The Bern Birth Cohort (BeBiCo) to study the development of the infant intestinal microbiota in a high-resource setting in Switzerland: rationale, design, and methods.

BACKGROUND: Microbiota composition is fundamental to human health with the intestinal microbiota undergoing critical changes within the first two years of life. The developing intestinal microbiota is shaped by maternal seeding, breast milk and its complex constituents, other nutrients, and the environment. Understanding microbiota-dependent pathologies requires a profound understanding of the early development of the healthy infant microbiota. METHODS: Two hundred and fifty healthy pregnant women (≥20 weeks of gestation) from the greater Bern area will be enrolled at Bern University hospital's maternity department. Participants will be followed as mother-baby pairs at delivery, week(s) 1, 2, 6, 10, 14, 24, 36, 48, 96, and at years 5 and 10 after birth. Clinical parameters describing infant growth and development, morbidity, and allergic conditions as well as socio-economic, nutritional, and epidemiological data will be documented. Neuro-developmental outcomes and behavior will be assessed by child behavior checklists at and beyond 2 years of age. Maternal stool, milk, skin and vaginal swabs, infant stool, and skin swabs will be collected at enrolment and at follow-up visits. For the primary outcome, the trajectory of the infant intestinal microbiota will be characterized by 16S and metagenomic sequencing regarding composition, metabolic potential, and stability during the first 2 years of life. Secondary outcomes will assess the cellular and chemical composition of maternal milk, the impact of nutrition and environment on microbiota development, the maternal microbiome transfer at vaginal or caesarean birth and thereafter on the infant, and correlate parameters of microbiota and maternal milk on infant growth, development, health, and mental well-being. DISCUSSION: The Bern birth cohort study will provide a detailed description and normal ranges of the trajectory of microbiota maturation in a high-resource setting. These data will be compared to data from low-resource settings such as from the Zimbabwe-College of Health-Sciences-Birth-Cohort study. Prospective bio-sampling and data collection will allow studying the association of the microbiota with common childhood conditions concerning allergies, obesity, neuro-developmental outcomes , and behaviour. Trial registration The trial has been registered at www. CLINICALTRIALS: gov , Identifier: NCT04447742.

4D Printing of Humidity-Driven Seed Inspired Soft Robots.

Geraniaceae seeds represent a role model in soft robotics thanks to their ability to move autonomously across and into the soil driven by humidity changes. The secret behind their mobility and adaptivity is embodied in the hierarchical structures and anatomical features of the biological hygroscopic tissues, geometrically designed to be selectively responsive to environmental humidity. Following a bioinspired approach, the internal structure and biomechanics of Pelargonium appendiculatum (L.f.) Willd seeds are investigated to develop a model for the design of a soft robot. The authors exploit the re-shaping ability of 4D printed materials to fabricate a seed-like soft robot, according to the natural specifications and model, and using biodegradable and hygroscopic polymers. The robot mimics the movement and performances of the natural seed, reaching a torque value of ≈30 µN m, an extensional force of ≈2.5 mN and it is capable to lift ≈100 times its own weight. Driven by environmental humidity changes, the artificial seed is able to explore a sample soil, adapting its morphology to interact with soil roughness and cracks.

Performance of the Dexcom G6 Continuous Glucose Monitoring System During Cardiac Surgery Using Hypothermic Extracorporeal Circulation.

OBJECTIVE: Continuous glucose monitoring (CGM) may be challenged by extreme conditions during cardiac surgery using hypothermic extracorporeal circulation (ECC). RESEARCH DESIGN AND METHODS: We evaluated the Dexcom G6 sensor in 16 subjects undergoing cardiac surgery with hypothermic ECC, of whom 11 received deep hypothermic circulatory arrest (DHCA). Arterial blood glucose, quantified by the Accu-Chek Inform II meter, served as reference. RESULTS: Intrasurgery mean absolute relative difference (MARD) of 256 paired CGM/reference values was 23.8%. MARD was 29.1% during ECC (154 pairs) and 41.6% immediately after DHCA (10 pairs), with a negative bias (signed relative difference: -13.7%, -26.6%, and -41.6%). During surgery, 86.3% pairs were in Clarke error grid zones A or B and 41.0% of sensor readings fulfilled the International Organization for Standardization (ISO) 15197:2013 norm. Postsurgery, MARD was 15.0%. CONCLUSIONS: Cardiac surgery using hypothermic ECC challenges the accuracy of the Dexcom G6 CGM although recovery appears to occur thereafter.

Perioperative Fully Closed-Loop Insulin Delivery in Patients Undergoing Elective Surgery: An Open-Label, Randomized Controlled Trial.

OBJECTIVE: Perioperative management of glucose levels remains challenging. We aimed to assess whether fully closed-loop subcutaneous insulin delivery would improve glycemic control compared with standard insulin therapy in insulin-requiring patients undergoing elective surgery. RESEARCH DESIGN AND METHODS: We performed a single-center, open-label, randomized controlled trial. Patients with diabetes (other than type 1) undergoing elective surgery were recruited from various surgical units and randomly assigned using a minimization schedule (stratified by HbA1c and daily insulin dose) to fully closed-loop insulin delivery with fast-acting insulin aspart (closed-loop group) or standard insulin therapy according to local clinical practice (control group). Study treatment was administered from hospital admission to discharge (for a maximum of 20 days). The primary end point was the proportion of time with sensor glucose in the target range (5.6-10.0 mmol/L). RESULTS: Forty-five patients were enrolled and assigned to the closed-loop (n = 23) or the control (n = 22) group. One patient (closed-loop group) withdrew from the study before surgery and was not analyzed. Participants underwent abdominal (57%), vascular (23%), orthopedic (9%), neuro (9%), or thoracic (2%) surgery. The mean proportion of time that sensor glucose was in the target range was 76.7 ± 10.1% in the closed-loop and 54.7 ± 20.8% in the control group (mean difference 22.0 percentage points [95% CI 11.9; 32.0%]; P < 0.001). No episodes of severe hypoglycemia (<3.0 mmol/L) or hyperglycemia with ketonemia or any study-related adverse events occurred in either group. CONCLUSIONS: In the context of mixed elective surgery, the use of fully closed-loop subcutaneous insulin delivery improves glucose control without a higher risk of hypoglycemia.

Morphological Computation in Plant Seeds for a New Generation of Self-Burial and Flying Soft Robots.

Plants have evolved different mechanisms to disperse from parent plants and improve germination to sustain their survival. The study of seed dispersal mechanisms, with the related structural and functional characteristics, is an active research topic for ecology, plant diversity, climate change, as well as for its relevance for material science and engineering. The natural mechanisms of seed dispersal show a rich source of robust, highly adaptive, mass and energy efficient mechanisms for optimized passive flying, landing, crawling and drilling. The secret of seeds mobility is embodied in the structural features and anatomical characteristics of their tissues, which are designed to be selectively responsive to changes in the environmental conditions, and which make seeds one of the most fascinating examples of morphological computation in Nature. Particularly clever for their spatial mobility performance, are those seeds that use their morphology and structural characteristics to be carried by the wind and dispersed over great distances (i.e. "winged" and "parachute" seeds), and seeds able to move and penetrate in soil with a self-burial mechanism driven by their hygromorphic properties and morphological features. By looking at their motion mechanisms, new design principles can be extracted and used as inspiration for smart artificial systems endowed with embodied intelligence. This mini-review systematically collects, for the first time together, the morphological, structural, biomechanical and aerodynamic information from selected plant seeds relevant to take inspiration for engineering design of soft robots, and discusses potential future developments in the field across material science, plant biology, robotics and embodied intelligence.

Triboelectric Characterization of Colloidal TiO2 for Energy Harvesting Applications.

Nowadays, energy-related issues are of paramount importance. Every energy transformation process results in the production of waste heat that can be harvested and reused, representing an ecological and economic opportunity. Waste heat to power (WHP) is the process of converting the waste heat into electricity. A novel approach is proposed based on the employment of liquid nano colloids. In this work, the triboelectric characterization of TiO2 nanoparticles dispersed in pure water and flowing in a fluorinated ethylene propylene (FEP) pipe was conducted. The idea is to exploit the waste heat to generate the motion of colloidal TiO2 through a FEP pipe. By placing an Al ring electrode in contact with the pipe, it was possible to accumulate electrostatic charges due to the triboelectric effect between the fluid and the inner pipe walls. A peristaltic pump was used to drive and control the flow in order to evaluate the performances in a broad fluid dynamic spectrum. The system generated as output relatively high voltages and low currents, resulting in extracted power ranging between 0.4 and 0.6 nW. By comparing the power of pressure loss due to friction with the extracted power, the electro-kinetic efficiency was estimated to be 20%.

An Intracerebral Hemorrhage Care Bundle Is Associated with Lower Case Fatality.

OBJECTIVE: Anticoagulation reversal, intensive blood pressure lowering, neurosurgery, and access to critical care might all be beneficial in acute intracerebral hemorrhage (ICH). We combined and implemented these as the "ABC" hyperacute care bundle and sought to determine whether the implementation was associated with lower case fatality. METHODS: The ABC bundle was implemented from June 1, 2015 to May 31, 2016. Key process targets were set, and a registry captured consecutive patients. We compared 30-day case fatality before, during, and after bundle implementation with multivariate logistic regression and used mediation analysis to determine which care process measures mediated any association. Difference-in-difference analysis compared 30-day case fatality with 32,295 patients with ICH from 214 other hospitals in England and Wales using Sentinel Stroke National Audit Programme data. RESULTS: A total of 973 ICH patients were admitted in the study period. Compared to before implementation, the adjusted odds of death by 30 days were lower in the implementation period (odds ratio [OR] = 0.62, 95% confidence interval [CI] = 0.38-0.97, p = 0.03), and this was sustained after implementation (OR = 0.40, 95% CI = 0.24-0.61, p < 0.0001). Implementation of the bundle was associated with a 10.8 percentage point (95% CI = -17.9 to -3.7, p = 0.003) reduction in 30-day case fatality in difference-in-difference analysis. The total effect of the care bundle was mediated by a reduction in do-not-resuscitate orders within 24 hours (52.8%) and increased admission to critical care (11.1%). INTERPRETATION: Implementation of the ABC care bundle was significantly associated with lower 30-day case fatality after ICH. ANN NEUROL 2019;86:495-503.

Clinical evidence for three distinct gastric cancer subtypes: time for a new approach.

BACKGROUND: Recently, a new classification for gastric cancer (GC) has been proposed, based on Lauren's histology and on anatomic tumour location, identifying three subtypes of disease: type 1 (proximal non diffuse GC), type 2 (diffuse GC) and type 3 (distal non diffuse GC). Aim of our analysis was to compare clinical outcome according to different GC subtypes (1,2,3) in metastatic GC patients receiving first-line chemotherapy. PATIENTS AND METHODS: Advanced GC pts treated with a first-line combination chemotherapy were included in our analysis. Pts were divided in three subgroups (type 1, type 2 and type 3) as previously defined. RESULTS: A total of 248 advanced GC pts were included: 45.2% belonged to type 2, 43.6% to type 3 and 11.2% to type 1. Patients received a fluoropyrimidine-based chemotherapy doublet or three drugs regimens including a platinum derivate and a fluoropyrimidine with the addition of an anthracycline, a taxane or mytomicin C. RR was higher in type 1 pts (RR = 46.1%) and type 3 (34,3%) compared to type 2 (20,4%), (p = 0.015). Type 2 presented a shorter PFS, median PFS = 4.2 months, compared to type 1, mPFS = 7.2 months, and type 3, mPFS = 5.9 months (p = 0.011) and also a shorter OS (p = 0.022). CONCLUSIONS: Our analysis suggests that GC subtypes may be important predictors of benefit from chemotherapy in advanced GC patients. Future clinical trials should take in account these differences for a better stratification of patients.

Cancer stem cell gene profile as predictor of relapse in high risk stage II and stage III, radically resected colon cancer patients.

Clinical data indicate that prognostic stratification of radically resected colorectal cancer based on disease stage only may not be always be adequate. Preclinical findings suggest that cancer stem cells may influence the biological behaviour of colorectal cancer independently from stage: objective of the study was to assess whether a panel of stemness markers were correlated with clinical outcome in resected stage II and III colon cancer patients. A panel of 66 markers of stemness were analysed and thus patients were divided into two groups (A and B) with most patients clustering in a manner consistent with different time to relapse by using a statistical algorithm. A total of 62 patients were analysed. Thirty-six (58%) relapsed during the follow-up period (range 1.63-86.5 months). Twelve (19%) and 50 (81%) patients were allocated into group A and B, respectively. A significantly different median relapse-free survival was observed between the 2 groups (22.18 vs 42.85 months, p=0.0296). Among of all genes tested, those with the higher "weight" in determining different prognosis were CD44, ALCAM, DTX2, HSPA9, CCNA2, PDX1, MYST1, COL1A1 and ABCG2. This analysis supports the idea that, other than stage, biological variables, such as expression levels of colon cancer stem cell genes, may be relevant in determining an increased risk of relapse in resected colorectal cancer patients.

Molecular biomarkers of resistance to anti-EGFR treatment in metastatic colorectal cancer, from classical to innovation.

BACKGROUND: Systematic dissection of the EGFR pathway was considered as the best way to identify putative markers of resistance to anti-EGFR therapies. This kind of approach leaves other, less known but by no means less important, putative mechanisms of resistance. We tried to shed some light on these mechanisms of resistance. MATERIALS AND METHODS: We performed a research through Pubmed database of all published articles highlighting mechanisms of resistance to Cetuximab and Panitumumab based therapies, published in 2000-2012 period. CONCLUSIONS: We reviewed the "classical" molecular factors, extensively analyzed as predictive factors for efficacy to anti-EGFR therapy, such as K-ras, B-raf, and PI3K-mTOR-Akt, focusing on their predictive or prognostic value and on the controversial aspects of the biomarker analysis for clinical practice. On the second part we will then move on to other less known molecular markers, for the future understanding of biological mechanisms underlying anti-EGFR therapy resistance, such as non-canonical heterodimer candidates, microRNA, IGF1-IGF1R, HGF-cMET and secondary mutations of EGFR.

End-of-life decision making in respiratory failure. The therapeutic choices in chronic respiratory failure in a 7-item questionnaire.

INTRODUCTION: The transition from paternalistic medicine to a healthcare culture centred on the patient's decision making autonomy presents problems of communication and understanding. Chronic respiratory failure challenges patients, their families and caregivers with important choices, such as invasive and non-invasive mechanical ventilation and tracheostomy, which, especially in the case of neuromuscular diseases, can significantly postpone the end of life. MATERIAL AND METHODS: A 7-item questionnaire was administered to 100 patients with advanced COPD, neuromuscular diseases and pulmonary fibrosis, all of them on oxygen therapy and receiving day-hospital treatment for respiratory failure. The objective was to find out whether or not patients, if faced with a deterioration of their health condition, would want to take part in the decision making process and, if so, how and with whom. RESULTS: Results showed that: 90% of patients wanted to be interviewed, 10% preferred not to be interviewed, 82% wanted to be regularly updated on their clinical situation, 75% wanted to be intubated, if necessary, and 56% would also agree to have a tracheostomy. These choices have been confirmed one year later, with 93% of respondents accepting the questionnaire and considering it useful. CONCLUSIONS: It is possible to conclude that a simple questionnaire can be a useful tool contributing to therapeutic decision making in respiratory failure.

Role of antithrombotic agents in heart failure.

Despite a vast body of research on antithrombotic therapy for patients with cardiac disease, there are few clinical settings where robust evidence of their benefit exists. Patients with heart failure often have vascular disease and atrial fibrillation contributing to their poor prognosis. For patients with heart failure and atrial fibrillation, anticoagulants are appropriate. For patients with heart failure in sinus rhythm, the weight of evidence suggests that doctors should generally avoid using any antithrombotic agent even if the patient has coronary artery disease. If there is a compulsion to treat, then there is less evidence of harm with clopidogrel or warfarin than with aspirin, although most receive aspirin. More research is required for this "evidence-light" problem. For those with the opportunity, engaging with a randomized trial is clinically and scientifically appropriate. The dilemma for such studies is the comparator. Should it be against or in addition to "standard of care" or both?

Mechanical ventilation in patients with end-stage idiopathic pulmonary fibrosis.

BACKGROUND: Acute respiratory failure (ARF) occurring during idiopathic pulmonary fibrosis (IPF) is associated with a poor prognosis. In this subset of individuals, mechanical ventilation (MV) may be required. OBJECTIVES: We analysed the characteristics of a group of IPF patients undergoing MV for ARF in order to give some indications on the supposed prognosis. METHODS: Hospital records of 34 consecutive patients with IPF, who underwent MV for ARF, were retrospectively examined. Demographic data, time from diagnosis, gas exchange, Acute Physiology and Chronic Health Evaluation (APACHE) II score, ARF causes and MV failure were recorded. RESULTS: Fifteen subjects (group A) underwent invasive MV and 19 patients (group B) non-invasive ventilation (NIV). The 2 groups were different for disease severity (APACHE II score 24.2 +/- 6 vs. 19.5 +/- 5.9; p = 0.01). Both ventilatory strategies temporarily increased PaO2/FiO2 as compared with spontaneous breathing (group A: 148.5 +/- 52 vs. 99 +/- 39, p = 0.0004; group B: 134 +/- 36 vs. 89 +/- 26, p = 0.0004). NIV reduced the respiratory rate (26 +/- 7 vs. 36 +/- 9 with spontaneous breathing; p = 0.002). Duration of MV correlated with the time of evolution of IPF (r = 0.45; p = 0.018). The in-hospital mortality rate was 85% (100% for invasive MV, 74% for NIV). Four of the 5 survivors died within 6 months from hospital discharge (range 2-6 months). CONCLUSIONS: MV does not appear to have a significant impact on the survival of patients with end-stage IPF. NIV may be useful for compassionate use, providing relief from dyspnoea and avoiding aggressive approaches.

Noninvasive positive pressure ventilation using a helmet in patients with acute exacerbation of chronic obstructive pulmonary disease: a feasibility study.

BACKGROUND: Noninvasive positive pressure ventilation (NPPV) with a facemask (FM) is effective in patients with acute exacerbation of their chronic obstructive pulmonary disease. Whether it is feasible to treat these patients with NPPV delivered by a helmet is not known. METHODS: Over a 4-month period, the authors studied 33 chronic obstructive pulmonary disease patients with acute exacerbation who were admitted to four intensive care units and treated with helmet NPPV. The patients were compared with 33 historical controls treated with FM NPPV, matched for simplified acute physiologic score (SAPS II), age, PaCO2, pH, and PaO2:fractional inspired oxygen tension. The primary endpoints were the feasibility of the technique, improvement of gas exchange, and need for intubation. RESULTS: The baseline characteristics of the two groups were similar. Ten patients in the helmet group and 14 in the FM group (P = 0.22) were intubated. In the helmet group, no patients were unable to tolerate NPPV, whereas five patients required intubation in the FM group (P = 0.047). After 1 h of treatment, both groups had a significant reduction of PaCO2 with improvement of pH; PaCO2 decreased less in the helmet group (P = 0.01). On discontinuing support, PaCO2 was higher (P = 0.002) and pH lower (P = 0.02) in the helmet group than in the control group. One patient in the helmet group, and 12 in the FM group, developed complications related to NPPV (P < 0.001). Length of intensive care unit stay, intensive care unit, and hospital mortality were similar in both groups. CONCLUSIONS: Helmet NPPV is feasible and can be used to treat chronic obstructive pulmonary disease patients with acute exacerbation, but it does not improve carbon dioxide elimination as efficiently as does FM NPPV.