Estimating Local Cellular Density in Glioma Using MR Imaging Data

BACKGROUND AND PURPOSE:Increased cellular density is a hallmark of gliomas, both in the bulk of the tumor and in areas of tumor infiltration into surrounding brain. Altered cellular density causes altered imaging findings, but the degree to which cellular density can be quantitatively estimated from imaging is unknown. The purpose of this study was to discover the best MR imaging and processing techniques to make quantitative and spatially specific estimates of cellular density.MATERIALS AND METHODS:We collected stereotactic biopsies in a prospective imaging clinical trial targeting untreated patients with gliomas at our institution undergoing their first resection. The data included preoperative MR imaging with conventional anatomic, diffusion, perfusion, and permeability sequences and quantitative histopathology on biopsy samples. We then used multiple machine learning methodologies to estimate cellular density using local intensity information from the MR images and quantitative cellular density measurements at the biopsy coordinates as the criterion standard.RESULTS:The random forest methodology estimated cellular density with R² = 0.59 between predicted and observed values using 4 input imaging sequences chosen from our full set of imaging data (T2, fractional anisotropy, CBF, and area under the curve from permeability imaging). Limiting input to conventional MR images (T1 pre- and postcontrast, T2, and FLAIR) yielded slightly degraded performance (R² = 0.52). Outputs were also reported as graphic maps.CONCLUSIONS:Cellular density can be estimated with moderate-to-strong correlations using MR imaging inputs. The random forest machine learning model provided the best estimates. These spatially specific estimates of cellular density will likely be useful in guiding both diagnosis and treatment.

Increased cellular density (CD) is a hallmark of cancer and a key feature in histologic glioma analysis.¹ Mapping cellular density throughout a tumor would be a valuable tool to probe how tumors infiltrate and analyze the transition between diseased and healthy brain. However, measuring CD requires tissue, which entails additional risks and is expensive to obtain. There is no currently accepted clinical algorithm to translate imaging data into quantitative assessments of CD.There is great need for a method to estimate CD noninvasively in human patients with gliomas. In this article, we describe the development of such a method using MR imaging data inputs by correlating with multiple biopsy specimens acquired during a prospective human clinical trial. We obtained comprehensive MR imaging, including conventional, diffusion, perfusion, and permeability imaging sequences. We used machine learning approaches to correlate imaging findings with CD measurements from pathology, devised an algorithm to estimate CD from MR imaging inputs, and generated CD maps for the visual display of the predictions. We identified the most informative imaging data subset. This work has multiple applications in the diagnosis and treatment of patients with gliomas: For example, the method can be used to guide biopsy, resection, and surgery and delineate tumor borderzones both pre- and postoperatively.²     

Citation analysis of the most influential articles on traumatic spinal cord injury

Objective: We conducted a citation analysis in order to catalog and pay tribute to the 100 most influential clinical research articles in traumatic spinal cord injury.

Design: The Thomson Reuters Web of Science was searched in a two-step process without time period limitations. Review articles were excluded. In the first stage of data extraction, a Boolean query was used to identify the top 100 most cited clinical papers on traumatic spinal cord injury. One hundred and seven keywords were manually chosen and extracted from titles and abstracts. A second Boolean query used these keywords to broaden search results. The top 100 articles from this second stage search comprised the final list.

Outcome Measures: For each article, measures evaluated were number of citations, average number of citations per year, time elapsed before first citation, and time elapsed until the year in which each article received its respective highest number of citations in a one-year period.

Results: 119,991 articles were found in the second stage search. The top 100 most cited articles meeting inclusion criteria were identified within the first 2,104 results. Archives of Physical Medicine and Rehabilitation was the most represented journal, with 20 of the top 100 articles. The top 100 list averaged 255 citations per article. The most highly cited article was the NASCIS 2 trial by Bracken et al., cited 1500 times, which investigated the efficacy of methylprednisolone or naloxone for spinal cord injury.

Conclusion: Clinical research in traumatic spinal cord injury has grown over time, expanding to encompass rehabilitation and experimental therapies in addition to acute management trials. The list may serve as an archive and reference for further studies in this field.     

Effects of short birth spacing on birth-order differences in child stunting: Evidence from India

Do firstborn children have a height advantage? Empirical findings have found mostly that, yes, second or higher-order children often lag behind firstborns in height outcomes, especially in developing countries. However, empirical investigations of birth-order effects on child height overlook the potential impact that birth spacing can have. We provide an explanation for the negative birth-order effect on stunting outcomes for young Indian children and show it is driven by short preceding-birth spacing. We find that firstborn children are taller than children of higher birth order: The height-for-age gap for third (or higher)-order children is twice the gap for children second in birth order. However, this pattern is observed when spacing between later-born children and their immediate elder siblings is fewer than 3 y. Interestingly, the firstborn height advantage disappears when later-born children are born at least 3 y after their elder siblings. Thus, our findings indicate that spacing length between children explains differences in height, over birth order. Although India’s family planning policy has resulted in a substantial reduction in total fertility, its achievement in spacing subsequent births has been less impressive. In showing that spacing can alleviate or aggravate birth-order effects on attained height, our study fills an evidence gap: Reducing fertility alone may not be sufficient in overcoming negative birth-order effects. To reduce the detrimental effects of birth order on child stunting, policy responses—and therefore research priorities—require a stronger focus on increasing the time period between births.

Child undernutrition continues to be a problem in low-and middle-income countries, and adversely affects child survival and well being (1). While child undernutrition is gauged by several indicators, stunting—a key marker of chronic undernutrition obtained by comparing child height with that of children in the same age group in a healthy reference population—is at the forefront of discussion because of its vast prevalence across all developing regions and its important consequences for health and development. Almost all of stunting takes place in the first 1,000 d from conception to 2 y of age, but its consequences follow throughout adulthood. These consequences are largely irreversible, making stunting an extremely critical condition (2, 3). Children who are stunted are vulnerable to disease and mortality during childhood and run a much higher risk of developing deficits in later-life outcomes, including in adult height, cognitive and intellectual ability, and as a consequence, on schooling attainment, productivity, and earnings (4–10). Furthermore, if stunting is accompanied by excessive weight gain later in childhood, there is an increased risk of developing adult obesity and nutrition-related chronic diseases, including cardiovascular disease, stroke, and type 2 diabetes in adult life (see, for example, ref. 6). In addition, stunted girls carry additional risk of having adverse pregnancy outcomes and reproductive complications as adults, leading to detrimental intergenerational effects (11, 12). Nevertheless, stunting is preventable, and reducing it is an important component of overall development for the well being of children.In recognition of the high social and economic costs of stunting, efforts are ongoing to address this public health issue, including programs aimed at reducing poverty and inequality, improving dietary intake and access to healthcare services, and improving the hygiene environment. Childhood stunting has declined by 35% from a global estimate of 253 million in 1990, with over 90 million children protected from suboptimal growth and a large number of child deaths prevented. However, this decrease is small relative to the overall burden, as over 161 million children under 5 y were reported to be stunted in 2011 (13). Furthermore, there is a large disparity in numbers across regions, with the highest number of over 69 million stunted children living in South Asia and with India bearing 90% of this regional burden (14). Thus, although stunting levels have been reduced, the progress has been both uneven and suboptimal (15). There is need to develop strategies, policies, and programs tailored to local conditions, which in turn require a case-by-case approach to identify what other conditions may be predisposing children to poor height in certain regions, and also, within regions.Birth order—an indicator of a child’s position in the age hierarchy of siblings—has been used time and again to explain variation in height outcomes in children. Children born to the same parents share the same genetic make-up; yet, the order in which they are born exposes them to different biological and behavioral environments (16, 17). Through differences in health endowments and parental investments, birth order often affects the health and nutritional outcomes of children. Hence, birth-order effects reflect differences in the unshared environment within a family. The literature on child stunting has provided significant evidence from across countries that children of lower birth order are at an advantage, compared to children of higher birth order. Firstborn children are taller compared to those born subsequently, and this height advantage increases sharply over the higher order of birth of siblings. Explanations for the firstborn height advantage have addressed issues, such as better health endowments of the firstborn at birth and parental favoritism toward some offspring over others—usually the eldest son—generating more prenatal and postnatal investments, greater time investment in child care, longer duration of breastfeeding, and also affecting the desire for having more children (18–24).However, an important factor in assessing the birth-order effects on child health and nutritional outcomes is the length of interval between two consecutive births: That is, birth spacing. A wealth of studies have shown that a short length of birth spacing is associated with higher risk of maternal mortality and adverse subsequent birth outcomes, such as child mortality, preterm birth, small for gestational age, and low birthweight, though the degree to which the relationship holds varies substantially across countries (25–29). These associations stem from the biological factor commonly referred to as maternal depletion syndrome (26, 30). Closely spaced pregnancies may not allow sufficient time for the mother to restore her depleted micronutrient and macronutrient stores from the previous birthing, which in turn may reduce her ability to provide a favorable fetal growth environment in subsequent pregnancies and sufficient breast milk production postdelivery. Literature also suggests short birth spacing is associated with suboptimal parental care practices, which adversely affect the health and nutritional outcomes of siblings born close to each other. For example, the birth of a new baby may reduce the parental care time devoted to older siblings, as well as result in poor postnatal investment; similarly, a new pregnancy may reduce or curtail breast milk production, which may lead to suboptimal feeding for older siblings.While the aforementioned channels show the potential for longer birth spacing to influence nutritional outcomes of children more positively, especially for the later born, empirical inquiry into the spacing order linkages is limited. We believe that birth order and height linkage can be better understood by examining the interaction between birth order and birth spacing. Using an illustrative example of India in this paper, we demonstrate that the negative association between increasing birth order and child height is driven by the short length of interval between births. We link height-for-age standardized scores (HAZ) of children under 5 y, recorded in the latest Indian Demographic and Health Survey (DHS), to an indicator of birth order, disaggregated by the length of preceding birth spacing. When birth order is considered alone, we find that firstborn children on average are taller than children of higher birth order. This result is consistent with previous research on birth order. However, we discover noteworthy changes in the patterns of the HAZ gap between firstborn and subsequent children on combining birth order with preceding birth spacing. We find that the firstborn height advantage is significant if birth spacing between the higher-order child and its immediate elder sibling is less than 3 y, and this advantage gets steeper with increasing order of birth; that is, the height advantage for firstborns, compared to children from third or higher-order births, is almost twice the height advantage for firstborns, compared to children of second-birth order. Interestingly, if the birth spacing between the higher birth-order child and its immediate elder sibling is 3 or more years, the firstborn height advantage disappears and becomes insignificant. This is true with respect to the gap for all higher birth-order children. Thus, higher birth-order children, on average, are as tall as firstborn children if they are appropriately spaced. Our results emphasize the importance of time between births in determining height outcomes of young children, over birth order, and demonstrate how spacing length may weaken or strengthen the birth-order effect on child height. Designing and implementing policies and interventions that affect knowledge and attitude toward healthy spacing could significantly impact the health, nutrition, and accomplishments of young children.However, we emphasize at the outset that our analysis is exploratory in nature. An ideal dataset for comparing height outcomes across birth orders would require longitudinal data, recording all pregnancies conceived by a woman with predelivery and postdelivery information related to healthcare, as well as feeding practices for every living child. Because of the absence of datasets that cover all these aspects, we rely on DHS data, which are closely but imperfectly suited to the question at hand. The nature of DHS is such that anthropometry is recorded only for children below 5 y, and for many healthcare and dietary intake variables the information is collected only for the youngest child born to the mother. Hence, the reduced sample size and data limitations preclude our ability to establish causality. However, the large sample size is sufficient to assess subgroup and interaction effects. We address several possible biases or limitations of using survey data with additional analyses.     

Acute phase protein, α – 1- acid glycoprotein (AGP-1), has differential effects on TLR-2 and TLR-4 mediated responses

Alpha-1-acid glycoprotein (AGP-1) is a major positive acute phase glycoprotein with unknown functions that likely play a role in inflammation. We tested its involvement in a variety of inflammatory responses using human AGP-1 purified to apparent homogeneity and confirmed its identity by immunoblotting and mass spectrometry. AGP-1 alone upregulated MAPK signaling in murine peritoneal macrophages. However, when given in combination with TLR ligands, AGP-1 selectively augmented MAPK activation induced by ligands of TLR-2 (Braun lipoprotein) but not TLR-4 (lipopolysaccharide). In vivo treatment of AGP-1 in a murine model of sepsis with or without TLR-2 or TLR-4 ligands, selectively potentiated TLR-2-mediated mortality, but was without significant effect on TLR-4-mediated mortality. Furthermore, in vitro, AGP-1 selectively potentiated TLR-2 mediated adhesion of human primary immune cell, neutrophils. Hence, our studies highlight a new role for the acute phase protein AGP-1 in sepsis via its interaction with TLR-2 signaling mechanisms to selectively promote responsiveness to one of the two major gram-negative endotoxins, contributing to the complicated pathobiology of sepsis.     

Awl versus intravenous cannula stillete in circummandibular wiring��a prospective comparative study

Purpose

The management of paediatric mandibular fractures using an acrylic splint is a time-tested procedure. Traditionally, an awl is used to place wires to secure such splints. In this article, we have designed prospective study to compare a new technique of using intravenous cannula stillete (IVCS) as against conventional awl in placement of the circummandibular wires.

Methods

A total of 45 patients were included in the study. Group I included 22 subjects in whom an awl was used, and group II included 23 subjects in whom IVCS was used for placement of circummandibular wires. Parameters such as post-operative pain, swelling and ease of penetration, size of entry and exit wound and injury to adjacent structures were compared.

Results

Statistically significant reduction in post-operative pain and swelling were noticed in groupie. The operating surgeons experienced greater ease in using IVCS, and the size of the entry and exit wounds were also relatively small as compared to using an awl.

Conclusion

The IVCS, which is disposable, having finer diameter, a sharp bevel and internal wire carrying capacity, clearly demonstrates statistically significant advantages over the usage of a conventional awl.     

Spontaneous closure of midline diastema following frenectomy

Maxillary midline diastema is a common aesthetic problem in mixed and early permanent dentitions. The space can occur either as a transient malocclusion or created by developmental, pathological or iatrogenical factors. Many innovative therapies varying from restorative procedures such as composite build-up to surgery (frenectomies) and orthodontics are available. Although literature says every frenectomy procedure should be preceded by orthodontic treatment, we opted for frenectomy technique without any orthodontic intervention. Presented herewith is a case report of a 9-year-old girl with a high frenal attachment that had caused spacing of the maxillary central incisors. A spontaneous closure of the midline diastema was noted within 2 months following frenectomy. The patient was followed up for 4 months after which the space remained closed and there was no necessity for an orthodontic treatment at a later stage.     

Fabrication of an auricular prosthesis: a case report

The fabrication of ear prosthesis is considered by many prosthetists to be one of the more difficult replacements in maxillofacial reconstruction. The severe undercuts and pronounced convolutions of the ear's surface present a challenge in simulating a natural proportioned prosthesis. The mould for the ear is generally made by creating a three surface die to reproduce the unique configuration adequately and to allow retrieval of the finished prosthesis without damage. This article presents an outlined procedure in the basic fabrication of a prosthetic ear by a conventional technique where the wax pattern is fabricated from the impression of an individual with a similarly proportioned ear. CLINICAL RELEVANCE: Fabricating an auricular prosthesis may be part of the work of a maxillofacial department.     

A comparison of costs in providing dental care for special needs patients under sedation or general anaesthesia in the North East of England.

OBJECTIVE: To compare the costs of providing dental treatment under general anaesthesia or sedation for special needs patients. METHODS: After a Delphi exercise, a questionnaire was designed, piloted and then sent to nine NHS Trust dental service managers, within the Salaried Dental Services in the North East of England, to obtain information on the costs incurred during the treatment of special needs patients using sedation or general anaesthesia. The questionnaire related to the average number of such patients treated per session, staff costs, depreciation cost for buildings and equipment, and overhead costs including consumables and drugs. RESULTS: All nine dental service managers returned completed questionnaires. The all-inclusive cost for treatment per patient under general anaesthesia ranged from 203.65-479.50 pounds (mean cost: 285.79 pounds) and for sedation from 57.60-153.50 pounds (mean cost: 90.81 pounds). On average three special needs patients were treated per session. The greatest variation in the costs for general anaesthesia was due to staffing costs, which ranged from 1064.10 to 350.00 pounds per session across the Trusts. CONCLUSIONS: In the small number of centres sampled, the cost of delivering dental care under sedation or general anaesthesia was shown to vary widely. Overall, the mean cost of sedation was one-third that of general anaesthesia. However, the cost of both was substantial and cognisance needs to be taken of the costs of such services.