So Many Choices, How Do I Choose? Considerations for Selecting Digital Health Interventions to Support Immunization Confidence and Demand.

Childhood vaccines are a safe, effective, and essential component of any comprehensive public health system. Successful and complete child immunization requires sensitivity and responsiveness to community needs and concerns while reducing barriers to access and providing respectful quality services. Community demand for immunization is influenced by multiple complex factors, involving attitudes, trust, and the dynamic relationship between caregivers and health workers. Digital health interventions have the potential to help reduce barriers and enhance opportunities for immunization access, uptake, and demand in low- and middle-income countries. But with limited evidence and many interventions to choose from, how do decision makers identify promising and appropriate tools? Early evidence and experiences with digital health interventions for immunization demand are presented in this viewpoint to help stakeholders make decisions, guide investment, coordinate efforts, as well as design and implement digital health interventions to support vaccine confidence and demand.

THE USE OF INTRADERMAL SKIN TESTING AND HYPOSENSITIZATION INJECTIONS TO CONTROL SEASONAL DERMATITIS IN GREATER ONE-HORNED RHINOCEROSES (RHINOCEROS UNICORNIS).

Allergic dermatitis was diagnosed in a 25-yr-old female greater one-horned rhinoceros (Rhinoceros unicornis) and her 6-yr-old female offspring by skin biopsy, intradermal skin testing (IDST), and allergen-specific serum IgE testing. Dam and offspring presented with seasonal, erosive, and ulcerative dermatitis affecting the face, legs, and trunk starting at 6 and 2 yr of age, respectively. IDST was performed at the caudal pinnal base using 61 regionally specific allergens. Specific serum allergen responses were detected using Heska's Equine ALLERCEPT® Allergen Panel. Histopathology of the lesions was consistent with an allergic etiology. Injectable allergen-specific immunotherapy was initiated in both animals and within 6 to 18 mon after commencing hyposensitization clinical improvement was noted. This report documents a repeatable methodology for IDST and serological allergen testing for use in rhinoceroses. The hyposensitization protocol detailed here can help guide future treatment protocols.

Every Child on the Map: A Theory of Change Framework for Improving Childhood Immunization Coverage and Equity Using Geospatial Data and Technologies.

The effective use of geospatial data and technologies to collect, manage, analyze, model, and visualize geographic data has great potential to improve data-driven decision-making for immunization programs. This article presents a theory of change for the use of geospatial technologies for immunization programming-a framework to illustrate the ways in which geospatial data and technologies can contribute to improved immunization outcomes and have a positive impact on childhood immunization coverage rates in low- and middle-income countries. The theory of change is the result of a review of the state of the evidence and literature; consultation with implementers, donors, and immunization and geospatial technology experts; and a review of country-level implementation experiences. The framework illustrates how the effective use of geospatial data and technologies can help immunization programs realize improvements in the number of children immunized by producing reliable estimates of target populations, identifying chronically missed settlements and locations with the highest number of zero-dose and under-immunized children, and guiding immunization managers with solutions to optimize resource distribution and location of health services. Through these direct effects on service delivery, geospatial data and technologies can contribute to the strengthening of the overall health system with equity in immunization coverage. Recent implementation of integrated geospatial data and technologies for the immunization program in Myanmar demonstrate the process that countries may experience on the path to achieving lasting systematic improvements. The theory of change presented here may serve as a guide for country program managers, implementers, donors, and other stakeholders to better understand how geospatial tools can support immunization programs and facilitate integrated service planning and equitable delivery through the unifying role of geography and geospatial data.

Before compassion: sympathy, tact and the history of the ideal nurse.

The word 'compassion' is ubiquitous in modern healthcare. Yet few writers agree on what the term means, and what makes it an essential trait in nursing. In this article, I take a historical approach to the problem of understanding compassion. Although many modern writers have assumed that compassion is a universal and unchanging trait, my research reveals that the term is extremely new to healthcare, only becoming widely used in 2009. Of course, even if compassion is a new term in nursing, the concept could have previously existed under another name. I thus consider the emotional qualities associated with the ideal nurse during the interwar period in the UK. While compassion was not mentioned in nursing guidance in this era another term, 'sympathy', made frequent appearance. The interwar concept of sympathy, however, differs significantly from the modern one of compassion. Sympathy was not an isolated concept. In the interwar era, it was most often linked to the nurse's tact or diplomacy. A closer investigation of this link highlights the emphasis laid on patient management in nursing in this period, and the way class differentials in emotion between nurse and patient were considered essential to the efficient running of hospitals. This model of sympathy is very different from the way the modern 'compassion' is associated with patient satisfaction or choice. Although contemporary healthcare policy assumes 'compassion' to be a timeless, personal characteristic rooted in the individual behaviours and choices of the nurse, this article concludes that compassionate nursing is a recent construct. Moreover, the performance of compassion relies on conditions and resources that often lie outside of the nurse's personal control. Compassion in nursing-in theory and in practice-is inseparable from its specific contemporary contexts, just as sympathy was in the interwar period.

ASSESSMENT OF MULTIANTIGEN PRINT IMMUNOASSAY AND RAPID LATERAL-FLOW TEST FOR THE DETECTION OF MYCOBACTERIUM BOVIS INFECTION IN MALAYAN TAPIR (TAPIRUS INDICUS).

A multiantigen print immunoassay (MAPIA) and rapid test (RT) developed and validated for detection of mycobacterial antibodies in elephants (Elephas maximus and Loxodonta africana) was assessed in Malayan tapir (Tapirus indicus). Retrospective analysis of banked serum from one Mycobacterium bovis infected and seven presumably uninfected tapir was performed by MAPIA and RT. A sample collected 2 mon prior to the death of a culture-confirmed M. bovis-infected tapir served as a positive control. Seroreactivity of this sample was demonstrated via both MAPIA and RT testing. Seven uninfected animals, including four without postmortem evidence of mycobacterial disease and three that remain healthy, were negative controls; none demonstrated seroreactivity to key antigens with either test. These results suggest that MAPIA and RT have potential utility for rapid detection of M. bovis infection in Malayan tapir.

Pseudomonas aeruginosa rugose small-colony variants evade host clearance, are hyper-inflammatory, and persist in multiple host environments.

Pseudomonas aeruginosa causes devastating infections in immunocompromised individuals. Once established, P. aeruginosa infections become incredibly difficult to treat due to the development of antibiotic tolerant, aggregated communities known as biofilms. A hyper-biofilm forming clinical variant of P. aeruginosa, known as a rugose small-colony variant (RSCV), is frequently isolated from chronic infections and is correlated with poor clinical outcome. The development of these mutants during infection suggests a selective advantage for this phenotype, but it remains unclear how this phenotype promotes persistence. While prior studies suggest RSCVs could survive by evading the host immune response, our study reveals infection with the RSCV, PAO1ΔwspF, stimulated an extensive inflammatory response that caused significant damage to the surrounding host tissue. In both a chronic wound model and acute pulmonary model of infection, we observed increased bacterial burden, host tissue damage, and a robust neutrophil response during RSCV infection. Given the essential role of neutrophils in P. aeruginosa-mediated disease, we investigated the impact of the RSCV phenotype on neutrophil function. The RSCV phenotype promoted phagocytic evasion and stimulated neutrophil reactive oxygen species (ROS) production. We also demonstrate that bacterial aggregation and TLR-mediated pro-inflammatory cytokine production contribute to the immune response to RSCVs. Additionally, RSCVs exhibited enhanced tolerance to neutrophil-produced antimicrobials including H2O2 and the antimicrobial peptide LL-37. Collectively, these data indicate RSCVs elicit a robust but ineffective neutrophil response that causes significant host tissue damage. This study provides new insight on RSCV persistence, and indicates this variant may have a critical role in the recurring tissue damage often associated with chronic infections.

Successes and failures of sixty years of vector control in French Guiana: what is the next step?

Since the 1940s, French Guiana has implemented vector control to contain or eliminate malaria, yellow fever, and, recently, dengue, chikungunya, and Zika. Over time, strategies have evolved depending on the location, efficacy of the methods, development of insecticide resistance, and advances in vector control techniques. This review summarises the history of vector control in French Guiana by reporting the records found in the private archives of the Institute Pasteur in French Guiana and those accessible in libraries worldwide. This publication highlights successes and failures in vector control and identifies the constraints and expectations for vector control in this French overseas territory in the Americas.

Histopathological comparisons of Staphylococcus aureus and Pseudomonas aeruginosa experimental infected porcine burn wounds.

Chronic skin wounds are a significant human health concern and are often complicated by infection with Pseudomonas aeruginosa and Staphylococcus aureus, particularly methicillin resistant S. aureus (MRSA). Translating the knowledge gained from extensive study of virulence mechanisms and pathogenesis of these bacterial species to new treatment modalities has been lacking in part due to a paucity of animal models able to recapitulate human disease. Our groups recently described a novel porcine chronic burn wound model for the study of bacterial infection; however, the histopathology of infection has yet to be described. The objective of this study is to define the histopathology of this model using important human chronic wound bacterial isolates. Porcine full-thickness burn wounds topically inoculated with P. aeruginosa strain PAO1, MRSA S. aureus strain USA300 or both bacteria were used to define and quantify histopathologic lesions. The development of a systemic, well-defined rubric for analysis allowed for evaluation of differences between infection groups. These differences, which included epithelial migration and proliferation, stromal necrosis, fluid accumulation and intensity and character of the innate and adaptive inflammatory cell responses, were identified temporally between infection groups. Mono-species infected wounds developed a hyper-proliferative wound edge. Coinfected wounds at day 35 had the largest wound sizes, increased amounts of neutrophilic inflammation, immaturity of the wound bed, and retention of necrotic tissue. Infection, regardless of species, inhibited wound contracture at all time points evaluated. Most importantly, this model recapitulated key features of chronic human wounds. Thus, this model will allow researchers to study novel treatment modalities in a biologically relevant animal model while monitoring both host and bacterial responses.

Mixed-species biofilm compromises wound healing by disrupting epidermal barrier function.

In chronic wounds, biofilm infects host tissue for extended periods of time. This work establishes the first chronic preclinical model of wound biofilm infection aimed at addressing the long-term host response. Although biofilm-infected wounds did not show marked differences in wound closure, the repaired skin demonstrated compromised barrier function. This observation is clinically significant, because it leads to the notion that even if a biofilm infected wound is closed, as observed visually, it may be complicated by the presence of failed skin, which is likely to be infected and/or further complicated postclosure. Study of the underlying mechanisms recognized for the first time biofilm-inducible miR-146a and miR-106b in the host skin wound-edge tissue. These miRs silenced ZO-1 and ZO-2 to compromise tight junction function, resulting in leaky skin as measured by transepidermal water loss (TEWL). Intervention strategies aimed at inhibiting biofilm-inducible miRNAs may be productive in restoring the barrier function of host skin.

Histone H1 phosphorylation in breast cancer.

Breast cancer is the second leading cause of cancer-related deaths in women. The need for new clinical biomarkers in breast cancer is necessary to further predict prognosis and therapeutic response. In this article, the LC-MS histone H1 phosphorylation profiles were established for three distinct breast cancer cell lines. The results show that the extent of H1 phosphorylation can distinguish between the different cell lines. The histone H1 from the metastatic cell line, MDA-MB-231, was subjected to chemical derivitization and LC-MS/MS analysis. The results suggest that the phosphorylation at threonine 146 is found on both histone H1.2 and histone H1.4. Cell lines were then treated with an extracellular stimulus, estradiol or kinase inhibitor LY294002, to monitor changes in histone H1 phosphorylation. The data show that histone H1 phosphorylation can increase and decrease in response to extracellular stimuli. Finally, primary breast tissues were stained for the histone H1 phosphorylation at threonine 146. Variable staining patterns across tumor grades and subtypes were observed with pT146 labeling correlating with tumor grade. These results establish the potential for histone H1 phosphorylation at threonine 146 as a clinical biomarker in breast cancer.

Surgical stabilization of traumatic elbow joint luxation and proximal ulnar fracture in a silvery langur (Trachypithecus cristatus).

CASE DESCRIPTION: A 3-year-old 5-kg sexually intact female silvery langur housed in a single-species group at a zoological institution was presented because of acute trauma to the left forelimb. CLINICAL FINDINGS: Radiography of the left forelimb revealed a type II Monteggia fracture (proximal ulnar fracture with cranial displacement and caudal luxation of the radial head). During surgery, disruption of the annular ligament and rupture of the lateral collateral ligament were noted. TREATMENT AND OUTCOME: The langur underwent open reduction and internal fixation of the ulnar fracture and placement of a radioulnar positional screw, a prosthetic lateral collateral ligament, and a temporary hinged type 1A external skeletal fixator. The langur was returned to group housing, underwent behavioral training, and was periodically anesthetized for physical therapy sessions to improve range of motion of the left elbow joint. The external skeletal fixator was removed 4 weeks after surgery, and the radioulnar positional screw was removed 6 weeks after surgery. Three months after surgery, the range of motion of the langur's left elbow joint was considered normal, and the animal returned to normal activity. CLINICAL RELEVANCE: For the captive silvery langur of the present report, surgical stabilization and postoperative management of a type II Monteggia fracture of the left forelimb were successful with recovery of elbow joint function. These techniques may be applied to other captive nonhuman primates, including those that brachiate or are members of social species that must be housed with conspecifics in the postoperative period to maintain group dynamics.

Pseudomonas aeruginosa Interstrain Dynamics and Selection of Hyperbiofilm Mutants during a Chronic Infection.

Opportunistic pathogens establishing new infections experience strong selection to adapt, often favoring mutants that persist. Capturing this initial dynamic is critical for identifying the first adaptations that drive pathogenesis. Here we used a porcine full-thickness burn wound model of chronic infection to study the evolutionary dynamics of diverse Pseudomonas aeruginosa infections. Wounds were infected with a mixed community of six P. aeruginosa strains, including the model PA14 strain (PA14-1), and biopsies taken at 3, 14, and 28 days postinfection. Hyperbiofilm-forming rugose small-colony variants (RSCVs) were the earliest and predominant phenotypic variant. These variants were detected on day 3 and persisted, with the majority evolved from PA14-1. Whole-genome sequencing of PA14-1 RSCV isolates revealed driver mutations exclusively in the wsp pathway, conferring hyperbiofilm phenotypes. Several of the wsp mutant RSCVs also acquired CRISPR-Cas adaptive immunity to prophages isolated from the P. aeruginosa wound isolate (B23-2) that was also present in the inoculum. These observations emphasize the importance of interstrain dynamics and the role of lysogenic phages in the survival of an invading pathogen. Rather than being a side effect of chronicity, the rapid rise of RSCVs in wounds is evidence of positive selection on the Wsp chemosensory system to produce mutants with elevated biofilm formation capacity. We predict that RSCVs provide a level of phenotypic diversity to the infecting bacterial community and are common, early adaptations during infections. This would likely have significant consequences for clinical outcomes.IMPORTANCE Bacteria adapt to infections by evolving variants that are more fit and persistent. These recalcitrant variants are typically observed in chronic infections. However, it is unclear when and why these variants evolve. To address these questions, we used a porcine chronic wound model to study the evolutionary dynamics of Pseudomonas aeruginosa in a mixed-strain infection. We isolated hyperbiofilm variants that persisted early in the infection. Interstrain interactions were also observed, where adapted variants acquired CRISPR-mediated immunity to phages. We show that when initiating infection, P. aeruginosa experiences strong positive selection for hyperbiofilm phenotypes produced by mutants of a single chemosensory system, the Wsp pathway. We predict that hyperbiofilm variants are early adaptations to infection and that interstrain interactions may influence bacterial burden and infection outcomes.

Use of a leukocyte-targeted peptide probe as a potential tracer for imaging the tuberculosis granuloma.

Granulomas are the histopathologic hallmark of tuberculosis (TB), both in latency and active disease. Diagnostic and therapeutic strategies that specifically target granulomas have not been developed. Our objective is to develop a probe for imaging relevant immune cell populations infiltrating the granuloma. We report the binding specificity of Cyanine 3 (Cy3)-labeled cFLFLFK-PEG12 to human leukocytes and cellular constituents within a human in vitro granuloma model. We also report use of the probe in in vivo studies using a mouse model of lung granulomatous inflammation. We found that the probe preferentially binds human neutrophils and macrophages in human granuloma structures. Inhibition studies showed that peptide binding to human neutrophils is mediated by the receptor formyl peptide receptor 1 (FPR1). Imaging the distribution of intravenously administered cFLFLFK-PEG12-Cy3 in the mouse model revealed probe accumulation within granulomatous inflammatory responses in the lung. Further characterization revealed that the probe preferentially associated with neutrophils and cells of the monocyte/macrophage lineage. As there is no current clinical diagnostic imaging tool that specifically targets granulomas, the use of this probe in the context of latent and active TB may provide a unique advantage over current clinical imaging probes. We anticipate that utilizing a FPR1-targeted radiopharmaceutical analog of cFLFLFK in preclinical imaging studies may greatly contribute to our understanding of granuloma influx patterns and the biological roles and consequences of FPR1-expressing cells in contributing to disease pathogenesis.

Small sarcocysts can be a feature of experimental infections with Sarcocystis neurona merozoites.

Several reports indicate the presence of small tissue cysts associated with Sarcocystis neurona infections. Several failed attempts to develop tissue cysts in potential intermediate host using in vitro derived parasites originally isolated from horses with equine protozoal myeloencephalitis suggest that the experimental methods to achieve bradyzoites with those isolates was not possible. Those prior studies reported the lack of detectable sarcocysts based on histology and in vivo feeding trials. A recent report of successful production and detection of small sarcocysts triggered us to review archived tissues from earlier experimental infection studies. The retrospective review sought to determine if small sized sarcocysts were not detected due to their relatively smaller size and infrequency as compared to larger sized sarcocysts produced with other isolates in these experimental inoculation trials. Tissues from two prior in vivo inoculation studies, involving in vitro-produced parasites inoculated into laboratory-reared cats and raccoons, were re-examined by immunohistochemistry staining to more easily detect the tissue cysts. In the experimental cat study no small tissue cysts were seen, consistent with the original publication results. However, in the experimental raccoon study, one raccoon inoculated with an EPM-derived isolate, SN-UCD1, had small sarcocysts not reported in the original publication. This retrospective study suggests that much closer scrutiny of tissues, including the use of immunohistochemistry on tissue sections is required to detect the smaller S. neurona sarcocysts associated with the experimental inoculations of the isolates originally derived from horses with EPM.

Sarcocystis neurona manipulation using culture-derived merozoites for bradyzoite and sporocyst production.

Equine protozoal myeloencephalitis (EPM) remains a significant central nervous system disease of horses in the American continents. Sarcocystis neurona is considered the primary causative agent and its intermediate life stages are carried by a wide host-range including raccoons (Procyon lotor) in North America. S. neurona sarcocysts mature in raccoon skeletal muscle and can produce central nervous system disease in raccoons, mirroring the clinical presentation in horses. The study aimed to develop laboratory tools whereby the life cycle and various life stages of S. neurona could be better studied and manipulated using in vitro and in vivo systems and compare the biology of two independent isolates. This study utilized culture-derived parasites from S. neurona strains derived from a raccoon or from a horse to initiate raccoon infections. Raccoon tissues, including fresh and cryopreserved tissues, were used to establish opossum (Didelphis virginiana) infections, which then shed sporocyts with retained biological activity to cause encephalitis in mice. These results demonstrate that sarcocysts can be generated using in vitro-derived S. neurona merozoites, including an isolate originally derived from a naturally infected horse with clinical EPM. This study indicates the life cycle can be significantly manipulated in the laboratory without affecting subsequent stage development, allowing further purification of strains and artificial maintenance of the life cycle.

'No "Sane" Person Would Have Any Idea': Patients' Involvement in Late Nineteenth-century British Asylum Psychiatry.

In his 1895 textbook, Mental Physiology, Bethlem Royal Hospital physician Theo Hyslop acknowledged the assistance of three fellow hospital residents. One was a junior colleague. The other two were both patients: Walter Abraham Haigh and Henry Francis Harding. Haigh was also thanked in former superintendent George Savage's book Insanity and Allied Neuroses (1884). In neither instance were the patients identified as such. This begs the question: what role did Haigh and Harding play in asylum theory and practice? And how did these two men interpret their experiences, both within and outside the asylum? By focusing on Haigh and Harding's unusual status, this paper argues that the notion of nineteenth-century 'asylum patient' needs to be investigated by paying close attention to specific national and institutional circumstances. Exploring Haigh and Harding's active engagement with their physicians provides insight into this lesser-known aspect of psychiatry's history. Their experience suggests that, in some instances, representations of madness at that period were the product of a two-way process of negotiation between alienist and patient. Patients, in other words, were not always mere victims of 'psychiatric power'; they participated in the construction and circulation of medical notions by serving as active intermediaries between medical and lay perceptions of madness.

Successes and failures of sixty years of vector control in French Guiana: what is the next step?

Since the 1940s, French Guiana has implemented vector control to contain or eliminate malaria, yellow fever, and, recently, dengue, chikungunya, and Zika. Over time, strategies have evolved depending on the location, efficacy of the methods, development of insecticide resistance, and advances in vector control techniques. This review summarises the history of vector control in French Guiana by reporting the records found in the private archives of the Institute Pasteur in French Guiana and those accessible in libraries worldwide. This publication highlights successes and failures in vector control and identifies the constraints and expectations for vector control in this French overseas territory in the Americas.