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1.
Mol Pharm ; 2020 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-32069060

RESUMO

Hydrophilic matrices are an effective option for oral controlled release but can face challenges in terms of bioavailability and efficacy when used in conjunction with poorly soluble, weakly basic drugs. Attenuated total reflectance Fourier transform infrared (ATR-FTIR) imaging provides dynamic information relating to the location and chemical nature of both the sustained release matrix and the active pharmaceutical ingredient (API) during hydration/dissolution. In this study we have identified a model system combining itraconazole (IT), a poorly soluble, weakly basic API that has a pKa in the physiological range, and hydroxypropyl methylcellulose (HPMC) which is a commonly used oral tablet matrix. This system was investigated to determine swelling kinetics at different pH at a fixed ionic strength and to facilitate the study of the influence of hydrating media pH on drug particle movement (translocation). Using ATR-FTIR imaging we were able to show that gel layer formation and swelling were independent of pH but highly dependent on the ionic strength of the hydrating medium in placebo tablets. When the ionic strength was fixed, gel layer formation and radial swelling were both shown to be pH dependent when IT was incorporated into the matrix. This was verified using optical imaging. The chemical specificity of ATR-FTIR imaging permitted the observation of transformational changes of IT from free base to the ionised form in the tablet core during hydration. This phenomenon was shown to be greater at pH 1.5 than pH 7. ATR-FTIR imaging was able to follow drug particle translocation at both pH 1.5 and pH 7, however, the extent of migration away from the tablet core was shown to be greater at lower pH. The location of the translocated particles within the gel layer was different between the two studied pHs with particles being located close to the erosion front at pH 7 and within the diffusion front at pH 1.5. In both pH environments translocated IT particles were shown to be predominantly in the free base form. No evidence of fully solubilised IT was observed in the surrounding medium due to the inherent aqueous solubility of IT being below the instrument detection limits. This work highlighted the value of utilising a chemically specific spectroscopic tool to increase the understanding of the nature of factors affecting the release of a pH-dependent, poorly soluble drug from a hydrophilic matrix at different pH and permitted greater insight into what happens inside the polymer matrix during drug release. Key Words Real time imaging, poorly soluble drug, itraconazole, gel layer, HPMC, extended release.

2.
Sci Transl Med ; 12(531)2020 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-32075944

RESUMO

Congenital heart valve disease has life-threatening consequences that warrant early valve replacement; however, the development of a growth-accommodating prosthetic valve has remained elusive. Thousands of children continue to face multiple high-risk open-heart operations to replace valves that they have outgrown. Here, we demonstrate a biomimetic prosthetic valve that is geometrically adaptable to accommodate somatic growth and structural asymmetries within the heart. Inspired by the human venous valve, whose geometry is optimized to preserve functionality across a wide range of constantly varying volume loads and diameters, our balloon-expandable synthetic bileaflet valve analog exhibits similar adaptability to dimensional and shape changes. Benchtop and acute in vivo experiments validated design functionality, and in vivo survival studies in growing sheep demonstrated that mechanical valve expansion accommodated growth. As illustrated in this work, dynamic size adaptability with preservation of unidirectional flow in prosthetic valves thus offers a paradigm shift in the treatment of heart valve disease.

3.
Arterioscler Thromb Vasc Biol ; : ATVBAHA119313046, 2020 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-31969015

RESUMO

Androgen deprivation therapy is a central part of prostate cancer treatment. Pharmacological androgen deprivation includes gonadotropin-releasing hormone agonism and antagonism, AR (androgen receptor) inhibition, and CYP17 inhibition. Studies in the past decade have raised concerns about the potential for androgen deprivation therapy to increase the risk of adverse cardiovascular events such as myocardial infarction, stroke, and cardiovascular mortality, possibly by exacerbating cardiovascular risk factors. In this review, we summarize existing data on the cardiovascular effects of androgen deprivation therapy. Among the therapies, abiraterone stands out for increasing risk of cardiac events in meta-analyses of both randomized controlled trials and observational studies. We find a divergence between observational studies, which show consistent positive associations between androgen deprivation therapy use and cardiovascular disease, and randomized controlled trials, which do not show these associations reproducibly.

4.
Camb Q Healthc Ethics ; 29(1): 144-155, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31858940
5.
JACC Basic Transl Sci ; 4(5): 567-574, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31768474

RESUMO

In this study low-input RNA-sequencing was used to annotate the molecular identity of endothelial cells isolated and immunopurified with CD144 microbeads. Using this technique, comparative gene expression profiling from healthy subjects and patients with type 2 diabetes mellitus identified both known and novel pathways linked with EC dysfunction. Modeling of diabetes by treating cultured ECs with high glucose identified shared changes in gene expression in diabetic cells. Overall, the data demonstrate how purified ECs from patients can be used to generate new hypotheses about mechanisms of human vascular disease.

6.
J Am Chem Soc ; 141(46): 18455-18466, 2019 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-31674178

RESUMO

Salt-doped diblock copolymers with microphase-separated domains of both an ion conductive and a mechanically strong polymer have been extensively studied due to their potential in transport applications. Several unusual or counterintuitive trends regarding their transport properties have been observed experimentally, such as increasing ion conduction as a function of molecular weight. A crucial feature of these systems is the strong solvation of ions in the conducting microphase due to its higher dielectric constant. Here, we perform molecular dynamics simulations using a coarse-grained model that includes a 1/r4 potential form to generically represent ion solvation, allowing us to reproduce experimentally observed trends and explore their molecular underpinnings. We find that increasing ion concentration can increase or decrease ion diffusion, depending on solvation strength. We also show that the trend of increasing diffusion with molecular weight becomes more dramatic as ions are solvated in one polymer block more strongly or as the ion-ion interactions get stronger. In contrast to expectations, the interfacial width or the overlap of ions with the nonconductive polymer block does not adequately explain this phenomenon; instead, local ion agglomeration best explains reduced diffusion. Interfacial sharpening, controlled by the Flory χ parameter and molecular weight, tends to allow ions to spread more uniformly, and this increases their diffusion.

7.
J Gen Virol ; 2019 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-31702542

RESUMO

Serological assays with modern influenza A/H3N2 viruses have become problematic due to the progressive reduction in the ability of viruses of this subtype to bind and agglutinate red blood cells (RBCs). This is due to reduced ability of the viral haemagglutinin (HA) glycoprotein to bind to the sialic acid-containing receptors presented by these cells. Additionally, as a result of reduced HA-mediated binding in cell culture, modern A/H3N2 viruses often acquire compensatory mutations during propagation that enable binding of cellular receptors through their neuraminidase (NA) surface protein. Viruses that have acquired this NA-mediated binding agglutinate RBCs through their NA, confusing the results of serological assays designed to assess HA antigenicity. Here we confirm with a large dataset that the acquisition of mutations that confer NA binding of RBCs is a culture artefact, and demonstrate that modern A/H3N2 isolates with acquired NA-binding mutations revert to a clinical-like NA sequence after a single passage in human airway epithelial (HAE) cells.

8.
PLoS Pathog ; 15(10): e1007956, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31589653

RESUMO

We report the analysis of a complex enveloped human virus, herpes simplex virus (HSV), assembled after in vivo incorporation of bio-orthogonal methionine analogues homopropargylglycine (HPG) or azidohomoalanine (AHA). We optimised protocols for the production of virions incorporating AHA (termed HSVAHA), identifying conditions which resulted in normal yields of HSV and normal particle/pfu ratios. Moreover we show that essentially every single HSVAHA capsid-containing particle was detectable at the individual particle level by chemical ligation of azide-linked fluorochromes to AHA-containing structural proteins. This was a completely specific chemical ligation, with no capsids assembled under normal methionine-containing conditions detected in parallel. We demonstrate by quantitative mass spectrometric analysis that HSVAHA virions exhibit no qualitative or quantitative differences in the repertoires of structural proteins compared to virions assembled under normal conditions. Individual proteins and AHA incorporation sites were identified in capsid, tegument and envelope compartments, including major essential structural proteins. Finally we reveal novel aspects of entry pathways using HSVAHA and chemical fluorochrome ligation that were not apparent from conventional immunofluorescence. Since ligation targets total AHA-containing protein and peptides, our results demonstrate the presence of abundant AHA-labelled products in cytoplasmic macrodomains and tubules which no longer contain intact particles detectable by immunofluorescence. Although these do not co-localise with lysosomal markers, we propose they may represent sites of proteolytic virion processing. Analysis of HSVAHA also enabled the discrimination from primary entering from secondary assembling virions, demonstrating assembly and second round infection within 6 hrs of initial infection and dual infections of primary and secondary virus in spatially restricted cytoplasmic areas of the same cell. Together with other demonstrated applications e.g., in genome biology, lipid and protein trafficking, this work further exemplifies the utility and potential of bio-orthogonal chemistry for studies in many aspects of virus-host interactions.

9.
Sci Transl Med ; 11(509)2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31511424

RESUMO

Aortic stenosis (AS) management is classically guided by symptoms and valvular metrics. However, the natural history of AS is dictated by coupling of the left ventricle, aortic valve, and vascular system. We investigated whether metrics of ventricular and vascular state add to the appreciation of AS state above valve gradient alone. Seventy patients with severe symptomatic AS were prospectively followed from baseline to 30 days after transcatheter aortic valve replacement (TAVR). Quality of life (QOL) was assessed using the Kansas City Cardiomyopathy Questionnaire. Left ventricular stroke work (SWLV) and vascular impedance spectrums were calculated noninvasively using in-house models based on central blood pressure waveforms, along with hemodynamic parameters from echocardiograms. Patients with higher preprocedural SWLV and lower vascular impedance were more likely to experience improved QOL after TAVR. Patients fell into two categories: those who did and those who did not exhibit increase in blood pressure after TAVR. In patients who developed hypertension (19%), vascular impedance increased and SWLV remained unchanged (impedance at zeroth harmonic: Z 0, from 3964.4 to 4851.8 dyne·s/cm3, P = 0.039; characteristic impedance: Z c, from 376.2 to 603.2 dyne·s/cm3, P = 0.033). SWLV dropped only in patients who did not develop new hypertension after TAVR (from 1.58 to 1.26 J; P < 0.001). Reduction in valvular pressure gradient after TAVR did not predict change in SWLV (r = 0.213; P = 0.129). Reduction of SWLV after TAVR may be an important metric in management of AS, rather than relying solely on the elimination of transvalvular pressure gradients.

10.
BMC Health Serv Res ; 19(1): 619, 2019 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-31477110

RESUMO

BACKGROUND: To establish which major disorders are susceptible to increased mortality following acute admissions on weekends, compared with week days, and how this may be explained. METHODS: Cohorts based on national administrative inpatient and mortality data for 14,168,443 hospitalised patients in England and 913,068 in Wales who were admitted for 66 disorders that were associated with at least 200 deaths within 30 days of acute admission. The main outcome measure was the weekend mortality effect (defined as the conventional mortality odds ratio for admissions on weekends compared with week days). RESULTS: There were large, statistically significant weekend mortality effects (> 20%) in England for 22 of the 66 conditions and in both countries for 14. These 14 were 4 of 13 cancers (oesophageal, colorectal, lung and lymphomas); 4 of 13 circulatory disorders (angina, abdominal aortic aneurysm, peripheral vascular disease and arterial embolism & thrombosis); one of 8 respiratory disorders (pleural effusion); 2 of 12 gastrointestinal disorders (alcoholic and other liver disease); 2 of 3 ageing-related disorders (Alzheimer's disease and dementia); none of 7 trauma conditions; and one of 10 other disorders (acute renal failure). Across the disorders, 64% of the variation in weekend mortality effects in England and Wales was explained by reductions in admission rates at weekends and the medical disease category. CONCLUSIONS: The effect of weekend admission on 30 day mortality is seen mainly for cancers, some circulatory disorders, liver disease and a few other conditions which are mainly ageing- or cancer-related. Most of the increased mortality is associated with reduced admission rates at weekends and the medical disease category.


Assuntos
Plantão Médico , Mortalidade Hospitalar/tendências , Admissão do Paciente , Doença Aguda , Lesão Renal Aguda , Idoso , Estudos de Coortes , Inglaterra , Feminino , Gastroenteropatias , Hospitalização , Humanos , Armazenamento e Recuperação da Informação , Hepatopatias , Masculino , Pessoa de Meia-Idade , País de Gales
11.
Nucleic Acid Ther ; 29(5): 231-244, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31393218

RESUMO

Small interfering RNAs (siRNAs) conjugated to N-acetylgalactosamine (GalNAc) ligands have been used to treat disease in patients. However, conjugates with other ligands deliver siRNA less efficiently, limiting the development of new targeted therapies. Most approaches to enhancing the potency of such conjugates have concentrated on increasing ligand effectiveness and/or the chemical stability of the siRNA drug. One complementary and unexplored alternative is to increase the number of siRNAs delivered per ligand. An ideal system would be a single chemical entity capable of delivering multiple copies of an oligonucleotide drug and/or several such drugs simultaneously. Here we report that siRNAs can be stably linked together under neutral aqueous conditions to form chemically defined siRNA "multimers," and that these multimers can be delivered in vivo by a GalNAc ligand. Conjugates containing multiple copies of the same siRNA showed enhanced activity per unit of ligand, whereas siRNAs targeting different genes linked to a single ligand facilitated multigene silencing in vivo; this is the first demonstration of silencing several genes simultaneously in vivo using ligand-directed multimeric siRNA. Multimeric oligonucleotides represent a powerful and practical new approach to improve intracellular conjugate delivery.

12.
mSphere ; 4(4)2019 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-31366707

RESUMO

Biofilms formed by nontypeable Haemophilus influenzae (NTHI) bacteria play an important role in multiple respiratory tract diseases. Visual inspection of the morphology of biofilms formed during chronic infections shows distinct differences from biofilms formed in vitro To better understand these differences, we analyzed images of NTHI biofilms formed in the middle ears of Chinchilla lanigera and developed an in silico agent-based model of the formation of NTHI biofilms in vivo We found that, as in vitro, NTHI bacteria are organized in self-similar patterns; however, the sizes of NTHI clusters in vivo are more than 10-fold smaller than their in vitro counterparts. The agent-based model reproduced these patterns and suggested that smaller clusters occur due to elimination of planktonic NTHI cells by the host responses. Estimation of model parameters by fitting simulation results to imaging data showed that the effects of several processes in the model change during the course of the infection.IMPORTANCE Multiple respiratory illnesses are associated with formation of biofilms within the human airway by NTHI. However, a substantial amount of our understanding of the mechanisms that underlie NTHI biofilm formation is obtained from in vitro studies. Our in silico model that describes biofilm formation by NTHI within the middle ears of Chinchilla lanigera will help isolate processes potentially responsible for the differences between the morphologies of biofilms formed in vivo versus those formed in vitro Thus, the in silico model can be used to glean mechanisms that underlie biofilm formation in vivo and connect those mechanisms to those obtained from in vitro experiments. The in silico model developed here can be extended to investigate potential roles of specific host responses (e.g., mucociliary clearance) on NTHI biofilm formation in vivo The developed computational tools can also be used to analyze and describe biofilm formation by other bacterial species in vivo.

14.
Arch Pathol Lab Med ; 143(9): 1058-1068, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31295016

RESUMO

CONTEXT.­: The rapid evolution of optical imaging modalities in recent years has opened the opportunity for ex vivo tissue imaging, which has significant implications for surgical pathology practice. These modalities have promising potential to be used as next-generation digital microscopy tools for examination of fresh tissue, with or without labeling with contrast agents. OBJECTIVE.­: To review the literature regarding various types of ex vivo optical imaging platforms that can generate digital images for tissue recognition with potential for utilization in anatomic pathology clinical practices. DATA SOURCES.­: Literature relevant to ex vivo tissue imaging obtained from the PubMed database. CONCLUSIONS.­: Ex vivo imaging of tissues can be performed by using various types of optical imaging techniques. These next-generation digital microscopy tools have a promising potential for utilization in surgical pathology practice.

15.
JCI Insight ; 4(11)2019 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-31167964

RESUMO

Atherosclerotic plaques feature local proliferation of leukocytes and vascular smooth muscle cells (VSMCs) and changes in cellular metabolism. Yet the relationship between glucose utilization and proliferation has been technically impossible to study directly in cells of atherosclerotic plaques in vivo. We used multi-isotope imaging mass spectrometry (MIMS), a quantitative imaging platform, to measure coincident cell division and glucose utilization at suborganelle resolution in atherosclerotic plaques. In established plaques, 65% of intimal foam cells and only 4% of medial VSMCs were labeled with 15N-thymidine after 1 week of isotope treatment. Dividing cells demonstrated heightened glucose labeling. MIMS detected 2H-glucose label in multiple subcellular compartments within foam cells, including lipid droplets, the cytosol, and chromatin. Unexpectedly, we identified an intensely focal region of 2H-label in VSMCs underlying plaques. This signal diminished in regions of aorta without atherosclerosis. In advanced plaques, 15N-thymidine and 2H-glucose labeling in foam cells and VSMCs significantly decreased. These data demonstrate marked heterogeneity in VSMC glucose metabolism that was dependent on both proliferative status and proximity of VSMCs to plaques. Furthermore, these results reveal how quantitative mass spectrometry coupled with isotope imaging can complement other methods used to study cell biology directly in the growing atherosclerotic plaque in vivo.

16.
Artigo em Inglês | MEDLINE | ID: mdl-31125974

RESUMO

A 68-year-old previously independent woman presented multiple times to hospital over the course of 3 months with a history of intermittent weakness, vacant episodes, word finding difficulty and reduced cognition. She was initially diagnosed with a TIA, and later with a traumatic subarachnoid haemorrhage following a fall; however, despite resolution of the haemorrhage, symptoms were ongoing and continued to worsen. Confusion screen blood tests showed no cause for the ongoing symptoms. More specialised investigations, such as brain imaging, cerebrospinal fluid analysis, electroencephalogram and serology also gave no clear diagnosis. The patient had a background of hypothyroidism, with plasma thyroid function tests throughout showing normal free thyroxine and a mildly raised thyroid-stimulating hormone (TSH). However plasma anti-thyroid peroxidise (TPO) antibody titres were very high. After discussion with specialists, it was felt she may have a rare and poorly understood condition known as Hashimoto's encephalopathy (HE). After a trial with steroids, her symptoms dramatically improved and she was able to live independently again, something which would have been impossible at presentation. Learning points: In cases of subacute onset confusion where most other diagnoses have already been excluded, testing for anti-thyroid antibodies can identify patients potentially suffering from HE. In these patients, and under the guidance of specialists, a trial of steroids can dramatically improve patient's symptoms. The majority of patients are euthyroid at the time of presentation, and so normal thyroid function tests should not prevent anti-thyroid antibodies being tested for. Due to high titres of anti-thyroid antibodies being found in a small percentage of the healthy population, HE should be treated as a diagnosis of exclusion, particularly as treatment with steroids may potentially worsen the outcome in other causes of confusion, such as infection.

17.
Aliment Pharmacol Ther ; 49(10): 1334-1345, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30972781

RESUMO

BACKGROUND: There is a known shortfall in hepatology service resources across England and Wales. AIM: To investigate early and late mortality following unscheduled admissions for severe liver disease, overall and by cause of death, and to determine how mortality is related to admissions to transplant centres, transplant surgery, hospital size, consultant specialty, patient socio-demographics, seasonal and geographical factors. METHODS: Cohorts of people with a first unscheduled admission for severe liver disease across England and Wales from 2004, based on record linkage of national inpatient and mortality data. FINDINGS: Mortality for alcoholic liver disease and hepatic failure was 23.4% and 35.4% respectively at 60 days and 61.8% and 57.1% at 5 years. Standardised mortality ratios (SMRs) were extremely high at 60 days (184 and 117 respectively) and remained highly increased at 5 years (16.7 and 6.3). Mortality at 5 years was most elevated from liver disease, viral hepatitis and varices. The 60-day mortality was significantly lower for patients seen by consultant hepatologists and gastroenterologists. Both early and late mortality were significantly reduced for patients admitted to transplant centres or larger hospitals, who received a liver transplant, or were resident in London. Early mortality was significantly higher for patients admitted in winter and autumn, while elevated mortality among the most vs least deprived quintile increased with longer follow-up. CONCLUSIONS: The study shows a very poor prognosis for people with unscheduled hospitalisation for severe liver disease. The findings suggest that access to specialist expertise and services improves survival, both in the short and long term.

18.
Neurobiol Stress ; 10: 100143, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30937349

RESUMO

The bed nucleus of the stria terminalis (BNST) is a sexually dimorphic brain region which plays a key role in stress, anxiety, and anxiety-related disorders. Human females have an increased susceptibility to anxiety-related disorders, however the physiological basis of this is not fully understood. Here we examined the effect of the oestrous cycle and sex on the electrophysiological properties of Type I and Type II cells in the anterolateral area of the BNST (BNSTALG) in unstressed animals. There was no significant effect of oestrous cycle on any of the parameters examined in either cell type. Compared to males, the female cohort had lower capacitance in Type I cells while having a higher capacitance in Type II cells. Type II cells also displayed decreased excitability in the female cohort. In order to confirm the effect of these populations on stress and anxiety, a correlation with behaviour on the elevated zero maze was carried out. We observed that increased excitability in Type II neurons correlated with a decrease in anxiety-like behaviour. These sex-specific differences in excitability may contribute to altered susceptibility to anxiety-related disorders.

19.
Psychiatr Serv ; 70(6): 499-502, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30841843

RESUMO

OBJECTIVE: This study examined the availability of primary care and wellness services in community mental health centers (CMHCs) and outpatient mental health facilities (OMHFs). METHODS: This study used data from the 2016 National Mental Health Services Survey to examine the proportion of facilities that reported offering integrated primary care and wellness services (smoking and tobacco cessation counseling, diet and exercise counseling, and chronic disease and illness management). The study used logistic regression to model the odds that a facility offered integrated primary care as a function of facility characteristics. RESULTS: Across states, 23% of CMHCs and 19% of OMHFs offered integrated primary care. The odds of offering integrated primary care were significantly higher among facilities that reported more quality improvement practices, prohibited smoking, or offered wellness services. Less than one third offered smoking and tobacco cessation counseling or other wellness services. CONCLUSIONS: Integrated primary care remains uncommon in CMHCs and OMHFs and is more likely among facilities with certain characteristics.

20.
Lancet Public Health ; 4(1): e49-e73, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30551974

RESUMO

BACKGROUND: To inform plans to achieve universal health coverage (UHC), we estimated utilisation and unit cost of outpatient visits and inpatient admissions, did a decomposition analysis of utilisation, and estimated additional services and funds needed to meet a UHC standard for utilisation. METHODS: We collated 1175 country-years of outpatient data on utilisation from 130 countries and 2068 country-years of inpatient data from 128 countries. We did meta-regression analyses of annual visits and admissions per capita by sex, age, location, and year with DisMod-MR, a Bayesian meta-regression tool. We decomposed changes in total number of services from 1990 to 2016. We used data from 795 National Health Accounts to estimate shares of outpatient and inpatient services in total health expenditure by location and year and estimated unit costs as expenditure divided by utilisation. We identified standards of utilisation per disability-adjusted life-year and estimated additional services and funds needed. FINDINGS: In 2016, the global age-standardised outpatient utilisation rate was 5·42 visits (95% uncertainty interval [UI] 4·88-5·99) per capita and the inpatient utilisation rate was 0·10 admissions (0·09-0·11) per capita. Globally, 39·35 billion (95% UI 35·38-43·58) visits and 0·71 billion (0·65-0·77) admissions were provided in 2016. Of the 58·65% increase in visits since 1990, population growth accounted for 42·95%, population ageing for 8·09%, and higher utilisation rates for 7·63%; results for the 67·96% increase in admissions were 44·33% from population growth, 9·99% from population ageing, and 13·55% from increases in utilisation rates. 2016 unit cost estimates (in 2017 international dollars [I$]) ranged from I$2 to I$478 for visits and from I$87 to I$22 543 for admissions. The annual cost of 8·20 billion (6·24-9·95) additional visits and 0·28 billion (0·25-0·30) admissions in low-income and lower-middle income countries in 2016 was I$503·12 billion (404·35-605·98) or US$158·10 billion (126·58-189·67). INTERPRETATION: UHC plans can be based on utilisation and unit costs of current health systems and guided by standards of utilisation of outpatient visits and inpatient admissions that achieve the highest coverage of personal health services at the lowest cost. FUNDING: Bill & Melinda Gates Foundation.

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