Global maps of travel time to healthcare facilities.

Access to healthcare is a requirement for human well-being that is constrained, in part, by the allocation of healthcare resources relative to the geographically dispersed human population1-3. Quantifying access to care globally is challenging due to the absence of a comprehensive database of healthcare facilities. We harness major data collection efforts underway by OpenStreetMap, Google Maps and academic researchers to compile the most complete collection of facility locations to date. Leveraging the geographically variable strengths of our facility datasets, we use an established methodology4 to characterize travel time to healthcare facilities in unprecedented detail. We produce maps of travel time with and without access to motorized transport, thus characterizing travel time to healthcare for populations distributed across the wealth spectrum. We find that just 8.9% of the global population (646 million people) cannot reach healthcare within one hour if they have access to motorized transport, and that 43.3% (3.16 billion people) cannot reach a healthcare facility by foot within one hour. Our maps highlight an additional vulnerability faced by poorer individuals in remote areas and can help to estimate whether individuals will seek healthcare when it is needed, as well as providing an evidence base for efficiently distributing limited healthcare and transportation resources to underserved populations both now and in the future.

A global map of travel time to cities to assess inequalities in accessibility in 2015.

The economic and man-made resources that sustain human wellbeing are not distributed evenly across the world, but are instead heavily concentrated in cities. Poor access to opportunities and services offered by urban centres (a function of distance, transport infrastructure, and the spatial distribution of cities) is a major barrier to improved livelihoods and overall development. Advancing accessibility worldwide underpins the equity agenda of 'leaving no one behind' established by the Sustainable Development Goals of the United Nations. This has renewed international efforts to accurately measure accessibility and generate a metric that can inform the design and implementation of development policies. The only previous attempt to reliably map accessibility worldwide, which was published nearly a decade ago, predated the baseline for the Sustainable Development Goals and excluded the recent expansion in infrastructure networks, particularly in lower-resource settings. In parallel, new data sources provided by Open Street Map and Google now capture transportation networks with unprecedented detail and precision. Here we develop and validate a map that quantifies travel time to cities for 2015 at a spatial resolution of approximately one by one kilometre by integrating ten global-scale surfaces that characterize factors affecting human movement rates and 13,840 high-density urban centres within an established geospatial-modelling framework. Our results highlight disparities in accessibility relative to wealth as 50.9% of individuals living in low-income settings (concentrated in sub-Saharan Africa) reside within an hour of a city compared to 90.7% of individuals in high-income settings. By further triangulating this map against socioeconomic datasets, we demonstrate how access to urban centres stratifies the economic, educational, and health status of humanity.

Concept and evaluation of the German War Surgery Course - Einsatzchirurgie-Kurs der Bundeswehr.

INTRODUCTION: Military surgeons must be prepared to care for severe and complex life-threatening injuries rarely seen in the civilian setting. Typical civilian training and practice do not provide adequate exposure to the broad set of surgical skills required. The German Bundeswehr Medical Service has developed and refined the War Surgery Course (WSC) to meet this training gap. This article describes the recent experience with this readiness curriculum. METHODS: Run annually since 1998, WSC consists nowadays of 5 days with 20 theoretical modules. Four sessions with standardised practical skills training use a live tissue porcine model, and the recently added cadaver-based Advanced Surgical Skills for Exposure in Trauma course. Sixteen military surgeons who participated in the WSC in January 2016 completed a survey of their self-rated readiness for 114 predefined emergency skills before and after completion, and provided an overall evaluation of the course. RESULTS: Self-assessed readiness improved significantly over baseline for all areas covered in both the practical skills and theoretical knowledge portions of the WSC curriculum. Additionally, all participants rated the course as important and universally recommended it to other military surgeons preparing for missions. CONCLUSIONS: The WSC course format was well received and perceived by learners as a valuable readiness platform. Ongoing evaluation of this course will enable data-driven evolution to ensure a maximum learning benefit for participants. With the increasing multinational nature of modern military missions, surgeons' training should follow international standards. Continuing evolution of military surgical training courses should further encourage the sharing and adoption of best educational practices.

[A tamponade complicating an acute eosinophilic pericarditis due to a myeloproliferative/myelodysplastic syndrome]. / Une tamponnade compliquant une péricardite à éosinophiles au cours d'un syndrome myéloprolifératif/myélodysplasique.

Cardiac involvement in eosinophilia is potentially fatal and requires early diagnosis and prompt treatment. We report here the case of a 71-year-old female patient with eosinophilia>10,000/mm(3) for 2 months due to a myeloproliferative/myelodysplastic syndrome, with a rapidly progressive exertional dyspnea explained by an important circumferential eosinophilic pericarditis. Due to a rapid evolution to a tamponade, an emergent surgical drainage was performed. Subsequent medical treatment combined high-dose corticosteroids (1mg/kg/day) with hydroxyurea and imatinib. The outcome was favourable with regression of the effusion, of the volume overload symptoms and decrease in eosinophilia.

[Near-infrared spectroscopy for the detection of traumatic intracranial hemorrhage: Feasibility study in a German army field hospital in Afghanistan]. / Nahinfrarotspektroskopie zur Detektion intrakranieller traumatischer Hirnblutungen: Praktikabilitätsstudie in einem Bundeswehrrettungszentrum in Afghanistan.

Traumatic brain injury (TBI) is one of the most common causes of death in ordinary accidents, natural disasters, or warfare. The gold standard for diagnosis of TBI is the CT scan; a delay of diagnostics or medical care is the strongest independent predictor of mortality of TBI patients--particularly in the case of a surgically treatable intracranial hematoma. The proper classification of these patients is of major importance in situations where a CT is not accessible. A portable screening device that uses near-infrared spectroscopy (NIRS) technology allows a preliminary estimate of an intracranial hematoma. This study assessing practicability shows that the use of the device in a military medical rescue center (Kunduz, Afghanistan) is easy to learn and can be repeatedly used even under emergency room conditions. The technique can be applied in penetrating and blunt TBIs in the absence of an immediately available CT scan in rural areas, preclinically, under mass casualty conditions (e.g., in disaster situations) as well as in humanitarian crises or war zones. Nevertheless, further studies to assess the validity of this device are necessary.

Chromatin structure of two genomic sites for targeted transgene integration in induced pluripotent stem cells and hematopoietic stem cells.

Achieving transgene integration into preselected genomic sites is currently one of the central tasks in stem cell gene therapy. A strategy to mediate such targeted integration involves site-specific endonucleases. Two genomic sites within the MBS85 and chemokine (C-C motif) receptor 5 (CCR5) genes (AAVS1 and CCR5 zinc-finger nuclease (CCR5-ZFN) sites, respectively) have recently been suggested as potential target regions for integration as their disruption has no functional consequence. We hypothesized that efficient transgene integration maybe affected by DNA accessibility of endonucleases and therefore studied the transcriptional and chromatin status of the AAVS1 and CCR5 sites in eight human induced pluripotent stem (iPS) cell lines and pooled CD34+ hematopoietic stem cells (HSCs). Matrix chromatin immunoprecipitation (ChIP) assays demonstrated that the CCR5 site and surrounding regions possessed a predominantly closed chromatin configuration consistent with its transcriptional inactivity in these cell types. In contrast, the AAVS1 site was located within a transcriptionally active region and exhibited an open chromatin configuration in both iPS cells and HSCs. To show that the AAVS1 site is readily amendable to genome modification, we expressed Rep78, an AAV2-derived protein with AAVS1-specific endonuclease activity, in iPS cells after adenoviral gene transfer. We showed that Rep78 efficiently associated with the AAVS1 site and triggered genome modifications within this site. On the other hand, binding to and modification of the CCR5-ZFN site by a ZFN was relatively inefficient. Our data suggest a critical influence of chromatin structure on efficacy of site-specific endonucleases used for genome editing.

Cardiovascular prevention: relationships between arterial aging and chronic drug treatment.

Drugs acting on cardiovascular (CV) prevention are, by definition, interconnected with age-induced arterial changes. However, this question has been poorly investigated along long-term treatment. This goal requires a major prerequisite: to determine statistical links associating age-induced changes in arterial stiffness and wave reflections with drug classes acting on CV prevention. We studied 347 subjects where CV prevention involved hypertension, diabetes mellitus and hypercholesterolaemia; and included six drug classes: diuretics, ß-blocking agents, angiotensin II (ANGII) and calcium-channel (CCB) blockers, insulin therapy and statins. For each class, the total population was divided into two subgroups according to the presence or absence of the corresponding class. Statistical comparisons between subgroups involved brachial and central blood pressure measurements, aortic pulse wave velocity (PWV), augmentation index (AIx), used as a marker of wave reflections. Non-invasive measurements included tonometry and pulse wave analysis. Appropriate adjustments indicated among results the respective role of age, sex, mean blood pressure (MBP), standard risk factors and other confounding variables. CCB and statins did not exhibit statistical association with PWV or AIx. ß-Blocking agents were significantly linked with heart rate reduction and resulting increase in AIx and central pulse pressure (PP). Increased PWV independent of age, MBP, CV risk factors were noticed under diuretics, ANGII blockers and insulin, pointing to intrinsic modifications of the arterial wall. Treatment of CV prevention involves alterations of the arterial wall depending on drug class. ß-Blocking agents and insulin are associated with the higher increases of central PP.

Adenovirus-mediated intratumoral expression of immunostimulatory proteins in combination with systemic Treg inactivation induces tumor-destructive immune responses in mouse models.

Tumor-associated antigens (TAAs) include overexpressed self-antigens (for example, Her2/neu) and tumor virus antigens (for example, HPV-16 E6/E7). Although in cancer patients, TAA-specific CD4+ and CD8+ cells are often present, they are not able to control tumor growth. In recent studies, it became apparent that tumor site-located immune evasion mechanisms contribute to this phenomenon and that regulatory T cells have a major role. We tested in Her2/neu+ breast cancer and HPV-16 E6/E7+ cervical cancer mouse models, whether intratumoral expression of immunostimulatory proteins (ISPs), for example, recombinant antibodies (αCTLA-4, αCD137, αCD3), cyto/chemokines (IL-15, LIGHT, mda-7) and costimulatory ligands (CD80), through adenovirus(Ad)-mediated gene transfer would overcome resistance. In both the breast and cervical cancer model, none of the Ad.ISP vectors displayed a significant therapeutic effect when compared with an Ad vector that lacked a transgene (Ad.zero). However, the combination of Ad.ISP vectors with systemic T regulatory (Treg) depletion, using anti-CD25 mAb (breast cancer model) or low-dose cyclophosphamide (cervical cancer model) resulted in a significant delay of tumor growth in mice treated with Ad.αCTLA4. In the cervical cancer model, we also demonstrated the induction of a systemic antitumor immune response that was able to delay the growth of distant tumors. Ad.αCTLA4-mediated tumor-destructive immune responses involved NKT and CD8+ T cells. In both models no autoimmune reactions were observed. This study shows that Ad.αCTLA4 in combination with systemic Treg depletion has potentials in the immunotherapy of cancer.

[Patterns and causes of injuries in a contemporary combat environment]. / Verletzungsmuster und -ursachen in modernen Kriegen.

Epidemiological analyses of injury patterns and mechanisms help to identify the expertise military surgeons need in a combat setting and accordingly help to adjust infrastructure and training requirements. Therefore, a MEDLINE search (1949-2009), World Wide Web search (keywords "combat, casualties, war, military, wounded and neurosurgery") and an analysis of deaths among allied war casualties in Afghanistan and Iraq were performed. Up to 10th December 2009 there had been 4,688 allied military deaths in Iraq and 1,538 in Afghanistan. Of these 22% died in non-hostile action, 33% in direct combat situations and the majority of 45% in indirect combat actions. The leading causes of injury were explosive devices (70%) and gunshot wounds. Chest or abdominal injuries (40%) and traumatic brain injuries (35%) were the main causes of death for soldiers killed in action. The case fatality rate in Iraq is approximately half that of the Vietnam War, whereas the killed-in-action rate in Afghanistan (18.7%) is similar to the Vietnam War (20%); however, the amputation rate is twice as high in modern conflicts. Approximately 8-15% of the fatal injuries seem to be potentially survivable.Military surgeons must have an excellent expertise in a wide variety of surgical specialties. Life saving emergency care, especially in the fields of thoracic, visceral and vascular surgery as well as practical skills in the fields of neurosurgery and oral and maxillofacial surgery are required. Additionally, it is of vital importance to ensure the availability of sufficient tactical and strategic medical evacuation capabilities for the wounded.

[The educational program for modern military surgeons]. / Weiterbildung zum modernen Militärchirurgen.

Casualties in military conflict produce patterns of injuries that are not seen in routine surgical practice at home. In an era of increasing surgical sub-specialization the deployed surgeon needs to acquire and maintain a wide range of skills from a variety of surgical specialties. Improvised explosive devices (IEDs) have become the modus operandi for terrorists and in the current global security situation these tactics can be equally employed against civilian targets. Therefore, knowledge and training in the management of these injuries are relevant to both military and civilian surgeons. To create this kind of military surgeon the so-called "DUO-plus" model for the training of surgical officers (specialization general surgery plus a second specialization either in visceral surgery or orthopedics/trauma surgery) has been developed in the Joint Medical Service of the German Bundeswehr. Other relevant skills, such as emergency neurotraumatology, battlefield surgery with integrated oral and craniomaxillofacial surgery and emergency gynecology, are integrated into this concept and will be taught in courses. Log books will be kept in accordance with the training curricula. On successful completion of the program medical officers will be officially appointed as Medical Officer "Einsatzchirurg" by their commanding officers for a maximum of 5 years and it will be necessary to renew it after this period. These refresher programs will require participation in visiting physicians programs in the complementary surgical disciplines in order to retain the essential specific skills.

[Spectrum of surgical procedures performed in German rescue centers and the field hospital in Afghanistan in 2008]. / Spektrum der Operationen in deutschen Sanitätseinrichtungen in Afghanistan im Jahr 2008.

From the military perspective detailed knowledge about the spectrum of operations undertaken abroad is of particular interest to provide indications of the skills that will be required by the surgeons. Therefore, all surgical reports produced in 2008 in the operation theatres of Mazar-e-Sharif, Feyzabad and Kunduz were reviewed. The overview shows that a total of 799 operations were performed equivalent to 0.4-1.6 operations/day. Most of the patients who underwent surgery were local civilians and most of these operations involved osteosynthesis, débridement and soft tissue procedures. Of the surgical procedures 11% involved patients who were German service personnel of which 85% were urgent or emergency procedures and 25% of these involved treatment of combat injuries. When civilian patients with life-threatening injuries or diseases are referred to the medical facilities there is little opportunity to make decisions with regard to acceptance. Often it may be necessary for surgeons to perform procedures which are outside their field of specialization. In order to ensure a favorable outcome in acute situations surgeons mainly required skills in emergency surgery of the body cavities (visceral and thoracic surgery).

[The value of thoracoscopy in thorax trauma]. / Hat die Thorakoskopie beim Thoraxtrauma einen Platz?

A hemodynamically stable patient presenting with persistent bleeding through his chest tube (ICD) is a classic indication for early thoracoscopic intervention in trauma. The source of bleeding and air leaks can be identified and often treated: bleeding and perforated pulmonary segments can be resected, and chest wall bleeding may be coagulated or sutured. Injuries to the diaphragm are difficult to diagnose, as they might not be seen in conventional trauma imaging without gross herniation of intra-abdominal contents into the thoracic cavity. Identifying the site of diaphragm perforation can give useful hints in thoracoabdominal trauma, identifying injured cavities and localizing the bullet or stab tract. Most often, diaphragmatic defects may be closed during diagnostic thoracoscopy as well. Non- or partially drainable hemothorax is another indication for thoracoscopy. Coagulated blood can be mechanically mobilised, and aspirated or primary bleeding may be stopped. Effective lavage and a high-performance suction device are required. Correct placement of the drainage is part of optimized therapy, along with inspection of all intrathoracic organs and surfaces. Furthermore, surgical and anaesthesiological teamwork and experience are prerequisites for the fast, professional application of a minimally invasive thoracoscopic approach in chest trauma patients. Diagnostically and theurapeutically, thoracoscopy plays an important role in the trauma setting--in the case of hemodynamically stable patients.

[What to do if incompressible bleeding from a stab wound occurs in EMS and ER? Temporary control with a Foley catheter]. / Was tun bei nicht komprimierbaren Stichkanalblutungen in Rettungsdienst und Notfallraum? Temporäre Versorgung mittels Blasenkatheter.

Exsanguination plays a key role in avoidable prehospital deaths. As some bleedings from deep stab wounds cannot be stopped with direct compression, the insertion of a Foley catheter can prevent ongoing bleedings. A case report of bleeding from a stab wound in the supraclavicular region is given. The simple measure of careful insertion and blocking of a Foley catheter proved to be a key resuscitative procedure which can be done under any suitable circumstances.

Evaluation of adenovirus vectors containing serotype 35 fibers for tumor targeting.

There is growing evidence from in vitro studies that subgroup B adenoviruses (Ad) can overcome the limitations in safety and tumor transduction efficiency seen with commonly used subgroup C serotype 5-based vectors. In this study, we confirm that the expression level of the B-group Ad receptor, CD46, correlates with the grade of malignancy of cervical cancer in situ. We also demonstrate the in vivo properties of Ad5-based vectors that contain the B-group Ad serotype 35 fiber (Ad5/35) in transgenic mice that express CD46 in a pattern and at a level similar to humans. Upon intravenous and intraperitoneal injection, an Ad5/35 vector did not efficiently transduce normal tissue, but was able to target metastatic or intraperitoneal tumors that express CD46 at levels comparable to human tumors. When an oncolytic Ad5/35-based vector was employed, in both tumor models antitumor effects were observed. Furthermore, injection of Ad5/35 vectors into CD46 transgenic mice caused less innate toxicity than Ad5 vectors. Our data demonstrate that Ad vectors that target CD46 offer advantages over Ad5-based vectors for treatment of cancer.

[Procedures of temporary wall closure in abdominal trauma and sepsis]. / Verfahren zum temporären Bauchdeckenverschluss bei Trauma und Sepsis.

Temporary abdominal closure methods differ mainly between vacuum-assisted and conventional approaches. Each method has its indications. Vacuum-assisted methods seem to be superior especially for trauma indications--in terms of lethality, the possibility of secondary closure during primary hospital stay, and frequency of enterocutaneous fistulas. Skin-only closure might be used as a short-term application (e.g. when damage control closure is needed), and the Bogota bag silo gives space to protruding bowels in pending or manifest abdominal compartment syndrome. Temporary fascial mesh closure enables repetitive laparotomies through the mesh, thus sparing the fascia. For that reason it is to be preferred, especially for its good practicability in clinical situations and on mission abroad.

Efficient infection of tumor endothelial cells by a capsid-modified adenovirus.

Targeted antiangiogenic gene therapy is an attractive approach to treat metastatic cancer. However, the relative paucity of the receptors of the commonly used adenovirus serotype 5 in endothelial cells as compared with liver cells undermines the use of this vector for targeting the endothelial cells in tumors. To overcome this problem, we analyzed the ability of a hybrid Ad5/35 virus, where the serotype 5 fiber has been replaced with the fiber from serotype 35, to target tumor vasculature. Infection of human umbilical vein endothelial cells (HUVECs) with Ad5/35 at MOI 120 infected 100% of cells. In contrast, infection with Ad5 at the same MOI infected only 10% HUVECs. Ad5/35 was even more effective in transducing human aortic endothelial cells (HAECs), as infection with Ad5/35 at MOI 3.6 was sufficient to transduce 95% of cells. Gene expression analyses demonstrated that infection of HUVECs and HAECs with Ad5/35 resulted in between 1 and 3 orders of magnitude higher gene expression than infection with Ad5. Furthermore, various liver-derived cells were less infectable with Ad5/35 than Ad5, indicating a favorable toxicity profile for this virus. In a rat colon carcinoma tumor model, Ad5 was located mainly in the liver parenchyma after hepatic artery administration. In contrast, Ad5/35 was found only in the angiogenesis-rich border region of the tumor. Double immunostaining revealed that Ad5/35 colocalized with CD31 and Flk-1 positive endothelial cells. These results indicate that Ad5/35 may be useful in anticancer strategies targeting tumor endothelial cells.

[German education for treatment of penetrating gut traumata in army service]. / Penetrierendes Bauchtrauma aus der Sicht der Bundeswehr.

On military missions abroad, surgical care for penetrating abdominal injuries differentiates from that given at home. The different conditions in the field usually include a single general surgeon with no further specialists or hospitals to rely upon. Thus a mismatch between treatment capacity and needs can be experienced in mass casualty situations. Therefore the focus is on damage control surgery, getting patients fit for evacuation, and transport home under intensive care if needed. Knowledge of ballistics and explosive devices are adjunct fields of interest, as they improve the understanding and treatment of military injuries. Although these aspects add up to additional training requirements to be met by our surgeons, we are convinced that the new German education standards will allow successful training of future military surgeons.

A continuous series of 96 laparoscopic inguinal hernia repairs in children by a new technique.

BACKGROUND: The aim of this study was evaluate a novel technique of laparoscopic hernia repair in children. METHODS: Eighty two consecutive patients aged >or=2 years old were operated on for hernia repair using a laparoscopic technique that reproduced every step of the conventional open procedure. Technical details and clinical results are reported. RESULTS: Ninety six sacs were divided in 82 patients (15 girls and 67 boys). Fourteen bilateral hernias that had been diagnosed before operation in nine cases and during laparoscopy in five cases were repaired. Nine controplateral dimples were left and not repaired. Mean operative time was 23 min in girls and 28 min in boys for unilateral hernias, and 30 min in girls and 40 min in boys for bilateral hernias. Sixty-seven of the children were followed up 6 months later. None of them suffered recurrences. No unsightly scars were observed at the port sites. Discomfort did not extend beyond 48 h after the operation, enabling a rapid return to normal activities. CONCLUSION: Dividing the sac and suturing the peritoneum is feasible and efficient by laparoscopy. Compared with the other techniques that have previously been reported, either without any dissection of the sac or any ligature, our technique seems to be advantageous. It is not time consuming and does not require any special laparoscopic skill.

Human papilloma virus E6 and E7 proteins support DNA replication of adenoviruses deleted for the E1A and E1B genes.

The action of transforming proteins from small DNA tumor viruses seems to be remarkably similar between different viruses, as they all use pRb and p53 pathways as cellular targets. This leads to deregulation of host cell cycling, which in turn creates an environment favorable for viral replication. Based on this, we hypothesized that regulatory proteins from human papillomaviruses (HPVs) can functionally trans-complement viral DNA replication of adenoviruses deleted for the E1A and E1B genes (AdE1-). To test this, we constructed AdE1- vectors expressing the human papilloma virus 16 (HPV-16) proteins E6 and E7. Expression of both E6 and E7 from these vectors partially complemented adenoviral DNA replication activity in vitro, in SK-Hep1 cells and primary human astrocytes, as well as in vivo in mouse liver. AdE1- vectors expressing E6 and E7 also increased hepatocellular DNA synthesis in vivo. Efficient AdE1- DNA replication was detected in HPV-associated cervical carcinoma cells but not in primary human cells. Linking the expression of regulatory oncoviral proteins to DNA replication of E1-mutant adenoviruses may provide a rationale for antitumor strategies.

Membrane-type matrix metalloproteinase-1 and -3 activity in primate smooth muscle cells.

Membrane-type matrix metalloproteinases-1 and -3 (MT1- and MT3-MMPs) are expressed by activated smooth muscle cells (SMCs) both in vitro and in vivo (19). To define their functions in SMCs, we transduced MT1- and MT3-MMP cDNAs into baboon SMCs by using adenoviral vectors. Overexpression of MT1-MMP increased the conversion of proMMP-2 to the intermediate and active forms. In contrast, in MT3-MMP-overexpressing cells, MMP-2 was activated partially. Immunoblot analyses revealed that MT1-MMP protein was present in the SMCs and accumulated in the presence of the synthetic MMP inhibitor, BB94, or tissue inhibitor of metalloproteinase-2 (TIMP-2). However, MT3-MMP protein was detectable only when BB94, but not TIMP-2, was present. Zymographic analyses showed that MT3-MMP had much stronger casein- and gelatin-degrading activities than did MT1-MMP. Furthermore, when MT3-MMP and MT1-MMP were coexpressed, MT1-MMP degradation was enhanced; this result supports the possibility that MT3-MMP can degrade MT1-MMP. SMCs overexpressing either MT1- or MT3-MMP exhibited altered morphology, without changing their proliferation. This alteration was prevented by BB94 addition. The cells, which underwent this change, showed reduced adhesion to both collagen and fibronectin and increased migration in a Boyden chamber. The present study demonstrates that MT1- and MT3-MMPs have different enzymatic activities but may nevertheless affect SMC function in the same way.