Assessing the Effect of Piperacillin/Tazobactam on Hematological Parameters in Patients Admitted with Moderate or Severe Foot Infections

Introduction: Piperacillin/tazobactam is a commonly used antibiotic for the empirical treatment of severe diabetic foot infections. One of the most feared complications of this drug is the development of pancytopenia. The aim of this study was to determine whether the use of piperacillin/tazobactam caused any hematological changes in patients admitted with severe diabetes-related foot infections from a specialist multidisciplinary foot clinic. Specifically, looking at whether it caused anemia, leukopenia, neutropenia, or thrombocytopenia. Methods: A 1-year retrospective analysis of patients admitted to a tertiary care center for treatment of diabetes-related foot infection using piperacillin/tazobactam. Hematological indices, urea and electrolytes, and C-reactive protein (CRP) were recorded pretreatment, during treatment, and posttreatment. HbA1c, vitamin B12, folate, thyroid-stimulating hormone, and free thyroxin were also analyzed to exclude any potential confounders as a cause of pancytopenia. Results: A total of 154 patients were admitted between 1 January 2016 and 31 December 2016 who received piperacillin/tazobactam for severe diabetes-related foot infection. On admission, white cell count and CRP were raised and fell significantly within the first 48 h. Other hematological factors did not change. Five patients developed a mild pancytopenia, of which three were unexplained. Conclusion: In this relatively small cohort, pancytopenia did not occur. As such, piperacillin/tazobactam appeared to have a low risk of adverse hematological outcomes and remains the treatment of choice for severe diabetes-related foot infections

MultiMetEval: comparative and multi-objective analysis of genome-scale metabolic models

Comparative metabolic modelling is emerging as a novel field, supported by the development of reliable and standardized approaches for constructing genome-scale metabolic models in high throughput. New software solutions are needed to allow efficient comparative analysis of multiple models in the context of multiple cellular objectives. Here, we present the user-friendly software framework Multi-Metabolic Evaluator (MultiMetEval), built upon SurreyFBA, which allows the user to compose collections of metabolic models that together can be subjected to flux balance analysis. Additionally, MultiMetEval implements functionalities for multi-objective analysis by calculating the Pareto front between two cellular objectives. Using a previously generated dataset of 38 actinobacterial genome-scale metabolic models, we show how these approaches can lead to exciting novel insights. Firstly, after incorporating several pathways for the biosynthesis of natural products into each of these models, comparative flux balance analysis predicted that species like Streptomyces that harbour the highest diversity of secondary metabolite biosynthetic gene clusters in their genomes do not necessarily have the metabolic network topology most suitable for compound overproduction. Secondly, multi-objective analysis of biomass production and natural product biosynthesis in these actinobacteria shows that the well-studied occurrence of discrete metabolic switches during the change of cellular objectives is inherent to their metabolic network architecture. Comparative and multi-objective modelling can lead to insights that could not be obtained by normal flux balance analyses. MultiMetEval provides a powerful platform that makes these analyses straightforward for biologists. Sources and binaries of MultiMetEval are freely available from https://github.com/PiotrZakrzewski/MetEv​al/downloads

Current Neonatal Skin Care Practices in Four African Sites

Data for this study on skin care practices and emollient use in four African sites were collected using in-depth interviews, focus-group discussions and observations. Respondents were mothers, grandmothers, fathers, health workers, birth attendants and people selling skin-care products. Analysis included content and framework analyses.Emollient use was a normative practice in all sites, with frequent application from an early age in most sites. There were variations in the type of emollients used, but reasons for use were similar and included improving the skin, keeping the baby warm, softening/strengthening the joints/bones, shaping the baby, ensuring flexibility and encouraging growth and weight gain. Factors that influenced emollient choice varied and included social pressure, cost, availability and deep-rooted traditional norms. Massage associated with application was strong and potentially damaging to the skin in some sites.Given the widespread use of emollients, the repeated exposure of newborns in the first month of life and the potential impact of emollients on mortality, trials such as those that have been conducted in Asia are needed in a range of African settings

Madagascar's grasses and grasslands:anthropogenic or natural?

Grasses, by their high productivity even under very low pCO2, their ability to survive repeated burning and to tolerate long dry seasons, have transformed the terrestrial biomes in the Neogene and Quaternary. The expansion of grasslands at the cost of biodiverse forest biomes in Madagascar is often postulated as a consequence of the Holocene settlement of the island by humans. However, we show that the Malagasy grass flora has many indications of being ancient with a long local evolutionary history, much predating the Holocene arrival of humans. First, the level of endemism in the Madagascar grass flora is well above the global average for large islands. Second, a survey of many of the more diverse areas indicates that there is a very high spatial and ecological turnover in the grass flora, indicating a high degree of niche specialization. We also find some evidence that there are both recently disturbed and natural stable grasslands: phylogenetic community assembly indicates that recently severely disturbed grasslands are phylogenetically clustered, whereas more undisturbed grasslands tend to be phylogenetically more evenly distributed. From this evidence, it is likely that grass communities existed in Madagascar long before human arrival and so were determined by climate, natural grazing and other natural factors. Humans introduced zebu cattle farming and increased fire frequency, and may have triggered an expansion of the grasslands. Grasses probably played the same role in the modification of the Malagasy environments as elsewhere in the tropics

A typology of longitudinal integrated clerkships

Context Longitudinal integrated clerkships (LICs) represent a model of the structural redesign of clinical education that is growing in the USA, Canada, Australia and South Africa. By contrast with time‐limited traditional block rotations, medical students in LICs provide comprehensive care of patients and populations in continuing learning relationships over time and across disciplines and venues. The evidence base for LICs reveals transformational professional and workforce outcomes derived from a number of small institution‐specific studies. Objectives This study is the first from an international collaborative formed to study the processes and outcomes of LICs across multiple institutions in different countries. It aims to establish a baseline reference typology to inform further research in this field. Methods Data on all LIC and LIC‐like programmes known to the members of the international Consortium of Longitudinal Integrated Clerkships were collected using a survey tool developed through a Delphi process and subsequently analysed. Data were collected from 54 programmes, 44 medical schools, seven countries and over 15 000 student‐years of LIC‐like curricula. Results Wide variation in programme length, student numbers, health care settings and principal supervision was found. Three distinct typological programme clusters were identified and named according to programme length and discipline coverage: Comprehensive LICs; Blended LICs, and LIC‐like Amalgamative Clerkships. Two major approaches emerged in terms of the sizes of communities and types of clinical supervision. These referred to programmes based in smaller communities with mainly family physicians or general practitioners as clinical supervisors, and those in more urban settings in which subspecialists were more prevalent. Conclusions Three distinct LIC clusters are classified. These provide a foundational reference point for future studies on the processes and outcomes of LICs. The study also exemplifies a collaborative approach to medical education research that focuses on typology rather than on individual programme or context

Safety, tumor trafficking and immunogenicity of chimeric antigen receptor (CAR)-T cells specific for TAG-72 in colorectal cancer.

BackgroundT cells engineered to express chimeric antigen receptors (CARs) have established efficacy in the treatment of B-cell malignancies, but their relevance in solid tumors remains undefined. Here we report results of the first human trials of CAR-T cells in the treatment of solid tumors performed in the 1990s.MethodsPatients with metastatic colorectal cancer (CRC) were treated in two phase 1 trials with first-generation retroviral transduced CAR-T cells targeting tumor-associated glycoprotein (TAG)-72 and including a CD3-zeta intracellular signaling domain (CART72 cells). In trial C-9701 and C-9702, CART72 cells were administered in escalating doses up to 1010 total cells; in trial C-9701 CART72 cells were administered by intravenous infusion. In trial C-9702, CART72 cells were administered via direct hepatic artery infusion in patients with colorectal liver metastases. In both trials, a brief course of interferon-alpha (IFN-α) was given with each CART72 infusion to upregulate expression of TAG-72.ResultsFourteen patients were enrolled in C-9701 and nine in C-9702. CART72 manufacturing success rate was 100% with an average transduction efficiency of 38%. Ten patients were treated in CC-9701 and 6 in CC-9702. Symptoms consistent with low-grade, cytokine release syndrome were observed in both trials without clear evidence of on target/off tumor toxicity. Detectable, but mostly short-term (≤14 weeks), persistence of CART72 cells was observed in blood; one patient had CART72 cells detectable at 48 weeks. Trafficking to tumor tissues was confirmed in a tumor biopsy from one of three patients. A subset of patients had 111Indium-labeled CART72 cells injected, and trafficking could be detected to liver, but T cells appeared largely excluded from large metastatic deposits. Tumor biomarkers carcinoembryonic antigen (CEA) and TAG-72 were measured in serum; there was a precipitous decline of TAG-72, but not CEA, in some patients due to induction of an interfering antibody to the TAG-72 binding domain of humanized CC49, reflecting an anti-CAR immune response. No radiologic tumor responses were observed.ConclusionThese findings demonstrate the relative safety of CART72 cells. The limited persistence supports the incorporation of co-stimulatory domains in the CAR design and the use of fully human CAR constructs to mitigate immunogenicity

Search for the Elusive Higgs Boson Using Jet Structure at LHC

We consider the production of a light non-standard model Higgs boson of order 100~\GEV with an associated $W$ boson at CERN Large Hadron Collider. We focus on an interesting scenario that, the Higgs boson decays predominately into two light scalars $\chi$ with mass of few GeV which sequently decay into four gluons, i.e. $h\to 2\chi \to 4g$. Since $\chi$ is much lighter than the Higgs boson, it will be highly boosted and its decay products, the two gluons, will move close to each other, resulting in a single jet for $\chi$ decay in the detector. By using electromagnetic calorimeter-based and jet substructure analyses, we show in two cases of different $\chi$ masses that it is quite promising to extract the signal of Higgs boson out of large QCD background.Comment: 20 pages, 7 figure

Cell-free (RNA) and cell-associated (DNA) HIV-1 and postnatal transmission through breastfeeding

<p>Introduction - Transmission through breastfeeding remains important for mother-to-child transmission (MTCT) in resource-limited settings. We quantify the relationship between cell-free (RNA) and cell-associated (DNA) shedding of HIV-1 virus in breastmilk and the risk of postnatal HIV-1 transmission in the first 6 months postpartum.</p> <p>Materials and Methods - Thirty-six HIV-positive mothers who transmitted HIV-1 by breastfeeding were matched to 36 non-transmitting HIV-1 infected mothers in a case-control study nested in a cohort of HIV-infected women. RNA and DNA were quantified in the same breastmilk sample taken at 6 weeks and 6 months. Cox regression analysis assessed the association between cell-free and cell-associated virus levels and risk of postnatal HIV-1 transmission.</p> <p>Results - There were higher median levels of cell-free than cell-associated HIV-1 virus (per ml) in breastmilk at 6 weeks and 6 months. Multivariably, adjusting for antenatal CD4 count and maternal plasma viral load, at 6 weeks, each 10-fold increase in cell-free or cell-associated levels (per ml) was significantly associated with HIV-1 transmission but stronger for cell-associated than cell-free levels [2.47 (95% CI 1.33–4.59) vs. aHR 1.52 (95% CI, 1.17–1.96), respectively]. At 6 months, cell-free and cell-associated levels (per ml) in breastmilk remained significantly associated with HIV-1 transmission but was stronger for cell-free than cell-associated levels [aHR 2.53 (95% CI 1.64–3.92) vs. 1.73 (95% CI 0.94–3.19), respectively].</p> <p>Conclusions - The findings suggest that cell-associated virus level (per ml) is more important for early postpartum HIV-1 transmission (at 6 weeks) than cell-free virus. As cell-associated virus levels have been consistently detected in breastmilk despite antiretroviral therapy, this highlights a potential challenge for resource-limited settings to achieve the UNAIDS goal for 2015 of eliminating vertical transmission. More studies would further knowledge on mechanisms of HIV-1 transmission and help develop more effective drugs during lactation.</p&gt

"Why not bathe the baby today?": A qualitative study of thermal care beliefs and practices in four African sites

BACKGROUND: Recommendations for care in the first week of a newborn's life include thermal care practices such as drying and wrapping, skin to skin contact, immediate breastfeeding and delayed bathing. This paper examines beliefs and practices related to neonatal thermal care in three African countries. METHODS: Data were collected in the same way in each site and included 16-20 narrative interviews with recent mothers, eight observations of neonatal bathing, and in-depth interviews with 12-16 mothers, 9-12 grandmothers, eight health workers and 0-12 birth attendants in each site. RESULTS: We found similarities across sites in relation to understanding the importance of warmth, a lack of opportunities for skin to skin care, beliefs about the importance of several baths per day and beliefs that the Vernix caseosa was related to poor maternal behaviours. There was variation between sites in beliefs and practices around wrapping and drying after delivery, and the timing of the first bath with recent behavior change in some sites. There was near universal early bathing of babies in both Nigerian sites. This was linked to a deep-rooted belief about body odour. When asked about keeping the baby warm, respondents across the sites rarely mentioned recommended thermal care practices, suggesting that these are not perceived as salient. CONCLUSION: More effort is needed to promote appropriate thermal care practices both in facilities and at home. Programmers should be aware that changing deep rooted practices, such as early bathing in Nigeria, may take time and should utilize the current beliefs in the importance of neonatal warmth to facilitate behaviour change