Summarizing the epidemiology of major depressive disorder (MDD) at a global level is complicated by significant heterogeneity in the data. The aim of this study is to present a global summary of the ...prevalence and incidence of MDD, accounting for sources of bias, and dealing with heterogeneity. Findings are informing MDD burden quantification in the Global Burden of Disease (GBD) 2010 Study.
A systematic review of prevalence and incidence of MDD was undertaken. Electronic databases Medline, PsycINFO and EMBASE were searched. Community-representative studies adhering to suitable diagnostic nomenclature were included. A meta-regression was conducted to explore sources of heterogeneity in prevalence and guide the stratification of data in a meta-analysis.
The literature search identified 116 prevalence and four incidence studies. Prevalence period, sex, year of study, depression subtype, survey instrument, age and region were significant determinants of prevalence, explaining 57.7% of the variability between studies. The global point prevalence of MDD, adjusting for methodological differences, was 4.7% (4.4-5.0%). The pooled annual incidence was 3.0% (2.4-3.8%), clearly at odds with the pooled prevalence estimates and the previously reported average duration of 30 weeks for an episode of MDD.
Our findings provide a comprehensive and up-to-date profile of the prevalence of MDD globally. Region and study methodology influenced the prevalence of MDD. This needs to be considered in the GBD 2010 study and in investigations into the ecological determinants of MDD. Good-quality estimates from low-/middle-income countries were sparse. More accurate data on incidence are also required.
Depressive disorders were a leading cause of burden in the Global Burden of Disease (GBD) 1990 and 2000 studies. Here, we analyze the burden of depressive disorders in GBD 2010 and present severity ...proportions, burden by country, region, age, sex, and year, as well as burden of depressive disorders as a risk factor for suicide and ischemic heart disease.
Burden was calculated for major depressive disorder (MDD) and dysthymia. A systematic review of epidemiological data was conducted. The data were pooled using a Bayesian meta-regression. Disability weights from population survey data quantified the severity of health loss from depressive disorders. These weights were used to calculate years lived with disability (YLDs) and disability adjusted life years (DALYs). Separate DALYs were estimated for suicide and ischemic heart disease attributable to depressive disorders. Depressive disorders were the second leading cause of YLDs in 2010. MDD accounted for 8.2% (5.9%-10.8%) of global YLDs and dysthymia for 1.4% (0.9%-2.0%). Depressive disorders were a leading cause of DALYs even though no mortality was attributed to them as the underlying cause. MDD accounted for 2.5% (1.9%-3.2%) of global DALYs and dysthymia for 0.5% (0.3%-0.6%). There was more regional variation in burden for MDD than for dysthymia; with higher estimates in females, and adults of working age. Whilst burden increased by 37.5% between 1990 and 2010, this was due to population growth and ageing. MDD explained 16 million suicide DALYs and almost 4 million ischemic heart disease DALYs. This attributable burden would increase the overall burden of depressive disorders from 3.0% (2.2%-3.8%) to 3.8% (3.0%-4.7%) of global DALYs.
GBD 2010 identified depressive disorders as a leading cause of burden. MDD was also a contributor of burden allocated to suicide and ischemic heart disease. These findings emphasize the importance of including depressive disorders as a public-health priority and implementing cost-effective interventions to reduce its burden. Please see later in the article for the Editors' Summary.
Senescence, a persistent form of cell-cycle arrest, is often associated with a diverse secretome, which provides complex functionality for senescent cells within the tissue microenvironment. We show ...that oncogene-induced senescence is accompanied by a dynamic fluctuation of NOTCH1 activity, which drives a TGF-β-rich secretome, while suppressing the senescence-associated pro-inflammatory secretome through inhibition of C/EBPβ. NOTCH1 and NOTCH1-driven TGF-β contribute to 'lateral induction of senescence' through a juxtacrine NOTCH-JAG1 pathway. In addition, NOTCH1 inhibition during senescence facilitates upregulation of pro-inflammatory cytokines, promoting lymphocyte recruitment and senescence surveillance in vivo. As enforced activation of NOTCH1 signalling confers a near mutually exclusive secretory profile compared with typical senescence, our data collectively indicate that the dynamic alteration of NOTCH1 activity during senescence dictates a functional balance between these two distinct secretomes: one representing TGF-β and the other pro-inflammatory cytokines, highlighting that NOTCH1 is a temporospatial controller of secretome composition.
Although the detrimental impact of major depressive disorder (MDD) at the individual level has been described, its global epidemiology remains unclear given limitations in the data. Here we present ...the modelled epidemiological profile of MDD dealing with heterogeneity in the data, enforcing internal consistency between epidemiological parameters and making estimates for world regions with no empirical data. These estimates were used to quantify the burden of MDD for the Global Burden of Disease Study 2010 (GBD 2010).
Analyses drew on data from our existing literature review of the epidemiology of MDD. DisMod-MR, the latest version of the generic disease modelling system redesigned as a Bayesian meta-regression tool, derived prevalence by age, year and sex for 21 regions. Prior epidemiological knowledge, study- and country-level covariates adjusted sub-optimal raw data.
There were over 298 million cases of MDD globally at any point in time in 2010, with the highest proportion of cases occurring between 25 and 34 years. Global point prevalence was very similar across time (4.4% (95% uncertainty: 4.2-4.7%) in 1990, 4.4% (4.1-4.7%) in 2005 and 2010), but higher in females (5.5% (5.0-6.0%) compared to males (3.2% (3.0-3.6%) in 2010. Regions in conflict had higher prevalence than those with no conflict. The annual incidence of an episode of MDD followed a similar age and regional pattern to prevalence but was about one and a half times higher, consistent with an average duration of 37.7 weeks.
We were able to integrate available data, including those from high quality surveys and sub-optimal studies, into a model adjusting for known methodological sources of heterogeneity. We were also able to estimate the epidemiology of MDD in regions with no available data. This informed GBD 2010 and the public health field, with a clearer understanding of the global distribution of MDD.
The Gravity Probe B mission provided two new quantitative tests of Einstein's theory of gravity, general relativity (GR), by cryogenic gyroscopes in Earth's orbit. Data from four gyroscopes gave a ...geodetic drift-rate of −6601.8 18.3 marc-s yr−1 and a frame-dragging of −37.2 7.2 marc-s yr−1, to be compared with GR predictions of −6606.1 and −39.2 marc-s yr−1 (1 marc-s = 4.848 × 10−9 radians). The present paper introduces the science, engineering, data analysis, and heritage of Gravity Probe B, detailed in the accompanying 20 CQG papers.
We describe the design and performance of the near-infrared (1.51-1.70 m), fiber-fed, multi-object (300 fibers), high resolution (R = λ/Δλ ∼ 22,500) spectrograph built for the Apache Point ...Observatory Galactic Evolution Experiment (APOGEE). APOGEE is a survey of ∼105 red giant stars that systematically sampled all Milky Way populations (bulge, disk, and halo) to study the Galaxy's chemical and kinematical history. It was part of the Sloan Digital Sky Survey III (SDSS-III) from 2011 to 2014 using the 2.5 m Sloan Foundation Telescope at Apache Point Observatory, New Mexico. The APOGEE-2 survey is now using the spectrograph as part of SDSS-IV, as well as a second spectrograph, a close copy of the first, operating at the 2.5 m du Pont Telescope at Las Campanas Observatory in Chile. Although several fiber-fed, multi-object, high resolution spectrographs have been built for visual wavelength spectroscopy, the APOGEE spectrograph is one of the first such instruments built for observations in the near-infrared. The instrument's successful development was enabled by several key innovations, including a "gang connector" to allow simultaneous connections of 300 fibers; hermetically sealed feedthroughs to allow fibers to pass through the cryostat wall continuously; the first cryogenically deployed mosaic volume phase holographic grating; and a large refractive camera that includes mono-crystalline silicon and fused silica elements with diameters as large as ∼400 mm. This paper contains a comprehensive description of all aspects of the instrument including the fiber system, optics and opto-mechanics, detector arrays, mechanics and cryogenics, instrument control, calibration system, optical performance and stability, lessons learned, and design changes for the second instrument.
The treatment of chronic lymphocytic leukemia (CLL) has been revolutionized by targeted therapies that either inhibit proliferation (ibrutinib) or reactivate apoptosis (venetoclax). Both ...significantly improve survival in CLL and replace chemoimmunotherapy for many patients. However, individually, they rarely lead to eradication of measurable residual disease (MRD) and usually are taken indefinitely or until progression. We present the CLARITY trial that combined ibrutinib with venetoclax to eradicate detectable CLL with the intention of stopping therapy.
CLARITY is a phase II trial that combined ibrutinib with venetoclax in patients with relapsed or refractory CLL. The primary end point was eradication of MRD after 12 months of combined therapy. Key secondary end points were response by International Workshop on CLL criteria, safety, and progression-free and overall survival.
In 53 patients after 12 months of ibrutinib plus venetoclax, MRD negativity (fewer than one CLL cell in 10,000 leukocytes) was achieved in the blood of 28 (53%) and the marrow of 19 (36%). Forty-seven patients (89%) responded, and 27 (51%) achieved a complete remission. After a median follow-up of 21.1 months, one patient progressed, and all patients were alive. A single case of biochemical tumor lysis syndrome was observed. Other adverse effects were mild and/or manageable and most commonly were neutropenia or GI events.
The combination of ibrutinib plus venetoclax was well tolerated in patients with relapsed or refractory CLL. There was a high rate of MRD eradication that led to the cessation of therapy in some patients. The progression-free and overall survival rates are encouraging for relapsed and refractory CLL.
Filoviruses, mainly consisting of Ebola viruses (EBOV) and Marburg viruses (MARV), are enveloped negative-strand RNA viruses which can infect humans to cause severe hemorrhagic fevers and outbreaks ...with high mortality rates. The filovirus infection is mediated by the interaction of viral envelope glycoprotein (GP) and the human endosomal receptor Niemann-Pick C1 (NPC1). Blocking this interaction will prevent the infection. Therefore, we utilized an In silico screening approach to conduct virtual compound screening against the NPC1 receptor-binding site (RBS). Twenty-six top-hit compounds were purchased and evaluated by in vitro cell based inhibition assays against pseudotyped or replication-competent filoviruses. Two classes (A and U) of compounds were identified to have potent inhibitory activity against both Ebola and Marburg viruses. The IC50 values are in the lower level of micromolar concentrations. One compound (compd-A) was found to have a sub-micromolar IC50 value (0.86 μM) against pseudotyped Marburg virus. The cytotoxicity assay (MTT) indicates that compd-A has a moderate cytotoxicity level but the compd-U has much less toxicity and the CC50 value was about 100 μM. Structure-activity relationship (SAR) study has found some analogs of compd-A and -U have reduced the toxicity and enhanced the inhibitory activity. In conclusion, this work has identified several qualified lead-compounds for further drug development against filovirus infection.
•In silico screening of 100K compounds against the receptor-binding site of Ebola virus.•Two classes of compounds were identified to have potent activities against filovirus entry from in vitro assays.•One compound was found to have a sub-micromolar IC50 (0.86 μM) against pseudotyped Marburg virus entry.•Molecular docking has deciphered the compound binding details including the interacting residues of the receptor.
Objective
A growing body of evidence suggests that individuals with eating disorders (EDs) have experienced deteriorating symptoms, increased isolation, and an increase in hospital admissions as a ...result of the COVID‐19 pandemic. Despite this, no systematic reviews have been conducted examining the COVID‐19 and ED peer‐reviewed literature. Therefore, this systematic review aimed to synthesize the impact of the COVID‐19 pandemic on individuals with EDs.
Method
Database searches of the peer‐reviewed literature were completed in the subsequent databases: CINAHL, Embase, MEDLINE, and PsycINFO (from November 2019 to October 20, 2021). All research reporting on the relationship between the COVID‐19 pandemic on individuals with EDs were included.
Results
Fifty‐three studies met the inclusion criteria, including 36,485 individuals with EDs.
The pooled hospital admissions across the studies demonstrated on average a 48% (pre = 591, post = 876, n = 10 studies) increase in admissions during the pandemic compared to previous pre‐pandemic timepoints. In this review, 36% of studies (n = 19) documented increases in eating disorder symptoms during the pandemic, this increase in eating disorder symptoms were documented in AN, BED, BN, and OFSED patients. Studies also demonstrated increases in anxiety (n = 9) and depression (n = 8), however patterns of change appeared to be diagnostic and timing specific (e.g., lockdowns).
Discussion
We found a large increase in the number of hospitalizations and an increase in ED symptoms, anxiety, depression, and changes to BMI in ED patients during the pandemic. However, these changes appeared to be diagnostic and timing specific. Many qualitative studies described deterioration in ED symptomatology due to decreased access to care and treatment, changes to routine and loss of structure, negative influence of the media, and social isolation. Future studies are needed to focus on pediatric populations, new ED diagnoses, and severity of illness at presentation.
Public Significance
The scientific literature suggests that individuals with eating disorders have experienced deteriorating symptoms, increased isolation, and an increase in hospital admissions as a result of the COVID‐19 pandemic. This study synthesized 53 articles and explored the impact of the COVID‐19 pandemic on patients with eating disorders. We found increases in eating disorder symptoms during the pandemic; this increase in eating disorder symptoms was documented in patients with common eating disorders including anorexia nervosa, binge‐eating disorder, bulimia nervosa, and other specified feeding and eating disorders. This review also demonstrated changes in body mass index (an index used to classify underweight, overweight, and obesity in adults) and increases in anxiety and depression during the pandemic compared to previous timepoints; patterns of change appeared to be related to timing of lockdowns. This review provides important information on the impact of COVID‐19 on the physical and mental health of individuals with eating disorders.
Resumen
Objetivo
Un creciente conjunto de evidencia sugiere que las personas con trastornos de la conducta alimentaria (TCA) han experimentado síntomas de deterioro, mayor aislamiento y un aumento en los ingresos hospitalarios como resultado de la pandemia de COVID‐19. A pesar de esto, no se han realizado revisiones sistemáticas que examinen la literatura revisada por pares de COVID‐19 y TCA. Por lo tanto, esta revisión sistemática tuvo como objetivo sintetizar el impacto de la pandemia de COVID‐19 en las personas con TCA.
Método
Las búsquedas en las bases de datos de la literatura revisada por pares se completaron en las bases de datos posteriores: CINAHL, Embase, MEDLINE y PsycINFO (de noviembre de 2019 al 20 de octubre de 2021). Se incluyeron todos los informes de investigación sobre la relación entre la pandemia de COVID‐19 en individuos con TCA.
Resultados
Cincuenta y tres estudios cumplieron los criterios de inclusión, incluyendo 36,485 individuos con TCA. Los ingresos hospitalarios agrupados en los estudios demostraron en promedio un aumento del 48% (antes = 591, después = 876, n = 10 estudios) en los ingresos durante la pandemia en comparación con los puntos de tiempo previos a la pandemia. En esta revisión, el 36% de los estudios (n = 19) documentaron aumentos en los síntomas del trastorno alimentario durante la pandemia, este aumento en los síntomas del trastorno de la conducta alimentaria se documentó en pacientes con AN, TpA, BN y OSFED. Los estudios también demostraron aumentos en la ansiedad (n = 9) y la depresión (n = 8), sin embargo, los patrones de cambio parecían ser diagnósticos y específicos del momento (por ejemplo, encierros).
Discusión
Encontramos un gran aumento en el número de hospitalizaciones y un aumento en los síntomas de TCA, ansiedad, depresión y los cambios en el IMC en pacientes con TCA durante la pandemia. Sin embargo, estos cambios parecían ser diagnósticos y específicos del momento. Muchos estudios cualitativos describieron un deterioro en la sintomatología del trastorno de la conducta alimentaria (TCA) debido a la disminución del acceso a la atención y el tratamiento, los cambios en la rutina y la pérdida de estructura, la influencia negativa de los medios de comunicación y el aislamiento social. Se necesitan estudios futuros para centrarse en las poblaciones pediátricas, los nuevos diagnósticos de TCA y la gravedad de la enfermedad al momento de la presentación.
Palabras clave
trastornos de la conducta alimentaria, pandemia, COVID‐19
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