Pray for the People Who Feed You : Voices of Pauper Children in the Industrial Age

Following the Industrial Revolution in the late nineteenth and early twentieth centuries, countries such as the United States and England experienced a widening gap between the rich industrialists and the impoverished working class. As a result, poverty quickly shifted from a localized problem to a national epidemic. Each country was faced with the challenges of addressing and alleviating poverty on a national scale. With a limited amount of resources, questions arose about who should receive relief. What should it look like? How should it be administered? And how would poverty and policy affect political, economic, social and familial structures? [excerpt]https://cupola.gettysburg.edu/artcatalogs/1016/thumbnail.jp

The Figure in Art: Selections from the Gettysburg College Collection

The Figure in Art: Selections from the Gettysburg College Collection is the second annual exhibition curated by students enrolled in the Art History Methods class. This exhibition is an exciting academic endeavor and provides an incredible opportunity for engaged learning, research, and curatorial experience. The eleven student curators are Diane Brennan, Rebecca Duffy, Kristy Garcia, Megan Haugh, Dakota Homsey, Molly Lindberg, Kathya Lopez, Kelly Maguire, Kylie McBride, Carolyn McBrady and Erica Schaumberg. Their research presents a multifaceted view of the representation of figures in various art forms from different periods and cultures.https://cupola.gettysburg.edu/artcatalogs/1017/thumbnail.jp

Explorations, Vol. 6, No. 1

Cover: Panthera pardus, Chui in Kiswatuli, was photographed by Dr. Linda Karbonit ar Dr. James A. Sherburne in Serengeti National Park, Tanzania. Karbonit was accompanying Sherburne who was working on the design and development of the University of Maine, U.S. Fish and Wildlife Service, assistance program in wildlife training and conservation education to Tanzania’s National Parks. Sherburne, who has worked in Tanzania for several years, was there most recently in 1988 and 1989 working on the parks project. He serves as the Director of International Natural Resources and Agricultural Programs at the University of Maine. Articles include: Research and Economic Development: from the U.S. Senate Statement, December 22, 1989, by Sen. George J. Mitchell Politics and Research: Providing a Key for Economic Development, by Sen. William S. Cohen. Publisher’s Perspective, by Gregory N. Brown, Vice President, Research and Public Service What’s EPSCoR? Editorial Reflections, by Carole J. Bombard Past and Present: Marine Geologists Explore the Old and Teach the Young, by Daniel Belknap and Joseph Kelley High Biological Productivity: Salt Marshes, by Mark E. Wood Barrier Beaches, by William Duffy Sediment Budgets & Bluff Slump, by Rebecca Smith Coastal Environments and Change, by Andrew Walsh Mapping What You Can\u27t See, by Donald Robbins Casco Bay: Sea Level and the Shoreline, by Bradley W.B. Hay Christmas at Sea, by Molly Horvath A Short Course and the Local Economy, by Richard Hale and James Philp Dr. Bernard Lown: Alumnus Receives Golden Door Award The Sky is Falling . . . well, maybe, by Carole J. Bombard A Growing Interest in Timberland, by Robert A. Strong and Bret P. Vicar

Chronic recurrent Gorham-Stout syndrome with cutaneous involvement

Type IV osteolysis or Gorham-Stout syndrome is a rare condition characterized by recurrent vascular tumors that disrupt normal anatomical architecture. Gorham-Stout syndrome is most commonly associated with the skeletal system with resulting replacement of bone with scar tissue following tumor regression. The loss of entire bones has given Gorham-Stout syndrome the moniker vanishing bone disease. Natural progression of Gorham-Stout syndrome is characterized by spontaneous disease resolution. However, rare variants of recurrent, progressive, and/or systemic disease have been reported. We present a patient with a history of recurrent Gorham- Stout disease refractory to all treatment options considered. In addition to skeletal disease, our patient had soft tissue and cutaneous involvement, thus reflecting the more aggressive disease variant. Previous surgical attempts to control disease had been ineffective and the patient was referred to us for radiation therapy. Treatment with external beam radiation therapy resulted in good local control and symptom palliation, but full disease resolution was never accomplished. In addition to presentation of this patient, a review of the literature on etiological hypotheses and past/future treatment options was conducted and is included

Dynamic loading of human engineered heart tissue enhances contractile function and drives a desmosome-linked disease phenotype

The role that mechanical forces play in shaping the structure and function of the heart is critical to understanding heart formation and the etiology of disease but is challenging to study in patients. Engineered heart tissues (EHTs) incorporating human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes have the potential to provide insight into these adaptive and maladaptive changes. However, most EHT systems cannot model both preload (stretch during chamber filling) and afterload (pressure the heart must work against to eject blood). Here, we have developed a new dynamic EHT (dyn-EHT) model that enables us to tune preload and have unconstrained contractile shortening of >10%. To do this, three-dimensional (3D) EHTs were integrated with an elastic polydimethylsiloxane strip providing mechanical preload and afterload in addition to enabling contractile force measurements based on strip bending. Our results demonstrated that dynamic loading improves the function of wild-type EHTs on the basis of the magnitude of the applied force, leading to improved alignment, conduction velocity, and contractility. For disease modeling, we used hiPSC-derived cardiomyocytes from a patient with arrhythmogenic cardiomyopathy due to mutations in the desmoplakin gene. We demonstrated that manifestation of this desmosome-linked disease state required dyn-EHT conditioning and that it could not be induced using 2D or standard 3D EHT approaches. Thus, a dynamic loading strategy is necessary to provoke the disease phenotype of diastolic lengthening, reduction of desmosome counts, and reduced contractility, which are related to primary end points of clinical disease, such as chamber thinning and reduced cardiac output

Tick-, mosquito-, and rodent-borne parasite sampling designs for the National Ecological Observatory Network

Parasites and pathogens are increasingly recognized as significant drivers of ecological and evolutionary change in natural ecosystems. Concurrently, transmission of infectious agents among human, livestock, and wildlife populations represents a growing threat to veterinary and human health. In light of these trends and the scarcity of long-term time series data on infection rates among vectors and reservoirs, the National Ecological Observatory Network (NEON) will collect measurements and samples of a suite of tick-, mosquito-, and rodent-borne parasites through a continental-scale surveillance program. Here, we describe the sampling designs for these efforts, highlighting sampling priorities, field and analytical methods, and the data as well as archived samples to be made available to the research community. Insights generated by this sampling will advance current understanding of and ability to predict changes in infection and disease dynamics in novel, interdisciplinary, and collaborative ways. (Résumé d'auteur

Potent dual inhibitors of Plasmodium falciparum M1 and M17 aminopeptidases through optimization of S1 pocket interactions

Malaria remains a global health problem, and though international efforts for treatment and eradication have made some headway, the emergence of drug-resistant parasites threatens this progress. Antimalarial therapeutics acting via novel mechanisms are urgently required. P. falciparum M1 and M17 are neutral aminopeptidases which are essential for parasite growth and development. Previous work in our group has identified inhibitors capable of dual inhibition of PfA-M1 and PfA-M17, and revealed further regions within the protease S1 pockets that could be exploited in the development of ligands with improved inhibitory activity. Herein, we report the structure-based design and synthesis of novel hydroxamic acid analogues that are capable of potent inhibition of both PfA-M1 and PfA-M17. Furthermore, the developed compounds potently inhibit Pf growth in culture, including the multi-drug resistant strain Dd2. The ongoing development of dual PfA-M1/PfA-M17 inhibitors continues to be an attractive strategy for the design of novel antimalarial therapeutics

Tick-, Mosquito-, and Rodent-Borne Parasite Sampling Designs for the National Ecological Observatory Network [Special Feature: NEON Design]

Parasites and pathogens are increasingly recognized as significant drivers of ecological and evolutionary change in natural ecosystems. Concurrently, transmission of infectious agents among human, livestock, and wildlife populations represents a growing threat to veterinary and human health. In light of these trends and the scarcity of long-term time series data on infection rates among vectors and reservoirs, the National Ecological Observatory Network (NEON) will collect measurements and samples of a suite of tick-, mosquito-, and rodent-borne parasites through a continental-scale surveillance program. Here, we describe the sampling designs for these efforts, highlighting sampling priorities, field and analytical methods, and the data as well as archived samples to be made available to the research community. Insights generated by this sampling will advance current understanding of and ability to predict changes in infection and disease dynamics in novel, interdisciplinary, and collaborative ways

Antidepressant treatment with sertraline for adults with depressive symptoms in primary care : the PANDA research programme including RCT

Background Despite a growing number of prescriptions for antidepressants (over 70 million in 2018), there is uncertainty about when people with depression might benefit from antidepressant medication and concern that antidepressants are prescribed unnecessarily. Objectives The main objective of the PANDA (What are the indications for Prescribing ANtiDepressAnts that will lead to a clinical benefit?) research programme was to provide more guidance about when antidepressants are likely to benefit people with depression. We aimed to estimate the minimal clinically important difference for commonly used self-administered scales for depression and anxiety, and to understand more about how patients respond to such assessments. We carried out an observational study of patients with depressive symptoms and a placebo-controlled randomised controlled trial of sertraline versus placebo to estimate the treatment effect in UK primary care. The hypothesis was that the severity and duration of symptoms were related to treatment response. Design The programme consisted of three phases. The first phase relied on the secondary analysis of existing data extracted from published trials. The second phase was the PANDA cohort study of patients with depressive symptoms who presented to primary care and were followed up 2, 4 and 6 weeks after a baseline assessment. Both quantitative and qualitative methods were used in the analysis. The third phase was a multicentre randomised placebo-controlled double-blind trial of sertraline versus placebo in patients presenting to primary care with depressive symptoms. Setting UK primary care in Bristol, London, Liverpool and York. Participants Patients aged 18–74 years who were experiencing depressive symptoms in primary care. Eligibility for the PANDA randomised controlled trial included that there was uncertainty about the benefits about treatment with an antidepressant. Interventions In the PANDA randomised controlled trial, patients were individually randomised to 100 mg daily of sertraline or an identical placebo. The PANDA cohort study was an observational study. Main outcome measures Depressive symptoms measured using the Patient Health Questionnaire were the primary outcome for the randomised controlled trial. Other outcomes included anxiety symptoms using the Generalised Anxiety Disorder-7; depressive symptoms using the Beck Depression Inventory, version 2; health-related quality of life; self-reported improvement; and cost-effectiveness. Results The secondary analysis of existing randomised controlled trials [GENetic and clinical Predictors Of treatment response in Depression (GenPod), TREAting Depression with physical activity (TREAD) and Clinical effectiveness and cost-effectiveness of cognitive Behavioural Therapy as an adjunct to pharmacotherapy for treatment-resistant depression in primary care (CoBalT)] found evidence that the minimal clinically important difference increased as the initial severity of depressive symptoms rose. Our estimates of minimal clinically important difference were a 17% and 18% reduction in Beck Depression Inventory scores for GenPod and TREAD, respectively. In CoBalT, a 32% reduction corresponded to the minimal clinically important difference but the participants in this study had depression that had not responded to antidepressants. In the PANDA study cohort, and from our analyses in existing data, we found that the minimal clinically important difference varies considerably with the initial severity of depressive and anxiety symptoms. Expressing the minimal clinically important difference as a percentage reduction reduces this variation at higher scores, but at low scores the percentage reduction increased substantially. The results from the qualitative studies pointed out many limitations of the Patient Health Questionnaire-9 items in assessing change and recovery from depression. In the PANDA randomised controlled trial, there was no evidence that sertraline resulted in a reduction in depressive symptoms within 6 weeks of randomisation, but there was some evidence of a reduction by 12 weeks. However, sertraline led to a reduction in anxiety symptoms, an improvement of mental health-related quality of life and an increased likelihood of reporting improvement. The mean Patient Health Questionnaire-9 items score at 6 weeks was 7.98 (standard deviation 5.63) in the sertraline group and 8.76 (standard deviation 5.86) in the placebo group (5% relative reduction, 95% confidence interval –7% to 15%; p = 0.41). Of the secondary outcomes, there was strong evidence that sertraline reduced anxiety symptoms (Generalised Anxiety Disorder-7 score reduced by 17% (95% confidence interval 9% to 25%; p = 0.00005). Sertraline had a high probability (> 90%) of being cost-effective at 12 weeks. The PANDA randomised controlled trial found no evidence that treatment response or cost-effectiveness was related to severity or duration of depressive symptoms. The minimal clinically important difference estimates suggested that sertraline’s effect on anxiety, but not on depression, was likely to be clinically important. Limitations The results from the randomised controlled trial and the estimates of minimal clinically important difference were not sufficiently precise to provide specific clinical guidance for individuals. We had low power in testing whether or not initial severity and duration of depressive symptoms are related to treatment response. Conclusions The results of the trial support the use of sertraline and probably other selective serotonin reuptake inhibitors because of their action in reducing anxiety symptoms and the likelihood of longer-term benefit on depressive symptoms. Sertraline could be prescribed for anxiety symptoms that commonly occur with depression and many patients will experience a clinical benefit. The Patient Health Questionnaire-9 items and similar self-administered scales should not be used on their own to assess clinical outcome, but should be supplemented with further clinical assessment. Future work We need to examine the longer-term effects of antidepressant treatment. We need more precise estimates of the treatment effects and minimal clinically important difference at different severities to provide more specific guidance for individuals. However, the methods we have developed provide an approach towards providing such detailed guidance. Trial registration Current Controlled Trials ISRCTN84544741 and EudraCT number 2013-003440-22. Funding This project was funded by the National Institute for Health Research (NIHR) Programme Grants for Applied Research programme and will be published in full in Programme Grants for Applied Research; Vol. 7, No. 10. See the NIHR Journals Library website for further project information

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment