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Background: Early and severe neuronal loss in the cholinergic basal forebrain is observed in Alzheimer's disease (AD). To date, cholinomimetics play a central role in the symptomatic treatment of AD dementia. Although basic research indicates that a cholinergic deficit is present in AD before dementia, the efficacy of cholinomimetics in mild cognitive impairment (MCI) remains controversial. Predictors of cholinergic impairment could guide individualized therapy.Objective: To investigate if the extent of the cholinergic deficit, measured using positron emission tomography (PET) and the tracer 11C-N-methyl-4-piperidyl acetate (MP4A), could be predicted from the volume of cholinergic basal forebrain nuclei in non-demented AD patients.Methods: Seventeen patients with a high likelihood of MCI due to AD and 18 age-matched cognitively healthy adults underwent MRI-scanning. Basal forebrain volume was assessed using voxel-based morphometry and a cytoarchitectonic atlas of cholinergic nuclei. Cortical acetylcholinesterase (AChE) activity was measured using MP4A-PET.Results: Cortical AChE activity and nucleus basalis of Meynert (Ch4 area) volume were significantly decreased in MCI. The extent of the cholinergic deficit varied considerably across patients. Greater volumes of anterior basal forebrain nuclei (Ch1/2 area) and younger age (Spearman's rho (17)  = -0.596, 95% -CI [-0.905, -0.119] and 0.593, 95% -CI [0.092, 0.863])) were associated with a greater cholinergic deficit.Conclusion: Data suggest that less atrophy of the Ch1/2 area and younger age are associated with a more significant cholinergic deficit in MCI due to AD. Further investigations are warranted to determine if the individual response to cholinomimetics can be inferred from these measures. [ABSTRACT FROM AUTHOR]

Background: The ability for independent bipedal locomotion is an important prerequisite for autonomous mobility and participation in everyday life. Walking requires not only a functional musculoskeletal unit but relies on coordinated activation of muscles and may even require cognitive resources. The time-resolved monitoring of the position of joints, feet, legs and other body segments relative to each other alone or in combination with simultaneous recording of ground reaction forces and concurrent measurement of electrical muscle activity, using surface electromyography, are well-established tools for the objective assessment of gait.Research Question: The Gait Real-time Analysis Interactive Lab (GRAIL) has been introduced for gait analysis in a highly standardized and well-controlled virtual environment. However, apart from high computing capacity and sophisticated software required to run the system, handling of GRAIL data is challenging due to the utilization of different software packages resulting in a huge amount of data stored using different file formats and different sampling rates. These issues make gait analysis even with such a sophisticated instrument rather tedious, especially within the frame of an experimental or clinical study.Methods: A user-friendly Matlab based toolset for automated processing of motion capturing data recorded using the GRAIL, with the inherent option for batch analysis was developed.Results: The toolset allows the reading, resampling, filtering and synchronization of data stored in different input files recorded with the GRAIL. It includes a coordinate-based algorithm for the detection of initial contact and toe-off events to split and normalize data relative to gait cycles. Batch processing of multiple measurements and automatic detection of outliers is possible.Significance: The authors hope that the toolset will be useful to the research community and invite everyone to use, modify or implement it in their own work. [ABSTRACT FROM AUTHOR]

Objective: To determine whether vaginal progesterone for programmed endometrial preparation is noninferior to intramuscular progesterone in terms of live birth rates from frozen embryo transfer (FET).Design: Three-armed, randomized, controlled noninferiority trial.Setting: Multicenter fertility clinic.Patient(s): A total of 1,346 volunteer subjects planning vitrified-warmed transfer of high-quality nonbiopsied blastocysts were screened, of whom 1,125 subjects were ultimately enrolled and randomly assigned to treatment.Intervention(s): The subjects were randomly assigned to receive, in preparation for FET, 50 mg daily of intramuscular progesterone (control group), 200 mg twice daily of vaginal micronized progesterone plus 50 mg of intramuscular progesterone every third day (combination treatment), or 200 mg twice daily of vaginal micronized progesterone.Main Outcome Measure(s): The primary outcome was live birth rate per vitrified-warmed embryo transfer. The secondary outcomes were a positive serum human chorionic gonadotropin test 2 weeks after FET, biochemical pregnancy loss, clinical pregnancy, clinical pregnancy loss, total pregnancy loss, serum luteal progesterone concentration 2 weeks after FET, and patient's experience and attitudes regarding the route of progesterone administration, on the basis of a survey administered to the subjects between FET and pregnancy test.Result(s): A total of 1,060 FETs were completed. The live birth rate was significantly lower in women receiving only vaginal progesterone (27%) than in women receiving intramuscular progesterone (44%) or combination treatment (46%). Fifty percent of pregnancies in women receiving only vaginal progesterone ended in miscarriage.Conclusion(s): The live birth rate after vaginal-only progesterone replacement was significantly reduced, due primarily to an increased rate of miscarriage. Vaginal progesterone supplemented with intramuscular progesterone every third day was noninferior to daily intramuscular progesterone, offering an effective alternative regimen with fewer injections.Clinical Trial Registration Number: NCT02254577. [ABSTRACT FROM AUTHOR]

Introduction: Empirical evidence on Ronald Inglehart's theory of value change shows that subsequent generations show a decline in values of physical and economic security (materialism) in favor of an increase in values of self-expression and autonomy (postmaterialism).Methods: We investigate in a pre-registered study whether Inglehart's theory also applies to partnership, such that millennials think less that they need a partner to be happy. We used data from the German Socio-Economic Panel (SOEP) study on 4540 17-year-olds from 16 birth cohorts.Results: Results show that adolescents' estimated importance of a romantic partner for personal happiness decreases on average with each subsequent birth cohort. Further significant predictors were socialization and relationship status of the parents, birth year of the father, as well as education and sex of the adolescent. Socioeconomic status and education level of the parents and birth year of the mother were not significant.Conclusions: Findings provide initial evidence that as society becomes more individualized, even personal happiness is increasingly seen as independent of significant others. Ronald Inglehart's theory of value change, however, seems to have only limited applicability as an explanatory model for this development. [ABSTRACT FROM AUTHOR]

Background: To date, it remains unclear how amyloid plaques and neurofibrillary tangles are related to neural activation and, consequently, cognition in Alzheimer's disease (AD). Recent findings indicate that tau accumulation may drive hippocampal hyperactivity in cognitively normal aging, but it remains to be elucidated how tau accumulation is related to neural activation in AD.Objective: To determine whether the association between tau accumulation and hippocampal hyperactivation persists in mild cognitive impairment (MCI) and mild dementia or if the two measures dissociate with disease progression, we investigated the relationship between local tau deposits and memory-related neural activation in MCI and mild dementia due to AD.Methods: Fifteen patients with MCI or mild dementia due to AD underwent a neuropsychological assessment and performed an item memory task during functional magnetic resonance imaging. Cerebral tau accumulation was assessed using positron emission tomography and [18F]-AV-1451.Results: Entorhinal, but not global tau accumulation, was highly correlated with hippocampal activation due to visual item memory encoding and predicted memory loss over time. Neural activation in the posterior cingulate cortex and the fusiform gyrus was not significantly correlated with tau accumulation.Conclusion: These findings extend previous observations in cognitively normal aging, demonstrating that entorhinal tau continues to be closely associated with hippocampal hyperactivity and memory performance in MCI and mild dementia due to AD. Furthermore, data suggest that this association is strongest in medial temporal lobe structures. In summary, our data provide novel insights into the relationship of tau accumulation to neural activation and memory in AD. [ABSTRACT FROM AUTHOR]

Aim: Current guidelines suggest the use of epinephrine in patients with cardiac arrest (CA). However, evidence for increased survival in good neurological condition is lacking. In experimental settings, epinephrine-induced impairment of microvascular flow was shown. The aim of our study was to analyze the association between epinephrine treatment and intestinal injury in patients after CA.Methods: We have included 52 patients with return of spontaneous circulation (ROSC) after CA admitted to our medical intensive care unit (ICU). Blood was taken on admission and levels of circulating intestinal fatty acid binding protein (iFABP) were analyzed.Results: Patients were 64 (49.8-73.8) years old and predominantly male (76.9%). After six months, 50% of patients died and 38.5% of patients had a cerebral performance category (CPC)-score of 1-2. iFABP levels were lower in survivors (234 IQR 90-399 pg/mL) as compared to non-survivors (283, IQR 86-11500 pg/mL; p < 0.05). Plasma levels of iFABP were not associated with time to ROSC but correlated with epinephrine-dose (R = 0.32; p < 0.05). 40% of patients receiving ≥3 mg of epinephrine as compared to 10.5% of patients treated with <3 mg (p < 0.05) developed iFABP plasma levels >1500 pg/mL, which was associated with dramatically increased mortality (HR4.87, 95%CI 1.95-12.1; p < 0.001). iFABP levels predicted mortality independent from time to ROSC and the disease severity score SAPS II. In contrast to mortality, iFABP plasma levels were not associated with neurological outcome.Conclusions: In this small, single centre study, cumulative dose of epinephrine used in cardiac arrest patients was associated with an increase in biomarker indicative of intestinal injury and 6-month mortality. [ABSTRACT FROM AUTHOR]

Objective: To evaluate characteristics associated with treatment failure 1 year after midurethral sling in women with mixed urinary incontinence.Methods: Four hundred three women who participated in a randomized trial that compared midurethral sling and behavioral and pelvic floor muscle therapy (combined group) against midurethral sling alone for mixed incontinence with 1 year of follow-up data were eligible for this planned secondary analysis. Overall treatment failure was defined as meeting criteria for subjective failure, objective failure, or both. Subjective failure was defined as not meeting the minimal clinically important difference for improvement on the UDI (Urogenital Distress Inventory)-total score (26.1 points). Objective failure was not achieving 70% improvement on mean incontinence episodes of any type per day or having undergone any additional treatment for urinary symptoms at 12 months postoperative. Logistic regression models for treatment failure were constructed. Independent variables included site and treatment group, and clinical and demographic variables based on bivariate comparisons (P<.2). Treatment group interaction effects were evaluated.Results: Previous overactive bladder medication use (unadjusted odds ratio [OR] 2.19, adjusted odds ratio [aOR] 1.89, 95% CI 1.10-3.25), detrusor overactivity on cystometrogram (OR 2.25, aOR 2.72, 95% CI 1.53-4.84), body mass index (OR 1.29, aOR 1.27, 95% CI 1.03-1.57), and Valsalva leak point pressure less than 60 cm H2O (OR 1.96, aOR 3.13, 95% CI 1.65-5.94) were associated with overall failure. Worse UDI urgency scores were associated with failure in the midurethral sling-alone group. Sling type (retropubic vs transobturator) was not associated with failure.Conclusion: Certain clinical and urodynamic variables are associated with treatment failure after midurethral sling among women with mixed urinary incontinence. Women with more severe urgency symptoms at baseline may benefit from perioperative behavioral and pelvic floor muscle therapy combined with midurethral sling. This information is helpful for counseling women with mixed incontinence who are considering surgery.Clinical Trial Registration: ClinicalTrials.gov, NCT01959347. [ABSTRACT FROM AUTHOR]

Background: Extracorporeal photopheresis (ECP) is an immunosuppressive treatment that involves leukocyte apheresis, psoralen and UV light treatment, and subsequent reinfusion. Patients treated with ECP are usually immunosuppressed. Bacterial contamination therefore poses a much unwanted risk, but incidence data are lacking.Patients and Methods: We screened all 1922 consecutive ECP procedures scheduled within a roughly 3-year period for eligibility. Those with missing data on ECP method (inline or offline) or type of venous access (peripheral or central) were excluded. ECPs with complete aerobic and anaerobic microbial testing of baseline patient blood samples (n = 1637) and of ECP cell concentrates (n = 1814) were included in the analysis.Results: A test for microbial contamination was positive for 1.82% of the cell concentrates, with central venous access was the most significant risk factor for the contamination (odds ratio = 19). Patient blood samples were positive in 3.85% of cases, but no patients became septic. Staphylococcus spp. were most abundant, and products with bacterial contamination did not cause side effects after reinfusion. There were no significant differences in contamination rates between inline and offline ECP.Conclusion: These findings stress the importance of sterile procedures and the benefits of using peripheral over central venous access for reducing the risk of bacterial contamination in ECP. [ABSTRACT FROM AUTHOR]

Objective: To determine the pharmacokinetics (PK) of drospirenone (DRSP), alone versus in combination with ethinyl estradiol (EE), after single and repeated administration.Study Design: We conducted a single-centre, open-label, crossover, 2-treatment, 2-period, 2-sequence study in which non-micronized DRSP 4 mg or a combination of DRSP 3 mg and EE 0.02 mg were administered to healthy female subjects on day 1 to obtain a single-dose kinetic profile, and from day 4 to day 15 to obtain a repeated-dose kinetic profile. The maximum observed concentration (Cmax) and area under the concentration/time curve (AUC) were determined in a model-independent way using non dose corrected data. Statistical analysis was based on a parametric method (ANOVA-log).Results: A total of 24 healthy female subjects were randomized 1:1 into the study. The mean relative, non-dose-corrected PK estimates after single-dose administration for the endpoints AUC(0-72h), AUC(0-24h) and Cmax were 543.5 ng*h/mL, 296.1 ng*h/mL and 27.3 ng/mL for DRSP alone, and 442.0 ng*h/mL, 264.7 ng*h/mL and 37.5 ng/mL for the DRSP/EE combination; p < 0.001. The mean relative, non-dose-corrected PK estimates after repeated dose administration for the endpoints AUC(0-72h), AUC(0-24h) and Cmax were 1066.8 ng*h/ml, 570.2 ng*h/mL and 41.0 ng/mL for DRSP alone, and 1394.5 ng*h/mL, 732.8 ng*h/mL and 61.4 ng/mL for the DRSP/EE combination; p < 0.001.Conclusions: DRSP alone exhibits a lower accumulation ratio than together with EE. The extent of systemic exposure at steady-state is about 32% less with the new formulation (AUC(0-24h), steady-state geometric mean ratio: 77.8%; 90% confidence interval: 74.6%-81.1%). This PK profile may be caused by EE.Implications: Our results suggest that metabolic pathways of DRSP can be inhibited by EE resulting in higher DRSP plasma concentrations in DRSP/EE formulations than in a DRSP-alone formulation. The enzymes CYP3A4 and SULT1A1 may play a role. Additional drug-drug-interaction studies are needed to better understand these metabolic pathways and their future clinical implications. [ABSTRACT FROM AUTHOR]

Objective: To explore antecedents and outcomes of nurse self-reported job satisfaction and dissatisfaction-based turnover cognitions, theorizing (using Self-Determination Theory) that leaders can foster work conditions that help fulfill innate needs, thereby fostering satisfaction of nurses and patients, and reducing adverse events.Data Sources/study Setting: Primary and secondary data were collected within a 4-month period in 2015, from 2,596 nurses in 110 Army treatment facilities (hospitals and clinics) across 35 health care systems.Data Collection/extraction: We collected individual nurse responses to the Practice Environment Scale-Nursing Work Index, in addition to aggregated archival data from the same timeframe, including both facility-level patient satisfaction records (the Army Provider Level Satisfaction Survey) and health care system-level adverse events records (provided by the Army Programming, Analysis, and Evaluation office).Principal Findings: Five predictors of nurse satisfaction and turnover cognitions emerged-supportive leadership, staffing levels, nurse-physician teamwork, adoption of nursing care practice, and advancement opportunities. Aggregated nurse satisfaction was the most consistent predictor of both patient satisfaction and adverse events.Conclusion: These findings provide evidence of the importance of nurse attitudes in improving perceived and actual performance across facilities and health care systems; in addition to practical steps, managers can take to improve satisfaction and retention. [ABSTRACT FROM AUTHOR]

Background: Early growth faltering accounts for one-third of child deaths, and adversely impacts the health and human capital of surviving children. Social as well as biological factors contribute to growth faltering, but their relative strength and interrelations in different contexts have not been fully described.Objective: The aim of this study was to use structural equation modelling to explore social and biological multidetermination of child height at age 2 y in longitudinal data from 4 birth cohort studies in low- and middle-income countries.Methods: We analyzed data from 13,824 participants in birth cohort studies in Brazil, India, the Philippines, and South Africa. We used exploratory structural equation models, with height-for-age at 24 mo as the outcome to derive factors, and path analysis to estimate relations among a wide set of social and biological variables common to the 4 sites.Results: The prevalence of stunting at 24 mo ranged from 14.0% in Brazil to 67.7% in the Philippines. Maternal height and birthweight were strongly predictive of height-for-age at 24 mo in all 4 sites (all P values <0.001). Three social-environmental factors, which we characterized as "child circumstances," "family socioeconomic status," and "community facilities," were identified in all sites. Each social-environmental factor was also strongly predictive of height-for-age at 24 mo (all P values <0.001), with some relations partly mediated through birthweight. The biological pathways accounted for 59% of the total explained variance and the social-environmental pathways accounted for 41%. The resulting path coefficients were broadly similar across the 4 sites.Conclusions: Early child growth faltering is determined by both biological and social factors. Maternal height, itself a marker of intergenerational deprivation, strongly influences child height at 2 y, including indirect effects through birthweight and social factors. However, concurrent social factors, many of which are modifiable, directly and indirectly contribute to child growth. This study highlights opportunities for interventions that address both biological and social determinants over the long and short term. [ABSTRACT FROM AUTHOR]

Background: Tyrosine kinase inhibitors (TKIs) have improved the survival of patients with chronic myeloid leukaemia. Many patients have deep molecular responses, a prerequisite for TKI therapy discontinuation. We aimed to define precise conditions for stopping treatment.Methods: In this prospective, non-randomised trial, we enrolled patients with chronic myeloid leukaemia at 61 European centres in 11 countries. Eligible patients had chronic-phase chronic myeloid leukaemia, had received any TKI for at least 3 years (without treatment failure according to European LeukemiaNet [ELN] recommendations), and had a confirmed deep molecular response for at least 1 year. The primary endpoint was molecular relapse-free survival, defined by loss of major molecular response (MMR; >0·1% BCR-ABL1 on the International Scale) and assessed in all patients with at least one molecular result. Secondary endpoints were a prognostic analysis of factors affecting maintenance of MMR at 6 months in learning and validation samples and the cost impact of stopping TKI therapy. We considered loss of haematological response, progress to accelerated-phase chronic myeloid leukaemia, or blast crisis as serious adverse events. This study presents the results of the prespecified interim analysis, which was done after the 6-month molecular relapse-free survival status was known for 200 patients. The study is ongoing and is registered with ClinicalTrials.gov, number NCT01596114.Findings: Between May 30, 2012, and Dec 3, 2014, we assessed 868 patients with chronic myeloid leukaemia for eligibility, of whom 758 were enrolled. Median follow-up of the 755 patients evaluable for molecular response was 27 months (IQR 21-34). Molecular relapse-free survival for these patients was 61% (95% CI 57-64) at 6 months and 50% (46-54) at 24 months. Of these 755 patients, 371 (49%) lost MMR after TKI discontinuation, four (1%) died while in MMR for reasons unrelated to chronic myeloid leukaemia (myocardial infarction, lung cancer, renal cancer, and heart failure), and 13 (2%) restarted TKI therapy while in MMR. A further six (1%) patients died in chronic-phase chronic myeloid leukaemia after loss of MMR and re-initiation of TKI therapy for reasons unrelated to chronic myeloid leukaemia, and two (<1%) patients lost MMR despite restarting TKI therapy. In the prognostic analysis in 405 patients who received imatinib as first-line treatment (learning sample), longer treatment duration (odds ratio [OR] per year 1·14 [95% CI 1·05-1·23]; p=0·0010) and longer deep molecular response durations (1·13 [1·04-1·23]; p=0·0032) were associated with increasing probability of MMR maintenance at 6 months. The OR for deep molecular response duration was replicated in the validation sample consisting of 171 patients treated with any TKI as first-line treatment, although the association was not significant (1·13 [0·98-1·29]; p=0·08). TKI discontinuation was associated with substantial cost savings (an estimated €22 million). No serious adverse events were reported.Interpretation: Patients with chronic myeloid leukaemia who have achieved deep molecular responses have good molecular relapse-free survival. Such patients should be considered for TKI discontinuation, particularly those who have been in deep molecular response for a long time. Stopping treatment could spare patients from treatment-induced side-effects and reduce health expenditure.Funding: ELN Foundation and France National Cancer Institute. [ABSTRACT FROM AUTHOR]

Objective: To assess the noninferiority of vaginal P (Endometrin) compared with daily intramuscular P for replacement in programmed vitrified-warmed blastocyst transfer cycles and to assess the noninferiority of vaginal P in combination with intramuscular progesterone every third day compared with daily intramuscular P.Design: Three-arm randomized controlled noninferiority study. To enable early recognition of inferiority if present, an a priori interim analysis was planned and completed once ongoing pregnancy data were available for 50% of the total enrollment goal. The results of this interim analysis are presented here.Setting: Assisted reproduction technology practice.Patient(s): Women undergoing transfer of nonbiopsied high quality vitrified-warmed blastocyst(s) in a programmed cycle.Intervention(s): Vitrified-warmed blastocyst transfer with mode of P replacement determined by randomization to either: (1) 50 mg daily intramuscular P only; (2) 200 mg twice daily vaginal Endometrin; or (3) 200 mg twice daily Endometrin plus 50 mg intramuscular P every 3rd day.Main Outcome Measure(s): Live birth. The primary outcome of this interim analysis was ongoing pregnancy.Result(s): A total of 645 cycles were randomly assigned to one of the three treatment arms, received at least one dose of P replacement therapy according to this assignment and underwent vitrified-warmed blastocyst transfer. These cycles were included in the intention-to-treat analysis. The study team, including the statistician, were blinded to the identity of the treatment arms, which were randomly labeled "A," "B," and "C" in the dataset. Ongoing pregnancy occurred in 50%, 47%, and 31% of cycles in arms A, B, and C respectively. Although arm C had an rate of positive hCG equivalent to the other two arms, the rate of pregnancy loss for arm C was significantly higher than for either of the two arms, resulting in a more than one-third lower rate of ongoing pregnancy. There were no statistically significant differences for any outcome tested between arms A and B. Results of a per-protocol analysis were nearly identical to those of the intention-to-treat analysis. On completion of these analyses, arm C was revealed to be the vaginal P only arm.Conclusion(s): Relative to regimens inclusive of intramuscular P, vaginal-only P replacement for vitrified-warmed blastocyst transfer results in decreased ongoing pregnancy, due to increased miscarriage, and should be avoided. Randomization to the vaginal-only arm was terminated with these findings. This trial is ongoing to assess the noninferiority of the vaginal plus every 3rd day intramuscular P arm compared with daily intramuscular P in terms of live birth.Clinical Trial Registration Number: NLM identifier NCT02254577. [ABSTRACT FROM AUTHOR]

Purpose: To determine the accuracy of particle range prediction for proton and heavier ion radiation therapy based on dual-energy computed tomography (DECT) in a realistic inhomogeneous geometry and to compare it with the state-of-the-art clinical approach.Methods and Materials: A 3-dimensional ground-truth map of stopping-power ratios (SPRs) was created for an anthropomorphic head phantom by assigning measured SPR values to segmented structures in a high-resolution CT scan. This reference map was validated independently comparing proton transmission measurements with Monte Carlo transport simulations. Two DECT-based methods for direct SPR prediction via the Bethe formula (DirectSPR) and 2 established approaches based on Hounsfield look-up tables (HLUTs) were chosen for evaluation. The SPR predictions from the 4 investigated methods were compared with the reference, using material-specific voxel statistics and 2-dimensional gamma analysis. Furthermore, range deviations were analyzed in an exemplary proton treatment plan.Results: The established reference SPR map was successfully validated for the discrimination of SPR and range differences well below 0.3% and 1 mm, respectively, even in complex inhomogeneous settings. For the phantom materials of larger volume (mainly brain, soft tissue), the investigated methods were overall able to predict SPR within 1% median deviation. The DirectSPR methods generally performed better than the HLUT approaches. For smaller phantom parts (such as cortical bone, air cavities), all methods were affected by image smoothing, leading to considerable SPR under- or overestimation. This effect was superimposed on the general SPR prediction accuracy in the exemplary treatment plan.Conclusions: DirectSPR predictions proved to be more robust, with high accuracy in particular for larger volumes. In contrast, HLUT approaches exhibited a fortuitous component. The evaluation of accuracy in a realistic phantom with validated ground-truth SPR represents a crucial step toward possible clinical application of DECT-based SPR prediction methods. [ABSTRACT FROM AUTHOR]

Objective: To assess the relationship between diminished ovarian reserve and pregnancy outcomes in a large cohort of women achieving pregnancy through in vitro fertilization (IVF). We evaluated antral follicle count (AFC) and baseline FSH as a measure of ovarian reserve. Secondarily, we assessed whether diminished ovarian reserve was associated with aneuploidy among spontaneous abortions.Design: Retrospective cohort study.Setting: Multicenter private practice.Patient(s): All patients aged 21-44 years undergoing fresh autologous IVF cycles during 2009-2013 that resulted in positive serum hCG with recorded baseline FSH levels.Intervention(s): None.Main Outcome Measure(s): Live births per early pregnancy, biochemical pregnancies, clinical pregnancy losses, and aneuploidy rates in products of conception among pregnancy losses.Result(s): A total of 9,489 cycles among 8,214 patients were analyzed. There was no association between live birth and ovarian reserve among pregnant IVF patients under the age of 35 years. Among patients 35 years of age and older, elevated baseline FSH was associated with a higher risk of pregnancy loss, which increased with increasing age. AFC was not significantly associated with pregnancy loss at any age. No associations were found between ovarian reserve measures and aneuploidy in products of conception in age-adjusted analyses, although the power to effectively evaluate this was limited.Conclusion(s): Diminished ovarian reserve is not associated with an increase in miscarriage among younger women achieving pregnancy through IVF. Elevated FSH is associated with a higher risk of IVF pregnancy loss among older patients. We found no evidence to confirm that diminished ovarian reserve is associated with increased aneuploidy among spontaneous abortions. [ABSTRACT FROM AUTHOR]

Purpose: This is the first study to evaluate the long-term effectiveness of a school-based prevention program in Germany. The aim is to determine the long-term effects of the primary prevention program PriMa (Primary prevention of anorexia nervosa in preadolescent girls) on disordered eating and body self-esteem from childhood to young adulthood.Methods: PriMa was conducted and successfully evaluated in a quasi-experimental pre-post design with a control group from 2007 to 2008 consisting of 11-13year old girls (N=1508) from Thuringian schools in Germany. Seven to eight years after the intervention, the same cohort (mean age 19.8years) was invited to complete an online survey. Disordered eating (EAT-26), body self-esteem (FBeK) and BMI were assessed via self-report. The response rate at seven-to-eight-year follow-up was very low (7%). Data of N=100 girls were analyzed.Results: Concerning changes in disordered eating, results revealed no significant long-term effect of PriMa seven to eight years after the intervention. During this time, disordered eating remained stable without a significant increase or decrease. Regarding changes in body self-esteem, group courses differed significantly from each other. The results revealed a significant main effect of group, indicating significant differences in changes of body self-esteem between the intervention and the control group. Following the analysis of these changes of body self-esteem over time, it was found that the intervention group revealed an increase of body self-esteem after program participation and remained stable over time. By contrast, the control group revealed a decrease of body self-esteem over time.Conclusions: Long-term intervention effects of PriMa could be found for body self-esteem but not for disordered eating. The findings suggest that PriMa prevented a decrease of body self-esteem from childhood to young adulthood. For a broader dissemination it is necessary to implement prevention programs consistently in school settings. In order to maintain the prevention effects, it would be interesting to investigate the effects of booster sessions which refresh the programs content on a regular basis. Furthermore, the results of this study revealed the implementation difficulties of primary prevention programs especially concerning the retention of the sample size. [ABSTRACT FROM AUTHOR]

The Child Feeding Questionnaire (CFQ) is a self-report questionnaire for assessing parental attitudes to child weight and parental feeding practices. Previous evaluations of its psychometric properties were conducted primarily with small to medium-sized samples (N < 500) and a small range of children's age. The present study aims to analyze the psychometric properties of the CFQ in a large German community sample and, for the first time, to establish normative data. Within the population-based LIFE Child study, the CFQ was administered to N = 982 mothers of 2- to 13-year-old children. Psychometric analyses on item statistics and internal consistency were conducted. Using structural equation modeling, four empirically-based factorial models of the CFQ were evaluated, and measurement invariance across child age groups and sex was examined. Age-specific norms for the CFQ subscales were computed. Item statistics were highly favorable for the majority of items, but floor and ceiling effects were found for 14 of 31 items. Internal consistency of the CFQ subscales ranged from acceptable to excellent (0.71 ≤ α ≤ 0.91), except for the subscale Perceived Responsibility (α = 0.65). Regarding factorial validity, an eight-factor model with the newly created Reward subscale provided the best fit to the data. This model was factorial invariant across child sex and adjacent age groups. Maternal and child weight status showed large effects on CFQ subscale scores. The analyses established good psychometric properties for the German version of the CFQ and confirmed an eight-factor model. The provided norms allow for the comparison of individual parental feeding practices and change over time. The CFQ's sensitivity to change and longitudinal associations of parental feeding practices and child weight status warrant further research. [ABSTRACT FROM AUTHOR]

Importance: Women with refractory urgency urinary incontinence are treated with sacral neuromodulation and onabotulinumtoxinA with limited comparative information.Objective: To assess whether onabotulinumtoxinA is superior to sacral neuromodulation in controlling refractory episodes of urgency urinary incontinence.Design, Setting, and Participants: Multicenter open-label randomized trial (February 2012-January 2015) at 9 US medical centers involving 381 women with refractory urgency urinary incontinence.Interventions: Cystoscopic intradetrusor injection of 200 U of onabotulinumtoxinA (n = 192) or sacral neuromodulation (n = 189).Main Outcomes and Measures: Primary outcome, change from baseline mean number of daily urgency urinary incontinence episodes over 6 months, was measured with monthly 3-day diaries. Secondary outcomes included change from baseline in urinary symptom scores in the Overactive Bladder Questionnaire Short Form (SF); range, 0-100, higher scores indicating worse symptoms; Overactive Bladder Satisfaction questionnaire; range, 0-100; includes 5 subscales, higher scores indicating better satisfaction; and adverse events.Results: Of the 364 women (mean [SD] age, 63.0 [11.6] years) in the intention-to-treat population, 190 women in the onabotulinumtoxinA group had a greater reduction in 6-month mean number of episodes of urgency incontinence per day than did the 174 in the sacral neuromodulation group (-3.9 vs -3.3 episodes per day; mean difference, 0.63; 95% CI, 0.13 to 1.14; P = .01). Participants treated with onabotulinumtoxinA showed greater improvement in the Overactive Bladder Questionnaire SF for symptom bother (-46.7 vs -38.6; mean difference, 8.1; 95% CI, 3.0 to 13.3; P = .002); treatment satisfaction (67.7 vs 59.8; mean difference, 7.8; 95% CI, 1.6 to 14.1; P = .01) and treatment endorsement (78.1 vs 67.6; mean difference; 10.4, 95% CI, 4.3 to 16.5; P < .001) than treatment with sacral neuromodulation. There were no differences in convenience (67.6 vs 70.2; mean difference, -2.5; 95% CI, -8.1 to 3.0; P = .36), adverse effects (88.4 vs 85.1; mean difference, 3.3; 95% CI, -1.9 to 8.5; P = .22), and treatment preference (92.% vs 89%; risk difference, -3%; 95% CI, -16% to 10%; P = .49). Urinary tract infections were more frequent in the onabotulinumtoxinA group (35% vs 11%; risk difference, -23%; 95% CI, -33% to -13%; P < .001). The need for self-catheterization was 8% and 2% at 1 and 6 months in the onabotulinumtoxinA group. Neuromodulation device revisions and removals occurred in 3%.Conclusions and Relevance: Among women with refractory urgency urinary incontinence, treatment with onabotulinumtoxinA compared with sacral neuromodulation resulted in a small daily improvement in episodes that although statistically significant is of uncertain clinical importance. In addition, it resulted in a higher risk of urinary tract infections and need for transient self-catheterizations. [ABSTRACT FROM AUTHOR]

Introduction: Few hospitals treat patients' tobacco dependence. To be effective, hospital-initiated cessation interventions must provide at least 1 month of supportive contact post-discharge.Study Design: Individually randomized clinical trial. Recruitment commenced July 2011; analyses were conducted October 2014-June 2015.Setting/participants: The study was conducted in two large Midwestern hospitals. Participants included smokers who were aged ≥18 years, planned to stay quit after discharge, and spoke English or Spanish.Intervention: Hospital-based cessation counselors delivered the intervention. For patients randomized to warm handoff, staff immediately called the quitline from the bedside and handed the phone to participants for enrollment and counseling. Participants randomized to fax were referred on the day of hospital discharge.Main Outcome Measures: Outcomes at 6 months included quitline enrollment/adherence, medication use, biochemically verified cessation, and cost effectiveness.Results: Significantly more warm handoff than fax participants enrolled in quitline (99.6% vs 59.6%; relative risk, 1.67; 95% CI=1.65, 1.68). One in four (25.4% warm handoff, 25.3% fax) were verified to be abstinent at 6-month follow-up; this did not differ significantly between groups (relative risk, 1.02; 95% CI=0.82, 1.24). Cessation medication use in the hospital and receipt of a prescription for medication at discharge did not differ between groups; however, significantly more fax participants reported using cessation medication post-discharge (32% vs 25%, p=0.01). The average incremental cost-effectiveness ratio of enrolling participants into warm handoff was $0.14. Hospital-borne costs were significantly lower in warm handoff than in fax ($5.77 vs $9.41, p<0.001).Conclusions: One in four inpatient smokers referred to quitline by either method were abstinent at 6 months post-discharge. Among motivated smokers, fax referral and warm handoff are efficient and comparatively effective ways to link smokers with evidence-based care. For hospitals, warm handoff is a less expensive and more effective method for enrolling smokers in quitline services. [ABSTRACT FROM AUTHOR]

Background: Leadership is a key feature in implementation efforts, which is highlighted in most implementation frameworks. However, in studying leadership and implementation, only few studies rely on established leadership theory, which makes it difficult to draw conclusions regarding what kinds of leadership managers should perform and under what circumstances. In industrial and organizational psychology, transformational leadership and contingent reward have been identified as effective leadership styles for facilitating change processes, and these styles map well onto the behaviors identified in implementation research. However, it has been questioned whether these general leadership styles are sufficient to foster specific results; it has therefore been suggested that the leadership should be specific to the domain of interest, e.g., implementation. To this end, an intervention specifically involving leadership, which we call implementation leadership, is developed and tested in this project. The aim of the intervention is to increase healthcare managers' generic implementation leadership skills, which they can use for any implementation efforts in the future.Methods/design: The intervention is conducted in healthcare in Stockholm County, Sweden, where first- and second-line managers were invited to participate. Two intervention groups are included, including 52 managers. Intervention group 1 consists of individual managers, and group 2 of managers from one division. A control group of 39 managers is additionally included. The intervention consists of five half-day workshops aiming at increasing the managers' implementation leadership, which is the primary outcome of this intervention. The intervention will be evaluated through a mixed-methods approach. A pre- and post-design applying questionnaires at three time points (pre-, directly after the intervention, and 6 months post-intervention) will be used, in addition to process evaluation questionnaires related to each workshop. In addition, interviews will be conducted over time to evaluate the intervention.Discussion: The proposed intervention represents a novel contribution to the implementation literature, being the first to focus on strengthening healthcare managers' generic skills in implementation leadership. [ABSTRACT FROM AUTHOR]

Objective: To analyze auditory nerve recovery function (REC), comparing the results after local anesthesia and sedation with those after general anesthesia.Methods: This was a prospective, cross-sectional and descriptive study in a tertiary referral center hospital. We included all patients (37 ears) who underwent surgery for cochlear implant under either general anesthesia or local anesthesia and sedation during 3 years. REC was measured according to the function of 3 components, 'T0', 'A' and 'tau', and was taken for 3 cochlear electrodes (apical, medial and basal).Results: There were no significant differences in 'tau' and in the current level used, but there were significant differences in the parameters 'T0' apical and 'A' basal.Conclusions: There were no significant differences in REC between the 2 types of anesthesia, except for the parameters 'T0' apical and 'A' basal. [ABSTRACT FROM AUTHOR]

Isolated chondral and osteochondral defects of the knee are challenging clinical entities, particularly in younger patients. Cartilage treatment strategies have previously been characterized as palliation (ie, chondroplasty and debridement), repair (ie, drilling and microfracture), or restoration (ie, autologous chondrocyte implantation, osteochondral autograft, and osteochondral allograft). The osteochondral autograft transplantation procedure allows defects to be filled immediately with mature, hyaline articular cartilage by utilizing either an arthroscopic or a mini-open procedure. Graft harvest and placement can be technically demanding, but results show trends toward greater longevity, durability, and improved outcomes in high-demand patients when compared with alternative techniques. Improved results are shown in younger patients with isolated lesions between 1 and 4 cm. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to quantify the variability in spinal radiosurgery (SRS) planning practices between five international institutions, all member of the Elekta Spine Radiosurgery Research Consortium.Methods: Four institutions provided one representative patient case each consisting of the medical history, CT and MR imaging. A step-wise planning approach was used where, after each planning step a consensus was generated that formed the basis for the next planning step. This allowed independent analysis of all planning steps of CT-MR image registration, GTV definition, CTV definition, PTV definition and SRS treatment planning. In addition, each institution generated one additional SRS plan for each case based on intra-institutional image registration and contouring, independent of consensus results.Results: Averaged over the four cases, image registration variability ranged between translational 1.1 mm and 2.4 mm and rotational 1.1° and 2.0° in all three directions. GTV delineation variability was 1.5 mm in axial and 1.6 mm in longitudinal direction averaged for the four cases. CTV delineation variability was 0.8 mm in axial and 1.2 mm in longitudinal direction. CTV-to-PTV margins ranged between 0 mm and 2 mm according to institutional protocol. Delineation variability was 1 mm in axial directions for the spinal cord. Average PTV coverage for a single fraction18 Gy prescription was 87 ± 5 %; Dmin to the PTV was 7.5 ± 1.8 Gy averaged over all cases and institutions. Average Dmax to the PRV_SC (spinal cord + 1 mm) was 10.5 ± 1.6 Gy and the average Paddick conformity index was 0.69 ± 0.06.Conclusions: Results of this study reflect the variability in current practice of spine radiosurgery in large and highly experienced academic centers. Despite close methodical agreement in the daily workflow, clinically significant variability in all steps of the treatment planning process was demonstrated. This may translate into differences in patient clinical outcome and highlights the need for consensus and established delineation and planning criteria. [ABSTRACT FROM AUTHOR]

Background: At the time of initial diagnosis, only 15-20% of patients with pancreatic cancer present with a resectable disease. Patients with pancreatic cancer face a poor prognosis. Progression-free survival and overall survival rates are very limited, so it is important to develop concepts to improve the quality of life for their remaining lives.Methods/design: The proposed trial is a randomized controlled intervention study. After pancreatic resection, the intervention group (cohort A, n = 30 patients) will take part in an intensified physiotherapy program consisting of endurance and muscle force exercises. The control group (cohort B, n = 30 patients) will take part in standard physiotherapy. Both groups will receive dietary counseling and, if necessary, substitution for endocrine/exocrine pancreatic insufficiency. Quality of life will be evaluated using the Short Form-8 Health Survey and the European Organization for Research and Treatment of Cancer QLQ-C30/QLQ-PAN26 questionnaires.Discussion: The aim of this study is to investigate whether intensive physiotherapy improves the quality of life of patients after pancreatic resection. If the results for the intervention group are positive, a multicenter study should be performed with appropriate statistical power. The progressive postresection program includes a structured follow-up after pancreatic resection. In this study, all patients will undergo abdominal computed tomography for follow-up 6 and 12 months postoperatively.Trial Registration: German Clinical Trials Register DRKS00006786. Date of registration 1 October 2014. [ABSTRACT FROM AUTHOR]

Background: Charcot osteo-neuroarthropathy (CN) of the foot can induce severe instability and deformity. Results of a consecutive clinical multi-centre study with Midfoot Fusion Bolt (MFB, Synthes GmbH, Oberdorf, Switzerland) are reported.Methods: All patients (aged 18 years and older) treated between 2009 and 2013 with surgical reconstruction of the midfoot with MFB for CN were included. Demographics, pre-surgical health status, details of foot pathology, details of surgery, postoperative treatment, treatment failure, and adverse events were registered. The following radiographic angles were measured on pre-op, post-op and last follow-up radiographs: talo-1st metatarsal (TMT) angle dorsoplantar and lateral view, and calcaneo-5th metatarsal angle.Results: Forty-seven patients (48 feet) were included in three centres. In 38 patients (80.1%) diabetes was diagnosed. Wound healing problems occurred in 21% of patients and recurrent ulceration in 13%. Revision surgery for loss of correction was performed in three cases (6%). Union rate at final follow-up was 98%. Major amputation for deep infection was performed in two patients (4%), minor amputation at the foot level in three cases (6%). Failure was more frequent when only one MFB (instead of 2 or 3) was used and no Gastrocnemius lengthening was performed. Radiographic alignment significantly improved pre- versus postoperatively and preoperatively versus follow-up.Conclusions: Realignment and fixation with MFB in severe CN result in adequate correction with minimal loss of correction in the observed clinical course. The non-union rate was lower than previously reported. Stable fixation with MFB is a valuable treatment option for CN with minimal loss of correction and high union rates. The use of a minimum of two bolts is recommended to avoid recurrent deformity. Clinical Trials.gov: NCT01770639. [ABSTRACT FROM AUTHOR]

ASD is a neurodevelopmental disorder impacting 1 in 44 children and early identification of children with ASD is critical for the intervention. Several screening measures have been developed for early identification, including the Autism Spectrum Rating Scales, 6–18 years Parent Report (ASRS). The ASRS has been understudied, and the current study assessed the validity of the ASRS in a clinical sample of 490 children at a tertiary ASD-specialty clinic. Results indicated that the ASRS demonstrated favorable sensitivity, but poor specificity. True positive screening results were more likely to occur for children with a multiracial background, while they were less likely to occur for children with a high social capital. Overall, though the ASRS has clinical utility as a screening measure, it did not perform effectively to differentiate ASD from Non-ASD clinical disorders. [ABSTRACT FROM AUTHOR]

Objectives: Toddler milk (i.e. a nutrient-fortified milk-based drink marketed for children 12-36 months old) is increasingly being marketed in the USA despite not being recommended for young children. There is evidence of targeted toddler milk marketing to Latinos in the USA. This study aimed to explore toddler milk perceptions and behaviours among Latino and non-Latino parents.Design: An online survey assessed toddler milk perceptions, behaviours and interpretations of nutrition-related claims. Multivariable logistic and linear regression explored socio-demographic correlates of parent reported past purchases and perceived healthfulness.Setting: Online.Participants: National convenience sample of 1078 US parents of children aged 2-12 years (48 % Latino).Results: About half of parents (51 %) had previously purchased toddler milk and few (11 %) perceived toddler milk as unhealthy. Latino parents were more likely to have purchased toddler milk than non-Latino parents (P < 0·001), but there were no differences in perceived product healthfulness (P = 0·47). Compared to parents born in the USA, parents living in the USA 10 years or less were more likely to have purchased toddler milk (P < 0·001) and perceive toddler milk as healthier (P = 0·002). Open-ended interpretations of claims were primarily positive, suggesting 'health halo' effects.Conclusions: Common misperceptions about toddler milk healthfulness suggest stronger labelling regulations are needed. Greater reported purchases by Latino parents and recent immigrants warrant further investigation. [ABSTRACT FROM AUTHOR]

Retrieval practice promotes retention more than restudying (i.e., the testing effect) and is applied to many educational settings. However, little research has investigated means to enhance this effect in educational settings. Theoretical accounts assume retrieval practice to be the most effective whenever retrieval is difficult but successful. Therefore, we developed a novel retrieval practice procedure, which adapts to learners' abilities and can be applied irrespective of learning content. This adaptive procedure aims to make retrieval gradually easier whenever students provide an incorrect answer. In a field experiment, students read book chapters as part of a weekly university course. In three consecutive weeks, they then practiced reading assignments by (a) adaptive testing, (b) non‐adaptive testing and (c) restudy. In Week 4, a surprise criterial test took place. Restudy outperformed both testing conditions, whereas adaptive testing performed equally well as non‐adaptive testing. However, exploratory analyses revealed that with increasing retention intervals, the superiority of restudy disappeared. Furthermore, whenever participants fully read the assignments and retention intervals increased, adaptive testing outperformed non‐adaptive testing. In sum, adaptive retrieval practice did not prove to be generally superior, but retention interval and students' preparation for class might be conditions rendering adaptive retrieval useful in educational settings. Lay Description: What is already known about this topic: Testing is a commonly used technique to assess progress in computer‐assisted learning environmentsStudents often benefit from the testing effect, that is practicing retrieval of information (testing) from memory benefits long‐term retention compared to restudyingCurrently, empirical evidence how to enhance the benefits of this technique in educational contexts is scarce What this paper adds: We propose a new approach to increase the benefit of the testing effect: For each question in retrieval practice the individual ability to retrieve this information from memory is consideredTo do so, cue informativeness of retrieval cues adapts to the individual ability level and thus makes the tests cognitively effortful but solvableThis adaptive approach is put to test in a higher education context and by using multiple‐choice questionsIn sum, adaptive retrieval practice did not prove to be generally superior to non‐adaptive retrieval practice or restudy However, retention interval and students' preparation for class might be conditions rendering adaptive retrieval useful in educational settings Implications for practice and/or policy: Findings can be implemented in educational contexts when multiple‐choice questions are used to enhance learningLearning can be optimized in computer‐assisted learning environments that allow adaptive testingWe advise adaptive retrieval only when students are well prepared for practice and when time between practice and final assessment exceeds two weeks [ABSTRACT FROM AUTHOR]

Objective: To evaluate factors associated with cryopreserved blastocyst transfer birth outcomes, including age, expansion time, cryopreservation protocol, cryodamage, and number of embryos transferred.Design: Retrospective cohort study.Setting: Private infertility practice.Patient(s): Cryopreserved blastocyst transfer patients from January 2003 to April 2012.Intervention(s): None.Main Outcome Measure(s): Birth per transfer and children per embryo.Result(s): Overall live birth per transfer was 32%, with 17% twin births and 0.3% triplets. Live birth per transfer was significantly higher for vitrification compared with slow-freeze (day 5 cryopreservation: 47% vs. 35%; day 6 cryopreservation: 46% vs. 24%), as was live born children per transferred embryo (39% vs. 29% for day 5; 36% vs. 18% for day 6). Birth rates declined only slightly with increasing age at cryopreservation through 37 years, followed by an increasingly rapid decline in success with increasing age thereafter. Live birth rates declined rapidly (49%-18% for vitrification and 37%-10% for slow-freeze) as the percentage of intact cells after cryopreservation decreased from 95%-100% to 70%-79%, with almost no births when the percentage of intact cells was <70%. Increasing numbers of embryos per transfer were associated with significant increase in live birth per transfer but significant decrease in children per transferred embryo. Birth rates were much lower for blastocysts with delayed expansion on day 7 (10% per transfer).Conclusion(s): Birth outcomes from cryopreserved blastocyst transfer are influenced by age, timing of expansion, cryopreservation protocol, visible cryodamage, and the number of embryos transferred. Vitrification substantially improves outcomes versus slow freezing. [ABSTRACT FROM AUTHOR]

Objective: Soft tissue sarcomas (STS) and gastrointestinal stromal tumours (GIST) are a group of rare malignant tumours with a high and heterogenous disease burden. As evidence is scarce, we analysed the prevalence of increased emotional distress and identified distress-associated factors in these patients.Methods: The PROSa-study (Burden and medical care of sarcoma) was conducted between 2017 and 2020 in 39 study centres. Cross-sectional data from adult STS and GIST patients were analysed. Distress was measured with the Patient Health Questionnaire (PHQ-4). The relation of socioeconomic and clinical factors with distress was explored in adjusted logistic regression models.Results: Among 897 patients, 17% reported elevated anxiety and 19% reported depression. Unemployed patients (odds ratio [OR] 6.6; 95% CI 2.9-15.0), and those with a disability pension (OR 3.1; 95% CI 1.9-5.0) were more likely to experience distress compared to employed patients. Also, patients with a disability pass had higher odds of increased distress than those without (OR 1.8; 95% CI 1.2-2.7). Lowest distress was observed in patients 2 to <5 years and ≥5 years after diagnosis (comparison: <6 months) (OR 0.4; 95% CI 0.2-0.6) and (0.3; 95% CI 0.2-0.6). Patients with thoracic STS (vs. lower limbs) had twice the odds to experience distress (OR 2.0; 95% CI 1.1-3.6). Distress was seen almost twice as often in patients with progressive disease (vs. complete remission) (OR 1.7; 95% CI 1.1-2.8).Conclusion: The prevalence of elevated distress in STS and GIST patients is high. In unemployed patients, in those with a disability pension and in newly diagnosed patients a noticeable increase was observed. Clinicians should be aware of these factors and consider the social aspects of the disease. [ABSTRACT FROM AUTHOR]

Objective: The prognosis for ovarian cancer patients remains poor. A key to maximizing survival rates is early detection and treatment. This requires an accurate prediction of malignancy. Our study seeks to improve the accuracy of prediction by focusing on early subjective assessment of malignancy. We therefore investigated the assessment of patients themselves in comparison to the assessment of physicians.Methods: One thousand three hundred and thirty patients participated in a prospective and multicenter study in six hospitals in Berlin. Using univariate analysis and multivariate logistic regression models, we measured the accuracy of the early subjective assessment in comparison to the final histological outcome. Moreover, we investigated factors related to the assessment of patients and physicians.Results: The patients' assessment of malignancy is remarkably accurate. With a positive predictive value of 58%, the majority of patients correctly assessed a pelvic mass as malignant. With more information available, physicians achieved only a slightly more accurate prediction of 63%.Conclusions: For the first time, our study considered subjective factors in the diagnostic process of pelvic masses. This paper demonstrates that the patients' personal assessment should be taken seriously as it can provide a significant contribution to earlier diagnosis and thus improved therapy and overall prognosis. [ABSTRACT FROM AUTHOR]

In chronic myeloid leukemia (CML), combination therapies with tyrosine kinase inhibitors (TKIs) aim to improve the achievement of deep molecular remission that would allow therapy discontinuation. IFN-α is one promising candidate, as it has long-lasting effects on both malignant and immune cells. In connection with a multicenter clinical trial combining dasatinib with IFN-α in 40 patients with chronic-phase CML (NordCML007, NCT01725204), we performed immune monitoring with single-cell RNA and T cell receptor (TCR) sequencing (n = 4, 12 samples), bulk TCRβ sequencing (n = 13, 26 samples), flow cytometry (n = 40, 106 samples), cytokine analyses (n = 17, 80 samples), and ex vivo functional studies (n = 39, 80 samples). Dasatinib drove the immune repertoire toward terminally differentiated NK and CD8+ T cells with dampened functional capabilities. Patients with dasatinib-associated pleural effusions had increased numbers of CD8+ recently activated effector memory T (Temra) cells. In vitro, dasatinib prevented CD3-induced cell death by blocking TCR signaling. The addition of IFN-α reversed the terminally differentiated phenotypes and increased the number of costimulatory intercellular interactions and the number of unique putative epitope-specific TCR clusters. In vitro IFN-α had costimulatory effects on TCR signaling. Our work supports the combination of IFN-α with TKI therapy, as IFN-α broadens the immune repertoire and restores immunological function. [ABSTRACT FROM AUTHOR]

Update: This article was updated on May 19, 2021 because of previous errors, which were discovered after the preliminary version of the article was posted online. In the legend for Figure 3-A, the phrase that had read "T1-weighted coronal MRI showing a right knee" now reads "T1-weighted coronal MRI showing a left knee." On page 924, in the section entitled "Materials and Methods," the sentence that had read "If there was no radiographic evidence or if there was a clinical note that documented visible deformity around the knee with no reduction maneuver being performed, then the patient was classified into the non-dislocated MLKI group." now reads "If there was no radiographic evidence or if there was no clinical note that documented visible deformity around the knee with no reduction maneuver being performed, then the patient was classified into the non-dislocated MLKI group." On page 925, in the section entitled "Analysis," the sentence that had read "Our study included 78 dislocated MLKIs and non-dislocated MLKIs, so both cohorts were adequately powered for the overall analysis." now reads "Our study included 45 dislocated MLKIs and 78 non-dislocated MLKIs, so both cohorts were adequately powered for the overall analysis." Finally, on page 927, in the section entitled "Discussion," the sentence that had read "Interestingly, we found that MLKIs with a documented knee dislocation had a substantially higher rate of vascular injury (23%) compared with those without (3%)." now reads "Interestingly, we found that MLKIs with a documented knee dislocation had a substantially higher rate of vascular injury (18%) compared with those without (4%)." [ABSTRACT FROM AUTHOR]

Background: The aim of this study is to systematically review the literature on clinical outcomes of patients who have undergone autologous matrix-induced chondrogenesis (AMIC) for treatment of osteochondral lesions of the talus (OCL) and compare the studies' outcomes.Methods: Pubmed and Embase were searched in January 2020 for articles concerning OCL surgery. Studies were included if they had a minimum 1-year follow-up and the primary measures were functional outcomes. The meta-analysis compared the Visual Analogic Score (VAS), the American Orthopedic Foot and Ankle Score (AOFAS), and the Foot Function Index (FFI) between baseline and follow-up of 1-2years, and 3-5years. A random effects model was used to evaluate outcome changes.Results: The search returned 15 studies, with a total of 492 patients. The VAS improved 4.45 and 4.6 points from baseline to the 1-2year and 3-5yearfollow-up, respectively (p<0.001). AOFAS improved 31.59 and 32.47 points from baseline to the 1-2year and 3-5yearfollow-up, respectively (p<0.001). The FFI showed a significant improvement of 30.93 points from baseline to year 3-5 (p<0.001). A total of 6 patients with revision surgeries have been reported within the follow up period. It was not possible to correlate clinical features like lesion size, surgical approach, and bone marrow stimulation technique to the reported outcome.Conclusion: Surgical treatment of OCL via the AMIC procedure provided significant improvement in the functional outcome and pain scores when compared to the pre-operative values. Improvements were observed up to 5years post-operatively. [ABSTRACT FROM AUTHOR]

Medium-chain fatty acids (MCFAs) have in rodents been shown to have protective effects on glucose homeostasis during high-fat overfeeding. In this study, we investigated whether dietary MCFAs protect against insulin resistance induced by a hypercaloric high-fat diet in humans. Healthy, lean men ingested a eucaloric control diet and a 3-day hypercaloric high-fat diet (increase of 75% in energy, 81-83% energy [E%] from fat) in randomized order. For one group (n = 8), the high-fat diet was enriched with saturated long-chain FAs (LCSFA-HFD), while the other group (n = 9) ingested a matched diet, but with ∼30 g (5E%) saturated MCFAs (MCSFA-HFD) in substitution for a corresponding fraction of the saturated long-chain fatty acids (LCFAs). A hyperinsulinemic-euglycemic clamp with femoral arteriovenous balance and glucose tracer was applied after the control and hypercaloric diets. In LCSFA-HFD, whole-body insulin sensitivity and peripheral insulin-stimulated glucose disposal were reduced. These impairments were prevented in MCSFA-HFD, accompanied by increased basal fatty acid oxidation, maintained glucose metabolic flexibility, increased nonoxidative glucose disposal related to lower starting glycogen content, and increased glycogen synthase activity, together with increased muscle lactate production. In conclusion, substitution of a small amount of dietary LCFAs with MCFAs rescues insulin action in conditions of lipid-induced energy excess. [ABSTRACT FROM AUTHOR]

Women with polycystic ovary syndrome (PCOS) have been shown to be less insulin sensitive compared with control (CON) women, independent of BMI. Training is associated with molecular adaptations in skeletal muscle, improving glucose uptake and metabolism in both healthy individuals and patients with type 2 diabetes. In the current study, lean hyperandrogenic women with PCOS (n = 9) and healthy CON women (n = 9) completed 14 weeks of controlled and supervised exercise training. In CON, the training intervention increased whole-body insulin action by 26% and insulin-stimulated leg glucose uptake by 53% together with increased insulin-stimulated leg blood flow and a more oxidative muscle fiber type distribution. In PCOS, no such changes were found, despite similar training intensity and improvements in VO2max In skeletal muscle of CON but not PCOS, training increased GLUT4 and HKII mRNA and protein expressions. These data suggest that the impaired increase in whole-body insulin action in women with PCOS with training is caused by an impaired ability to upregulate key glucose-handling proteins for insulin-stimulated glucose uptake in skeletal muscle and insulin-stimulated leg blood flow. Still, other important benefits of exercise training appeared in women with PCOS, including an improvement of the hyperandrogenic state. [ABSTRACT FROM AUTHOR]

Background: Minimally invasive mitral valve surgery is standard of care in many centres and it is commonly associated with the need for cardiopulmonary bypass. Conventional external aortic clamping (exoclamping) is not always feasible, so endoaortic clamping (endoclamping) has evolved as a viable alternative. The aim of this study is to compare endoclamping (Intraclude™, Edwards Lifesciences) with exoclamping (Chitwood) during minimally invasive mitral valve procedures.Methods: This single-centre study included 822 consecutive patients undergoing minimally invasive mitral valve procedures. The endoclamp was used in 64 patients and the exoclamp in 758. Propensity-score (PS) matching was performed resulting in 63 patients per group. Outcome measures included procedural variables, length of intensive care unit (ICU) and hospital stay, major adverse cardiac and cerebrovascular events (MACCE) and repeat surgery.Results: The mean age was similar in the two group (62.2 [endoclamp] vs. 63.5 [exoclamp] years; p = 0.554), as were the cardiopulmonary bypass (145 vs. 156 min; p = 0.707) and the procedure time (203 vs. 211 min; p = 0.648). The X-clamp time was significantly shorter in the endoclamp group (88 vs. 99 min; p = 0.042). Length of ICU stay (25.0 vs. 23.0 h) and length of hospital stay (10.0 vs. 9.0 days) were slightly longer in the endoclamp group, but without statistical significance. There were nominal but no statistically significant differences between the groups in the rates of stroke, vascular complications, myocardial infarction or repeat mitral valve surgery. The conversion rate to open sternotomy approach was 2.4% without difference between groups. The estimated 7-year survival rate was similar for both groups (89.9% [endoclamp]; 84.0% [exoclamp]) with a hazard ratio of 1.291 (95% CI 0.453-3.680).Conclusions: Endoaortic clamping is an appropriate and reasonably safe alternative to the conventional Chitwood exoclamp for patients in which the exoclamp cannot be used because the ascending aorta cannot be safely mobilised. [ABSTRACT FROM AUTHOR]

Background: Depression and the experience of early adversity are associated with impairments in interpersonal and social cognitive functioning. The neural mechanisms involved in these impairments remain insufficiently understood.Methods: In a sample of 48 depressed and 50 healthy participants, we explored seed-to-voxel functional connectivity (FC) during the recall of formative relationship episodes using functional magnetic resonance imaging.Results: While depressive symptoms were associated with increased FC of brain regions that form an introspective socio-affective network, such as the precuneus, bilateral anterior insula, dorsal anterior cingulate cortex, left amygdala, and medial prefrontal cortex, early adversity linked to decreased FC of brain regions mediating emotion processing such as the bilateral anterior insula and increased FC of the bilateral parahippocampal gyrus.Limitations: We report both results that are corrected for the number of seeds tested in FC analyses using strict Bonferroni adjustments and unadjusted results as part of an exploratory analysis.Discussion: Our findings suggest that depression and early adversity are associated with differential FC patterns in the brain during the recall of formative relationship episodes. Hyperconnectivity of an introspective socio-affective network associated with depressive symptoms may link to enhanced self-focus and emotional reactivity. Patterns of neural activation associated with early adversity may underpin numbed affective states or enhanced affective memory regulation. Overall, these findings inform about the neural underpinnings of a reflective ability that is predictive of the adaptation to depression and to early adversity and relevant for psychotherapy outcomes. [ABSTRACT FROM AUTHOR]

Objectives: To explore the association between fetal umbilical and middle cerebral artery (MCA) Doppler abnormalities and outcome in late preterm pregnancies at risk of fetal growth restriction.Methods: This was a prospective cohort study of singleton pregnancies at risk of fetal growth restriction at 32 + 0 to 36 + 6 weeks of gestation, enrolled in 33 European centers between 2017 and 2018, in which umbilical and fetal MCA Doppler velocimetry was performed. Pregnancies were considered at risk of fetal growth restriction if they had estimated fetal weight and/or abdominal circumference (AC) < 10th percentile, abnormal arterial Doppler and/or a fall in AC growth velocity of more than 40 percentile points from the 20-week scan. Composite adverse outcome comprised both immediate adverse birth outcome and major neonatal morbidity. Using a range of cut-off values, the association of MCA pulsatility index and umbilicocerebral ratio (UCR) with composite adverse outcome was explored.Results: The study population comprised 856 women. There were two (0.2%) intrauterine deaths. Median gestational age at delivery was 38 (interquartile range (IQR), 37-39) weeks and birth weight was 2478 (IQR, 2140-2790) g. Compared with infants with normal outcome, those with composite adverse outcome (n = 93; 11%) were delivered at an earlier gestational age (36 vs 38 weeks) and had a lower birth weight (1900 vs 2540 g). The first Doppler observation of MCA pulsatility index < 5th percentile and UCR Z-score above gestational-age-specific thresholds (1.5 at 32-33 weeks and 1.0 at 34-36 weeks) had the highest relative risks (RR) for composite adverse outcome (RR 2.2 (95% CI, 1.5-3.2) and RR 2.0 (95% CI, 1.4-3.0), respectively). After adjustment for confounders, the association between UCR Z-score and composite adverse outcome remained significant, although gestational age at delivery and birth-weight Z-score had a stronger association.Conclusion: In this prospective multicenter study, signs of cerebral blood flow redistribution were found to be associated with adverse outcome in late preterm singleton pregnancies at risk of fetal growth restriction. Whether cerebral redistribution is a marker describing the severity of fetal growth restriction or an independent risk factor for adverse outcome remains unclear, and whether it is useful for clinical management can be answered only in a randomized trial. © 2020 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]

Introduction: Smoking is a key determinant of mortality among people living with HIV (PLWH).Methods: To better understand the effects of smoking cessation interventions in PLWH, we conducted a pooled analysis of four randomized controlled trials of hospital-initiated smoking interventions conducted through the Consortium of Hospitals Advancing Research on Tobacco (CHART). In each study, cigarette smokers were randomly assigned to usual care or a smoking cessation intervention. The primary outcome was self-reported past 30-day tobacco abstinence at 6-month follow-up. Abstinence rates were compared between PLWH and participants without HIV and by treatment arm, using both complete-case and intention-to-treat analyses. Multivariable logistic regression was used to determine the effect of HIV status on 6-month tobacco abstinence and to determine predictors of smoking cessation within PLWH.Results: Among 5550 hospitalized smokers, there were 202 (3.6%) PLWH. PLWH smoked fewer cigarettes per day and were less likely to be planning to quit than smokers without HIV. At 6 months, cessation rates did not differ between intervention and control groups among PLWH (28.9% vs. 30.5%) or smokers without HIV (36.1% vs. 34.1%). In multivariable regression analysis, HIV status was not significantly associated with smoking cessation at 6 months. Among PLWH, confidence in quitting was the only clinical factor independently associated with smoking cessation (OR 2.0, 95% CI = 1.4 to 2.8, p < .01).Conclusions: HIV status did not alter likelihood of quitting smoking after hospital discharge, whether or not the smoker was offered a tobacco cessation intervention, but power was limited to identify potentially important differences.Implications: PLWH had similar quit rates to participants without HIV following a hospital-initiated smoking cessation intervention. The findings suggest that factors specific to HIV infection may not influence response to smoking cessation interventions and that all PLWH would benefit from efforts to assist in quitting smoking.Trial Registration: (1) Using "warm handoffs" to link hospitalized smokers with tobacco treatment after discharge: study protocol of a randomized controlled trial: NCT01305928. (2) Web-based smoking cessation intervention that transitions from inpatient to outpatient: NCT01277250. (3) Effectiveness of smoking-cessation interventions for urban hospital patients: NCT01363245. (4) Effectiveness of Post-Discharge Strategies for Hospitalized Smokers (HelpingHAND2): NCT01714323. [ABSTRACT FROM AUTHOR]

A single bout of exercise enhances insulin action in the exercised muscle. However, not all human studies find that this translates into increased whole-body insulin action, suggesting that insulin action in rested muscle or other organs may be decreased by exercise. To investigate this, eight healthy men underwent a euglycemic-hyperinsulinemic clamp on 2 separate days: one day with prior one-legged knee-extensor exercise to local exhaustion (∼2.5 h) and another day without exercise. Whole-body glucose disposal was ∼18% lower on the exercise day as compared with the resting day due to decreased (∼37%) insulin-stimulated glucose uptake in the nonexercised muscle. Insulin signaling at the level of Akt2 was impaired in the nonexercised muscle on the exercise day, suggesting that decreased insulin action in nonexercised muscle may reduce GLUT4 translocation in response to insulin. Thus, the effect of a single bout of exercise on whole-body insulin action depends on the balance between local effects increasing and systemic effects decreasing insulin action. Physiologically, this mechanism may serve to direct glucose into the muscles in need of glycogen replenishment. For insulin-treated patients, this complex relationship may explain the difficulties in predicting the adequate insulin dose for maintaining glucose homeostasis following physical activity. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this paper is to communicate two new concepts with the potential to cause major morbidity in hernia repair, effective porosity and biofilm. These 2 concepts are interrelated and have the potential to result in mesh-related complications. Effective porosity is a term well described in the textile industry. It is best defined as the changes to pore morphology after implantation of mesh in situ. It is heavily dependent on mesh construct and repair technique and has the potential to impact hernia repair by reducing mesh tissue integration and promoting fibrosis. Bacterial biofilm is a well-described condition affecting prosthesis in breast and join replacement surgery with catastrophic consequences. There is a paucity of information on bacterial biofilm in mesh hernia repair. We speculate that bacterial biofilm has the potential to reduce the effective porosity of mesh, resulting in non-suppurative mesh-related complications as well as the potential for late suppurative infections. We describe the aetiology, pathogenesis, diagnosis, treatment and preventative measures to address bacterial biofilm in mesh hernia surgery. Hernia surgeons should be familiar with these two new concepts which have the potential to cause major morbidity in hernia repair and know how to address them.Methods: Ovid Medline and PubMed were searched for communications on "effective porosity" and "bacterial biofilm".Results: There is a paucity of information in the literature of these conditions and their impact on outcomes following mesh hernia repair.Conclusions: We discuss the two concepts of effective porosity and biofilm and propose potential measures to reduce mesh-related complications. This includes choosing mesh with superior mesh construct and technical nuances in implanting mesh to improve effective porosity. Furthermore, measures to reduce bacterial biofilm and its consequences are suggested. [ABSTRACT FROM AUTHOR]

Background: Resection (triangular or quadrangular) is considered the gold standard for the treatment of posterior leaflet prolapse and loop implantation a more recent alternative. We aimed to compare the long-term outcomes of triangular or quadrangular resection vs loop implantation.Methods: Single-centre, retrospective analysis of mitral valve (MV) surgeries conducted from January 2005 to December 2015. Propensity score matching was based on seven key baseline variables.Results: Data from 721 patients were analyzed; 358 patients received loop implantation and 363 patients underwent resection. Patients had a mean age of 62 years, 33.0% were female and 50.6% had hypertension. Propensity score matching resulted in a matched group of 263 patients who received loop implantation or underwent resection, respectively. Postoperatively, the patients' mitral insufficiency was reduced from grade III/IV to either zero or trace (45.8%) or I (49.8%) and New York Heart Association class reduced from 66.9% in class III/IV preoperatively to 8.3% with no significant differences between groups. Fewer patients receiving loops had procedure-related complications. Fewer patients in the loop implantation group required permanent pacemaker implantation at 30 days (8.4% vs 2.3%; P = .002). The 10-year survival for patients in the resection (88.0%) and loop implantation (89.3%) groups had a hazard ratio of 1.224 (95% confidence interval, 0.633-2.367).Conclusion: Our study showed that both loop implantation and resection were associated with comparable long-term survival in patients with posterior leaflet prolapse. Loop implantation is associated with a significantly higher rate of a successful repair, a significantly lower rate of MV replacement after repair failure, fewer procedure-related complications and better 30-day at comparable long-term outcomes. [ABSTRACT FROM AUTHOR]

Introduction: Despite several successful studies with low-cost meshes (LCM) for the treatment of inguinal hernias in India and Africa, a nationwide application has not been possible for a variety of reasons. One problem is the special preparation and sterilization of these meshes-naturally, they should comply with international standards and demands, which is often difficult to achieve in Africa. Our primary approach was to determine whether there are differences in the biocompatibility of fibroblasts between non-sterile and sterile LCMs and commercial meshes (CM).Materials and Methods: Two polyester CMs with different pore size and a polyester LCM were examined as both sterile and non-sterile. LCM was plasma sterilized at 60 °C and steam sterilized at 134 °C. Sterile and non-sterile meshes were soaked with an antibiotic (penicillin/streptomycin) and antimycotic solution (amphotericin B). Human fibroblasts from healthy subcutaneous tissue were used. Various tests for evaluating the growth behavior and cell morphology of human fibroblasts were conducted. Semiquantitative (light microscopy) and qualitative (scanning electron microscopy) analyses were performed after 1 week and again after 12 weeks. The metabolism of fibroblasts was checked by pH measurements and glucose analyses. Biocompatibility of fibroblasts on sterile and non-sterile meshes was carried out by luminescence methods (cell viability and apoptosis) as well as calorimetric methods for proliferation determination (BrDU assay) and cytotoxicity (LDH assay).Results: Light and electron microscopy revealed a moderate growth of fibroblasts on all investigated mesh types. The results of glycolysis and the pH value were within the normal range for all sterile and non-sterile meshes. In biocompatibility studies, no elevated level of apoptosis was detected. The viability measurement of mitochondrial activity of fibroblasts showed a 50% inhibition of mitochondria in all nets, with the exception of non-sterile CM, whereas mitochondrial activity was increased in the non-sterile CM. A proliferation measurement (BrdU test) revealed different growth inhibition in the sterile and non-sterile meshes. This growth inhibition was significantly stronger, particularly for non-sterile CM light meshes, than it was for the non-sterile LCM.Conclusion: Again, our studies show no significant differences in biocompatibility of fibroblasts between expensive and low-cost meshes. In addition, we detected fibroblast growth even in sterile meshes, independent of the mesh group. To our knowledge, the present study is the first of its kind in terms of qualitative equivalence of sterile and non-sterile in vitro mesh samples. We do not wish to create future patient studies with non-sterilized meshes saturated with antibiotics/antimycotics. However, perhaps we can prove in future studies that under semi-sterile conditions with certain LCMs, wound infection rates can be acceptable. [ABSTRACT FROM AUTHOR]

Background: Cessation counseling and pharmacotherapy are recommended for hospitalized smokers, but better coordination between cessation counselors and providers might improve utilization of pharmacotherapy and enhance smoking cessation.Objective: To compare smoking cessation counseling combined with care coordination post-hospitalization to counseling alone on uptake of pharmacotherapy and smoking cessation.Design: Unblinded, randomized clinical trial PARTICIPANTS: Hospitalized smokers referred from primarily rural hospitals INTERVENTIONS: Counseling only (C) consisted of telephone counseling provided during the hospitalization and post-discharge. Counseling with care coordination (CCC) provided similar counseling supplemented by feedback to the smoker's health care team and help for the smoker in obtaining pharmacotherapy. At 6 months post-hospitalization, persistent smokers were re-engaged with either CCC or C.Main Measures: Utilization of pharmacotherapy and smoking cessation at 3, 6, and 12 months post-discharge.Key Results: Among 606 smokers randomized, 429 (70.8%) completed the 12-month assessment and 580 (95.7%) were included in the primary analysis. Use of any cessation pharmacotherapy between 0 and 6 months (55.2%) and between 6 and 12 months (47.1%) post-discharge was similar across treatment arms though use of prescription-only pharmacotherapy between months 6-12 was significantly higher in the CCC group (30.1%) compared with the C group (18.6%) (RR, 1.61 (95% CI, 1.08, 2.41)). Self-reported abstinence rates of 26.2%, 20.3%, and 23.4% at months 3, 6, and 12, respectively, were comparable across the two treatment arms. Of those smoking at month 6, 12.5% reported abstinence at month 12. Validated smoking cessation at 12 months was 19.3% versus 16.9% in the CCC and C groups, respectively (RR, 1.13 (95% CI, 0.80, 1.61)).Conclusion: Supplemental care coordination, provided by counselors outside of the health care team, failed to improve smoking cessation beyond that achieved by cessation counseling alone. Re-engagement of smokers 6 months post-discharge can lead to new quitters, at which time care coordination might facilitate use of prescription medications.Trial Registration: NCT01063972. [ABSTRACT FROM AUTHOR]

Although the CNS is immune privileged, continuous search for pathogens and tumours by immune cells within the CNS is indispensable. Thus, distinct immune-cell populations also cross the blood-brain barrier independently of inflammation/under homeostatic conditions. It was previously shown that effector memory T cells populate healthy CNS parenchyma in humans and, independently, that CCR5-expressing lymphocytes as well as CCR5 ligands are enriched in the CNS of patients with multiple sclerosis. Apart from the recently described CD8+ CNS tissue-resident memory T cells, we identified a population of CD4+CCR5high effector memory cells as brain parenchyma-surveilling cells. These cells used their high levels of VLA-4 to arrest on scattered VCAM1, their open-conformation LFA-1 to crawl preferentially against the flow in search for sites permissive for extravasation, and their stored granzyme K (GZMK) to induce local ICAM1 aggregation and perform trans-, rather than paracellular diapedesis through unstimulated primary brain microvascular endothelial cells. This study included peripheral blood mononuclear cell samples from 175 healthy donors, 29 patients infected with HIV, with neurological symptoms in terms of cognitive impairment, 73 patients with relapsing-remitting multiple sclerosis in remission, either 1-4 weeks before (n = 29), or 18-60 months after the initiation of natalizumab therapy (n = 44), as well as white matter brain tissue of three patients suffering from epilepsy. We here provide ex vivo evidence that CCR5highGZMK+CD4+ effector memory T cells are involved in CNS immune surveillance during homeostasis, but could also play a role in CNS pathology. Among CD4+ T cells, this subset was found to dominate the CNS of patients without neurological inflammation ex vivo. The reduction in peripheral blood of HIV-positive patients with neurological symptoms correlated to their CD4 count as a measure of disease progression. Their peripheral enrichment in multiple sclerosis patients and specific peripheral entrapment through the CNS infiltration inhibiting drug natalizumab additionally suggests a contribution to CNS autoimmune pathology. Our transcriptome analysis revealed a migratory phenotype sharing many features with tissue-resident memory and Th17.1 cells, most notably the transcription factor eomesodermin. Knowledge on this cell subset should enable future studies to find ways to strengthen the host defence against CNS-resident pathogens and brain tumours or to prevent CNS autoimmunity. [ABSTRACT FROM AUTHOR]

Background: Lithium augmentation (LA) of antidepressants is an effective strategy for treatment-resistant depression (TRD). Nevertheless, it is rarely used in geriatric patients. The purpose of this study was to investigate treatment response of LA in geriatric compared to non-geriatric patients.Method: In a prospective multicenter cohort study, severity of depression was measured weekly in 167 patients with unipolar depression (nage≥65years = 22; nage<65years = 145) at baseline and over at least four weeks of LA.Results: Geriatric patients showed a significantly better response to LA compared to non-geriatric patients (Hazard Ratio = 1.91; p = 0.04).Limitations: An important limitation of our study is the lack of a control group of LA and the missing evaluation of side effects in both groups.Conclusions: This is the first study investigating the efficacy of LA for TRD in geriatric compared to non-geriatric patients. Our data suggest that LA is an effective treatment option in geriatric patients that clinicians might consider more frequently and earlier on in the course of treatment. [ABSTRACT FROM AUTHOR]

Charcot-Marie-Tooth disease type 4C is the most common recessively inherited demyelinating neuropathy that results from loss of function mutations in the SH3TC2 gene. Sh3tc2-/- mice represent a well characterized disease model developing early onset progressive peripheral neuropathy with hypo- and demyelination, slowing of nerve conduction velocities and disturbed nodal architecture. The aim of this project was to develop a gene replacement therapy for treating Charcot-Marie-Tooth disease type 4C to rescue the phenotype of the Sh3tc2-/- mouse model. We generated a lentiviral vector LV-Mpz.SH3TC2.myc to drive expression of the human SH3TC2 cDNA under the control of the Mpz promoter specifically in myelinating Schwann cells. The vector was delivered into 3-week-old Sh3tc2-/- mice by lumbar intrathecal injection and gene expression was assessed 4-8 weeks after injection. Immunofluorescence analysis showed presence of myc-tagged human SH3TC2 in sciatic nerves and lumbar roots in the perinuclear cytoplasm of a subset of Schwann cells, in a dotted pattern co-localizing with physiologically interacting protein Rab11. Quantitative PCR analysis confirmed SH3TC2 mRNA expression in different peripheral nervous system tissues. A treatment trial was initiated in 3 weeks old randomized Sh3tc2-/- littermate mice which received either the full or mock (LV-Mpz.Egfp) vector. Behavioural analysis 8 weeks after injection showed improved motor performance in rotarod and foot grip tests in treated Sh3tc2-/- mice compared to mock vector-treated animals. Moreover, motor nerve conduction velocities were increased in treated Sh3tc2-/- mice. On a structural level, morphological analysis revealed significant improvement in g-ratios, myelin thickness, and ratios of demyelinated fibres in lumbar roots and sciatic nerves of treated Sh3tc2-/- mice. Finally, treated mice also showed improved nodal molecular architecture and reduction of blood neurofilament light levels, a clinically relevant biomarker for axonal injury/degeneration. This study provides a proof of principle for viral gene replacement therapy targeted to Schwann cells to treat Charcot-Marie-Tooth disease type 4C and potentially other similar demyelinating inherited neuropathies. [ABSTRACT FROM AUTHOR]

Objectives: The features of a newly established, web-based surveillance system for hospital antibiotic consumption are described and data on broad-spectrum antibiotic use in German acute care hospitals are presented.Methods: The watch- and reserve-group antibiotics, two categories of antibiotics derived from the WHO Essential Medicines List comprising key agents for antimicrobial stewardship, were used as a framework for data analysis. The median antibiotic consumption densities (ACDs; DDD/100 patient days) for the years 2015/16 based on data from 137 acute care hospitals have been calculated for whole facilities, ICUs and medical and surgical departments, stratified by type of care.Results: The new web-based system provides real-time surveillance at unit and facility levels, accessible to all relevant stakeholders. User-defined reports are available via an interactive database, various report types support different approaches to analysis, and different complementing quantification measures of antimicrobial consumption are available. Watch- and reserve-group antibiotics accounted for 42% and 2% of total antibiotic use, respectively. Surgical services presented with considerably lower median ACDs of the watch-group antibiotics compared with medical services. Tertiary care hospitals exhibited higher ACDs of the reserve-group antibiotics and carbapenems than primary/secondary care hospitals, while the ACDs of the watch-group antibiotics as a whole did not differ significantly. Comparing the proportional use with other European countries revealed a relatively high use of the watch-group, ranking beyond the 75th percentile.Conclusions: Because of its particular features the new web-based surveillance system is a valuable tool for antimicrobial stewardship. The WHO categories of watch- and reserve-group antibiotics proved to be a useful framework for the analysis of hospital antibiotic consumption data. [ABSTRACT FROM AUTHOR]

Purpose: Single-source dual-spiral dual-energy computed tomography (DECT) provides additional patient information but is prone to motion between the 2 consecutively acquired computed tomography (CT) scans. Here, the clinical applicability of dual-spiral time-resolved DECT (4D-DECT) for proton treatment planning within the thoracic region was evaluated.Methods and Materials: Dual-spiral 4D-DECT scans of 3 patients with lung cancer were acquired. For time-averaged datasets and 4 breathing phases, the geometric conformity of 80 kVp and 140 kVp 4D-DECT scans before image post-processing was assessed by normalized cross correlation (NCC). Additionally, the conformity of the corresponding DECT-derived 58 keV and 79 keV pseudo-monoenergetic CT datasets after image post-processing, including deformable image registration (DIR), was determined. To analyze the reliability of proton dose calculation, clinical (PlanClin) and artificial worst-case (PlanWorstCase, targeting the diaphragm) treatment plans were calculated on 140 kVp and 79 keV datasets and compared with gamma analyses (0.1% dose-difference and 1 mm distance-to-agreement criterion). The applicability of a patient-specific DECT-based prediction of stopping-power ratio (SPR) was investigated and proton range shifts compared with the clinical heuristic CT-number-to-SPR conversion were assessed. Finally, the delineation variability of an experienced radiation oncologist was quantified.Results: Dual-spiral 4D-DECT scans without DIR showed a high geometric conformity, with an average NCC ± standard deviation of 98.7% ± 1.0% when including all patient voxels or 88.2% ± 7.8% when considering only lung. DIR improved the conformity, leading to an average NCC of 99.9% ± 0.1% and 99.6% ± 0.5%, respectively. PlanClin dose distributions on 140 kVp and 79 keV datasets were similar, with an average gamma passing rate of 99.9% (99.2%-100%). The worst-case evaluation still revealed high passing rates (99.3% on average, 92.4% as minimum). Clinically relevant mean range shifts of 2.2% ± 1.2% were determined between patient-specific DECT-based SPR prediction and clinical heuristic CT-number-to-SPR conversion. The intra-observer delineation variability was slightly reduced using additional DECT-derived datasets.Conclusions: The 79 keV pseudo-monoenergetic CT datasets can be consistently obtained from dual-spiral 4D-DECT and are applicable for dose calculation. Patient-specific DECT-based SPR prediction performed well and potentially reduces range uncertainty in proton therapy of patients with lung cancer. [ABSTRACT FROM AUTHOR]