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Abstract The Notch receptor is a pleiotropic signaling protein that translates intercellular ligand interactions into changes in gene expression via the nuclear localization of the Notch intracellular Domain (NICD). Using a combination of immunohistochemistry, RNA in situ, Optogenetics and super-resolution live imaging of transcription in human cells, we show that the N1ICD can form condensates that positively facilitate Notch target gene expression. We determined that N1ICD undergoes Phase Separation Coupled Percolation (PSCP) into transcriptional condensates, which recruit, enrich, and encapsulate a broad set of core transcriptional proteins. We show that the capacity for condensation is due to the intrinsically disordered transcriptional activation domain of the N1ICD. In addition, the formation of such transcriptional condensates acts to promote Notch-mediated super enhancer-looping and concomitant activation of the MYC protooncogene expression. Overall, we introduce a novel mechanism of Notch1 activity in which discrete changes in nuclear N1ICD abundance are translated into the assembly of transcriptional condensates that facilitate gene expression by enriching essential transcriptional machineries at target genomic loci.

Abstract Spontaneous polarization and crystallographic orientations within ferroelectric domains are investigated using an epitaxially grown BiFeO3 thin film under bi-axial tensile strain. Four dimensional-scanning transmission electron microscopy (4D-STEM) and atomic resolution STEM techniques revealed that the tensile strain applied is not enough to cause breakdown of equilibrium BiFeO3 symmetry (rhombohedral with space group: R3c). 4D-STEM data exhibit two types of BiFeO3 ferroelectric domains: one with projected polarization vector possessing out-of-plane component only, and the other with that consisting of both in-plane and out-of-plane components. For domains with only out-of-plane polarization, convergent beam electron diffraction (CBED) patterns exhibit “extra” Bragg’s reflections (compared to CBED of cubic-perovskite) that indicate rhombohedral symmetry. In addition, beam damage effects on ferroelectric property measurements were investigated by systematically changing electron energy from 60 to 300 keV.

Abstract A BiFeO3 film is grown epitaxially on a PrScO3 single crystal substrate which imparts ~ 1.45% of biaxial tensile strain to BiFeO3 resulting from lattice misfit. The biaxial tensile strain effect on BiFeO3 is investigated in terms of crystal structure, Poisson ratio, and ferroelectric domain structure. Lattice resolution scanning transmission electron microscopy, precession electron diffraction, and X-ray diffraction results clearly show that in-plane interplanar distance of BiFeO3 is the same as that of PrScO3 with no sign of misfit dislocations, indicating that the biaxial tensile strain caused by lattice mismatch between BiFeO3 and PrScO3 are stored as elastic energy within BiFeO3 film. Nano-beam electron diffraction patterns compared with structure factor calculation found that the BiFeO3 maintains rhombohedral symmetry, i.e., space group of R3c. The pattern analysis also revealed two crystallographically distinguishable domains. Their relations with ferroelectric domain structures in terms of size and spontaneous polarization orientations within the domains are further understood using four-dimensional scanning transmission electron microscopy technique.

Introduction Family-Focused Adolescent & Lifelong Health Promotion (FLOURISH) project will adapt, implement and evaluate a programme to support adolescent mental health and well-being through strategies, such as strengthening parenting practices, adolescent-caregiver relationships, adolescent and parent socioemotional skills, and social support.Methods and analysis The project will focus on adolescents aged 10–14 years and their caregivers in North Macedonia and Moldova. The countries were selected based on implementation readiness of two organisations and a need for accessible evidence-informed services to help mitigate health risks due to economic, social and political challenges. Parenting for Lifelong Health (PLH) for Parents and Teens is a family-based programme developed for low-resource settings. PLH has been adapted with input from advisory groups. The programme includes additional components to strengthen impacts on adolescents: adolescent mental health tools, based on UNICEF’s Helping Adolescents Thrive, adolescent peer support and participation booster. This pilot is first of three study phases. The pilot will be a feasibility testing of the adapted intervention and the assessment and implementation procedures to determine further refinements. The pilot will examine if the adapted programme is acceptable for adolescents, their families and providers, explore contextual factors relevant to embedding this programme into longer-term scale-up and investigate whether the programme can be delivered with fidelity and participation; whether the participants report changes in adolescent emotional and behavioural problems, well-being and other outcomes; and whether the study tools are feasible and appropriate. Pre-post adolescent and caregiver questionnaires will provide outcome data. Process evaluation will include attendance and fidelity data, and focus groups. We will examine delivery cost and resource requirements.Ethics and dissemination The study was approved at the University of Klagenfurt (Austria), Medical Faculty at St. Cyril and Methodius University (North Macedonia) and National Committee of Ethical Expertise for Clinical Trials (Moldova). Through stakeholder engagement and dissemination, FLOURISH will advance scale-up of open-source family interventions.Trial registration number Trial registration: ID101095528; project page: https://www.flourish-study.org/about.html; https://www.linkedin.com/company/flourish-study/

Abstract Smith‐Lemli‐Opitz syndrome (SLOS) is a relatively common genetic cause of developmental delay and may only present in conjunction with 2,3 toe syndactyly. This case series illustrates a milder phenotype of SLOS, where the predominant findings are neurocognitive in the presence of 2,3 toe syndactyly.

Abstract Concussion is a global health concern. Despite its high prevalence, a sound understanding of the mechanisms underlying this type of diffuse brain injury remains elusive. It is, however, well established that concussions cause significant functional deficits; that children and youths are disproportionately affected and have longer recovery time than adults; and that individuals suffering from a concussion are more prone to experience additional concussions, with each successive injury increasing the risk of long term neurological and mental health complications. Currently, the most significant challenge in concussion management is the lack of objective, clinically- accepted, brain-based approaches for determining whether an athlete has suffered a concussion. Here, we report on our efforts to address this challenge. Specifically, we introduce a deep learning long short-term memory (LSTM)-based recurrent neural network that is able to distinguish between non-concussed and acute post-concussed adolescent athletes using only short (i.e. 90 s long) samples of resting state EEG data as input. The athletes were neither required to perform a specific task nor expected to respond to a stimulus during data collection. The acquired EEG data were neither filtered, cleaned of artefacts, nor subjected to explicit feature extraction. The LSTM network was trained and validated using data from 27 male, adolescent athletes with sports related concussion, benchmarked against 35 non-concussed adolescent athletes. During rigorous testing, the classifier consistently identified concussions with an accuracy of > 90% and achieved an ensemble median Area Under the Receiver Operating Characteristic Curve (ROC/AUC) equal to 0.971. This is the first instance of a high-performing classifier that relies only on easy-to-acquire resting state, raw EEG data. Our concussion classifier represents a promising first step towards the development of an easy-to-use, objective, brain-based, automatic classification of concussion at an individual level.

Abstract Donor cell leukemia is a very rare cause of relapse after allogeneic hematopoietic cell transplantation (alloHCT). Herein, we describe an unprecedented case of donor cell‐derived chronic myelomonocytic leukemia (CMML) presenting seven years after a 51‐year‐old man received a matched‐related alloHCT from his 59‐year‐old brother for T‐cell acute lymphoblastic leukemia.

Cryptorchidism is the most common congenital sex development disorder in dogs. Despite this, little progress has been made in understanding its genetic background. Extensive genetic testing of dogs through consumer and veterinary channels using a high-density SNP genotyping microarray coupled with links to clinical records presents the opportunity for a large-scale genome-wide association study to elucidate the molecular risk factors associated with cryptorchidism in dogs. Using an inter-breed genome-wide association study approach, a significant statistical association on canine chromosome 10 was identified, with the top SNP pinpointing a variant of HMGA2 previously associated with adult weight variance. In further analysis we show that incidence of cryptorchidism is skewed towards smaller dogs in concordance with the identified variant's previous association with adult weight. This study represents the first putative variant to be associated with cryptorchidism in dogs.

Objective This study investigated seroprevalence of SARS-CoV-2-specific IgG antibodies, using the Abbott antinucleocapsid IgG chemiluminescent microparticle immunoassay (CMIA) assay, in five prespecified healthcare worker (HCW) subgroups following the first wave of the COVID-19 pandemic.Setting An 800-bed tertiary-level teaching hospital in the south of Ireland.Participants Serum was collected for anti-SARS-CoV-2 nucleocapsid IgG using the Abbott ARCHITECT SARS-CoV-2 IgG CMIA qualitative assay, as per the manufacturer’s specifications.The groups were as follows: (1) HCWs who had real-time PCR (RT-PCR) confirmed COVID-19 infection (>1-month postpositive RT-PCR); (2) HCWs identified as close contacts of persons with COVID-19 infection and who subsequently developed symptoms (virus not detected by RT-PCR on oropharyngeal/nasopharyngeal swab); (3) HCWs identified as close contacts of COVID-19 cases and who remained asymptomatic (not screened by RT-PCR); (4) HCWs not included in the aforementioned groups working in areas determined as high-risk clinical areas; and (5) HCWs not included in the aforementioned groups working in areas determined as low-risk clinical areas.Results Six of 404 (1.49%) HCWs not previously diagnosed with SARS-CoV-2 infection (groups 2–5) were seropositive for SARS-CoV-2 at the time of recruitment into the study.Out of the 99 participants in group 1, 72 had detectable IgG to SARS-CoV-2 on laboratory testing (73%). Antibody positivity correlated with shorter length of time between RT-PCR positivity and antibody testing.Quantification cycle value on RT-PCR was not found to be correlated with antibody positivity.Conclusions Seroprevalence of SARS-CoV-2 antibodies in HCWs who had not previously tested RT-PCR positive for COVID-19 was low compared with similar studies.

Bortezomib and the other licensed 20S proteasome inhibitors show robust activity against liquid tumors like multiple myeloma, but have disappointed against solid tumors including ovarian cancer. Consequently, interest is mounting in alternative non-peptide based drugs targeting the proteasome's 19S regulatory particle subunit, including its ubiquitin receptor RPN13. RA183 and RA375 are more potent analogs of the prototypic inhibitor of RPN13 (iRPN13) called RA190, and they show promise for the treatment of ovarian cancer. Here we demonstrate that rendering these candidate RPN13 inhibitors chiral and asymmetric through the addition of a single methyl to the core piperidone moiety increases their potency against cancer cell lines, with the S-isomer being more active than the R-isomer. The enhanced cancer cell cytotoxicities of these compounds are associated with improved binding to RPN13 in cell lysates, ATP depletion by inhibition of glycolysis and mitochondrial electron chain transport, mitochondrial depolarization and perinuclear clustering, oxidative stress and glutathione depletion, and rapid accumulation of high molecular weight polyubiquitinated proteins with a consequent unresolved ubiquitin proteasome system (UPS) stress response. Cytotoxicity was associated with an early biomarker of apoptosis, increased surface annexin V binding. As for cisplatin, BRCA2 and ATM deficiency conferred increased sensitivity to these iRPN13s. Ubiquitination plays an important role in coordinating DNA damage repair and the iRPN13s may compromise this process by depletion of monomeric ubiquitin following its sequestration in high molecular weight polyubiquitinated protein aggregates. Indeed, a synergistic cytotoxic response was evident upon treatment of several ovarian cancer cell lines with either cisplatin or doxorubicin and our new candidate iRPN13s, suggesting that such a combination approach warrants further exploration for the treatment of ovarian cancer.

We sought to design ubiquitin-proteasome system inhibitors active against solid cancers by targeting ubiquitin receptor RPN13 within the proteasome's 19S regulatory particle. The prototypic bis-benzylidine piperidone-based inhibitor RA190 is a michael acceptor that adducts Cysteine 88 of RPN13. In probing the pharmacophore, we showed the benefit of the central nitrogen-bearing piperidone ring moiety compared to a cyclohexanone, the importance of the span of the aromatic wings from the central enone-piperidone ring, the contribution of both wings, and that substituents with stronger electron withdrawing groups were more cytotoxic. Potency was further enhanced by coupling of a second warhead to the central nitrogen-bearing piperidone as RA375 exhibited ten-fold greater activity against cancer lines than RA190, reflecting its nitro ring substituents and the addition of a chloroacetamide warhead. Treatment with RA375 caused a rapid and profound accumulation of high molecular weight polyubiquitinated proteins and reduced intracellular glutathione levels, which produce endoplasmic reticulum and oxidative stress, and trigger apoptosis. RA375 was highly active against cell lines of multiple myeloma and diverse solid cancers, and demonstrated a wide therapeutic window against normal cells. For cervical and head and neck cancer cell lines, those associated with human papillomavirus were significantly more sensitive to RA375. While ARID1A-deficiency also enhanced sensitivity 4-fold, RA375 was active against all ovarian cancer cell lines tested. RA375 inhibited proteasome function in muscle for >72h after single i.p. administration to mice, and treatment reduced tumor burden and extended survival in mice carrying an orthotopic human xenograft derived from a clear cell ovarian carcinoma.

Introduction Over 30% of Canadians between the ages of 16 and 24 years attend university. This period of life coincides with the onset of common mental illnesses. Yet, data to inform university-based mental health prevention and early intervention initiatives are limited. The U-Flourish longitudinal study based out of Queen’s University, Canada and involving Oxford University in the UK, is a student informed study funded by the Canadian Institute for Health Research Strategy for Patient Oriented Research (CIHR-SPOR). The primary goal of U-Flourish research is to examine the contribution of risk and resiliency factors to outcomes of well-being and academic success in first year students transitioning to university.Methods and analysis The study is a longitudinal survey of all first-year undergraduate students entering Queen’s University in the fall term of 2018 (and will launch at Oxford University in fall of 2019). In accordance with the CIHR-SPOR definitions, students represent the target population (ie, patient equivalent). Student peer health educators were recruited to inform the design, content and implementation of the study. Baseline surveys of Queen’s first year students were completed in the fall of 2018, and follow-up surveys at the end of first year in the spring of 2019. Extensive student-led engagement campaigns were used to maximise participation rates. The baseline survey included measures of personal factors, family factors, environmental factors, psychological and emotional health, and lifestyle factors. Main outcomes include self-reported indicators of mental health at follow-up and mental health service access, as well as objective measures of academic success through linkage to university administrative and academic databases. A combination of mixed effects regression techniques will be employed to determine associations between baseline predictive factors and mental health and academic outcomes.Ethics and dissemination Ethical approval was obtained by the Health Sciences and Affiliated Teaching Hospitals Research Ethics Board (HSREB) (#6023126) at Queen’s University. Findings will be disseminated through international and national peer-reviewed scientific articles and other channels including student-driven support and advocacy groups, newsletters and social media.

Sepsis represents a continuum of illness due to systemic inflammation caused by an infection that requires prompt recognition and treatment. While sepsis is a significant cause of death worldwide, its mortality is believed to be disproportionately high in low- and middle-income countries (LMICs). Since 1992, its definition has become standardized, and beginning in 2002, an international collaboration has produced a set of consensus guidelines on the optimal management of septic patients. Based on new evidence, significant updates have been made since then. It is known that application of a bundled approach to patient care with the use of specific resuscitation endpoints to guide therapy leads to significant reductions in mortality from sepsis. However, it is also recognized that the implementation of such interventions in LMICs is extremely challenging. Consequently, a body of literature on practical guidelines for sepsis in developing countries has emerged. This article provides a review of the evidence for the best practice of sepsis management, with recommendations for resource-limited settings.

Chronic obstructive pulmonary disease (COPD) is a preventable condition affecting more than 230 million people globally, and is expected to become the world’s third largest cause of mortality by 2030. Despite this fact, it is thought to be widely underdiagnosed and underreported across the African continent. This presents a challenge to emergency medicine (EM) providers in the region, who are faced with treating large numbers of patients presenting with exacerbation of previously undiagnosed COPD. This is complicated by other factors, including lack of public awareness, high prevalence of other chronic respiratory illnesses, and difficulties in access to healthcare. The purpose of this paper is to outline the current state of research and international guidelines surrounding the management of acute exacerbation of COPD in the emergency centre. Strict adherence to international guidelines for management of acute exacerbation of COPD may be difficult for many African providers given factors affecting diagnosis, treatment, and access to care for many Africans suffering from COPD. Research looking into the role of the African EM practitioner in providing more cost-effective means of diagnosis and treatment of COPD is limited.

The toxic side effects of doxorubicin (Dox) limit its long-term use as a lung cancer chemotherapeutic. Additionally, drug delivery to the deep lung is challenging. To address these challenges, isolated rat Sertoli cells (SCs) were preloaded with Dox conjugated to lipid micelle nanoparticles (SC-DLMNs) and delivered to mouse lungs. These immunocompetent cells, when injected intravenously, travel to the lung, deliver the payload, and get cleared by the system quickly without causing any adverse reaction. We observed that SC-DLMNs effectively treated Lewis lung carcinoma 1-induced lung tumors in mice and the drug efficacy was comparable to SC-Dox treatment. Mice treated with SC-DLMNs also showed significantly less toxicity compared to those treated with SC-Dox. The encapsulation of Dox in lipid micelle nanoparticles reduced the toxicity of Dox and the SC-based delivery method ensured drug delivery to the deep lung without evoking any immune response. Taken together, these results provide a novel SC-based nanoparticle drug delivery method for improved therapeutic outcome of cardiotoxic antilung cancer drugs.

Introduction: In 2002, the West-African nation of Gabon established an emergency medical system (EMS), Service d’Aide Médicale Urgente (SAMU), in Libreville, yet few people access it. Our objective was to describe Libreville residents’ knowledge and attitudes toward the SAMU in an effort to understand why this service is underutilized. Methods: Qualitative interviews consisting of nine open-ended questions were conducted on a convenience sample of twenty patients, three visitors and two patient/visitor dyads at the Jeanne Ebori Hospital Emergency Centre in October 2009. Eligible subjects arrived in vehicles other than the SAMU and were ill enough to require hospital admission. Exclusion criteria were: under 21 years old, unable to speak French, or medically unstable. A bilingual team member audio-recorded the interviews in French and transcribed them into English. Investigators organized text into codes, then into themes and theoretical constructs. Intercoder agreement was excellent. Data were collected until theoretical saturation was achieved. Results: Analysis of data revealed no difference in response between patients and visitors. People underused SAMU because of financial costs, lack of awareness of the program, use of traditional modes of transportation, infrastructure flaws, perceived response times and other misconceptions. Conclusion: We identified remediable barriers to EMS (SAMU) access in Libreville, Gabon: lack of awareness, misperceptions, established alternatives, and cost. Interventions and future investigations designed to increase EMS utilization in Gabon should target these four areas.

Asthma is a chronic, reversible obstructive disease that when in exacerbation can present to the emergency department in a spectrum of severity. Prompt recognition of the potentially severely ill asthmatic requires a careful history and physical exam while considering alternative diagnoses for the presenting symptoms. Early administration of salbutamol and corticosteroids is indicated in almost all patients with other medications such as ipratropium and magnesium and supportive modalities like BiPAP reserved for sicker patients. The global impact of asthma is increasing, especially amongst children. While the benign clinical presentation is most common and mortality has decreased in recent decades due to improved recognition and care, the ubiquity of the condition and frequent lack of regular outpatient management contribute to the disease claiming 250,000 lives worldwide annually. The emergency physician must be prepared to assess and appropriately manage both the young child with a mild wheeze and the adult in respiratory failure.

The prevalence of cardiovascular disease is growing rapidly in developing countries, leading to an increasing incidence of acute coronary syndrome (ACS). The modalities available for diagnosing and treating this disease continue to evolve, and considerations must be made of local resources when making diagnostic and therapeutic choices. This article provides an evidence-based guide to the management of ACS, with specific recommendations for clinicians working in low and middle-income countries (LAMICs). Diagnosis of ACS, including both non ST-elevation (NSTE) and ST elevation (STE) ACS, focuses on risk stratification, vigilance for subtle or atypical presentations, and consideration of alternative causes of chest pain. The diagnostic process involves assessment of risk factors, knowledge of high yield history and physical exam findings (including variations that may exist in various populations), and utilization of appropriate diagnostic tests. Aspirin should be used as initial treatment in conjunction with an additional anti-platelet drug. Prasugrel is preferred over clopidogrel if the patient is having STE-ACS and planned for percutaneous coronary intervention (PCI). Bivalirudin should be the first choice for anti-coagulation in STE-ACS, followed by enoxaparin (which does not require a drip), and then unfractionated heparin. For the patient with NSTE-ACS and an increased bleeding risk, fondaparinux should be considered in place of enoxaparin. Oxygen should be administered to patients with breathlessness, signs of heart failure, shock, or arterial oxyhemoglobin saturation less than 94%. Beta blockade should be given if there are no signs of instability such as heart rate greater than 100 beats per minute or hypotension. Nitrates or morphine may be given to control symptoms, but do not confer morbidity or mortality advantages and are therefore not critical if a patient is comfortable. PCI should be performed if indicated and available. Fibrinolysis should be administered instead if delay to PCI would be greater than 90 min. Abstract La prévalence des maladies cardiovasculaires connaît une croissance rapide dans les pays en développement, entraînant une incidence croissante du syndrome coronarien aigu (SCA). Les modalités de diagnostic et de traitement de cette maladie continuent d’évoluer, et il convient de tenir compte des ressources locales lors de la réalisation d’un diagnostic et la détermination des options thérapeutiques. Cet article constitue un guide à la prise en charge du SCA fondé sur l’expérience, et fournit des recommandations spécifiques destinées aux médecins hospitaliers travaillant dans les pays à bas et moyen revenu. Le diagnostic du SCA, y compris les SCA sans élévation du ST et avec élévation du ST, se concentre sur la stratification du risque, la vigilance relative aux manifestations subtiles ou atypiques, et la prise en considération d’autres causes des douleurs poitrinaires. Le processus de diagnostic implique l’évaluation des facteurs de risque, la connaissance des antécédents médicaux défavorables et les conclusions de l’examen physique (des variantes étant susceptibles d’exister dans les différentes populations), ainsi que l’utilisation de tests de diagnostic appropriés. Il est recommandé d’utiliser de l’aspirine à titre de traitement initial, parallèlement à un antiagrégant plaquettaire supplémentaire. Le prasugrel est préféré au clopidogrel si le patient présente un SCA avec élévation du ST et qu’une intervention coronaire percutanée (ICP) est prévue. La bivalidurine devrait être le premier choix pour éviter la coagulation dans les SCA avec élévation du ST, suivie de l’enoxaparine (qui ne nécessite pas de perfusion), puis d’héparine non fractionnée. Pour les patients présentant un SCA sans élévation du ST et en cas de risque de saignement accru, le fondaparinux devrait être envisagé à la place de l’énoxaparine. Les patients souffrant de dyspnée, présentant des signes d’insuffisance cardiaque, de choc ou de saturation oxyhémoglobinée artérielle inférieure à 94% doivent se voir administrer de l’oxygène. Des bêtabloquants ne devraient être administrés que dans le cas où aucun signe d’instabilité n’est observé, comme un rythme cardiaque supérieur à 100 pulsations par minute ou de l’hypotension. Des nitrates ou de la morphine peuvent être administrés afin de contrôler les symptômes mais n’apportent aucun bénéfice en termes de morbidité ou de mortalité, et ne sont donc pas essentiels si le patient n’est pas mal à l’aise. Une ICP ne devrait être réalisée que si cela est indiqué et qu’une telle intervention est disponible. Une fibrinolyse devrait être réalisée à la place si le délai pour réaliser une ICP est supérieur à 90 min.

Despite the frequency and severity of burns in Low Income Countries, including many in Africa, there is a paucity of research and funding for these populations to aid in prevention, treatment and recovery of burn patients. The objectives of this paper are four-fold. First, by addressing the pathophysiology of burns the reader may strengthen understanding of the clinical progression of burns. Second, through describing proper assessment of burn patients one will learn how to decide if patients can be discharged, admitted or transferred to burn centre. Third, the inclusion of treatments solidifies the steps necessary to manage a patient in a hospital setting. Lastly, the overall goal of the paper, is to raise awareness that more research, publication and funding is required to create a better understanding of burns in Africa and why they continue to be devastating social and economic burdens.

The first detailed cases of crush syndrome were described in 1941 in London after victims trapped beneath bombed buildings presented with swollen limbs, hypovolemic shock, dark urine, renal failure, and ultimately perished. The majority of the data and studies on this topic still draw from large databases of earthquake victims. However, in Africa, a continent with little seismic activity, the majority of crush syndrome cases are instead victims of severe beatings rather than earthquake casualties, and clinical suspicion by emergency personnel must be high in this patient group presenting with oliguria or pigmenturia. Damaged skeletal muscle fibres and cell membranes lead to an inflammatory cascade resulting in fluid sequestration in the injured extremity, hypotension, hyperkalemia and hypocalcemia and their complications, and renal injury from multiple sources. Elevations in the serum creatinine, creatine kinase (CK), and potassium levels are frequent findings in these patients, and can help guide critical steps in management. Fluid resuscitation should begin prior to extrication of trapped victims or as early as possible, as this basic intervention has been shown to in large part prevent progression of renal injury to requiring haemodialysis. Alkalinization of the urine and use of mannitol for forced diuresis are recommended therapies under specific circumstances and are supported by studies done in animal models, but have not been shown to change clinical outcomes in human crush victims. In the past 70 years the crush syndrome and its management have been studied more thoroughly, however clinical practice guidelines continue to evolve.

Human umbilical cord blood (HUCB) cell therapies have shown promising results in reducing brain infarct volume and most importantly in improving neurobehavioral function in rat permanent middle cerebral artery occlusion, a model of stroke. In this study, we examined the gene expression profile in neurons subjected to oxygen-glucose deprivation (OGD) with or without HUCB treatment and identified signaling pathways (Akt/MAPK) important in eliciting HUCB-mediated neuroprotective responses. Gene chip microarray analysis was performed using RNA samples extracted from the neuronal cell cultures from four experimental groups: normoxia, normoxia + HUCB, OGD, and OGD + HUCB. Both quantitative RT-PCR and immunohistochemistry were carried out to verify the microarray results. Using the Genomatix software program, promoter regions of selected genes were compared to reveal common transcription factor-binding sites and, subsequently, signal transduction pathways. Under OGD condition, HUCB cells significantly reduced neuronal loss from 68% to 44% [one-way ANOVA, F (3, 16) = 11, p = 0.0003]. Microarray analysis identified mRNA expression of Prdx5, Vcam1, CCL20, Alcam, and Pax6 as being significantly altered by HUCB cell treatment. Inhibition of the Akt pathway significantly abolished the neuroprotective effect of HUCB cells [one-way ANOVA, F (3, 11) = 8.663, p = 0.0031]. Our observations show that HUCB neuroprotection is dependent on the activation of the Akt signaling pathway that increases transcription of the Prdx5 gene. We concluded that HUCB cell therapy would be a promising treatment for stroke and other forms of brain injury by modifying acute gene expression to promote neural cell protection.

Uncertainties about future conditions and the effects of chosen actions, as well as increasing resource scarcity, have been driving forces in the utilization of adaptive management strategies. However, many applications of adaptive management have been criticized for a number of shortcomings, including a limited ability to learn from actions and a lack of consideration of stakeholder objectives. To address these criticisms, we supplement existing adaptive management approaches with a decision-analytical approach that first informs the initial selection of management alternatives and then allows for periodic re-evaluation or phased implementation of management alternatives based on monitoring information and incorporation of stakeholder values. We describe the application of this enhanced adaptive management (EAM) framework to compare remedial alternatives for mercury in the South River, based on an understanding of the loading and behavior of mercury in the South River near Waynesboro, VA. The outcomes show that the ranking of remedial alternatives is influenced by uncertainty in the mercury loading model, by the relative importance placed on different criteria, and by cost estimates. The process itself demonstrates that a decision model can link project performance criteria, decision-maker preferences, environmental models, and short- and long-term monitoring information with management choices to help shape a remediation approach that provides useful information for adaptive, incremental implementation.

Mobile phone penetration rates have reached 63% in sub-Saharan Africa (SSA) and are projected to pass 70% by 2013. In SSA, millions of people who never used traditional landlines now use mobile phones on a regular basis. Mobile health, or mHealth, is the utilization of short messaging service (SMS), wireless data transmission, voice calling, and smartphone applications to transmit health-related information or direct care. This systematic review analyzes and summarizes key articles from the current body of peer-reviewed literature on PubMed on the topic of mHealth in SSA. Studies included in the review demonstrate that mHealth can improve and reduce the cost of patient monitoring, medication adherence, and healthcare worker communication, especially in rural areas. mHealth has also shown initial promise in emergency and disaster response, helping standardize, store, analyze, and share patient information. Challenges for mHealth implementation in SSA include operating costs, knowledge, infrastructure, and policy among many others. Further studies of the effectiveness of mHealth interventions are being hindered by similar factors as well as a lack of standardization in study design. Overall, the current evidence is not strong enough to warrant large-scale implementation of existing mHealth interventions in SSA, but rapid progress of both infrastructure and mHealth-related research in the region could justify scale-up of the most promising programs in the near future.