Preoperative MRI-radiomics features improve prediction of survival in glioblastoma patients over MGMT methylation status alone

Background: Glioblastoma (GBM) is the most common malignant central nervous system tumor, and MGMT promoter hypermethylation in this tumor has been shown to be associated with better prognosis. We evaluated the capacity of radiomics features to add complementary information to MGMT status, to improve the ability to predict prognosis. Methods: 159 patients with untreated GBM were included in this study and divided into training and independent test sets. 286 radiomics features were extracted from the magnetic resonance images acquired prior to any treatments. A least absolute shrinkage selection operator (LASSO) selection followed by Kaplan-Meier analysis was used to determine the prognostic value of radiomics features to predict overall survival (OS). The combination of MGMT status with radiomics was also investigated and all results were validated on the independent test set. Results: LASSO analysis identified 8 out of the 286 radiomic features to be relevant which were then used for determining association to OS. One feature (edge descriptor) remained significant on the external validation cohort after multiple testing (p=0.04) and the combination with MGMT identified a group of patients with the best prognosis with a survival probability of 0.61 after 43 months (p=0.0005). Conclusion: Our results suggest that combining radiomics with MGMT is more accurate in stratifying patients into groups of different survival risks when compared to with using these predictors in isolation. We identified two subgroups within patients who have methylated MGMT: one with a similar survival to unmethylated MGMT patients and the other with a significantly longer OS

Adjuvant interferon gamma in patients with drug – resistant pulmonary tuberculosis: a pilot study

BACKGROUND: Tuberculosis (TB) is increasing in the world and drug-resistant (DR) disease beckons new treatments. METHODS: To evaluate the action of interferon (IFN) gamma as immunoadjuvant to chemotherapy on pulmonary DR-TB patients, a pilot, open label clinical trial was carried out in the Cuban reference ward for the management of this disease. The eight subjects existing in the country at the moment received, as in-patients, 1 × 10(6 )IU of recombinant human IFN gamma intramuscularly, daily for one month and then three times per week up to 6 months as adjuvant to the indicated chemotherapy, according to their antibiograms and WHO guidelines. Sputum samples collection for direct smear observation and culture as well as routine clinical and thorax radiography assessments were done monthly. RESULTS: Sputum smears and cultures became negative for acid-fast-bacilli before three months of treatment in all patients. Lesion size was reduced at the end of 6 months treatment; the lesions disappeared in one case. Clinical improvement was also evident; body mass index increased in general. Interferon gamma was well tolerated. Few adverse events were registered, mostly mild; fever and arthralgias prevailed. CONCLUSIONS: These data suggest that IFN gamma is useful and well tolerated as adjunctive therapy in patients with DR-TB. Further controlled clinical trials are encouraged

Listeria pathogenesis and molecular virulence determinants

The gram-positive bacterium Listeria monocytogenes is the causative agent of listeriosis, a highly fatal opportunistic foodborne infection. Pregnant women, neonates, the elderly, and debilitated or immunocompromised patients in general are predominantly affected, although the disease can also develop in normal individuals. Clinical manifestations of invasive listeriosis are usually severe and include abortion, sepsis, and meningoencephalitis. Listeriosis can also manifest as a febrile gastroenteritis syndrome. In addition to humans, L. monocytogenes affects many vertebrate species, including birds. Listeria ivanovii, a second pathogenic species of the genus, is specific for ruminants. Our current view of the pathophysiology of listeriosis derives largely from studies with the mouse infection model. Pathogenic listeriae enter the host primarily through the intestine. The liver is thought to be their first target organ after intestinal translocation. In the liver, listeriae actively multiply until the infection is controlled by a cell-mediated immune response. This initial, subclinical step of listeriosis is thought to be common due to the frequent presence of pathogenic L. monocytogenes in food. In normal indivuals, the continual exposure to listerial antigens probably contributes to the maintenance of anti-Listeria memory T cells. However, in debilitated and immunocompromised patients, the unrestricted proliferation of listeriae in the liver may result in prolonged low-level bacteremia, leading to invasion of the preferred secondary target organs (the brain and the gravid uterus) and to overt clinical disease. L. monocytogenes and L. ivanovii are facultative intracellular parasites able to survive in macrophages and to invade a variety of normally nonphagocytic cells, such as epithelial cells, hepatocytes, and endothelial cells. In all these cell types, pathogenic listeriae go through an intracellular life cycle involving early escape from the phagocytic vacuole, rapid intracytoplasmic multiplication, bacterially induced actin-based motility, and direct spread to neighboring cells, in which they reinitiate the cycle. In this way, listeriae disseminate in host tissues sheltered from the humoral arm of the immune system. Over the last 15 years, a number of virulence factors involved in key steps of this intracellular life cycle have been identified. This review describes in detail the molecular determinants of Listeria virulence and their mechanism of action and summarizes the current knowledge on the pathophysiology of listeriosis and the cell biology and host cell responses to Listeria infection. This article provides an updated perspective of the development of our understanding of Listeria pathogenesis from the first molecular genetic analyses of virulence mechanisms reported in 1985 until the start of the genomic era of Listeria research

Global fertility in 204 countries and territories, 1950–2021, with forecasts to 2100: a comprehensive demographic analysis for the Global Burden of Disease Study 2021

Background Accurate assessments of current and future fertility—including overall trends and changing population age structures across countries and regions—are essential to help plan for the profound social, economic, environmental, and geopolitical challenges that these changes will bring. Estimates and projections of fertility are necessary to inform policies involving resource and health-care needs, labour supply, education, gender equality, and family planning and support. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 produced up-to-date and comprehensive demographic assessments of key fertility indicators at global, regional, and national levels from 1950 to 2021 and forecast fertility metrics to 2100 based on a reference scenario and key policy-dependent alternative scenarios. Methods To estimate fertility indicators from 1950 to 2021, mixed-effects regression models and spatiotemporal Gaussian process regression were used to synthesise data from 8709 country-years of vital and sample registrations, 1455 surveys and censuses, and 150 other sources, and to generate age-specific fertility rates (ASFRs) for 5-year age groups from age 10 years to 54 years. ASFRs were summed across age groups to produce estimates of total fertility rate (TFR). Livebirths were calculated by multiplying ASFR and age-specific female population, then summing across ages 10–54 years. To forecast future fertility up to 2100, our Institute for Health Metrics and Evaluation (IHME) forecasting model was based on projections of completed cohort fertility at age 50 years (CCF50; the average number of children born over time to females from a specified birth cohort), which yields more stable and accurate measures of fertility than directly modelling TFR. CCF50 was modelled using an ensemble approach in which three sub-models (with two, three, and four covariates variously consisting of female educational attainment, contraceptive met need, population density in habitable areas, and under-5 mortality) were given equal weights, and analyses were conducted utilising the MR-BRT (meta-regression—Bayesian, regularised, trimmed) tool. To capture time-series trends in CCF50 not explained by these covariates, we used a first-order autoregressive model on the residual term. CCF50 as a proportion of each 5-year ASFR was predicted using a linear mixed-effects model with fixed-effects covariates (female educational attainment and contraceptive met need) and random intercepts for geographical regions. Projected TFRs were then computed for each calendar year as the sum of single-year ASFRs across age groups. The reference forecast is our estimate of the most likely fertility future given the model, past fertility, forecasts of covariates, and historical relationships between covariates and fertility. We additionally produced forecasts for multiple alternative scenarios in each location: the UN Sustainable Development Goal (SDG) for education is achieved by 2030; the contraceptive met need SDG is achieved by 2030; pro-natal policies are enacted to create supportive environments for those who give birth; and the previous three scenarios combined. Uncertainty from past data inputs and model estimation was propagated throughout analyses by taking 1000 draws for past and present fertility estimates and 500 draws for future forecasts from the estimated distribution for each metric, with 95% uncertainty intervals (UIs) given as the 2·5 and 97·5 percentiles of the draws. To evaluate the forecasting performance of our model and others, we computed skill values—a metric assessing gain in forecasting accuracy—by comparing predicted versus observed ASFRs from the past 15 years (2007–21). A positive skill metric indicates that the model being evaluated performs better than the baseline model (here, a simplified model holding 2007 values constant in the future), and a negative metric indicates that the evaluated model performs worse than baseline. Findings During the period from 1950 to 2021, global TFR more than halved, from 4·84 (95% UI 4·63–5·06) to 2·23 (2·09–2·38). Global annual livebirths peaked in 2016 at 142 million (95% UI 137–147), declining to 129 million (121–138) in 2021. Fertility rates declined in all countries and territories since 1950, with TFR remaining above 2·1—canonically considered replacement-level fertility—in 94 (46·1%) countries and territories in 2021. This included 44 of 46 countries in sub-Saharan Africa, which was the super-region with the largest share of livebirths in 2021 (29·2% [28·7–29·6]). 47 countries and territories in which lowest estimated fertility between 1950 and 2021 was below replacement experienced one or more subsequent years with higher fertility; only three of these locations rebounded above replacement levels. Future fertility rates were projected to continue to decline worldwide, reaching a global TFR of 1·83 (1·59–2·08) in 2050 and 1·59 (1·25–1·96) in 2100 under the reference scenario. The number of countries and territories with fertility rates remaining above replacement was forecast to be 49 (24·0%) in 2050 and only six (2·9%) in 2100, with three of these six countries included in the 2021 World Bank-defined low-income group, all located in the GBD super-region of sub-Saharan Africa. The proportion of livebirths occurring in sub-Saharan Africa was forecast to increase to more than half of the world's livebirths in 2100, to 41·3% (39·6–43·1) in 2050 and 54·3% (47·1–59·5) in 2100. The share of livebirths was projected to decline between 2021 and 2100 in most of the six other super-regions—decreasing, for example, in south Asia from 24·8% (23·7–25·8) in 2021 to 16·7% (14·3–19·1) in 2050 and 7·1% (4·4–10·1) in 2100—but was forecast to increase modestly in the north Africa and Middle East and high-income super-regions. Forecast estimates for the alternative combined scenario suggest that meeting SDG targets for education and contraceptive met need, as well as implementing pro-natal policies, would result in global TFRs of 1·65 (1·40–1·92) in 2050 and 1·62 (1·35–1·95) in 2100. The forecasting skill metric values for the IHME model were positive across all age groups, indicating that the model is better than the constant prediction. Interpretation Fertility is declining globally, with rates in more than half of all countries and territories in 2021 below replacement level. Trends since 2000 show considerable heterogeneity in the steepness of declines, and only a small number of countries experienced even a slight fertility rebound after their lowest observed rate, with none reaching replacement level. Additionally, the distribution of livebirths across the globe is shifting, with a greater proportion occurring in the lowest-income countries. Future fertility rates will continue to decline worldwide and will remain low even under successful implementation of pro-natal policies. These changes will have far-reaching economic and societal consequences due to ageing populations and declining workforces in higher-income countries, combined with an increasing share of livebirths among the already poorest regions of the world

Disrupted third visual pathway function in schizophrenia: Evidence from real and implied motion processing

Impaired motion perception in schizophrenia has been associated with deficits in social-cognitive processes and with reduced activation of visual sensory regions, including the middle temporal area (MT+) and posterior superior temporal sulcus (pSTS). These findings are consistent with the recent proposal of the existence of a specific ‘third visual pathway’ specialized for social perception in which motion is a fundamental component. The third visual pathway transmits visual information from early sensory visual processing areas to the STS, with MT+ acting as a critical intermediary. We used functional magnetic resonance imaging to investigate functioning of this pathway during processing of naturalistic videos with explicit (real) motion and static images with implied motion cues. These measures were related to face emotion recognition and motion-perception, as measured behaviorally. Participants were 28 individuals with schizophrenia (Sz) and 20 neurotypical controls. Compared to controls, individuals with Sz showed reduced activation of third visual pathway regions (MT+, pSTS) in response to both real- and implied-motion stimuli. Dysfunction of early visual cortex and pulvinar were also associated with aberrant real-motion processing. Implied-motion stimuli additionally engaged a wide network of brain areas including parietal, motor and frontal nodes of the human mirror neuron system. The findings support concepts of MT+ as a mediator between visual sensory areas and higher-order brain and argue for greater focus on MT+ contributions to social-cognitive processing, in addition to its well-documented role in visual motion processing

変化する環境での生態リスクと健康を結ぶ研究 : エコヘルスアプローチ

EcoHealthとは、人々の暮らしや環境と、人間の健康との間の代替関係を効果的に扱うための新しい知識を生み出す、革新的かつ効果的な研究アプローチである。世界各地において、長期的な環境の危機や環境変化、高度経済成長が、貧しい人々の健康と暮らしに悪影響を与えていることが指摘されている。多くの脆弱な共同体では、人々が健康を脅かされる劣化した生態系に住んでいることが多く、環境汚染や新旧の伝染病の危険に直面している。そこでこのEcoHealth研究プロジェクトでは、生態リスクと人間の健康との関係のつながりを明らかにし、熱帯地域における健康問題をより効果的に扱うための方法論を開発することを目的としている。具体的には、フィリピンラグナ地域を研究対象として、過去から現在への土地利用変化の性質と程度、水質や堆積物汚染に関連したリスクが人々の健康へ与える影響を分析し、問題点を明らかにする。さらにこのEcoHealthアプローチでは、人間の健康の永続的な改善を目的とした、土地利用や公衆衛生制度の向上に貢献する実用的な政策提言を行うとともに、本研究を通して、日本とフィリピンの研究者相互の国際的な共同研究能力を向上させることを目指す。EcoHealth is an innovative and effective way to generate new knowledge to better address the trade-offs between livelihoods, environment, and human health. It is reported that long-standing environmental hazards, environmental changes, and rapid economic growth are affecting the health and livelihoods of poor people around the world. These vulnerable communities live in degraded ecosystems that threaten their health. With few resources to face these problems, they get exposed to environmental pollution, and new and old infectious diseases. This research aims to link environmental risks to health. More specifically, this study aims at identifying and analyzing the nature of current land use, water and sediment related risks to the health status, with focus on soil-transmitted helminth infections, of the people in selected sites in the Laguna region, Philippines. In the long run, outputs from this study can help suggesting practical policy recommendations to improve current land use and development planning as well as public health systems, while enhancing mutual international level research collaborations between researchers from Japan and the Philippines. The current paper is an introduction of the research project and gives some snapshots of preliminary results.EcoHealthとは、人々の暮らしや環境と、人間の健康との間の代替関係を効果的に扱うための新しい知識を生み出す、革新的かつ効果的な研究アプローチである。世界各地において、長期的な環境の危機や環境変化、高度経済成長が、貧しい人々の健康と暮らしに悪影響を与えていることが指摘されている。多くの脆弱な共同体では、人々が健康を脅かされる劣化した生態系に住んでいることが多く、環境汚染や新旧の伝染病の危険に直面している。そこでこのEcoHealth研究プロジェクトでは、生態リスクと人間の健康との関係のつながりを明らかにし、熱帯地域における健康問題をより効果的に扱うための方法論を開発することを目的としている。具体的には、フィリピンラグナ地域を研究対象として、過去から現在への土地利用変化の性質と程度、水質や堆積物汚染に関連したリスクが人々の健康へ与える影響を分析し、問題点を明らかにする。さらにこのEcoHealthアプローチでは、人間の健康の永続的な改善を目的とした、土地利用や公衆衛生制度の向上に貢献する実用的な政策提言を行うとともに、本研究を通して、日本とフィリピンの研究者相互の国際的な共同研究能力を向上させることを目指す。EcoHealth is an innovative and effective way to generate new knowledge to better address the trade-offs between livelihoods, environment, and human health. It is reported that long-standing environmental hazards, environmental changes, and rapid economic growth are affecting the health and livelihoods of poor people around the world. These vulnerable communities live in degraded ecosystems that threaten their health. With few resources to face these problems, they get exposed to environmental pollution, and new and old infectious diseases. This research aims to link environmental risks to health. More specifically, this study aims at identifying and analyzing the nature of current land use, water and sediment related risks to the health status, with focus on soil-transmitted helminth infections, of the people in selected sites in the Laguna region, Philippines. In the long run, outputs from this study can help suggesting practical policy recommendations to improve current land use and development planning as well as public health systems, while enhancing mutual international level research collaborations between researchers from Japan and the Philippines. The current paper is an introduction of the research project and gives some snapshots of preliminary results