6 research outputs found
L'IPERAMMONIEMIA INDOTTA: CORRELATI NEUROPSICHICI, CORRELATI ELETTROFISIOLOGICI E NUOVE STRATEGIE TERAPEUTICHE
No full textABSTRACT
Introduction.
Hepatic encephalopathy (HE) is a neuropsychological syndrome which may accompany acute or chronic liver failure, being mainly due to the toxic effect of ammonia on the central nervous system [83]. HE encompasses a wide clinical spectrum, ranging from minimal forms, which are only detected by use of neuropsychological and/or electrophysiological techniques, to coma [7,8, 11, 144, 175, 190]. HE, even in its minimal form, impinges on quality of life and self-sufficiency [10, 76, 120, 164] and it carries negative prognostic value in terms of survival. Thus it is useful to identify patients with HE and reduced life expectancy, also for purposes of transplant selection procedures. The electrophysiological diagnosis of HE is based on the detection of slow wake-EEG frequencies [8]. However, some studies have shown that the regional distribution of the wake-EEG rhythms is also abnormal [126]. The detection of HE through psychometric and electrophysiological techniques is usually carried out in "standard" conditions. More recently, it has been proposed to artificially induce a condition of hyperammonaemia, thus simulating HE, by the oral administration of an amino-acid load (AAL). These amino-acids mimic the composition of hemoglobin, thus reproducing, at least to some extent, the HE which is observed after a gastrointestinal bleed [4, 65]. This allows doctors and researchers to measure more directly a patient's sensitivity to hyperammonaemia.
Disorders of the sleep-wake rhythm are common in patients with cirrhosis, heavily affecting their quality of life [129]. Sleep is regulated by the interaction of two processes: a homeostatic and a circadian process [31]. The former determines the propensity to fall asleep in connection to prior sleep-wake history (i.e. the need for sleep increases with prolonged wakefulness). The latter, which is reflected in the 24-hour rhythm of the hormone melatonin (high plasma levels at night and extremely low levels in the daytime), determines the alternation of periods of low/high sleep propensity in relation to environmental light/dark conditions. The interaction of such two processes results in a high likelihood of falling asleep after a prolonged period of wakefulness and when it gets dark, namely in the evening.
The alterations of the sleep-wake rhythm in patients with liver have traditionally been interpreted as being part of the HE syndrome [175]. More recent data suggest that this is the case for excessive daytime sleepiness, while insomnia probably has a different pathogenesis [128]. The causes of sleep-wake abnormalities in patients with cirrhosis are not completely clear. The documented changes in the circadian system (reduced sensitivity to light and altered rhythm/metabolism of melatonin) do not offer a complete explanation [128, 129]. Sleep can also be studied by polysomnography, which reflects homeostatic regulation. Information on homeostatic regulation in these patients is limited [179]. The exact neurochemical correlates of human sleep homeostasis remain unknown, although adenosinergic neurotransmission is likely to be implicated. In healthy subjects caffeine, an adenosine receptor antagonist, significantly affects both the wake EEG (reduction in theta activity, which increases with the increase of sleep pressure) and the sleep EEG, and attenuates the subjective sleepiness which is associated with prolonged wakefulness and sleep deprivation [106].
This set of studies was performed in order to evaluate:
- the effect of induced hyperammonaemia on neuropsychological performance and the wake EEG (Study 1);
- the relationship between daytime sleepiness, HE, and the sleep EEG (Study 2);
- the effects of ammonia-lowering drugs (L-ornithine-L-aspartate, LOLA) and caffeine on the wake and sleep EEG (Study3).
Materials and methods.
Well-characterized patients with compensated cirrhosis and with no history of HE and matched healthy volunteers were enrolled and underwent:
- Assessing and monitoring the quality and time of sleep with questionnaires and sleep diaries.
- Oral load of amino acids (AAL), mixture of 54 grams of amino acids mimicking the hemoglobin contained in 400 ml of blood, taken in the morning per os.
- Detection time of subjective sleepiness and capillary ammonia.
- Neuropsychological assessment, including psychometric paper and pencil (PHES battery), computerized psychometry and EEG recording of wakefulness.
- Polysomnographic recording. Patients were given the opportunity to sleep between 17:00 and 19:00 in favorable environmental conditions (dark and isolated room).
- Administration of LOLA 20g in 500cc of saline in 4-hour infusion (8-12) or 200mg caffeine per os(at 10 am) under inducedhyperammonemia (Study 3).
Results.
Study 1. Effects of hyperammonaemia on neuropsychological performance and waking EEG.
- The study population included 10 patients with liver cirrhosis (9 men, mean ± SD, age: 54 ± 14 years) and 10 healthy volunteers matched for age and sex (5 men, 49 ± 13 years). One patient (male 55 years) underwent EEG recording also after the insertion of a trans-jugular portal-systemic shunt (TIPS), a procedure which is associated with increased risk of HE.
- The subjects were studied with a neuropsychological evaluation and monitoring of capillary ammonia at baseline (4th or 8th day of the study) and after oral amino acids (AAL) (4th or 8th day of the study).
- At baseline, patients had higher ammonia levels than healthy volunteers [median (interquartile range): 30 (22-44) vs. 38 (34-47)mmol/L, p < 0.1]. The AAL has produced the expected increase in ammonia in both groups, the peak of ammonia was higher (ammonia 11:00, p < 0.03) and more prolonged in patients.
- The AAL has produced a significant slowing of EEG waking such as to define the presence of a minimal HE in 2 (20 %) patients. By contrast, the AAL no significant changes in the psychometric performance paper & pencil or computerized.
- At baseline, the dominant frequency EEG activity was slower in patients compared to healthy volunteers in most derivations(p < 0.05). The AAL did not alter the dominant frequency in healthy volunteers, while that of patients slowed further along the midline (p < 0.05).
- At baseline, the waking EEG spectral power had an occipital-temporal predominance in both groups. The patients had higher power in all derivations (p < 0.05). The AAL induced a significant increase of power in almost all derivations in healthy volunteers (p < 0.05), while it did not affect power in patients.
- In the patient studied on three occasions, the spectral power of dominant wake EEG progressively increased from baseline after AAL and after TIPS, while there was a decrease in the frequency of the wake EEG after insertion of TIPS.
Study 2. Effect of hyperammonaemia on sleepiness and sleep EEG.
- The study population (see Study 1) was subjected to neuropsychological assessment, detection time of sleepiness and ammonia and polysomnographic recording, in basal conditions (4th or 8th day of the study) and after AAL (4th or 8th day of the study).
The AAL has produced
- an increase in subjective sleepiness parallel to increased concentrations of ammonia both in patients and in healthy volunteers;in both groups, the peak of sleepiness (at 11 am), absent in basal condition, coincides with the peak concentration of ammonia (p <0.01);
- an increase in sleep duration in healthy volunteers compared with baseline (mean ± SD, 49.3 ± 26.6vs. 30.4 ± 15.6 min), although the differences are not statistically significant (p 0.08). No changes arebeen observedon the duration of sleep in patients;
- significant decrease in the relative power beta (fast activity)of the sleep EEG in healthy volunteers (p < 0.05);
- significant reduction in the relative power of delta (activity very slow)of thesleep EEG in patients (p < 0.05).
Study 3. Effects of L-ornithine-L-aspartate (LOLA, substance that reduce ammonia) and caffeine (adenosine receptor antagonist) on cognitive performance,wake and sleep EEG in conditions of induced hyperammonaemia.
- The study population consisted of 6 patients with liver cirrhosis (5 men, mean ± SD, age: 61 ± 9 years) and 5 healthy volunteers matched for age, sex and level of education (4 men, 49 ± 12 years).
- The subjects were studied with neuropsychological assessment, detection sleepiness and ammonia hourly and polysomnographic recording, after AAL, AAL+LOLA, AAL+caffeine) on the 4th, 11th and 18th day of the study.
- patients presented a paper and pencil and computerized psychometric performance significantly worse than the healthy volunteers (p < 0.05);
- patients had levels of ammonia above those of healthy volunteers in all conditions;
the AAL has produced the expected increase of ammonia in both groups, with a peak higher and more prolonged in patients.
- The LOLA has resulted in a reduction although not significant levels of plasmatic ammonia in both groups.
- Neither the LOLA nor caffeine resulted in significant changes of subjective sleepiness, on psychometric performance and the wake EEG.
- Sleep EEG data are being analyzed (at the Institute of Pharmacology and Toxicology, University of Zurich, Switzerland).
Conclusions.
- The waking EEG is extremely sensitive to hyperammonaemia.
- A moderate/chronic (patients in baseline) or acute (healthy volunteers after AAL) hyperammonaemia results in an increased power of the dominant EEG rhythm, especially over posterior and central areas of the scalp.
- An acute on chronic hyperammonaemia (patients after AAL) slows further the dominant EEG frequency.
- EEG parameters based on power can provide useful information to the neurophysiological definition of HE.
- Hyperammonaemia leads to a significant increase in subjective daytime sleepiness.
- Hyperammonaemia causes opposing changes in the sleep EEG of patients and controls, making the sleep of patients fragmented and more superficial, and that of healthy volunteers deeper and more stable.
- L-ornithine-L-aspartate leads to a reduction in the levels of ammonia
Levels of microbial contamination of domestic refrigerators in Italy
No full textAim: According to the EFSA Report 2013, 32.7% of outbreaks of foodborne illness registered in Europe
occurs within the home, due to inadequate hygienic behaviour of consumers when preparing foods in
the kitchen. The efficacy of proper cleaning of cutting boards, dishes and cutlery in limiting microbial
cross-contaminations in the kitchen has been documented many times, whereas few researches have
been performed to determine the microbial load of the internal walls of domestic refrigerators, in Italy.
The aim of this investigation is to ascertain the role played by internal surfaces of home refrigerators as
possible sources of microbial contamination of foods.
Material and methods: We analyzed 293 domestic refrigerators of students or workers at the university
campus of Agripolis (Legnaro, Italy). For each refrigerator, 2 internal surfaces were sampled using
sponge-bags. The amounts of total viable count (TVC), Gram-negative spoiling bacteria, moulds and
yeasts and the main pathogenic bacterial species were determined.
Results: TVCs greater than 1 log CFU cm2 are in a little over 50% of the samples analyzed and are found
mainly on the bottom of the refrigerator (61%) compared to the walls (39%) (P < 0.001). Even for other
microbial counts the risk ratio of finding them on the bottom of the refrigerator is significantly higher
than on the walls; the possibility of there being a finding on the bottom with respect to the walls varies
from 2.5 to 8.5 times respectively for moulds and Aeromonas spp. Salmonella spp. was found in 1.7% of the
samples, Bacillus cereus in 5.6%, Coagulase-positive staphylococci (CPS) in 4%, the prevalence of which is
always higher on the bottom of the refrigerator. Listeria monocytogenes and Yersinia enterocolitica were
never found.
Conclusions: It is necessary to better educate consumers to clean their appliances more frequentl
La torsione del funicolo spermatico: criticità cliniche e medico-legali
No full text[Torsion of the spermatic cord: clinical and medicolegal critical states]Although an exhaustive statistics is not available nowadays, the torsion of the spermatic cord is a common cause of medical-legal contentious. This is due to the diversified symptoms, to the difficult differential diagnosis (e.g.: epididymitis/acute orchiepididymitis, torsion of testicular appendixes or of epididymis, strangulated hernia, hematocele, hydrocele, testicular neoplasia, symptomatic spermatocele and idiopathic scrotal oedema) and to the importance of a sudden therapeutic intervention (within few hours): in fact a late intervention leads to testicular necrosis and subsequently to orchiectomy. The article shows also the different classifications of medical errors used to establish the possible fault and indemnity for the physician to pay
Changing life expectancy in European countries 1990–2021: a subanalysis of causes and risk factors from the Global Burden of Disease Study 2021
No full textBackground: Decades of steady improvements in life expectancy in Europe slowed down from around 2011, well before the COVID-19 pandemic, for reasons which remain disputed. We aimed to assess how changes in risk factors and cause-specific death rates in different European countries related to changes in life expectancy in those countries before and during the COVID-19 pandemic. Methods: We used data and methods from the Global Burden of Diseases, Injuries, and Risk Factors Study 2021 to compare changes in life expectancy at birth, causes of death, and population exposure to risk factors in 16 European Economic Area countries (Austria, Belgium, Denmark, Finland, France, Germany, Greece, Iceland, Ireland, Italy, Luxembourg, the Netherlands, Norway, Portugal, Spain, and Sweden) and the four UK nations (England, Northern Ireland, Scotland, and Wales) for three time periods: 1990–2011, 2011–19, and 2019–21. Changes in life expectancy and causes of death were estimated with an established life expectancy cause-specific decomposition method, and compared with summary exposure values of risk factors for the major causes of death influencing life expectancy. Findings: All countries showed mean annual improvements in life expectancy in both 1990–2011 (overall mean 0·23 years [95% uncertainty interval [UI] 0·23 to 0·24]) and 2011–19 (overall mean 0·15 years [0·13 to 0·16]). The rate of improvement was lower in 2011–19 than in 1990–2011 in all countries except for Norway, where the mean annual increase in life expectancy rose from 0·21 years (95% UI 0·20 to 0·22) in 1990–2011 to 0·23 years (0·21 to 0·26) in 2011–19 (difference of 0·03 years). In other countries, the difference in mean annual improvement between these periods ranged from –0·01 years in Iceland (0·19 years [95% UI 0·16 to 0·21] vs 0·18 years [0·09 to 0·26]), to –0·18 years in England (0·25 years [0·24 to 0·25] vs 0·07 years [0·06 to 0·08]). In 2019–21, there was an overall decrease in mean annual life expectancy across all countries (overall mean –0·18 years [95% UI –0·22 to –0·13]), with all countries having an absolute fall in life expectancy except for Ireland, Iceland, Sweden, Norway, and Denmark, which showed marginal improvement in life expectancy, and Belgium, which showed no change in life expectancy. Across countries, the causes of death responsible for the largest improvements in life expectancy from 1990 to 2011 were cardiovascular diseases and neoplasms. Deaths from cardiovascular diseases were the primary driver of reductions in life expectancy improvements during 2011–19, and deaths from respiratory infections and other COVID-19 pandemic-related outcomes were responsible for the decreases in life expectancy during 2019–21. Deaths from cardiovascular diseases and neoplasms in 2019 were attributable to high systolic blood pressure, dietary risks, tobacco smoke, high LDL cholesterol, high BMI, occupational risks, high alcohol use, and other risks including low physical activity. Exposure to these major risk factors differed by country, with trends of increasing exposure to high BMI and decreasing exposure to tobacco smoke observed in all countries during 1990–2021. Interpretation: The countries that best maintained improvements in life expectancy after 2011 (Norway, Iceland, Belgium, Denmark, and Sweden) did so through better maintenance of reductions in mortality from cardiovascular diseases and neoplasms, underpinned by decreased exposures to major risks, possibly mitigated by government policies. The continued improvements in life expectancy in five countries during 2019–21 indicate that these countries were better prepared to withstand the COVID-19 pandemic. By contrast, countries with the greatest slowdown in life expectancy improvements after 2011 went on to have some of the largest decreases in life expectancy in 2019–21. These findings suggest that government policies that improve population health also build resilience to future shocks. Such policies include reducing population exposure to major upstream risks for cardiovascular diseases and neoplasms, such as harmful diets and low physical activity, tackling the commercial determinants of poor health, and ensuring access to affordable health services. Funding: Gates Foundation. © 2025 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licens
Autoantibodies against type I IFNs in patients with life-threatening COVID-19
No full textInterindividual clinical vari-ability is vast in humans infected withsevere acute respiratory syndrome corona-virus 2 (SARS-CoV-2), ranging from silent in-fection to rapid death. Three risk factors forlife-threatening coronavirus disease 2019(COVID-19) pneumonia have been identified—being male, being elderly, or having othermedical conditions—but these risk factorscannot explain why critical disease remainsrelatively rare in any given epidemiologicalgroup. Given the rising toll of the COVID-19pandemic in terms of morbidity and mortality,understanding the causes and mechanisms oflife-threatening COVID-19 is crucial.The Laboratory of Human Genetics of Infectious Diseases is supported by the Howard Hughes Medical Institute, The Rockefeller University, the St. Giles Foundation, the National Institutes of Health (NIH) (R01AI088364), the National Center for Advancing Translational Sciences (NCATS), NIH Clinical and Translational Science Award (CTSA) program (UL1 TR001866), a Fast Grant from Emergent Ventures, the Mercatus Center at George Mason University, the Yale Center for Mendelian Genomics and the GSP Coordinating Center funded by the National Human Genome Research Institute (NHGRI) (UM1HG006504 and U24HG008956), the French National Research Agency (ANR) under the Investments for the Future program (ANR-10-IAHU-01), the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID), the French Foundation for Medical Research (FRM) (EQU201903007798), the FRM and ANR GENCOVID project (ANRS-COV05), the Square Foundation, Grandir – Fonds de solidarité pour l’enfance, the SCOR Corporate Foundation for Science, the Institut Institut National de la Santé et de la Recherche Médicale (INSERM), and the University of Paris. Samples from San Raffaele Hospital were obtained through the Covid-BioB project and by healthcare personnel of San Raffaele Hospital, San Raffaele Telethon Institute for Gene Therapy (SR-TIGET) clinical laboratory and clinical research unit, funded by the Program Project COVID-19 OSR-UniSR and Fondazione Telethon. The French COVID Cohort Study Group was sponsored by INSERM and supported by the REACTing consortium and by a grant from the French Ministry of Health (PHRC 20-0424). The Cov-Contact Cohort was supported by the REACTing consortium, the French Ministry of Health, and the European Commission (RECOVER WP 6). The Milieu Intérieur Consortium was supported by the French Government’s Investissement d’Avenir program, Laboratoire d’Excellence Milieu Intérieur grant (ANR-10-LABX-69-01) (primary investigators: L.Q.-M. and D.Du.). The Simoa experiment was supported by the PHRC-20-0375 COVID-19 grant “DIGITAL COVID” (primary investigator: G.G.). S.G.T. is supported by a Leadership 3 Investigator Grant awarded by the National Health and Medical Research Council of Australia and a COVID19 Rapid Response Grant awarded by UNSW Sydney. C.R.-G. and colleagues were supported by the Instituto de Salud Carlos III (COV20_01333 and COV20_01334, Spanish Ministry of Science and Innovation RTC-2017-6471-1; AEI/FEDER, UE) and Cabildo Insular de Tenerife (CGIEU0000219140 and “Apuestas científicas del ITER para colaborar en la lucha contra la COVID-19”). S.T.-A. and A.B. were supported by ANR-20-COVI-0064 (primary investigator: A.Be.). This work is supported by the French Ministry of Health “Programme Hospitalier de Recherche Clinique Inter regional 2013,” by the Contrat de Plan Etat-Lorraine and FEDER Lorraine, and by a public grant overseen by the French National Research Agency (ANR) as part of the second Investissements d’Avenir program FIGHT-HF (reference no. ANR-15-RHU-0004) and by the French PIA project “Lorraine Université d’Excellence” (reference no. ANR-15-IDEX-04-LUE) (45); and biobanking is performed by the Biological Resource Center Lorrain BB-0033-00035. This study was supported by the Fonds IMMUNOV, for Innovation in Immunopathology; by a grant from the Agence National de la Recherche (ANR-flash Covid19 “AIROCovid” to F.R.-L.); and by the FAST Foundation (French Friends of Sheba Tel Hashomer Hospital). Work in the Laboratory of Virology and Infectious Disease was supported by NIH grants P01AI138398-S1, 2U19AI111825, and R01AI091707-10S1; a George Mason University Fast Grant; and the G. Harold and Leila Y. Mathers Charitable Foundation. The Amsterdam UMC Covid-19 Biobank was supported by grants from the Amsterdam Corona Research Fund, the Dr. C.J. Vaillant Fund, and the Netherlands Organization for Health Research and Development [ZonMw; NWO-Vici-Grant (grant no. 918·19·627 to D.v.d.B.)]. This work was also supported by the Division of Intramural Research of the National Institute of Dental Craniofacial Research and the National Institute of Allergy and Infectious Diseases, National Institutes of Health, and by Regione Lombardia, Italy (project “Risposta immune in pazienti con COVID-19 e comorbidita”). The opinions and assertions expressed herein are those of the author(s) and do not necessarily reflect the official policy or position of the Uniformed Services University or the Department of Defense. J.H. holds an Institut Imagine M.D.-Ph.D. fellowship from the Fondation Bettencourt Schueller. J.R. is supported by the INSERM Ph.D. program (“poste d’accueil Inserm”). P.Ba. was supported by the French Foundation for Medical Research (FRM, EA20170638020) and the M.D.-Ph.D. program of the Imagine Institute (with the support of the Fondation Bettencourt-Schueller). We thank the Association “Turner et vous” for their help and support. Sample processing at IrsiCaixa was possible thanks to the crowdfunding initiative YoMeCorono. D.C.V. is supported by the Fonds de la recherche en santé du Québec clinician-scientist scholar program. K.K. was supported by the Estonian Research Council grant PUT1367. We thank the GEN-COVID Multicenter Study (https://sites.google.com/dbm.unisi.it/gen-covid). We thank the NIAID Office of Cyber Infrastructure and Computational Biology, Bioinformatics and Computational Biosciences Branch (contract no. HHSN316201300006W/HHSN27200002 to MSC, Inc.), the Operations Engineering Branch for developing the HGRepo system to enable streamlined access to the data, and the NCI Advanced Biomedical Computational Science (ABCS) for data transformation support. Biomedical Advanced Research and Development Authority was supported under contract no. HHSO10201600031C (to J.H.). Financial support was provided by the National Institute of Allergy and Infectious Diseases (NIAID) K08AI135091; the Burroughs Wellcome Fund CAMS; the Clinical Immunology Society; and the American Academy of Allergy, Asthma, and Immunology
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
No full textBackground: 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. © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licens
