.80 ( p p p ⩽0.001) with EVR. Among patients TW12neg, two independent factors remained highly predictive of SVR by MV analysis ( p ⩽0.001): genotype 2/3 (odds ratio=2.9), fibrosis estimated with FT (4.3) or by biopsy (1.5). Conclusions FibroTest at baseline is a possible non-invasive alternative to biopsy for the prediction of EVR at 12weeks and SVR, in patients with previous failures and advanced fibrosis, retreated with PEG-IFN alfa-2b and ribavirin.