Prospective Study of Prevalence and Risk Factors for Hepatitis C in Pregnant Egyptian Women and Its Transmission to Their Infants

Aim To estimate the hepatitis C virus (HCV) vertical transmission rate, the effect of potential risk factors, and the pattern of HCV antibody response and viremia in HCV-infected infants in Benha, Egypt. Methods A total of 1224 pregnant women who were treated at Benha University Hospital, Egypt, were included in the study. They completed a questionnaire about risk factors for HCV acquisition and suspected risk factors for mother-to-infant transmission and were tested for HCV antibody using a third-generation ELISA test. Women positive for HCV antibody were tested for HCV RNA by polymerase chain reaction. Peripheral blood of infants of positive HCVRNA women was tested for HCV antibody and HCV-RNA at 1 and after 6 months of age. Results Out of 1224 pregnant women, 105 (8.6%; 95% confidence interval, 7.05-10.17) were positive for HCV antibody. Only 83 (6.8%; 5.39-7.21) were positive for HCV-RNA. HCV infection was associated with older age (1.16; 1.1-1.2, P = 0.001), blood transfusion (2.69; 1.2-6.0, P = 0.016), and HCV infection of the husband (5.47; 1.4-21, P = 0.014) or other household members (2.29; 1.2-4.6, P = 0.019). Out of 53 infants tested at first month, 43 (81%; 71-92%) were positive for HCV antibody, but only 7 (13%; 4.1-22%) were positive for HCV-RNA. After 6 months, only 2 (3.8%; 0-8.95%) remained positive for HCV RNA. Conclusions The prevalence of HCV in pregnant women in Egypt is lower than previously reported and the potential risk factors associated with HCV infection suggest intra- familial transmission. The frequency of vertical transmission of HCV in Egypt is not substantially different from other countries and does not play a role in the high prevalence of HCV in Egypt

Prospective Study of Prevalence and Risk Factors for Hepatitis C in Pregnant Egyptian Women and Its Transmission to Their Infants

Aim To estimate the hepatitis C virus (HCV) vertical transmission rate, the effect of potential risk factors, and the pattern of HCV antibody response and viremia in HCV-infected infants in Benha, Egypt. Methods A total of 1224 pregnant women who were treated at Benha University Hospital, Egypt, were included in the study. They completed a questionnaire about risk factors for HCV acquisition and suspected risk factors for mother-to-infant transmission and were tested for HCV antibody using a third-generation ELISA test. Women positive for HCV antibody were tested for HCV RNA by polymerase chain reaction. Peripheral blood of infants of positive HCV-RNA women was tested for HCV antibody and HCV-RNA at 1 and after 6 months of age. Results Out of 1224 pregnant women, 105 (8.6%; 95% confidence interval, 7.05-10.17) were positive for HCV antibody. Only 83 (6.8%; 5.39-7.21) were positive for HCV-RNA. HCV infection was associated with older age (1.16; 1.1-1.2, P = 0.001), blood transfusion (2.69; 1.2-6.0, P = 0.016), and HCV infection of the husband (5.47; 1.4-21, P = 0.014) or other household members (2.29; 1.2-4.6, P = 0.019). Out of 53 infants tested at first month, 43 (81%; 71-92%) were positive for HCV antibody, but only 7 (13%; 4.1-22%) were positive for HCV-RNA. After 6 months, only 2 (3.8%; 0-8.95%) remained positive for HCV RNA. Conclusions The prevalence of HCV in pregnant women in Egypt is lower than previously reported and the potential risk factors associated with HCV infection suggest intra-familial transmission. The frequency of vertical transmission of HCV in Egypt is not substantially different from other countries and does not play a role in the high prevalence of HCV in Egypt. CLINICAL SCIENCES doi: 10.3325/cmj.2010.51.219 CLINICAL SCIENCE 220 Croat Med J. 2010; 51: 219-28 www.cmj.hr Worldwide, hepatitis C virus (HCV) infection is one of the most prevalent causes of liver diseases. There are estimated 300 million carriers of the virus all over the world (1). In the USA, the overall prevalence of HCV antibodies in the general population is 1.8%, the prevalence in children 6-11 years is 0.2%, and in adolescents 12-19 years old is 0.4% (2). In most developed countries, HCV infection is associated with percutaneous blood exposure, primarily as a result of blood transfusion and intravenous drug addiction (3). Egypt has the highest prevalence of hepatitis C in the world. Studies have found widely varying levels (10-50%) of the prevalence, depending on the populations covered; overall, estimates of the HCV rate in the general population range between 10 and 20% (4,5). Geographically, hepatitis C prevalence is higher in Lower Egypt (Nile delta) than Upper Egypt, and it is lower in urban than rural areas (6). In Egypt, the use of contaminated needles and syringes during mass schistosomiasis treatment campaigns during the period the 1960s-1980s has been identified as a key mode of transmission for HCV infection, suggesting that parenteral exposure continues to cause infections (7). Evidence of high interfamilial HCV transmission was found in a study in a rural community in the Nile Delta in the 1990s (5-8), although the exact modes of transmission were not identified. Vertical transmission may help to explain the high prevalence in Egypt. This type of transmission in France is estimated to be less than 6% in HIV-negative patients (9). Indeed, a review of 13 studies on vertical transmission of HCV showed that the overall rate was 5.2% (10). However, a brief report from Egypt showed that vertical transmission of HCV was 36% (11), but this study looked at a small sample of 19 out of 100 pregnant women positive for HCV antibody, and only 14 of them were positive for HCV RNA. The sample of Kassem et al (11) comprised 100 randomly selected HIV-negative pregnant women and was too small for a valid estimation of the proportion of vertical transmission. It also used a limited definition of vertical transmission, defining it as the presence of HCV RNA in cord blood, and it did not repeat the polymerase chain reaction (PCR) test for HCV-RNA for infants after 6 months. The aim of the present article was to perform a more extensive study to estimate the HCV vertical transmission rate, the effect of potential risk factors, and the pattern of HCV antibody response and viremia in HCV-infected infants in Benha, Egypt. MetHodS Site The study was conducted in Benha, the capital of Qualyabia governorate, a small city 35 km north of Cairo. It is a semi-urban area with irrigated farmlands and surrounded by canals, a feature typical of the Nile delta. It has the characteristics typical of a Lower Egyptian community: a mixture of urban and rural areas, with significant influence of Egyptian traditions and attitudes. Benha University Hospital is one of the largest hospitals in Benha city. This hospital accepts patients from Benha city and the rural areas from Menufia and Sharkia governorates nearby (village households, inhabited mainly by farmers and their families). Most of the community studies on HCV in Nile delta have been conducted in Qualyabia and Menoufia. Study design and population This prospective study was conducted in two stages: the first stage was a cross-sectional study to identify the prevalence of HCV among pregnant women and the second stage was a longitudinal study of the infants of infected women to identify the rate of vertical transmission. The study population included all pregnant women who were admitted at the obstetric emergency department at Benha University Hospital (Benha, Egypt) for delivery between October 2003 and July 2008. The women who gave birth more than once during the study period were not included in the study. We did not test for HIV, which is exceedingly rare in rural Egyptian communities. The study protocol was approved by the clinical research committee of Benha University Hospital, the Institutional Review Board of the Egyptian Ministry of Health and Population, and the National Hepatology and Tropical Medicine Research Institute (Cairo). Patients were asked to sign a written consent for the study. data collection After signing the consent form, the authors conducted interviews with the women using a standardized questionnaire designed by a team of sociologists, epidemiologists, and clinicians familiar with the risk factors for HCV acquisition and suspected risk factors for mother-to-infant transmission of HCV (older age, history of blood transfusion, duration of marriage, parity of more than two, husband and other household members positive for HCV). This ques- tionnaire assessed sociodemographic characteristics, present and past health, and potential risk factors for exposure to HCV and mother-to-infant transmission of HCV. The address and phone number of the patients and the name and phone number of close relatives were taken to facilitate follow-up and decrease patient loss during the study. Specimen collection and serological testing of pregnant women. After the questionnaire was filled out, blood samples (10 mL) were taken from the pregnant women and sent to the laboratory. Serum alanine transaminase level (ALT) was assessed within 6 hours of sampling using ALT FLEX TM , AR model of the DIMENSION TM system (Dade Behring Inc., Newark, DE, USA). When ALT was found to be elevated, additional tests were performed to exclude metabolic and viral liver disease other than hepatitis C. The serum was separated and aliquoted into 3 cryotubes, one aliquot was sent in an ice bag to the HCV Reference Laboratory at the National Hepatology and Tropical Medicine Research Institute (Cairo), where the serum was tested for HCV antibodies using a third-generation ELISA test (Axsym System HCV, version 3.0, Abbott Diagnostics Division; Wiesbaden, Germany) as recommended by the manufacturer. The other two aliquots were stored in -70°C freezers to be tested later if needed. Infected pregnant women were identified by testing serum for the presence of HCV antibody. Serological samples that were positive for HCV antibody were tested for the presence of HCV-RNA using a procedure of whole-serum amplification of DNA based on an in-house reverse transcription-nested polymerase chain reaction (RT-PCR). Pregnant women were considered infected only if both the HCV antibody and HCV-RNA tests were positive. Serological testing of infants and classification of results Infected patients who tested positive were called back to get a peripheral blood sample from their infants. HCV antibody testing was done first on the infants and then positive HCV antibody samples were tested for HCV-RNA. Infants were considered uninfected if they had never been positive for HCV RNA or if they cleared anti-HCV antibodies after 6 months of age. Infants were considered to have perinatal mother-to-infant transmission if they were HCV-RNA positive at any time following birth or showed anti-HCV antibodies after 6 months of age. They were considered to have transient perinatal HCV infection if they were positive for HCV RNA at the 6-month visit, but negative for both anti-HCV and HCV-RNA after the 6-month visit. The children continuing to have HCV-RNA after the 6-month visit were considered to have persistent perinatal HCV infections. Anti-HCV antibodies detected in the blood of children whose mothers tested positive for anti-HCV antibodies 2-6 months after delivery were considered to be maternally acquired (12). PCR-based detection of HCV-RNA The protocol was based on a previously published procedure (13) modified to increase the sensitivity of the assay. HCV RNA was detected by PCR (HCV AMPLICOR TM , Roche Diagnostic systems, Inc., Branchburg, NJ, USA) and quantified by the branched DNA signal amplification test (b-DNA) (Quantiplex TM HCV RNA 2.0, Chiron diagnostics, Emeryville, CA, USA). Samples were prepared as a 3:10 dilution using 3 µL of serum and 7 µL of phosphate buffered saline in thin-walled PCR tubes. Tubes were incubated at 95°C for 4 minutes and chilled on ice for 10 minutes, prior to the addition of RT-PCR master mix (Promega, Madison, WI, USA). RT-PCR reactions were carried out in a total volume of 100 µL containing 1X Taq buffer with 1.5 mM MgCl 2 , 0.2 mM dNTPs (Promega), 20 pmol each of primer 1 (PSEA-HCV-1, 5′ HEX-AAG GAC CCG GTC GTC CT 3'; Sigma-Genosys, Woodlands, TX, USA) and primer 2 (PSEA-HCV-2, 5' FAM-TAT CCA AGA AAG GAC CCA 3'; Sigma-Genosys), 20 units of ribonuclease inhibitor (RNasin; Promega), 10 units of MV Reverse Transcriptase (RT; Promega), and 2.5 units of Taq DNA polymerase (Roche Diagnostic Systems). Master mix (90 µL) (Promega) was added to each sample and the mixture was incubated at 42°C for 30 minutes and at 95°C for 4 minutes followed immediately by 35 cycles at the following conditions: 94°C for 1 minute, 50°C for 1 minute, 72°C for 1 minute, and a final cycle of 72°C for 10 minutes. The second PCR, using the inner primer 3 (PSEA-HCV-3, 5' FAM-CAA CAC TAC TCG GCT AGT 3'; Sigma-Genosys) and primer 4 (PSEA-HCV-4, 5' HEX-CAT GGC GTT AGT ATG AGT GTT 3'; Sigma-Genosys), was performed by transferring 10 µL from the initial reaction to 90 µL of master mix (1X Taq buffer, 0.2 mM dNTPs, 20 pmol of each nested primer, and 2.5 units of Taq polymerase). The samples were incubated for 35 cycles as in step 2 without the RT step. The PCR products were analyzed on 3% agarose in 0.5X TBE buffer. The primers were derived from the highly conserved 5'-untranslated region of the HCV genome to allow nested amplification of a 237-base pair product. Negative samples were retested for PCR after RNA extraction using the QIAamp Viral RNA kit (catalog No. 52906, Qiagen, Hilden, Germany). The sensitivity of the assay was 50 IU/mL according to the manufacturer's information. Despite CLINICAL SCIENCE 222 Croat Med J. 2010; 51: 219-28 www.cmj.hr its greater sensitivity, an in-house nested RT-PCR invites problems with contamination and should be used with extreme care in the clinical setting. Statistical analysis The sample size for this study was calculated according to the primary aim (assess the prevalence of HCV among pregnant women). Demographic and laboratory data were compared for the infected pregnant women with non-infected group using χ 2 and Fischer exact tests for categorical or dichotomous variables, and the unpaired independent t-test for continuous variables. Differences were considered significant for P values of 0.05 or less. Significant parameters were included in a multivariate logistic regression analysis to identify independent predictors of HCV positivity among pregnant women, and the odds ratio was calculated for each significant parameter. Rate of vertical transmission was calculated based on the frequencies of HCV-RNA PCR positivity in mothers and their infants. ReSultS Design and follow up are shown in Out of the 83 infected mothers, samples of only 47 mothers and 53 children (6 mothers delivered twins) were available. Of these 83 infected mothers, 3 (3.5%) mothers had still births, 27 (33%) were lost to follow-up, 6 (7%) withdrew consent, and 6 (7%) had twins. Out of the 53 infants tested in the first month of life, 43 (81%) were positive for HCV antibodies, and 10 (19%) were negative. The latter group was considered as non-infected infants without maternally-acquired antibodies. Of the 43 infants positive for HCV antibodies, only 7 (13%) were found positive for HCV-RNA by PCR; these were considered to be HCV-infected infants. HCV-RNA was not detected in 36 of 43 (87%) of infants born to HCV-RNA positive mothers; this group was considered as non-infected infants with maternally-acquired antibodies. At 6 months of age, 6 children who had been found positive for HCV-RNA by PCR were examined again; one mother withdrew consent for her children. Only two of the 53 (3.8%) remained positive for HCV-RNA; this pair was considered to show persistent HCV infection. The other 4 infants (7.6%) cleared their HCV-RNA and sero-reverted to become negative for HCV antibodies; this group was considered to show clearance of perinatal HCV infection. Patients lost to follow-up did not show significant demographic differences in comparison with patients who continued to participate. Loss of follow-up in infants who were tested during the first month was not high (14.2%). dISCuSSIoN Our study showed that the risk factors for HCV infection among pregnant women in an Egypt regions were older age, HCV-positive husband, administration of blood transfusion, and HCV-positive other member of the household members. Egypt is considered one of the countries with the highest prevalence of HCV in the world (5), and a country with a high prevalence among children. There some reports claim that vertical transmission is higher in Egypt than in other countries (11), although these studies show some limitations in sample size and diagnostic method for determining vertical transmission. In the present study, we aimed to assess the prevalence and risk factors of HCV among pregnant women in a small city in the Nile Delta, Egypt. We also sought to determine whether vertical transmission plays a major role in HCV endemicity in Egypt. Prevalence of HCV among pregnant women We found the prevalence of pregnant women positive for HCV-RNA to be 6.8%. This study included women ranging in age from 16 to 45 years, with a mean age of 25.3. The prevalence in this age group was lower than reported in Egypt before: 37.5% among those older than 30 years, with a marked increase among those in their thirties and forties, and a peak of over 60% among those in their sixties (5). Our lower prevalence may be explained by a cohort phenomenon among patients treated by parenteral anti-schistosoma therapy (PAT) in Egypt from 1960s-1980s. Our study group contained a smaller proportion of PAT-treated cohort than did the studies conducted more than 10 years ago, which may explain the lower prevalence of HCV. Our study also found a slightly higher rate of infection among women living in rural areas than in urban areas, though this difference was not significant. As reported by Frank et al (7), higher infection rates among older women and rural residents may be partially explained by the differential exposure of these groups to schistosomiasis campaigns in Egypt, and the use of contaminated needles or syringes during treatment campaigns, suggesting that parenteral exposure continues to be a major transmission route for HCV infection in Egypt Evidence suggests that our data indeed reflect a decrease in HCV prevalence. Our patients came from the same areas as in the studies reporting higher prevalence of HCV (5). In addition, other studies published recently have shown a decrease in HCV prevalence in Egypt (14). Although the prevalence of HCV in Egypt appears to have decreased, our prevalence of 6.8% is still higher than in other countries such as the USA (3.2%), Taiwan (1.5%), Zaire (6%), and Saudi Arabia (0.6%) (2,15,16). Risk factors for this high prevalence should be studied, especially the avoidable ones. Risk factors for HCV infection Although in this study there were many factors associated with HCV infection in univariate analysis, multivariate analysis found only 4 independent risk factors. Old age was the first independent factor, which suggests the same cohort phenomenon described above and the cumulative effect of exposure to HCV due to the long period of viral exposure over one's lifetime, as well as exposure to other potential HCV risk factors. Our results are in agreement with Costa et al Further independent risk factors were having a husband or another household member positive for HCV. This association suggests that the significance of intrafamilial transmission of HCV is comparable with that of sexual transmission. Intra-familial transmission of HCV has also been reported by Mohamed et al (8). Another risk factor was blood transfusion. Several patients in our group had received blood transfusions before blood donors in Egypt underwent routine screening for HCV. These patients also had other risk factors, like hospitalization and major operations. Although blood transfusion is now considered a less important risk factor, it should be considered carefully, especially in a country with such a high prevalence of the disease. Our results are in agreement with those of Sangha et al We did not test for other hepatitis viruses or for HIV, which is exceedingly rare in rural Egyptian communities. A UN-AIDS/WHO report from 2008 (20) estimated that HIV/AIDS was present in 9000 Egyptians, predominately men with high risk behaviors, who account for less than 0.1% of the total population. No HIV-positive pregnant women were reported during sentinel site surveillance outside of ''major urban areas'' from 1992 to 1996 and in 2004. Mother-to-infant transmission for HCV We found that only 13% of the 43 infants who were positive for HCV antibodies in the first month of life were also positive for HCV-RNA. We considered this group as HCVinfected infants. This result is compatible with previous studies, which have found that most infants born to HCVpositive mothers have HCV antibodies in their blood and that we cannot use the presence of these antibodies to diagnose vertical transmission until after 18 months (21). Although 43 of 53 (81%) infants had HCV antibodies in the first month of life, only 7 (13%) were positive for HCV-RNA at the same time. At 6 months of life, only 2 (3.8%) were positive for HCV-RNA, indicating persistent HCV infection, while the other 4 infants had cleared their HCV-RNA indicating clearance of perinatal HCV infection. A similar figure for vertical transmission of HCV (4.6%) was reported recently from Egypt at one year of age (12). These results show that a large proportion of infants were only temporarily positive for HCV-RNA during the first weeks of life and the PCR test should be repeated again at 6 months of life. Studies that do not test infants when they are older may lead to overestimates of HCV prevalence and this may be the case with community-based study of perina- Frequent clearances of perinatal HCV infection may explain the previous reports of a high incidence of vertical transmission in Egypt. These reports have relied on cord blood samples or PCR results taken only once within a few weeks after delivery (11). Together with previous studies, the present study confirms that the incidence of vertical transmission of HCV in Egypt is similar to that in other parts of the world, where it varies from 4.5% to 6.0% Our definition of perinatal transmission of HCV was that infants had to be positive for both anti-HCV antibodies and HCV RNA. HCV-RNA was not detected in 36 of 43 (87%) of infants born to HCV-RNA positive mothers; this group was considered as non-infected infants with maternallyacquired antibodies. Only 2 of the 53 infants (3.8%) remained positive for HCV-RNA; this pair was considered to show persistent HCV infection. The other 4 infants (7.6%) cleared their HCV-RNA and sero-reverted to become negative for HCV antibodies; this group was considered to show clearance of perinatal HCV infection. Consistent with our approach, the European Pediatric HCV Network (EPHN) criterion for perinatal transmission of HCV in their multicenter trial of 1787 mother-child pairs was two or more positive HCV-RNA PCR test results and/or anti-HCV antibody positivity after 18 months of age We suggest that a higher proportion of infants born to HCV-infected mothers have infections and then clear their infections than is generally reported. In our study, this proportion was 13.2% in infants whose mothers were HCV-RNA positive, but it may have been greater if we had sampled the infants earlie

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Surgical site infection after gastrointestinal surgery in high-income, middle-income, and low-income countries: a prospective, international, multicentre cohort study

Background: Surgical site infection (SSI) is one of the most common infections associated with health care, but its importance as a global health priority is not fully understood. We quantified the burden of SSI after gastrointestinal surgery in countries in all parts of the world. Methods: This international, prospective, multicentre cohort study included consecutive patients undergoing elective or emergency gastrointestinal resection within 2-week time periods at any health-care facility in any country. Countries with participating centres were stratified into high-income, middle-income, and low-income groups according to the UN's Human Development Index (HDI). Data variables from the GlobalSurg 1 study and other studies that have been found to affect the likelihood of SSI were entered into risk adjustment models. The primary outcome measure was the 30-day SSI incidence (defined by US Centers for Disease Control and Prevention criteria for superficial and deep incisional SSI). Relationships with explanatory variables were examined using Bayesian multilevel logistic regression models. This trial is registered with ClinicalTrials.gov, number NCT02662231. Findings: Between Jan 4, 2016, and July 31, 2016, 13 265 records were submitted for analysis. 12 539 patients from 343 hospitals in 66 countries were included. 7339 (58·5%) patient were from high-HDI countries (193 hospitals in 30 countries), 3918 (31·2%) patients were from middle-HDI countries (82 hospitals in 18 countries), and 1282 (10·2%) patients were from low-HDI countries (68 hospitals in 18 countries). In total, 1538 (12·3%) patients had SSI within 30 days of surgery. The incidence of SSI varied between countries with high (691 [9·4%] of 7339 patients), middle (549 [14·0%] of 3918 patients), and low (298 [23·2%] of 1282) HDI (p < 0·001). The highest SSI incidence in each HDI group was after dirty surgery (102 [17·8%] of 574 patients in high-HDI countries; 74 [31·4%] of 236 patients in middle-HDI countries; 72 [39·8%] of 181 patients in low-HDI countries). Following risk factor adjustment, patients in low-HDI countries were at greatest risk of SSI (adjusted odds ratio 1·60, 95% credible interval 1·05–2·37; p=0·030). 132 (21·6%) of 610 patients with an SSI and a microbiology culture result had an infection that was resistant to the prophylactic antibiotic used. Resistant infections were detected in 49 (16·6%) of 295 patients in high-HDI countries, in 37 (19·8%) of 187 patients in middle-HDI countries, and in 46 (35·9%) of 128 patients in low-HDI countries (p < 0·001). Interpretation: Countries with a low HDI carry a disproportionately greater burden of SSI than countries with a middle or high HDI and might have higher rates of antibiotic resistance. In view of WHO recommendations on SSI prevention that highlight the absence of high-quality interventional research, urgent, pragmatic, randomised trials based in LMICs are needed to assess measures aiming to reduce this preventable complication

Measuring universal health coverage based on an index of effective coverage of health services in 204 countries and territories, 1990–2019 : A systematic analysis for the Global Burden of Disease Study 2019

Background Achieving universal health coverage (UHC) involves all people receiving the health services they need, of high quality, without experiencing financial hardship. Making progress towards UHC is a policy priority for both countries and global institutions, as highlighted by the agenda of the UN Sustainable Development Goals (SDGs) and WHO's Thirteenth General Programme of Work (GPW13). Measuring effective coverage at the health-system level is important for understanding whether health services are aligned with countries' health profiles and are of sufficient quality to produce health gains for populations of all ages. Methods Based on the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019, we assessed UHC effective coverage for 204 countries and territories from 1990 to 2019. Drawing from a measurement framework developed through WHO's GPW13 consultation, we mapped 23 effective coverage indicators to a matrix representing health service types (eg, promotion, prevention, and treatment) and five population-age groups spanning from reproductive and newborn to older adults (≥65 years). Effective coverage indicators were based on intervention coverage or outcome-based measures such as mortality-to-incidence ratios to approximate access to quality care; outcome-based measures were transformed to values on a scale of 0–100 based on the 2·5th and 97·5th percentile of location-year values. We constructed the UHC effective coverage index by weighting each effective coverage indicator relative to its associated potential health gains, as measured by disability-adjusted life-years for each location-year and population-age group. For three tests of validity (content, known-groups, and convergent), UHC effective coverage index performance was generally better than that of other UHC service coverage indices from WHO (ie, the current metric for SDG indicator 3.8.1 on UHC service coverage), the World Bank, and GBD 2017. We quantified frontiers of UHC effective coverage performance on the basis of pooled health spending per capita, representing UHC effective coverage index levels achieved in 2019 relative to country-level government health spending, prepaid private expenditures, and development assistance for health. To assess current trajectories towards the GPW13 UHC billion target—1 billion more people benefiting from UHC by 2023—we estimated additional population equivalents with UHC effective coverage from 2018 to 2023. Findings Globally, performance on the UHC effective coverage index improved from 45·8 (95% uncertainty interval 44·2–47·5) in 1990 to 60·3 (58·7–61·9) in 2019, yet country-level UHC effective coverage in 2019 still spanned from 95 or higher in Japan and Iceland to lower than 25 in Somalia and the Central African Republic. Since 2010, sub-Saharan Africa showed accelerated gains on the UHC effective coverage index (at an average increase of 2·6% [1·9–3·3] per year up to 2019); by contrast, most other GBD super-regions had slowed rates of progress in 2010–2019 relative to 1990–2010. Many countries showed lagging performance on effective coverage indicators for non-communicable diseases relative to those for communicable diseases and maternal and child health, despite non-communicable diseases accounting for a greater proportion of potential health gains in 2019, suggesting that many health systems are not keeping pace with the rising non-communicable disease burden and associated population health needs. In 2019, the UHC effective coverage index was associated with pooled health spending per capita (r=0·79), although countries across the development spectrum had much lower UHC effective coverage than is potentially achievable relative to their health spending. Under maximum efficiency of translating health spending into UHC effective coverage performance, countries would need to reach $1398 pooled health spending per capita (US$ adjusted for purchasing power parity) in order to achieve 80 on the UHC effective coverage index. From 2018 to 2023, an estimated 388·9 million (358·6–421·3) more population equivalents would have UHC effective coverage, falling well short of the GPW13 target of 1 billion more people benefiting from UHC during this time. Current projections point to an estimated 3·1 billion (3·0–3·2) population equivalents still lacking UHC effective coverage in 2023, with nearly a third (968·1 million [903·5–1040·3]) residing in south Asia. Interpretation The present study demonstrates the utility of measuring effective coverage and its role in supporting improved health outcomes for all people—the ultimate goal of UHC and its achievement. Global ambitions to accelerate progress on UHC service coverage are increasingly unlikely unless concerted action on non-communicable diseases occurs and countries can better translate health spending into improved performance. Focusing on effective coverage and accounting for the world's evolving health needs lays the groundwork for better understanding how close—or how far—all populations are in benefiting from UHC

Measuring universal health coverage based on an index of effective coverage of health services in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019

Background Achieving universal health coverage (UHC) involves all people receiving the health services they need, of high quality, without experiencing financial hardship. Making progress towards UHC is a policy priority for both countries and global institutions, as highlighted by the agenda of the UN Sustainable Development Goals (SDGs) and WHO's Thirteenth General Programme of Work (GPW13). Measuring effective coverage at the health-system level is important for understanding whether health services are aligned with countries' health profiles and are of sufficient quality to produce health gains for populations of all ages. Methods Based on the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019, we assessed UHC effective coverage for 204 countries and territories from 1990 to 2019. Drawing from a measurement framework developed through WHO's GPW13 consultation, we mapped 23 effective coverage indicators to a matrix representing health service types (eg, promotion, prevention, and treatment) and five population-age groups spanning from reproductive and newborn to older adults (≥65 years). Effective coverage indicators were based on intervention coverage or outcome-based measures such as mortality-to-incidence ratios to approximate access to quality care; outcome-based measures were transformed to values on a scale of 0–100 based on the 2·5th and 97·5th percentile of location-year values. We constructed the UHC effective coverage index by weighting each effective coverage indicator relative to its associated potential health gains, as measured by disability-adjusted life-years for each location-year and population-age group. For three tests of validity (content, known-groups, and convergent), UHC effective coverage index performance was generally better than that of other UHC service coverage indices from WHO (ie, the current metric for SDG indicator 3.8.1 on UHC service coverage), the World Bank, and GBD 2017. We quantified frontiers of UHC effective coverage performance on the basis of pooled health spending per capita, representing UHC effective coverage index levels achieved in 2019 relative to country-level government health spending, prepaid private expenditures, and development assistance for health. To assess current trajectories towards the GPW13 UHC billion target—1 billion more people benefiting from UHC by 2023—we estimated additional population equivalents with UHC effective coverage from 2018 to 2023. Findings Globally, performance on the UHC effective coverage index improved from 45·8 (95% uncertainty interval 44·2–47·5) in 1990 to 60·3 (58·7–61·9) in 2019, yet country-level UHC effective coverage in 2019 still spanned from 95 or higher in Japan and Iceland to lower than 25 in Somalia and the Central African Republic. Since 2010, sub-Saharan Africa showed accelerated gains on the UHC effective coverage index (at an average increase of 2·6% [1·9–3·3] per year up to 2019); by contrast, most other GBD super-regions had slowed rates of progress in 2010–2019 relative to 1990–2010. Many countries showed lagging performance on effective coverage indicators for non-communicable diseases relative to those for communicable diseases and maternal and child health, despite non-communicable diseases accounting for a greater proportion of potential health gains in 2019, suggesting that many health systems are not keeping pace with the rising non-communicable disease burden and associated population health needs. In 2019, the UHC effective coverage index was associated with pooled health spending per capita (r=0·79), although countries across the development spectrum had much lower UHC effective coverage than is potentially achievable relative to their health spending. Under maximum efficiency of translating health spending into UHC effective coverage performance, countries would need to reach $1398 pooled health spending per capita (US$ adjusted for purchasing power parity) in order to achieve 80 on the UHC effective coverage index. From 2018 to 2023, an estimated 388·9 million (358·6–421·3) more population equivalents would have UHC effective coverage, falling well short of the GPW13 target of 1 billion more people benefiting from UHC during this time. Current projections point to an estimated 3·1 billion (3·0–3·2) population equivalents still lacking UHC effective coverage in 2023, with nearly a third (968·1 million [903·5–1040·3]) residing in south Asia. Interpretation The present study demonstrates the utility of measuring effective coverage and its role in supporting improved health outcomes for all people—the ultimate goal of UHC and its achievement. Global ambitions to accelerate progress on UHC service coverage are increasingly unlikely unless concerted action on non-communicable diseases occurs and countries can better translate health spending into improved performance. Focusing on effective coverage and accounting for the world's evolving health needs lays the groundwork for better understanding how close—or how far—all populations are in benefiting from UHC

Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019

Background: In an era of shifting global agendas and expanded emphasis on non-communicable diseases and injuries along with communicable diseases, sound evidence on trends by cause at the national level is essential. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) provides a systematic scientific assessment of published, publicly available, and contributed data on incidence, prevalence, and mortality for a mutually exclusive and collectively exhaustive list of diseases and injuries. Methods: GBD estimates incidence, prevalence, mortality, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life-years (DALYs) due to 369 diseases and injuries, for two sexes, and for 204 countries and territories. Input data were extracted from censuses, household surveys, civil registration and vital statistics, disease registries, health service use, air pollution monitors, satellite imaging, disease notifications, and other sources. Cause-specific death rates and cause fractions were calculated using the Cause of Death Ensemble model and spatiotemporal Gaussian process regression. Cause-specific deaths were adjusted to match the total all-cause deaths calculated as part of the GBD population, fertility, and mortality estimates. Deaths were multiplied by standard life expectancy at each age to calculate YLLs. A Bayesian meta-regression modelling tool, DisMod-MR 2.1, was used to ensure consistency between incidence, prevalence, remission, excess mortality, and cause-specific mortality for most causes. Prevalence estimates were multiplied by disability weights for mutually exclusive sequelae of diseases and injuries to calculate YLDs. We considered results in the context of the Socio-demographic Index (SDI), a composite indicator of income per capita, years of schooling, and fertility rate in females younger than 25 years. Uncertainty intervals (UIs) were generated for every metric using the 25th and 975th ordered 1000 draw values of the posterior distribution. Findings: Global health has steadily improved over the past 30 years as measured by age-standardised DALY rates. After taking into account population growth and ageing, the absolute number of DALYs has remained stable. Since 2010, the pace of decline in global age-standardised DALY rates has accelerated in age groups younger than 50 years compared with the 1990–2010 time period, with the greatest annualised rate of decline occurring in the 0–9-year age group. Six infectious diseases were among the top ten causes of DALYs in children younger than 10 years in 2019: lower respiratory infections (ranked second), diarrhoeal diseases (third), malaria (fifth), meningitis (sixth), whooping cough (ninth), and sexually transmitted infections (which, in this age group, is fully accounted for by congenital syphilis; ranked tenth). In adolescents aged 10–24 years, three injury causes were among the top causes of DALYs: road injuries (ranked first), self-harm (third), and interpersonal violence (fifth). Five of the causes that were in the top ten for ages 10–24 years were also in the top ten in the 25–49-year age group: road injuries (ranked first), HIV/AIDS (second), low back pain (fourth), headache disorders (fifth), and depressive disorders (sixth). In 2019, ischaemic heart disease and stroke were the top-ranked causes of DALYs in both the 50–74-year and 75-years-and-older age groups. Since 1990, there has been a marked shift towards a greater proportion of burden due to YLDs from non-communicable diseases and injuries. In 2019, there were 11 countries where non-communicable disease and injury YLDs constituted more than half of all disease burden. Decreases in age-standardised DALY rates have accelerated over the past decade in countries at the lower end of the SDI range, while improvements have started to stagnate or even reverse in countries with higher SDI. Interpretation: As disability becomes an increasingly large component of disease burden and a larger component of health expenditure, greater research and developm nt investment is needed to identify new, more effective intervention strategies. With a rapidly ageing global population, the demands on health services to deal with disabling outcomes, which increase with age, will require policy makers to anticipate these changes. The mix of universal and more geographically specific influences on health reinforces the need for regular reporting on population health in detail and by underlying cause to help decision makers to identify success stories of disease control to emulate, as well as opportunities to improve. Funding: Bill & Melinda Gates Foundation. © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licens

Global, regional, and national disability-adjusted life-years (DALYs) for 333 diseases and injuries and healthy life expectancy (HALE) for 195 countries and territories, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016

BACKGROUND: Measurement of changes in health across locations is useful to compare and contrast changing epidemiological patterns against health system performance and identify specific needs for resource allocation in research, policy development, and programme decision making. Using the Global Burden of Diseases, Injuries, and Risk Factors Study 2016, we drew from two widely used summary measures to monitor such changes in population health: disability-adjusted life-years (DALYs) and healthy life expectancy (HALE). We used these measures to track trends and benchmark progress compared with expected trends on the basis of the Socio-demographic Index (SDI). METHODS: We used results from the Global Burden of Diseases, Injuries, and Risk Factors Study 2016 for all-cause mortality, cause-specific mortality, and non-fatal disease burden to derive HALE and DALYs by sex for 195 countries and territories from 1990 to 2016. We calculated DALYs by summing years of life lost and years of life lived with disability for each location, age group, sex, and year. We estimated HALE using age-specific death rates and years of life lived with disability per capita. We explored how DALYs and HALE differed from expected trends when compared with the SDI: the geometric mean of income per person, educational attainment in the population older than age 15 years, and total fertility rate. FINDINGS: The highest globally observed HALE at birth for both women and men was in Singapore, at 75·2 years (95% uncertainty interval 71·9-78·6) for females and 72·0 years (68·8-75·1) for males. The lowest for females was in the Central African Republic (45·6 years [42·0-49·5]) and for males was in Lesotho (41·5 years [39·0-44·0]). From 1990 to 2016, global HALE increased by an average of 6·24 years (5·97-6·48) for both sexes combined. Global HALE increased by 6·04 years (5·74-6·27) for males and 6·49 years (6·08-6·77) for females, whereas HALE at age 65 years increased by 1·78 years (1·61-1·93) for males and 1·96 years (1·69-2·13) for females. Total global DALYs remained largely unchanged from 1990 to 2016 (-2·3% [-5·9 to 0·9]), with decreases in communicable, maternal, neonatal, and nutritional (CMNN) disease DALYs offset by increased DALYs due to non-communicable diseases (NCDs). The exemplars, calculated as the five lowest ratios of observed to expected age-standardised DALY rates in 2016, were Nicaragua, Costa Rica, the Maldives, Peru, and Israel. The leading three causes of DALYs globally were ischaemic heart disease, cerebrovascular disease, and lower respiratory infections, comprising 16·1% of all DALYs. Total DALYs and age-standardised DALY rates due to most CMNN causes decreased from 1990 to 2016. Conversely, the total DALY burden rose for most NCDs; however, age-standardised DALY rates due to NCDs declined globally. INTERPRETATION: At a global level, DALYs and HALE continue to show improvements. At the same time, we observe that many populations are facing growing functional health loss. Rising SDI was associated with increases in cumulative years of life lived with disability and decreases in CMNN DALYs offset by increased NCD DALYs. Relative compression of morbidity highlights the importance of continued health interventions, which has changed in most locations in pace with the gross domestic product per person, education, and family planning. The analysis of DALYs and HALE and their relationship to SDI represents a robust framework with which to benchmark location-specific health performance. Country-specific drivers of disease burden, particularly for causes with higher-than-expected DALYs, should inform health policies, health system improvement initiatives, targeted prevention efforts, and development assistance for health, including financial and research investments for all countries, regardless of their level of sociodemographic development. The presence of countries that substantially outperform others suggests the need for increased scrutiny for proven examples of best practices, which can help to extend gains, whereas the presence of underperforming countries suggests the need for devotion of extra attention to health systems that need more robust support. FUNDING: Bill & Melinda Gates Foundation

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P &lt; 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

Global economic burden of unmet surgical need for appendicitis

Background: There is a substantial gap in provision of adequate surgical care in many low-and middle-income countries. This study aimed to identify the economic burden of unmet surgical need for the common condition of appendicitis. Methods: Data on the incidence of appendicitis from 170 countries and two different approaches were used to estimate numbers of patients who do not receive surgery: as a fixed proportion of the total unmet surgical need per country (approach 1); and based on country income status (approach 2). Indirect costs with current levels of access and local quality, and those if quality were at the standards of high-income countries, were estimated. A human capital approach was applied, focusing on the economic burden resulting from premature death and absenteeism. Results: Excess mortality was 4185 per 100 000 cases of appendicitis using approach 1 and 3448 per 100 000 using approach 2. The economic burden of continuing current levels of access and local quality was US $92 492 million using approach 1 and$73 141 million using approach 2. The economic burden of not providing surgical care to the standards of high-income countries was $95 004 million using approach 1 and$75 666 million using approach 2. The largest share of these costs resulted from premature death (97.7 per cent) and lack of access (97.0 per cent) in contrast to lack of quality. Conclusion: For a comparatively non-complex emergency condition such as appendicitis, increasing access to care should be prioritized. Although improving quality of care should not be neglected, increasing provision of care at current standards could reduce societal costs substantially