Protocol for the CUPIDO trials; multicenter randomized controlled trials to assess the value of combining prolapse surgery and incontinence surgery in patients with genital prolapse and evident stress incontinence (CUPIDO I) and in patients with genital prolapse and occult stress incontinence (CUPIDO II)

Background: About 40% of all patients with genital prolapse report stress-incontinence. In about half of the 60% patients that do not report stress-incontinence, occult urinary stress-incontinence can be detected. In these patients stress-incontinence is masked due to kinking or compression of the urethra by the prolapse. In case surgical correction is indicated there are two strategies to manage patients with combined prolapse and (occult) stress incontinence. This strategy is either (i) a combination of prolapse surgery and stress-incontinence surgery or (ii) to correct the prolapse first and evaluate afterwards whether additional stress-incontinence surgery is indicated. The advantage of combining prolapse and stress-incontinence surgery is that only few patients report stress-incontinence following such combination. However, this combination has been associated with an increased risk on complications, of which the development of obstructive micturition symptoms, overactive bladder symptoms and bladder retention are the most important ones. Furthermore, combining two procedures may be unnecessary as performing only prolapse surgery may cure stress-incontinence In the randomized CUPIDO trials both strategies are compared in patients with prolapse and evident stress incontinence (CUPIDO I trial) and in patients with prolapse and occult stress incontinence (CUPIDO II trial). Methods/Design: The CUPIDO trials are two multicenter randomized controlled trials in which women with stress urinary incontinence (SUI) or occult stress urinary incontinence (OSUI) are randomized to prolapse surgery combined with anti incontinence surgery (concomitant surgery) or to prolapse surgery only. Patients with at least stage 2 POP are eligible, women with evident SUI are randomized in CUPIDO I. Patients without SUI are eligible for CUPIDO II and will have urodynamic evaluation or a standardized redression test. Women with OSUI are randomized, women without OSUI are followed up but not randomized. The primary outcome measure is absence of SUI twelve months after surgery. Furthermore, economic evaluations are conducted, and the effectiveness of urodynamic investigation is evaluated against a non-invasive way to determine SUI in women with POP. A total of 450 women will be included in the study

Study design and methods of the BoTULS trial: a randomised controlled trial to evaluate the clinical effect and cost effectiveness of treating upper limb spasticity due to stroke with botulinum toxin type A

Background Following a stroke, 55–75% of patients experience upper limb problems in the longer term. Upper limb spasticity may cause pain, deformity and reduced function, affecting mood and independence. Botulinum toxin is used increasingly to treat focal spasticity, but its impact on upper limb function after stroke is unclear. The aim of this study is to evaluate the clinical and cost effectiveness of botulinum toxin type A plus an upper limb therapy programme in the treatment of post stroke upper limb spasticity. Methods Trial design : A multi-centre open label parallel group randomised controlled trial and economic evaluation. Participants : Adults with upper limb spasticity at the shoulder, elbow, wrist or hand and reduced upper limb function due to stroke more than 1 month previously. Interventions : Botulinum toxin type A plus upper limb therapy (intervention group) or upper limb therapy alone (control group). Outcomes : Outcome assessments are undertaken at 1, 3 and 12 months. The primary outcome is upper limb function one month after study entry measured by the Action Research Arm Test (ARAT). Secondary outcomes include: spasticity (Modified Ashworth Scale); grip strength; dexterity (Nine Hole Peg Test); disability (Barthel Activities of Daily Living Index); quality of life (Stroke Impact Scale, Euroqol EQ-5D) and attainment of patient-selected goals (Canadian Occupational Performance Measure). Health and social services resource use, adverse events, use of other antispasticity treatments and patient views on the treatment will be compared. Participants are clinically reassessed at 3, 6 and 9 months to determine the need for repeat botulinum toxin type A and/or therapy. Randomisation : A web based central independent randomisation service. Blinding : Outcome assessments are undertaken by an assessor who is blinded to the randomisation group. Sample size : 332 participants provide 80% power to detect a 15% difference in treatment successes between intervention and control groups. Treatment success is defined as improvement of 3 points for those with a baseline ARAT of 0–3 and 6 points for those with ARAT of 4–56

Segregation of object and background motion in the retina

An important task in vision is to detect objects moving within a stationary scene. During normal viewing this is complicated by the presence of eye movements that continually scan the image across the retina, even during fixation. To detect moving objects, the brain must distinguish local motion within the scene from the global retinal image drift due to fixational eye movements. We have found that this process begins in the retina: a subset of retinal ganglion cells responds to motion in the receptive field centre, but only if the wider surround moves with a different trajectory. This selectivity for differential motion is independent of direction, and can be explained by a model of retinal circuitry that invokes pooling over nonlinear interneurons. The suppression by global image motion is probably mediated by polyaxonal, wide-field amacrine cells with transient responses. We show how a population of ganglion cells selective for differential motion can rapidly flag moving objects, and even segregate multiple moving objects

Outcomes of the first global multidisciplinary consensus meeting including persons living with obesity to standardize patient-reported outcome measurement in obesity treatment research

Quality of life is a key outcome that is not rigorously measured in obesity treatment research due to the lack of standardization of patient-reported outcomes (PROs) and PRO measures (PROMs). The S.Q.O.T. initiative was founded to Standardize Quality of life measurement in Obesity Treatment. A first face-to-face, international, multidisciplinary consensus meeting was conducted to identify the key PROs and preferred PROMs for obesity treatment research. It comprised of 35 people living with obesity (PLWO) and healthcare providers (HCPs). Formal presentations, nominal group techniques, and modified Delphi exercises were used to develop consensus-based recommendations. The following eight PROs were considered important: self-esteem, physical health/functioning, mental/psychological health, social health, eating, stigma, body image, and excess skin. Self-esteem was considered the most important PRO, particularly for PLWO, while physical health was perceived to be the most important among HCPs. For each PRO, one or more PROMs were selected, except for stigma. This consensus meeting was a first step toward standardizing PROs (what to measure) and PROMs (how to measure) in obesity treatment research. It provides an overview of the key PROs and a first selection of the PROMs that can be used to evaluate these PROs

The cryo-electron microscopy supramolecular structure of the bacterial stressosome unveils its mechanism of activation

How the stressosome, the epicenter of the stress response in bacteria, transmits stress signals from the environment has remained elusive. The stressosome consists of multiple copies of three proteins RsbR, RsbS and RsbT, a kinase that is important for its activation. Using cryo-electron microscopy, we determined the atomic organization of the Listeria monocytogenes stressosome at 3.38 Å resolution. RsbR and RsbS are organized in a 60-protomers truncated icosahedron. A key phosphorylation site on RsbR (T209) is partially hidden by an RsbR flexible loop, whose "open" or "closed" position could modulate stressosome activity. Interaction between three glutamic acids in the N-terminal domain of RsbR and the membrane-bound mini-protein Prli42 is essential for Listeria survival to stress. Together, our data provide the atomic model of the stressosome core and highlight a loop important for stressosome activation, paving the way towards elucidating the mechanism of signal transduction by the stressosome in bacteria

Sequestration and Tissue Accumulation of Human Malaria Parasites: Can We Learn Anything from Rodent Models of Malaria?

The sequestration of Plasmodium falciparum–infected red blood cells (irbcs) in the microvasculature of organs is associated with severe disease; correspondingly, the molecular basis of irbc adherence is an active area of study. In contrast to P. falciparum, much less is known about sequestration in other Plasmodium parasites, including those species that are used as models to study severe malaria. Here, we review the cytoadherence properties of irbcs of the rodent parasite Plasmodium berghei ANKA, where schizonts demonstrate a clear sequestration phenotype. Real-time in vivo imaging of transgenic P. berghei parasites in rodents has revealed a CD36-dependent sequestration in lungs and adipose tissue. In the absence of direct orthologs of the P. falciparum proteins that mediate binding to human CD36, the P. berghei proteins and/or mechanisms of rodent CD36 binding are as yet unknown. In addition to CD36-dependent schizont sequestration, irbcs accumulate during severe disease in different tissues, including the brain. The role of sequestration is discussed in the context of disease as are the general (dis)similarities of P. berghei and P. falciparum sequestration

Renewable energy from Cyanobacteria: energy production optimization by metabolic pathway engineering

The need to develop and improve sustainable energy resources is of eminent importance due to the finite nature of our fossil fuels. This review paper deals with a third generation renewable energy resource which does not compete with our food resources, cyanobacteria. We discuss the current state of the art in developing different types of bioenergy (ethanol, biodiesel, hydrogen, etc.) from cyanobacteria. The major important biochemical pathways in cyanobacteria are highlighted, and the possibility to influence these pathways to improve the production of specific types of energy forms the major part of this review