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Lancet (London, England) May 2024Accurate assessments of current and future fertility-including overall trends and changing population age structures across countries and regions-are essential to help...
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.
FUNDING
Bill & Melinda Gates Foundation.
Topics: Humans; Birth Rate; Adult; Female; Global Burden of Disease; Middle Aged; Adolescent; Young Adult; Male; Global Health; Child; Forecasting; Fertility; Population Forecast; Child, Preschool; Demography
PubMed: 38521087
DOI: 10.1016/S0140-6736(24)00550-6 -
Current Pharmaceutical Design 2013The cancer drug discovery field has placed much emphasis on the identification of novel and cancer-specific molecular targets. A rich source of such targets for the... (Review)
Review
The cancer drug discovery field has placed much emphasis on the identification of novel and cancer-specific molecular targets. A rich source of such targets for the design of novel anti-tumor agents is the ubiqutin-proteasome system (UP-S), a tightly regulated, highly specific pathway responsible for the vast majority of protein turnover within the cell. Because of its critical role in almost all cell processes that ensure normal cellular function, its inhibition at one point in time was deemed non-specific and therefore not worth further investigation as a molecular drug target. However, today the proteasome is one of the most promising anti-cancer drug targets of the century. The discovery that tumor cells are in fact more sensitive to proteasome inhibitors than normal cells indeed paved the way for the design of its inhibitors. Such efforts have led to bortezomib, the first FDA approved proteasome inhibitor now used as a frontline treatment for newly diagnosed multiple myeloma (MM), relapsed/refractory MM and mantle cell lymphoma. Though successful in improving clinical outcomes for patients with hematological malignancies, relapse often occurs in those who initially responded to bortezomib. Therefore, the acquisition of bortezomib resistance is a major issue with its therapy. Furthermore, some neuro-toxicities have been associated with bortezomib treatment and its efficacy in solid tumors is lacking. These observations have encouraged researchers to pursue the next generation of proteasome inhibitors, which would ideally overcome bortezomib resistance, have reduced toxicities and a broader range of anti-cancer activity. This review summarizes the success and limitations of bortezomib, and describes recent advances in the field, including, and most notably, the most recent FDA approval of carfilzomib in July, 2012, a second generation proteasome inhibitor. Other proteasome inhibitors currently in clinical trials and those that are currently experimental grade will also be discussed.
Topics: Animals; Antineoplastic Agents; Boronic Acids; Bortezomib; Humans; Neoplasms; Proteasome Endopeptidase Complex; Pyrazines
PubMed: 23181572
DOI: 10.2174/1381612811319220012 -
Advanced Science (Weinheim,... Sep 2022The kernmantle construction, a kind of braiding structure that is characterized by the kern absorbing most of the stress and the mantle protecting the kern, is widely...
The kernmantle construction, a kind of braiding structure that is characterized by the kern absorbing most of the stress and the mantle protecting the kern, is widely employed in the field of loading and rescue services, but rarely in flexible electronics. Here, a novel kernmantle electronic braid (E-braid) for high-impact sports monitoring, is proposed. The as-fabricated E-braids not only demonstrate high strength (31 Mpa), customized elasticity, and nice machine washability (>500 washes) but also exhibit excellent electrical stability (>200 000 cycles) during stretching. For demonstration, the E-braids are mounted to different parts of the trampoline for athletes' locomotor behavior monitoring. Furthermore, the E-braids are proved to act as multifarious intelligent sports gear or wearable equipment such as electronic jump rope and respiration monitoring belt. This study expands the kernmantle structure to soft flexible electronics and then accelerates the development of quantitative analysis in modern sports industry and athletes' healthcare.
Topics: Athletes; Elasticity; Electronics; Humans; Monitoring, Physiologic; Sports
PubMed: 35758560
DOI: 10.1002/advs.202202489 -
European Review For Medical and... May 2022This study aimed to analyze the current research status and trends of publications on relapsed/refractory Non-Hodgkin lymphoma (r/r NHL) using CiteSpace software and to...
OBJECTIVE
This study aimed to analyze the current research status and trends of publications on relapsed/refractory Non-Hodgkin lymphoma (r/r NHL) using CiteSpace software and to know which centers and authors we should follow in the first place while doing research on r/r NHL.
MATERIALS AND METHODS
The publications were retrieved from the Web of Science Core collection database, and CiteSpace (5.5.R5) software was used to analyze the authors, institutions, countries, and keywords.
RESULTS
A total of 567 publications from 2009 to 2021 were retrieved, and the most fertile authors, institutions, nationalities and keywords in the field of r/r NHL were identified. Pier Luigi Zinzani team, Kensei Tobinai team, Andre Goy team, and Julie M. Vose team are recognized the main research teams in this field. USA makes the greatest contribution having research funds for r/r NHL. Key cluster areas of research include mantle cell lymphoma, pathway, lymphoma, relapse, pixantrone, Non-Hodgkin lymphoma, romidepsin, relapsed, T-cell lymphoma, and activated T cells. According to the keywords' timeline, the research trends of r/r NHL changed from bone marrow transplantation, radioimmunotherapy, chemotherapy to novel target drugs (like ibritumomab tiuxetan, inhibitor) and criteria EBM.
CONCLUSIONS
The bibliometric study provides insights into hotspots and trends in the field of r/r NHL in the past 12 years. It serves us to extract useful information from complex data and provide information for clinicians and researchers.
Topics: Bibliometrics; Humans; Lymphoma, Mantle-Cell; Lymphoma, Non-Hodgkin; Neoplasm Recurrence, Local; Radioimmunotherapy
PubMed: 35647836
DOI: 10.26355/eurrev_202205_28850 -
Diabetes Sep 2020The human brain has inherent methodology to efficiently interpret complex environmental stimuli into understanding. This visual perception is governed by the law of...
The human brain has inherent methodology to efficiently interpret complex environmental stimuli into understanding. This visual perception is governed by the law of simplicity, which is fundamental to Gestalt theory. First introduced in a seminal article by Wertheimer in 1923, the theory explains how the mind groups similar images and fills in gaps in order to perceive an amenable version of reality. The world we see consists of complex visual scenes, but rarely is the entire picture visible to us. Since it is inefficient for all visual data to be analyzed at once, certain patterns are given higher importance and made to stand out from the rest of the field in our brain. Here we propose that Gestalt theory may explain why rodent islet architecture has historically been seen as having a core-mantle arrangement. By filling in apparent gaps in the non-β-cell lining, the mind interprets it as a "whole" mantle, which may have further led to widely accepted notions regarding islet microcirculation, intra-islet signaling, and islet development. They are largely based on the prevailing stereotypic islet architecture in which an enclosed structure is presumed. Three-dimensional analysis provides more integrated views of islet and pancreatic microcirculation.
Topics: Animals; Humans; Islets of Langerhans; Pancreas
PubMed: 32669392
DOI: 10.2337/db20-0304 -
Cells Mar 2020Apoptosis is a highly conserved mechanism enabling the removal of unwanted cells. Mitochondrial apoptosis is governed by the B-cell lymphoma (BCL-2) family, including... (Review)
Review
Apoptosis is a highly conserved mechanism enabling the removal of unwanted cells. Mitochondrial apoptosis is governed by the B-cell lymphoma (BCL-2) family, including anti-apoptotic and pro-apoptotic proteins. Apoptosis evasion by dysregulation of anti-apoptotic BCL-2 members (BCL-2, MCL-1, BCL-X) is a common hallmark in cancers. To divert this dysregulation into vulnerability, researchers have developed BH3 mimetics, which are small molecules that restore effective apoptosis in neoplastic cells by interfering with anti-apoptotic proteins. Among them, venetoclax is a potent and selective BCL-2 inhibitor, which has demonstrated the strongest clinical activity in mature B-cell malignancies, including chronic lymphoid leukemia, mantle-cell lymphoma, and multiple myeloma. Nevertheless, mechanisms of primary and acquired resistance have been recently described and several features such as cytogenetic abnormalities, BCL-2 family expression, and ex vivo drug testing have to be considered for predicting sensitivity to BH3 mimetics and helping in the identification of patients able to respond. The medical need to overcome resistance to BH3 mimetics supports the evaluation of innovative combination strategies. Novel agents including MCL-1 targeting BH3 mimetics are currently evaluated and may represent new therapeutic options in the field. The present review summarizes the current knowledge regarding venetoclax and other BH3 mimetics for the treatment of mature B-cell malignancies.
Topics: Apoptosis; B-Lymphocytes; Cell Line, Tumor; Humans; Lymphoma, B-Cell; Peptide Fragments; Proto-Oncogene Proteins
PubMed: 32183335
DOI: 10.3390/cells9030717 -
Cold Spring Harbor Perspectives in... Oct 2010Earth is the one known example of an inhabited planet and to current knowledge the likeliest site of the one known origin of life. Here we discuss the origin of Earth's... (Review)
Review
Earth is the one known example of an inhabited planet and to current knowledge the likeliest site of the one known origin of life. Here we discuss the origin of Earth's atmosphere and ocean and some of the environmental conditions of the early Earth as they may relate to the origin of life. A key punctuating event in the narrative is the Moon-forming impact, partly because it made Earth for a short time absolutely uninhabitable, and partly because it sets the boundary conditions for Earth's subsequent evolution. If life began on Earth, as opposed to having migrated here, it would have done so after the Moon-forming impact. What took place before the Moon formed determined the bulk properties of the Earth and probably determined the overall compositions and sizes of its atmospheres and oceans. What took place afterward animated these materials. One interesting consequence of the Moon-forming impact is that the mantle is devolatized, so that the volatiles subsequently fell out in a kind of condensation sequence. This ensures that the volatiles were concentrated toward the surface so that, for example, the oceans were likely salty from the start. We also point out that an atmosphere generated by impact degassing would tend to have a composition reflective of the impacting bodies (rather than the mantle), and these are almost without exception strongly reducing and volatile-rich. A consequence is that, although CO- or methane-rich atmospheres are not necessarily stable as steady states, they are quite likely to have existed as long-lived transients, many times. With CO comes abundant chemical energy in a metastable package, and with methane comes hydrogen cyanide and ammonia as important albeit less abundant gases.
Topics: Atmosphere; Earth, Planet; Moon; Origin of Life
PubMed: 20573713
DOI: 10.1101/cshperspect.a004895 -
Molecules (Basel, Switzerland) Dec 2023Bruton tyrosine kinase (BTK) is an essential enzyme in the signaling pathway of the B-cell receptor (BCR) and is vital for the growth and activation of B-cells.... (Review)
Review
Bruton tyrosine kinase (BTK) is an essential enzyme in the signaling pathway of the B-cell receptor (BCR) and is vital for the growth and activation of B-cells. Dysfunction of BTK has been linked to different types of B-cell cancers, autoimmune conditions, and inflammatory ailments. Therefore, focusing on BTK has become a hopeful approach in the field of therapeutics. Small-molecule inhibitors of BTK have been developed to selectively inhibit its activity and disrupt B-cell signaling pathways. These inhibitors bind to the active site of BTK and prevent its phosphorylation, leading to the inhibition of downstream signaling cascades. Regulatory authorities have granted approval to treat B-cell malignancies, such as chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), with multiple small-molecule BTK inhibitors. This review offers a comprehensive analysis of the synthesis and clinical application of conventional small-molecule BTK inhibitors at various clinical stages, as well as presents promising prospects for the advancement of new small-molecule BTK inhibitors.
Topics: Humans; Adult; Agammaglobulinaemia Tyrosine Kinase; Protein-Tyrosine Kinases; B-Lymphocytes; Signal Transduction; Leukemia, Lymphocytic, Chronic, B-Cell
PubMed: 38138527
DOI: 10.3390/molecules28248037 -
Translational Breast Cancer Research :... 2022In today's world, the concept of gender has been scrutinized and an appreciation for those who experience dysphoria with their birth sex and gender classification is...
BACKGROUND
In today's world, the concept of gender has been scrutinized and an appreciation for those who experience dysphoria with their birth sex and gender classification is becoming more commonplace. Keeping in mind the patients gender orientation in addition to their birth sex is necessary when assessing health conditions more prevalent in one sex, such as breast cancer.
CASE DESCRIPTION
In this report, we present a 51-year-old African American transgender female with history of chemotherapy and mantle-field radiation treatment for sub-clavicular and mediastinal Hodgkin's lymphoma 24 years prior to presentation of a new left neck mass. The enlarged lymph node was removed revealing metastatic salivary adenocarcinoma with features corresponding to metastatic breast carcinoma. Computed tomography (CT) of the chest, abdomen, and pelvis detected metastasis to the pelvis and a few lucent bone lesions in the lumbar spine. Of note, the patient underwent free silicone injections into both breasts to emphasize her desired gender three years after treatment for Hodgkin's lymphoma. Based on her history of metastatic disease and history of mantle radiation, it was determined that her previous cancer diagnoses were likely due to metastatic breast cancer that was obscured by silicone injections. Bilateral skin-sparing mastectomy was performed, patient recovered well, and continued with palliative care at follow up.
CONCLUSIONS
Even though there is significant data regarding the incidence of breast cancer in the separate female and male populations, review of the literature shows minimal information regarding incidence in the transgender population. Our hope is that this report will contribute to the current base of knowledge present in the literature while also bringing attention to the need for further investigation of sex-specific diseases in transgender individuals.
PubMed: 38751536
DOI: 10.21037/tbcr-22-25 -
International Journal of Molecular... May 2023Chimeric antigen receptor (CAR) T-cell therapy has greatly transformed the treatment and prognosis of B-cell hematological malignancies. As CAR T-cell therapy continues...
Chimeric antigen receptor (CAR) T-cell therapy has greatly transformed the treatment and prognosis of B-cell hematological malignancies. As CAR T-cell therapy continues to be more readily adopted and indications increase, the field's recognition of emerging toxicities will continue to grow. Among the adverse events associated with CAR T-cell therapy, cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity (ICANS) are the most common toxicities, while thrombotic events represent an under-reported, life-endangering complication. To determine thrombosis incidence post CAR T-cell therapy, we performed a multi-center, retrospective study on CAR T-cell therapy adult patients (N = 140) from Indiana University Simon Cancer Center and the University of North Carolina Medical Center treated from 2017 to 2022 for relapsed and refractory B-cell acute lymphoblastic leukemia (B-ALL, N = 3), diffuse large B-cell lymphoma (DLBCL, N = 92), follicular lymphoma (FL, N = 9), mantle cell lymphoma (MCL, N = 2), and multiple myeloma (MM, N = 34). We report 10 (7.14%) thrombotic events related to CAR T-cell therapy (DLBCL: N = 8, FL: N = 1, MM: N = 1) including 9 primary venous events and 1 arterial event that occurred with median time of 23.5 days post CAR T-cell infusion. In search of parameters associated with such events, we performed multivariate analyses of coagulation parameters (i.e., PT, PTT, and D-Dimer), scoring for adverse events (Padua Score and ISTH DIC Score) and grading for CAR T-cell toxicity severity (CRS grade and ICANS grade) and found that D-Dimer peak elevation and ICANS grade were significantly associated with post-CAR T-cell infusion thrombosis. While the pathophysiology of CAR T-cell associated coagulopathy remains unknown, our study serves to develop awareness of these emerging and unusual complications.
Topics: Humans; Adult; Immunotherapy, Adoptive; Receptors, Chimeric Antigen; Retrospective Studies; T-Lymphocytes; Thrombosis; Receptors, Antigen, T-Cell
PubMed: 37176053
DOI: 10.3390/ijms24098349