Refinement of 1p36 Alterations Not Involving PRDM16 in Myeloid and Lymphoid Malignancies

Fluorescence in situ hybridization was performed to characterize 81 cases of myeloid and lymphoid malignancies with cytogenetic 1p36 alterations not affecting the PRDM16 locus. In total, three subgroups were identified: balanced translocations (N = 27) and telomeric rearrangements (N = 15), both mainly observed in myeloid disorders; and unbalanced non-telomeric rearrangements (N = 39), mainly observed in lymphoid proliferations and frequently associated with a highly complex karyotype. The 1p36 rearrangement was isolated in 12 cases, mainly myeloid disorders. The breakpoints on 1p36 were more widely distributed than previously reported, but with identifiable rare breakpoint cluster regions, such as the TP73 locus. We also found novel partner loci on 1p36 for the known multi-partner genes HMGA2 and RUNX1. We precised the common terminal 1p36 deletion, which has been suggested to have an adverse prognosis, in B-cell lymphomas [follicular lymphomas and diffuse large B-cell lymphomas with t(14;18)(q32;q21) as well as follicular lymphomas without t(14;18)]. Intrachromosomal telomeric repetitive sequences were detected in at least half the cases of telomeric rearrangements. It is unclear how the latter rearrangements occurred and whether they represent oncogenic events or result from chromosomal instability during oncogenesis

Hybrid Stromal Vascular Fraction (Hybrid-SVF): A New Paradigm in Mechanical Regenerative Cell Processing

Background:. Enzymatic digestion of extracellular matrix (ECM) from lipoaspirate is the conventional form of harvesting stromal vascular fraction (SVF) called enzymatically digested SVF (E-SVF). Mechanical SVF (M-SVF) isolation has emerged as an alternative method, but it has also some limitations in terms of lower cell viability and diminished cell counts. To enhance the SVF qualitatively and quantitatively, we propose a novel concept called "hybrid-SVF,” in which we combine M-SVF with the concentrated parts of adipose tissue after centrifugation, which is called stromal vascular matrix (SVM). Methods:. Hybrid-SVF injection was applied as an adjunctive therapy to fat grafting in 88 patients and 11 samples were evaluated in the laboratory for cell count, viability and cell activity. Results:. Experimental results determined that SVM part showed higher cellular activity. SVM and M-SVF showed higher cellular potency than E-SVF. Clinically, none of the patients required an additional session for fat grafting since there was no significant graft resorption. However, seven patients asked for further volume augmentation due to their individual preferences. No major complication was encountered. Conclusions:. The usage of hybrid-SVF has a very high regenerative potential due to the ECM support and exceptionally high cell yield in addition to preserved cell potency. Although there are ongoing studies focusing on optimizing cell counts and further clinical applications, we believe that our preliminary results might create a paradigm shift in the area of regenerative fat grafting

Clinical Practice Guideline: Hoarseness (Dysphonia) (Update) Executive Summary

Objective This guideline provides evidence-based recommendations on treating patients presenting with dysphonia, which is characterized by altered vocal quality, pitch, loudness, or vocal effort that impairs communication and/or quality of life. Dysphonia affects nearly one-third of the population at some point in its life. This guideline applies to all age groups evaluated in a setting where dysphonia would be identified or managed. It is intended for all clinicians who are likely to diagnose and treat patients with dysphonia. Purpose The primary purpose of this guideline is to improve the quality of care for patients with dysphonia, based on current best evidence. Expert consensus to fill evidence gaps, when used, is explicitly stated and supported with a detailed evidence profile for transparency. Specific objectives of the guideline are to reduce inappropriate variations in care, produce optimal health outcomes, and minimize harm. For this guideline update, the American Academy of Otolaryngology-Head and Neck Surgery Foundation selected a panel representing the fields of advanced practice nursing, bronchoesophagology, consumer advocacy, family medicine, geriatric medicine, internal medicine, laryngology, neurology, otolaryngology-head and neck surgery, pediatrics, professional voice, pulmonology, and speech-language pathology. Action Statements The guideline update group made strong recommendations for the following key action statements (KASs): (1) Clinicians should assess the patient with dysphonia by history and physical examination to identify factors where expedited laryngeal evaluation is indicated. These include but are not limited to recent surgical procedures involving the head, neck, or chest; recent endotracheal intubation; presence of concomitant neck mass; respiratory distress or stridor; history of tobacco abuse; and whether the patient is a professional voice user. (2) Clinicians should advocate voice therapy for patients with dysphonia from a cause amenable to voice therapy. The guideline update group made recommendations for the following KASs: (1) Clinicians should identify dysphonia in a patient with altered voice quality, pitch, loudness, or vocal effort that impairs communication or reduces quality of life (QOL). (2) Clinicians should assess the patient with dysphonia by history and physical examination for underlying causes of dysphonia and factors that modify management. (3) Clinicians should perform laryngoscopy, or refer to a clinician who can perform laryngoscopy, when dysphonia fails to resolve or improve within 4 weeks or irrespective of duration if a serious underlying cause is suspected. (4) Clinicians should perform diagnostic laryngoscopy, or refer to a clinician who can perform diagnostic laryngoscopy, before prescribing voice therapy and document/communicate the results to the speech-language pathologist (SLP). (5) Clinicians should advocate for surgery as a therapeutic option for patients with dysphonia with conditions amenable to surgical intervention, such as suspected malignancy, symptomatic benign vocal fold lesions that do not respond to conservative management, or glottic insufficiency. (6) Clinicians should offer, or refer to a clinician who can offer, botulinum toxin injections for the treatment of dysphonia caused by spasmodic dysphonia and other types of laryngeal dystonia. (7) Clinicians should inform patients with dysphonia about control/preventive measures. (8) Clinicians should document resolution, improvement or worsened symptoms of dysphonia, or change in QOL of patients with dysphonia after treatment or observation. The guideline update group made a strong recommendation against 1 action: (1) Clinicians should not routinely prescribe antibiotics to treat dysphonia. The guideline update group made recommendations against other actions: (1) Clinicians should not obtain computed tomography (CT) or magnetic resonance imaging (MRI) for patients with a primary voice complaint prior to visualization of the larynx. (2) Clinicians should not prescribe antireflux medications to treat isolated dysphonia, based on symptoms alone attributed to suspected gastroesophageal reflux disease (GERD) or laryngopharyngeal reflux (LPR), without visualization of the larynx. (3) Clinicians should not routinely prescribe corticosteroids in patients with dysphonia prior to visualization of the larynx. The policy level for the following recommendation about laryngoscopy at any time was an option: (1) Clinicians may perform diagnostic laryngoscopy at any time in a patient with dysphonia. Differences from Prior Guideline (1) Incorporating new evidence profiles to include the role of patient preferences, confidence in the evidence, differences of opinion, quality improvement opportunities, and any exclusion to which the action statement does not apply (2) Inclusion of 3 new guidelines, 16 new systematic reviews, and 4 new randomized controlled trials (3) Inclusion of a consumer advocate on the guideline update group (4) Changes to 9 KASs from the original guideline (5) New KAS 3 (escalation of care) and KAS 13 (outcomes) (6) Addition of an algorithm outlining KASs for patients with dysphonia

Burden of disease scenarios for 204 countries and territories, 2022–2050: a forecasting analysis for the Global Burden of Disease Study 2021

BackgroundFuture trends in disease burden and drivers of health are of great interest to policy makers and the public at large. This information can be used for policy and long-term health investment, planning, and prioritisation. We have expanded and improved upon previous forecasts produced as part of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) and provide a reference forecast (the most likely future), and alternative scenarios assessing disease burden trajectories if selected sets of risk factors were eliminated from current levels by 2050.MethodsUsing forecasts of major drivers of health such as the Socio-demographic Index (SDI; a composite measure of lag-distributed income per capita, mean years of education, and total fertility under 25 years of age) and the full set of risk factor exposures captured by GBD, we provide cause-specific forecasts of mortality, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life-years (DALYs) by age and sex from 2022 to 2050 for 204 countries and territories, 21 GBD regions, seven super-regions, and the world. All analyses were done at the cause-specific level so that only risk factors deemed causal by the GBD comparative risk assessment influenced future trajectories of mortality for each disease. Cause-specific mortality was modelled using mixed-effects models with SDI and time as the main covariates, and the combined impact of causal risk factors as an offset in the model. At the all-cause mortality level, we captured unexplained variation by modelling residuals with an autoregressive integrated moving average model with drift attenuation. These all-cause forecasts constrained the cause-specific forecasts at successively deeper levels of the GBD cause hierarchy using cascading mortality models, thus ensuring a robust estimate of cause-specific mortality. For non-fatal measures (eg, low back pain), incidence and prevalence were forecasted from mixed-effects models with SDI as the main covariate, and YLDs were computed from the resulting prevalence forecasts and average disability weights from GBD. Alternative future scenarios were constructed by replacing appropriate reference trajectories for risk factors with hypothetical trajectories of gradual elimination of risk factor exposure from current levels to 2050. The scenarios were constructed from various sets of risk factors: environmental risks (Safer Environment scenario), risks associated with communicable, maternal, neonatal, and nutritional diseases (CMNNs; Improved Childhood Nutrition and Vaccination scenario), risks associated with major non-communicable diseases (NCDs; Improved Behavioural and Metabolic Risks scenario), and the combined effects of these three scenarios. Using the Shared Socioeconomic Pathways climate scenarios SSP2-4.5 as reference and SSP1-1.9 as an optimistic alternative in the Safer Environment scenario, we accounted for climate change impact on health by using the most recent Intergovernmental Panel on Climate Change temperature forecasts and published trajectories of ambient air pollution for the same two scenarios. Life expectancy and healthy life expectancy were computed using standard methods. The forecasting framework includes computing the age-sex-specific future population for each location and separately for each scenario. 95% uncertainty intervals (UIs) for each individual future estimate were derived from the 2·5th and 97·5th percentiles of distributions generated from propagating 500 draws through the multistage computational pipeline.FindingsIn the reference scenario forecast, global and super-regional life expectancy increased from 2022 to 2050, but improvement was at a slower pace than in the three decades preceding the COVID-19 pandemic (beginning in 2020). Gains in future life expectancy were forecasted to be greatest in super-regions with comparatively low life expectancies (such as sub-Saharan Africa) compared with super-regions with higher life expectancies (such as the high-income super-region), leading to a trend towards convergence in life expectancy across locations between now and 2050. At the super-region level, forecasted healthy life expectancy patterns were similar to those of life expectancies. Forecasts for the reference scenario found that health will improve in the coming decades, with all-cause age-standardised DALY rates decreasing in every GBD super-region. The total DALY burden measured in counts, however, will increase in every super-region, largely a function of population ageing and growth. We also forecasted that both DALY counts and age-standardised DALY rates will continue to shift from CMNNs to NCDs, with the most pronounced shifts occurring in sub-Saharan Africa (60·1% [95% UI 56·8–63·1] of DALYs were from CMNNs in 2022 compared with 35·8% [31·0–45·0] in 2050) and south Asia (31·7% [29·2–34·1] to 15·5% [13·7–17·5]). This shift is reflected in the leading global causes of DALYs, with the top four causes in 2050 being ischaemic heart disease, stroke, diabetes, and chronic obstructive pulmonary disease, compared with 2022, with ischaemic heart disease, neonatal disorders, stroke, and lower respiratory infections at the top. The global proportion of DALYs due to YLDs likewise increased from 33·8% (27·4–40·3) to 41·1% (33·9–48·1) from 2022 to 2050, demonstrating an important shift in overall disease burden towards morbidity and away from premature death. The largest shift of this kind was forecasted for sub-Saharan Africa, from 20·1% (15·6–25·3) of DALYs due to YLDs in 2022 to 35·6% (26·5–43·0) in 2050. In the assessment of alternative future scenarios, the combined effects of the scenarios (Safer Environment, Improved Childhood Nutrition and Vaccination, and Improved Behavioural and Metabolic Risks scenarios) demonstrated an important decrease in the global burden of DALYs in 2050 of 15·4% (13·5–17·5) compared with the reference scenario, with decreases across super-regions ranging from 10·4% (9·7–11·3) in the high-income super-region to 23·9% (20·7–27·3) in north Africa and the Middle East. The Safer Environment scenario had its largest decrease in sub-Saharan Africa (5·2% [3·5–6·8]), the Improved Behavioural and Metabolic Risks scenario in north Africa and the Middle East (23·2% [20·2–26·5]), and the Improved Nutrition and Vaccination scenario in sub-Saharan Africa (2·0% [–0·6 to 3·6]).InterpretationGlobally, life expectancy and age-standardised disease burden were forecasted to improve between 2022 and 2050, with the majority of the burden continuing to shift from CMNNs to NCDs. That said, continued progress on reducing the CMNN disease burden will be dependent on maintaining investment in and policy emphasis on CMNN disease prevention and treatment. Mostly due to growth and ageing of populations, the number of deaths and DALYs due to all causes combined will generally increase. By constructing alternative future scenarios wherein certain risk exposures are eliminated by 2050, we have shown that opportunities exist to substantially improve health outcomes in the future through concerted efforts to prevent exposure to well established risk factors and to expand access to key health interventions.FundingBill & Melinda Gates Foundation.</p

A global metagenomic map of urban microbiomes and antimicrobial resistance

We present a global atlas of 4,728 metagenomic samples from mass-transit systems in 60 cities over 3 years, representing the first systematic, worldwide catalog of the urban microbial ecosystem. This atlas provides an annotated, geospatial profile of microbial strains, functional characteristics, antimicrobial resistance (AMR) markers, and genetic elements, including 10,928 viruses, 1,302 bacteria, 2 archaea, and 838,532 CRISPR arrays not found in reference databases. We identified 4,246 known species of urban microorganisms and a consistent set of 31 species found in 97% of samples that were distinct from human commensal organisms. Profiles of AMR genes varied widely in type and density across cities. Cities showed distinct microbial taxonomic signatures that were driven by climate and geographic differences. These results constitute a high-resolution global metagenomic atlas that enables discovery of organisms and genes, highlights potential public health and forensic applications, and provides a culture-independent view of AMR burden in cities.Funding: the Tri-I Program in Computational Biology and Medicine (CBM) funded by NIH grant 1T32GM083937; GitHub; Philip Blood and the Extreme Science and Engineering Discovery Environment (XSEDE), supported by NSF grant number ACI-1548562 and NSF award number ACI-1445606; NASA (NNX14AH50G, NNX17AB26G), the NIH (R01AI151059, R25EB020393, R21AI129851, R35GM138152, U01DA053941); STARR Foundation (I13- 0052); LLS (MCL7001-18, LLS 9238-16, LLS-MCL7001-18); the NSF (1840275); the Bill and Melinda Gates Foundation (OPP1151054); the Alfred P. Sloan Foundation (G-2015-13964); Swiss National Science Foundation grant number 407540_167331; NIH award number UL1TR000457; the US Department of Energy Joint Genome Institute under contract number DE-AC02-05CH11231; the National Energy Research Scientific Computing Center, supported by the Office of Science of the US Department of Energy; Stockholm Health Authority grant SLL 20160933; the Institut Pasteur Korea; an NRF Korea grant (NRF-2014K1A4A7A01074645, 2017M3A9G6068246); the CONICYT Fondecyt Iniciación grants 11140666 and 11160905; Keio University Funds for Individual Research; funds from the Yamagata prefectural government and the city of Tsuruoka; JSPS KAKENHI grant number 20K10436; the bilateral AT-UA collaboration fund (WTZ:UA 02/2019; Ministry of Education and Science of Ukraine, UA:M/84-2019, M/126-2020); Kyiv Academic Univeristy; Ministry of Education and Science of Ukraine project numbers 0118U100290 and 0120U101734; Centro de Excelencia Severo Ochoa 2013–2017; the CERCA Programme / Generalitat de Catalunya; the CRG-Novartis-Africa mobility program 2016; research funds from National Cheng Kung University and the Ministry of Science and Technology; Taiwan (MOST grant number 106-2321-B-006-016); we thank all the volunteers who made sampling NYC possible, Minciencias (project no. 639677758300), CNPq (EDN - 309973/2015-5), the Open Research Fund of Key Laboratory of Advanced Theory and Application in Statistics and Data Science – MOE, ECNU, the Research Grants Council of Hong Kong through project 11215017, National Key RD Project of China (2018YFE0201603), and Shanghai Municipal Science and Technology Major Project (2017SHZDZX01) (L.S.

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field

Erratum to: Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition) (Autophagy, 12, 1, 1-222, 10.1080/15548627.2015.1100356

non present