Global Retinoblastoma Presentation and Analysis by National Income Level.

Importance: Early diagnosis of retinoblastoma, the most common intraocular cancer, can save both a child's life and vision. However, anecdotal evidence suggests that many children across the world are diagnosed late. To our knowledge, the clinical presentation of retinoblastoma has never been assessed on a global scale. Objectives: To report the retinoblastoma stage at diagnosis in patients across the world during a single year, to investigate associations between clinical variables and national income level, and to investigate risk factors for advanced disease at diagnosis. Design, Setting, and Participants: A total of 278 retinoblastoma treatment centers were recruited from June 2017 through December 2018 to participate in a cross-sectional analysis of treatment-naive patients with retinoblastoma who were diagnosed in 2017. Main Outcomes and Measures: Age at presentation, proportion of familial history of retinoblastoma, and tumor stage and metastasis. Results: The cohort included 4351 new patients from 153 countries; the median age at diagnosis was 30.5 (interquartile range, 18.3-45.9) months, and 1976 patients (45.4%) were female. Most patients (n = 3685 [84.7%]) were from low- and middle-income countries (LMICs). Globally, the most common indication for referral was leukocoria (n = 2638 [62.8%]), followed by strabismus (n = 429 [10.2%]) and proptosis (n = 309 [7.4%]). Patients from high-income countries (HICs) were diagnosed at a median age of 14.1 months, with 656 of 666 (98.5%) patients having intraocular retinoblastoma and 2 (0.3%) having metastasis. Patients from low-income countries were diagnosed at a median age of 30.5 months, with 256 of 521 (49.1%) having extraocular retinoblastoma and 94 of 498 (18.9%) having metastasis. Lower national income level was associated with older presentation age, higher proportion of locally advanced disease and distant metastasis, and smaller proportion of familial history of retinoblastoma. Advanced disease at diagnosis was more common in LMICs even after adjusting for age (odds ratio for low-income countries vs upper-middle-income countries and HICs, 17.92 [95% CI, 12.94-24.80], and for lower-middle-income countries vs upper-middle-income countries and HICs, 5.74 [95% CI, 4.30-7.68]). Conclusions and Relevance: This study is estimated to have included more than half of all new retinoblastoma cases worldwide in 2017. Children from LMICs, where the main global retinoblastoma burden lies, presented at an older age with more advanced disease and demonstrated a smaller proportion of familial history of retinoblastoma, likely because many do not reach a childbearing age. Given that retinoblastoma is curable, these data are concerning and mandate intervention at national and international levels. Further studies are needed to investigate factors, other than age at presentation, that may be associated with advanced disease in LMICs

Jacob Boehme : The Way To Christ

New Yorkxviii, 307 p.; 23 c

Evaluation of Xpert MTB/RIF for detection of tuberculosis from blood samples of HIV-infected adults confirms Mycobacterium tuberculosis bacteremia as an indicator of poor prognosis.

Tuberculosis (TB) remains a leading cause of death among HIV-infected adults, in part because of delayed diagnosis and therefore delayed initiation of treatment. Recently, the Gene-Xpert platform, a rapid, PCR-based diagnostic platform, has been validated for the diagnosis of TB with sputum. We have evaluated the Xpert MTB/RIF assay for the diagnosis of Mycobacterium tuberculosis bacteremia and investigated its impact on clinical outcomes. Consecutive HIV-infected adults with fever and cough presenting to Queen Elizabeth Central Hospital, Blantyre, Malawi, were recruited and followed up for 2 months. At presentation, three sputum samples were examined by smear, culture, and Xpert MTB/RIF assay for the presence of M. tuberculosis and blood was drawn for PCR with Xpert, for mycobacterial culture (Myco/F Lytic), and for aerobic culture. One hundred four patients were recruited, and 44 (43%) were sputum culture positive for M. tuberculosis. Ten were Xpert blood positive, for a sensitivity of 21% and a specificity of 100%. The 2-week mortality rate was significantly higher among patients who were Xpert blood positive than among those who were negative (40% versus 3%; multivariate odds ratio [OR] for death if positive, 44; 95% confidence interval [CI], 3 to 662). This effect persisted on assessment of the mortality rate at 2 months (40% versus 11%; OR, 5.6; 95% CI, 1.3 to 24.6). When screening uncomplicated patients presenting with a productive cough for pulmonary TB, Xpert blood offers no diagnostic advantage over sputum testing. Despite this, Xpert blood positivity is highly predictive of early death and this test rapidly identifies a group of patients in urgent need of initiation of treatment

Bioengineering of a full-thickness skin equivalent in a 96-well insert format for substance permeation studies and organ-on-a-chip applications

The human skin is involved in protecting the inner body from constant exposure to outer environmental stimuli. There is an evident need to screen for toxicity and the efficacy of drugs and cosmetics applied to the skin. To date, animal studies are still the standard method for substance testing, although they are currently controversially discussed Therefore, the multi-organ chip is an attractive alternative to replace animal testing. The two-organ chip is designed to hold 96-well cell culture inserts (CCIs). Small-sized skin equivalents are needed for this. In this study, full-thickness skin equivalents (ftSEs) were generated successfully inside 96-well CCIs. These skin equivalents developed with in vivo-like histological architecture, with normal differentiation marker expressions and proliferation rates. The 96-well CCI-based ftSEs were successfully integrated into the two-organ chip. The permeation of fluorescein sodium salt through the ftSEs was monitored during the culture. The results show a decreasing value for the permeation over time, which seems a promising method to track the development of the ftSEs. Additionally, the permeation was implemented in a computational fluid dynamics simulation, as a tool to predict results in long-term experiments. The advantage of these ftSEs is the reduced need for cells and substances, which makes them more suitable for high throughput assays.The human skin is involved in protecting the inner body from constant exposure to outer environmental stimuli. There is an evident need to screen for toxicity and the efficacy of drugs and cosmetics applied to the skin. To date, animal studies are still the standard method for substance testing, although they are currently controversially discussed Therefore, the multi-organ chip is an attractive alternative to replace animal testing. The two-organ chip is designed to hold 96-well cell culture inserts (CCIs). Small-sized skin equivalents are needed for this. In this study, full-thickness skin equivalents (ftSEs) were generated successfully inside 96-well CCIs. These skin equivalents developed with in vivo-like histological architecture, with normal differentiation marker expressions and proliferation rates. The 96-well CCI-based ftSEs were successfully integrated into the two-organ chip. The permeation of fluorescein sodium salt through the ftSEs was monitored during the culture. The results show a decreasing value for the permeation over time, which seems a promising method to track the development of the ftSEs. Additionally, the permeation was implemented in a computational fluid dynamics simulation, as a tool to predict results in long-term experiments. The advantage of these ftSEs is the reduced need for cells and substances, which makes them more suitable for high throughput assays.Deutsche Forschungsgesellschaft (DFG) under grant No. PO413/12-1 and LA 1028/7-

Implementing rapid testing for tuberculosis in Mozambique

PROBLEM: In Mozambique, pulmonary tuberculosis is primarily diagnosed with sputum smear microscopy. However this method has low sensitivity, especially in people infected with human immunodeficiency virus (HIV). Patients are seldom tested for drug-resistant tuberculosis. APPROACH: The national tuberculosis programme and Health Alliance International introduced rapid testing of smear-negative sputum samples. Samples were tested using a polymerase-chain-reaction-based assay that detects Mycobacterium tuberculosis deoxyribonucleic acid and a mutation indicating rifampicin resistance; Xpert® MTB/RIF (Xpert®). Four machines were deployed in four public hospitals along with a sputum transportation system to transfer samples from selected health centres. Laboratory technicians were trained to operate the machines and clinicians taught to interpret the results. LOCAL SETTING: In 2012, Mozambique had an estimated 140 000 new tuberculosis cases, only 34% of which were diagnosed and treated. Of tuberculosis patients, 58% are HIV-infected. RELEVANT CHANGES: From 2012–2013, 1558 people were newly diagnosed with tuberculosis using sputum smears at intervention sites. Xpert® detected M. tuberculosis in an additional 1081 sputum smear-negative individuals, an increase of 69%. Rifampicin resistance was detected in 58/1081 (5%) of the samples. However, treatment was started in only 82% of patients diagnosed by microscopy and 67% of patients diagnosed with the rapid test. Twelve of 16 Xpert® modules failed calibration within 15 months of implementation. LESSONS LEARNT: Using rapid tests to diagnose tuberculosis is promising but logistically challenging. More affordable and durable platforms are needed. All patients diagnosed with tuberculosis need to start and complete treatment, including those who have drug resistant strains

Towards a Strategic Concept: A NATO Strategy for Eurasia in the 2020s

The North Atlantic Treaty Organization (NATO) is an alliance in crisis, part of a larger, global crisis surrounding the credibility and survival of the American-led world order at a systemic level. NATO was originally created in 1949 to defend Europe against the Soviet threat, or in the words of Lord Ismay, to “keep the Soviet Union out, the Americans in, and the Germans down.” In other words, NATO’s main goal was collective defense, exemplified by Article 5 of the Washington Treaty. However, after the end of the Cold War and the elimination of the Soviet threat, NATO’s responsibilities expanded to collective defense, crisis management, and collective security, taking on more out of area operations in new locations across the Eurasian super continent – such as in the Balkans and Afghanistan. The title of this report, “Towards a Strategic Concept,” makes clear its objective. The 12 members of this Task Force have drawn on their own areas of interest and specialization to make a limited set of recommendations towards a new NATO strategic concept for the next decade. To tackle this broad issue, we have divided our report into three geographical areas that will have a significant impact on NATO in the coming decades (West Eurasia, Mid-Eurasia, and East Eurasia) with a final section dedicated to discussions of emerging issues affecting the globe – such as climate change and cybersecurity