Evaluation of alternative surfactants as stabilizers for therapeutical protein formulations

Surfactants are potent stabilizers of proteins, preventing protein unfolding and aggregation presumably by competitive adsorption to interfaces. Due to limited data on e.g. performance and safety, only three surfactants are routinely found within marketed formulations of parenteral protein products: polysorbate 20 (PS20), polysorbate 80 (PS80), or poloxamer 188 (Px188). These molecules are well-established and safe for parenteral administration but possess liabilities such as degradation of the surfactant itself and/or chemical inhomogeneity (PS) or show decreased stabilizing effects at silicone oil-water interfaces (Px188). Thus, there is a need to evaluate alternative surfactants to expand the toolbox for product development and to ensure optimal drug product stability and quality. In our studies, potential alternative surfactants were evaluated and compared to PS20 and Px188 (e.g. during real-time and stress stability studies using a model mAb). Data from these efforts will be presented

Plant secondary metabolites and primate food choices : a meta-analysis and future directions

The role of plant secondary metabolites (PSMs) in shaping the feeding decisions, habitat suitability, and reproductive success of herbivorous mammals has been a major theme in ecology for decades. Although primatologists were among the first to test these ideas, studies of PSMs in the feeding ecology of non-human primates have lagged in recent years, leading to a recent call for primatologists to reconnect with phytochemists to advance our understanding of the primate nutrition. To further this case, we present a formal meta-analysis of diet choice in response to PSMs based on field studies on wild primates. Our analysis of 155 measurements of primate feeding response to PSMs is drawn from 53 studies across 43 primate species which focussed primarily on the effect of three classes of PSMs tannins, phenolics, and alkaloids. We found a small but significant effect of PSMs on the diet choice of wild primates, which was largely driven by the finding that colobine primates showed a moderate aversion to condensed tannins. Conversely, there was no evidence that PSMs had a significant deterrent effect on food choices of non-colobine primates when all were combined into a single group. Furthermore, within the colobine primates, no other PSMs influenced feeding choices and we found no evidence that foregut anatomy significantly affected food choice with respect to PSMs. We suggest that methodological improvements related to experimental approaches and the adoption of new techniques including metabolomics are needed to advance our understanding of primate diet choice

Community-based rehabilitation for people with disabilities in low- and middle-income countries: a systematic review

Review question: We reviewed the evidence about the impact of community-based rehabilitation on the lives of people with disabilities and their carers in low- and middle-income countries. Background: People with disabilities include those who have long-term physical, mental, intellectual or sensory impairments, which in interaction with various barriers may hinder their full and effective participation in society on an equal basis with others. There are estimated to be over one billion people with disabilities globally and 80% of them live in low- and middle-income countries. They are often excluded from education, health, and employment and other aspects of society leading to an increased risk of poverty. Community-based rehabilitation interventions are the strategy endorsed by the World Health Organization and other international organisations (e.g. ILO, IDDC) for addressing the needs of this group of people in low- and middle-income countries. These interventions aim to enhance the quality of life of people with disabilities and their carers, by trying to meet their basic needs and ensuring inclusion and participation using predominantly local resources. These interventions are composed of up to five components: health, education, livelihood, social and empowerment. Currently only few people who need them benefit from these interventions, and so it is important to assess the available evidence to identify how to best implement these programmes. Study characteristics: The evidence in this review is current to July 2012. This review identified 15 studies that assessed the impact of community-based rehabilitation on the lives of people with disabilities and their carers in low- and middle-income countries. The studies included in the review used different types of community-based rehabilitation interventions and targeted different types of physical (stroke, arthritis, chronic 7 The Campbell Collaboration | www.campbellcollaboration.org obstructive pulmonary disease) and mental disabilities (schizophrenia, dementia, intellectual impairment). Key results: Overall, randomised controlled trials suggested a beneficial effect of community-based rehabilitation interventions in the lives of people with physical disabilities (stroke and chronic obstructive pulmonary disease). Similar results were found for non-randomised studies for physical disabilities (stroke and arthritis) with the exception of one non-randomised study on stroke showing community-based rehabilitation was less favourable than hospital-based rehabilitation. Overall, randomised controlled trials suggested a modest beneficial effect of community-based rehabilitation interventions for people with mental disabilities (schizophrenia, dementia, intellectual impairment), and for their carers (dementia). Similar results were found for non-randomised studies for mental disabilities (schizophrenia). However, the methodological constraints of many of these studies limit the strength of our results. In order to build stronger evidence, future studies will need to adopt better study designs, will need to focus on broader clients group, and to include economic evaluations

Lessons learnt: Undertaking rapid reviews on public health and social measures during a global pandemic.

Public health and social measures (PHSM) have been central to the COVID-19 response. Consequently, there has been much pressure on decision-makers to make evidence-informed decisions and on researchers to synthesize the evidence regarding these measures. This article describes our experiences, responses and lessons learnt regarding key challenges when planning and conducting rapid reviews of PHSM during the COVID-19 pandemic. Stakeholder consultations and scoping reviews to obtain an overview of the evidence inform the scope of reviews that are policy-relevant and feasible. Multiple complementary reviews serve to examine the benefits and harms of PHSM across different populations and contexts. Conceiving reviews of effectiveness as adaptable living reviews helps to respond to evolving evidence needs and an expanding evidence base. An appropriately skilled review team and good planning, coordination and communication ensures smooth and rigorous processes and efficient use of resources. Scientific rigor, the practical implications of PHSM-related complexity and likely time savings should be carefully weighed in deciding on methodological shortcuts. Making the best possible use of modeling studies represents a particular challenge, and methods should be carefully chosen, piloted and implemented. Our experience raises questions regarding the nature of rapid reviews and regarding how different types of evidence should be considered in making decisions about PHSM during a global pandemic. We highlight the need for readily available protocols for conducting studies on the effectiveness, unintended consequences and implementation of PHSM in a timely manner, as well as the need for rapid review standards tailored to "rapid" versus "emergency" mode reviewing

The worldwide clinical trial research response to the COVID-19 pandemic - the first 100 days

Background: Never before have clinical trials drawn as much public attention as those testing interventions for COVID-19. We aimed to describe the worldwide COVID-19 clinical research response and its evolution over the first 100 days of the pandemic. Methods: Descriptive analysis of planned, ongoing or completed trials by April 9, 2020 testing any intervention to treat or prevent COVID-19, systematically identified in trial registries, preprint servers, and literature databases. A survey was conducted of all trials to assess their recruitment status up to July 6, 2020. Results: Most of the 689 trials (overall target sample size 396,366) were small (median sample size 120; interquartile range [IQR] 60-300) but randomized (75.8%; n=522) and were often conducted in China (51.1%; n=352) or the USA (11%; n=76). 525 trials (76.2%) planned to include 155,571 hospitalized patients, and 25 (3.6%) planned to include 96,821 health-care workers. Treatments were evaluated in 607 trials (88.1%), frequently antivirals (n=144) or antimalarials (n=112); 78 trials (11.3%) focused on prevention, including 14 vaccine trials. No trial investigated social distancing. Interventions tested in 11 trials with >5,000 participants were also tested in 169 smaller trials (median sample size 273; IQR 90-700). Hydroxychloroquine alone was investigated in 110 trials. While 414 trials (60.0%) expected completion in 2020, only 35 trials (4.1%; 3,071 participants) were completed by July 6. Of 112 trials with detailed recruitment information, 55 had recruited <20% of the targeted sample; 27 between 20-50%; and 30 over 50% (median 14.8% [IQR 2.0-62.0%]). Conclusions: The size and speed of the COVID-19 clinical trials agenda is unprecedented. However, most trials were small investigating a small fraction of treatment options. The feasibility of this research agenda is questionable, and many trials may end in futility, wasting research resources. Much better coordination is needed to respond to global health threats

RESPONDER – diagnosis of pathological complete response by vacuum-assisted biopsy after neoadjuvant chemotherapy in breast Cancer - a multicenter, confirmative, one-armed, intra-individually-controlled, open, diagnostic trial

Background: Neoadjuvant chemotherapy (NACT) is a standard approach of the multidisciplinary treatment of breast cancer. Depending on the biological subtype a pathological complete response in the breast (bpCR) can be achieved in up to 60% of the patients. However, only limited accuracy can be reached when using imaging for prediction of bpCR prior to surgery. Due to this diagnostic uncertainty, surgery after NACT is considered to be obligatory for all patients in order to either completely remove residual disease or to diagnose a bpCR histologically. The purpose of this trial is to evaluate the accuracy of a vacuum-assisted biopsy (VAB) to diagnose a bpCR after NACT prior to surgery. Methods: This study is a multicenter, confirmative, one-armed, intra-individually-controlled, open, diagnostic trial. The study will take place at 21 trial sites in Germany. Six hundred female patients with breast cancer after completed NACT showing at least a partial response to NACT treatment will be enrolled. A vacuum-assisted biopsy (VAB) guided either by ultrasound or mammography will be performed followed by histopathological evaluation of the VAB specimen before standard, guideline-adherent breast surgery. The study is designed to prove that the false negative rate of the VAB is below 10%. Discussion: As a bpCR is becoming a more frequent result after NACT, the question arises whether breast surgery is therapeutically necessary in such cases. To study this subject further, it will be crucial to develop a reliable test to diagnose a bpCR without surgery. During the study we anticipate possible problems in patient recruitment as the VAB intervention does not provide participating patients with any personal benefit. Hence, a proficient informed consent discussion with the patient and a detailed explanation of the study aim will be crucial for patient recruitment. Another critical issue is the histopathological VAB evaluation of a non-tumorous specimen as this may have been taken either from the former tumor region (bpCR) or outside of the (former) tumor region (non-representative VAB, sampling error). Trial registration: The trial has been registered at clinicaltrials.gov with the identifier NCT02948764 on October 28, 2016 and at the German Clinical Trials Register ( DRKS00011761 ) on February 20, 2017. The date of enrolment of the first participant to the trial was on March 8, 2017

Noise-Driven Stem Cell and Progenitor Population Dynamics

BACKGROUND: The balance between maintenance of the stem cell state and terminal differentiation is influenced by the cellular environment. The switching between these states has long been understood as a transition between attractor states of a molecular network. Herein, stochastic fluctuations are either suppressed or can trigger the transition, but they do not actually determine the attractor states. METHODOLOGY/PRINCIPAL FINDINGS: We present a novel mathematical concept in which stem cell and progenitor population dynamics are described as a probabilistic process that arises from cell proliferation and small fluctuations in the state of differentiation. These state fluctuations reflect random transitions between different activation patterns of the underlying regulatory network. Importantly, the associated noise amplitudes are state-dependent and set by the environment. Their variability determines the attractor states, and thus actually governs population dynamics. This model quantitatively reproduces the observed dynamics of differentiation and dedifferentiation in promyelocytic precursor cells. CONCLUSIONS/SIGNIFICANCE: Consequently, state-specific noise modulation by external signals can be instrumental in controlling stem cell and progenitor population dynamics. We propose follow-up experiments for quantifying the imprinting influence of the environment on cellular noise regulation.Engineering and Applied SciencesOther Research Uni