Education as Risk Factor of Mild Cognitive Impairment: The Link to the Gut Microbiome.

BACKGROUND: With differences apparent in the gut microbiome in mild cognitive impairment (MCI) and dementia, and risk factors of dementia linked to alterations of the gut microbiome, the question remains if gut microbiome characteristics may mediate associations of education with MCI. OBJECTIVES: We sought to examine potential mediation of the association of education and MCI by gut microbiome diversity or composition. DESIGN: Cross-sectional study. SETTING: Luxembourg, the Greater Region (surrounding areas in Belgium, France, Germany). PARTICIPANTS: Control participants of the Luxembourg Parkinson's Study. MEASUREMENTS: Gut microbiome composition, ascertained with 16S rRNA gene amplicon sequencing. Differential abundance, assessed across education groups (0-10, 11-16, 16+ years of education). Alpha diversity (Chao1, Shannon and inverse Simpson indices). Mediation analysis with effect decomposition was conducted with education as exposure, MCI as outcome and gut microbiome metrics as mediators. RESULTS: After exclusion of participants below 50, or with missing data, n=258 participants (n=58 MCI) were included (M [SD] Age=64.6 [8.3] years). Higher education (16+ years) was associated with MCI (Odds ratio natural direct effect=0.35 [95% CI 0.15-0.81]. Streptococcus and Lachnospiraceae-UCG-001 genera were more abundant in higher education. CONCLUSIONS: Education is associated with gut microbiome composition and MCI risk without clear evidence for mediation. However, our results suggest signatures of the gut microbiome that have been identified previously in AD and MCI to be reflected in lower education and suggest education as important covariate in microbiome studies.

Long-term outcomes of a randomized, open-label, phase II study comparing cabazitaxel versus paclitaxel as neoadjuvant treatment in patients with triple-negative or luminal B/HER2-negative breast cancer (GENEVIEVE).

BACKGROUND: The GENEVIEVE study, comparing neoadjuvant cabazitaxel versus paclitaxel in triple-negative breast cancer (TNBC) and luminal B/human epidermal growth factor receptor 2 (HER2)-negative breast cancer (BC), previously reported significant differences in pathological complete response (pCR) rates. Effects on long-term outcome are unknown. PATIENTS AND METHODS: GENEVIEVE randomized patients with cT2-3, any cN or cT1, cN+/pNSLN+, centrally confirmed TNBC or luminal B/HER2-negative BC (latter defined as estrogen/progesterone receptor-positive and >14% Ki-67-stained cells) to receive either cabazitaxel 25 mg/m2 q3w for four cycles or paclitaxel 80 mg/m2 weekly for 12 weeks. Anthracycline-containing chemotherapy was allowed in case of histologically proven invasive residuals as neoadjuvant treatment or after surgery as adjuvant treatment. Here we report the secondary endpoints invasive disease-free survival (iDFS), distant disease-free survival (DDFS), and overall survival (OS). RESULTS: Of the 333 patients randomized, 74.7% and 83.2% completed treatment in the cabazitaxel and paclitaxel arms, respectively. After a median follow-up of 89.3 months (interquartile range 68.8-97.3 months), 80 iDFS events (43 after cabazitaxel and 37 after paclitaxel) and 47 deaths (23 after cabazitaxel and 24 after paclitaxel) were reported. IDFS rates were not significantly different between the cabazitaxel and paclitaxel arms after a 3-year (83.6% versus 85.0%) and 5-year follow-up (76.2% versus 78.3%) [hazard ratio (HR) = 1.27, 95% confidence interval 0.82-1.96, P = 0.294], respectively. DDFS rates at 3 years (88.6% versus 87.8%) and 5 years (82.1% versus 82.8%) for cabazitaxel and paclitaxel were comparable (HR = 1.15, P = 0.573). Similarly, OS rates at 3 years (91.6% versus 91.8%) and 5 years (89.2% versus 86.8%) showed no significant differences (HR = 1.05, P = 0.872). Subgroup analysis for TNBC and luminal B/HER2-negative BCs indicated no significant variations in 3- or 5-year iDFS, DDFS, or OS. CONCLUSIONS: The significant differences in pCR rates observed in both treatment arms did not significantly impact long-term outcomes for patients treated with cabazitaxel versus paclitaxel in the GENEVIEVE trial.

Alterations of oral microbiota and impact on the gut microbiome in type 1 diabetes mellitus revealed by integrated multi-omic analyses.

BACKGROUND: Alterations to the gut microbiome have been linked to multiple chronic diseases. However, the drivers of such changes remain largely unknown. The oral cavity acts as a major route of exposure to exogenous factors including pathogens, and processes therein may affect the communities in the subsequent compartments of the gastrointestinal tract. Here, we perform strain-resolved, integrated meta-genomic, transcriptomic, and proteomic analyses of paired saliva and stool samples collected from 35 individuals from eight families with multiple cases of type 1 diabetes mellitus (T1DM). RESULTS: We identified distinct oral microbiota mostly reflecting competition between streptococcal species. More specifically, we found a decreased abundance of the commensal Streptococcus salivarius in the oral cavity of T1DM individuals, which is linked to its apparent competition with the pathobiont Streptococcus mutans. The decrease in S. salivarius in the oral cavity was also associated with its decrease in the gut as well as higher abundances in facultative anaerobes including Enterobacteria. In addition, we found evidence of gut inflammation in T1DM as reflected in the expression profiles of the Enterobacteria as well as in the human gut proteome. Finally, we were able to follow transmitted strain-variants from the oral cavity to the gut at the individual omic levels, highlighting not only the transfer, but also the activity of the transmitted taxa along the gastrointestinal tract. CONCLUSIONS: Alterations of the oral microbiome in the context of T1DM impact the microbial communities in the lower gut, in particular through the reduction of "mouth-to-gut" transfer of Streptococcus salivarius. Our results indicate that the observed oral-cavity-driven gut microbiome changes may contribute towards the inflammatory processes involved in T1DM. Through the integration of multi-omic analyses, we resolve strain-variant "mouth-to-gut" transfer in a disease context. Video Abstract.

Isolated amyloidosis of the gastro-intestinal tract.

Amyloidosis is a very rare condition, which, due to its rarity, is often missed or diagnosed in an advanced stage of the disease, causing significant morbidity and mortality. In this review we describe the existing types of amyloidosis focusing on the gastro-intestinal tract. Amyloidosis occurs when abnormal protein fibrils (amyloid) deposit in the muscularis mucosae. This can cause an array of symptoms ranging from (in order of occurrence): gastro-intestinal bleeding, heartburn, unintentional weight loss, early satiety, constipation, diarrhea, nausea, vomiting and fecal incontinence (1). Treatment is focused on the underlying condition (if any) causing the production and deposition of the abnormal fibrils, in combination of symptomatic treatment.

Triple tibial osteotomy for the correction of severe bilateral varus deformity in a patient with late-onset Blount's disease.

A 14-year-old girl suffering from severe bilateral late-onset Blount's disease was treated by triple proximal tibial osteotomy. Surgical procedures included dome, respectively, closing wedge valgus osteotomy of the tibia, elevating osteotomy of the medial tibial plateau and lateralising osteotomy of the anterior tibial tuberosity. Mechanical leg axis was restored close to normal, the depression of the medial tibial plateau corrected and the extensor apparatus of the knee realigned. At 7.5 (right side) and 5.5 (left side) months of follow-up, all osteotomies had radiologically consolidated and the patient did not complain of knee pain or instability. Level of evidence IV.

A clinical, radiological and computational analysis of the thrust plate prosthesis in young patients.

BACKGROUND AND PURPOSE: A thrust plate prosthesis can be used as an alternative to a conventional stem prosthesis, preserving the diaphyseal bone stock. Recent findings however predict a higher rate of aseptic loosening than with intramedullary devices. The purpose of our investigation was to compare the clinical outcome and radiological findings with a finite element analysis of bone remodeling. The hypothesis was that aseptic loosening after thrust plate prosthesis of the hip is inherent to the design. METHODS: From 1997 to 2001, 58 thrust plates were implanted in 52 patients. Average age at the time of surgery was 40.9 years. Ninety four percent returned for follow up at an average of 26 months. A finite element model of the thrust plate within the femur was developed and stress shielding as well as bone remodeling were analyzed. RESULTS: A total of 4 patients required revision surgery (6.9%). Data from the finite element analysis revealed an inherent failure mechanism to the implant, facilitating stress shielding and loosening. INTERPRETATION: Lacking the ideal total hip prosthesis in young patients, the thrust plate can still be regarded as a feasible implant. However, surgeons and patients should be aware of possible mechanical problems regarding the design of the thrust plate. There is evidence that thrust plate prostheses are prone to early aseptic loosening. Clinical and radiological observations are in agreement with the results from the numerical simulations. Stress concentrations computed at the leash are interpreted as an explanation for leash pain. The authors regard computational methods as an aid to improve existing prosthesis design and future developments.

A non-invasive device to objectively measure tibial rotation: verification of the device.

The purpose of this study was the correlation of the results of a new measurement device for tibial rotation (Rotameter) in comparison with the measurements of a knee navigation system as standard method. In a biomechanical laboratory study, all soft tissues were removed from 20 human cadaveric knees leaving only the intact capsule and the bone. Specific tracers were bicortically fixed in the bone in order to measure tibial rotation using a knee navigation system. The knees were fixed to a custom-made inside-boot to rule out undesirable rotation of the reconstruction inside the Rotameter measurement device. Internal and external rotation values were measured at an applied torque of 5, 10 and 15 Nm. The different methods to evaluate tibial rotation were compared using the Pearson correlation coefficient. The correlations were deemed to be reliable if a value of >or=0.80 was achieved. At 5 Nm of applied torque, high correlations for the internal rotation, external rotation and the entire rotational range were found in the Pearson correlation coefficient between the Rotameter testing device in comparison with the knee navigation system as invasive reference method. These results were also confirmed at an applied torque of 10 and 15 Nm. In conclusion, the Rotameter testing device showed high correlations compared with the knee navigation system as an invasive standard method. It might be used as a non-invasive and easy alternative to investigate tibial rotation.

Reliability testing of a new device to measure tibial rotation.

The purpose of this study was to evaluate the reliability of a new developed device to measure tibial rotation, the Rotameter. Thirty healthy subjects (15 males, 15 females, 24 years) were examined with the Rotameter measurement device. External and internal rotation was performed at an applied torque of 5, 10 and 15 Nm by two independent examiners in order to test the inter-observer reliability. The patients were measured again after a mean of 31 +/- 43 days by the same examiners to test the intra-observer reliability. Statistical analysis was performed using the intra-class correlation coefficient. The Pearson Correlation coefficient was used to compare the measurements of the left with the right side of the participants. In the measurements, a high inter- and intra-observer reliability was found at 5, 10 and 15 Nm of applied torque for the external rotation, internal rotation and the rotational range (internal + external rotation). Comparison of the left and the right knee of the same participant also revealed high correlations in the Pearson correlation coefficient at all applied torques. In conclusion, the Rotameter testing device for the measurement of tibial rotation showed a high inter-observer and intra-observer reliability. It is easy to perform and might be used in a wide field as a non-invasive instrument to objectively determine rotational stability and to investigate the restoration of the rotational stability after surgical procedures.

[Complications with all-inside devices used in reconstructive meniscal surgery]. / Komplikationen mit arthroskopischen Implantaten in der rekonstruktiven Meniskuschirurgie.

All-inside devices have become increasingly popular in reconstructive meniscal surgery since their introduction at the beginning of the 1990s. Although the latest clinical investigations show better results for conventional suture techniques, meniscal devices are an important alternative because of the low risk of neurovascular injury and the easy handling of the instruments. Over the years, many reports on specific complications related to all-inside devices have been published. Especially chondral injuries, implant loosening, device migration and capsular or neural irritations have been described. Furthermore, some authors reported on foreign body reactions and cystic granulomas after the use of meniscal fixation devices. However, there is no evidence for a higher infection rate or for specific infections after the use of intra-articular techniques. Clinical reports on complications along with biomechanical studies on meniscal repair devices have led to the enhancement of all-inside techniques through substantial modifications of established products as well as to the development of new implants. After reviewing the latest literature, the complication rate seems to be decreasing. In many ways, all-inside devices are an interesting alternative to conventional suture techniques. A precise knowledge of their potential complications and the pitfalls during surgery however is crucial to make a risk evaluation in the choice of the right technique for meniscal reconstruction.

[Complications related to implants in arthroscopic shoulder surgery]. / Implantatkomplikationen in der Schulterarthroskopie.

With the increase in shoulder arthroscopies are increased complications related to shoulder implants frequently used for arthroscopic rotator cuff repair and shoulder stabilisation. The biggest problem is malpositioning of the suture anchor, which might lead to persistent pain, serious cartilage damage, decreased range of motion, and failure of the reconstruction, resulting in revision surgery. Especially in osteoporotic bone, it is important to choose an implant that provides sufficient mechanical strength. Other possible complications are related to the sutures of the anchor. Suture damage or accidental removal of the sutures from the anchor could leave them useless in situ. Tangling of the sutures, especially in massive reconstructions of the rotator cuff, can lead the surgeon to switch to an open technique. Compared with metal implants, bioabsorbable implants have advantages concerning possible revision surgery. However, implant costs, anchor hole enlargement, and possible higher failure rates compared with metallic implants should be considered. A rare but serious complication is allergic reaction to the implant.

Towards exposure of elusive metabolic mixed-culture processes: the application of metaproteomic analyses to activated sludge.

Protein expression is a direct reflection of specific microbial activities in any ecosystem. In order to assess protein expression in mixed microbial communities, the feasibility of applying proteomic techniques to activated sludge samples has recently been demonstrated. We report the application of metaproteomics to two activated sludges from a laboratory-scale sequencing batch reactor with dissimilar phosphorus removal performances. Fluorescence in situ hybridization (FISH) revealed that the sludge with good enhanced biological phosphorus removal performance (EBPR) was dominated by Betaproteobacteria (65% of EUBMIX binding cells) and gave positive signals for the Rhodocyclus-type PAO specific probe (59%). The non-EBPR sludge was dominated by tetrad-forming Alphaproteobacteria (75%). With regard to the proteomic investigation, 630 individual protein spots were matched across the replicate groups of the anaerobic and aerobic phases of the EBPR sludge with 9.4% of all spots being statistically different between the two phases. The non-EBPR metaproteomic maps exhibited 590 matched spots with 14.7% statistical differences between the two phases. Overall, the non-EBPR sludge expressed around 30% more significant differences than the EBPR sludge. The comparison of protein expression in the two sludges showed that their metaproteomes were substantially different and this was reflected in their microbial community structures and metabolic transformations.

Methotrexate-associated liver toxicity in a patient with breast cancer: case report and literature review.

A patient with breast cancer developed severe asthenia, accompanied with progressively increasing transaminases, during adjuvant chemotherapy with CMF (cyclophosphamide, methotrexate and 5-fluorouracil). Additional blood tests and imaging were negative. A liver biopsy revealed a grade II toxic hepatitis. Because methotrexate was suspected to be the cause of the hepatotoxicity, the administration of this drug was stopped and mitoxantrone was given instead. A recovery of clinical symptoms and normalisation of the liver function tests was observed afterwards. In that sense, mitoxantrone appears to be a valuable alternative to methotrexate in cases of hepatotoxicity in patients with breast cancer. An overview of the literature regarding methotrexate hepatotoxicity is presented.

Erroneous monocyte and neutrophil counts with the Sysmex NE-1500 in patients recovering from bone marrow aplasia.

The Sysmex NE-1500 is a haematological analyser which offers five-part differential counts. The instrument was submitted to an extensive evaluation procedure before acceptance to the laboratory and was found to perform satisfactorily. However, problems arose in clinical practice with the analysis of samples from patients recovering from bone marrow aplasia. Falsely low monocyte counts and, controversely, falsely high neutrophil counts were found in these patients. Only a minority (13%) of these samples were flagged as abnormal by the instrument. The most alarming consequence of these results is the overestimation of neutrophils and the exclusion of these patients from reimbursement for treatment with growth factors. We conclude that in patients recovering from aplasia, differential counts performed with the Sysmex NE series should always be checked manually.