Patterns of invasive recurrence among patients originally treated for ductal carcinoma in situ by breast-conserving surgery versus mastectomy

Breast Cancer Research and Treatment -     

Promoting learning on reintegration of children into family-based care: implications for monitoring approaches and tools. Experiences from the RISE learning network

ABSTRACT

Between 2015 and 2018, the RISE Learning Network facilitated learning on approaches, practices, methods, and tools that promote recovery and reintegration of children affected by sexual exploitation. Spanning three regions (Sub-Saharan Africa, South Central Asia, and Latin America and the Caribbean), the RISE Learning Network implemented two learning projects. The first project focused on monitoring (M&E Learning Project) and aimed to generate understanding of approaches and tools that could effectively monitor children and families’ reintegration outcomes. The specific purpose of RISE is to promote learning on reintegration of children affected by sexual exploitation; however, the remit of this Learning Project was to generate evidence on the reintegration of children who have been separated from their families for a range of reasons. This is to ensure that learning from different, but often related, areas of work can be included and compared to strengthen understanding of what successful reintegration of children could look like. The mid- and end-term reviews of the M&E Learning Project have captured lessons learned on how practitioners can approach monitoring of reintegration to mainstream it into their programme cycle. Key lessons learned include the importance of focusing on monitoring outcomes through participatory tools and the benefit of flexible, peer-to-peer learning approaches between practitioners using a variety of monitoring tools. This learning contributes to the nascent evidence base on what effective and efficient capturing of reintegration outcomes on children can look like, in addition to strengthening understanding of what successful reintegration for children and families means. The learnings can inform programming; monitoring, evaluation and learning frameworks; and other interventions around reintegration to ensure the holistic wellbeing of children and families.     

Singular value based characterization and analysis of thermal patches for early breast abnormality detection

The purpose of this study is to develop a novel breast abnormality detection system by utilizing the potential of infrared breast thermography (IBT) in early breast abnormality detection. Since the temperature distributions are different in normal and abnormal thermograms and hot thermal patches are visible in abnormal thermograms, the abnormal thermograms possess more complex information than the normal thermograms. Here, the proposed method exploits the presence of hot thermal patches and vascular changes by using the power law transformation for pre-processing and singular value decomposition to characterize the thermal patches. The extracted singular values are found to be statistically significant (p?<?0.001) in breast abnormality detection. The discriminability of the singular values is evaluated by using seven different classifiers incorporating tenfold cross-validations, where the thermograms of the Department of Biotechnology-Tripura University-Jadavpur University (DBT-TU-JU) and Database of Mastology Research (DMR) databases are used. In DMR database, the highest classification accuracy of 98.00% with the area under the ROC curve (AUC) of 0.9862 is achieved with the support vector machine using polynomial kernel. The same for the DBT-TU-JU database is 92.50% with AUC of 0.9680 using the same classifier. The comparison of the proposed method with the other reported methods concludes that the proposed method outperforms the other existing methods as well as other traditional feature sets used in IBT based breast abnormality detection. Moreover, by using Rank1 and Rank2 singular values, a breast abnormality grading (BAG) index has also been developed for grading the thermograms based on their degree of abnormality.     

Utilization of extracellular information before ligand-receptor binding reaches equilibrium expands and shifts the input dynamic range

Cell signaling systems sense and respond to ligands that bind cell surface receptors. These systems often respond to changes in the concentration of extracellular ligand more rapidly than the ligand equilibrates with its receptor. We demonstrate, by modeling and experiment, a general “systems level” mechanism cells use to take advantage of the information present in the early signal, before receptor binding reaches a new steady state. This mechanism, pre-equilibrium sensing and signaling (PRESS), operates in signaling systems in which the kinetics of ligand-receptor binding are slower than the downstream signaling steps, and it typically involves transient activation of a downstream step. In the systems where it operates, PRESS expands and shifts the input dynamic range, allowing cells to make different responses to ligand concentrations so high as to be otherwise indistinguishable. Specifically, we show that PRESS applies to the yeast directional polarization in response to pheromone gradients. Consideration of preexisting kinetic data for ligand-receptor interactions suggests that PRESS operates in many cell signaling systems throughout biology. The same mechanism may also operate at other levels in signaling systems in which a slow activation step couples to a faster downstream step.Detecting and responding to a chemical gradient is a central feature of a multitude of biological processes (1). For this behavior, organisms use signaling systems that sense information about the extracellular world, transmit this information into the cell, and orchestrate a response. Measurements of the direction and proximity of the extracellular stimuli usually rely on the binding of diffusing chemical particles (ligands) to specific cell surface receptors. Different organisms have evolved different strategies to make use of this information. Small motile organisms, including certain bacteria, use a temporal sensing strategy, measuring and comparing concentration signals over time along their swimming tracks (2). In contrast, some eukaryotic cells, including Saccharomyces cerevisiae, are sufficiently large to implement a spatial sensing mechanism, measuring concentration differences across their cell bodies (3).The observation that some eukaryotes that use spatial sensing exhibit remarkable precision in response to shallow gradients (1–2% differences in ligand concentration between front and rear) (4, 5) has led to several proposed models in which large amplification is achieved by positive feedback loops in the signaling pathways triggered by the ligand-receptor binding (6, 7). Here, we describe a different mechanism, dependent on ligand-receptor binding dynamics, which improves gradient sensing when the concentration of external ligand is close to saturation. We use the budding yeast S. cerevisiae to study the efficiency of this mechanism.Haploid yeast cells exist in two mating types, MATa and MATα (also referred to as a and α cells). Mating occurs when a and α cells sense each other’s secreted mating pheromones: a-factor and α-factor (αF) (8). The pheromone secreted by the nearby mating partner diffuses, forming a gradient surrounding the sensing cell. Pheromone binds a membrane receptor, Ste2, in MATa yeast (9) that activates a pheromone response system (PRS), which cells use to decide whether to fuse with a mating partner or not. At high enough αF concentrations, cells develop a polarized chemotropic growth toward the pheromone source (4). To do that, the nonmotile yeast determines the direction of the potential mating partner measuring on which side there are more bound pheromone receptors, which are initially distributed homogeneously on the cell surface (10). However, this sensing modality can only work when external pheromone is nonsaturating: If all receptors are bound, cells should not be able to determine the direction of the gradient. Surprisingly, even at high pheromone concentrations, yeast tend to polarize in the correct direction (4, 11). Different amplification mechanisms have been proposed to account for the conversion of small differences in ligand concentration across the yeast cell, as is the case for dense mating mixtures, into chemotropic growth (6).We previously studied induction of reporter gene output by the PRS after step increases in the concentration of αF. We found large cell-to-cell variability, the bulk of which was due to large differences in the ability of individual cells to send signal through the system and in their general capacity to express proteins (12). The level of induced gene expression matches well the equilibrium binding curve of αF to receptor (13, 14), a phenomenon known as dose–response alignment (DoRA), common to many other signaling systems (14). In the PRS, DoRA persists for several hours of stimulation.During these studies, we realized that the binding dynamics of αF to its receptor is remarkably slow: At concentrations near the dissociation constant (K_d), binding takes about 20 min to reach 90% of the equilibrium level (15, 16). This dynamics is slow relative not only to the 90-min cell division cycle but also to the pheromone-dependent activation of the mitogen-activated protein kinase (MAPK) Fus3, which takes 2 to 5 min to reach steady-state levels (14). An unavoidable conclusion is that the machinery downstream of the αF receptor must be using pre-equilibrium binding information for its operation.This observation led us to study the consequences of fast and slow ligand-receptor dynamics on the ability of cells to sense extracellular cues. In biology, the rates of ligand binding and unbinding to membrane receptors span a large range, including many cases with dynamics similar to, or even slower than, that of mating pheromone (e.g., rates for EGF, insulin, glucagon, IFN-α1a, and IL-2 in

Declines in violence and police arrest among female sex workers in Karnataka state,south India,following a comprehensive HIV prevention programme

Introduction

Female sex workers (FSWs) frequently experience violence, harassment and arrest by the police or their clients, but there is little evidence as to the impact that such factors may have on HIV risk or whether community interventions could mitigate this impact.

Methods

As part of the evaluation of the Avahan programme in Karnataka, serial integrated behavioural and biological assessment (IBBA) surveys (four districts) (2005 to 2011) and anonymous polling booth surveys (PBS) (16 districts) (2007 to 2011) were conducted with random samples of FSWs. Logistic regression analysis was used to assess 1) changes in reported violence and arrests over time and 2) associations between violence by non-partners and police arrest and HIV/STI risk and prevalence. Mediation analysis was used to identify mediating factors.

Results

5,792 FSWs participated in the IBBAs and 15,813 participated in the PBS. Over time, there were significant reductions in the percentages of FSWs reporting being raped in the past year (PBS) (30.0% in 2007, 10.0% in 2011, p<0.001), being arrested in the past year [adjusted odds ratio (AOR) 0.57 (0.35, 0.93), p=0.025] and being beaten in the past six months by a non-partner (clients, police, pimps, strangers, rowdies) [AOR 0.69 (0.49, 0.95), p=0.024)] (IBBA). The proportion drinking alcohol (during the past week) also fell significantly (32.5% in 2005, 24.9% in 2008, 16.8% in 2011; p<0.001). Violence by non-partners (being raped in the past year and/or beaten in the past six months) and being arrested in the past year were both strongly associated with HIV infection [AOR 1.59 (1.18, 2.15), p=0.002; AOR 1.91 (1.17, 3.12), p=0.01, respectively]. They were also associated with drinking alcohol (during the past week) [AOR 1.98 (1.54, 2.53), p<0.001; AOR 2.79 (1.93, 4.04), p<0.001, respectively], reduced condom self-efficacy with clients [AOR 0.36 (0.27, 0.47), p<0.001; AOR 0.62 (0.39, 0.98), p=0.039, respectively], symptomatic STI (during the past year) [AOR 2.62 (2.07, 3.30), p<0.001; AOR 2.17 (1.51, 3.13), p<0.001, respectively], gonorrhoea infection [AOR 2.79 (1.51, 5.15), p=0.001; AOR 2.69 (0.96, 7.56), p=0.060, respectively] and syphilis infection [AOR 1.86 (1.04, 3.31), p=0.036; AOR 3.35 (1.78, 6.28), p<0.001, respectively], but not with exposure to peer education, community mobilization or HIV testing uptake. Mediation analysis suggests that alcohol use and STIs may partially mediate the association between violence or arrests and HIV prevalence.

Discussion

Violence by non-partners and arrest are both strongly associated with HIV infection among FSWs. Large-scale, comprehensive HIV prevention programming can reduce violence, arrests and HIV/STI infection among FSWs.     

Covalent Polymyxin B Conjugate with Human Immunoglobulin G as an Antiendotoxin Reagent

Polymyxin B (PMB) is a cyclic decapeptide antibiotic which also binds and neutralizes endotoxin. Unfortunately, PMB can be considerably nephrotoxic at clinically utilized doses, thereby limiting its utility as a therapeutic antiendotoxin reagent. We sought to change the pharmacokinetics and toxicity profile of PMB by covalently linking it to a human immunoglobulin G (IgG) carrier. Conjugates of PMB with IgG were prepared by EDAC [1-ethyl-3-(3-dimethylaminopropyl) carbodiimide]-mediated amide formation. Analysis by dot enzyme-linked immunosorbent assay with an anti-PMB monoclonal antibody showed that the purified conjugate contained bound PMB. The IgG-PMB conjugate reacted with lipid A and J5 lipopolysaccharide in Western blot assays in a manner comparable to that of whole antiserum with anti-lipid A reactivity; unconjugated IgG had no reactivity. The PMB bound in the conjugate retained its endotoxin-neutralizing activity compared to that of unbound PMB as evidenced by its dose-dependent inhibition of tumor necrosis factor release by endotoxin-stimulated human monocytes in vitro; unconjugated IgG had no activity. By this assay, the PMB-IgG conjugate was determined to have approximately 3.0 μg of bound functional PMB per 100 μg of total protein of conjugate (five molecules of PMB per IgG molecule). The PMB-IgG conjugate was also bactericidal against clinical strains of Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae relative to unconjugated IgG with MBCs of <4 μg of conjugate per ml for each of the tested strains. The conjugate appeared to be nontoxic at the highest doses deliverable and provided statistically significant protection from death to galactosamine-sensitized, lipopolysaccharide-challenged mice in a dose-dependent fashion when administered prophylactically 2 h before challenge. However, neither free PMB nor the PMB-IgG conjugate could protect mice challenged with endotoxin 2 h after administration. This suggests that these reagents can play a role in prophylaxis but not in therapy of sepsis. These experiments demonstrated that the PMB-IgG conjugate retains bound yet functional PMB as evidenced by its endotoxin-neutralizing activity both in vitro and in vivo. Further work is required to define the role that this or related conjugate compounds may play in the prophylaxis of endotoxin-mediated disease.     

Clinical profile and follow-up of 51 pediatric neurocysticercosis cases: A study from Eastern India

Introduction:

Our present observational study attempted to evaluate the clinical profiles, diagnosis, treatment and follow-up results of 51 pediatric neurocysticercosis patients over a mean duration of five years (from January 2006 to December 2010).

Materials and Methods:

Diagnosis was mainly based on clinical features, computed tomography (CT)/magnetic resonance imaging scan and exclusion of other causes. Patients with active, transitional cysts and seizure were treated with albendazole for 28 days, steroids and anticonvulsants.

Results:

A total of 38 patients completed this study. Mean age of the presentation was 8.47 ± 3.19 years 52.6% of the patients were female. Overall patients presented with generalized seizure in 55.3%, focal in 31.6%, headache ± vomiting in 63.2%, focal neurodeficit in 10.5% and combination of symptoms in 60.5% cases. Contrast CT brain showed a solitary lesion in 27 (71.1%) and multiple in the rest. At presentation lesions were transitional in 58.2%, inactive in 20% and mixed in 14.6%. After a mean of 2 years, seizure persisted in 9 (23.7%) and headache in 8 (21.1%) of whom six had normal electroencephalography (EEG) while one each showed focal slowing, generalized slowing and epileptiform discharges. During the follow-up, CT scan brain 44.7% lesions calcified, 31.6% disappeared, 10.5% regressed and the rest persisted.

Conclusion:

Solitary ring enhancing lesions (transitional stage) involving the parietal lobe was the commonest CT picture at presentation. Generalized tonic-clonic seizure was the most common type of seizure. Number of lesions, persistence of lesion, number of seizures, EEG abnormality at presentation were not found to be prognostically significant (P > 0.05).Key Words: Brain, epilepsy, lesion, neurocysticercosis, parenchyma, solitary     

A study on the standard of documentation of lumbar puncture in neurology department of a major Irish Teaching Hospital in Ireland

Objective:

Poor documentation following lumbar puncture (LP) had always been a matter of concern. This study aimed to investigate the documentation pattern of neurology house officers, registrars (Regs), and specialist Regs following LP in a major teaching hospital.

Materials and Methods:

Total hundred patient records were examined in the light of a carefully designed proforma containing 15 important indicators of good-quality LP documentation.

Result:

Mean number of indicators overall documented by doctors was found to be 6.24 ± 3.0037. The mean number of indicators recorded by house officers was 5.11 ± 3.01 and Regs was 7.56 ± 3.28. A total of 33% LPs were performed without a documented consent. Only 36% performers documented the type and size of needle they used during the procedure. Only 46% documents revealed the strength and name of the local anesthetic used. Statistically significant difference between senior house officers and Regs in terms of numbers of indicators documented was noted.

Conclusion:

The documentation standard among neurology junior doctors remained poor.Key Words: Consent, documentation, knowledge, lumbar, neurology, puncture