Palbociclib as single agent or in combination with the endocrine therapy received before disease progression for estrogen receptor-positive, HER2-negative metastatic breast cancer: TREnd trial.

Background: The activity of palbociclib as a single agent in advanced breast cancer has not been extensively studied, with the only available clinical data limited to heavily pretreated patients. Preclinical data suggests palbociclib may partially reverse endocrine resistance, though this hypothesis has not been evaluated in previous clinical studies. This phase II, open-label, multicenter study examined the activity of palbociclib monotherapy, as well as palbociclib given in combination with the same endocrine therapy (ET) that was received prior to disease progression, in postmenopausal women with moderately pretreated, estrogen receptor-positive, HER2 negative advanced breast cancer. Patients and methods: Eligible women with advanced disease which had progressed on one or two prior ETs were randomized 1 : 1 to receive either palbociclib alone, or palbociclib in combination with the ET as previously received. Primary end point was clinical benefit rate (CBR); secondary end points included progression-free survival (PFS). Results: Between October 2012 and July 2016, a total of 115 patients were randomized. The CBR was 54% [95% confidence interval (CI): 41.5-63.7] for combination therapy, and 60% (95% CI: 47.8-72.9) for monotherapy. Median PFS was 10.8 months (95% CI: 5.6-12.7) for combination therapy, and 6.5 months (95% CI: 5.4-8.5) for monotherapy [hazard ratio (HR) 0.69; 95% CI: 0.4-1.1, exploratory P-value = 0.12]. Exploratory analyses revealed the PFS advantage for combination therapy was seen in the subgroup of patients who received prior ET for >6 months (HR 0.53; 95% CI: 0.3-0.9, exploratory P-value = 0.02), but not in those who received prior ET for ≤6 months. Conclusion: Palbociclib has clinical activity as a single agent in women with moderately pretreated, oestrogen receptor-positive, HER2-negative advanced breast cancer. Palbociclib may have potential to reverse endocrine resistance in patients with a history of previous durable response to ET. Clinical trial information: NCT02549430.

Survival after pathogen exposure in group-living insects: don't forget the stress of social isolation!

A major cost of group-living is its inherent risk of pathogen infection. To limit this risk, many group-living animals have developed the capability to prophylactically boost their immune system in the presence of group members and/or to mount collective defences against pathogens. These two phenomena, called density-dependent prophylaxis and social immunity, respectively, are often used to explain why, in group-living species, individuals survive better in groups than in isolation. However, this survival difference may also reflect an alternative and often overlooked process: a cost of social isolation on individuals' capability to fight against infections. Here, we disentangled the effects of density-dependent prophylaxis, social immunity and stress of social isolation on the survival after pathogen exposure in group-living adults of the European earwig Forficula auricularia. By manipulating the presence of group members both before and after pathogen exposure, we demonstrated that the cost of being isolated after infection, but not the benefits of social immunity or density-dependent prophylaxis, explained the survival of females. Specifically, females kept constantly in groups or constantly isolated had higher survival rates than females that were first in groups and then isolated after infection. Our results also showed that this cost of social isolation was absent in males and that social isolation did not reduce the survival of noninfected individuals. Overall, this study gives a new perspective on the role of pathogens in social evolution, as it suggests that an apparently nonadaptive, personal immune process may promote the maintenance of group-living under pathogenic environments.

A machine learning approach to identify risk factors for running-related injuries: study protocol for a prospective longitudinal cohort trial.

BACKGROUND: Running is a very popular sport among both recreational and competitive athletes. However, participating in running is associated with a comparably high risk of sustaining an exercise-related injury. Due to the often multifactorial and individual reasons for running injuries, a shift in thinking is required to account for the dynamic process of the various risk factors. Therefore, a machine learning approach will be used to comprehensively analyze biomechanical, biological, and loading parameters in order to identify risk factors and to detect risk patterns in runners. METHODS: The prospective longitudinal cohort study will include competitive adult athletes, running at least 20 km per week and being free of injuries three months before the start of the study. At baseline and the end of the study period, subjective questionnaires (demographics, injury history, sports participation, menstruation, medication, psychology), biomechanical measures (e.g., stride length, cadence, kinematics, kinetics, tibial shock, and tibial acceleration) and a medical examination (BMI, laboratory: blood count, creatinine, calcium, phosphate, parathyroid hormone, vitamin D, osteocalcin, bone-specific alkaline phosphatase, DPD cross-links) will be performed. During the study period (one season), continuous data collection will be performed for biomechanical parameters, injuries, internal and external load. Statistical analysis of the data is performed using machine learning (ML) methods. For this purpose, the correlation of the collected data to possible injuries is automatically learned by an ML model and from this, a ranking of the risk factors can be determined with the help of sensitivity analysis methods. DISCUSSION: To achieve a comprehensive risk reduction of injuries in runners, a multifactorial and individual approach and analysis is necessary. Recently, the use of ML processes for the analysis of risk factors in sports was discussed and positive results have been published. This study will be the first prospective longitudinal cohort study in runners to investigate the association of biomechanical, bone health, and loading parameters as well as injuries via ML models. The results may help to predict the risk of sustaining an injury and give way for new analysis methods that may also be transferred to other sports. TRIAL REGISTRATION: DRKS00026904 (German Clinical Trial Register DKRS), date of registration 18.10.2021.

The effect of α-linolenic acid enrichment in perinatal diets in preventing high fat diet-induced SCD1 increased activity and lipid disarray in adult offspring of low density lipoprotein receptor knockout (LDLRKO) mice.

The present study examined the effects of maternal perinatal dietary ALA enrichment on the high fat diet (HFD)-induced lipid disarray in the adult offspring of low density lipoprotein receptor knock-out (LDLRKO) mice. Female LDLRKO mice received, during pregnancy and lactation, isocaloric diets with either corn oil, RD, or flax oil, ALA. The weaning offspring was given a regular chow diet for a washout period of eight weeks, which was followed by HFD for eight weeks. Plasma and liver lipids and SCD1 activity were then analyzed. The HFD-fed RD adult offspring had substantially higher plasma cholesterol levels than the HFD-fed ALA offspring (15.7 versus 9.7 mmole/l, p<0.00001) and non-alcoholic fatty liver disease (NAFLD) (65.0 versus 23.9 mg/g lipids, p<0.00001). Liver lipids oleic acid (OA) content and monounsaturated to saturated fatty acids (MUFA/SAT) ratio, were two times lower in RD compared to ALA (p<0.0001). The threefold HFD-induced SCD1 raised activity (p<0.00001), and OA produced from SA, observed in RD adult offspring were prevented by perinatal ALA. In conclusion, the resilience of SCD1 to HFD- induced increased activity may account for the beneficial effects of perinatal ALA dietary enrichment in preventing NAFLD and hypercholesterolemia from occurring in adult LDLRKO offspring mice.

An open randomized pilot trial on the differential effects of aripiprazole versus risperidone on anhedonia and subjective well-being.

INTRODUCTION: Negative symptoms of schizophrenia often predict an unfavorable clinical outcome. Disturbed dopamine transmission in different brain parts may underlie different aspects of negative symptoms, and the effect of antipsychotics on them may also differ. This pilot study investigated the potentially therapeutic effects of the partial dopamine agonist aripiprazole on different negative symptoms. METHODS: This pilot study randomly assigned patients with schizophrenia (N=40) to either aripiprazole or risperidone. After 6 weeks of treatment, the severity of negative symptoms was determined by the PANSS. Subscales of self-report questionnaires were used to assess differences in initiative, anhedonia, social functioning and subjective well-being. RESULTS: Patients treated with aripiprazole showed a significant improvement on measures for anhedonia and subjective wellbeing. Negative symptoms in general, lack of initiative and social inhibition were also lower in the aripiprazole treated group, but without reaching statistical significance. DISCUSSION: According to this pilot study, aripiprazole appears to specifically improve anhedonia and subjective wellbeing compared to risperidone. This may be caused by a specific effect of aripiprazole on the limbic branch of the dopamine system. Future studies should replicate this finding with a larger sample size.

Improving Running Economy by Transitioning to Minimalist Footwear: A Randomised Controlled Trial.

OBJECTIVES: Ongoing debates about benefits and risks of barefoot- and minimally-shod running have, to date, revealed no conclusive findings for long-term effects on physical performance. The purpose of this study was to examine the effects of an 8-week transition to minimalist footwear (MFW) on running economy (RE). DESIGN: Randomised controlled trial. METHODS: Thirty-two male, habitually-shod runners were assigned randomly to an 8-week training intervention either in minimalist (=intervention group) or conventional running shoes (=control group). The intervention consisted of a gradual increase in use of the new footwear by 5% of the individual weekly distance. Before and after the intervention, a VO2max test was followed by a submaximal RE test at 70% and 80% of vVO2max in both shoe conditions 7days later. RE was measured at the submaximal tests and expressed as caloric unit cost (kcalkg-1km-1) and oxygen consumption (mlkg-1km-1). RESULTS: RE improved in the intervention group over time compared to the control group with small to moderate effect sizes (ES) in both shoe conditions: Effects on RE (kcalkg-1km-1) in conventional running shoes: ES vVO270%: 0.68 (95% CI: -0.14 to 1.51), ES vVO280%: 0.78 (95% CI: 0-1.56). In minimalist footwear: ES vVO270%: 0.3 (95% CI: -0.54 to 1.14), ES vVO280%: 0.42 (95% CI: -0.41 to 1.25). These effects were not statistically significant (p>0.05). The repeated-measures ANOVA also showed no group by time interactions for all submaximal RE testing conditions (p>0.05). CONCLUSIONS: Although not reaching statistical significance, training in MFW compared to CRS resulted in small to moderate improvements in RE.

The radiological assessment of pelvic obliquity in cerebral palsy and the impact on hip development.

Pelvic obliquity is a common finding in adolescents with cerebral palsy, however, there is little agreement on its measurement or relationship with hip development at different gross motor function classification system (GMFCS) levels. The purpose of this investigation was to study these issues in a large, population-based cohort of adolescents with cerebral palsy at transition into adult services. The cohort were a subset of a three year birth cohort (n = 98, 65M: 33F, with a mean age of 18.8 years (14.8 to 23.63) at their last radiological review) with the common features of a migration percentage greater than 30% and a history of adductor release surgery. Different radiological methods of measuring pelvic obliquity were investigated in 40 patients and the angle between the acetabular tear drops (ITDL) and the horizontal reference frame of the radiograph was found to be reliable, with good face validity. This was selected for further study in all 98 patients. The median pelvic obliquity was 4° (interquartile range 2° to 8°). There was a strong correlation between hip morphology and the presence of pelvic obliquity (effect of ITDL on Sharpe's angle in the higher hip; rho 7.20 (5% confidence interval 5.59 to 8.81, p < 0.001). This was particularly true in non-ambulant adolescents (GMFCS IV and V) with severe pelvic obliquity, but was also easily detectable and clinically relevant in ambulant adolescents with mild pelvic obliquity. The identification of pelvic obliquity and its management deserves closer scrutiny in children and adolescents with cerebral palsy.

[Materials surveillance, a surveillance performed on the use of medical devices]. / La matériovigilance, une vigilance exercée sur l'utilisation des dispositifs médicaux.

One of the missions of the Agence Française due Sang was to set up a haemovigilance system based on a national network of surveillance and alert, for the whole blood chain from blood collection to receivers' follow-up. This system is now operational and contributes with efficacy to the safety of blood transfusions (see: A quoi sert l'hémovigilance? Transfus Clin Biol 1998; 5: 415-21.). The French law No. 98-535 dated July 1st 1998, whose enforcement orders were published in March 1999, is the legal foundation of the system. In this article the national and regional structures of the national system of sanitary safety are described, and the main guidelines of material vigilance, the last element of this system, is presented.

Dietary enrichment with alpha-linolenic acid during pregnancy attenuates insulin resistance in adult offspring in mice.

OBJECTIVE: Our objective was to test the contribution of dietary enrichment in essential or saturated fatty acids, in normocaloric diets, on the lipid accumulation and insulin resistance in the adult offspring in a C57Bl6/J mice model. METHODS: Pregnant mothers were fed normocaloric diets containing 6% fat enriched in essential fatty acids (EFA): alpha-linolenic (ALA-18:3, n-3), linoleic (LA-18:2, n-6), or saturated fatty acids (SFA). After a washing-out period with regular diet, the offspring received a high-fat diet before euthanization. RESULTS: Adult mice fed maternal ALA showed lower body weight gain and lower liver fat accumulation, lower HOMA index and lower stearoyl-CoA desaturase (SCD1) activity than those fed maternal SFA. CONCLUSION: The results observed using this novel model suggest that ALA in maternal diet may have the potential to inhibit insulin resistance in adult offspring.

[Clinical-radiological studies on 3 siblings with double-formations of their milk front teeth]. / Klinisch-rötgenologische Untersuchung von drei Geschwistern mit Doppelbildungen von Milchfrontzhnen.

Double anomalies of the lower lateral anterior deciduous teeth of three siblings were studied clinically and radiographically. In one case, the double anomalies were demonstrable in the permanent tooth germs. Various differentiation stages of schizodontia were observed. Apparently, the anomalies were genetically determined in the three cases. Effects on the change of teeth as well as anomalies in the shape and number of the permanent teeth were reported.

[Clinical field study on the frequency and topographical distribution of lichen ruber including the question of etiological influence factors]. / Klinische Feldstudie zur Häufigkeit und topographischen Verteilung des Lichen ruber einschliesslich der Frage ätiologischer Einflussfaktoren.

A total of 374 Patients with lichen ruber of skin and/or mucous membranes, treated at our Department during a period of 7 years, have been studied retrospectively. The prevalence rate, the distribution pattern as well as the dependence on localisation of different types of clinical lesions have been examined. In 54% of the cases studied, the oral mucosa was involved, in about half of these cases without any other manifestation. In 92 hospitalised patients, a statistically significant correlation between lichen ruber and chronic hepatic disorders was revealed. On the other hand, chronic alcoholism and/or smoking habits did not show any close correlation with lichen ruber.